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Cochrane Database of Systematic Reviews Review - Intervention

Interventions for preventing ophthalmia neonatorum

Authors' declarations of interest

Version published: 21 September 2020 Version history

https://doi.org/10.1002/14651858.CD001862.pub4
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Background

Ophthalmia neonatorum is an infection of the eyes in newborns that can lead to blindness, particularly if the infection is caused by Neisseria gonorrhoeae. Antiseptic or antibiotic medication is dispensed into the eyes of newborns, or dispensed systemically, soon after delivery to prevent neonatal conjunctivitis and potential vision impairment.

Objectives

1. To determine if any type of systemic or topical eye medication is better than placebo or no prophylaxis in preventing ophthalmia neonatorum.

2. To determine if any one systemic or topical eye medication is better than any other medication in preventing ophthalmia neonatorum.

Search methods

We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers, date of last search 4 October 2019. We also searched references of included studies and contacted pharmaceutical companies. 

Selection criteria

We included randomised and quasi‐randomised controlled trials of any topical, systemic, or combination medical interventions used to prevent ophthalmia neonatorum in newborns compared with placebo, no prophylaxis, or with each other.

Data collection and analysis

We used standard methods expected by Cochrane. Outcomes were: blindness or any adverse visual outcome at 12 months, conjunctivitis at 1 month (gonococcal (GC), chlamydial (CC), bacterial (BC), any aetiology (ACAE), or unknown aetiology (CUE)), and adverse effects. 

Main results

We included 30 trials with a total of 79,198 neonates. Eighteen studies were conducted in high‐income settings (the USA, Europe, Israel, Canada), and 12 were conducted in low‐ and middle‐income settings (Africa, Iran, China, Indonesia, Mexico). Fifteen of the 30 studies were quasi‐randomised. We judged every study to be at high risk of bias in at least one domain. Ten studies included a comparison arm with no prophylaxis. There were 14 different prophylactic regimens and 12 different medications in the 30 included studies.

Any prophylaxis compared to no prophylaxis 

Unless otherwise indicated, the following evidence comes from studies assessing one or more of the following interventions: tetracycline 1%, erythromycin 0.5%, povidone‐iodine 2.5%, silver nitrate 1%. None of the studies reported data on the primary outcomes: blindness or any adverse visual outcome at any time point. There was only very low‐certainty evidence on the risk of GC with prophylaxis (4/5340 newborns) compared to no prophylaxis (5/2889) at one month (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.24 to 2.65, 3 studies). Low‐certainty evidence suggested there may be little or no difference in effect on CC (RR 0.96, 95% CI 0.57 to 1.61, 4874 newborns, 2 studies) and BC (RR 0.84, 95% CI 0.37 to 1.93, 3685 newborns, 2 studies). Moderate‐certainty evidence suggested a probable reduction in risk of ACAE at one month (RR 0.65, 95% 0.54 to 0.78, 9666 newborns, 8 studies assessing tetracycline 1%, erythromycin 0.5%, povidone‐iodine 2.5%, silver nitrate 1%, colostrum, bacitracin‐phenacaine ointment). There was only very low‐certainty evidence on CUE  (RR 1.75, 95% CI 0.37 to 8.28, 330 newborns, 1 study). Very low‐certainty evidence on adverse effects suggested no increased nasolacrimal duct obstruction (RR 0.93, 95% CI 0.68 to 1.28, 404 newborns, 1 study of erythromycin 0.5% and silver nitrate 1%) and no increased keratitis (single study of 40 newborns assessing silver nitrate 1% with no events).   

Any prophylaxis compared to another prophylaxis

Overall, evidence comparing different interventions did not suggest any consistently superior intervention. However, most of this evidence was of low‐certainty and was extremely limited.

Authors' conclusions

There are no data on whether prophylaxis for ophthalmia neonatorum prevents serious outcomes such as blindness or any adverse visual outcome. Moderate‐certainty evidence suggests that the use of prophylaxis may lead to a reduction in the incidence of ACAE in newborns but the evidence for effect on GC, CC or BC was less certain. Comparison of individual interventions did not suggest any consistently superior intervention, but data were limited. A trial comparing tetracycline, povidone‐iodine (single administration), and chloramphenicol for GC and CC could potentially provide the community with an effective, universally applicable prophylaxis against ophthalmia neonatorum. 

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Medication to prevent infection of the eye in newborns

What was the aim of the review?
The aim of this Cochrane Review was to determine if any medication is better than placebo or no preventive action in preventing ophthalmia neonatorum. Cochrane Review authors collected and analysed all relevant studies to answer this question and found 30 studies. 

Key messages
There are no data on whether prophylaxis for ophthalmia neonatorum prevents serious outcomes such as blindness or visual impairment. Moderate‐certainty evidence suggests that the use of prophylaxis may lead to a reduction in the incidence of any conjunctivitis of any cause in newborns but the evidence for effect on gonococcal or chlamydial conjunctivitis was of low to very‐low certainty. Comparison of individual interventions did not suggest any consistently superior intervention, but data were limited.

What was studied in the review?
Ophthalmia neonatorum, also known as neonatal conjunctivitis, is an infection of the eye surface that affects newborn babies within the first month of life. It is usually caused by infection (bacterial or viral) picked up during birth. If left untreated, it can lead to blindness. The World Health Organization (WHO) recommends the following treatments to prevent ophthalmia neonatorum:

• tetracycline hydrochloride 1% eye ointment;
• erythromycin 0.5% eye ointment;
• povidone‐iodine 2.5% solution (water‐based);
• silver nitrate 1% solution;
• chloramphenicol 1% eye ointment.

Cochrane Review authors considered these treatments and others to prevent the development of conjunctivitis in newborns. They assessed the two main types of conjunctivitis separately ‐ gonococcal conjunctivitis (caused by Neisseria gonorrhoeae) and chlamydial conjunctivitis (caused by Chlamydia trachomatis) ‐ as well as conjunctivitis due to any bacteria (including Neisseria gonorrhoeae and Chlamydia trachomatis), conjunctivitis due to any cause or conjunctivitis of unknown cause. 

What are the main results of the review?
Cochrane Review authors identified 30 studies with a total of 79,198 newborns. Eighteen studies took place in high‐income settings (the USA, Europe, Israel, Canada), and 12 were conducted in low‐ and middle‐income settings (Africa, Iran, China, Indonesia, Mexico). The main preventive medications evaluated in the included studies were: tetracycline 1%, erythromycin 0.5%, povidone‐iodine 2.5%, and silver nitrate 1%.

Newborns given preventive medication are likely to have a lower chance of conjunctivitis within one month of birth compared with newborns not given preventive medication (moderate‐certainty evidence). The evidence for specific causes of conjunctivitis (gonococcal, chlamydial) was less certain as these occurred less frequently in the included studies. None of the studies collected data on blindness or adverse vision outcomes.

How up‐to‐date is the review?
Cochrane Review authors searched for studies published up to 4 October 2019.

Authors' conclusions

Implications for practice

Overall, evidence comparing different interventions did not suggest any consistently superior intervention as most of the available evidence was of low‐certainty and was limited.  

Our findings lead to the following implications for practice.

  1. Prophylaxis for ophthalmia neonatorum reduces risk of neonatal clinical conjunctivitis (any conjunctivitis of any aetiology (ACAE), based on moderate‐certainty evidence.

  2. Our analyses did not identify any medication as effective against gonococcal conjunctivitis (GC), but in general studies were underpowered for this rare outcome and we judged the evidence to be low‐certainty. Thus practice should be based on knowledge about known sensitivity of Neisseria gonorrhoeae to antibiotics. This is especially relevant in the context of world‐wide concern regarding anti‐microbial resistance.

  3. Silver nitrate and tetracycline may be considered for prophylaxis of GC, although it seems that silver nitrate is no longer manufactured. Low‐certainty evidence including data from all available comparisons (i.e., povidone‐iodine versus any prophylaxis, silver nitrate, and erythromycin), suggests that povidone‐iodine appears to be effective for prophylaxis against chlamydial conjunctivitis (CC). Although some have suggested that povidone‐iodine may be associated with an elevated risk of chemical conjunctivitis (Moore 2015), our findings indicate that it is in fact associated with a lower risk of chemical conjunctivitis.

  4. While chloramphenicol appeared to be more effective than povidone‐iodine for prophylaxis against CC based on low‐certainty evidence, data on its effectiveness for preventing GC were limited. Similarly, tetracycline may be an alternative for povidone‐iodine against CC based on low‐certainty evidence, but the data were insufficient in this regard.

  5. Finally, there are no data on whether prophylaxis for ophthalmia neonatorum prevents serious outcomes such as blindness or any adverse visual outcome.

Although moderate‐certainty statistically significant evidence in this review suggests that prophylaxis with antibiotics is more effective than silver nitrate for neonatal clinical conjunctivitis (ACAE), instituting antibiotic prophylaxis may be erroneous. Studies demonstrate an increasing prevalence of antibiotic resistance across the globe, specifically for N gonorrhoeae (Lewis 2014). Furthermore, this resistance appeared to be specific against antibiotics found to be more effective than silver nitrate for ACAE in our review, including erythromycin, tetracycline, sulfacetamide, and penicillin (Unemo 2016). Policy regarding prophylaxis should thus also be informed by the prevalence of Neisseria and Chlamydia, their resistance profile against specific antibiotics, as well as access to prenatal screening and care. In areas of high prevalence of N gonorrhoeae infection in pregnant women, low access to antenatal maternal screening, and low access to high‐quality care, ophthalmia neonatorum prophylaxis may be considered an effective strategy to prevent blindness. A recent systematic review has found that N gonorrhoeae prevalence in pregnancy can be as high as 4.6% (95% CI 4.0% to 5.2%) in low‐income countries (Davey 2016). UNICEF statistics further indicate that only 42% of pregnant women in least‐developed countries attended at least four antenatal care visits, and only 77% attended at least one visit, suggesting that 23% women did not receive any antenatal care (UNICEF ). Considering that neonates born to untreated N gonorrhoeae‐infected mothers have a 30% to 50% risk of developing gonococcal ophthalmia, the risk of blindness in endemic areas is therefore high (Laga 1989). In areas where rates of N gonorrhoeae are low in pregnancy, rates of antenatal screening are high, and there is good access to high‐quality care, resource utilisation concerns may render ophthalmia neonatorum prophylaxis a relatively less attractive strategy to prevent blindness.

Implications for research

Our findings lead to the following implications for research.

  1. A trial comparing tetracycline, povidone‐iodine (single administration), and chloramphenicol for GC and CC is likely to provide the community with an effective, universally applicable prophylaxis against ophthalmia neonatorum. Our findings suggest that silver nitrate is more effective than erythromycin and povidone‐iodine for GC with limited evidence against tetracycline and chloramphenicol (Figure 13). In addition, povidone‐iodine appeared to be more effective than silver nitrate and erythromycin but less effective than chloramphenicol for CC (Figure 14). Well‐designed trials to determine whether povidone‐iodine is more effective than tetracycline and whether chloramphenicol is more effective than povidone‐iodine for GC and CC will thus yield a universally applicable prophylaxis for ophthalmia neonatorum.

  2. Although the eventual goal for prophylaxis for ophthalmia neonatorum is to prevent vision loss and blindness, it is unlikely that trials may be designed to address these outcomes. This is because the outcomes are rare, necessitating large sample sizes to detect meaningful effects. It is also imperative that infections such as gonorrhoea and chlamydia be effectively treated when prenatally diagnosed in the mother. A realistic approach to determine the effect of prophylaxis for preventing GC, and the relative effectiveness of medications to do so, is thus to conduct well‐designed randomised controlled trials in targeted settings, for example in populations with high risk or prevalence of infections such as gonorrhoea and chlamydia. The design of such trials should emphasise procedures to minimise losses to follow‐up and prompt treatment of positive gonococcal or chlamydial cultures with the goal of avoiding severe adverse visual outcomes.

  3. A control group with no intervention or placebo is not acceptable in future trials on prophylaxis for ophthalmia neonatorum.

  4. Any future trials on the effectiveness of colostrum for prophylaxis of ophthalmia neonatorum must adequately justify the rationale for why colostrum may potentially prevent ophthalmia neonatorum, particularly GC and CC.

  5. Gonococcal and chlamydial infections in the newborn may affect and manifest within organs other than the eye. It is possible that prophylaxis for ophthalmia neonatorum may inadvertently mask such infection in non‐ocular sites, but subsequently manifest with non‐ocular symptoms and complications. This hypothesis may be addressed in future trials on prophylaxis for ophthalmia neonatorum by following up neonates for non‐ocular manifestations of gonococcal and chlamydial infections despite successful prevention of ophthalmia neonatorum.

  6. Finally, in this review, we did not address the relative effectiveness of available medications as prophylaxis for ophthalmia neonatorum. Whilst we included some pairwise comparisons, a network meta‐analysis is needed to address the relative effects of different interventions using both direct and indirect evidence. Our findings suggest that the data available from the trials identified in this systematic review may be sufficient for a network meta‐analysis for some outcomes such as ACAE, but not for others such as GC.

Finally, some have suggested that strategies other than prophylaxis at birth may be effective to prevent ophthalmia neonatorum, for example screening and treating pregnant women for gonococcal or chlamydial infections (Moore 2015). However, randomised controlled trials may not be the optimal study design to obtain evidence on the relative effects of different strategies for preventing ophthalmia neonatorum due to ethical reasons, for example withholding treatment from women infected with chlamydia or gonorrhoea. Other study designs such as interrupted time series may be optimal to determine the relative effect of different strategies to prevent ophthalmia neonatorum in different settings, for example defined by levels of prenatal screening, baseline risk of maternal gonorrhoeal and chlamydial infections, or access to prenatal care and treatment.

Summary of findings

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Summary of findings 1. Any prophylaxis compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Any prophylaxis compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: any prophylaxis, including povidone‐iodine, erythromycin, tetracycline, silver nitrate, bacitracin‐phenacaine, colostrum

Comparison: no prophylaxis (none of the studies used a placebo or sham treatment)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with any prophylaxis

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Low risk

RR 0.79
(0.24 to 2.65)

8229
(3 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

In 2 of these 3 studies there were no cases of gonococcal conjunctivitis in either study arm.

1 per 1000

1 per 1000
(0 to 3)

High risk

50 per 1000

38 per 1000
(10 to 142)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 0.96
(0.57 to 1.61)

4874
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

5 per 1000

5 per 1000
(3 to 8)

High risk

100 per 1000

96 per 1000
(57 to 161)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain
follow‐up: 1 month

Low risk

RR 0.84
(0.37 to 1.93)

3685
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

3 per 1000

3 per 1000
(1 to 6)

High risk

50 per 1000

42 per 1000
(19 to 97)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.65
(0.54 to 0.78)

9666
(8 RCTs)

⊕⊕⊕⊝
MODERATE1

3 per 1000

2 per 1000
(2 to 2)

High risk

300 per 1000

195 per 1000
(162 to 134)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.75
(0.37 to 8.28)

330
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

20 per 1000

35 per 1000
(7 to 166)

Adverse effects

In a single study (Bell 1993), any prophylaxis (erythromycin 0.5% or silver nitrate 1%) did not appear to be associated with an increased risk of nasolacrimal duct obstruction compared with no prophylaxis (RR 0.93, 95% CI 0.68 to 1.28).

A single study of 40 newborns comparing silver nitrate 1% with control reported that no events of keratitis were observed in the prophylaxis and no‐prophylaxis groups (Graf 1994).

⊕⊝⊝⊝
VERY LOW 1,2

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded (‐1) for risk of bias: studies were at high or unclear risk of bias.
2Downgraded (‐2) for imprecision: sparse data.

3Downgraded (‐1) for imprecision: 95% confidence interval includes no effect.

Background

Description of the condition

Ophthalmia neonatorum, also called neonatal conjunctivitis, is an inflammatory disorder of the eye surface in newborns in the first month of life (WHO 1986). In Europe in the late 1800s, a significant percentage of blind people were blind due to gonococcal ophthalmia neonatorum. Specifically, it was reported that the percentage of blindness from ophthalmia neonatorum was 8% in Copenhagen, 20% in Berlin, 30% in Vienna, and 45% in Paris (Buller 1900; Haussman 1895; Milot 2008). It has been estimated that during the same period 20% to 80% of children in blind institutions in Germany were blind due to ophthalmia neonatorum caused by Neisseria gonorrhoeae (Konigstein 1882). In the USA, amongst new admissions into schools for the blind between 1906 and 1911, approximately 24% were due to ophthalmia neonatorum caused by N gonorrhoeae, with a range of 8% to 45% (Barsam 1966). In 1918, St Margaret's Hospital in London (UK) was opened specifically for the treatment of neonates with ophthalmia neonatorum (Anonymous 1918; Anonymous 1919).

To this day, ophthalmia neonatorum remains a significant cause of childhood corneal blindness in low‐ and middle‐income countries, mainly from N gonorrhoeae (Whitcher 2001). There are major epidemiological challenges in determining the prevalence and incidence of blindness from ophthalmia neonatorum. Notwithstanding these limitations, cross‐sectional surveys have estimated the percentage of blindness or severe visual impairment due to ophthalmia neonatorum to be 3% in Ethiopia (Kello 2003), 0.7% in Bangladesh (Muhit 2007), 0.4% in Malaysia (Koay 2015), 5% in East Africa (Foster 1991), 0.8% in India (Rahi 1995), and 2% in Tanzania (Foster 1987).

Gonococcal ophthalmia neonatorum is associated with the most severe consequences. Gonococcal ophthalmia neonatorum is mainly contracted from the mother's infected birth canal during delivery, but can also be contracted in utero by ascending infections. Neonates born to gonorrhoea‐infected mothers have a 30% to 50% risk of developing gonococcal conjunctivitis (Laga 1989). Untreated or inappropriately treated gonococcal conjunctivitis can result in corneal perforation and vision loss in 24 hours (Donham 2008; Duke‐Elder 1965). In one case series, the mean duration of corneal perforation from untreated gonococcal conjunctivitis was 11 days (Kawashima 2009). In areas with low incidence of gonococcal ophthalmia neonatorum or limited access to appropriate health care, appropriate clinical diagnosis and appropriate therapy may be delayed, which can lead to loss of vision (Bastion 2006; McElnea 2015; Schwab 1985; Wan 1986). After historical declines in rates of gonorrhoea, it made a resurgence in some high‐income countries In 2012, amongst adults aged 15 to 49 years, it is estimated there were 27 million cases of gonorrhoea globally (Newman 2015). Furthermore, there is increasing incidence of drug‐resistant strains of N gonorrhoeae globally (Martin 2015; Van de Laar 2012; WHO 2012). The pooled mean prevalence of N gonorrhoeae was estimated at 3.7% (95% confidence interval (CI) 2.8% to 4.6%) in pregnant women in Eastern and Southern Africa, and 2.7% (95% CI 1.7% to 3.7%) in pregnant women in West and Central Africa (Chico 2012). 

Chlamydial ophthalmia neonatorum is also associated with a high risk of corneal and conjunctival scarring, haemorrhagic conjunctivitis, and rarely, loss of vision if left untreated (Chang 2006; Darville 2015; Whitcher 2001). It is caused by transmission of Chlamydia trachomatis from the mother to the newborn during delivery. The risk of chlamydial transmission from an infected mother to newborns is 15% on average (range = 8% to 44%; Rosenman 2003). Furthermore, an increased prevalence of chlamydial infection in some high‐income countries is associated with a commensurate rise in risk of chlamydial conjunctivitis (Quirke 2008). Chlamydial ophthalmia neonatorum is much more prevalent than gonococcal ophthalmia neonatorum, and has historically been underdiagnosed due to lack of accurate diagnostic techniques (Darville 2015; Yip 2008). Pooled mean prevalence of C trachomatis was higher at 6.9% (95% CI 5.1% to 8.6%) in pregnant women in Eastern and Southern Africa, and 6.1% (95% CI 4.0% to 8.3%) in pregnant women in West and Central Africa (Chico 2012).

Ophthalmia neonatorum may be caused by bacteria other than Neisseria and Chlamydia. The relative frequencies of bacterial causes of ophthalmia neonatorum reported in the literature vary by study and geographic location (Amini 2008; Chhabra 2008; Di Bartolomeo 2001; Di Bartolomeo 2005; Hammerschlag 1993; Mohile 2002; Sandström 1984). Even though certain bacteria are frequently cultured from neonates with conjunctivitis (e.g. Staphylococcus aureus), their role as the causative agent of conjunctivitis is uncertain because these bacteria may be frequently cultured from the eyes of asymptomatic neonates (Amini 2008; Fransen 1987; Krohn 1993).

Finally, some viruses such as herpes simplex and adenovirus can cause ophthalmia neonatorum (Albert 1994). Often, no causative pathogen can be found in newborns with ophthalmia neonatorum due to methods for obtaining and culturing for bacteria, or due to causes other than bacteria such as chemical conjunctivitis or nasolacrimal duct obstruction (Sandström 1987).

While most micro‐organisms that cause ophthalmia neonatorum are acquired during passage through the birth canal, others are acquired after birth from caregivers or the nasopharyngeal passages of the newborn (Krohn 1993). The relative importance of intrapartum versus postpartum sources of infection varies based on extraneous factors such as socioeconomic status of mothers (Isenberg 1995; Vedantham 2004; Verma 1994).

Description of the intervention

There are four strategies to achieve the public health goal of eliminating ophthalmia neonatorum and its adverse vision consequences:

  1. preventing spread of sexually transmitted infections;

  2. screening women who are pregnant for genital infection;

  3. administering prophylaxis to newborns soon after birth;

  4. diagnosing and treating eye infections in newborns at an early stage (Foster 1995; Laga 1989).

German‐born obstetrician and gynaecologist Carl Siegmund Franz Credé introduced the third strategy, ophthalmia neonatorum prophylaxis (Crede 1884; Dunn 2000; Oriel 1991). In a seminal study, albeit a case series, Credé showed that silver nitrate administered to newborns reduced the incidence of ophthalmia neonatorum from 13.6% to 0.05% (Crede 1881). The relevance of prophylaxis for ophthalmia neonatorum and debate about the optimal medication has since evolved in response to the discovery of new antibiotics; concerns about side effects with silver nitrate such as chemical conjunctivitis and impact on maternal‐infant bonding; and the declining prevalence of N gonorrhoeae in some countries and increased reporting rates of chlamydial ophthalmia neonatorum in others (Napchan 2005; Wahlberg 1982).

Initially, studies looking for alternatives to silver nitrate mainly examined penicillin as ophthalmia neonatorum prophylaxis. Later, erythromycin and tetracycline were studied in comparison to silver nitrate, and more recently, povidone‐iodine. There have been studies of other prophylactic agents, but the majority of jurisdictions in the world today appear to use either erythromycin or povidone‐iodine as ophthalmia neonatorum prophylaxis. However, there remains a high degree of variability in the agents used for ophthalmia neonatorum prophylaxis, with some jurisdictions using prophylactic medications that are uncommon or not well‐studied (Guala 2005; Zloto 2016).

Erythromycin and tetracycline gained acceptance as prophylactic agents in the 1980s because of their allegedly superior activity against C trachomatis and because they lacked some of the side effects of silver nitrate, such as chemical conjunctivitis (Isenberg 1994a). However, it remains unresolved whether these antibiotic agents are, in fact, any more effective than silver nitrate in preventing chlamydial conjunctivitis. Furthermore, the emergence of beta‐lactamase‐producing N gonorrhoeae has reduced the prophylactic effectiveness of erythromycin and tetracycline (Ison 1998; Martin 2015; Van de Laar 2012; WHO 2012). Povidone‐iodine, introduced in studies in the 1960s as a surgical antiseptic and disinfectant agent, has been used relatively more recently as a candidate for ophthalmia neonatorum prophylaxis. It allegedly has many advantages over silver nitrate, erythromycin, and tetracycline, including economic feasibility, broader antibacterial spectrum, lack of generation of bacterial resistance, and no reports of anaphylaxis (Grzybowski 2018; Isenberg 1994b). Other prophylactic measures that have been used beyond antimicrobial or antiseptic agents include cleansing the eyelids with sterile swabs; cleansing the eyes with distilled water and wiping dry; and physiological saline.

Credé’s original procedure for ophthalmic prophylaxis called for administration “directly after birth” (Crede 1881). Timing of prophylaxis of ophthalmia neonatorum after birth has been addressed by one small study (Muhe 1986). This study suggested that increasing delay in administration of prophylaxis after birth can lead to a trend to increasing failure of the intervention (Muhe 1986). This study also suggested that a delay in prophylaxis greater than four hours can lead to a four‐ to five‐fold risk of gonococcal ophthalmia neonatorum (Laga 1989; Muhe 1986). Three guidelines have suggested optimal timing of prophylaxis, but cited no evidence: In 2002, the Canadian Pediatric Society Guideline suggested prophylaxis administration within one hour after birth (CPS 2002); in 2011, the United States Preventive Services Task Force recommendation suggested timing of prophylaxis administration no later than 24 hours after birth (USPSTF 2011); and in 2017, the World Health Organization (WHO) suggested timing of prophylaxis to be “immediately after birth” (WHO 2017).

How the intervention might work

Ophthalmia neonatorum prophylaxis agents used around the world are antimicrobial or antiseptic agents, which, when administered topically, or rarely systemically, destroy or inhibit micro‐organisms in the eye to prevent conjunctivitis and keratitis (Kramer 2002). The micro‐organisms may be acquired from the mother’s infected birth canal, in utero by ascending infections, or from the hospital or home environment.

Why it is important to do this review

Launched in 1999, Vision 2020 is a global initiative of the WHO and the International Agency for the Prevention of Blindness with the goal to eliminate avoidable blindness by 2020 (WHO 1999). Vision 2020 was updated by the WHO in 2013 to develop a Global Action Plan from 2014 to 2019 “to reduce the prevalence of avoidable visual impairment by 25% by 2019” (WHO 2013). Controlling childhood blindness is a high priority of this plan, as it has been estimated that 4% of all global blindness is due to childhood blindness, and that 45% of all childhood blindness is avoidable. Corneal scarring is one of five childhood blindness conditions prioritised for control. While vitamin A and measles are responsible for the majority of corneal scarring, ophthalmia neonatorum is a significant cause of corneal blindness, mainly in low‐ and middle‐income countries such as those in sub‐Saharan Africa (Gilbert 2012; Robaei 2014; Whitcher 2001; WHO 2013).

In sub‐Saharan Africa, the two major agents responsible for corneal blindness and scarring, N gonorrhoeae and C trachomatis, have high prevalence in pregnant women.

The WHO, in conjunction with the United Nations Children’s Fund and the United Nations Population Fund, has developed guidelines through its Integrated Management of Pregnancy and Childbirth (IMPAC) strategy to reduce child and maternal mortality and morbidity. The IMPAC approach includes preventative and curative elements, targeting health systems, health workers, families, and communities. The Pregnancy, Childbirth, Postpartum and Newborn Care guide’s evidence‐based recommendations include eye prophylaxis for prevention of ophthalmia neonatorum. Evidence on this intervention and the relative effectiveness of different prophylactic regimens is therefore essential to this intervention (WHO 2015).

There is considerable global variability in recommendations on whether to use ophthalmia neonatorum prophylaxis, and the prophylactic agent used. Certain jurisdictions still carry out ophthalmia neonatorum prophylaxis, including Brazil (Caligaris 2010), the USA (USPSTF 2011), Italy (Guala 2005), Spain (Luna 2009), Canada (Moore 2015), Slovenia (Jug Došler 2015), France (Dageville 2015), Turkey (Eser 2009), certain areas of Central America, some countries in Africa, parts of the Far East, areas of the Middle East, and sections of Central Asia (Zloto 2016). Norway, Great Britain, Sweden, the Netherlands (Rours 2008; Volksgezondheid 1980), Australia (Shaw 1977), Belgium (Tribolet 2016), and Denmark (Pande 2006), discontinued ophthalmia neonatorum prophylaxis several years ago (Kramer 2002). As recently as 2010, England and Wales removed ophthalmia neonatorum from the list of notifiable diseases, even though there is some evidence of significant under‐reporting of the incidence of ophthalmia neonatorum (Department of Health, UK 2010; Dharmasena 2015). In Canada, there have been recent recommendations that ophthalmia neonatorum be discontinued, although no legislative changes have been made in the country as yet (Moore 2015). Some groups in Canada oppose this recommendation (Mulholland 2015), and others question whether the alternative strategy of prenatal screening is an optimal sole substitute for prophylaxis (Poliquin 2015). The Canadian recommendation to discontinue prophylaxis has been made in spite of the fact that the rate of chlamydia in Canada has increased 57.6% (Totten 2015a), and the rate of gonorrhoea has increased 38.9% from 2003 to 2012, mainly in women (Totten 2015b). In France, ophthalmia neonatorum prophylaxis is no longer universally recommended. Ocular prophylaxis is only recommended for neonates where there is a risk of sexually transmitted infections in the mother, and where the mother has had poor prenatal care (AFSSAPS 2010). Still, other jurisdictions are looking to implement ophthalmia neonatorum prophylaxis (Pastor 2015).

The global variability in practices regarding prophylaxis for ophthalmia neonatorum may be explained by the following:

  1. there is uncertainty about the evidence of effectiveness and risk‐benefit ratio of the various prophylactic agents, particularly against C trachomatis and N gonorrhoeae;

  2. the prevalence and distribution of N gonorrhoeae and C trachomatis is variable, and has evolved over time, raising the possibility that universal prophylaxis may no longer be justified;

  3. the relative effectiveness of different medications for prophylaxis of ophthalmia neonatorum remains to be determined.

In this systematic review, we aimed to synthesise the available evidence to inform care and policy regarding prophylaxis for ophthalmia in the newborn.

Objectives

1. To determine if any type of systemic or topical eye medication is better than placebo or no prophylaxis in preventing ophthalmia neonatorum.

2. To determine if any one systemic or topical eye medication is better than any other medication in preventing ophthalmia neonatorum.

Methods

Criteria for considering studies for this review

Types of studies

We considered randomised and quasi‐randomised controlled trials.

Types of participants

Trials that enrolled newborn infants were eligible for inclusion in the review.

Types of interventions

We included trials comparing any topical, systemic, or combination medical interventions with placebo, no prophylaxis, or with each other.

Types of outcome measures

We considered the following outcomes: 

Primary outcomes

  1. Proportion of infants developing blindness, defined as a visual acuity of 20/200 or worse measured, e.g., using a Teller visual acuity card at 12 months.

  2. Proportion of infants developing any adverse visual outcome measured, e.g., with a Teller visual acuity card at 12 months.

  3. Proportion of neonates developing gonococcal conjunctivitis (GC) within 28 days of birth, where diagnosis was made with a laboratory‐based method to identify the infecting organism. We anticipated that most studies would not have studied blindness as an outcome. Because severe GC is associated with a substantial risk for loss of vision, we considered this outcome as a substitute for the more important measure of blindness.

Secondary outcomes

  1. Proportion of neonates developing chlamydial conjunctivitis (CC) within 28 days of birth.

  2. Proportion of neonates developing bacterial conjunctivitis (BC) within 28 days of birth: this includes cases of conjunctivitis confirmed to be of bacterial origin by culture or Gram stain, or both. In addition to conjunctivitis cases of other bacterial aetiology, this category includes GC and CC.

  3. Proportion of neonates developing any clinical conjunctivitis within 28 days of birth, referred to as any conjunctivitis cases of any aetiology (ACAE): this includes all cases of conjunctivitis clinically diagnosed, irrespective of aetiology. This would include infectious and non‐infectious conjunctivitis. Infectious conjunctivitis includes BC, mycoplasma conjunctivitis, chlamydial or viral conjunctivitis. Non‐infectious conjunctivitis includes chemical, toxic, or mechanical conjunctivitis. In cases where there was selective outcome reporting, and all cases of clinical conjunctivitis were not reported, this outcome was not included in comparisons.

  4. Proportion of neonates developing conjunctivitis of unknown aetiology (CUE) within 28 days of birth: this includes cases of conjunctivitis that are culture‐negative, where the aetiology is unknown. These may be infectious, but showing no growth of pathogenic agents on culture media, or on other methods to identify microbiologic aetiology. This may include non‐infectious conjunctivitis, such as chemical conjunctivitis. Finally, it may be a mix of the aforementioned causes of conjunctivitis. In many cases, it is calculated by subtracting the total conjunctivitis cases of any aetiology from the conjunctivitis cases proven to be of bacterial origin.

  5. Proportion of neonates developing the following adverse effects of ophthalmia neonatorum prophylaxis:

    1. keratitis within 28 days of birth;

    2. nasolacrimal duct obstruction within 60 days of birth.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist conducted systematic searches in the following databases for randomised controlled trials and controlled clinical trials. There were no restrictions to language or year of publication. The databases were last searched on 4 October 2019.

  • Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 10) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 4 October 2019) (Appendix 1).

  • MEDLINE Ovid (1946 to 4 October 2019) (Appendix 2).

  • Embase Ovid (1980 to 4 October 2019) (Appendix 3).

  • LILACS (Latin American and Caribbean Health Science Information database (1982 to 4 October 2019) (Appendix 4).

  • ISRCTN registry (www.isrctn.com/editAdvancedSearch; searched 4 October 2019) (Appendix 5).

  • US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/; searched 4 October 2019) (Appendix 6).

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/; searched 4 October 2019) (Appendix 7).

Searching other resources

We checked the reference lists of identified trial reports and existing review articles and contacted pharmaceutical companies to locate additional trials.

Data collection and analysis

Selection of studies

Two review authors independently screened titles and abstracts of records retrieved from the searches, categorising each record as either include, exclude, or unclear. We retrieved full‐text articles of records that any of the review authors marked as include or unclear. Two review authors independently assessed the full‐text articles and marked them as include or exclude. We reported reasons for full‐text articles excluded in this process. The review authors resolved disagreements through discussion and consensus. In cases where additional information was needed before a decision could be made on the eligibility of full‐text articles, we attempted to obtain this information from the study investigator.

Data extraction and management

For each eligible study (using all reports from the study), two review authors independently extracted information on methods, participants, interventions, outcomes, and funding sources using data forms developed for this review. We contacted the study authors for information missing from available reports.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias in each included study according to methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We assessed risk of bias for generation and concealment of the allocation sequence; masking of participants, caregivers/study personnel, and outcome assessors; completeness of follow‐up; reporting biases (selective outcome reporting); and other sources of potential bias such as funding.

The review authors judged the risk of bias for each item as high, low, or unclear. We contacted study authors if the information in the available reports was insufficient to make an assessment. We used the available information if study authors did not respond within six weeks.

Measures of treatment effect

We computed the risk ratio for dichotomous outcomes.

Unit of analysis issues

We considered the individual as the unit of analysis. The assigned intervention was typically administered to both eyes, and we considered infants to be infected if at least one eye was affected. We excluded studies in which each eye within an infant was randomised to a different intervention, even if data were reported separately for each eye. No cluster‐randomised or cross‐over randomised controlled trials were identified and indeed they are not anticipated in this topic area.

Dealing with missing data

We contacted authors of included trials where we identified missing data on risk of bias or outcomes. If authors provided information on risk of bias that was not described in the trial reports, then this information was marked as such in the review. If missing data on an outcome were not available from study authors, then we assessed whether a meta‐analysis was possible using an intention‐to‐treat or available‐case approach.

Assessment of heterogeneity

We assessed heterogeneity in effect estimates from the included trials through a visual examination of the forest plot and based on the I2 statistic. We considered I2 values of 60% or greater to indicate substantial heterogeneity. We did not perform a meta‐analysis when we found substantial heterogeneity, and instead provided a narrative summary of the findings. We also considered the nature of interventions and the patient population to evaluate clinical heterogeneity in the included trials.

Assessment of reporting biases

For meta‐analyses in which we included more than 10 trials, we planned to construct funnel plots to assess the potential for publication bias. We planned that if a trial protocol was available, we would assess whether all outcomes relevant to this review that were specified in the protocol were also described in the published reports.

Data synthesis

We performed a meta‐analysis for comparisons where we found minimal or no clinical heterogeneity and without substantial statistical heterogeneity. We used a random‐effects model, except for comparisons with two eligible studies, when we used a fixed‐effect model. For trials with more than one comparison group, we included the trial in relevant non‐overlapping comparisons. In addition, we collapsed data across intervention groups to include such trials in the comparison of any prophylaxis versus no prophylaxis. We used the number allocated in the denominator for our calculations in all cases except when these data were not available in the trial reports. We did not explicitly consider risk of bias as a factor when determining whether to include eligible trials in meta‐analyses. We considered sensitivity analyses based on risk of bias as discussed below.

For outcomes where at least one trial explicitly reported that no events were observed in either the treatment or control arm, we performed a meta‐analysis using the Mantel‐Haenszel method and a continuity correction proportional to the inverse of the opposite arm (Sweeting 2004). Specifically, the continuity correction we used was 1/(r + 1) in the treatment arm and r/(r + 1) in the control group, where r is the ratio of sample sizes in the two arms. We used R (version 3.3.2) to conduct meta‐analyses that included the continuity correction (R Core Team 2013).

Subgroup analysis and investigation of heterogeneity

We planned to consider subgroups by cause of infection, however the available data were insufficient to permit such analyses. We also planned to separately analyse studies conducted in high‐income versus low‐income countries using the classification specified by the United Nations (WESP2016). However, this was not possible given the diversity in settings in which the included trials were conducted.

Sensitivity analysis

Where data were available, we excluded studies with high risk of selection bias in sensitivity analyses.

Summary of findings and assessment of the certainty of the evidence

We prepared 'Summary of findings' tables using the GRADE approach for the following eight outcomes (Langendam 2013).

  1. Blindness

  2. Any adverse visual outcome

  3. Gonococcal conjunctivitis (GC)

  4. Chlamydial conjunctivitis (CC)

  5. Bacterial conjunctivitis (BC)

  6. Any conjunctivitis of any aetiology (ACAE)

  7. Conjunctivitis of unknown aetiology (CUE)

  8. Adverse effects

Results

Description of studies

Results of the search

The electronic searches yielded a total of 498 records (Figure 1). After removal of 32 duplicates, we screened the remaining 466 records. We obtained the full‐text reports of 105 records for further assessment. Of these, we included 34 reports of 30 studies (see Characteristics of included studies for details). We excluded 70 reports of 63 studies (see Characteristics of excluded studies for details). One study (Matinzadeh 2007)is currently awaiting classification (see Characteristics of studies awaiting classification); if we receive further information on this study we will assess it for inclusion in future updates of this review.

Figure 1
PRISMA flow diagram

PRISMA flow diagram

Included studies

Setting and participants

Specific details on each included study are shown in the Characteristics of included studies table.

Design

Half of the included studies were quasi‐randomised (15/30; 50%), and half were randomised (15/30; 50%); see Figure 2.

Figure 2
Table of Trial Settings

Table of Trial Settings

Sample sizes

The total number of neonates included in the review across all 30 studies was 79,198. The sample size in individual trials ranged from 40 to 32,058 neonates. The average number of neonates in the included studies was 2988, with a median of 654.5.

Setting

Of the 30 trials, 18 studies (60%) were conducted in high‐income economies (9 in the USA, 7 in Europe, 1 each in Canada and Israel), and 12 (40%) were conducted in low‐ and middle‐income economies (3 in Kenya, 4 in Iran, 1 each in Zaire, Mexico, Indonesia, China, and Angola). Two studies explicitly reported recruiting participants at high risk, for example inner‐city populations (Figure 2) (Hammerschlag 1980; Hammerschlag 1989).

Time period of trials

A significant number of trials were conducted more than 50 years ago. Of the 30 included trials, seven (23%) trials were conducted between 1940 and 1960, with most of these trials (six) taking place between 1950 and 1960. Four trials (13%) were conducted between 1960 and 1980; eight trials (27%) between 1980 and 2000; seven trials (23%) between 2000 and 2010; and four trials (13%) from 2010 to the present.

Interventions

Fourteen different prophylactic regimens and 12 different prophylactic interventions were studied across the 30 included trials (Figure 3). Silver nitrate was used in the majority of trials (18 out of 30); mainly in older trials up to the early 1990s. Erythromycin was used in 10 trials; tetracycline in 9 trials; and povidone‐iodine in 9 trials. Povidone‐iodine was used mainly in more recent trials from the 1990s to the present. The route of delivery for medications was topical ocular administration, with the exception of two trials that used intramuscular penicillin. No prophylaxis was used as one arm of the study in 10 of the 30 trials. Of all trials that included no prophylaxis in one arm of the study, placebo was used in only one trial: Wahlberg 1982 used physiological normal saline in one arm of the trial.

Figure 3
Table of Trials, Interventions, Method of Allocation, Settings

Table of Trials, Interventions, Method of Allocation, Settings

The full list of interventions used in the included studies is as follows.

  1. Silver nitrate solution (18 studies: all 1%)

  2. Erythromycin ointment (10 studies: all 0.5%, except for one study in which concentration was not specified)

  3. Tetracycline (9 studies: all 1%; 2 studies used solution instead of ointment)

  4. Povidone‐iodine:

    1. solution (9 studies: all 2.5%);

    2. double application (1 study).

  5. Hexarginum (1 study: 10% solution contains 1 g AgNO3 + 36 g CH3NH2 dissolved in 63 g sterile water)

  6. Penicillin:

    1. ointment (2 studies: 1 study: penicillin G 1% ointment; 1 study: penicillin ointment 100,000 units/g);

    2. intramuscular injection (IM) (2 studies: 1 study: penicillin 10,000 units per IM injection; 1 study: penicillin G 25,000 to 50,000 units per IM injection depending on birthweight)

  7. Cetyl‐pyridinium chloride solution (2 studies: 1 study: 0.1%; 1 study: 0.05%)

  8. Bacitracin‐phenacaine ointment (1 study: bacitracin 500 units/g; 2% phenacaine hydrochloride)

  9. Sulphacetimide ointment (1 study: 10% ointment)

  10. Chloramphenicol solution (2 studies)

  11. Carbethopendecinium bromide solution (1 study)

  12. Colostrum (1 study: 2 drops of mother's colostrum in each eye)

Follow‐up time

The included trials varied widely in duration of follow‐up and the time at which outcomes were analysed and reported. Eleven out of 30 (37%) studies followed up neonates for one month. Four trials (13%) followed up neonates for more than one month. In 12 trials (40%), follow‐up was less than one month. In three trials (10%), no follow‐up period was specified. Of the four trials that followed up neonates for more than one month, two trials followed up neonates for three to five months, and two trials for 60 days. Of the two trials that followed up neonates for 60 days, we were able to extract 30‐day data from one trial, and in the other trial, follow‐up was only for the outcome of nasolacrimal duct obstruction. Of the 12 trials that followed up neonates for less than a month, nine trials followed neonates for 10 days or less, and three trials followed neonates for two weeks.

Outcomes

Eighteen of the 30 included trials (60%) reported the outcome of gonococcal conjunctivitis (GC). Thirteen of these 18 trials (43%) reported no actual cases of GC in any arm of the study. Consequently, only five studies out of the 30 included trials (17%) reported any cases of neonates with GC.

Thirteen of the 30 included studies (43%) reported the outcome of chlamydial conjunctivitis (CC). One of these 13 studies found no cases of CC in either arm of the study. Seven of the 30 trials (23%) were conducted between 1940 to 1960, when methods to detect C trachomatis were not readily available. Ten out of 30 trials (33%) reported rates of bacterial conjunctivitis (BC). Twenty‐four out of 30 trials (80%) reported the outcome of total number of clinical conjunctivitis cases. In 10 of 30 trials (33%), we were able to determine rates of conjunctivitis that were culture‐negative.

We were unable to extract outcome data from four studies. In Richter 2006, the outcomes of conjunctivitis were not well defined, such that they could not be extracted. In Wahlberg 1982, the outcomes of total conjunctivitis, culture‐negative conjunctivitis, BC, GC, and CC were not presented by allocation group; the denominators did not correspond to allocation groups; and the data were presented as percentages. In Bramantyo 2016, there were no conjunctivitis cases; follow‐up time was only 24 hours; and conjunctivitis was not specified in the methods as an outcome. Finally, in Pastor 2015, there was a high loss to follow‐up, and repeated communications with the study authors failed to clarify confusion over the remaining data, so that we felt the data could not be extracted.

Excluded studies

We excluded 63 studies (see Figure 1, Characteristics of excluded studies)

Risk of bias in included studies

The risk of bias is summarised in Figure 4 and Figure 5.

Figure 4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 5
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Of the 15 quasi‐randomised trials, three trials alternated by day, six trials alternated by week, two trials alternated by month, and three trials applied prophylaxis to alternate neonates. In the remaining quasi‐randomised trial, the prophylaxis for each day was selected from a previously prepared random sequence of assignments. Amongst the 15 randomised trials, only four trials reported the method of randomisation; the remaining 11 trials described allocation using the word “random” or “randomised” but did not provide any further information on how the random sequence was generated.

We assessed 15 out of the 30 included trials (50%) as having a high risk of selection bias based on random sequence generation. These 15 trials were generally quasi‐randomised studies using alternation by neonate or by day, week, or month. Eleven of the 30 included trials (37%) used the word “random” or “randomised” in the methods, but provided no further information on the random sequence generation process. We found only four trials (13%) to have a low risk of selection bias based on random sequence generation.

Similarly, amongst the 30 included trials, we assessed 15 trials (50%) as having a high risk of selection bias based on inadequate concealment of allocations prior to assignment. Again, these 15 trials were generally quasi‐randomised studies as mentioned above. Twelve of the 30 included trials (40%) used the word “random” or “randomised” in the methods, but provided no further information on the allocation concealment. We found only five trials (17%) to have a low risk of selection bias based on the fact that participants or investigators could not foresee the assignment.

Blinding

We assessed masking (blinding) of participants, personnel, and outcome assessors for studies in this review. We further categorised “personnel” into three subcategories: 1. mothers of infants; 2. people administering prophylaxis; and 3. people involved in postnatal care.

In none of the trials was there any explicit mention of any attempt to make the interventions look the same, or dispense them from containers that made them indistinguishable from the other interventions. In only one trial, Wahlberg 1982, it may have been the case that the interventions looked the same, and were dispensed from containers that looked the same, but this was not explicit. The ophthalmic medications used in each of the included studies did not look the same, except possibly in Wahlberg 1982. For instance, silver nitrate is a clear solution; erythromycin is an ointment; and povidone‐iodine is an orange‐red solution. The physical characteristics of the interventions studied in the included trials are described in Table 1.

Open in table viewer
Table 1. Physical characteristics of interventions studied in included trials

Interventions studied in included trials

Physical characteristics/method of delivery

Silver nitrate solution

Clear solution, topical instillation

Erythromycin ointment

Translucent/white ointment, topical application

Tetracycline ointment

Light‐yellow ointment, topical application

Oxytetracycline hydrochlorate solution

Unknown colour/consistency, aqueous solution, topical instillation

Povidone‐iodine solution

Orange‐red, clear solution, topical instillation

Hexarginum solution

Colour unknown, solution with 1 g silver nitrate + 36 g methylamine dissolved in 63 g sterile water, topical application

Penicillin G ointment

Clear/white ointment, topical application

Penicillin G intramuscular injection

Clear, aqueous solution, intramuscular injection

Cetyl‐pyridinium chloride solution

Solution of unknown colour/consistency, topical instillation

Bacitracin‐phenacaine ointment

Ointment of unknown colour, topical application

Sulfacetamide ointment

Ointment of unknown colour, topical application

Chloramphenicol solution

Clear, colourless to slightly yellow solution, topical instillation

Chloramphenicol ointment

Colourless ointment; topical instillation

Colostrum

Yellowish, white or clear liquid, topical instillation

Carbethopendecinium bromide solution

Yellowish to white powder in solution, solution colour unknown, topical instillation

Mechanical cleansing

Eyes swabbed with clear, distilled water and wiped dry

In all but five of the 30 included trials, the medications would have looked strikingly different, either because of colour or consistency. The difference in appearance of the medication would prevent masking for the person administering the medication and could lead to bias, which could influence the outcome. In fact, one study, Fischer 1988, demonstrated lack of adherence to application of medication secondary to lack of masking, which influenced rates of conjunctivitis in one arm of the study.

Masking is further affected by the fact that the majority of the medications leave a stain on the eyes after dispensing. Silver nitrate leaves lid stains that may last 30 to 48 hours. Povidone‐iodine may stain periocular skin for minutes to hours. Antibiotic ointments such as erythromycin, tetracycline, and penicillin can leave a residue that may last for hours. In four of the five above‐mentioned trials in which the medications may have looked the same, one of the interventions was silver nitrate, which would have affected masking of mothers and people involved in postnatal care due to silver nitrate’s propensity to cause lid stains. In the remaining trial in which the medications may have looked the same, there were three intervention arms, with two arms using erythromycin and tetracycline ointment, and the last arm having no prophylaxis. In this trial the ointment allocation groups could therefore be distinguished from the no‐prophylaxis group. In fact, in only one of the 10 trials where no prophylaxis was one of the arms of the study was any placebo used; hence, there was lack of masking for the person administering the medication in the remaining nine trials with a no‐prophylaxis arm.

To summarise, in no studies was it possible to mask the person administering the prophylaxis for ophthalmia neonatorum. There are also risks of compromising masking in mothers of neonates and people involved in postnatal care due to the presence of prophylaxis staining and residue. Finally, for outcome assessments conducted soon after prophylaxis administration, particularly for the interventions of silver nitrate, antibiotic ointments, and povidone‐iodine, masking could be compromised.

In spite of the performance bias and detection bias introduced by the appearance and residual staining of the prophylaxis medications, trials were scored on these categories, by subjective and objective outcome. We classified clinical conjunctivitis as a subjective outcome, and BC, CC and GC as an objective outcome. We considered CUE, which was essentially culture‐negative conjunctivitis, as objective, given that it was derived from subtracting BC cases from total clinical conjunctivitis cases. Our 'risk of bias' assessment for masking essentially found that there was much similarity in the classifications between the subjective and objective outcomes of conjunctivitis. In summary, the vast majority of studies had a high or unclear risk of performance bias, and unclear risk of detection bias, across most outcomes.

There is an additional aspect of silver nitrate that introduces a form of detection bias. Sixteen of the 30 included trials (53%) used silver nitrate. In 13 of these trials, there was an outcome derived from eye culture results. In any trial with silver nitrate, there could be biased outcome assessment. Silver nitrate causes a chemical conjunctivitis in the first 72 hours. As a result, more neonates in the silver nitrate allocation group could be referred for culture in the first 72 hours. Finding bacteria in the culture does not necessarily prove that the bacteria caused the conjunctivitis. The conjunctivitis could be chemical, but growing normal flora of the eye. Alternatively, the conjunctivitis could be chemical with a chlamydial carrier. Finally, the conjunctivitis could very well be caused by the bacteria or chlamydia. Considerations about incubation periods, and assessing for carriers and normal flora with asymptomatic cases, could have assisted with differential diagnosis, but no trial made an attempt to distinguish these possible outcomes.

Incomplete outcome data

We assessed eight of the 24 studies that reported the outcome of total clinical conjunctivitis cases as at high risk of bias due to the high proportion of missing outcome data in proportion to event rates. We judged 13 of these 24 studies to be at unclear risk of bias due to poor reporting in the study. We graded only three studies as at low risk of attrition bias. Of the 20 studies that reported BC, CC or GC we assessed 10 as at high risk and 10 as at unclear risk of attrition bias. The two studies reporting nasolacrimal duct obstruction as an outcome had a high risk of attrition bias. We graded the single study that reported the outcome of keratitis as at low risk of attrition bias.

Selective reporting

We did not have access to the protocols for any of the included studies, therefore we compared the outcomes listed in the methods section of the trial with those reported in the results. We judged 19 of the 30 included trials to be at high risk of bias for selective outcome reporting. We assessed seven studies as at unclear risk and only four studies as at low risk of reporting bias.

Other potential sources of bias

More than half of the included studies (18/30; 60%) did not specify a source of funding. Of the remaining 12 studies (40%), nine studies were funded by a non‐governmental organisation, charitable foundation, government agency, hospital, or medical school; funding sources that would seem unlikely to have biased the methodology or results. Three studies were funded by pharmaceutical companies, which supplied one of the interventions in the trial (Davidson 1951; Hammerschlag 1980; Posner 1959). In all three studies, outcomes favoured the intervention supplied and funded by the pharmaceutical company. We were unable to determine if any aspect of the methodology may have been affected to the point of risk of bias by any pharmaceutical funding.

Only five of the 30 included trials (17%) made a declaration of interest, specifying there was no conflict of interest. The remaining 25 trials (83%) made no reference to any declaration of interest.

Only three of the 30 included trials (10%) provided sufficiently detailed information in the study report to enable ruling out other potential sources of bias.

We contacted the study authors if the information in the available reports was insufficient to permit assessment. Some authors were not contacted due to the age of the studies. We contacted the study authors of 14 of the 30 included trials, of which authors of nine studies provided a response.

Effects of interventions

See: Summary of findings 1 Any prophylaxis compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

None of the trials reported any data on two of the primary outcomes specified for this review: incidence of blindness and visual impairment. Data on the remaining outcomes are discussed below (Table 2). In this review, we did not attempt to rank the relative effectiveness of the various interventions; this has to be addressed in a subsequent network meta‐analysis. Instead, we discuss our findings for important pairwise comparisons of interventions along with an overall comparison of any prophylaxis versus no prophylaxis. The individual pairwise comparisons are organised as follows: interventions compared with silver nitrate; interventions compared with erythromycin; interventions compared with tetracycline; and other comparisons.

Open in table viewer
Table 2. Summary results

Gonococcal conjunctivitis

Chlamydial conjunctivitis

Bacterial conjunctivitis

Any conjunctivitis of any aetiology

Conjunctivitis of unknown aetiology

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Any prophylaxis vs no prophylaxis

3

0.79 (0.24 to 2.65)

2

0.96 (0.57 to 1.61)

2

0.84 (0.37 to 1.93)

8

0.65 (0.54 to 0.78)

1

1.75 (0.37 to 8.28)

Silver nitrate vs no prophylaxis

1

No events reported in 1 or both arms.

1

1.06 (0.55 to 2.02)

No data were available.

3

0.67 (0.52 to 0.87)

No data were available.

Erythromycin vs no prophylaxis

2

No events reported in 1 or both arms.

2

0.93 (0.49 to 1.77)

1

0.80 (0.22 to 2.90)

6

0.68 (0.51 to 0.89)

1

1.50 (0.26 to 8.80)

Tetracycline vs no prophylaxis

1

No events reported in 1 or both arms.

1

0.82 (0.42 to 1.63)

No data were available.

2

0.72 (0.55 to 0.94)

No data were available.

Povidone‐iodine vs no prophylaxis

1

No events reported in 1 or both arms.

1

2.00 (0.18 to 21.74)

1

1.00 (0.30 to 3.36)

1

0.38 (0.18 to 0.77)

1

2.00 (0.37 to 10.70)

Bacitracin‐phenacaine vs no prophylaxis

1

0.76 (0.20 to 2.83)

No data were available.

No data were available.

No data were available.

No data were available.

Colostrum vs no prophylaxis

No data were available.

No data were available.

No data were available.

1

0.72 (0.45 to 1.14)

No data were available.

Erythromycin vs silver nitrate

4

2.28 (0.88 to 5.90)

4

0.75 (0.51 to 1.09)

2

0.83 (0.69 to 1.01)

No data were available.

Tetracycline vs silver nitrate

5

0.66 (0.21 to 2.05)

4

0.64 (0.40 to 1.02)

No data were available.

4

0.80 (0.66 to 0.98)

No data were available.

Sulfacetamide vs silver nitrate

1

No events reported in 1 or both arms.

No data were available.

1

0.88 (0.45 to 1.74)

1

0.54 (0.32 to 0.89)

1

0.27 (0.11 to 0.66)

Cetyl‐pyridinium chloride vs silver nitrate

No data were available.

No data were available.

2

1.79 (0.59 to 5.41)

2

1.08 (0.40 to 2.90)

2

No events reported in 1 or both arms.

Penicillin vs silver nitrate

1

No events reported in 1 or both arms.

No data were available.

Topical penicillin: 2; IM penicillin: 1

Topical penicillin: 0.34 (0.18 to 0.65); IM penicillin: 0.75 (0.46 to 1.24)

Topical penicillin: 2; IM penicillin: 1

Topical penicillin:* Davidson 1951: 0.15 (0.12 to 0.20); Harris 1957: 0.78 (0.35 to 1.70); IM penicillin: 0.26 (0.21 to 0.32)

Topical penicillin: 1; IM penicillin: 1

Topical penicillin: 0.13 (0.10 to 0.18); IM penicillin: 0.21 (0.17 to 0.27)

Povidone‐iodine vs silver nitrate

1

1.94 (0.60 to 6.29)

1

0.52 (0.38 to 0.71)

1

0.75 (0.61 to 0.92)

1

0.72 (0.63 to 0.84)

1

0.70 (0.55 to 0.89)

Tetracycline vs erythromycin

2

0.73 (0.18 to 2.95)

2

0.72 (0.42 to 1.25)

No data were available.

2*

Chen 1992: 0.75 (0.54 to 1.02); Ghotbi 2012: 1.38 (0.76 to 2.47)

No data were available.

Colostrum vs erythromycin

No data were available.

No data were available.

No data were available.

1

1.49 (0.80 to 2.78)

No data were available.

Povidone‐iodine vs erythromycin

2

0.85 (0.36 to 2.01)

2

0.74 (0.54 to 1.02)

2

0.87 (0.71 to 1.07)

2*

0.78 (0.68 to 0.90)

2

0.74 (0.58 to 0.93)

Penicillin IM vs tetracycline

1

No events reported in 1 or both arms.

1

0.75 (0.48 to 1.17)

No data were available.

No data were available.

No data were available.

Povidone‐iodine vs tetracycline

1

No events reported in 1 or both arms.

1

No events reported in 1 or both arms.

1

2.04 (0.99 to 4.22)

1

3.01 (1.52 to 5.98)

1

No events reported in 1 or both arms.

Povidone‐iodine vs chloramphenicol

1

No events reported in 1 or both arms.

1

1.77 (0.97 to 3.22)

No data were available.

No data were available.

No data were available.

Povidone‐iodine vs carbethopendecinium bromide

No data were available.

No data were available.

No data were available.

1

0.44 (0.15 to 1.35)

No data were available.

Povidone‐iodine twice vs povidone‐iodine once

1

No events reported in 1 or both arms.

1

1.27 (0.26 to 6.24)

1

1.69 (0.59 to 4.82)

1

1.32 (0.99 to 1.75)

1

1.29 (0.95 to 1.74)

Penicillin IM vs topical penicillin

1

No events reported in 1 or both arms.

1

No events reported in 1 or both arms.

1

2.19 (1.14 to 4.24)

1

1.71 (1.26 to 2.32)

1

1.58 (1.12 to 2.25)

IM: intramuscular

*Indicates statistically significant heterogeneity precluding a meta‐analysis.

Any prophylaxis versus no prophylaxis

See summary of findings Table 1.

Any prophylaxis was associated with a statistically significant reduction in risk for any conjunctivitis of any aetiology (ACAE) but not for GC, BC, CC, or conjunctivitis of unknown aetiology (CUE). The certainty of evidence was moderate for ACAE but low for all other outcomes. For the sake of clarity in the narrative, within each outcome under the overall comparison of any prophylaxis versus no prophylaxis, we will describe effects for individual medications versus no prophylaxis (see Table 3; Table 4; Table 5; Table 6; Table 7; Table 8).

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Table 3. Silver nitrate compared to no prophylaxis for prevention of ophthalmia neonatorum in newborn children

Silver nitrate compared to no prophylaxis for prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: silver nitrate
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with silver nitrate

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2225
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

No cases of gonococcal conjunctivitis were reported in this study.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 1.06
(0.55 to 2.02)

2225
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

5 per 1000

5 per 1000
(3 to 10)

High risk

100 per 1000

106 per 1000
(55 to 202)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain
follow‐up: 1 month

2 of the 3 studies did not measure or report bacterial conjunctivitis (Bell 1993; Graf 1994). 1 study measured bacterial conjunctivitis but did not report this outcome by study arm (Chen 1992).

 

 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.67
(0.52 to 0.87)

2713
(3 RCTs)

⊕⊕⊕⊝
MODERATE 4

3 per 1000

2 per 1000
(2 to 3)

High risk

300 per 1000

201 per 1000
(156 to 261)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

2 of the 3 studies did not measure did not measure or report conjunctivitis of unknown aetiology (Bell 1993; Graf 1994). 1 study measured conjunctivitis of unknown aetiology but did not report this outcome by trial arm (Chen 1992).

 
 
 

Adverse effects

In a single study (Bell 1993), silver nitrate prophylaxis appeared to be associated with an increased risk of nasolacrimal duct obstruction compared with no prophylaxis, but the variance in the estimate was imprecise with wide confidence intervals (RR 1.28, 95% CI 0.40 to 4.02).

A single study comparing silver nitrate with control reported that no events of keratitis were observed in the prophylaxis and no‐prophylaxis groups (Graf 1994).

⊕⊝⊝⊝
VERY LOW 1,5

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study with high risk of selection bias, unclear and high risk of performance bias, unclear risk of detection bias.
2Downgraded for imprecision (‐2): no events in either arm of trial; study underpowered to assess relative effects of treatment on this outcome.
3Downgraded for imprecision (‐1): 95% confidence interval includes no effect.
4Downgraded for risk of bias (‐1): largest trial has high or unclear risk of bias; second‐largest trial has low risk of selection bias, but higher risk of performance or detection bias.
5Downgraded (‐2) for imprecision: sparse data.

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Table 4. Erythromycin compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Erythromycin compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: erythromycin
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with erythromycin

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2526
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

No cases of gonococcal conjunctivitis were reported in these studies.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 0.93
(0.49 to 1.77)

2526
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

5 per 1000

5 per 1000
(2 to 9)

High risk

100 per 1000

93 per 1000
(49 to 177)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain.
follow‐up: 1 month

Low risk

RR 0.80
(0.22 to 2.90)

220
(1 RCT)

⊕⊕⊝⊝
LOW 3,4

 

3 per 1000

2 per 1000
(1 to 9)

High risk

50 per 1000

40 per 1000

(11 to 145)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.68
(0.51 to 0.89)

3509
(6 RCTs)

⊕⊕⊕⊝
MODERATE 1

 

3 per 1000

2 per 1000
(2 to 3)

High risk

300 per 1000

204 per 1000

(153 to 267)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.50
(0.26 to 8.80)

220
(1 RCT)

⊕⊝⊝⊝
VERY LOW 4,5

 

18 per 1000

27 per 1000
(5 to 160)

Adverse effects

In a single study of 269 people, there was no clear relationship between erythromycin and nasolacrimal duct obstruction (RR 0.83, 95% CI 0.56 to 1.23).

⊕⊝⊝⊝
VERY LOW 4,5

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies were at high risk or unclear risk of bias. High loss to follow‐up in one trial, and unclear if follow‐up time is two weeks or one month in same trial. No placebo used in either trial.
2Downgraded for imprecision (‐2): no events in either arm of trial.
3Downgraded for imprecision (‐1): 95% confidence interval includes no effect; very few events; one study; small sample size.
4Downgraded for risk of bias (‐1): study has high or unclear risk of bias with high loss to follow‐up. No placebo used.
5Downgraded for imprecision (‐2): very wide confidence intervals.

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Table 5. Tetracycline compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Tetracycline compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: tetracycline
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with tetracycline

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2299
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1

No cases of gonococcal conjunctivitis were reported in this study.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 0.82
(0.42 to 1.63)

2299
(1 RCT)

⊕⊕⊝⊝
LOW 2,3

.

5 per 1000

4 per 1000
(7 to 26)

High risk

100 per 1000

82 per 1000

(42 to 163)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain
follow‐up: 1 month

1 study did not measure or report bacterial conjunctivitis (Ghotbi 2012), whilst the other study measured bacterial conjunctivitis but did not report by allocation group (Chen 1992).

 
 
 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.72
(0.55 to 0.94)

2519
(2 RCTs)

⊕⊕⊝⊝
LOW 3,4

3 per 1000

2 per 1000
(2 to 3)

High risk

300 per 1000

216 per 1000

(1165 to 282)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

1 study did not measure or report conjunctivitis of unknown aetiology (CUE) (Ghotbi 2012), whilst the other study measured CUE but did not report by allocation group (Chen 1992).

 
 
 

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for imprecision (‐3): no events in this trial.
2Downgraded for risk of bias (‐1): single trial with high risk of bias for sequence generation, allocation concealment, and masking, and unclear risk of bias for detection and attrition bias, which could affect outcomes considering the low event rates.
3Downgraded for imprecision (‐1): optimal information size not met, and confidence interval overlaps no effect in this single study.
4Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.

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Table 6. Povidone‐iodine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

220
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1

No cases of gonococcal conjunctivitis were reported in this study.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 2.00
(0.18 to 21.7)

220
(1 RCT)

⊕⊕⊝⊝
LOW 2,3

.

5 per 1000

10 per 1000
(1 to 109)

High risk

100 per 1000

200 per 1000

(18 to 1000)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain.
follow‐up: 1 month

Low risk

RR 1.00
(0.30 to 3.36)

220
(1 RCT)

⊕⊕⊝⊝
LOW 2,3

 

3 per 1000

3 per 1000
(1 to 10)

High risk

50 per 1000

50 per 1000

(15 to 168)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.38
(0.18 to 0.77)

220
(1 RCT)

⊕⊕⊕⊝
MODERATE 2

 

3 per 1000

1 per 1000
(1 to 2)

High risk

300 per 1000

114 per 1000

(54 to 231)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 2.00
(0.37 to 10.70)

220
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2,4

 

18 per 1000

36 per 1000
(7 to 195)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for imprecision (‐3): no events in either arm of this study.
2Downgraded for risk of bias (‐1): the study is unclear regarding sequence generation and allocation concealment. Masking is a concern as there was no placebo. Very high losses to follow‐up.
3Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

4Downgraded for imprecision (‐2): very wide confidence intervals.

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Table 7. Bacitracin‐phenacaine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Bacitracin‐phenacaine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: bacitracin‐phenacaine
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Risk with no prophylaxis

Risk with bacitracin‐phenacaine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Low risk

RR 0.76
(0.20 to 2.83)

3355
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

1 per 1000

1 per 1000
(0 to 3)

High risk

100 per 1000

76 per 1000

(20 to 283 per 1000)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

The 1 study does not seem to have measured or reported cases of chlamydial conjunctivitis (Posner 1959). Diagnostic methods for chlamydia would not have been readily available in 1959.

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

It is unknown if bacterial conjunctivitis was measured in the 1 study (Posner 1959), as it categorises conjunctivitis only as "nonspecific conjunctivitis" and "gonorrhoeal ophthalmia".

 
 
 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

It is unknown if all conjunctivitis were measured in the 1 study (Posner 1959), as it categorises conjunctivitis only as "nonspecific conjunctivitis" and "gonorrhoeal ophthalmia".

 

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The category of "nonspecific conjunctivitis" reported in the 1 study is undefined and may or may not also include bacterial conjunctivitis cases (Posner 1959).

 

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial with high risk of selection bias, unclear risk of performance and detection bias, high risk of selective outcome reporting.
2Downgraded for imprecision (‐2): very wide confidence intervals, which include no effect.

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Table 8. Colostrum compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Colostrum compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: colostrum
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Risk with no prophylaxis

Risk with colostrum

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

No discussion of gonococcal conjunctivitis in this study (Ghaemi 2014). The trial excluded culture‐positive neonates before application of prophylaxis.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

No discussion of chlamydial conjunctivitis in this 1 study (Ghaemi 2014). It is unknown if it was measured. Chlamydial conjunctivitis cases were not reported.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

The 1 trial trial does not report bacterial conjunctivitis cases as distinguished from all conjunctivitis cases (Ghaemi 2014). It is unknown if bacterial conjunctivitis was measured.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.72
(0.45 to 1.14)

186
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

3 per 1000

2 per 1000
(1 to 3)

High risk

300 per 1000

216 per 1000

(135 to 342)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The 1 trial only reports all conjunctivitis cases, and does not distinguish bacterial conjunctivitis cases from cases of conjunctivitis of unknown aetiology (Ghaemi 2014).

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study at high or unclear risk of performance, detection, and attrition bias.
2Downgraded for imprecision (‐1): 95% confidence interval includes no effect.

Gonococcal conjunctivitis 

There was only very low‐certainty evidence on the risk of GC with prophylaxis (4/5340 newborns) compared to no prophylaxis (5/2889) at one month (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.24 to 2.65, 3 studies, I2 = 0%; Figure 6). 

Figure 6
Forest plot of comparison: 1 Any prophylaxis versus no prophylaxis, outcome: 1.1 Gonococcal conjunctivitis

Forest plot of comparison: 1 Any prophylaxis versus no prophylaxis, outcome: 1.1 Gonococcal conjunctivitis

Data on GC were available for the following medications individually compared with no prophylaxis: silver nitrate, erythromycin, tetracycline, povidone‐iodine, and bacitracin. For all these medications, a single trial provided data on comparison with no prophylaxis except erythromycin for which data were provided by two trials. No events of GC were observed when silver nitrate (Chen 1992), erythromycin (Ali 2007; Chen 1992), tetracycline (Chen 1992), or povidone‐iodine (Ali 2007), were compared with no prophylaxis. It was thus not possible to estimate the effect of prophylaxis with these medications against GC. Bacitracin was associated with a RR of 0.76 for GC but with very wide CIs (RR 0.76, 95% CI 0.20 to 2.83) (Posner 1959).

Chlamydial conjunctivitis 

In a meta‐analysis of two trials, any prophylaxis did not appear to reduce the incidence of CC (RR 0.96, 95% CI 0.57 to 1.61, 4874 participants, 2 studies; I2 = 0%; Analysis 1.1). GRADE certainty of the evidence was low.

Data on CC were available for the following medications individually compared with no prophylaxis: silver nitrate, erythromycin, tetracycline, and povidone‐iodine. For all these medications, a single trial provided data on comparison with no prophylaxis except erythromycin for which data were provided by two trials. There was little or no difference with the risk of CC for silver nitrate (RR 1.06, 95% CI 0.55 to 2.02; Chen 1992) . Povidone‐iodine was associated with an increased risk of CC (RR 2.00, 95% CI 0.18 to 22.74; Ali 2007), but this association was not statistically significant. There was little or no difference in CC with erythromycin (RR 0.93, 95% CI 0.49 to 1.77, 2526 participants, 2 studies; I2 = 0%; Analysis 3.2) and tetracycline (RR 0.82, 95% CI 0.42 to 1.63)  compared with no prophylaxis (Chen 1992).

Bacterial conjunctivitis 

In a meta‐analysis of two trials, any prophylaxis did not appear to reduce the incidence of BC (RR 0.84, 95% CI 0.37 to 1.93, 3685 participants, 2 studies; I2 = 0%; Analysis 1.2). GRADE certainty of the evidence was low.

Data on BC were available for the following medications individually compared with no prophylaxis: erythromycin and povidone‐iodine. A single trial provided data on BC for both these medications (Ali 2007). There was no evidence that erythromycin was associated with a reduced risk of BC compared with no prophylaxis (RR 0.80, 95% CI 0.22 to 2.90) (Ali 2007). Povidone‐iodine did not appear to reduce the incidence of BC compared with no prophylaxis (RR 1.00, 95% CI 0.30 to 3.36) (Ali 2007).

Any conjunctivitis of any aetiology 

In a meta‐analysis of eight trials, any prophylaxis was associated with a 35% (95% CI 22% to 46%) reduction in risk of ACAE compared with no prophylaxis (RR 0.65, 95% CI 0.54 to 0.78, 9666 participants, 8 studies; I2 = 11%; Analysis 1.3). GRADE certainty of the evidence was moderate.

Data on ACAE were available for the following medications individually compared with no prophylaxis: silver nitrate, erythromycin, tetracycline, povidone‐iodine, and colostrum. In a meta‐analysis of three trials, silver nitrate was associated with a reduced risk of ACAE compared with no prophylaxis (RR 0.67, 95% CI 0.52 to 0.87, 2713 participants, 3 studies; I2 = 0%; Analysis 2.3). In a meta‐analysis of six trials, erythromycin was associated with a reduced risk of ACAE compared with no prophylaxis (RR 0.68, 95% CI 0.51 to 0.89, 3509 participants, 6 studies; I2 = 38%; Analysis 3.4). Similarly, in a meta‐analysis of two trials, tetracycline was associated with a reduced risk of ACAE compared with no prophylaxis (RR 0.72, 95% CI 0.55 to 0.94, 2519 participants, 2 studies; I2 = 0%; Analysis 4.3). Data from a single trial suggest that povidone‐iodine reduces the risk of ACAE compared with no prophylaxis (RR 0.38, 95% CI 0.18 to 0.77) (Ali 2007). Finally, a single trial indicates colostrum is associated with a reduction in risk of ACAE compared with no prophylaxis that was not statistically significant (RR 0.72, 95% CI 0.45 to 1.14) (Ghaemi 2014).

Conjunctivitis of unknown aetiology 

In a single trial (Ali 2007), any prophylaxis was associated with an increased risk of CUE compared with no prophylaxis, but the CIs were very wide (RR 1.75, 95% CI 0.37 to 8.28). GRADE certainty of the evidence was very low.

Adverse events

In a single trial (Bell 1993), any prophylaxis (erythromycin 0.5% or silver nitrate 1%) did not appear to be associated with an increased risk of nasolacrimal duct obstruction compared with no prophylaxis (RR 0.93, 95% CI 0.68 to 1.28). GRADE certainty of the evidence was very low. A single trial of silver nitrate 1% in 40 newborn children reported that no events of keratitis were observed in the prophylaxis and no‐prophylaxis groups (Graf 1994).

Erythromycin versus silver nitrate

See summary of findings in Table 9.

Open in table viewer
Table 9. Erythromycin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Erythromycin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: erythromycin
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with erythromycin

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 2.28
(0.88 to 5.90)

14,855
(4 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

In 2 of the 4 trials, there were no cases of gonococcal conjunctivitis in either study arm.

Follow‐up: range 8 days to 19 weeks

1 per 1000

2 per 1000
(1 to 6)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.75
(0.51 to 1.09)

13,472
(4 RCTs)

⊕⊕⊝⊝
LOW 3,4

Follow‐up: range 4 weeks to 19 weeks

21 per 1000

16 per 1000
(11 to 23)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.83
(0.69 to 1.01)

6333
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

Follow‐up: range 9 days to 60 days

57 per 1000

47 per 1000
(39 to 58)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

See comment

‐

9021
(4 RCTs)

⊕⊝⊝⊝
VERY LOW 1,3,5

A meta‐analysis was not conducted considering the considerable statistical heterogeneity (I2 = 90%). Therefore, there was no pooled effect.

Follow‐up: range 9 days to 60 days

Any conjunctivitis of any aetiology assessed with: clinical assessment of conjunctivitis

follow‐up: 1 month

Study population

RR 1.02
(0.80 to 1.30)

4729
(3 RCTs)

⊕⊕⊝⊝
LOW 1,3

After excluding 1 study (Christian 1960), I2 declined to 51%, but was still moderate. A pooled effect was then presented for these 3 remaining studies.

Follow‐up: range 9 days to 60 days

170 per 1000

173 per 1000
(136 to 221)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.96
(0.77 to 1.19)

2041
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

139 per 1000

133 per 1000
(107 to 165)

Adverse effects

In 1 study, erythromycin was associated with a reduced risk of nasolacrimal duct obstruction compared with silver nitrate. This association was not statistically significant (RR 0.81, 95% CI 0.55 to 1.20).

⊕⊕⊝⊝
LOW 1,3

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.
2Downgraded for imprecision (‐2): very wide 95% confidence intervals including no effect.
3Downgraded for imprecision (‐1): 95% confidence intervals include no effect.
4Downgraded for risk of bias (‐1): one of the four studies, the smallest one (Hammerschlag 1980), was funded by the pharmaceutical company that produces erythromycin (Dista Pharmaceuticals). That trial favoured erythromycin, and was the only trial amongst four trials with no chlamydial conjunctivitis in the erythromycin arm (12 cases in the silver nitrate arm). There were 36 infants in the silver nitrate arm and only 24 in the erythromycin arm. Furthermore, 7 of 67 chlamydia‐positive mothers remained unaccounted for. Their distribution in the allocation arms is unknown. With a transmission rate of about 30%, low event rates, and small sample size, these missing mothers could have a significant effect on the results.
5Downgraded for inconsistency (‐1): confidence intervals do not overlap; point estimates vary widely and on either side of no effect; I2 is 90%; and Chi2 P < 0.001. Heterogeneity could be explained by one older trial that did not define conjunctivitis, and review authors applied definition to eye reaction classifications.

Gonococcal conjunctivitis 

In a meta‐analysis of four trials, two of which reported no incidence of GC, erythromycin was associated with a 2.28‐fold increase in risk of GC compared with silver nitrate (RR 2.28, 95% CI 0.88 to 5.90, 14,855 participants, 4 studies; I2 = 0%; Figure 7). GRADE certainty of the evidence was very low. The wide CIs indicate that the estimate is compatible with a 12% reduction in risk and a 5.9‐fold increase in risk.

Figure 7
Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.1 Gonococcal conjunctivitis.

Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.1 Gonococcal conjunctivitis.

Chlamydial conjunctivitis

In a meta‐analysis of four trials, erythromycin was associated with a 25% reduction (95% CI 49% reduction to 9% increase) in risk of CC compared with silver nitrate (RR 0.75, 95% CI 0.51 to 1.09, 13,472 participants, 4 studies; I2 = 30%;  Analysis 8.1; Figure 8). GRADE certainty of the evidence was low.

Figure 8
Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.2 Chlamydial conjunctivitis.

Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.2 Chlamydial conjunctivitis.

Bacterial conjunctivitis 

In a meta‐analysis of two trials, erythromycin was associated with a lower incidence of BC compared with silver nitrate (RR 0.83, 95% CI 0.69 to 1.01, 6333 participants; 2 studies; I2 = 55%; Analysis 8.2). GRADE certainty of the evidence was low. The two trials had considerable differences in study design, which explains the observed I2 of 55%. The trials were conducted about 35 years apart. While both trials allocated infants by alternation and were thus at high risk of selection bias, Christian 1960 alternated infants and reported inadequate alternation for the first two months of the trial.

Any conjunctivitis of any aetiology 

There was considerable statistical heterogeneity (I2 = 90%) amongst the four trials that compared erythromycin versus silver nitrate and reported data for this outcome (Analysis 8.3), thus we did not conduct a meta‐analysis of the four trials. The protective effect of erythromycin in Christian 1960 was about three orders of magnitude higher than that seen in the remaining three trials, which may be explained by its high risk of selection bias. GRADE certainty of the evidence was very low. In a sensitivity analysis excluding Christian 1960, which was at a high risk of selection bias, there was no evidence that erythromycin reduced the risk of ACAE any more than silver nitrate (RR 1.02, 95% CI 0.80 to 1.30). GRADE certainty of the evidence was low.

Conjunctivitis of unknown aetiology 

In a single trial (Isenberg 1995), there was little evidence of any difference between erythromycin and silver nitrate for risk of CUE (RR 0.96, 95% CI 0.77 to 1.19). GRADE certainty of the evidence was low (Analysis 8.4).

Adverse events

In one trial, erythromycin was associated with a reduced risk of nasolacrimal duct obstruction compared with silver nitrate. This association was not statistically significant (RR 0.81, 95% CI 0.55 to 1.20; Analysis 8.5) (Bell 1993). GRADE certainty of the evidence was low.

Overall, we rated the certainty of the evidence for erythromycin versus silver nitrate to be moderate for GC, CC, and BC (see Table 9). We considered the certainty of the evidence for ACAE to be very low, owing to heterogeneous estimates in the included studies.

Tetracycline versus silver nitrate

See summary of findings in Table 10.

Open in table viewer
Table 10. Tetracycline compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Tetracycline compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: tetracycline
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with tetracycline

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 0.66
(0.21 to 2.05)

14,501
(5 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2,3

Amongst the 5 included trials, 3 had no events in either study arm.

Range 4 weeks to 19 weeks

1 per 1000

1 per 1000
(0 to 2)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.64
(0.40 to 1.02)

14,142
(4 RCTs)

⊕⊕⊝⊝
LOW 1,4

Range 4 weeks to 19 weeks

7 per 1000

4 per 1000
(3 to 7)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Amongst 5 studies, 4 measured bacterial conjunctivitis but did not report the results (2) or the data could not be extracted (2). 1 study did not measure or report bacterial conjunctivitis.

 
 
 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.80
(0.66 to 0.98)

6229
(4 RCTs)

⊕⊕⊕⊝
MODERATE 1

64 per 1000

51 per 1000
(42 to 63)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Amongst 5 trials, 4 measured conjunctivitis of unknown aetiology (CUE) but did not report the results (2) or the data could not be extracted (2). 1 trial did not measure or report CUE.

 
 
 

Adverse effects

In 1 trial, tetracycline appeared to be associated with a higher risk of nasolacrimal duct obstruction, but the estimate was imprecise and included no effect (RR 1.57, 95% CI 0.63 to 3.91).

⊕⊕⊝⊝
LOW 1,5

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.
2Downgraded for inconsistency (‐1): I2 is 60%, Chi2 P value is 0.11. Two trials had no events in either arm. Downgraded due to variable methods and length of follow‐up.
3Downgraded for imprecision (‐1): optimal information size is not met, but large sample size (7721 neonates in tetracycline group and 6780 neonates in silver nitrate group) with low baseline risk; however, confidence intervals are quite wide around relative effects, but around absolute effects relatively narrow. Outcome of gonococcal conjunctivitis is of critical significance and can affect vision. Therefore, downgraded one level for imprecision.
4Downgraded for imprecision (‐1): optimal information size is not met, but large sample size (7598 neonates in tetracycline group and 6544 neonates in silver nitrate group) with low baseline risk; confidence intervals are wide around relative effects, but around absolute effects relatively narrow. Confidence interval overlaps no effect. RR of 60% with tetracycline versus RR increase of 2% with tetracycline. Confidence interval fails to exclude important benefit. Chlamydial conjunctivitis outcome is important. Downgraded for imprecision.
5Downgraded for imprecision (‐1): confidence intervals include benefit and harm

Gonococcal conjunctivitis 

In a meta‐analysis of five trials, tetracycline was associated with a 34% reduction in risk of GC when compared with silver nitrate, but this effect was consistent with both a 79% reduction in risk and a 2.05‐fold increase in risk (RR 0.66, 95% CI 0.21 to 2.05, 14,501 participants, 5 studies; I2 = 0%; Figure 9). GRADE certainty of the evidence was very low. While the statistical heterogeneity was not high, all five trials were at high or unclear risk of bias for all 'Risk of bias' domains assessed. Furthermore, three of the five trials reported no events of GC. We thus considered the overall certainty of evidence for this analysis to be low.

Figure 9
Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.1 Gonococcal conjunctivitis.

Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.1 Gonococcal conjunctivitis.

Chlamydial conjunctivitis 

In a meta‐analysis of four trials, tetracycline was associated with a reduced risk of CC, but the effect was not statistically significant (RR 0.64, 95% CI 0.40 to 1.02, 14,142 participants, 4 studies; I2 = 0%; Analysis 9.1; Figure 10). GRADE certainty of the evidence was low.

Figure 10
Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.2 Chlamydia conjunctivitis.

Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.2 Chlamydia conjunctivitis.

Bacterial conjunctivitis 

No data were available for BC comparing tetracycline versus silver nitrate.

Any conjunctivitis of any aetiology

In a meta‐analysis of four trials, tetracycline was associated with a lower risk of ACAE compared with silver nitrate (RR 0.80, 95% CI 0.66 to 0.98, 6229 participants, 4 studies; I2 = 0%; Figure 11). One of the four trials included in this meta‐analysis reported no events in infants treated with silver nitrate. GRADE certainty of the evidence was moderate.

Figure 11
Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.3 Any conjunctivitis of any aetiology

Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.3 Any conjunctivitis of any aetiology

Conjunctivitis of unknown aetiology

No data were available for CUE comparing tetracycline versus silver nitrate.

Adverse events

In one trial, tetracycline appeared to be associated with a higher risk of nasolacrimal duct obstruction, but the variance in the estimate was high (RR 1.57, 95% CI 0.63 to 3.91, 145 participants, 1 study) (Analysis 9.2). GRADE certainty of the evidence was low.

Sulfacetamide versus silver nitrate

See summary of findings in Table 11.

Open in table viewer
Table 11. Sulfacetamide compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Sulfacetamide compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: sulfacetamide
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with sulfacetamide

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

640
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study reported no cases of gonococcal conjunctivitis (Cousineau 1952).

follow‐up: 3 to 9 days

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

It is likely that chlamydial conjunctivitis was measured in this 1952 study but not reported in this trial. It is described in other observational studies in the same paper ("virus inclusion bodies").

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.88
(0.45 to 1.74)

640
(1 RCT)

⊕⊕⊝⊝
LOW1,3

Follow‐up: 3 to 9 days

53 per 1000

47 per 1000
(24 to 92)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.54
(0.32 to 0.89)

640
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 3 to 9 days

122 per 1000

66 per 1000
(39 to 109)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.27
(0.11 to 0.66)

640
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 3 to 9 days

69 per 1000

19 per 1000
(8 to 46)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study with high risk of selection bias, high risk of performance bias, unclear risk of detection bias.
2Downgraded for imprecision (‐2): no events in either arm of trial; study was underpowered to assess this outcome.
3Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval overlaps no effect.

Gonococcal conjunctivitis 

No events of GC were reported in one trial comparing sulfacetamide versus silver nitrate (Cousineau 1952). GRADE certainty of the evidence was very low.

Chlamydial conjunctivitis 

No data on CC were available in one trial comparing sulfacetamide versus silver nitrate (Cousineau 1952).

Bacterial conjunctivitis 

In one trial (Cousineau 1952), sulfacetamide was associated with little or no difference in risk of BC compared with silver nitrate (RR 0.88, 95% CI 0.45 to 1.74). This association was not statistically significant. GRADE certainty of the evidence was low.

Any conjunctivitis of any aetiology

In one trial (Cousineau 1952), sulfacetamide was associated with a lower risk of ACAE than silver nitrate (RR 0.54, 95% CI 0.32 to 0.89). GRADE certainty of the evidence was moderate.

Conjunctivitis of unknown aetiology

In one trial (Cousineau 1952), sulfacetamide was associated with a lower risk of CUE than silver nitrate (RR 0.27, 95% CI 0.11 to 0.66). GRADE certainty of the evidence was moderate.

Adverse events

No adverse events data were available comparing sulfacetamide versus silver nitrate.

Cetyl‐pyridinium chloride versus silver nitrate

See summary of findings in Table 12.

Open in table viewer
Table 12. Cetyl‐pyridinium chloride compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Cetyl‐pyridinium chloride compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: cetyl‐pyridinium chloride
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with cetyl‐pyridinium chloride

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Gonococcal conjunctivitis not measured and not reported. Study explicitly reported that there was no culture method used to detect Neisseria gonorrhoeae.

 

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

None of the studies reported the diagnosis of chlamydial conjunctivitis. None of the studies specified if chlamydia was measured, which was unlikely considering publication date of 1965.

 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 1.79
(0.59 to 5.41)

599
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

Follow‐up: 2 weeks

17 per 1000

30 per 1000
(10 to 92)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.08
(0.40 to 2.90)

599
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2,3

Follow‐up: 2 weeks

27 per 1000

29 per 1000
(11 to 78)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.14
(0.01 to 2.71)

599
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

Follow‐up: 2 weeks

10 per 1000

1 per 1000
(0 to 27)

Adverse effects

No studies reported this outcome.

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high risk of bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval overlaps no effect. Confidence intervals very wide.
3Downgraded for inconsistency (‐1): point estimates on opposite sides of no effect. I2 is 60%, but confidence intervals overlap and and Chi2 P value is 0.11. Borderline. Downgraded.

Gonococcal conjunctivitis

No data were available on GC comparing cetyl‐pyridinium chloride versus silver nitrate.

Chlamydial conjunctivitis

No data were available on CC comparing cetyl‐pyridinium chloride versus silver nitrate.

Bacterial conjunctivitis

In a meta‐analysis of two trials, cetyl‐pyridinium chloride was associated with a higher risk of BC compared with silver nitrate; this association was not statistically significant (RR 1.79, 95% CI 0.59 to 5.41, 599 participants, 2 studies; I2 = 15%). GRADE certainty of the evidence was low.

Any conjunctivitis of any aetiology

In a meta‐analysis of two trials, cetyl‐pyridinium chloride was associated with a higher risk of ACAE compared with silver nitrate; this association was not statistically significant (RR 1.08, 95% CI 0.40 to 2.90, 599 participants, 2 studies; I2 = 60%). GRADE certainty of the evidence was very low.

Conjunctivitis of unknown aetiology

In a meta‐analysis of two trials, cetyl‐pyridinium chloride was associated with a lower risk of CUE compared with silver nitrate; this association was not statistically significant (RR 0.14, 95% CI 0.01 to 2.71, 599 participants, 2 studies; I2 = 60%) (Kaivonen 1965a; Kaivonen 1965b). GRADE certainty of the evidence was low.

Adverse events

No adverse events data were available comparing cetyl‐pyridinium chloride versus silver nitrate.

Penicillin versus silver nitrate

See summary of findings in Table 13 and Table 14.

Open in table viewer
Table 13. Penicillin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Penicillin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with penicillin

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2804
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study with this comparison measured gonococcal conjunctivitis but found no cases of gonococcal conjunctivitis in either study arm (Davidson 1951). follow‐up: 10 days

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Studies comparing penicillin to silver nitrate do not report the diagnosis of chlamydial conjunctivitis. They do not specify if chlamydia was measured, which is understandable considering 1950s publication dates.

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.34
(0.18 to 0.65)

2804
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Davidson 1951

follow‐up: 10 days

26 per 1000

9 per 1000
(5 to 17)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

‐

5228
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

Significant statistical heterogeneity, therefore meta‐analysis not conducted. Heterogeneity may be explained by differing definitions of conjunctivitis between trials.

follow‐up: 10 days

See comment

See comment

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.13
(0.10 to 0.18)

2804
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

Follow‐up: 10 days

263 per 1000

34 per 1000
(26 to 47)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial with high risk of selection bias, unclear and high risk of performance bias, and high risk of attrition bias.
2Downgraded for imprecision (‐2): no events in either penicillin or silver nitrate arms of trial. Study was underpowered to assess this outcome.
3Downgraded for inconsistency (‐1): point estimates vary; confidence intervals do not overlap; I2 is 93%; Chi2 P < 0.001.

Open in table viewer
Table 14. Penicillin IM compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Penicillin IM compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin IM

Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with penicillin IM

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2727
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study with follow‐up: 10 days measured gonococcal conjunctivitis but found no cases of gonococcal conjunctivitis in either study arm (Davidson 1951).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

1 study comparing penicillin IM to silver nitrate does not report chlamydial conjunctivitis and does not specify if chlamydia was measured, which is understandable considering the study was published in 1951.

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.75
(0.46 to 1.24)

2727
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

Follow‐up 10 days (Davidson 1951).

26 per 1000

20 per 1000
(12 to 32)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.26
(0.21 to 0.32)

2727
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 10 days

289 per 1000

75 per 1000
(61 to 93)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.21
(0.17 to 0.27)

2727
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 10 days

263 per 1000

55 per 1000
(45 to 71)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; IM: intramuscular; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias: single trial with high risk of selection bias, unclear to high risk of performance bias, and unclear to high risk of attrition bias.
2Downgraded for imprecision (‐2): no events in either arm, likely not meeting optimal information size criteria.
3Downgraded for imprecision (‐1): optimal information size criteria not met; confidence interval wide and crosses null effect.

Gonococcal conjunctivitis

One trial reported no events of GC comparing topical and intramuscular (IM) penicillin versus silver nitrate (Davidson 1951). GRADE certainty of the evidence was very low.

Chlamydial conjunctivitis

No data were available on CC comparing topical and IM penicillin versus silver nitrate.

Bacterial conjunctivitis

In one trial, topical penicillin was associated with a reduced risk of BC compared with silver nitrate (RR 0.34, 95% CI 0.18 to 0.65) (Davidson 1951). GRADE certainty of the evidence was moderate.

In one trial, IM penicillin was associated with a reduced risk of BC compared with silver nitrate; this association was not statistically significant (RR 0.75, 95% CI 0.46 to 1.24) (Davidson 1951). GRADE certainty of the evidence was very low.

Any conjunctivitis of any aetiology

Two trials compared topical penicillin versus silver nitrate for ACAE. While both trials reported that penicillin was associated with a lower risk of ACAE compared with silver nitrate, their estimates were statistically heterogeneous (I2 = 93%; Analysis 12.3), precluding a meta‐analysis. The RR for ACAE was 0.15 (95% CI 0.12 to 0.20) in Davidson 1951 and 0.78 (95% CI 0.35 to 1.70) in Harris 1957. GRADE certainty of the evidence was very low. Both trials were reported in the 1950s, and were at high risk of selection bias and unclear risk of performance, detection, and attrition biases. Multiple factors may explain the heterogeneity observed in this analysis, including lack of a specific definition of conjunctivitis in Davidson 1951, requiring interpretation by the review authors; and use of wax ampoules that the study authors reported were sometimes defective, leading to evaporation and potentially increased concentration of silver nitrate, and eventually frequency of chemical conjunctivitis.

In one trial, IM penicillin was associated with a reduced risk of ACAE compared with silver nitrate (RR 0.26, 95% CI 0.21 to 0.32) (Davidson 1951). GRADE certainty of the evidence was moderate.

Conjunctivitis of unknown aetiology

In one trial, topical penicillin was associated with a reduced risk of CUE compared with silver nitrate (RR 0.13, 95% CI 0.10 to 0.18) (Davidson 1951). GRADE certainty of the evidence was low.

In one trial, IM penicillin was associated with a reduced risk of CUE compared with silver nitrate (RR 0.21, 95% CI 0.17 to 0.27) (Davidson 1951). GRADE certainty of the evidence was moderate.

Adverse events

No adverse events data were available comparing penicillin versus silver nitrate.

Povidone‐iodine versus silver nitrate

See summary of findings in Table 15.

Open in table viewer
Table 15. Povidone‐iodine compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 1.94
(0.60 to 6.29)

2005
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

Isenberg 1995

4 per 1000

8 per 1000
(3 to 25)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.52
(0.38 to 0.71)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

105 per 1000

55 per 1000
(40 to 75)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.75
(0.61 to 0.92)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

175 per 1000

132 per 1000
(107 to 161)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.72
(0.63 to 0.84)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

314 per 1000

226 per 1000
(198 to 264)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.70
(0.55 to 0.89)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

139 per 1000

97 per 1000
(76 to 124)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial has high or unclear risk of selection bias, performance bias, and attrition bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

Gonococcal conjunctivitis

In a single trial (Isenberg 1995), povidone‐iodine was associated with a higher risk of GC than silver nitrate, which was not statistically significant (RR 1.94, 95% CI 0.60 to 6.29). GRADE assessment of the evidence was low.

Chlamydial conjunctivitis

In a single trial (Isenberg 1995), povidone‐iodine was associated with a lower risk of CC than silver nitrate (RR 0.52, 95% CI 0.38 to 0.71). GRADE certainty of the evidence was moderate.

Bacterial conjunctivitis

In a single trial (Isenberg 1995), povidone‐iodine was associated with a lower risk of BC than silver nitrate (RR 0.75, 95% CI 0.61 to 0.92). GRADE certainty of the evidence was moderate.

Any conjunctivitis of any aetiology

In a single trial (Isenberg 1995), povidone‐iodine was associated with a lower risk of ACAE than silver nitrate (RR 0.72, 95% CI 0.63 to 0.84). GRADE certainty of the evidence was moderate.

Conjunctivitis of unknown aetiology

In a single trial (Isenberg 1995), povidone‐iodine was associated with a lower risk of CUE than silver nitrate (RR 0.70, 95% CI 0.55 to 0.89). GRADE certainty of the evidence was moderate.

Adverse events

No adverse events data were available comparing povidone‐iodine versus silver nitrate.

Tetracycline versus erythromycin

See summary of findings in Table 16.

Open in table viewer
Table 16. Tetracycline compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Tetracycline compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: tetracycline
Comparison: erythromycin

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with erythromycin

Risk with tetracycline

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 0.73
(0.18 to 2.95)

10,946
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

1 of 2 included studies did not identify any cases of gonococcal conjunctivitis (Chen 1992).

1 per 1000

1 per 1000
(0 to 3)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.72
(0.42 to 1.25)

10,946
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

6 per 1000

4 per 1000
(3 to 8)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Amongst the 3 studies comparing these interventions, Chen 1992 measured and reported bacterial conjunctivitis, but data could not be extracted, and Hammerschlag 1989 and Ghotbi 2012 did not report and outcome was unlikely measured.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

‐

2539
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2,3

Data not pooled because of significant heterogeneity. I2 is 69% and point estimates on opposite side of line of no effect.

See comment

See comment

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Amongst the 3 studies comparing these interventions, Chen 1992 measured and reported conjunctivitis of unknown aetiology, but data could not be extracted, and Hammerschlag 1989 and Ghotbi 2012 did not report and outcome was unlikely measured.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at unclear or high risk of bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, but sample size is large at 5624 in tetracycline group and 5322 in erythromycin group. However, confidence interval includes no effect, confidence intervals wide, and one trial has no events.
3Downgraded for inconsistency (‐1): significant statistical heterogeneity. Point estimates on either side of line of no effect. I2 is 69%.

Gonococcal conjunctivitis

In a meta‐analysis of two trials, there was no evidence that tetracycline was associated with a statistically significant reduction in risk of GC compared with erythromycin (RR 0.73, 95% CI 0.18 to 2.95, 10,946 participants, 2 studies; I2 = 0%). GRADE certainty of the evidence was low.

Chlamydial conjunctivitis

In a meta‐analysis of two trials, tetracycline was associated with a lower risk of CC than erythromycin, but the reduction in risk was not statistically significant (RR 0.72, 95% CI 0.42 to 1.25, 10,946 participants, 2 studies; I2 = 0%). GRADE certainty of the evidence was low.

Bacterial conjunctivitis

No data were available on BC comparing tetracycline versus erythromycin.

Any conjunctivitis of any aetiology

There was significant heterogeneity (I2 = 69%) in estimates for risk of ACAE from two trials comparing tetracycline and erythromycin, which precluded a meta‐analysis (Analysis 15.2). A 25% risk reduction (95% CI 46% reduction to 2% increase) was observed in Chen 1992 (RR 0.75, 95% CI 0.54 to 1.02), whilst a 38% increase in risk (95% CI 24% reduction to 2.47‐fold increase) was observed in Ghotbi 2012 (RR 1.38, 95% CI 0.76 to 2.47). GRADE certainty of the evidence was very low. The heterogeneity observed between the two trials may be explained by methodological and clinical factors. Ghotbi 2012 reported randomly allocating neonates to interventions, whilst Chen 1992 alternated the interventions monthly. Furthermore, Ghotbi 2012 was described as “single‐blind”, whilst Chen 1992 did not involve any masking. Clinically, the causative agents of conjunctivitis in neonates could differ between the two trials. However, only Chen 1992 reported culture results, and we are unable to definitively ascertain diversity in aetiology of conjunctivitis as a source of heterogeneity. Separately, the ointments used in the two studies were of identical concentrations, but they were manufactured by different companies. This difference may explain heterogeneous outcomes to the extent that the manufacturing protocols contributed to differential efficacy of the antibiotics.

Conjunctivitis of unknown aetiology

No data were available on CUE comparing tetracycline versus erythromycin.

Adverse events

No adverse events data were available comparing tetracycline versus erythromycin.

Colostrum versus erythromycin

See summary of findings in Table 17.

Open in table viewer
Table 17. Colostrum compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Colostrum compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: colostrum
Comparison: erythromycin

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with erythromycin

Risk with colostrum

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Gonococcal conjunctivitis was not reported, and there is no evidence that it was measured.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Chlamydial conjunctivitis was not reported, and there is no evidence that it was measured.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Bacterial conjunctivitis was reported, but data could not be extracted.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.49
(0.80 to 2.78)

171
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

159 per 1000

236 per 1000
(127 to 442)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Conjunctivitis of unknown aetiology was not reported, and there was no evidence that it was measured.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial at unclear or high risk of performance bias and attrition bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

Gonococcal conjunctivitis

No data were available on GC comparing colostrum versus erythromycin.

Chlamydial conjunctivitis

No data were available on CC comparing colostrum versus erythromycin.

Bacterial conjunctivitis

No data were available on BC comparing colostrum versus erythromycin.

Any conjunctivitis of any aetiology

In a single trial (Ghaemi 2014), colostrum was associated with a higher risk of ACAE compared with erythromycin, but the effect was not statistically significant (RR 1.49, 95% CI 0.80 to 2.78). The trial was at low risk of selection bias but at high risk of attrition bias. GRADE certainty of the evidence was low.

Conjunctivitis of unknown aetiology

No data were available on CUE comparing colostrum versus erythromycin.

Adverse events

No adverse events data were available comparing colostrum versus erythromycin.

Povidone‐iodine versus erythromycin

See summary of findings in Table 18.

Open in table viewer
Table 18. Povidone‐iodine compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: erythromycin

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with erythromycin

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 0.85
(0.36 to 2.01)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

1 of the 2 studies had no cases of gonococcal conjunctivitis in intervention or control arm (Ali 2007).

9 per 1000

8 per 1000
(3 to 18)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.74
(0.54 to 1.02)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

69 per 1000

51 per 1000
(37 to 70)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.87
(0.71 to 1.07)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

 

142 per 1000

123 per 1000
(101 to 152)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.78
(0.68 to 0.90)

2408
(2 RCTs)

⊕⊕⊕⊝
MODERATE 1

 

275 per 1000

215 per 1000
(187 to 248)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.74
(0.58 to 0.93)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

 

124 per 1000

91 per 1000
(72 to 115)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.
2Downgraded for imprecision (‐1): confidence interval overlaps no effect and optimal information size criteria not met.
3Downgraded for imprecision (‐1): optimal information size criterion not met.

Gonococcal conjunctivitis

Two trials compared povidone‐iodine with erythromycin and reported data on GC; one of the trials reported no events in both groups (Ali 2007). The second trial (Isenberg 1995) was larger by about 10 times; only a few events of GC were observed, resulting in high variance in the estimate. Povidone‐iodine was associated with a lower risk of GC compared with erythromycin, but the effect was not statistically significant (RR 0.85, 95% CI 0.36 to 2.01, 2408 participants, 2 studies; I2 = 0%; Figure 12). GRADE certainty of the evidence was low.

Figure 12
Forest plot of comparison: 17 Povidone‐iodine versus erythromycin, outcome: 17.1 Gonococcal conjunctivitis

Forest plot of comparison: 17 Povidone‐iodine versus erythromycin, outcome: 17.1 Gonococcal conjunctivitis

Chlamydial conjunctivitis

In a meta‐analysis of two trials, povidone‐iodine was associated with a lower risk of CC compared with erythromycin, but the effect was not statistically significant (RR 0.74, 95% CI 0.54 to 1.02, 2408 participants, 2 studies; I2 = 0%; Analysis 17.1). GRADE certainty of the evidence was low.

Bacterial conjunctivitis

Povidone‐iodine was associated with a lower risk of BC compared with erythromycin, but the effect was not statistically significant (RR 0.87, 95% CI 0.71 to 1.07; Analysis 17.2). GRADE certainty of the evidence was low.

Any conjunctivitis of any aetiology

In a meta‐analysis of two trials, povidone‐iodine was associated with a lower risk of ACAE compared with erythromycin; there was some statistical heterogeneity (RR 0.78, 95% CI 0.68 to 0.90; I2 = 45%; Analysis 17.3). GRADE certainty of the evidence was moderate.

Conjunctivitis of unknown aetiology

In a meta‐analysis of two trials, povidone‐iodine was associated with a lower risk of CUE compared with erythromycin (RR 0.74, 95% CI 0.58 to 0.93; Analysis 17.4). GRADE certainty of the evidence was low.

Adverse events

No adverse events data were available comparing povidone‐iodine versus erythromycin.

Penicillin IM versus tetracycline

See summary of findings in Table 19.

Open in table viewer
Table 19. Penicillin IM compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Penicillin IM compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin IM
Comparison: tetracycline

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with tetracycline

Risk with penicillin IM

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

32,058
(1 RCT)

⊕⊕⊕⊝
MODERATE 1,2

The 1 study with this comparison measured gonococcal conjunctivitis but reported no cases in either study arm (Siegel 1982).

follow‐up: 41 months

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.75
(0.48 to 1.17)

32,058
(1 RCT)

⊕⊕⊕⊝
MODERATE1,2

Siegel 1982

follow‐up: 41 months

3 per 1000

2 per 1000
(1 to 4)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

In the 1 study with these 2 interventions (Siegel 1982), it is uncertain whether all cases of bacterial conjunctivitis were measured. Bacterial conjunctivitis was not reported in this study.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Total conjunctivitis cases of any aetiology (ACAE) was not reported in the 1 study with this comparison (Siegel 1982). It is uncertain whether ACAE was measured.

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

In the 1 study comparing these interventions (Siegel 1982), conjunctivitis of unknown aetiology was not reported, and it is uncertain if it was measured.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk taken from the study population in the included studies.

CI: confidence interval; IM: intramuscular; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of

1Downgraded for risk of bias (‐1): single trial has high risk of selection bias, high to unclear risk of performance bias, unclear attrition bias.
2We did not downgrade for imprecision even though number of events were low, sample sizes are very large (close to 16,000 in each group). Long follow‐up time of 41 months.

Gonococcal conjunctivitis

None of the 32,058 participants in a single trial comparing IM penicillin versus tetracycline developed GC (Siegel 1982). GRADE certainty of the evidence was moderate.

Chlamydial conjunctivitis

In a single trial (Siegel 1982), IM penicillin was associated with a lower risk of CC compared with tetracycline, but the effect was not statistically significant (RR 0.75, 95% CI 0.48 to 1.17). GRADE certainty of the evidence was moderate.

Bacterial conjunctivitis

No data were available on BC comparing IM penicillin versus tetracycline.

Any conjunctivitis of any aetiology

No data were available on ACAE comparing IM penicillin versus tetracycline.

Conjunctivitis of unknown aetiology

No data were available on CUE comparing IM penicillin versus tetracycline.

Adverse events

No adverse events data were available comparing IM penicillin versus tetracycline.

Povidone‐iodine versus tetracycline

See summary of findings in Table 20.

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Table 20. Povidone‐iodine compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: tetracycline

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with tetracycline

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

The 1 study included in this comparison measured gonococcal conjunctivitis but did not find any cases in either study arm (David 2011).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

See comment

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

The 1 study included in this comparison measured chlamydial conjunctivitis but did not identify any cases in either study arm (David 2011).

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 2.04
(0.99 to 4.22)

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,4

50 per 1000

101 per 1000
(49 to 209)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 3.01
(1.52 to 5.98)

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,5

 

50 per 1000

149 per 1000
(75 to 296)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 months

Study population

RR 20.4
(1.2 to 345.8)

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,6

There were no cases of conjunctivitis in the comparator group. The value of 1 per 1000 is the risk for tetracycline for illustrative purposes only.

1 per 1000

20 per 1000
(1 to 346)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): study has unclear or high risk of bias, which could influence outcome.
2Downgraded for imprecision (‐1): small trial size and lack of detection of any gonorrhoea cases.
3Downgraded for imprecision (‐1): small trial size and lack of detection of any chlamydia cases.
4Downgraded for imprecision (‐1): optimal information size criteria not met; confidence interval overlaps no effect; small trial size.
5Downgraded for imprecision (‐1): optimal information size criteria met, but one trial, wide confidence interval, low event rates, small sample size.
6Downgraded for imprecision (‐1): optimal information size criteria possibly met, but one trial, wide confidence interval, low event rates, small sample size.

Gonococcal conjunctivitis

No incidence of GC was reported in a single trial of 410 infants (David 2011). GRADE certainty of the evidence was low.

Chlamydial conjunctivitis

No incidence of CC was reported in a single trial of 410 infants (David 2011). GRADE certainty of the evidence was low.

Bacterial conjunctivitis

In a single trial (David 2011), povidone‐iodine was associated with a higher risk of BC compared with tetracycline; the association was not statistically significant (RR 2.04, 95% CI 0.99 to 4.22). GRADE certainty of the evidence was low.

Any conjunctivitis of any aetiology

In a single trial (David 2011), povidone‐iodine was associated with a higher risk of ACAE compared with tetracycline; the association was not statistically significant (RR 3.01, 95% CI 1.52 to 5.98). GRADE certainty of the evidence was low.

Conjunctivitis of unknown aetiology

In a single trial comparing povidone‐iodine versus tetracycline (David 2011), 10 events of CUE were reported with povidone‐iodine but no events of CUE were reported with tetracycline, thus the effect was not estimable. GRADE certainty of the evidence was low.

Adverse events

No adverse events data were available comparing povidone‐iodine versus tetracycline.

Povidone‐iodine versus chloramphenicol

See summary of findings in Table 21.

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Table 21. Povidone‐iodine compared to chloramphenicol for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to chloramphenicol for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: chloramphenicol

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with chloramphenicol

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2004
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

1 included study measured gonococcal conjunctivitis but did not find any cases in either study arm (Ramirez‐Ortiz 2007).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 1.77
(0.97 to 3.22)

2004
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

Ramirez‐Ortiz 2007

16 per 1000

28 per 1000
(16 to 52)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

The 1 study measured and reported cases of bacterial conjunctivitis, but data could not be extracted (Ramirez‐Ortiz 2007).

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

The 1 study measured and reported cases of any conjunctivitis of any aetiology, but data could not be extracted (Ramirez‐Ortiz 2007).

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The 1 study likely measured conjunctivitis of unknown aetiology, but data could not be extracted (Ramirez‐Ortiz 2007).

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): masking not addressed or unclear; high losses to follow‐up, which can create plausible bias about results.
2Downgraded for imprecision (‐1): zero event rates, sample size small, and unable to determine relative effects; single trial.
3Downgraded for imprecision (‐1): optimal information size not met, and confidence interval overlaps no effect; single trial.

Gonococcal conjunctivitis

None of the 2004 infants in a single trial comparing povidone‐iodine versus chloramphenicol developed GC (Ramirez‐Ortiz 2007). GRADE certainty of the evidence was low.

Chlamydial conjunctivitis

In a single trial (Ramirez‐Ortiz 2007), povidone‐iodine was associated with a higher risk of CC compared with chloramphenicol, but the association was not statistically significant (RR 1.77, 95% CI 0.97 to 3.22). GRADE certainty of the evidence was low.

Bacterial conjunctivitis

No data were available on BC for povidone‐iodine versus chloramphenicol.

Any conjunctivitis of any aetiology

No data were available on ACAE for povidone‐iodine versus chloramphenicol.

Conjunctivitis of unknown aetiology

No data were available on CUE for povidone‐iodine versus chloramphenicol.

Adverse events

No adverse events data were available for povidone‐iodine versus chloramphenicol.

Povidone‐iodine versus carbethopendecinium bromide

See summary of findings in Table 22.

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Table 22. Povidone‐iodine compared to carbethopendecinium bromide for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to carbethopendecinium bromide for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: carbethopendecinium bromide

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with carbethopendecinium bromide

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome. 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Translation of the 1 study does not make any reference to gonococcal conjunctivitis (GC). There is no reference to culturing. It is unknown if GC was measured. GC cases were not reported.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Translation of the 1 study does not make any reference to chlamydial conjunctivitis (CC). It unknown if CC was measured. No reference to culturing. No CC cases were reported.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Translation of the 1 study does not make reference to bacterial conjunctivitis (BC). It unknown if BC was measured. No reference to culturing. No BC cases reported.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.44
(0.15 to 1.35)

100
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

1 trial only (Zbojan 2004).

180 per 1000

79 per 1000
(27 to 243)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Translation of the 1 study does not make reference to conjunctivitis of unknown aetiology (CUE). It unknown if CUE was measured. No CUE cases were reported and CUE could not be calculated.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial with unclear risk of selection bias, performance bias, detection bias, and attrition bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect; small trial.

Gonococcal conjunctivitis

No data were available on GC for povidone‐iodine versus carbethopendecinium bromide.

Chlamydial conjunctivitis

No data were available on CC for povidone‐iodine versus carbethopendecinium bromide.

Bacterial conjunctivitis

No data were available on BC for povidone‐iodine versus carbethopendecinium bromide.

Any conjunctivitis of any aetiology

In a single trial (Zbojan 2004), povidone‐iodine was associated with a lower risk of ACAE, but the effect was not statistically significant (RR 0.44, 95% CI 0.15 to 1.35). GRADE certainty of the evidence was low.

Conjunctivitis of unknown aetiology

No data were available on CUE for povidone‐iodine versus carbethopendecinium bromide.

Adverse events

No adverse events data were available for povidone‐iodine versus carbethopendecinium bromide.

Povidone‐iodine twice versus povidone‐iodine once

See summary of findings in Table 23.

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Table 23. Double application of povidone‐iodine compared to single application of povidone‐iodine for the prevention of ophthalmia neonatorum in newborn children

Double application of povidone‐iodine compared to single application of povidone‐iodine for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: double application of povidone‐iodine
Comparison: single application of povidone‐iodine

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with single application of povidone‐iodine

Risk with double application of povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

719
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study measured cases of gonococcal conjunctivitis, but no cases were found in either study arm (Isenberg 2003).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 1.27
(0.26 to 6.24)

719
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

Isenberg 2003

7 per 1000

9 per 1000
(2 to 44)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 1.69
(0.59 to 4.82)

719
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

15 per 1000

25 per 1000
(9 to 72)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.32
(0.99 to 1.75)

719
(1 RCT)

⊕⊕⊝⊝
LOW 1,

 

184 per 1000

243 per 1000
(182 to 322)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.29
(0.95 to 1.74)

719
(1 RCT)

⊕⊕⊝⊝
LOW 1,4

 

169 per 1000

218 per 1000
(161 to 294)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial has high risk of selection bias, unclear risk of performance bias, and unclear risk of attrition bias.
2Downgraded for imprecision (‐2): no events in either arm.
3Downgraded for imprecision (‐2): limited number of events in each arm, very wide confidence intervals.
4Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

Gonococcal conjunctivitis

No incidence of GC was reported amongst 719 infants in a single trial comparing povidone‐iodine administered twice versus once (Isenberg 2003). GRADE certainty of the evidence was very low.

Chlamydial conjunctivitis

In a single trial (Isenberg 2003), povidone‐iodine administered twice was associated with a higher risk of CC compared with a single dose of povidone‐iodine, but the variance in the estimate was large (RR 1.27, 95% CI 0.26 to 6.24). GRADE certainty of the evidence was very low.

Bacterial conjunctivitis

In a single trial (Isenberg 2003), povidone‐iodine administered twice was associated with a higher risk of BC compared with a single dose of povidone‐iodine, but the effect was not statistically significant (RR 1.69, 95% CI 0.59 to 4.82). GRADE certainty of the evidence was very low.

Any conjunctivitis of any aetiology

In a single trial (Isenberg 2003), povidone‐iodine administered twice was associated with a higher risk of ACAE compared with a single dose of povidone‐iodine, but the effect was not statistically significant (RR 1.32, 95% CI 0.99 to 1.75). GRADE certainty of the evidence was low.

Conjunctivitis of unknown aetiology

In a single trial (Isenberg 2003), povidone‐iodine administered twice was associated with a higher risk of CUE compared with a single dose of povidone‐iodine, but the effect was not statistically significant (RR 1.29, 95% CI 0.95 to 1.74). GRADE certainty of the evidence was low.

Adverse events

No adverse events data were available for povidone‐iodine administered twice versus once.

Penicillin IM versus topical penicillin

See summary of findings in Table 24.

Open in table viewer
Table 24. Pencillin IM compared to topical penicillin ointment for the prevention of ophthalmia neonatorum in newborn children

Pencillin IM compared to topical penicillin ointment for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin IM

Comparison: topical penicillin ointment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with topical penicillin ointment

Risk with penicillin IM

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2795
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study measured cases of gonococcal conjunctivitis, but no cases were found in either study arm (Davidson 1951).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

This 1 study from 1951 did not report the diagnosis of chlamydial conjunctivitis, nor did the authors specify if chlamydia was measured. It is unlikely that techniques to detect chlamydia were used in this time period.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 2.19
(1.14 to 4.24)

2795
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

9 per 1000

20 per 1000
(10 to 38)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.71
(1.26 to 2.32)

2795
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

44 per 1000

75 per 1000
(55 to 102)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.58
(1.12 to 2.25)

2795
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

35 per 1000

55 per 1000
(39 to 79)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; IM: intramuscular; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study at high risk or unclear risk of bias.
2Downgraded for imprecision (‐2): optimal information size criteria likely not met; no events.
3Downgraded for imprecision (‐1): optimal information size criteria not met. However, confidence interval excludes no effect.

Gonococcal conjunctivitis

No incidence of GC was reported amongst 2795 infants in a single trial comparing IM versus topical penicillin (Davidson 1951). GRADE certainty of the evidence was very low.

Chlamydial conjunctivitis

No incidence of CC was reported amongst 2795 infants in a single trial comparing IM versus topical penicillin (Davidson 1951).

Bacterial conjunctivitis

In a single trial (Davidson 1951), IM penicillin was associated with a higher risk of BC compared with topical penicillin (RR 2.19, 95% CI 1.14 to 4.24). GRADE certainty of the evidence was low.

Any conjunctivitis of any aetiology

In a single trial (Davidson 1951), IM penicillin was associated with a higher risk of ACAE compared with topical penicillin (RR 1.71, 95% CI 1.26 to 2.32). GRADE certainty of the evidence was low.

Conjunctivitis of unknown aetiology

In a single trial (Davidson 1951), IM penicillin was associated with a higher risk of CUE compared with topical penicillin (RR 1.58, 95% CI 1.12 to 2.25). GRADE certainty of the evidence was low.

Adverse events

No adverse events data were available for penicillin IM versus topical penicillin.

Discussion

Summary of main results

No data were available from the included trials for the primary vision outcomes of blindness and any adverse visual outcome. Gonococcal conjunctivitis (GC) may be considered a surrogate for vision outcomes because it is associated with a high risk of blindness.

For prophylaxis of GC, the protective effect of none of the interventions we examined was statistically significant, but in general studies were underpowered for this rare outcome and we judged the evidence to be low‐certainty. Based on effect estimates, silver nitrate appeared to be more effective for prophylaxis of GC than erythromycin or povidone‐iodine (Figure 13). A similar protective effect with silver nitrate was not observed against tetracycline, however.

Figure 13
Prophylaxis of GC

Prophylaxis of GC

For prophylaxis of chlamydial conjunctivitis (CC), the protective effect of povidone‐iodine relative to silver nitrate was statistically significant, and a consistent effect was seen relative to erythromycin (Figure 14). There were limited data against tetracycline. However, povidone‐iodine was associated with a higher risk of CC compared with chloramphenicol, which was not statistically significant.

Figure 14
Prophylaxis of CC

Prophylaxis of CC

For prophylaxis of bacterial conjunctivitis (BC), povidone‐iodine appeared to be more effective than silver nitrate and erythromycin but less effective than tetracycline (Figure 15). Furthermore, erythromycin, sulfacetamide, and penicillin were associated with a protective effect against BC compared with silver nitrate; only the effect of topical penicillin relative to silver nitrate was statistically significant. Our findings also indicate that administering povidone‐iodine twice was associated with a higher risk of CC, BC, and any conjunctivitis of any aetiology (ACAE) compared with single administration of povidone‐iodine.

Figure 15
Prophylaxis of BC

Prophylaxis of BC

For prophylaxis of ACAE, any prophylaxis was associated with a lower incidence (Figure 16). Povidone‐iodine, erythromycin, silver nitrate, and tetracycline had a statistically significant protective effect against ACAE compared with no prophylaxis. However, colostrum did not show a statistically significant protective effect against ACAE. Furthermore, povidone‐iodine, erythromycin, tetracycline, penicillin, and sulfacetamide seemed to be more protective against ACAE compared with silver nitrate and povidone‐iodine appeared to be less protective against ACAE compared with tetracycline.

Figure 16
Prophylaxis of ACAE

Prophylaxis of ACAE

Finally, our findings demonstrate that silver nitrate is associated with a statistically significant increased risk of chemical conjunctivitis when compared with povidone‐iodine, cetyl‐pyridinium chloride, sulfacetamide, and penicillin (Figure 17). Povidone‐iodine was associated with a reduced risk of chemical conjunctivitis when compared with erythromycin. There was high variance in the estimates showing an apparent increased risk of chemical conjunctivitis observed with povidone‐iodine relative to no prophylaxis and to tetracycline.

Figure 17
Prophylaxis of CUE

Prophylaxis of CUE

Overall completeness and applicability of evidence

No trials included the primary outcome of blindness or any adverse visual outcome. There could be ethical and logistical barriers to conducting such a trial. The very low incidence of blindness following ophthalmia neonatorum means trials must be very large to have adequate power to detect clinically meaningful differences in treatment effects. The low event rate makes it difficult to determine if prophylaxis is effective for GC, and difficult to determine the relative effect of the various prophylactic medications for the critical outcome of GC.

This review included studies conducted all over the world, in low‐, middle‐ and high‐income countries, and various settings within countries, with high and low baseline prevalence of sexually transmitted and other infections that may be causal agents of ophthalmia neonatorum. Twelve (40%) of the 30 studies were conducted in low‐ and middle‐income economies, with the majority in Iran and Kenya. Three studies took place in Kenya, four studies in Iran and one each in Zaire, Mexico, Indonesia, China, and Angola). Eighteen studies (60%) were conducted in high‐income countries, with the majority in the USA and Europe. Nine studies were conducted in the USA, seven in European countries, one in Canada, and one in Israel.

More than 50% of the trials were conducted more than 20 years ago, and about a third of them were conducted more than 40 years ago. Healthcare systems, the epidemiology of infectious diseases, and drug resistance have changed during this time in many settings, which makes generalisability difficult.

The majority of trials studied silver nitrate (61%), erythromycin (38%), tetracycline (35%), povidone‐iodine (27%), and no prophylaxis (31%). Silver nitrate does not appear to be manufactured anymore, and, a limited global survey of agents used for ophthalmia neonatorum prophylaxis found that silver nitrate is no longer used in the world (Zloto 2016). However, a variation containing organically bound silver, and alleged to have a similar effect to silver nitrate, called Targesin (1% silver protein acetyl tannate eye drops) is still used in Slovenia (Jug Došler 2015). The majority of the world seems to use erythromycin or povidone‐iodine for ophthalmia neonatorum prophylaxis.

The practice of ophthalmia neonatorum prophylaxis varies globally, with many countries no longer considering it to be an important public health intervention, and some countries continuing with prophylaxis. This review provides some moderate‐certainty evidence on the use of prophylaxis to prevent all‐cause cases of ophthalmia neonatorum, but not specifically gonococcal ophthalmia neonatorum, which has a high risk of blindness, and was the original purpose of prophylaxis. The results provide data on the relative effectiveness of the predominant medications used in the world for ophthalmia neonatorum prophylaxis, but no conclusions on which prophylaxis is most effective for the critical outcome of GC, which leads to an adverse visual outcome.

Quality of the evidence

The certainty of evidence available to address objectives specified for this review was at best moderate, and was low or very low for most of the comparisons studied. Major factors that affected our assessment of the certainty of the evidence included high potential for selection bias (inadequate randomisation), performance/detection bias due to masking that was either insufficient or impossible, and attrition bias. Our assessment of the certainty of the evidence was affected by heterogeneity across trials in only a few instances.

Potential biases in the review process

We conducted an extensive search of the literature; our search may not have identified studies presented at conferences in paediatrics and neonatal medicine. We specified a broad inclusion criteria to encompass quasi‐randomised and randomised studies, therefore we rated several of the included studies to be at high risk of bias and the certainty of the evidence as low. Furthermore, several trials included in this review were published over a period of about six decades. Trial reporting has significantly varied over time. Consequently, there was insufficient information to assess the risk of bias for many of the included trials, which we judged as unclear and moderated our evaluation of the certainty of the evidence. The duration of follow‐up and time at which outcomes were assessed were highly varied in the included trials. Whilst our approach to combine data across trials, which assessed outcomes at different times in the 28‐day period after birth, may have added uncertainty to our estimates, it is unlikely that our approach would have led to biased estimates. We used an intention‐to‐treat analysis for all but three trials. This approach is likely to have led to an underestimation of effect in some instances of our meta‐analyses. We chose this approach because an available‐case analysis would have limited the data only to the subgroup of trial participants who were followed up.

Agreements and disagreements with other studies or reviews

Another detailed systematic review on the subject of ophthalmia neonatorum has been published (Darling 2010). This review was conducted with methods similar to Cochrane methodology, and the inclusion criteria were similar to those specified for our review. However, Darling 2010 included trials only reporting data on gonococcal and chlamydial ophthalmia neonatorum. In contrast, our systematic review included these outcomes, but also included the outcomes of BC, culture‐negative conjunctivitis, and all clinical conjunctivitis cases irrespective of aetiology. The data reported by Darling 2010 for the outcomes of CC and GC were similar to those identified in our review. Darling 2010 concluded that the evidence supports the use of ophthalmia prophylaxis where there is high prevalence of maternal gonorrhoeal and chlamydial infection at birth. However, the review questioned the current evidence for North American laws mandating universal neonatal eye prophylaxis and suggested a "reexamination of this policy". The Darling 2010 review served as a major catalyst reference for the revised 6 March 2015 (and reaffirmed in 28 February 2018) Canadian Pediatric Society Position Statement on Preventing Ophthalmia Neonatorum, which states: "Paediatricians and other physicians caring for newborns should advocate to rescind ocular prophylaxis regulations in jurisdictions in which this is still legally mandated".

The findings of our review are consistent with the evidence review supporting the recommendations provided by the World Health Organization (WHO 2017). This evidence review only examined the outcomes of CC and GC. This review also included randomised and non‐randomised studies. For all neonates, the May 2017 World Health Organization Recommendations on Newborn Health, and the 2016 World Health Organization Sexually Transmitted Infection guidelines "recommend topical ocular prophylaxis for the prevention of gonococcal and chlamydial ophthalmia neonatorum". The WHO based this recommendation on low‐certainty evidence, although categorised the recommendation as strong.

The findings of our review are less consistent with the evidence review supporting the January 2019 updated recommendation published by the US Preventive Services Task Force (USPSTF) (Guirguis‐Blake 2019; USPSTF 2019). The USPSTF recommendations were based upon a systematic review that only reported data on the outcome of gonococcal ophthalmia neonatorum. In this review, the USPSTF concluded "with high certainty that the net benefit of topical ocular prophylaxis of all newborns to prevent gonococcal ophthalmia neonatorum is substantial". Our review did not find high‐certainty evidence for prevention of gonococcal ophthalmia neonatorum but moderate‐certainty evidence of an effect on clinical conjunctivitis more generally.

PRISMA flow diagram

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Figure 1

PRISMA flow diagram

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Table of Trial Settings

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Figure 2

Table of Trial Settings

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Table of Trials, Interventions, Method of Allocation, Settings

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Figure 3

Table of Trials, Interventions, Method of Allocation, Settings

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 5

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Forest plot of comparison: 1 Any prophylaxis versus no prophylaxis, outcome: 1.1 Gonococcal conjunctivitis

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Figure 6

Forest plot of comparison: 1 Any prophylaxis versus no prophylaxis, outcome: 1.1 Gonococcal conjunctivitis

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Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.1 Gonococcal conjunctivitis.

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Figure 7

Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.1 Gonococcal conjunctivitis.

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Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.2 Chlamydial conjunctivitis.

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Figure 8

Forest plot of comparison: 8 Erythromycin versus silver nitrate, outcome: 8.2 Chlamydial conjunctivitis.

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Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.1 Gonococcal conjunctivitis.

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Figure 9

Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.1 Gonococcal conjunctivitis.

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Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.2 Chlamydia conjunctivitis.

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Figure 10

Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.2 Chlamydia conjunctivitis.

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Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.3 Any conjunctivitis of any aetiology

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Figure 11

Forest plot of comparison: 9 Tetracycline versus silver nitrate, outcome: 9.3 Any conjunctivitis of any aetiology

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Forest plot of comparison: 17 Povidone‐iodine versus erythromycin, outcome: 17.1 Gonococcal conjunctivitis

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Figure 12

Forest plot of comparison: 17 Povidone‐iodine versus erythromycin, outcome: 17.1 Gonococcal conjunctivitis

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Prophylaxis of GC

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Figure 13

Prophylaxis of GC

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Prophylaxis of CC

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Figure 14

Prophylaxis of CC

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Prophylaxis of BC

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Figure 15

Prophylaxis of BC

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Prophylaxis of ACAE

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Figure 16

Prophylaxis of ACAE

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Prophylaxis of CUE

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Figure 17

Prophylaxis of CUE

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Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 1: Chlamydial conjunctivitis

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Analysis 1.1

Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 1: Chlamydial conjunctivitis

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Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 2: Bacterial conjunctivitis

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Analysis 1.2

Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 2: Bacterial conjunctivitis

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Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 1.3

Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 1.4

Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 4: Conjunctivitis of unknown aetiology

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Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 5: Nasolacrimal duct obstruction

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Analysis 1.5

Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 5: Nasolacrimal duct obstruction

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Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 6: Keratitis

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Analysis 1.6

Comparison 1: Any prophylaxis versus no prophylaxis, Outcome 6: Keratitis

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Comparison 2: Silver nitrate versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Analysis 2.1

Comparison 2: Silver nitrate versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Comparison 2: Silver nitrate versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Analysis 2.2

Comparison 2: Silver nitrate versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Comparison 2: Silver nitrate versus no prophylaxis, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 2.3

Comparison 2: Silver nitrate versus no prophylaxis, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 2: Silver nitrate versus no prophylaxis, Outcome 4: Corneal abrasion

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Analysis 2.4

Comparison 2: Silver nitrate versus no prophylaxis, Outcome 4: Corneal abrasion

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Comparison 2: Silver nitrate versus no prophylaxis, Outcome 5: Nasolacrimal duct obstruction

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Analysis 2.5

Comparison 2: Silver nitrate versus no prophylaxis, Outcome 5: Nasolacrimal duct obstruction

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Comparison 3: Erythromycin versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Analysis 3.1

Comparison 3: Erythromycin versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Comparison 3: Erythromycin versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Analysis 3.2

Comparison 3: Erythromycin versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Comparison 3: Erythromycin versus no prophylaxis, Outcome 3: Bacterial conjunctivitis

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Analysis 3.3

Comparison 3: Erythromycin versus no prophylaxis, Outcome 3: Bacterial conjunctivitis

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Comparison 3: Erythromycin versus no prophylaxis, Outcome 4: Any conjunctivitis of any aetiology

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Analysis 3.4

Comparison 3: Erythromycin versus no prophylaxis, Outcome 4: Any conjunctivitis of any aetiology

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Comparison 3: Erythromycin versus no prophylaxis, Outcome 5: Conjunctivitis of unknown aetiology

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Analysis 3.5

Comparison 3: Erythromycin versus no prophylaxis, Outcome 5: Conjunctivitis of unknown aetiology

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Comparison 3: Erythromycin versus no prophylaxis, Outcome 6: Nasolacrimal duct obstruction

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Analysis 3.6

Comparison 3: Erythromycin versus no prophylaxis, Outcome 6: Nasolacrimal duct obstruction

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Comparison 4: Tetracycline versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Analysis 4.1

Comparison 4: Tetracycline versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Comparison 4: Tetracycline versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Analysis 4.2

Comparison 4: Tetracycline versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Comparison 4: Tetracycline versus no prophylaxis, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 4.3

Comparison 4: Tetracycline versus no prophylaxis, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Analysis 5.1

Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Analysis 5.2

Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 2: Chlamydial conjunctivitis

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Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 3: Bacterial conjunctivitis

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Analysis 5.3

Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 3: Bacterial conjunctivitis

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Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 4: Any conjunctivitis of any aetiology

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Analysis 5.4

Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 4: Any conjunctivitis of any aetiology

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Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 5: Conjunctivitis of unknown aetiology

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Analysis 5.5

Comparison 5: Povidone‐iodine versus no prophylaxis, Outcome 5: Conjunctivitis of unknown aetiology

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Comparison 6: Bacitracin‐phenacaine versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Analysis 6.1

Comparison 6: Bacitracin‐phenacaine versus no prophylaxis, Outcome 1: Gonococcal conjunctivitis

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Comparison 7: Colostrum versus no prophylaxis, Outcome 1: Any conjunctivitis of any aetiology

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Analysis 7.1

Comparison 7: Colostrum versus no prophylaxis, Outcome 1: Any conjunctivitis of any aetiology

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Comparison 8: Erythromycin versus silver nitrate, Outcome 1: Chlamydial conjunctivitis

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Analysis 8.1

Comparison 8: Erythromycin versus silver nitrate, Outcome 1: Chlamydial conjunctivitis

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Comparison 8: Erythromycin versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Analysis 8.2

Comparison 8: Erythromycin versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Comparison 8: Erythromycin versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 8.3

Comparison 8: Erythromycin versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 8: Erythromycin versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 8.4

Comparison 8: Erythromycin versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Comparison 8: Erythromycin versus silver nitrate, Outcome 5: Nasolacrimal duct obstruction

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Analysis 8.5

Comparison 8: Erythromycin versus silver nitrate, Outcome 5: Nasolacrimal duct obstruction

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Comparison 9: Tetracycline versus silver nitrate, Outcome 1: Chlamydial conjunctivitis

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Analysis 9.1

Comparison 9: Tetracycline versus silver nitrate, Outcome 1: Chlamydial conjunctivitis

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Comparison 9: Tetracycline versus silver nitrate, Outcome 2: Nasolacrimal duct obstruction

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Analysis 9.2

Comparison 9: Tetracycline versus silver nitrate, Outcome 2: Nasolacrimal duct obstruction

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Comparison 10: Sulfacetamide versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Analysis 10.1

Comparison 10: Sulfacetamide versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Comparison 10: Sulfacetamide versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Analysis 10.2

Comparison 10: Sulfacetamide versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Comparison 10: Sulfacetamide versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 10.3

Comparison 10: Sulfacetamide versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 10: Sulfacetamide versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 10.4

Comparison 10: Sulfacetamide versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Comparison 11: Cetyl‐pyridinium chloride versus silver nitrate, Outcome 1: Bacterial conjunctivitis

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Analysis 11.1

Comparison 11: Cetyl‐pyridinium chloride versus silver nitrate, Outcome 1: Bacterial conjunctivitis

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Comparison 11: Cetyl‐pyridinium chloride versus silver nitrate, Outcome 2: Any conjunctivitis of any aetiology

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Analysis 11.2

Comparison 11: Cetyl‐pyridinium chloride versus silver nitrate, Outcome 2: Any conjunctivitis of any aetiology

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Comparison 11: Cetyl‐pyridinium chloride versus silver nitrate, Outcome 3: Conjunctivitis of unknown aetiology

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Analysis 11.3

Comparison 11: Cetyl‐pyridinium chloride versus silver nitrate, Outcome 3: Conjunctivitis of unknown aetiology

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Comparison 12: Penicillin versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Analysis 12.1

Comparison 12: Penicillin versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Comparison 12: Penicillin versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Analysis 12.2

Comparison 12: Penicillin versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Comparison 12: Penicillin versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 12.3

Comparison 12: Penicillin versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 12: Penicillin versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 12.4

Comparison 12: Penicillin versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Comparison 13: Penicillin IM versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Analysis 13.1

Comparison 13: Penicillin IM versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Comparison 13: Penicillin IM versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Analysis 13.2

Comparison 13: Penicillin IM versus silver nitrate, Outcome 2: Bacterial conjunctivitis

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Comparison 13: Penicillin IM versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 13.3

Comparison 13: Penicillin IM versus silver nitrate, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 13: Penicillin IM versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 13.4

Comparison 13: Penicillin IM versus silver nitrate, Outcome 4: Conjunctivitis of unknown aetiology

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Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Analysis 14.1

Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 1: Gonococcal conjunctivitis

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Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 2: Chlamydial conjunctivitis

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Analysis 14.2

Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 2: Chlamydial conjunctivitis

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Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 3: Bacterial conjunctivitis

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Analysis 14.3

Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 3: Bacterial conjunctivitis

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Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 4: Any conjunctivitis of any aetiology

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Analysis 14.4

Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 4: Any conjunctivitis of any aetiology

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Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 5: Conjunctivitis of unknown aetiology

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Analysis 14.5

Comparison 14: Povidone‐iodine versus silver nitrate, Outcome 5: Conjunctivitis of unknown aetiology

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Comparison 15: Tetracycline versus erythromycin, Outcome 1: Chlamydial conjunctivitis

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Analysis 15.1

Comparison 15: Tetracycline versus erythromycin, Outcome 1: Chlamydial conjunctivitis

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Comparison 15: Tetracycline versus erythromycin, Outcome 2: Any conjunctivitis of any aetiology

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Analysis 15.2

Comparison 15: Tetracycline versus erythromycin, Outcome 2: Any conjunctivitis of any aetiology

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Comparison 16: Colostrum versus erythromycin, Outcome 1: Any conjunctivitis of any aetiology

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Analysis 16.1

Comparison 16: Colostrum versus erythromycin, Outcome 1: Any conjunctivitis of any aetiology

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Comparison 17: Povidone‐iodine versus erythromycin, Outcome 1: Chlamydial conjunctivitis

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Analysis 17.1

Comparison 17: Povidone‐iodine versus erythromycin, Outcome 1: Chlamydial conjunctivitis

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Comparison 17: Povidone‐iodine versus erythromycin, Outcome 2: Bacterial conjunctivitis

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Analysis 17.2

Comparison 17: Povidone‐iodine versus erythromycin, Outcome 2: Bacterial conjunctivitis

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Comparison 17: Povidone‐iodine versus erythromycin, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 17.3

Comparison 17: Povidone‐iodine versus erythromycin, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 17: Povidone‐iodine versus erythromycin, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 17.4

Comparison 17: Povidone‐iodine versus erythromycin, Outcome 4: Conjunctivitis of unknown aetiology

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Comparison 18: Pencillin IM versus tetracycline, Outcome 1: Gonococcal conjunctivitis

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Analysis 18.1

Comparison 18: Pencillin IM versus tetracycline, Outcome 1: Gonococcal conjunctivitis

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Comparison 18: Pencillin IM versus tetracycline, Outcome 2: Chlamydial conjunctivitis

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Analysis 18.2

Comparison 18: Pencillin IM versus tetracycline, Outcome 2: Chlamydial conjunctivitis

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Comparison 19: Povidone‐iodine versus tetracycline, Outcome 1: Gonococcal conjunctivitis

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Analysis 19.1

Comparison 19: Povidone‐iodine versus tetracycline, Outcome 1: Gonococcal conjunctivitis

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Comparison 19: Povidone‐iodine versus tetracycline, Outcome 2: Chlamydial conjunctivitis

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Analysis 19.2

Comparison 19: Povidone‐iodine versus tetracycline, Outcome 2: Chlamydial conjunctivitis

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Comparison 19: Povidone‐iodine versus tetracycline, Outcome 3: Bacterial conjunctivitis

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Analysis 19.3

Comparison 19: Povidone‐iodine versus tetracycline, Outcome 3: Bacterial conjunctivitis

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Comparison 19: Povidone‐iodine versus tetracycline, Outcome 4: Any conjunctivitis of any aetiology

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Analysis 19.4

Comparison 19: Povidone‐iodine versus tetracycline, Outcome 4: Any conjunctivitis of any aetiology

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Comparison 19: Povidone‐iodine versus tetracycline, Outcome 5: Conjunctivitis of unknown aetiology

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Analysis 19.5

Comparison 19: Povidone‐iodine versus tetracycline, Outcome 5: Conjunctivitis of unknown aetiology

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Comparison 20: Povidone‐iodine versus chloramphenicol, Outcome 1: Gonococcal conjunctivitis

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Analysis 20.1

Comparison 20: Povidone‐iodine versus chloramphenicol, Outcome 1: Gonococcal conjunctivitis

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Comparison 20: Povidone‐iodine versus chloramphenicol, Outcome 2: Chlamydial conjunctivitis

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Analysis 20.2

Comparison 20: Povidone‐iodine versus chloramphenicol, Outcome 2: Chlamydial conjunctivitis

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Comparison 21: Povidone‐iodine versus carbethopendecinium bromide, Outcome 1: Any conjunctivitis of any aetiology

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Analysis 21.1

Comparison 21: Povidone‐iodine versus carbethopendecinium bromide, Outcome 1: Any conjunctivitis of any aetiology

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Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 1: Gonococcal conjunctivitis

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Analysis 22.1

Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 1: Gonococcal conjunctivitis

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Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 2: Chlamydial conjunctivitis

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Analysis 22.2

Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 2: Chlamydial conjunctivitis

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Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 3: Bacterial conjunctivitis

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Analysis 22.3

Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 3: Bacterial conjunctivitis

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Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 4: Any conjunctivitis of any aetiology

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Analysis 22.4

Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 4: Any conjunctivitis of any aetiology

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Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 5: Conjunctivitis of unknown aetiology

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Analysis 22.5

Comparison 22: Povidone‐iodine twice versus povidone‐iodine once, Outcome 5: Conjunctivitis of unknown aetiology

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Comparison 23: Penicillin IM versus topical penicillin, Outcome 1: Gonococcal conjunctivitis

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Analysis 23.1

Comparison 23: Penicillin IM versus topical penicillin, Outcome 1: Gonococcal conjunctivitis

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Comparison 23: Penicillin IM versus topical penicillin, Outcome 2: Bacterial conjunctivitis

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Analysis 23.2

Comparison 23: Penicillin IM versus topical penicillin, Outcome 2: Bacterial conjunctivitis

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Comparison 23: Penicillin IM versus topical penicillin, Outcome 3: Any conjunctivitis of any aetiology

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Analysis 23.3

Comparison 23: Penicillin IM versus topical penicillin, Outcome 3: Any conjunctivitis of any aetiology

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Comparison 23: Penicillin IM versus topical penicillin, Outcome 4: Conjunctivitis of unknown aetiology

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Analysis 23.4

Comparison 23: Penicillin IM versus topical penicillin, Outcome 4: Conjunctivitis of unknown aetiology

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Summary of findings 1. Any prophylaxis compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Any prophylaxis compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: any prophylaxis, including povidone‐iodine, erythromycin, tetracycline, silver nitrate, bacitracin‐phenacaine, colostrum

Comparison: no prophylaxis (none of the studies used a placebo or sham treatment)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with any prophylaxis

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Low risk

RR 0.79
(0.24 to 2.65)

8229
(3 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

In 2 of these 3 studies there were no cases of gonococcal conjunctivitis in either study arm.

1 per 1000

1 per 1000
(0 to 3)

High risk

50 per 1000

38 per 1000
(10 to 142)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 0.96
(0.57 to 1.61)

4874
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

5 per 1000

5 per 1000
(3 to 8)

High risk

100 per 1000

96 per 1000
(57 to 161)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain
follow‐up: 1 month

Low risk

RR 0.84
(0.37 to 1.93)

3685
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

3 per 1000

3 per 1000
(1 to 6)

High risk

50 per 1000

42 per 1000
(19 to 97)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.65
(0.54 to 0.78)

9666
(8 RCTs)

⊕⊕⊕⊝
MODERATE1

3 per 1000

2 per 1000
(2 to 2)

High risk

300 per 1000

195 per 1000
(162 to 134)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.75
(0.37 to 8.28)

330
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

20 per 1000

35 per 1000
(7 to 166)

Adverse effects

In a single study (Bell 1993), any prophylaxis (erythromycin 0.5% or silver nitrate 1%) did not appear to be associated with an increased risk of nasolacrimal duct obstruction compared with no prophylaxis (RR 0.93, 95% CI 0.68 to 1.28).

A single study of 40 newborns comparing silver nitrate 1% with control reported that no events of keratitis were observed in the prophylaxis and no‐prophylaxis groups (Graf 1994).

⊕⊝⊝⊝
VERY LOW 1,2

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded (‐1) for risk of bias: studies were at high or unclear risk of bias.
2Downgraded (‐2) for imprecision: sparse data.

3Downgraded (‐1) for imprecision: 95% confidence interval includes no effect.

Figures and Tables -
Summary of findings 1. Any prophylaxis compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children
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Table 1. Physical characteristics of interventions studied in included trials

Interventions studied in included trials

Physical characteristics/method of delivery

Silver nitrate solution

Clear solution, topical instillation

Erythromycin ointment

Translucent/white ointment, topical application

Tetracycline ointment

Light‐yellow ointment, topical application

Oxytetracycline hydrochlorate solution

Unknown colour/consistency, aqueous solution, topical instillation

Povidone‐iodine solution

Orange‐red, clear solution, topical instillation

Hexarginum solution

Colour unknown, solution with 1 g silver nitrate + 36 g methylamine dissolved in 63 g sterile water, topical application

Penicillin G ointment

Clear/white ointment, topical application

Penicillin G intramuscular injection

Clear, aqueous solution, intramuscular injection

Cetyl‐pyridinium chloride solution

Solution of unknown colour/consistency, topical instillation

Bacitracin‐phenacaine ointment

Ointment of unknown colour, topical application

Sulfacetamide ointment

Ointment of unknown colour, topical application

Chloramphenicol solution

Clear, colourless to slightly yellow solution, topical instillation

Chloramphenicol ointment

Colourless ointment; topical instillation

Colostrum

Yellowish, white or clear liquid, topical instillation

Carbethopendecinium bromide solution

Yellowish to white powder in solution, solution colour unknown, topical instillation

Mechanical cleansing

Eyes swabbed with clear, distilled water and wiped dry
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Table 1. Physical characteristics of interventions studied in included trials
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Table 2. Summary results

Gonococcal conjunctivitis

Chlamydial conjunctivitis

Bacterial conjunctivitis

Any conjunctivitis of any aetiology

Conjunctivitis of unknown aetiology

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Number of trials

Risk ratio (95% confidence interval)

Any prophylaxis vs no prophylaxis

3

0.79 (0.24 to 2.65)

2

0.96 (0.57 to 1.61)

2

0.84 (0.37 to 1.93)

8

0.65 (0.54 to 0.78)

1

1.75 (0.37 to 8.28)

Silver nitrate vs no prophylaxis

1

No events reported in 1 or both arms.

1

1.06 (0.55 to 2.02)

No data were available.

3

0.67 (0.52 to 0.87)

No data were available.

Erythromycin vs no prophylaxis

2

No events reported in 1 or both arms.

2

0.93 (0.49 to 1.77)

1

0.80 (0.22 to 2.90)

6

0.68 (0.51 to 0.89)

1

1.50 (0.26 to 8.80)

Tetracycline vs no prophylaxis

1

No events reported in 1 or both arms.

1

0.82 (0.42 to 1.63)

No data were available.

2

0.72 (0.55 to 0.94)

No data were available.

Povidone‐iodine vs no prophylaxis

1

No events reported in 1 or both arms.

1

2.00 (0.18 to 21.74)

1

1.00 (0.30 to 3.36)

1

0.38 (0.18 to 0.77)

1

2.00 (0.37 to 10.70)

Bacitracin‐phenacaine vs no prophylaxis

1

0.76 (0.20 to 2.83)

No data were available.

No data were available.

No data were available.

No data were available.

Colostrum vs no prophylaxis

No data were available.

No data were available.

No data were available.

1

0.72 (0.45 to 1.14)

No data were available.

Erythromycin vs silver nitrate

4

2.28 (0.88 to 5.90)

4

0.75 (0.51 to 1.09)

2

0.83 (0.69 to 1.01)

No data were available.

Tetracycline vs silver nitrate

5

0.66 (0.21 to 2.05)

4

0.64 (0.40 to 1.02)

No data were available.

4

0.80 (0.66 to 0.98)

No data were available.

Sulfacetamide vs silver nitrate

1

No events reported in 1 or both arms.

No data were available.

1

0.88 (0.45 to 1.74)

1

0.54 (0.32 to 0.89)

1

0.27 (0.11 to 0.66)

Cetyl‐pyridinium chloride vs silver nitrate

No data were available.

No data were available.

2

1.79 (0.59 to 5.41)

2

1.08 (0.40 to 2.90)

2

No events reported in 1 or both arms.

Penicillin vs silver nitrate

1

No events reported in 1 or both arms.

No data were available.

Topical penicillin: 2; IM penicillin: 1

Topical penicillin: 0.34 (0.18 to 0.65); IM penicillin: 0.75 (0.46 to 1.24)

Topical penicillin: 2; IM penicillin: 1

Topical penicillin:* Davidson 1951: 0.15 (0.12 to 0.20); Harris 1957: 0.78 (0.35 to 1.70); IM penicillin: 0.26 (0.21 to 0.32)

Topical penicillin: 1; IM penicillin: 1

Topical penicillin: 0.13 (0.10 to 0.18); IM penicillin: 0.21 (0.17 to 0.27)

Povidone‐iodine vs silver nitrate

1

1.94 (0.60 to 6.29)

1

0.52 (0.38 to 0.71)

1

0.75 (0.61 to 0.92)

1

0.72 (0.63 to 0.84)

1

0.70 (0.55 to 0.89)

Tetracycline vs erythromycin

2

0.73 (0.18 to 2.95)

2

0.72 (0.42 to 1.25)

No data were available.

2*

Chen 1992: 0.75 (0.54 to 1.02); Ghotbi 2012: 1.38 (0.76 to 2.47)

No data were available.

Colostrum vs erythromycin

No data were available.

No data were available.

No data were available.

1

1.49 (0.80 to 2.78)

No data were available.

Povidone‐iodine vs erythromycin

2

0.85 (0.36 to 2.01)

2

0.74 (0.54 to 1.02)

2

0.87 (0.71 to 1.07)

2*

0.78 (0.68 to 0.90)

2

0.74 (0.58 to 0.93)

Penicillin IM vs tetracycline

1

No events reported in 1 or both arms.

1

0.75 (0.48 to 1.17)

No data were available.

No data were available.

No data were available.

Povidone‐iodine vs tetracycline

1

No events reported in 1 or both arms.

1

No events reported in 1 or both arms.

1

2.04 (0.99 to 4.22)

1

3.01 (1.52 to 5.98)

1

No events reported in 1 or both arms.

Povidone‐iodine vs chloramphenicol

1

No events reported in 1 or both arms.

1

1.77 (0.97 to 3.22)

No data were available.

No data were available.

No data were available.

Povidone‐iodine vs carbethopendecinium bromide

No data were available.

No data were available.

No data were available.

1

0.44 (0.15 to 1.35)

No data were available.

Povidone‐iodine twice vs povidone‐iodine once

1

No events reported in 1 or both arms.

1

1.27 (0.26 to 6.24)

1

1.69 (0.59 to 4.82)

1

1.32 (0.99 to 1.75)

1

1.29 (0.95 to 1.74)

Penicillin IM vs topical penicillin

1

No events reported in 1 or both arms.

1

No events reported in 1 or both arms.

1

2.19 (1.14 to 4.24)

1

1.71 (1.26 to 2.32)

1

1.58 (1.12 to 2.25)

IM: intramuscular

*Indicates statistically significant heterogeneity precluding a meta‐analysis.
Figures and Tables -
Table 2. Summary results
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Table 3. Silver nitrate compared to no prophylaxis for prevention of ophthalmia neonatorum in newborn children

Silver nitrate compared to no prophylaxis for prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: silver nitrate
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with silver nitrate

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2225
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

No cases of gonococcal conjunctivitis were reported in this study.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 1.06
(0.55 to 2.02)

2225
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

5 per 1000

5 per 1000
(3 to 10)

High risk

100 per 1000

106 per 1000
(55 to 202)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain
follow‐up: 1 month

2 of the 3 studies did not measure or report bacterial conjunctivitis (Bell 1993; Graf 1994). 1 study measured bacterial conjunctivitis but did not report this outcome by study arm (Chen 1992).

 

 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.67
(0.52 to 0.87)

2713
(3 RCTs)

⊕⊕⊕⊝
MODERATE 4

3 per 1000

2 per 1000
(2 to 3)

High risk

300 per 1000

201 per 1000
(156 to 261)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

2 of the 3 studies did not measure did not measure or report conjunctivitis of unknown aetiology (Bell 1993; Graf 1994). 1 study measured conjunctivitis of unknown aetiology but did not report this outcome by trial arm (Chen 1992).

 
 
 

Adverse effects

In a single study (Bell 1993), silver nitrate prophylaxis appeared to be associated with an increased risk of nasolacrimal duct obstruction compared with no prophylaxis, but the variance in the estimate was imprecise with wide confidence intervals (RR 1.28, 95% CI 0.40 to 4.02).

A single study comparing silver nitrate with control reported that no events of keratitis were observed in the prophylaxis and no‐prophylaxis groups (Graf 1994).

⊕⊝⊝⊝
VERY LOW 1,5

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study with high risk of selection bias, unclear and high risk of performance bias, unclear risk of detection bias.
2Downgraded for imprecision (‐2): no events in either arm of trial; study underpowered to assess relative effects of treatment on this outcome.
3Downgraded for imprecision (‐1): 95% confidence interval includes no effect.
4Downgraded for risk of bias (‐1): largest trial has high or unclear risk of bias; second‐largest trial has low risk of selection bias, but higher risk of performance or detection bias.
5Downgraded (‐2) for imprecision: sparse data.

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Table 3. Silver nitrate compared to no prophylaxis for prevention of ophthalmia neonatorum in newborn children
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Table 4. Erythromycin compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Erythromycin compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: erythromycin
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with erythromycin

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2526
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

No cases of gonococcal conjunctivitis were reported in these studies.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 0.93
(0.49 to 1.77)

2526
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

5 per 1000

5 per 1000
(2 to 9)

High risk

100 per 1000

93 per 1000
(49 to 177)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain.
follow‐up: 1 month

Low risk

RR 0.80
(0.22 to 2.90)

220
(1 RCT)

⊕⊕⊝⊝
LOW 3,4

 

3 per 1000

2 per 1000
(1 to 9)

High risk

50 per 1000

40 per 1000

(11 to 145)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.68
(0.51 to 0.89)

3509
(6 RCTs)

⊕⊕⊕⊝
MODERATE 1

 

3 per 1000

2 per 1000
(2 to 3)

High risk

300 per 1000

204 per 1000

(153 to 267)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.50
(0.26 to 8.80)

220
(1 RCT)

⊕⊝⊝⊝
VERY LOW 4,5

 

18 per 1000

27 per 1000
(5 to 160)

Adverse effects

In a single study of 269 people, there was no clear relationship between erythromycin and nasolacrimal duct obstruction (RR 0.83, 95% CI 0.56 to 1.23).

⊕⊝⊝⊝
VERY LOW 4,5

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies were at high risk or unclear risk of bias. High loss to follow‐up in one trial, and unclear if follow‐up time is two weeks or one month in same trial. No placebo used in either trial.
2Downgraded for imprecision (‐2): no events in either arm of trial.
3Downgraded for imprecision (‐1): 95% confidence interval includes no effect; very few events; one study; small sample size.
4Downgraded for risk of bias (‐1): study has high or unclear risk of bias with high loss to follow‐up. No placebo used.
5Downgraded for imprecision (‐2): very wide confidence intervals.

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Table 4. Erythromycin compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children
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Table 5. Tetracycline compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Tetracycline compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: tetracycline
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with tetracycline

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2299
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1

No cases of gonococcal conjunctivitis were reported in this study.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 0.82
(0.42 to 1.63)

2299
(1 RCT)

⊕⊕⊝⊝
LOW 2,3

.

5 per 1000

4 per 1000
(7 to 26)

High risk

100 per 1000

82 per 1000

(42 to 163)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain
follow‐up: 1 month

1 study did not measure or report bacterial conjunctivitis (Ghotbi 2012), whilst the other study measured bacterial conjunctivitis but did not report by allocation group (Chen 1992).

 
 
 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.72
(0.55 to 0.94)

2519
(2 RCTs)

⊕⊕⊝⊝
LOW 3,4

3 per 1000

2 per 1000
(2 to 3)

High risk

300 per 1000

216 per 1000

(1165 to 282)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

1 study did not measure or report conjunctivitis of unknown aetiology (CUE) (Ghotbi 2012), whilst the other study measured CUE but did not report by allocation group (Chen 1992).

 
 
 

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for imprecision (‐3): no events in this trial.
2Downgraded for risk of bias (‐1): single trial with high risk of bias for sequence generation, allocation concealment, and masking, and unclear risk of bias for detection and attrition bias, which could affect outcomes considering the low event rates.
3Downgraded for imprecision (‐1): optimal information size not met, and confidence interval overlaps no effect in this single study.
4Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.

Figures and Tables -
Table 5. Tetracycline compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children
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Table 6. Povidone‐iodine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no prophylaxis

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

220
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1

No cases of gonococcal conjunctivitis were reported in this study.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Low risk

RR 2.00
(0.18 to 21.7)

220
(1 RCT)

⊕⊕⊝⊝
LOW 2,3

.

5 per 1000

10 per 1000
(1 to 109)

High risk

100 per 1000

200 per 1000

(18 to 1000)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture, smear, or Gram stain.
follow‐up: 1 month

Low risk

RR 1.00
(0.30 to 3.36)

220
(1 RCT)

⊕⊕⊝⊝
LOW 2,3

 

3 per 1000

3 per 1000
(1 to 10)

High risk

50 per 1000

50 per 1000

(15 to 168)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.38
(0.18 to 0.77)

220
(1 RCT)

⊕⊕⊕⊝
MODERATE 2

 

3 per 1000

1 per 1000
(1 to 2)

High risk

300 per 1000

114 per 1000

(54 to 231)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 2.00
(0.37 to 10.70)

220
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2,4

 

18 per 1000

36 per 1000
(7 to 195)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for imprecision (‐3): no events in either arm of this study.
2Downgraded for risk of bias (‐1): the study is unclear regarding sequence generation and allocation concealment. Masking is a concern as there was no placebo. Very high losses to follow‐up.
3Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

4Downgraded for imprecision (‐2): very wide confidence intervals.

Figures and Tables -
Table 6. Povidone‐iodine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children
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Table 7. Bacitracin‐phenacaine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Bacitracin‐phenacaine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: bacitracin‐phenacaine
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Risk with no prophylaxis

Risk with bacitracin‐phenacaine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Low risk

RR 0.76
(0.20 to 2.83)

3355
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

1 per 1000

1 per 1000
(0 to 3)

High risk

100 per 1000

76 per 1000

(20 to 283 per 1000)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

The 1 study does not seem to have measured or reported cases of chlamydial conjunctivitis (Posner 1959). Diagnostic methods for chlamydia would not have been readily available in 1959.

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

It is unknown if bacterial conjunctivitis was measured in the 1 study (Posner 1959), as it categorises conjunctivitis only as "nonspecific conjunctivitis" and "gonorrhoeal ophthalmia".

 
 
 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

It is unknown if all conjunctivitis were measured in the 1 study (Posner 1959), as it categorises conjunctivitis only as "nonspecific conjunctivitis" and "gonorrhoeal ophthalmia".

 

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The category of "nonspecific conjunctivitis" reported in the 1 study is undefined and may or may not also include bacterial conjunctivitis cases (Posner 1959).

 

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial with high risk of selection bias, unclear risk of performance and detection bias, high risk of selective outcome reporting.
2Downgraded for imprecision (‐2): very wide confidence intervals, which include no effect.

Figures and Tables -
Table 7. Bacitracin‐phenacaine compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children
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Table 8. Colostrum compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Colostrum compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: colostrum
Comparison: no prophylaxis

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Risk with no prophylaxis

Risk with colostrum

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

No discussion of gonococcal conjunctivitis in this study (Ghaemi 2014). The trial excluded culture‐positive neonates before application of prophylaxis.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

No discussion of chlamydial conjunctivitis in this 1 study (Ghaemi 2014). It is unknown if it was measured. Chlamydial conjunctivitis cases were not reported.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

The 1 trial trial does not report bacterial conjunctivitis cases as distinguished from all conjunctivitis cases (Ghaemi 2014). It is unknown if bacterial conjunctivitis was measured.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Low risk

RR 0.72
(0.45 to 1.14)

186
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

3 per 1000

2 per 1000
(1 to 3)

High risk

300 per 1000

216 per 1000

(135 to 342)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The 1 trial only reports all conjunctivitis cases, and does not distinguish bacterial conjunctivitis cases from cases of conjunctivitis of unknown aetiology (Ghaemi 2014).

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risks (low and high) in the comparison group were estimated from relevant prevalence studies (Appendix 8).

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study at high or unclear risk of performance, detection, and attrition bias.
2Downgraded for imprecision (‐1): 95% confidence interval includes no effect.

Figures and Tables -
Table 8. Colostrum compared to no prophylaxis for the prevention of ophthalmia neonatorum in newborn children
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Table 9. Erythromycin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Erythromycin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: erythromycin
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with erythromycin

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 2.28
(0.88 to 5.90)

14,855
(4 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

In 2 of the 4 trials, there were no cases of gonococcal conjunctivitis in either study arm.

Follow‐up: range 8 days to 19 weeks

1 per 1000

2 per 1000
(1 to 6)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.75
(0.51 to 1.09)

13,472
(4 RCTs)

⊕⊕⊝⊝
LOW 3,4

Follow‐up: range 4 weeks to 19 weeks

21 per 1000

16 per 1000
(11 to 23)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.83
(0.69 to 1.01)

6333
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

Follow‐up: range 9 days to 60 days

57 per 1000

47 per 1000
(39 to 58)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

See comment

‐

9021
(4 RCTs)

⊕⊝⊝⊝
VERY LOW 1,3,5

A meta‐analysis was not conducted considering the considerable statistical heterogeneity (I2 = 90%). Therefore, there was no pooled effect.

Follow‐up: range 9 days to 60 days

Any conjunctivitis of any aetiology assessed with: clinical assessment of conjunctivitis

follow‐up: 1 month

Study population

RR 1.02
(0.80 to 1.30)

4729
(3 RCTs)

⊕⊕⊝⊝
LOW 1,3

After excluding 1 study (Christian 1960), I2 declined to 51%, but was still moderate. A pooled effect was then presented for these 3 remaining studies.

Follow‐up: range 9 days to 60 days

170 per 1000

173 per 1000
(136 to 221)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.96
(0.77 to 1.19)

2041
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

139 per 1000

133 per 1000
(107 to 165)

Adverse effects

In 1 study, erythromycin was associated with a reduced risk of nasolacrimal duct obstruction compared with silver nitrate. This association was not statistically significant (RR 0.81, 95% CI 0.55 to 1.20).

⊕⊕⊝⊝
LOW 1,3

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.
2Downgraded for imprecision (‐2): very wide 95% confidence intervals including no effect.
3Downgraded for imprecision (‐1): 95% confidence intervals include no effect.
4Downgraded for risk of bias (‐1): one of the four studies, the smallest one (Hammerschlag 1980), was funded by the pharmaceutical company that produces erythromycin (Dista Pharmaceuticals). That trial favoured erythromycin, and was the only trial amongst four trials with no chlamydial conjunctivitis in the erythromycin arm (12 cases in the silver nitrate arm). There were 36 infants in the silver nitrate arm and only 24 in the erythromycin arm. Furthermore, 7 of 67 chlamydia‐positive mothers remained unaccounted for. Their distribution in the allocation arms is unknown. With a transmission rate of about 30%, low event rates, and small sample size, these missing mothers could have a significant effect on the results.
5Downgraded for inconsistency (‐1): confidence intervals do not overlap; point estimates vary widely and on either side of no effect; I2 is 90%; and Chi2 P < 0.001. Heterogeneity could be explained by one older trial that did not define conjunctivitis, and review authors applied definition to eye reaction classifications.

Figures and Tables -
Table 9. Erythromycin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 10. Tetracycline compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Tetracycline compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: tetracycline
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with tetracycline

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 0.66
(0.21 to 2.05)

14,501
(5 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2,3

Amongst the 5 included trials, 3 had no events in either study arm.

Range 4 weeks to 19 weeks

1 per 1000

1 per 1000
(0 to 2)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.64
(0.40 to 1.02)

14,142
(4 RCTs)

⊕⊕⊝⊝
LOW 1,4

Range 4 weeks to 19 weeks

7 per 1000

4 per 1000
(3 to 7)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Amongst 5 studies, 4 measured bacterial conjunctivitis but did not report the results (2) or the data could not be extracted (2). 1 study did not measure or report bacterial conjunctivitis.

 
 
 

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.80
(0.66 to 0.98)

6229
(4 RCTs)

⊕⊕⊕⊝
MODERATE 1

64 per 1000

51 per 1000
(42 to 63)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Amongst 5 trials, 4 measured conjunctivitis of unknown aetiology (CUE) but did not report the results (2) or the data could not be extracted (2). 1 trial did not measure or report CUE.

 
 
 

Adverse effects

In 1 trial, tetracycline appeared to be associated with a higher risk of nasolacrimal duct obstruction, but the estimate was imprecise and included no effect (RR 1.57, 95% CI 0.63 to 3.91).

⊕⊕⊝⊝
LOW 1,5

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.
2Downgraded for inconsistency (‐1): I2 is 60%, Chi2 P value is 0.11. Two trials had no events in either arm. Downgraded due to variable methods and length of follow‐up.
3Downgraded for imprecision (‐1): optimal information size is not met, but large sample size (7721 neonates in tetracycline group and 6780 neonates in silver nitrate group) with low baseline risk; however, confidence intervals are quite wide around relative effects, but around absolute effects relatively narrow. Outcome of gonococcal conjunctivitis is of critical significance and can affect vision. Therefore, downgraded one level for imprecision.
4Downgraded for imprecision (‐1): optimal information size is not met, but large sample size (7598 neonates in tetracycline group and 6544 neonates in silver nitrate group) with low baseline risk; confidence intervals are wide around relative effects, but around absolute effects relatively narrow. Confidence interval overlaps no effect. RR of 60% with tetracycline versus RR increase of 2% with tetracycline. Confidence interval fails to exclude important benefit. Chlamydial conjunctivitis outcome is important. Downgraded for imprecision.
5Downgraded for imprecision (‐1): confidence intervals include benefit and harm

Figures and Tables -
Table 10. Tetracycline compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 11. Sulfacetamide compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Sulfacetamide compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: sulfacetamide
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with sulfacetamide

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

640
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study reported no cases of gonococcal conjunctivitis (Cousineau 1952).

follow‐up: 3 to 9 days

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

It is likely that chlamydial conjunctivitis was measured in this 1952 study but not reported in this trial. It is described in other observational studies in the same paper ("virus inclusion bodies").

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.88
(0.45 to 1.74)

640
(1 RCT)

⊕⊕⊝⊝
LOW1,3

Follow‐up: 3 to 9 days

53 per 1000

47 per 1000
(24 to 92)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.54
(0.32 to 0.89)

640
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 3 to 9 days

122 per 1000

66 per 1000
(39 to 109)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.27
(0.11 to 0.66)

640
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 3 to 9 days

69 per 1000

19 per 1000
(8 to 46)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study with high risk of selection bias, high risk of performance bias, unclear risk of detection bias.
2Downgraded for imprecision (‐2): no events in either arm of trial; study was underpowered to assess this outcome.
3Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval overlaps no effect.

Figures and Tables -
Table 11. Sulfacetamide compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 12. Cetyl‐pyridinium chloride compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Cetyl‐pyridinium chloride compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: cetyl‐pyridinium chloride
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with cetyl‐pyridinium chloride

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Gonococcal conjunctivitis not measured and not reported. Study explicitly reported that there was no culture method used to detect Neisseria gonorrhoeae.

 

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

None of the studies reported the diagnosis of chlamydial conjunctivitis. None of the studies specified if chlamydia was measured, which was unlikely considering publication date of 1965.

 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 1.79
(0.59 to 5.41)

599
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

Follow‐up: 2 weeks

17 per 1000

30 per 1000
(10 to 92)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.08
(0.40 to 2.90)

599
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2,3

Follow‐up: 2 weeks

27 per 1000

29 per 1000
(11 to 78)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.14
(0.01 to 2.71)

599
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

Follow‐up: 2 weeks

10 per 1000

1 per 1000
(0 to 27)

Adverse effects

No studies reported this outcome.

 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high risk of bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval overlaps no effect. Confidence intervals very wide.
3Downgraded for inconsistency (‐1): point estimates on opposite sides of no effect. I2 is 60%, but confidence intervals overlap and and Chi2 P value is 0.11. Borderline. Downgraded.

Figures and Tables -
Table 12. Cetyl‐pyridinium chloride compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 13. Penicillin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Penicillin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with penicillin

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2804
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study with this comparison measured gonococcal conjunctivitis but found no cases of gonococcal conjunctivitis in either study arm (Davidson 1951). follow‐up: 10 days

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Studies comparing penicillin to silver nitrate do not report the diagnosis of chlamydial conjunctivitis. They do not specify if chlamydia was measured, which is understandable considering 1950s publication dates.

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.34
(0.18 to 0.65)

2804
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Davidson 1951

follow‐up: 10 days

26 per 1000

9 per 1000
(5 to 17)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

‐

5228
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2

Significant statistical heterogeneity, therefore meta‐analysis not conducted. Heterogeneity may be explained by differing definitions of conjunctivitis between trials.

follow‐up: 10 days

See comment

See comment

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.13
(0.10 to 0.18)

2804
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

Follow‐up: 10 days

263 per 1000

34 per 1000
(26 to 47)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial with high risk of selection bias, unclear and high risk of performance bias, and high risk of attrition bias.
2Downgraded for imprecision (‐2): no events in either penicillin or silver nitrate arms of trial. Study was underpowered to assess this outcome.
3Downgraded for inconsistency (‐1): point estimates vary; confidence intervals do not overlap; I2 is 93%; Chi2 P < 0.001.

Figures and Tables -
Table 13. Penicillin compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 14. Penicillin IM compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Penicillin IM compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin IM

Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with penicillin IM

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

 
 
 

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2727
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study with follow‐up: 10 days measured gonococcal conjunctivitis but found no cases of gonococcal conjunctivitis in either study arm (Davidson 1951).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

1 study comparing penicillin IM to silver nitrate does not report chlamydial conjunctivitis and does not specify if chlamydia was measured, which is understandable considering the study was published in 1951.

 
 
 

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.75
(0.46 to 1.24)

2727
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

Follow‐up 10 days (Davidson 1951).

26 per 1000

20 per 1000
(12 to 32)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.26
(0.21 to 0.32)

2727
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 10 days

289 per 1000

75 per 1000
(61 to 93)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.21
(0.17 to 0.27)

2727
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Follow‐up: 10 days

263 per 1000

55 per 1000
(45 to 71)

Adverse effects

No studies reported this outcome.

 
 
 

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; IM: intramuscular; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias: single trial with high risk of selection bias, unclear to high risk of performance bias, and unclear to high risk of attrition bias.
2Downgraded for imprecision (‐2): no events in either arm, likely not meeting optimal information size criteria.
3Downgraded for imprecision (‐1): optimal information size criteria not met; confidence interval wide and crosses null effect.

Figures and Tables -
Table 14. Penicillin IM compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 15. Povidone‐iodine compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: silver nitrate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with silver nitrate

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 1.94
(0.60 to 6.29)

2005
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

Isenberg 1995

4 per 1000

8 per 1000
(3 to 25)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.52
(0.38 to 0.71)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

105 per 1000

55 per 1000
(40 to 75)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.75
(0.61 to 0.92)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

175 per 1000

132 per 1000
(107 to 161)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.72
(0.63 to 0.84)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

314 per 1000

226 per 1000
(198 to 264)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.70
(0.55 to 0.89)

2005
(1 RCT)

⊕⊕⊕⊝
MODERATE1

Isenberg 1995

139 per 1000

97 per 1000
(76 to 124)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial has high or unclear risk of selection bias, performance bias, and attrition bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

Figures and Tables -
Table 15. Povidone‐iodine compared to silver nitrate for the prevention of ophthalmia neonatorum in newborn children
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Table 16. Tetracycline compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Tetracycline compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: tetracycline
Comparison: erythromycin

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with erythromycin

Risk with tetracycline

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 0.73
(0.18 to 2.95)

10,946
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

1 of 2 included studies did not identify any cases of gonococcal conjunctivitis (Chen 1992).

1 per 1000

1 per 1000
(0 to 3)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.72
(0.42 to 1.25)

10,946
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

6 per 1000

4 per 1000
(3 to 8)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Amongst the 3 studies comparing these interventions, Chen 1992 measured and reported bacterial conjunctivitis, but data could not be extracted, and Hammerschlag 1989 and Ghotbi 2012 did not report and outcome was unlikely measured.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

‐

2539
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1,2,3

Data not pooled because of significant heterogeneity. I2 is 69% and point estimates on opposite side of line of no effect.

See comment

See comment

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Amongst the 3 studies comparing these interventions, Chen 1992 measured and reported conjunctivitis of unknown aetiology, but data could not be extracted, and Hammerschlag 1989 and Ghotbi 2012 did not report and outcome was unlikely measured.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at unclear or high risk of bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, but sample size is large at 5624 in tetracycline group and 5322 in erythromycin group. However, confidence interval includes no effect, confidence intervals wide, and one trial has no events.
3Downgraded for inconsistency (‐1): significant statistical heterogeneity. Point estimates on either side of line of no effect. I2 is 69%.

Figures and Tables -
Table 16. Tetracycline compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children
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Table 17. Colostrum compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Colostrum compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: colostrum
Comparison: erythromycin

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with erythromycin

Risk with colostrum

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Gonococcal conjunctivitis was not reported, and there is no evidence that it was measured.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Chlamydial conjunctivitis was not reported, and there is no evidence that it was measured.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Bacterial conjunctivitis was reported, but data could not be extracted.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.49
(0.80 to 2.78)

171
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

159 per 1000

236 per 1000
(127 to 442)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The 1 study excluded neonates with any positive cultures before administration of prophylaxis. Conjunctivitis of unknown aetiology was not reported, and there was no evidence that it was measured.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial at unclear or high risk of performance bias and attrition bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

Figures and Tables -
Table 17. Colostrum compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children
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Table 18. Povidone‐iodine compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: erythromycin

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with erythromycin

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Study population

RR 0.85
(0.36 to 2.01)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

1 of the 2 studies had no cases of gonococcal conjunctivitis in intervention or control arm (Ali 2007).

9 per 1000

8 per 1000
(3 to 18)

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.74
(0.54 to 1.02)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

69 per 1000

51 per 1000
(37 to 70)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 0.87
(0.71 to 1.07)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,2

 

142 per 1000

123 per 1000
(101 to 152)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.78
(0.68 to 0.90)

2408
(2 RCTs)

⊕⊕⊕⊝
MODERATE 1

 

275 per 1000

215 per 1000
(187 to 248)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 0.74
(0.58 to 0.93)

2408
(2 RCTs)

⊕⊕⊝⊝
LOW 1,3

 

124 per 1000

91 per 1000
(72 to 115)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): studies at high or unclear risk of bias.
2Downgraded for imprecision (‐1): confidence interval overlaps no effect and optimal information size criteria not met.
3Downgraded for imprecision (‐1): optimal information size criterion not met.

Figures and Tables -
Table 18. Povidone‐iodine compared to erythromycin for the prevention of ophthalmia neonatorum in newborn children
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Table 19. Penicillin IM compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Penicillin IM compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin IM
Comparison: tetracycline

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with tetracycline

Risk with penicillin IM

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

32,058
(1 RCT)

⊕⊕⊕⊝
MODERATE 1,2

The 1 study with this comparison measured gonococcal conjunctivitis but reported no cases in either study arm (Siegel 1982).

follow‐up: 41 months

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 0.75
(0.48 to 1.17)

32,058
(1 RCT)

⊕⊕⊕⊝
MODERATE1,2

Siegel 1982

follow‐up: 41 months

3 per 1000

2 per 1000
(1 to 4)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

In the 1 study with these 2 interventions (Siegel 1982), it is uncertain whether all cases of bacterial conjunctivitis were measured. Bacterial conjunctivitis was not reported in this study.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Total conjunctivitis cases of any aetiology (ACAE) was not reported in the 1 study with this comparison (Siegel 1982). It is uncertain whether ACAE was measured.

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

In the 1 study comparing these interventions (Siegel 1982), conjunctivitis of unknown aetiology was not reported, and it is uncertain if it was measured.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk taken from the study population in the included studies.

CI: confidence interval; IM: intramuscular; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of

1Downgraded for risk of bias (‐1): single trial has high risk of selection bias, high to unclear risk of performance bias, unclear attrition bias.
2We did not downgrade for imprecision even though number of events were low, sample sizes are very large (close to 16,000 in each group). Long follow‐up time of 41 months.

Figures and Tables -
Table 19. Penicillin IM compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children
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Table 20. Povidone‐iodine compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: tetracycline

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with tetracycline

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

The 1 study included in this comparison measured gonococcal conjunctivitis but did not find any cases in either study arm (David 2011).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

See comment

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

The 1 study included in this comparison measured chlamydial conjunctivitis but did not identify any cases in either study arm (David 2011).

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 2.04
(0.99 to 4.22)

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,4

50 per 1000

101 per 1000
(49 to 209)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 3.01
(1.52 to 5.98)

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,5

 

50 per 1000

149 per 1000
(75 to 296)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 months

Study population

RR 20.4
(1.2 to 345.8)

410
(1 RCT)

⊕⊕⊝⊝
LOW 1,6

There were no cases of conjunctivitis in the comparator group. The value of 1 per 1000 is the risk for tetracycline for illustrative purposes only.

1 per 1000

20 per 1000
(1 to 346)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): study has unclear or high risk of bias, which could influence outcome.
2Downgraded for imprecision (‐1): small trial size and lack of detection of any gonorrhoea cases.
3Downgraded for imprecision (‐1): small trial size and lack of detection of any chlamydia cases.
4Downgraded for imprecision (‐1): optimal information size criteria not met; confidence interval overlaps no effect; small trial size.
5Downgraded for imprecision (‐1): optimal information size criteria met, but one trial, wide confidence interval, low event rates, small sample size.
6Downgraded for imprecision (‐1): optimal information size criteria possibly met, but one trial, wide confidence interval, low event rates, small sample size.

Figures and Tables -
Table 20. Povidone‐iodine compared to tetracycline for the prevention of ophthalmia neonatorum in newborn children
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Table 21. Povidone‐iodine compared to chloramphenicol for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to chloramphenicol for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: chloramphenicol

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with chloramphenicol

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2004
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

1 included study measured gonococcal conjunctivitis but did not find any cases in either study arm (Ramirez‐Ortiz 2007).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 1.77
(0.97 to 3.22)

2004
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

Ramirez‐Ortiz 2007

16 per 1000

28 per 1000
(16 to 52)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

The 1 study measured and reported cases of bacterial conjunctivitis, but data could not be extracted (Ramirez‐Ortiz 2007).

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

The 1 study measured and reported cases of any conjunctivitis of any aetiology, but data could not be extracted (Ramirez‐Ortiz 2007).

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

The 1 study likely measured conjunctivitis of unknown aetiology, but data could not be extracted (Ramirez‐Ortiz 2007).

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): masking not addressed or unclear; high losses to follow‐up, which can create plausible bias about results.
2Downgraded for imprecision (‐1): zero event rates, sample size small, and unable to determine relative effects; single trial.
3Downgraded for imprecision (‐1): optimal information size not met, and confidence interval overlaps no effect; single trial.

Figures and Tables -
Table 21. Povidone‐iodine compared to chloramphenicol for the prevention of ophthalmia neonatorum in newborn children
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Table 22. Povidone‐iodine compared to carbethopendecinium bromide for the prevention of ophthalmia neonatorum in newborn children

Povidone‐iodine compared to carbethopendecinium bromide for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: povidone‐iodine
Comparison: carbethopendecinium bromide

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with carbethopendecinium bromide

Risk with povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome. 

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

Translation of the 1 study does not make any reference to gonococcal conjunctivitis (GC). There is no reference to culturing. It is unknown if GC was measured. GC cases were not reported.

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Translation of the 1 study does not make any reference to chlamydial conjunctivitis (CC). It unknown if CC was measured. No reference to culturing. No CC cases were reported.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Translation of the 1 study does not make reference to bacterial conjunctivitis (BC). It unknown if BC was measured. No reference to culturing. No BC cases reported.

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 0.44
(0.15 to 1.35)

100
(1 RCT)

⊕⊕⊝⊝
LOW 1,2

1 trial only (Zbojan 2004).

180 per 1000

79 per 1000
(27 to 243)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Translation of the 1 study does not make reference to conjunctivitis of unknown aetiology (CUE). It unknown if CUE was measured. No CUE cases were reported and CUE could not be calculated.

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial with unclear risk of selection bias, performance bias, detection bias, and attrition bias.
2Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect; small trial.

Figures and Tables -
Table 22. Povidone‐iodine compared to carbethopendecinium bromide for the prevention of ophthalmia neonatorum in newborn children
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Table 23. Double application of povidone‐iodine compared to single application of povidone‐iodine for the prevention of ophthalmia neonatorum in newborn children

Double application of povidone‐iodine compared to single application of povidone‐iodine for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: double application of povidone‐iodine
Comparison: single application of povidone‐iodine

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with single application of povidone‐iodine

Risk with double application of povidone‐iodine

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

719
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study measured cases of gonococcal conjunctivitis, but no cases were found in either study arm (Isenberg 2003).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

Study population

RR 1.27
(0.26 to 6.24)

719
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

Isenberg 2003

7 per 1000

9 per 1000
(2 to 44)

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 1.69
(0.59 to 4.82)

719
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

15 per 1000

25 per 1000
(9 to 72)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.32
(0.99 to 1.75)

719
(1 RCT)

⊕⊕⊝⊝
LOW 1,

 

184 per 1000

243 per 1000
(182 to 322)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.29
(0.95 to 1.74)

719
(1 RCT)

⊕⊕⊝⊝
LOW 1,4

 

169 per 1000

218 per 1000
(161 to 294)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single trial has high risk of selection bias, unclear risk of performance bias, and unclear risk of attrition bias.
2Downgraded for imprecision (‐2): no events in either arm.
3Downgraded for imprecision (‐2): limited number of events in each arm, very wide confidence intervals.
4Downgraded for imprecision (‐1): optimal information size criteria not met, and 95% confidence interval includes no effect.

Figures and Tables -
Table 23. Double application of povidone‐iodine compared to single application of povidone‐iodine for the prevention of ophthalmia neonatorum in newborn children
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Table 24. Pencillin IM compared to topical penicillin ointment for the prevention of ophthalmia neonatorum in newborn children

Pencillin IM compared to topical penicillin ointment for the prevention of ophthalmia neonatorum in newborn children

Patient or population: newborn children
Setting: any maternity setting
Intervention: penicillin IM

Comparison: topical penicillin ointment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with topical penicillin ointment

Risk with penicillin IM

Blindness (visual acuity less than 20/200)
follow‐up: 12 months

No studies reported this outcome.

Any adverse visual outcome
follow‐up: 12 months

No studies reported this outcome.

Gonococcal conjunctivitis
assessed with: Neisseria gonorrhoeae‐positive culture
follow‐up: 1 month

See comment

2795
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

The 1 study measured cases of gonococcal conjunctivitis, but no cases were found in either study arm (Davidson 1951).

Chlamydial conjunctivitis
assessed with: Chlamydia trachomatis culture, PCR, or direct fluorescent monoclonal antibody stain
follow‐up: 1 month

This 1 study from 1951 did not report the diagnosis of chlamydial conjunctivitis, nor did the authors specify if chlamydia was measured. It is unlikely that techniques to detect chlamydia were used in this time period.

Bacterial conjunctivitis
assessed with: any bacteria‐positive culture
follow‐up: 1 month

Study population

RR 2.19
(1.14 to 4.24)

2795
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

9 per 1000

20 per 1000
(10 to 38)

Any conjunctivitis of any aetiology assessed with: clinical assessment
follow‐up: 1 month

Study population

RR 1.71
(1.26 to 2.32)

2795
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

44 per 1000

75 per 1000
(55 to 102)

Conjunctivitis of unknown aetiology assessed with: culture negative
follow‐up: 1 month

Study population

RR 1.58
(1.12 to 2.25)

2795
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

35 per 1000

55 per 1000
(39 to 79)

Adverse effects

No studies reported this outcome.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk is taken from the study population in the included studies.

CI: confidence interval; IM: intramuscular; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low‐certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Downgraded for risk of bias (‐1): single study at high risk or unclear risk of bias.
2Downgraded for imprecision (‐2): optimal information size criteria likely not met; no events.
3Downgraded for imprecision (‐1): optimal information size criteria not met. However, confidence interval excludes no effect.

Figures and Tables -
Table 24. Pencillin IM compared to topical penicillin ointment for the prevention of ophthalmia neonatorum in newborn children
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Comparison 1. Any prophylaxis versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Chlamydial conjunctivitis Show forest plot

2

4874

Risk Ratio (IV, Fixed, 95% CI)

0.96 [0.57, 1.61]

1.2 Bacterial conjunctivitis Show forest plot

2

3685

Risk Ratio (IV, Fixed, 95% CI)

0.84 [0.37, 1.93]

1.3 Any conjunctivitis of any aetiology Show forest plot

8

9666

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.54, 0.78]

1.4 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

1.5 Nasolacrimal duct obstruction Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

1.6 Keratitis Show forest plot

1

40

Risk Ratio (IV, Fixed, 95% CI)

Not estimable
Figures and Tables -
Comparison 1. Any prophylaxis versus no prophylaxis
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Comparison 2. Silver nitrate versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Gonococcal conjunctivitis Show forest plot

1

2225

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

2.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

2.3 Any conjunctivitis of any aetiology Show forest plot

3

2713

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.52, 0.87]

2.4 Corneal abrasion Show forest plot

1

40

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

2.5 Nasolacrimal duct obstruction Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 2. Silver nitrate versus no prophylaxis
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Comparison 3. Erythromycin versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Gonococcal conjunctivitis Show forest plot

2

2526

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

3.2 Chlamydial conjunctivitis Show forest plot

2

2526

Risk Ratio (IV, Fixed, 95% CI)

0.93 [0.49, 1.77]

3.3 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

3.4 Any conjunctivitis of any aetiology Show forest plot

6

3509

Risk Ratio (IV, Random, 95% CI)

0.68 [0.51, 0.89]

3.5 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

3.6 Nasolacrimal duct obstruction Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 3. Erythromycin versus no prophylaxis
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Comparison 4. Tetracycline versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Gonococcal conjunctivitis Show forest plot

1

2299

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

4.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

4.3 Any conjunctivitis of any aetiology Show forest plot

2

2519

Risk Ratio (IV, Fixed, 95% CI)

0.72 [0.55, 0.94]
Figures and Tables -
Comparison 4. Tetracycline versus no prophylaxis
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Comparison 5. Povidone‐iodine versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Gonococcal conjunctivitis Show forest plot

1

220

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

5.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

5.3 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

5.4 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

5.5 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 5. Povidone‐iodine versus no prophylaxis
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Comparison 6. Bacitracin‐phenacaine versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Gonococcal conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 6. Bacitracin‐phenacaine versus no prophylaxis
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Comparison 7. Colostrum versus no prophylaxis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 7. Colostrum versus no prophylaxis
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Comparison 8. Erythromycin versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Chlamydial conjunctivitis Show forest plot

4

13472

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.51, 1.09]

8.2 Bacterial conjunctivitis Show forest plot

2

6333

Risk Ratio (IV, Fixed, 95% CI)

0.83 [0.69, 1.01]

8.3 Any conjunctivitis of any aetiology Show forest plot

3

4729

Risk Ratio (IV, Random, 95% CI)

1.02 [0.80, 1.30]

8.4 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

8.5 Nasolacrimal duct obstruction Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 8. Erythromycin versus silver nitrate
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Comparison 9. Tetracycline versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

9.1 Chlamydial conjunctivitis Show forest plot

4

14142

Risk Ratio (IV, Random, 95% CI)

0.64 [0.40, 1.02]

9.2 Nasolacrimal duct obstruction Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 9. Tetracycline versus silver nitrate
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Comparison 10. Sulfacetamide versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

10.1 Gonococcal conjunctivitis Show forest plot

1

640

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

10.2 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

10.3 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

10.4 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 10. Sulfacetamide versus silver nitrate
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Comparison 11. Cetyl‐pyridinium chloride versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

11.1 Bacterial conjunctivitis Show forest plot

2

599

Risk Ratio (IV, Fixed, 95% CI)

1.79 [0.59, 5.41]

11.2 Any conjunctivitis of any aetiology Show forest plot

2

599

Risk Ratio (IV, Fixed, 95% CI)

1.08 [0.40, 2.90]

11.3 Conjunctivitis of unknown aetiology Show forest plot

2

599

Risk Ratio (IV, Fixed, 95% CI)

0.14 [0.01, 2.71]
Figures and Tables -
Comparison 11. Cetyl‐pyridinium chloride versus silver nitrate
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Comparison 12. Penicillin versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

12.1 Gonococcal conjunctivitis Show forest plot

1

2804

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

12.2 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

12.3 Any conjunctivitis of any aetiology Show forest plot

2

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

12.4 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 12. Penicillin versus silver nitrate
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Comparison 13. Penicillin IM versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

13.1 Gonococcal conjunctivitis Show forest plot

1

2727

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

13.2 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

13.3 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

13.4 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 13. Penicillin IM versus silver nitrate
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Comparison 14. Povidone‐iodine versus silver nitrate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

14.1 Gonococcal conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

14.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

14.3 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

14.4 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

14.5 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 14. Povidone‐iodine versus silver nitrate
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Comparison 15. Tetracycline versus erythromycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

15.1 Chlamydial conjunctivitis Show forest plot

2

10946

Risk Ratio (IV, Fixed, 95% CI)

0.72 [0.42, 1.25]

15.2 Any conjunctivitis of any aetiology Show forest plot

2

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 15. Tetracycline versus erythromycin
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Comparison 16. Colostrum versus erythromycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

16.1 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 16. Colostrum versus erythromycin
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Comparison 17. Povidone‐iodine versus erythromycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

17.1 Chlamydial conjunctivitis Show forest plot

2

2408

Risk Ratio (IV, Fixed, 95% CI)

0.74 [0.54, 1.02]

17.2 Bacterial conjunctivitis Show forest plot

2

2408

Risk Ratio (IV, Fixed, 95% CI)

0.87 [0.71, 1.07]

17.3 Any conjunctivitis of any aetiology Show forest plot

2

2408

Risk Ratio (IV, Fixed, 95% CI)

0.78 [0.68, 0.90]

17.4 Conjunctivitis of unknown aetiology Show forest plot

2

2408

Risk Ratio (IV, Fixed, 95% CI)

0.74 [0.58, 0.93]
Figures and Tables -
Comparison 17. Povidone‐iodine versus erythromycin
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Comparison 18. Pencillin IM versus tetracycline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

18.1 Gonococcal conjunctivitis Show forest plot

1

32058

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

18.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 18. Pencillin IM versus tetracycline
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Comparison 19. Povidone‐iodine versus tetracycline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

19.1 Gonococcal conjunctivitis Show forest plot

1

410

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

19.2 Chlamydial conjunctivitis Show forest plot

1

410

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

19.3 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

19.4 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

19.5 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 19. Povidone‐iodine versus tetracycline
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Comparison 20. Povidone‐iodine versus chloramphenicol

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

20.1 Gonococcal conjunctivitis Show forest plot

1

2004

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

20.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 20. Povidone‐iodine versus chloramphenicol
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Comparison 21. Povidone‐iodine versus carbethopendecinium bromide

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

21.1 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 21. Povidone‐iodine versus carbethopendecinium bromide
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Comparison 22. Povidone‐iodine twice versus povidone‐iodine once

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

22.1 Gonococcal conjunctivitis Show forest plot

1

719

Risk Ratio (IV, Fixed, 95% CI)

Not estimable

22.2 Chlamydial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

22.3 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

22.4 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected

22.5 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 22. Povidone‐iodine twice versus povidone‐iodine once
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Comparison 23. Penicillin IM versus topical penicillin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

23.1 Gonococcal conjunctivitis Show forest plot

1

2795

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

23.2 Bacterial conjunctivitis Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Subtotals only

23.3 Any conjunctivitis of any aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Subtotals only

23.4 Conjunctivitis of unknown aetiology Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Subtotals only
Figures and Tables -
Comparison 23. Penicillin IM versus topical penicillin
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