Paracetamol use in pregnancy: Not as safe as we may think?

Abstract

Paracetamol is used by more than 50% of women worldwide during pregnancy; headache representing the most frequent indication. Several studies report that long‐term exposure to paracetamol in utero is associated with adverse neurodevelopmental outcomes in children, indicating a dose–response effect. However, less or no risk is found to be associated with short‐term exposure. Paracetamol most likely crosses the placenta through passive diffusion, and there are several possible mechanisms for how paracetamol might affect fetal brain development. Although the literature suggests an association between prenatal paracetamol exposure and neurodevelopmental outcomes, the role of confounders cannot be ruled out. Consequently, as a precaution, we believe that pregnant women should be recommended ideally to only use paracetamol to treat conditions that might harm the fetus, such as severe pain or a high fever. This Comment aims to put focus on the potential fetal risks of paracetamol exposure in utero.

Abbreviations

ADHD

attention deficit/hyperactivity disorder

ASD

autism spectrum disorder

MoBa

mother, father and child cohort study

Key message.

Long‐term prenatal paracetamol exposure is associated with adverse neurodevelopmental outcomes in children in some studies. Pregnant women and their caretakers should have a precautionary approach to paracetamol use and only use it to treat conditions that might harm the fetus.

1. INTRODUCTION

In this Comment we summarize existing literature with the aim of highlighting paracetamol use during pregnancy and potential fetal risks. The use of paracetamol during pregnancy is quite common. It is estimated that more than 65% of women in the USA, more than 50% in Europe, and 61.5% in northern Europe use paracetamol during pregnancy. ¹ , ² Paracetamol is an over‐the‐counter drug and is therefore easily accessible. Paracetamol is a recommended antipyretic and analgesic for use during pregnancy when used at the lowest effective dose and for the shortest possible time. ³ Several studies have found an association between paracetamol exposure in utero and neurodevelopmental outcomes in offspring. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ However, there have also been a few studies reporting an inconsistent relation between prenatal paracetamol exposure and adverse neurodevelopmental outcomes in children. ¹⁷ , ¹⁸ , ¹⁹ Based on recent studies, this has led researchers to recommend a precautionary approach to paracetamol use during pregnancy. ²⁰ , ²¹

2. INDICATION AND PREVALENCE OF PARACETAMOL USE

Left untreated, a high fever or severe pain might adversely affect the fetus or the mother, and paracetamol is the recommended treatment. ²² In the USA and Canada, the most frequent reported indications for paracetamol use during pregnancy have been found to be headaches (50%), pain (19%), cold/flu (17%), fever (8%), and sleep problems (1%). ²³ In Norway, Brandlistuen et al ⁴ have reported similar findings, where the most common indication for long‐term paracetamol use (for more than 20 days during pregnancy) in the Norwegian Mother, Father and Child Cohort study (MoBa) was headache/migraine (63%), fever (20%), pain (20%), or cold/flu (12%). The largest discrepancy between these studies is the higher rate of paracetamol use for fever in the MoBa study.

As reviewed by Bauer et al, ²² studies have suggested that paracetamol has limited efficacy against headaches, and that those who suffer from migraines might have fewer migraine days by reducing the use of analgesics, which includes paracetamol. There is also little evidence for the efficacy of paracetamol in chronic pain, lower back pain, or in treating influenza symptoms.

3. BIOMARKERS AS A MEASURE FOR PRENATAL PARACETAMOL EXPOSURE

Most studies rely on self‐reported use of paracetamol. Some recent studies have also used biomarkers to measure prenatal paracetamol exposure ⁵ , ⁶ , ⁷ , ⁸ , ⁹ and found an association between prenatal paracetamol exposure and adverse neurodevelopmental outcomes. In a MoBa study, Gervin et al ⁵ found differences in DNA methylation measured in cord blood from children with attention deficit/hyperactivity disorder (ADHD) exposed in utero to long‐term (>20 days) maternal paracetamol use compared with children unexposed to paracetamol with ADHD. The cord blood DNA methylation differences in paracetamol‐exposed pregnancies were found in genes that are involved in oxidative stress, neural transmission pathways, and olfactory sensory pathways. ⁵ Likewise, studies based on the Boston Birth Cohort have found levels of paracetamol metabolites in umbilical cord to be associated with an increased risk for ADHD and autism spectrum disorder (ASD). ⁷ In another study, Ji et al ⁶ examined maternal plasma from 1–3 days postpartum and found a significant association between maternal biomarkers for paracetamol use and increased risk for ADHD in the offspring, but not for other neurodevelopmental disorders. In a 2020 prospective birth cohort study from Canada, ⁸ a positive association between prenatal paracetamol exposure measured in newborn meconium and ADHD in children aged 6 and 7 years was found. The offspring exposed to prenatal paracetamol had an approximately more than twofold increased odds of ADHD, compared with those without paracetamol in the meconium. The same child cohort was investigated with a resting‐state magnetic resonance imaging at age 9–11 years. The prenatal paracetamol exposure was found to be associated with increased negative connectivity in the frontoparietal network and the right precentral/frontal gyrus. The latter results were correlated with hyperactivity and behavioral problems. Furthermore, these four studies found a dose–response effect of paracetamol exposure in utero.

4. DURATION OF PARACETAMOL EXPOSURE IN UTERO

Several studies have investigated the association between duration of paracetamol exposure in utero and adverse neurodevelopmental outcomes in offspring. Long‐term prenatal paracetamol exposure is often classified as paracetamol use more than 20–30 days, ⁴ , ⁵ , ¹³ , ¹⁶ and several studies reported that long‐term paracetamol exposure in utero was associated with higher risk of adverse offspring outcomes. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ However, less or no risk was associated with short‐term exposure. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹³ , ¹⁶ In 2021, a sibling–control study ¹⁶ found that long‐term prenatal paracetamol exposure was associated with a twofold increase in risk for ADHD, but no such association was found for short‐term use. This indicates a dose–response effect between paracetamol exposure in utero and potential adverse neurodevelopmental outcomes.

5. TRANSFER OF PARACETAMOL ACROSS THE PLACENTA AND THE BLOOD–BRAIN BARRIER

Paracetamol is known to rapidly cross the placenta and the blood–brain barrier. ²⁴ , ²⁵ Placental transfer of paracetamol is most likely through passive diffusion. It is flow‐limited and not permeability limited, and there is little evidence that drug transporters in placenta are involved in paracetamol transfer. ²⁶ During pregnancy there is a major increase in paracetamol clearance. Consequently, it is reasonable to expect that the therapeutic effect of paracetamol will decrease faster during pregnancy, and that higher doses will be needed to achieve the desired maternal effects. Higher doses might however be unsafe, as they lead to an increase in oxidative toxic metabolites. ²⁵

A recent study in rodents ²⁷ investigated the effect of paracetamol on the placenta by using RNA sequencing. For paracetamol to reach the fetal brain it must first cross the placenta and then the fetal blood–brain barrier. ²⁷ The latter study suggests that exposure to paracetamol induces an inflammatory response in the placenta, but only on the fetal side. An increased placental permeability was only seen from fetus to mother, and there was no evidence of an altered permeability in the fetal blood–brain barrier. ²⁷ These results indicate that responses to paracetamol exposure during pregnancy seem to be tissue‐specific and dependent on the duration of paracetamol exposure. ²⁷ In pregnant rats, long‐term exposure (5 days) to paracetamol, which corresponds to approximately one‐third of gestation, led to a much smaller concentration reaching the maternal brain (21%), than the fetal brain (45%). ²⁸ A single acute treatment with paracetamol in these animals led to similar amounts reaching the maternal and fetal brains (30% and 28%, respectively). If this is transferrable to humans, then the consequence is that the pregnant mother experiences less effect of paracetamol treatment, but the fetal brain is exposed to an increased concentration of paracetamol during its development.

6. POSSIBLE MECHANISMS FOR HOW PARACETAMOL CAN AFFECT NEURODEVELOPMENT

There are several possible mechanisms for how paracetamol might affect neurodevelopment, as reviewed in Bauer et al ²⁵ and Nilsen. ²⁹ One potential mechanism for paracetamol to disrupt neurodevelopment is through inhibition of prostaglandin synthesis. Prostaglandins have important and diverse roles in the brain, including spatial learning and synaptic plasticity, cerebellar development, and long‐term potentiation. Another possible way is for paracetamol to act on the endocannabinoid system. Alterations of the endocannabinoid system have been found in both the brain and immune system of humans with ASD. The endocannabinoid system has a crucial role in the development of the nervous system. The cannabinoid receptor 1 is of great consequence for neuron differentiation, neural migration, and establishment of neuronal connectivity, and interference with this system during critical times is suggested to adversely affect brain development. The cannabinoid receptor 2 first and foremost has a role in regulation of the immune system.

There might be two processes that together trigger neurodevelopmental outcomes from paracetamol exposure in utero: (1) maternal immune activation induced by illness, which leads to paracetamol use, and (2) the mechanisms of paracetamol itself. This concept is consistent with the idea that the pathophysiological mechanisms of ADHD and ASD are multifactorial, and such adverse neurodevelopmental outcomes may be caused by a combination of genetic and environmental factors. Maternal immune activation manifests as activation of inflammatory pathway genes in the placenta, production of maternal immunoglobulin G that are reactive against fetal proteins, and a change in the pro‐ and/or anti‐inflammatory maternal cytokines. All of these can affect the fetus adversely and can induce long‐lasting changes in the fetal immune and endocrine systems, the gut microbiota, and brain development. Combined, this can lead to altered neurodevelopment in the fetus.

Maternal immune activation activation is also suggested to alter fetal brain development. ³⁰ A mouse study showed that elevation of interleukin‐6 (IL‐6) levels induced by maternal immune activation caused changes in offspring behavior and brain gene expression. ³⁰ The mechanisms include activation of the maternal immune system, causing elevated IL‐6 levels. The latter leads to activation of endogenous immune cells in the maternal endometrium in pregnancy (named decidua), that start producing more IL‐6, which leads to activation of the Janus kinase/signal transducer and activator of transcription STAT3 pathways, expression of acute phase proteins, and a downregulation of placental growth hormone. Combined, these maternal immune activation‐induced IL‐6 effects on the placenta represent possible indirect ways for maternal immune activation to alter fetal brain development. ³⁰

Another potential mechanism is that paracetamol use increases the predisposition for oxidative stress and inflammation, disrupting normal development of microglia and their interaction with neurons. Changes in microglia development can have long‐term effects on brain connectivity and behavior. In a previously mentioned MoBa study, changes in DNA methylation in cord blood from children exposed to paracetamol in utero were found in genes that are involved in oxidative stress and neural transmission pathways. ⁵

Paracetamol is known to have endocrine disrupting properties, altering hormones that are critical for fetal development. ³¹ The placenta mediates maternal–fetal interactions and is also an endocrine organ that produces hormones required for maintenance of pregnancy and fetal development. ²⁴ , ³¹ Previous studies in humans and rodents have shown that a variety of maternal exposures, including medications and endocrine disrupting compounds, induces several alterations in placental physiology, including epigenetic modifications, changes in gene expression, and hormone synthesis. ³¹ A 2019 study found an association between prenatal paracetamol use and DNA methylation changes in the human placenta, ²⁴ indicating that the placenta might be a target for paracetamol‐induced toxicity during fetal development. ³¹ Disruption of the fetal placental steroid hormone synthesis might lead to changes in fetal development. The placenta synthesizes two key proteins, estrogen and progesterone. Estrogen is crucial in pregnancy maintenance and fetal development, and estradiol is important for the development of reproductive organs and the fetal brain. ³¹ Therefore, disruption of estrogen or estradiol during pregnancy might lead to adverse outcomes. Estradiol influences the developing brain in terms of masculinization of neural pathways, neurodevelopment, and sex‐specific behaviors; these effects are generally permanent. ³¹ Studies have found an association between estrogen disruption during fetal development and neurodevelopmental disorders such as ADHD and ASD. ³¹ A recent study, ³¹ found that paracetamol changed the expression of several genes in the human placenta, especially those involved in steroidogenesis, and reduced estradiol levels in placental cells in a dose‐dependent manner. ³¹ Furthermore, these results indicate that paracetamol might disrupt levels of hormones that are critical for both fetal development and maintenance of pregnancy, representing a plausible mediator between prenatal paracetamol exposure and adverse offspring health outcomes.

7. CONCLUSION

The literature suggests a potential effect of paracetamol on the fetal brain, and some studies find an association between long‐term prenatal paracetamol exposure and neurodevelopmental outcomes, including higher risk of ADHD and ASD. This field has gained a lot of attention with a number of studies being published recently. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²³ However, it is important to emphasize that others claim the results are weak, inconsistent, and with methodological limitations. ²¹ , ³²

Furthermore, a causal relation between paracetamol exposure in utero and neurodevelopmental outcomes has not been confirmed. Confounding by unmeasured factors cannot be ruled out as a possible explanation for the association reported in several studies. The sibling–control study ¹⁶ found that children of mothers with long‐term use in any pregnancy had increased risk of receiving an ADHD diagnosis. This indicated that the observed association between long‐term paracetamol use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors.

The prevalence of paracetamol use during pregnancy is quite high and there are several indications for its use. Our opinion is, while we wait for more evidence that may further corroborate a causal relation between prenatal paracetamol exposure and adverse neurodevelopmental outcomes in offspring, pregnant women should ideally only use paracetamol to treat conditions that might harm the fetus, such as severe pain or a high fever.

AUTHOR CONTRIBUTIONS

KN drafted the manuscript and ACF and SKK revised it critically for important intellectual content. All authors contributed substantially to the work and revisions, and gave final approval for its publication.

CONFLICT OF INTEREST STATEMENT

The authors have of no conflict of interest to declare.

Nilsen K, Staff AC, Krogsrud SK. Paracetamol use in pregnancy: Not as safe as we may think? Acta Obstet Gynecol Scand. 2023;102:652‐656. doi: 10.1111/aogs.14557