Acetaminophen to Prevent Symptomatic PDA: Another Drug Bites the Dust?

The attitude of neonatal medicine specialists towards the treatment of a patent ductus arteriosus (PDA) has changed dramatically over the years, resulting in multiple pro/con debates regarding “to treat or not to treat a PDA” at major scientific meetings across the globe. The current approach has shifted from aggressively closing all PDAs by using indomethacin or ibuprofen to careful watching of ductal shunting while awaiting spontaneous closure, that is, virtually withholding therapeutic intervention in all neonates with a PDA except in the few neonates who are hemodynamically severely jeopardized.

This shift in approach has been based on a lack of evidence to continue the once-common practice of early aggressive pharmacologic closure in combination with the serious side effects of the drugs, such as indomethacin and ibuprofen, used for closure. These side effects include altered platelet function, decreased cerebral, mesenteric, and renal blood flow resulting in diminished renal function, and gastrointestinal perforation.

In the case of using these same drugs to prevent the appearance of a PDA, the most recent systematic reviews have shown that prophylactic indomethacin has short-term benefits for preterm infants, including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular hemorrhage.1 There is currently no evidence, however, to support decreased mortality and/or improved neurodevelopmental outcome. Prophylactic use of ibuprofen decreased the incidence of PDA and also the need for surgical closure. In the control group, however, the PDA closed spontaneously by day 3 in 58% of the neonates. On the basis of this finding, it was concluded that prophylactic treatment exposes many infants to a treatment that has concerning renal and gastrointestinal side effects, as mentioned previously, without providing any important short-term benefits and, as such, should not be recommended.2 Finally, the authors of this review stated that no further trials of prophylactic ibuprofen are indicated nor recommended.

In other words there is currently, on the basis of the available scientific data, no indication for the prophylactic use of either indomethacin or ibuprofen in preterm infants that might develop a hemodynamically important PDA.

Another Drug, Another Opportunity

The recent availability of intravenous acetaminophen in many parts of the world has resulted in a dramatic increase of the use of this drug in neonates, infants, and children. In neonates and infants undergoing major noncardiac surgery, it was shown that the use of intravenous acetaminophen significantly decreased the amount of morphine needed to treat their pain.3 Furthermore Härmä et al4 showed that the use of intravenous acetaminophen also decreased the use of morphine in very preterm infants.

It was clearly only a matter of time before intravenous acetaminophen was used for closure of a PDA with the idea that, if effective, this drug might have fewer side effects compared with indomethacin and/or ibuprofen. The authors of a very recent systematic review, however, concluded that long-term follow-up to at least 18-24 months' postnatal age should be part of any studies of acetaminophen used for closure of a PDA.5 Moreover, the authors of that Cochrane review underscored that without these kinds of trials, no single recommendation can be made for the use of acetaminophen in the neonate.

As such, the report by Härkin et al6 in this volume of The Journal is extremely timely and might help in the discussion of whether the use of intravenous acetaminophen in preterm infants to prevent the appearance of a PDA already is justified on the basis of our current knowledge. The authors found in their small but prospective, placebo-controlled randomized trial that prophylactic use of acetaminophen resulted in more early closure of the ductus arteriosus compared with the placebo group. Furthermore, no adverse events were detected. Wisely, the authors advised to conduct further trials to determine whether the use of acetaminophen for this purpose is indeed safe.

The Good, the Bad, and the Ugly

Attempts to investigate therapeutic interventions with drugs that might be effective with fewer side effects than currently available treatments begin with good intentions. To assure that these good intentions will indeed improve the care of our patients, it is important to consider the rationale behind our studies, the dose or dosing regimen of the drug selected for our interventions, the short-term pros (efficacy) and cons (side effects) of the therapy, and, most importantly, the long-term outcomes of our patients.

The rationale for using intravenous acetaminophen to prevent a symptomatic PDA is driven by the available information on the use of ibuprofen and indomethacin as outlined in this article and the potential for fewer side effects from acetaminophen compared with indomethacin/ibuprofen. The question is whether that provides sufficient rationale to expose neonates to this drug if other interventions have never shown convincing long-term benefit.

The next step will be to determine the dosing regimen for acetaminophen for the prevention of a symptomatic ductus arteriosus. Fortunately, there is already a lot of information on the pharmacokinetics of acetaminophen in preterm infants with a gestational age of more than 28 weeks and even for those with a gestational age between 24 and 28 weeks.7, 8, 9 These data, however, are based on studies in which the authors investigated the effect of acetaminophen on pain relief. Unfortunately, there are no pharmacokinetic-pharmacodynamic studies on the use of acetaminophen for the prevention of a PDA. As such, it is questionable if the use of the same dosing regimen for treating neonatal pain might be the best to use for prevention of a PDA.

The short-term pros and cons of the use of acetaminophen in prevention of a PDA in a very small group of preterm infants seem favorable as reported by Härkin et al,6 but clearly the jury is still out based on the limitations of the current investigation. What about the long-term benefit? On the basis of the mechanism of action, it does not seem plausible that the use of intravenous acetaminophen will result in better effects compared with the use of indomethacin or ibuprofen for the same indication.

Finally, what about the perceived superior safety of acetaminophen compared with indomethacin and ibuprofen? Unfortunately, reports have emerged questioning the perceived superior safety of the use of acetaminophen in these young patients. There are reports on the link between acetaminophen use during pregnancy or in early neonatal life and neurocognitive impairment, including attention deficit/hyperactivity disorder symptoms at ages 7 and 11 years or autism spectrum disorder.10, 11 Furthermore, in mice, the presence of acetaminophen during a critical period of brain development induced long-lasting effects on cognitive function.12 The same research group recently showed that the developmental neurotoxicity of acetaminophen is noncyclooxygenase-mediated because exposure to ibuprofen did not produce these cognitive effects.13

In summary, the need to prevent a symptomatic PDA remains under debate. As such, there is a need to improve communication between neonatologists, pharmaceutical industry, parents, and regulators to assure that the rationale, optimal dosing regimen, and short- and long-term safety and efficacy measures of any drug-related intervention in this vulnerable population are considered fully before these studies are initiated. Neonates are the last therapeutic orphans, and there is a huge opportunity to improve the current situation. One of the most recent initiatives that will be of great support of these efforts is the International Neonatal Consortium, an initiative led by the Critical Path Institute.14

(van den Anker JN, Allegaert K. J Pediatr. 2016 Oct;177:7-9)



1-Fowlie, P.W., Davis, P.G., and McGuire, W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010; (CD000174)

2-Ohlsson, A. and Shah, S.S. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2011; (CD004213)

3-Ceelie, I., de Wildt, S.N., van Dijk, M., van den Bergh, M., van den Bosch, G., Duivenvoorden, H.J. et al. Effects of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery. JAMA. 2013; 309: 149–154

4-Härmä, A., Aikio, O., Hallman, M., and Saarela, T. Intravenous paracetamol decreases requirements of morphine in very preterm infants. J Pediatr. 2016; 168: 36–40

5-Ohlsson, A. and Shah, P.S. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm of low-birth-weight infants. Cochrane Database Syst Rev. 2015; (CD010061)

6-Härkin, P., Härmä, A., Aikio, O., Valkama, M., Leskinen, M., Saarela, T. et al. Paracetamol accelerates closure of the ductus arteriosus after premature birth: a randomized trial. J Pediatr. 2016; 177: 72–77

7-Allegaert, K., Palmer, G.M., and Anderson, B.J. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child. 2011; 96: 575–580

8-Cook, S., Roberts, J., Samiee-Zafarghandy, S., Stockmann, C., King, A., Deutsch, N. et al. Population pharmacokinetics of intravenous paracetamol (acetaminophen) in preterm and term neonates: model development and external evaluation. Clin Pharmacokinet. 2016; 55: 107–119

9-Cook, S., Stockmann, C., Samiee-Zafarghandy, S., King, A., Deutsch, N., Williams, E. et al. Neonatal maturation of paracetamol (acetaminophen) glucuronidation, sulphation, and oxidation based on a parent-metabolite population pharmacokinetic model. Clin Pharmacokinet. 2016; DOI: (Epub 21 May 2016)

10-Liew, Z., Ritz, B., Rebordosa, C., Lee, P.C., and Olsen, J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014; 168: 313–320

11-Cooper, M., Langley, K., and Thapar, A. Antenatal acetaminophen use and attention-deficit/hyperactivity disorder: an interesting observed association but too early to infer causality. JAMA Pediatr. 2014; 168: 306–307

12-Viberg, H., Eriksson, P., Gordh, T., and Frederiksson, A. Paracetamol (acetaminophen) administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice. Toxicol Sci. 2014; 138: 139–147

13-Phillippot, G., Nyberg, F., Gordh, T., Frederiksson, A., and Viberg, H. Short-term exposure and long-term consequences of neonatal exposure to Δ(9)-tetrahydrocannabinol (THC) and ibuprofen in mice. Behav Brain Res. 2016; 307: 137–144

14-Davis, J.M. and Turner, M.A. Global collaboration to develop new and exciting drugs for neonates. JAMA Pediatr. 2015; 169: 887–888