Description of the condition

The ductus arteriosus connects the pulmonary artery to the descending aorta (Clyman 2000). Normal fetal circulation is dependent on the placenta and the patency of the ductus arteriosus (PDA) (Mathew 1998). During fetal life it diverts most of the combined ventricular output away from the lungs (Clyman 2000). Following birth, and with the separation of the placenta and initiation of breathing, the circulation changes and the ductus closes (Mathew 1998). In full term newborns this happens within 24 to 48 hours after birth (Clyman 2000). In preterm newborns the ductus frequently fails to close. As a result, 70% of infants born before 28 weeks postmenstrual age (PMA) require medical or surgical closure of the PDA (Clyman 2000). The failure of the ductus arteriosus to constrict after birth is due to lower intrinsic tone, less ductal muscle fibre and fewer subendothelial cushions in preterm as compared to term infants (Hammerman 1995). The immature ductus arteriosus has higher sensitivity to the vasodilating effects of prostaglandins and nitric oxide (Hammerman 1995). This is aggravated by haemodynamic derangements due to respiratory distress syndrome and surfactant therapy (Hammerman 1995). The clinical consequences of a PDA are related to the degree of left to right shunting through the ductus. Despite the ability of the left ventricle, in preterm infants, to increase its output in the face of a left to right shunt, blood flow distribution to vital organs is altered due to a drop in diastolic pressure and localized vasoconstriction (Clyman 2000). The presence of a PDA is associated with reduced middle cerebral artery blood flow velocity (Weir 1999). The haemodynamic instability caused by the left to right shunt has been associated with gastrointestinal, cerebral and renal effects including spontaneous intestinal perforation and necrotizing enterocolitis (NEC), intraventricular haemorrhage (IVH), decreased kidney function and bronchopulmonary dysplasia (BPD) and, if not managed, may lead to death.

In the two Cochrane reviews of prophylactic use of ibuprofen and indomethacin to close a PDA in preterm infants, the spontaneous closure rate in the control group was 58% and 57% respectively (Fowlie 2010; Ohlsson 2011).

Description of the intervention

A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Surgical closure of a symptomatic PDA improves haemodynamics and lung compliance (Naulty 1978). However, medical treatment is still considered the treatment of choice because of the risks related to the surgery. In a large Canadian cohort (n = 3779) of very low‐birth‐weight infants, 28% required treatment for a PDA; 75% were treated with indomethacin alone, 8% with surgical ligation alone, and 17% required both indomethacin and surgical ligation (Lee 2000). Infants with lower birth weights were more likely to be treated surgically (Lee 2000). Prostaglandins play a significant role in keeping the ductus arteriosus patent (Mathew 1998). Inhibiting prostaglandin synthesis with non‐selective blockers of both cyclo‐oxygenase (COX) 1 and 2 is effective for the non‐surgical closure of PDA (Clyman 2000). However, indomethacin use is associated with transient or permanent derangement of renal function, NEC, gastrointestinal haemorrhage or perforation, alteration of platelet function and impairment of cerebral blood flow or cerebral blood flow velocity (Edwards1990; Ohlsson 1993; Seyberth 1983; Wolf 1989).

Ibuprofen, a propionic acid derivative and non‐selective COX inhibitor, is as effective as indomethacin in closing a PDA and reduces the risk of NEC (Ohlsson 2015). There is less evidence of transient renal insufficiency following treatment with ibuprofen compared to indomethacin (Ohlsson 2015).

Another non‐steroidal anti‐inflammatory drug, mefenamic acid, has been reported to close a PDA (Sakhalkar 1992), but no randomised controlled trials have been reported (Ohlsson 2011; Ohlsson 2015).

In the sheep fetus, Peterson (Peterson 1985) showed that acetaminophen has potent activity on the ductus arteriosus and produces a constriction in therapeutic analgesic quantities. In humans, Simbi 2002 reported on a pregnant woman near term who took nimesulide 400 mg and acetaminophen 500 mg twice daily for three days as a medication for pain. The women noticed diminished fetal movements and one day later ultrasound confirmed lack of fetal movements and breathing. A constricted ductus arteriosus was confirmed by fetal echocardiography. Following cesarean section the male infant presented with severe mixed acidosis. An echocardiogram showed an almost completely constricted ductus arteriosus. Following intensive care the infant improved and was discharged home on day 12 after birth. At three months follow‐up the infant was doing well. Either nimesulide or acetaminophen, or both, could be responsible for ductal closure in this case.

The complications associated with the use of indomethacin and possibly ibuprofen have encouraged the search for an alternative drug to treat a PDA. In 2011 paracetamol was suggested as an alternative (Hammerman 2011). Hammerman reported on five preterm infants (PMA 26 to 32 weeks at birth and postnatal age of 3 to 35 days) with large, haemodynamically significant PDAs (Hammerman 2011). The infants had failed or had contraindications for treatment with ibuprofen. All infants were treated with oral paracetamol 15 mg/kg per dose every 6 hours. The treatment resulted in ductal closure in all infants within three days. No side effects were observed. The authors suggested that paracetamol could offer important therapeutic advantages over non‐steroidal anti‐inflammatory drugs (NSAIDs) (indomethacin and ibuprofen) as paracetamol has no peripheral vasoconstrictive effect, can be given to infants with clinical contraindications to NSAIDs, and appears to be effective after ibuprofen treatment failure (Hammerman 2011).

Paracetamol is used to treat pain in infants. At the Astrid Lindgren Children's Hospital in Stockholm, Sweden, it is used for postoperative pain. An intravenous dose of paracetamol of 7.5 mg/kg every 8 hours for infants with a PMA of 28 to 32 weeks; 7.5 mg/kg every 6 hours for infants with a PMA of 33 to 36 weeks, and 10 to 15 mg/kg every 6 hours for infants with a PMA of 37 weeks or more is described in their protocol (Bartocci 2007).

In a survey of intravenous paracetamol use in neonates and infants under one year of age by UK anaesthetists, maintenance doses were either 7.5 mg/kg or 10 mg/kg with a dosing interval of six or eight hours in preterm infants (Wilson‐Smith 2009).

In a study of the pharmacokinetics of intravenous acetaminophen, conducted in Australia, the postoperative dose given every 6 hours was 10 mg/kg for infants with a PMA of 28 to 32 weeks; 12.5 mg/kg for infants of a PMA of 32 to 36 weeks and 15 mg/kg for infants ≥ 36 weeks. Following the study the unit continues to use the reported doses based on PMA (Palmer 2008).

Unconjugated hyperbilirubinaemia impacts upon clearance of paracetamol (Palmer 2008). Acetaminophen‐induced hepatic failure with encephalopathy has been described in a term newborn who received oral acetaminophen every four hours by the parents following circumcision (Walls 2007).

How the intervention might work

Paracetamol is an analgesic, antipyretic derivative of acetanilide with weak anti‐inflammatory properties and is used as a common analgesic in all age groups, but may cause liver, blood cell and kidney damage (Drug Information Portal 2012). In low concentrations paracetamol stimulates and in high concentrations inhibits the synthesis of prostaglandins. In vivo (in adults) 500 mg of paracetamol causes a pronounced reduction of prostacyclin synthesis but has no effect on thromboxane synthesis (Grèen 1989). Because in vitro paracetamol is a weak inhibitor of both COX 1 and COX 2, the possibility exists that it inhibits a so far unidentified form of COX, perhaps a COX 3 (Botting 2000). In a murine model paracetamol was found to be less potent than indomethacin for construction of the mouse ductus arteriosus in vitro (El‐Khuffash 2014).

Since the report in 2011 by Hammerman and co‐workers (Hammerman 2011) there have been many case series of treatment of a PDA with paracetamol in preterm infants. In five recent case series (Kessel 2014; Nadir 2014; Sinah 2013; Terrin 2014; Yurttutan 2013) a total of 38 infants with different contraindications for the use of ibuprofen or indomethacin were included. Paracetamol was administered orally, intravenously or via nasogastric tube and the dose and duration of treatment varied; orally 15 mg/kg 8 hourly for 48 hours (Sinah 2013); 15 mg/kg 6 hourly for 3 days (Yurttutan 2013); 15 mg/kg 6 hourly for up to 7 days (Nadir 2014); via nasogastric tube 15 mg/kg 6 hourly for 3 to 7 days (Kessel 2014); or intravenously 7.5 to 15 mg/kg every 4 to 6 hours, with a maximum daily dose of 60 mg/kg (duration of treatment 3 days in 5 of 7 cases) (Terrin 2014). In these case reports the PDA closed in 33 of the 38 cases treated with paracetamol (86%). Kessel and co‐workers (Kessel 2014) measured plasma paracetamol concentrations before the fifth dose and ninth dose and 24 hours after the last dose. Most measured paracetamol blood concentrations were comparable to those recommended for pain and fever control (10 to 20 mg/ml) (Arana 2001).

In the most recently published case series, El‐Khuffash and co‐workers (El‐Khuffash 2014) retrospectively evaluated the clinical effectiveness of paracetamol on the closure of a PDA, and prospectively examined its effect on the in vitro term and preterm murine ductus arteriosus. A total of 21 infants were included in the study from the Mount Sinai Hospital, Toronto, Ontario, Canada and the Rotunda Maternity Maternity Hospital, Dublin, Ireland. At the Canadian site paracetamol was either given orally as a short course (15 mg/kg 6 hourly for 48 hours) or a long course of 15 mg/kg 6 hourly for 7 days. At the Irish site paracetamol was given intravenously, 15 mg/kg 6 hourly for a minimum of 48 hours until PDA closure was confirmed on echocardiography or up to a maximum of 6 days. In both centres, the decision to administer paracetamol treatment to neonates with a haemodynamically significant PDA was after failure of two courses of either ibuprofen or indomethacin or if there were contraindications to medical treatments (El‐Khuffash 2014). No changes in PDA haemodynamics were seen in the five infants treated with a short course of paracetamol. In six of the seven infants treated with a long course the PDA closed. In eight of the nine infants treated with intravenous paracetamol the PDA closed (El‐Khuffash 2014). Paracetamol drug levels were not ascertained. The authors concluded that the efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration (El‐Khuffash 2014). The inhibitory effect of paracetamol on prostaglandin E₂ (PGE₂) may not be present at lower gestational ages (El‐Khuffash 2014).

Recently there have been concerns raised that prenatal or neonatal exposure, or both, to paracetamol could have adverse effects on brain development. Viberg and co‐workers (Viberg 2014) examined whether neonatal paracetamol exposure in mice could affect the development of the brain, manifested as adult behaviour and cognitive deficits, as well as changes in the response to paracetamol. Ten day‐old mice were administered a single dose of paracetamol (30 mg/kg body weight) or repeated doses of paracetamol (30 + 30 mg/kg body weight, 4 hours apart). Concentrations of paracetamol and brain‐derived neurotrophic factor (BDNF) were measured in the neonatal brain and behavioural testing was done when animals reached adulthood. Acute neonatal exposure to paracetamol (2 x 30 mg) resulted in altered locomotor activity on exposure to a novel home cage arena and failure to acquire spatial learning in adulthood, without affecting thermal nociceptive responding or anxiety‐related behaviour. However, mice exposed to paracetamol (2 x 30 mg) as neonates failed to exhibit paracetamol‐induced antinociceptive and anxiogenic‐like behaviour in adulthood. The authors suggested that behavioural alterations in adulthood may, in part, be due to paracetamol‐induced changes in BDNF levels in key brain regions at a critical time during development. They concluded that in mice exposure to and presence of paracetamol during a critical period of brain development can induce long‐lasting effects on cognitive function and alter the adult response to paracetamol in mice (Viberg 2014).

In an ecological study conducted in humans and using country‐level data for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism or autism spectrum disorder (ASD) (Bauer 2013). To explore the relationship of early neonatal paracetamol exposure to autism and ASD, population weighted average male autism prevalence rates for all available countries and US states were compared to male circumcision rates, a procedure for which paracetamol has been widely prescribed since the mid‐1990s. For studies including boys born after 1995, there was a strong correlation between country‐level autism and ASD prevalence in males and a country's circumcision rate (r = 0.98) (Bauer 2013).

It is therefore of extreme importance that infants enrolled in trials of paracetamol either for pain relief or for closure of a PDA be followed long‐term with conventional developmental tests and tests to diagnose autism and ASD (American Psychiatric Association 2013).

Why it is important to do this review

Currently there are at least three ongoing trials on this topic (NCT01938261; NCT01291654; NCT02002741). It is likely that several trials will be conducted in the near future and, with regular updates, this review will track the progress of the research in a timely fashion. It is expected that paracetamol will be compared with oral or intravenous ibuprofen or intravenous indomethacin for the efficacy of closing a PDA. In view of recent findings in mice of adverse effects on brain development following neonatal exposure to paracetamol and an association of neonatal exposure to paracetamol and autism or ASD it is important that long‐term follow‐up is included in individual studies and in this systematic review.