Acetaminophen Use in Pregnancy Tied to Higher Autism, ADHD Risk

Batya Swift Yasgur, MA, LSW

April 26, 2018

UPDATED May 4, 2018 // Prolonged use of acetaminophen during pregnancy is associated with an increased risk for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), new research shows.

Investigators reviewed studies of mother-child pairs and found a 30% increase in relative risk for ADHD and a 20% increase for ASD in children whose mothers took acetaminophen during pregnancy, compared to children whose mothers did not.

"Our study was the first systematic review and meta-analysis of the developmental outcomes in children whose mothers took prolonged acetaminophen during pregnancy," lead investigator Ilan Matok, PhD, of the Institute for Drug Research in the School of Pharmacy, Hebrew University, Jerusalem, Israel, told Medscape Medical News.

"Since this is an observational study, with all the limitations that observational studies have, we cannot be sure that acetaminophen is actually the cause for the increased risk, so we don't recommend changing the treatment guidelines for pregnant women experiencing pain," he said.

The study was published online April 24 in the American Journal of Epidemiology.

Previous Discrepancies

Acetaminophen is "the most commonly used analgesic and antipyretic medication during pregnancy" and is "widely considered the drug of choice for fever and pain in pregnant and lactating women," the authors write.

Recent research has suggested that acetaminophen may have harmful effects in children of mothers who used it during pregnancy, including an increased risk for neurodevelopmental disorders.

Animal models suggest that acetaminophen might have neurodisruptive properties. Because acetaminophen crosses the human placenta barrier, the neurodisruption might be transmitted to a baby and lead to future impairments, such as ADHD and ASD.

"While the neural disruption and its potential impact on neurodevelopment is only a hypothesis and not validated right now," some previous research has pointed to a potential association between acetaminophen use and these conditions, Matok said.

Previous findings have been inconsistent, however.

"Some reports have shown an association with increased risk, while other studies didn't show this, so we wanted to investigate this discrepancy, and the best way to do so was to conduct a systematic review and meta-analysis," Matok explained.

The researchers conducted searches of three study databases through January 2017 and selected seven retrospective cohorts (n = 132,738 mother and child pairs). The mean follow-up period was 6.7 years (range, 3 to 12 years).

Of these mother-child pairs, 61,601 were exposed to acetaminophen during pregnancy.

Six studies reported ADHD diagnosis, and five reported ASD diagnosis.

Studies employed a wide means of assessing exposure to acetaminophen during pregnancy, including telephone interviews, pre- and postnatal questionnaires, self-reports of medication and dose at various points during the pregnancy, and interviews with mothers soon after childbirth.

Duration of exposure varied from 7 to 28 days and ≥28 days. The mean duration of exposure, calculated from three studies, ranged from 4 to 7 days.

Gestational week at exposure varied between studies, with some reporting results during the first 32 weeks of pregnancy and others reporting results for exposure any time during the pregnancy.

Short-term Use Safe

The pooled risk ratios (RRs) for ADHD, ASD, and hyperactivity symptoms were 1.32 (95% confidence interval [CI], 1.18 - 1.45; I2 = 61%), 1.23 (95% CI, 1.13 - 1.32; I2=17%), and 1.23 (95% CI, 1.01 - 1.49; I2 = 94%), respectively.

Additionally, use of acetaminophen during pregnancy was found to be significantly associated with an increased risk for the development of conduct disorder (RR = 1.28; 95% CI, 1.05 - 1.52; I2 = 94%), as evaluated in five studies.

To explore sources of heterogeneity between studies in the association between acetaminophen during pregnancy and ADHD diagnosis, the researchers conducted moderator analyses. Several covariates were evaluated as potentially modifying factors and were subjected to exploratory metaregression models.

When the data were subjected to this metaregression analysis, the researchers found that the association between exposure and ADHD increased with the child's age upon follow-up (β = 0.0354; 95% CI, 0.001 - 0.07) and with the mean duration of gestational acetaminophen exposure (β = 0.006; 95% CI, 0.009 - 0.01).

Maternal age was a "significant" moderator. In studies that enrolled younger women, the association between acetaminophen use and the development of ADHD in offspring was decreased (β = -0.17; 95% CI, -0.28 to -0.6).

On the other hand, maternal fever, maternal smoking, high socioeconomic status, Newcastle-Ottawa Scale (NOS) score (the NOS measures the quality of nonrandomized trials), and geographic latitude were not found to be significant moderators.

"We concluded that the increased relative risk of autism was possible up to 20%, and 30% for ADHD, but it is important to remember that this is relative risk, which is considerably lower than absolute risk," Matok emphasized.

Additionally, "we are looking at prolonged use of acetaminophen, with more prolonged use increasing the risk, but we think that its use is safe in the short term," he said.

No Change to Clinical Practice

Commenting on the study for Medscape Medical News, Matitiahu Berkovitch, MD, director, Clinical Pharmacology and Toxicology Unit, Drug Consultation Center, Assaf Harofeh Medical Center, which is affiliated with Sackler School of Medicine, Tel Aviv University, Israel, who was not involved with the study, called it "a very nice, well-done, but problematic meta-analysis."

The reason for his concern is that "the studies which were being analyzed themselves have problems of heterogeneity, bias, and many confounders."

Berkovitch noted that the "baseline risk for malformations in the general population, in every pregnancy, is 3% to 5%, and the current study suggests that if a woman takes acetaminophen every day for more than a month, the risk for autism and ADHD will be minimally increased beyond the baseline risk, if at all."

Moreover, "prolonged use" means that the woman would have to take it for more than a month "and if she is taking it for that length of time, it means that there is an underlying disease that itself may be a contributor to the findings," he pointed out.

Additionally, "a fever of over 39°C [102.2°F] for more than 24 hours has been shown, in animal models, to be teratogenic, and prolonged high fever would be far more dangerous than use of acetaminophen," he said.

He cautioned against applying these findings to clinical practice.

"Acetaminophen is safe and accepted throughout pregnancy, and the bottom line is that we not change our policies and practices based on these types of studies and these findings."

Matok agreed that fever — especially high fever — and pain are "more dangerous to the mother and fetus than taking acetaminophen."

Matok recommended that pregnant women who experience symptoms for "longer periods of time, who then are likely to take more than a few acetaminophen doses" should consult their physicians about treatment approaches to their condition.

Cause for Concern

Also commenting on the study for Medscape Medical News, Christina Chambers, PhD, MPH, professor of pediatrics, University of California, San Diego, School of Medicine, who was not involved with the study, said that although the "relative risks identified are quite modest, given the high prevalence of use of acetaminophen in pregnancy, these risks, if causal, are concerning."

She noted that, "while the published findings cannot prove that acetaminophen causes ASD or ADHD, they do suggest that clinicians might advise their patients to be cautious about use of this product in pregnancy, especially if the pregnant woman is using acetaminophen on a regular basis."

However, she concurred that maternal fever in pregnancy, "depending on the timing and magnitude, is associated with increased risks for fetal effects," so "clinicians should be reminded that the recommendation to reduce fever in pregnancy still stands, and the preferred antipyretic has been acetaminophen."

The study received no funding. The study authors, Dr Berkovitch, and Dr Chambers have disclosed no relevant financial relationships.

Am J Epidemiol. Published online April 24, 2018. Abstract

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