Prenatal acetaminophen exposure in meconium and the risk of ADHD- Role of Confounding by Indication

Motherisk Int J 2020;1;24

 

Gideon Koren MD FRCPC FACMT
Professor and Head of Pharmacology, Adelson School of Medicine, Ariel University, Israel
E mail: gidiup_2000@yahoo.com
Tel 972587194777

Jacob V. Aranda MD, PhD, FRCPC, FAAP
Professor of Pediatrics and Ophthalmology and Director of Neonatology
State University of New York Downstate Health Sciences University

 

Question:

In September 28, 2020, Baker and colleagues reported on a prospective study showing an association between meconium acetaminophen measures and the diagnosis of attention deficit hyperactivity disorder (ADHD) (1). They concluded that” caution should be used in administering acetaminophen during pregnancy”. Do you think this evidence strengthens the fetal risk of acetaminophen?

 

Answer:

We believe that this “biological assumption” is wrong. Meconium measurements of acetaminophen are merely a proof of exposure. It is very likely that the association between acetaminophen and ADHD are the result of bias by indication.

 

The potential association between fetal exposure to acetaminophen and ADHD has been tested in numerous recent studies and meta analyses and there is little doubt that such an association exists (2). Baker et al argue that the use of a biological marker of fetal acetaminophen exposure helps move this association into the direction of causation(1). We believe that this “biological assumption” is wrong. There is ample epidemiological evidence that acetaminophen is used very widely in pregnancy, by up to two thirds of women (3). Because drugs are accumulated in meconium over the second and third trimesters, a positive meconium acetaminophen test does not disclose either the time, or the dose of exposure, information that does exist in carefully performed epidemiological studies. Hence, presenting the meconium- acetaminophen measures as a robust biological proof may be false.

We believe that the big elephant in the room is the role of confounding by indication, i.e. the possibility that it is not the acetaminophen but the indications for taking it in general, and in large amounts in particular. The present meconium study does not help even minimally to address this issue. Previous studies have examined the extent and length of exposure to acetaminophen and putative neuronal damage (4). Women who experience prolonged fever may experience infections that affect fetal brain development. Moreover, increased duration of acetaminophen exposure is associated with smoking, obesity, depression and anxiety, and use of antidepressants (3). There are known associations between maternal depression, SSRIs use and risk of ADHD in the offspring (5).

We are concerned that the quasi” biological” evidence presented by Baker et al. may lead women not to manage optimally pain and fever. Acetaminophen is the only analgesic-antipyretic medication recommended for early and late pregnancy. Scaring the medical community and pregnant women against acetaminophen may lead many not to manage pain effectively during pregnancy, or to use narcotic analgesics.

In Baker’s study, the meconium biomarker is merely a rough marker of maternal exposure. Presenting it as a biological evidence of causation is a dangerous direction.

 

References:

1)Baker B, Lugo-Candelas C, Wu H, et al. Association of prenatal acetaminophen exposure measured in meconium with risk of ADHD mediated by frontoparietal network brian connectivity. JAMA Ped doi:10.1001/jamapediatrics.2020.3080

2) Massarwa R, Levine H, Gorelik E, et L. Prenatal exposure to acetaminophen and the risk for attention deficit hyperactivity disorder and autistic spectrum disorder: a systematic review, meta analysis and meta-regression analysis of cohort studies. Am J Epidemiol 2018; 187:1817-27

3) Bandoli G, Palmsten K, Chambers C. Acetaminophen use in pregnancy: examining prevalence, timing and indication of use in a prospective birth cohort. Ped Perinat Epidemiol 2019; 34: doi.org/10.1111/ppe.125295

4) Avella-Garcia CB, Julvez J, Fortuny I et al. Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol 2016;45:1987-96

5) Uguz F. Maternal antidepressant use during pregnancy and the risk of attention-deficit/hyperactivity disorder in children: A systematic review of the current literature. J Clin Psychopharmacol 2018 Jun;38(3):254-259.