On 23 September 2021, researchers from USA, Sweden, Brazil, Denmark, Scotland and France published in Nature Reviews Endocrinology, a new Consensus Statement which calls for precautionary action around the use of paracetamol in pregnancy, through focused research and by increasing awareness. This statement reflects the concerns and is currently supported by 91 scientists, clinicians and public health professionals from these countries.

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The researchers noted that paracetamol (N-acetyl-para-aminophenol (APAP), which is also known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever.

While conceding that this drug is an important medication and alternatives for the treatment of high fever and severe pain are limited, they "recommend that pregnant women should be cautioned at the beginning of pregnancy to forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether the use is indicated and before using on a long-term basis, and minimise exposure by using the lowest effective dose for the shortest possible time."

The researchers noted that a growing body of experimental and epidemiological research suggests that prenatal exposure to the drug might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders.

"As scientists, medical experts and public health professionals, we are concerned about increasing rates of neurological, urogenital and reproductive disorders. We are witnessing disturbing increases in the number of children with cognitive, learning and/or behavioural problems," they said.

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Developmental disability data

They revealed that the US National Health Interview Survey reported that between 2009 and 2017, approximately one in six children aged 3–17 years had a developmental disability diagnosis. They observed a 9.5% increase in the overall rate of developmental disabilities between 2009–2011 and 2015–2017.

The researchers disclosed that in Western regions the prevalence of male reproductive and urogenital disorders has increased. These disorders include cryptorchidism (a condition in which one or both of the testes fail to descend from the abdomen into the scrotum), hypospadias (a birth defect in boys in which the opening of the urethra is not located at the tip of the penis) and testicular germ cell cancer, together with early puberty, decreased sperm counts and levels of sex hormones, and decreased fertility.

"Data support the contribution of environmental exposure during fetal life, including exposure to pharmaceuticals, to this increase in rates of neurological, urogenital and reproductive disorders," they clarified.

In the statement, they summarised the epidemiological research and animal studies that have examined neurological, urogenital and reproductive outcomes that have been associated with maternal and perinatal use of APAP.

This research, led them to believe that they know enough to be concerned about the potential developmental risks associated with prenatal APAP exposure and therefore call for precautionary action.

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Other related observations

APAP is one of the most commonly used medications globally. For instance, in the USA, 65% of pregnant women are estimated to use APAP. Worldwide, more than 50% of pregnant women are estimated to use APAP.

APAP has long been considered an option by regulatory bodies such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in pregnancy for pain and fever when used as directed, as NSAIDs are contraindicated for use in pregnant women in later pregnancy.

Pharmacotherapy during pregnancy involves a benefit–risk assessment, in which there is a trade‐off between the potential benefits to the mother and fetus and possible risks to the fetus.

The researchers recall that FDA formerly gave APAP a ‘B’ rating for use in pregnancy in all three trimesters, meaning that animal studies have failed to demonstrate any risks of congenital birth defects from fetal exposure and that researchers have not performed adequate and well-controlled studies in pregnant women. In addition, the EMA has found epidemiological data inconclusive and that experimental data do not meet their standards.

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Study methods

The international group of experts in the present study, included clinicians (specialising in neurology, obstetrics and gynaecology, and paediatrics), epidemiologists and basic scientists (specialising in toxicology, endocrinology, reproductive medicine and neurodevelopment). They developed the statement independently of specific societies and colleges by the 13 authors.

Two researchers comprehensively reviewed both the experimental and epidemiological literature in English available on PubMed published between 1 January 1995 and 25 October 2020 using 11 relevant key words. They included only studies that investigated APAP as an independent exposure. The authors have described the process of review and the transparent way they arrived at the consensus statement approved by all the seventy-eight signees and 13 authors. The final statement considered differing international perspectives, prescribing practices and clinical considerations.

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Review of epidemiological studies.

The human epidemiological studies summarised by the researchers suggest that prenatal APAP exposure might confer an increased risk of cryptorchidism and/or reduced anogenital distance in boys and neurodevelopmental disorders in girls and boys, primarily attention deficit hyperactivity disorder.

While agreeing that these studies have limitations, including potential confounding and exposure or outcome misclassification, they pointed out that experimental studies in animal and in vitro models supported their observations. "Owing to differences in size and physiology between humans and model systems, further human studies should be carried out before any firm conclusions can be drawn," the researchers clarified.

They summarised the evidence from epidemiological studies and called for precautionary action through a focused research effort. The researchers conceded that although this Consensus Statement calls for caution, APAP is still the safest available drug to treat pain and fever in pregnant people.

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Response from the American College of Obstetricians and Gynecologists (ACOG)

On 29 September the ACOG responded thus:

"ACOG and obstetrician-gynaecologists across the country have always identified acetaminophen as one of the only safe pain relievers for pregnant individuals during pregnancy. This consensus statement, and studies that have been conducted in the past, show no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues."

"Neurodevelopmental disorders, in particular, are multifactorial and very difficult to associate with a singular cause. The brain does not stop developing until at least 15 months of age, which leaves room for children to be exposed to a number of factors that could potentially lead to these issues. The authors are not recommending anything counter to what is already done by obstetrician-gynaecologists when prescribing acetaminophen for a given clinical condition."

The ACOG asserted that ACOG’s clinical guidance remains the same and physicians should not change clinical practice until definitive prospective research is done.

The organisation cautioned:

"Most importantly, patients should not be frightened away from the many benefits of acetaminophen. However, as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the pregnant patient has consulted with their doctor", the organization cautioned the physicians.

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Expert comments

In a press release published by the Science Media Centre on 23 September 2021, Prof Andrew Shennan, Professor of Obstetrics, King’s College London, noted that this consensus statement from the researchers is a balanced view of the potential risk/benefit of paracetamol in pregnancy.

"They point out that treating pain and fever could reduce pregnancy risks, and alternatives to paracetamol have got evidence of harm. The evidence that paracetamol is harmful is not strong but observations in humans regarding possible developmental issues are supported by animal studies." he cautioned

He added, “It is always important to take medication in pregnancy with specialist advice. A good principle is to only use medications with a proven track record of both efficacy and safety. Paracetamol is one of those drugs that can be safely used. Like with many medications, excessive use when not indicated is not justified in case there are unknown harmful effects at higher doses, as get undiscovered. The baby is fully formed by 10 weeks of pregnancy and it is unlikely a drug will cause significant harm in fetal development after this point."

Prof Shennan concluded, “Prudent surveillance and more research should continue but paracetamol can be used to treat pain and fevers in pregnancy.” Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said, “Avoidance of unnecessary drugs is to be encouraged at all times, and most pregnant women are aware of this. At the same time raising anxiety about their unborn child is often itself unnecessary and has obvious adverse consequences."

Professor Evans felt that this paper and the consensus statement could be used to raise anxiety, almost undoubtedly unnecessarily. He said, “The larger epidemiological studies tended to find no adverse effect of the mother taking paracetamol on the child. Those that do find some apparent effects are inconsistent, so their findings may be due to chance or bias. It is clear that paracetamol usage is extremely common and, as with all medicines able to be bought without a prescription, studying their effects is hard to do and hence can be subject to a number of biases."

He said, “It might be reasonable to suggest that regulatory authorities re-examine the issues, but it is not a message for current or prospective pregnant mothers. The usage of all non-prescription analgesics or non-steroidal anti-inflammatory drugs is very high indeed, including among pregnant women. There is no obvious drug that could be suggested as an alternative to paracetamol, so this is not very helpful. There is no epidemic of malformations that might be caused by paracetamol. Animal studies can be helpful but are not necessarily good predictors of effects in humans."

As the authors say “indiscriminate use” is to be discouraged (as with any drug) but raising anxiety should also be discouraged. I sent the critical views of Professor Evans to Dr David M Kristensen, a senior author of the paper for his response. He did not respond.

Based on their extensive review, the researchers recommended specific actions to implement the goals of raising awareness amongst patients and healthcare providers.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.