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Original Investigation |

Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood Evidence Against Confounding ONLINE FIRST

Evie Stergiakouli, PhD1; Anita Thapar, FRCPsych, PhD2; George Davey Smith, MD, DSc1
[+] Author Affiliations
1Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol, United Kingdom
2Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, Wales
JAMA Pediatr. Published online August 15, 2016. doi:10.1001/jamapediatrics.2016.1775
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Importance  Acetaminophen (paracetamol) is used by a large proportion of pregnant women. Research suggests that acetaminophen use in pregnancy is associated with abnormal fetal neurodevelopment. However, it is possible that this association might be confounded by unmeasured behavioral factors linked to acetaminophen use.

Objective  To examine associations between offspring behavioral problems and (1) maternal prenatal acetaminophen use, (2) maternal postnatal acetaminophen use, and (3) partner’s acetaminophen use.

Design, Setting, and Participants  From February 2015 to March 2016, we collected and analyzed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort. We studied 7796 mothers enrolled in ALSPAC between 1991 and 1992 along with their children and partners.

Exposures  Acetaminophen use was assessed by questionnaire completion at 18 and 32 weeks of pregnancy and when the child was 61 months old.

Main Outcomes and Measures  Maternal reports of behavioral problems using the Strengths and Difficulties Questionnaire (SDQ) when the children were 7 years old. We estimated risk ratios for behavioral problems in children after prenatal, postnatal, and partner’s exposure to acetaminophen and mutually adjusted each association.

Results  Maternal prenatal acetaminophen use at 18 (n = 4415; 53%) and 32 weeks of pregnancy (n = 3381; 42%) was associated with higher odds of having conduct problems (risk ratio [RR], 1.42; 95% CI, 1.25-1.62) and hyperactivity symptoms (RR, 1.31; 95% CI, 1.16-1.49), while maternal acetaminophen use at 32 weeks was also associated with higher odds of having emotional symptoms (RR, 1.29; 95% CI, 1.09-1.53) and total difficulties (RR, 1.46; 95% CI, 1.21-1.77). This was not the case for maternal postnatal (n = 6916; 89%) or partner’s (n = 3454; 84%) acetaminophen use. We found the associations between maternal prenatal acetaminophen use and all the SDQ domains unchanged even after adjusting for maternal postnatal or partner’s acetaminophen use.

Conclusions and Relevance  Children exposed to acetaminophen prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use. Although these results could have implications for public health advice, further studies are required to replicate the findings and to understand mechanisms.

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Submit a Comment
NASAID use in pregnancy
Posted on August 20, 2016
Robert James Carpenter, Jr MD JD
Baylor College of Medicine OB/GYN MFM
Conflict of Interest: None Declared
The article is informative and disturbing in that since acetaminophen (Tylenol) use is discussed as stand alone exposure/effects, the same effects may well be attributable to the entire class of all NASAIDs much as was the case with the original increase of myocardial infarction that removed one specific NASAID from the market. At the time some of us believed that it would be seen in other agents of the class and subsequent research as shown that the same effect in similar degree occurs when one looks for the outcome.

Since the pain relieving and especially the antipyretic effect of Tylenol is the most frequent reason for use of the drug, other confounders that were not looked at in the study such as degree of fever, type of pain for which agent chosen, and even the specific infection fever reduction was being sought for can not be analyzed.

The database was prospective and collection robust so conclusion stands as it is. But now we have the problem of what drug is to be used as a substitute and from a strictly medical-legal issue since now that the association has been developed some lawyers will be looking at a class action suit using the data to extort monies from the various makers of drug including generics.

All OBs and any primary care MD/DO using the drug will be required to discuss the study and its implications with patients prior to its use as will any provider/manufacturer of medication be wise to consider a \"black box\" warning of its use in pregnancy.

Time will give us more insight into the repercussions of this observation.
This article should be retracted immediately.
Posted on August 16, 2016
Daniel Baldor
MS3 MD/MPH UMiami Miller School of Medicine
Conflict of Interest: None Declared
This article should be retracted. There is no significance to the outcomes once the confounders of smoking or alcohol consumption during pregnancy (higher in the acetaminophen usage group), and maternal psychiatric illness (also higher in the acetaminophen usage group) are included in the analysis. This outcome was hidden in supplementary content (eTable 3) and we should all be worried that JAMA participates in this level of malfeasance.

Most troubling is the language used by the authors to cover this fact up: “Inclusion of covariates did not change the RRs, although CIs were wider owing to the reduced sample size when covariates were included.” Noticeably absent from this statement is the fact that the “wider” CIs crossed 1.0 for every outcome.

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