Introduction
Methods
Evaluation of Data
Compliance with Ethics Guidelines
Results
Articles Selected
Incidence of RSVH in Preterm Infants
Study | Country | Design | Hospitalization rate | ||||
---|---|---|---|---|---|---|---|
36–37 wGA | 32–35/36 wGA | ≤33 wGA | <28 wGA | ≥38 wGA | |||
Straňák 2016 [12] | Multinational (23 countries)t
| 1-year multicenter prospective study (2013–2014); 2390 infants ≤6 months of age born at 33–35 wGA (excluded infants with BPD/CLD or hsCHD or who received/planned to receive RSV immunoprophylaxis) | – | 61.0a
| – | – | – |
Resch 2006 [56] | Austria | 2-year multicenter retrospective/prospective study (2001–2003); 863 children <2 years old born at 29–32 wGA (included some infants with BPD, CHD or neurological diseases; 29.7% received RSV immunoprophylaxis) | – | – | 45.0c, d
| – | – |
Law 2004 [9] | Canada | 2-year multicenter, prospective, observational cohort study (2001–2002, 2002–2003); 1832 infants <1 year old born at 33–35 wGA; excluded infants receiving RSV immunoprophylaxis) | – | 36.0c, g
| – | – | – |
Haerskjold 2015 [48] | Denmark | 7-year retrospective, population-based cohort study (1997–2003); 6 national registries; children ≤2 years old (included 5200 [1.2%] infants 23–32 wGA, 11,193 [2.7%] infants 33–35 wGA, 9815 [2.3%] infants 36 wGA (excluded infants receiving RSV immunoprophylaxis) | 22.6b, k
| 28.0b, g
| 50.8b, l
| – | 14.1b, i
11.5b, n
|
Gouyon 2013 [50] | France | 1-year retrospective/prospective study (2008–2009); 9 regional networks; 498 infants <6 months old (249 preterm infants <33 wGA without BPD, CHD or immunodeficiency; 249 matched full term infants; excluded infants receiving RSV immunoprophylaxis) | – | – | 64.0c
| – | 16.0c
|
Doering 2006 [55] | Germany/Austriao
| 2-year retrospective study (1998–1999; 2001–2002); 1158 infants <1 year old born at 29–35 wGA (included some infants with CLD, CHD or neurological diseases; excluded infants receiving RSV immunoprophylaxis) | – | 42.0c,
d
| – | – | – |
Pezzotti 2009 [59] | Italy | 6-year retrospective, longitudinal study (2000–2006); 2 local health units; 2407 children <3 years old born at <36 wGA (201 [8.3%] born <29 wGA (included some infants with BPD or CHD; 13.5% received RSV immunoprophylaxis) | – | 46.0a, j
| – | – | – |
Korsten 2016 [11] | Netherlands | 4-year prospective study (2011–2015); 41 hospitals; 4088 healthy infants ≤1 year old born at 33–35 wGA (excluded infants receiving RSV immunoprophylaxis)s
| – | 35.0c
| – | – | – |
Gijtenbeek 2015 [43] | Netherlands | Retrospective study of children born 2002–2003; community-based cohort; 524 children born <32 wGA, 964 children born 32–36 wGA, 572 born 38–42 wGA | – | 39.0c
| – | 32.0 c
| 12.0c
|
Blanken 2013 [10] | Netherlands | 2-year prospective study (2008–2011)p; 41 hospitals; 2421 healthy preterm infants ≤1 year old born at 33–35 wGA (excluded infants receiving RSV immunoprophylaxis) | – | 51.0c, g
| – | – | – |
Fjaerli 2004 [24] | Norway | 8-year, retrospective, population-based study (1993–2000); single center/region; 764 children ≤2 years old (included 58 [7.6%] infants <37 wGA; majority previously healthy) | <1 year:f 23.5c
1–2 years:f 8.7c
≤2 years:f 16.2c
| – | – | – | – |
Figueras-Aloy 2008 [8] | Spain | 2-year prospective 2-cohort study (2005–2006, 2006–2007); 37 hospitals; 5441 preterm infants ≤1 year old born at 32–35 wGA (202 RSV + cases; some infants received RSV immunoprophylaxis) | – | 37.0c
| – | – | – |
Cilla 2006 [32] | Spain | 4-year retrospective study (1996–2000); single-center; 357 children <2 years old admitted with virologically-confirmed RSV infection (included 80 infants ≤37 wGA; majority previously healthy) | 29.4c
| 78.1c
| 44.2c
| – | 19.1c
|
Spain | 2-year observational, prospective, longitudinal, multicenter study (1998–1999, 1999–2000); 14 neonatal units; preterm infants ≤32 wGA (584 in 2000 season and 999 in 2001 season) | – | – | 131.0–134.0c
| – | – | |
Ericksson 2002 [47] | Sweden | 12-year retrospective study (1987–1998); single center/tertiary; 1503 children <2 years old (included infants <33 wGA without CLD) | – | – | Early season: 16.0c
Late season: 32.0c
| – | Early season: 14.0c
Late season: 8.0c
|
Deshpande 2003 [31] | UK | 3-year retrospective study (1996–1999); county; 561 children <2 years old hospitalized for bronchiolitis (53 preterm infants ≤36 wGA hospitalized with RSV) | – | 89.0c, m
| – | 125.0c, m
| 24.0–36.0c, j
|
Helfrich 2015 [49] | USA | Retrospective cohort study (2005–2011); military health system; 599,535 preterm infants ≤2 years old born at 33 + 0 through 36 + 6 wGA | – | 12.1a, g
| – | – | 7.8a, g
|
Ambrose 2014 [57] | USA | 2-year prospective study (2009–2010 and 2010–2011); 188 US sites; 1642 infants <6 months old born at 32–25 wGA (excluded infants receiving RSV immunoprophylaxis) | – | 49.0a
| – | – | – |
Hall 2013 [4] | USA | 5-year prospective, population-based study (2000–2005); 2149 children <2 years old (10% <37 wGAe; included children with comorbid conditions; 23% RSV + preterms received RSV immunoprophylaxis) | 4.6c,f
| – | – | 18.7c, h
| – |
Hampp 2011 [51] | USA | 1 RSV season retrospective study (2004–2005); Florida Medicaid claims data; 159,790 infants (included infants ≤6 months born at ≤32 wGA and infants <2 years with CLD, CHD, or neither co-morbidity) | – | – | 42.1c, q
| – | 12.5c, r
|
Boyce 2000 [5] | USA | 4-year retrospective cohort study (1989–1993); state; children <3 years old (included infants <36 wGA and infants with BPD, CHD); 248,652 child-years of follow-up | – | 0–6 months: 79.8c,g
6–12 months: 34.5c,g
1–2 years: 10.8c, g
2–3 years: 0.9c, g
| – | 0–6 months: 93.8c
6–12 months:46.1c
1–2 years: 30.0c
2–3 years:0.0c
| 0–6 months: 44.1c
6–12 months: 15.0c
1–2 years: 3.7c
2–3 years: 1.0c
|
Summary | ||||
---|---|---|---|---|
wGA | Number of studies | Number of countries | Population age range and timeframe of studies | Hospitalization rate |
36–37 | 4 | 4 | ≤2 years; 1993–2005 | 4.6–29.4c; 22.6b
|
32–35/36 | 14 | 31 | <3 years; 1989–2015 | 0.9–89.0c; 28.0b; 12.1–46.0a; 49.0a
|
≤33 | 7 | 6 | ≤2 years; 1987–2009 | 16.0–134.0c; 50.8b
|
<28 | 4 | 3 | <3 years; 1989–2005 | 0.0–125.0c
|
≥38 | 9 | 7 | <3 years; 1989–2011 | 1.0–44.1c; 11.5–14.1b; 7.8a
|
RSVH Rates by Gestational Age
Rehospitalization Rates for RSV Infection Following Discharge from Neonatal ICUs
Morbidity and Mortality Associated with Severe RSV Infection
Morbidity
Study | Country | Study participants | Hospital LOS, median days (range) | ICU admission (%) | ICU LOS, median days (range) | Oxygen therapy (%) | Mechanical ventilation (%) | Non-invasive ventilation (%) | Case-fatality rate (%) |
---|---|---|---|---|---|---|---|---|---|
Straňák 2016 [12] | Multinational (23 countries)l
| 1-year prospective (2013–2014); multicenter; 2390 infants ≤6 months old born at 33–35 wGA (infants with BPD/CLD or CHD or who received or were planned to receive RSV immunoprophylaxis were excluded) | NR | 29.7 | 6 (5–12) | 73.4 | 10.9 | NR | NR |
Van de Steen 2016 [46] | Central and Eastern Europe (12 countries)m
| 2-year retrospective (2009–2011); multicenter; 266 infants <1 year old born at <37 wGA (34.2% with co-morbidities) hospitalized with confirmed RSV bronchiolitis | 17 (20)e
| 41.4 | 13 (15)e
| 72.9 | NR | NR | 2.6 |
Gouyon 2013 [50] | France | 1-year retrospective/prospective (2008–2009); 498 infants <6 months old (249 preterm [<33 wGA] without BPD and 249 matched term infants) hospitalized with bronchiolitis (RSV-confirmed and all types) | 5 (2–13)c
| 5.9 | NR | 54.5c
| NR | 15.2c
| NR |
Tsolia 2003 [72] | Greece | 4-year retrospective/prospective (1997–2000); 636 infants <1 year old admitted with bronchiolitis (61% had confirmed RSV and 12% of these were preterm infants ≤36 wGA) | NR | 26 | NR | NR | NR | NR | 5.7 |
Bala 2005 [80] | Ireland | 5-year retrospective (1997–2001); 174 preterm infants (<32 wGA) hospitalized with bronchiolitis | 5 | 0 | NA | NR | NR | NR | 0 |
Fjaerli 2004 [24] | Norway | 8-year retrospective, (1993–2000); 764 children <2 years old (7.6% preterm [<37 wGA], some with additional comorbidities) hospitalized with RSV bronchiolitis | 8 (2–7) | NR | NR | NR | 3.4% | NR | 0 |
Figueras-Aloy 2008 [8] | Spain | 2-year prospective (2005–2006, 2006–2007); 37 hospitals; 5441 preterm infants born at 32–35 wGA (202 RSV + cases; some infants received RSV immunoprophylaxis) | 7 (4–10)i
| 17.8 | 5 (3–10.8)i
| NR | 7.4 | NR | 0 |
Shefali-Patel 2012 [16] | UK | 8-year retrospective (2000–2007); 158 children <2 years old born at 32–35 wGA with respiratory and non-respiratory admissions (20 with RSV infection) | 4.5 (1–110) | 75 | 0 (0–29) | NR | NR | NR | NR |
Deshpande 2003 [31] | UK | 3-year retrospective study (1996–1999); 561 children <2 years old with bronchiolitis-associated hospitalizations (53 preterm infants ≤36 wGA hospitalized for RSV) | 2 (1–4)d
| NR | NR | ≥28 days: 9.5f
<28 days: 6.6f
| 12.6f
| NR | NR |
Anderson 2016 [74] | USA | 1-year retrospective/prospective (2014–2015); 709 infants <1 year old born at 29–35 wGA hospitalized with RSV | Overall: 5 (1–135)j
29–32 wGA: 6 (1–67)j
33–34 wGA: 6 (1–101)
j
35 wGA: 5 (1–135)j
| Overall: 42j
29–32 wGA: 49j
33–34 wGA: 43
j
35 wGA: 31j
| Overall: 6 (1–91)j
29–32 wGA: 8 (1–61)j
33–34 wGA: 6 (1–91)
j
35 wGA: 5 (1–59)j
| NR | Overall: 20j
29–32 wGA: 24j
33–34 wGA: 20
j
35 wGA: 13j
| NR | 0.1h
|
Ambrose 2014 [57] | USA | 2-year prospective (2009–2010 and 2010–2011); 1642 preterm infants (32–35 wGA) <6 months old | 4 (2–18) | 16 | NR | NR | 11 | NR | NR |
Underwood 2007 [79] | USA | 9-year retrospective (1992–2000); 263,883 premature infants (<36 wGA) readmitted to hospital (1.6% hospitalized for RSV) | 5.6 | NR | NR | NR | NR | NR | NR |
Horn 2003 [14]k
| USA | 17-month retrospective (1995–1996); 304 infants ≤1 year old (89 < 37 wGA)n
| ≤32 wGA: 6.8e
33–35 wGA: 8.4
e
36 wGA: 4.9e
| ≤32 wGA: 39.3 33–35 wGA: 48.4 36 wGA: 30 | ≤32 wGA: 5.8e
33–35 wGA: 7.7
e
36 wGA: 4.2e
| NR | ≤32 wGA: 21.4 33–35 wGA: 38.7 36 wGA: 20 | NR | 0 |
Willson 2003 [75]k
| USA | 17-month retrospective (1995–1996); 684 infants ≤1 year old hospitalized for bronchiolitis or RSV pneumonia (12.7% preterm infants ≤35 wGA)n
| ≤32 wGA: 4.0 33–35 wGA: 5.0 36 wGA: 3.5 ≥37 wGA: 3.0 | NR | ≤32 wGA: 3.9 33–35 wGA: 5.0 36 wGA: 4.5 ≥37 wGA: 2.5 | NR | NR | NR | NR |
Care 2016 [81] | Turkey | 1 RSV season (2013–2014); 250 infants hospitalized for RSV (median age 23 [4–153] days); 79 preterm infants ≤36 wGA | NR | NR | NR | NR | NR | NR | 2.5 |
Summary | ||||
---|---|---|---|---|
Outcome | Number of studies | Number of countries | Population age range and timeframe of studies | Value |
Hospital LOS | 12 | 18 | <2 years; 1992–2015 | 2–17a
|
ICU admission | 10 | 33 | <2 years; 1995–2015 | 0–75b
|
ICU LOS | 7 | 32 | <2 years; 1995–2015 | 0–6a
|
Oxygen therapy | 4 | 30 | <2 years; 1996–2014 | 54.5–73.4b; ≥28 days: 9.5b, <28 days: 6.6b
|
Mechanical ventilation | 7 | 26 | <2 years; 1993–2015 | 3.4–38.7b
|
Non-invasive ventilation | 1 | 1 | <6 months; 2008–2009 | 15.2b
|
Case-fatality rate | 8 | 18 | <2 years; 1993–2015 | 0–5.7b
|
Gestational Age-Specific Complications and Hospital Resource Use
Variable | wGA |
P value | ||||
---|---|---|---|---|---|---|
29–32 (n = 237) | 33–34 (n = 283) | 35 (n = 182) | 29–32 vs. 33–34 wGA | 29–32 vs. 35 wGA | 33–34 vs. 35 wGA | |
Age at admission, monthsa
| 3 (2–5) | 2 (1–4) | 2 (1–5) | <0.001 | <0.01 | <0.001 |
Hospital LOS, daysa
| 6 (3–12) | 6 (3–10) | 5 (3–7) | NS | 0.001 | <0.05 |
ICU admission, n (%) | 115 (49) | 117 (43) | 56 (31) | NS | <0.001 | 0.01 |
ICU LOS, daysa
| 8 (3–14) | 6 (3–12) | 5 (3–9) | NS | NS | NS |
Mechanical ventilation among all admissions, n (%) | 58 (24) | 53 (20) | 23 (13) | NS | <0.01 | NS |
Case-Fatality Rates
RSVH and Health-Related Quality of Life
Independent Gestational Age-Specific Risk Factors for RSVH
Risk factors | Odds ratio (95% confidence interval) | |||||
---|---|---|---|---|---|---|
FLIP study [7] (n = 557) | FLIP-2 study [8] (n = 5441) | PICNIC study [9] (n = 1758) | RISK study [10] (n = 2421) | RISK-II study [11] (n = 1564) | PONI study [12] (n = 2390) | |
Exposure | ||||||
Age at start of RSV season (a≤10 weeks, bbirth November-January, cbirth August 14th to December 1st, ≤3 monthsd) | 3.95a (2.65–5.90)
P ≤ 0.001 | 2.99a (2.23–4.01)
P ≤ 0.001 | 4.88b (2.57–9.29)
P < 0.001 | 2.6c (1.6–4.2)
P < 0.001 | 2.4c (1.8–3.2)
P < 0.001 | 2.10d
P = 0.0422 |
Siblings (aschool age, bschool-age siblings or day care attendance, cpre-school-age, dsiblings or day care attendance, echildren aged 4–5 years) | 2.85a (1.88–4.33)
P ≤ 0.001 | 2.04b (1.53–2.74)
P ≤ 0.001 | 2.76c (1.51–5.03)
P = 0.001 | 4.7d (1.7–13.1)
P = 0.003 | 5.3d (2.8–10.10)
P < 0.001 | 2.28e
P = 0.0038 |
Crowding at home (≥4a without subject and school age siblings, >5b counting subject) | 1.91a (1.19–3.07)
P = 0.0074 | – | 1.69b (0.93–3.10)
P = 0.088 | – | – | – |
Day care attendance | – | – | 12.32 (2.56–59.34)
P = 0.002 | – | – | – |
Social factors | ||||||
Exposure to ≥2 smokersa, smoking of familyb
| – | – | 1.71a (0.97–3.00)
P = 0.064 | – | – | 3.18
P < 0.0001 |
Smoking during pregnancy | – | 1.61 (1.16–2.25)
P = 0.0044 | – | – | – | – |
Breast feeding ≤2 monthsa
| 3.26a (1.96–5.42)
P ≤ 0.001 | – | – | 1.7a (1.0–2.7)
P = 0.04 | 1.6b (1.2–2.2)
P = 0.003 | – |
Biological factors | ||||||
Small for gestational age (<10th percentile) | – | – | 2.19 (1.14–4.22)
P = 0.019 | – | – | – |
Male sex | – | – | 1.91 (1.10–3.31)
P = 0.02 | – | – | – |
Family history of wheezing | 1.90 (1.19–3.01)
P = 0.0068 | – | – | – | – | – |
Family history of eczemaa/atopyb in first degree relative, maternal atopic constitutionc, paternal atopyd
| – | – | 0.42a (0.18–0.996)
P = 0.049 | 1.9b (1.1–3.2)
P = 0.01 | 1.5c (1.1–2.1)
P = 0.01 | 3.28d
P < 0.0001 |
Non-hemodynamically significant congenital heart disease diagnosis | – | – | – | – | – | 4.09
P = 0.0077 |
Maternal age ≤25 years | – | – | – | – | – | 2.72
P = 0.0009 |
Low maternal education | – | – | – | – | – | 1.79
P = 0.0426 |
Medical factors | ||||||
Neonatal respiratory support | – | – | – | – | 2.2 (1.6–3.0)
P < 0.001 | – |
Hospital stay <7 days (at birth) | – | – | – | – | – | 2.14
P = 0.0113 |
FLIP [91] | FLIP 2 [93] | PICNIC [92] | RISK [10] | RISK-II [11] | PONI [12] | |
---|---|---|---|---|---|---|
Risk factors | 7 Birth ± 10 weeks of season start Birth weight Breast feeding ≤2 months Number of siblings ≥2 years Number of family members with atopy Number of family members with wheeze Sex | 4 Birth ± 10 weeks of season start School-age siblings or day care attendance Mother smoking during pregnancy Sex | 7 Small (<10th percentile) GA Sex Born during RSV season (Nov–Jan) Family history without eczema Subject or siblings attending day care >5 individuals in the home, including the subject >1 smoker in the household | 4 Born Aug 14th to Dec 1st Presence of siblings or subject day care attendance Breast fed ≤2 months or not Atopy in 1st degree family member | 5
Birth between Aug 14th and Dec 1st Day care attendance and/or siblings Neonatal respiratory support Breastfeeding ≤4 months Maternal atopic constitution | 6 Age on 1st October ≤3 months Smoking of family members Age of mother at delivery ≤25 years Children 4–5 years old present Smoking of mother during pregnancy Subject day care attendance |
Sensitivity/specificity | 0.72/0.71 | 0.062/0.99 | 0.68/0.72 | 0.46/0.79 | Low risk (1% hospitalization): 0.90/0.35 High risk (13% hospitalization): 0.32/0.90 | NR |
ROC AUCa
| 0.791 | 0.687 | 0.762 | 0.703 | 0.72 | 0.755 |
Conclusions
Level of evidencea
| |
---|---|
Key statements/findings | |
Studies have shown that preterm infants, particularly those born at lower gestational ages, are at high risk for RSVH and tended to have higher rates of hospitalization for RSV compared with otherwise healthy term infants | 1 (Level 1 studies: n = 8; risk of biasb: 10.9) |
RSVH rates for preterm infants ranged from >100 per 1000 children to ~5 per 1000, with the highest rates shown in the lowest gestational age infants | 1 (Level 1 studies: n = 8; risk of biasb: 11.0) |
Compared to otherwise healthy/term infants, premature infants have Longer median hospital stays Increased complication rates Increased risk for ICU admission | 1 (Level 1 studies: n = 9; risk of biasb: 10.6) |
A number of independent risk factors associated with RSVH in premature infants have been reported including exposure (e.g. proximity of birth to the RSV season, living with school-age siblings), social factors (e.g. smoking of mother during pregnancy or environmental smoking, reduced breast feeding), and biological factors (e.g. male sex, familial asthma) | 1 (Level 1 studies: n = 6; risk of biasb: 11.0) |
Predictive models for RSVH in 32–35 wGA infants have been developed using 4 or 7 risk factors with areas under the ROC curves ranging from 0.687 to 0.791 (fair to good predictive accuracy) | 1 (Level 1 studies: n = 6; risk of biasb: 11.0) |
Key areas for research | |
In light of the continuing burden and long-term sequelae of severe RSV infection in otherwise healthy preterm infants, further research is needed on gestation-specific prevalence and burden of RSV disease to confirm the vulnerability of these children | |
Further prospective studies should be undertaken to fully explore the changing risk of RSVH during the first year of life in preterm infants |