Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third‐trimester paracetamol use: evaluation of the German Embryotox cohort

Abstract

A recent case series evaluated a potential link between paracetamol use during pregnancy and premature constriction or closure of the fetal ductus arteriosus (Allegaert et al. Br J Clin Pharmacol 2019;85:245-51). Criteria from the World Health Organization Uppsala Monitoring Centre causality assessment tool were applied, and in 15 of 25 cases, causality was classified as probable or certain, with another nine cases classified as possible. How should this information be interpreted clinically given that there are no denominators and attributable risk cannot be determined? Ultimately, what providers and patients want to know is, what amount of risk, if any, is present. Given how common paracetamol use is in pregnancy (Werler et al. Am J Obstet Gynecol. 2005;193(3,pt 1):771-7) and how rare premature closure of the fetal ductus arteriosus is (Enzensberger et al. 2012;31:1285-91), risk, if present, is likely extraordinarily low. Another important consideration is that it is possible that with tens of millions of exposures there could be a handful of clinical scenarios which, by pure chance, could have demonstrated clinical findings suggestive of an association between paracetamol exposure and the outcome.While these broad inferences from cross-sectional epidemiology provide reassurance, the study by Dathe et al. (BJOG 2019;126:1560-7) provides more focused evidence. Dathe et al. performed a cohort analysis with prospectively enrolled patients comparing first and second trimester paracetamol exposure to third trimester exposure. Evaluating 604 women with third trimester exposure and 1192 women with first and second trimester exposure, no increased risk was seen for a broad range of fetal and neonatal outcomes. Compared with other analgesia options including NSAIDs and opioids, these findings support the continued use of paracetamol as a first-line agent in pregnancy.Although the evidence from the current trial should be reassuring for patients and clinicians, future research is indicated. It is possible that there is a non-negligible risk for specific subpopulations including women who received relatively high doses of acetaminophen for prolonged periods during the third trimester. The case series by Allegart et al. included several women taking a much greater cumulative dose of acetaminophen than is typical during pregnancy. That acetaminophen is available over the counter precludes some study approaches; for example, examining payer data for pharmacy receipts and outcomes. Given the known risks of alternative drugs such as NSAIDs in the third trimester of pregnancy, this article adds support to the present recommendation that paracetamol should be the primary therapy for fever and pain during this gestational period. However, there remain limitations in our knowledge and therefore large or prolonged doses should be avoided if possible.

Acetaminophen in late pregnancy and potential for in utero closure of the ductus arteriosus—a pharmacokinetic evaluation and critical review of the literature

“…Patients who used acetaminophen in the third trimester of pregnancy (n¼604) showed no increased risk of premature closure of the DA compared with those who had only used it within only the first two trimesters of pregnancy (n¼1192), a control group selected to control for medical comorbidities that are the reason for analgesic use in pregnancy. 19 In this study, frequent or daily use in the third trimester of pregnancy was only recorded in 31 of 604 patients (5.1%), with most patients only using acetaminophen for a short term of 7 days (364 of 604 patients [60.3%]) and an unspecified number of exposure days in 154 of 604 patients (25.5%). The median last exposure to acetaminophen was 35 3/7 weeks' gestation (range, 32 0/7e38 4/ 7 weeks' gestation).…”

“…The only published study reporting a control group in a retrospective cohort did not find an association. 19 Appraisal of the pharmacokinetic and pharmacodynamic literature also supports that premature closure of the DA is an unlikely effect associated with prenatal acetaminophen use. Pharmacokinetic studies found that fetal levels are approximated from maternal levels, which range from 4.5 to 12.3 mg/L.…”

“…To date, 1 large prospective cohort study has evaluated the risk of premature closure of the DA with prenatal acetaminophen use. 19 This is the only study available that has a control group. Patients who used acetaminophen in the third trimester of pregnancy (n¼604) showed no increased risk of premature closure of the DA compared with those who had only used it within only the first two trimesters of pregnancy (n¼1192), a control group selected to control for medical comorbidities that are the reason for analgesic use in pregnancy.…”

“…The same article also identified cases reported to the Embryotox institute as suspected adverse drug reactions in pregnancy. 19 From the years 1994 to 2018, 96 retrospective reports with third-trimester paracetamol exposure were identified. Of these, only 3 cases reported adverse outcomes consistent with premature closure of the DA, in infants born at 41 weeks' gestation with right ventricular hypertrophy and primary pulmonary hypertension.…”

How to translate neuro-cognitive and behavioural outcome data in animals exposed to paracetamol to the human perinatal setting?

“…Furthermore, paracetamol also became one of the drugs used to treat (symptomatic) patent ductus arteriosus in preterm neonates [10]. Also, the association between maternal paracetamol use and fetal ductus arteriosus constriction or closure has more recently been reported, although this risk is difficult to quantify and is likely very low [11,12].…”