Long-Term Safety of Prenatal and Neonatal Exposure to Paracetamol: A Systematic Review

Abstract

Introduction: Paracetamol is the most commonly used antipyretic and analgesic in pregnancy. It is also increasingly used off-label in the neonatal intensive care unit. Despite the frequent use of paracetamol, concerns have been raised regarding the high variability in neonatal dosing regimens and the long-term safety of early life exposure. Objective: To investigate the available evidence on the long-term safety of prenatal and neonatal paracetamol exposure. Methods: We conducted a systematic search of the electronic databases Ovid Medline, Ovid Embase and Web of Science from inception to August 2021 for original research studies of any design that described the use of paracetamol in the prenatal or neonatal (within the first four weeks of life) periods and examined the occurrence of neurodevelopmental, atopic or reproductive adverse outcomes at or beyond birth. Results: We identified 1313 unique articles and included 30 studies in the final review. Of all studies, 27 (90%), two (7%) and one (3%) were on the long-term safety of prenatal, neonatal and both prenatal and neonatal exposure, respectively. Thirteen (46%), 11 (39%) and four (15%) studies examined neurodevelopmental, atopic and reproductive outcomes. Eleven (100%), 11 (100%), and three (27%) studies on prenatal exposure reported adverse neurodevelopmental, atopic and reproductive outcomes. Only one study found a possible correlation between neonatal paracetamol exposure and long-term adverse outcomes. Conclusions: The available evidence, although limited, suggests a possible association between prenatal paracetamol exposure and an increased risk of neurodevelopmental, atopic and reproductive adverse outcomes. There is an immediate need for robust data on the long-term safety of paracetamol exposure in the prenatal and neonatal periods.

Analysis of potential risks between acetaminophen and ibuprofen use during pregnancy via the FAERS database

“…23 Prenatal exposure to acetaminophen is associated with an increased risk of neurodevelopmental, preeclampsia, atopic, and reproductive adverse outcomes. 24,25 In addition to cryptorchidism, acetaminophen and ibuprofen use during pregnancy has also been associated with hypospadias and cerebral palsy in children. 26 A cohort study suggested that ibuprofen may consider an analgesic and antipyretic of choice in the rst trimester.…”

Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation

“…Although the median PNA of our population is 5 days, there are sufficient PCM observations to support the modeling and therefore dosing regimen until 30 days of PNA (71 PCM observations for PNA between 10–20 days and 52 observations for PNA between 20–30 days). It is important to note that the target concentration used in this study is based on limited efficacy and short-term safety studies in neonates [ 20 , 40 ], and there are still concerns regarding long term-safety of PCM for prenatal and neonatal use [ 41 ]. In addition, the high concentration of PCM-sulfate in the most immature neonates may be of concern, as studies have reported the depletion of sulfated sex hormones after using paracetamol [ 41 , 42 ].…”

“…It is important to note that the target concentration used in this study is based on limited efficacy and short-term safety studies in neonates [ 20 , 40 ], and there are still concerns regarding long term-safety of PCM for prenatal and neonatal use [ 41 ]. In addition, the high concentration of PCM-sulfate in the most immature neonates may be of concern, as studies have reported the depletion of sulfated sex hormones after using paracetamol [ 41 , 42 ].…”

Acetaminophen causes neurodevelopmental injury in susceptible babies and children: no valid rationale for controversy

“…Evidence points conclusively to the induction of autism spectrum disorder (ASD) with possible connections to both developmental delay and attention deficits [ 2 ]. Furthermore, evidence points toward exposure between birth and approximately 5 years of age as the period of highest risk, with the risk during prenatal exposure being significant in numerous studies [ 4 ] albeit less consequential [ 2 , 3 ]. Much of this evidence has recently been reviewed in detail elsewhere [ 2 , 3 ].…”