In September 2021, a group of scientists issued what they named a “Consensus Statement” on the use of the pain reliever and fever reducer acetaminophen during pregnancy.
The statement, which was published in Nature Reviews Endocrinology, has been supported by 91 scientists, clinicians, and public health professionals. It reads in part:
“A growing body of experimental and epidemiological research suggests that prenatal exposure to paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) might alter fetal development, which could in turn increase the risks of certain neurodevelopmental reproductive and urogenital disorders [including Autism Spectrum Disorders and ADHD].”
This statement will not be taken lightly by a mother who took acetaminophen for fever or pain while pregnant, especially the mother of a child with a neurodevelopmental disorder. She may have even called her physician at the time and was told to go ahead and take it, especially in a case of fever which can lead to dangerous complications for unborn children.
That mother did everything right. But now, racked with guilt, she worries that her child’s health challenges were caused by the choices she made. Eventually that guilt might turn to anger, and she might even join a lawsuit against the manufacturers and sellers of acetaminophen.
There’s just one problem: sound science has not reached the same conclusion as the group who signed the Consensus Statement.
In fact, Nature Reviews Endocrinology has since published three rebuttals by additional groups and scientists that discuss the problems with the science in the Consensus Statement. The first rebuttal, contributed by 13 scientists, lists several reasons for caution. Among them:
- The Consensus Statement makes clinical conclusions using data from which causality cannot be effortlessly inferred.
- Many of the studies referenced within it used unvalidated outcome measurements, for example, parent or teacher-filled questionnaires on Likert scales that were not created or validated for the purpose and context in which they were used.
- It fails to account for a significant potential confounder: the hereditary aspects of autism spectrum disorders (ASD), neurodevelopment, and ADHD.
- It appears to favor studies that confirm the pre-existing beliefs of the authors regardless of the quality of the evidence (also known as “confirmation bias”). For example, there is an uncritical appraisal of a study from the Boston Birth Cohort, was given a great deal of weight by the Consensus authors to determine acetaminophen exposure using umbilical cord plasma concentrations (and then correlating exposure levels with childhood ADHD, ASD, and other neurodevelopmental diagnoses). The rebuttal authors believe that both the external and internal validity of this study are compromised—as acetaminophen or its metabolites were found in every one of the umbilical cord samples. Among the study children, a surprisingly large proportion were diagnosed with ADHD or ASD (37%). Only 33% of children had no “developmental disability” diagnosis.
The second rebuttal, offered by 50 scientists, clinicians, epidemiologists, and specialists who are affiliated with the Organization of Teratology Information Specialists and other partner groups, completed its own review of the literature and concluded the following:
- The studies used in the Statement are limited by serious methodological problems, such as potential differential exposure and misclassification of the timing, dose, and duration of the use of acetaminophen during pregnancy, as well as possible confusion with other pain-relief medications, which could lead to an over-estimation of the true effect.
- It fails to account for a potential confounder: Pregnant women also use acetaminophen to treat migraines or fever, both of which have been associated with adverse effects on fetal neurological development.
- It did not consider the potential for genetic susceptibility to neurodevelopmental and psychiatric conditions passed from parent to child.
And the third rebuttal, signed by 16 organizations and 63 individual researchers and clinicians, added the following insights:
- There is a tendency to make direct fetal risks the priority and to overlook other risks, especially to mothers.
- The Consensus Statement claims 65% of pregnant women report taking acetaminophen, but doesn’t say anything about typical use. It admits that timing and duration are likely essential factors, with evidence suggesting that exposure for more than two weeks in the late first or second trimester might be important. The rebuttal authors cite a 2020 survey which reported that half of women taking acetaminophen in pregnancy only do so for less than three days.
- Reports on the dangers of established medications might create problems in accepting new therapies, including vaccines, potentially increasing hesitancy during pregnancy.
Many high-level groups in the U.S. continue to support the safety of acetaminophen when used as directed, including the FDA, the American College of Obstetrics and Gynecology, the Society for Maternal and Fetal Medicine, and the Organization of Teratology Information Specialists.
The American College of Obstetrics and Gynecology states on its website:
“ACOG and obstetrician-gynecologists 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 Consensus Statement is far from achieving scientific consensus. However, there’s one thing all three rebuttal groups, as well as others, have agreed on: the need for more research.
Observational studies are not designed for (nor meant to be used in) establishing causality. The value of such studies lies in their ability to point out associations that should be considered when designing studies that will begin to establish cause.
Certainly the confounding factors listed in the current literature, such as the underlying fevers and pains experienced by the mothers, are one place to look for causal relationships. Also, the fact that the women in the studies who took the pain reliever drug for the longest duration of time were more likely to have diagnosed anxiety or depression needs to be followed up on.
Epidemiologists, risk analysts, teratologists, and others should work together to establish good, sound, causal research studies and convince funding agencies of the importance in conducting them. While this takes time, the end result will be product and policy decisions based on sound science rather than the all-too-familiar race to the courtroom to sue for damages.
Pregnant women and their unborn babies need safe treatment options for fever and pain. The evidence presented in the Consensus Statement is not sufficient to change the current clinical best practices for medical professionals.
As the American College of Obstetrics and Gynecology concludes:
“The authors [of the Consensus Statement] are not recommending anything counter to what is already done by obstetrician-gynecologists when prescribing acetaminophen for a given clinical condition. ACOG’s clinical guidance remains the same and physicians should not change clinical practice until definitive prospective research is done.”
“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.”
Needlessly scaring women who have used it in the past will not do any families any favors—and could lead to long-term emotional and psychological harm.