Paracetamol use in pregnancy — caution over causal inference from available data

Alwan, Sura; Conover, Elizabeth; Harris-Sagaribay, Lorrie; Lamm, Steven H.; Lavigne, Sharon Voyer; Lusskin, Shari I.; Običan, Sarah; Romeo, Alfred N.; Wisner, Katherine L.

doi:10.1038/s41574-021-00606-x

Cited by 15 publications

(8 citation statements)

References 10 publications

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“…While acetaminophen is recommended during pregnancy, especially to reduce fever, meta-analyses have reported associations between prenatal exposure to acetaminophen and neurobehavioral problems in children, including attention-deficit hyperactivity disorders [1][2][3]. Recently, there is a debate in the literature on whether or not clinicians should recommend reduced acetaminophen use during pregnancy [4,8,9].…”

Section: Introductionmentioning

confidence: 99%

Maternal use of acetaminophen during pregnancy and neurobehavioral problems in offspring at 3 years: A prospective cohort study

2022

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Background Acetaminophen is one of the most commonly used drugs during pregnancy globally. Recent studies have reported associations between prenatal exposure to acetaminophen and neurobehavioral problems in children, including attention-deficit hyperactivity disorders. Little research has investigated these associations in preschool-age children or the potential confounding effects of prenatal stress. The purpose of this study was to examine associations between prenatal acetaminophen exposure and offspring neurobehavioral problems at the age of 3 years, with a focus on the potentially confounding effects of prenatal stress. Methods We used data from the First Baby Study, a prospective cohort study conducted in Pennsylvania, USA, with 2,423 mother-child pairs. Women reported medication use and completed a prenatal stress inventory during their third trimester. Child behavioral problems were measured at the age of 3 years, using the 7 syndrome scale scores from the Child Behavior Checklist (CBCL) for ages 1 ½ to 5. Results There were 1,011 women (41.7%) who reported using acetaminophen during pregnancy. Children who were exposed to acetaminophen during pregnancy scored significantly higher on 3 of the 7 CBCL syndrome scales: withdrawn, sleep problems and attention problems. Scores on all 7 of the CBCL syndrome scales were significantly associated with prenatal stress. After adjustment for prenatal stress and other confounders, 2 syndrome scales remained significantly higher in children exposed to acetaminophen: sleep problems (aOR = 1.23, 95% CI = 1.01–1.51) and attention problems (aOR = 1.21, 95% CI = 1.01–1.45). Conclusions These findings corroborate previous studies reporting associations between prenatal exposure to acetaminophen and attention problems in offspring and also show an association with sleep problems at age 3 years. Because use of acetaminophen during pregnancy is common, these results are of public health concern and suggest caution in the use of medications containing acetaminophen during pregnancy.

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Section: Introductionmentioning

confidence: 99%

Maternal use of acetaminophen during pregnancy and neurobehavioral problems in offspring at 3 years: A prospective cohort study

2022

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“…Given the vivid research debate regarding the long-term safety of prolonged use of acetaminophen during pregnancy ( Bauer et al, 2021 ; Alwan et al, 2022 ), it is of interest to evaluate the strength of association between this exposure and maternal personality traits. We found that high neurotic disposition in the woman was associated with a modest increased likelihood of extended use of acetaminophen in pregnancy, but for openness the association was the converse.…”

Section: Discussionmentioning

confidence: 99%

Association of maternal personality traits with medication use during pregnancy to appraise unmeasured confounding in long-term pharmacoepidemiological safety studies

2023

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Maternal personality is a possible confounder on the association between prenatal medication exposure and long-term developmental outcomes in offspring, but it is often unmeasured. This study aimed to (i) estimate the association between five maternal personality traits and prenatal use of acetaminophen (including extended use), opioid analgesics, antidepressants, benzodiazepines/z-hypnotics, and antipsychotics; (ii) evaluate, using an applied example, whether unmeasured confounding by maternal neuroticism would make the association between prenatal antidepressant-child ADHD null, using the E-value framework. We used data from 8,879 pregnant women and recent mothers who participated in the Multinational Medication Use in Pregnancy Study, a web-based cross-sectional study performed within the period from 1-Oct-2011 to 29-Feb-2012 in Europe, North America and Australia. Medication use in pregnancy was self-reported by the women. Personality was assessed with the Big Five Inventory, capturing the dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness. Adjusted logistic regression analyses were conducted for each trait-medication pair, using the survey weighting. There was a strong association between having high neuroticism and prenatal use of antidepressants (Odds Ratio (OR): 5.63, 95% Confidence Interval (CI): 3.96-8.01), benzodiazepines/z-hypnotics (OR: 6.66, 95% CI: 4.05-10.95), and analgesic opioids (OR: 2.24, 95% CI: 1.41-3.56), but not with antipsychotics. Among women with mental illness, this association attenuated for benzodiazepines/z-hypnotics, but decreased to the null for antidepressants. High neuroticism (OR: 1.31, 95% CI: 1.08-1.59) and high openness (OR: 0.77, 95% CI: 0.64-0.93) were associated with extended use of acetaminophen. The E-value for the Hazard Ratio 1.93 in the applied example was 3.27. If the example study was conducted using a population comparison group, high maternal neuroticism could have explained away the association antidepressant-ADHD. Because the example study included only women with a mental illness, this risk of bias was assessed as minimal. Various personality dispositions in the mother are associated, with a different degree, to prenatal use of medication. The strength of these association can aid researchers in evaluating the influence of uncontrolled confounding by maternal personality in long-term safety studies in pregnancy, using the E-value. This assessment should always be performed in addition to a rigorous study design using approaches to triangulate the evidence.

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“…In 2021, Ann Bauer of the Department of Public Health, University of Massachusetts School of Health Sciences in the USA, reviewed the literature and published a consensus statement signed by 90 scientists ( https://doi.org/10.1038/s41574-021-00553-7 ) recommending ‘that pregnant women should be cautioned at the beginning of pregnancy to: forego [paracetamol] unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time.’ A reply was subsequently published by Alwan et al (2022) pouring scorn on the data available and stating that:…”

Section: Discussionmentioning

confidence: 99%

Maternal prenatal paracetamol ingestion and scholastic attainments of the offspring

Golding,

Tunstall,

Gregory

et al. 2023

Front. Pharmacol.

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Background: Fetal exposure to paracetamol (acetaminophen) has been shown to be associated with asthma and other atopic disorders, as well as behavioural problems including hyperactivity, in childhood. However, there is little information on scholastic abilities among children exposed to paracetamol in pregnancy.Objectives: To determine whether there are any differences in scholastic abilities among the offspring of women who ingested paracetamol during pregnancy compared with non-exposed children.Methods: Mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) had recorded the frequency with which they had taken the medication over two time periods during pregnancy: i) the first 18 weeks and ii) 18–32 weeks. The offspring have been followed up ever since. For this study we use as outcomes: a) 14 tests of ability at reading and 2 of spelling using the study’s tests and the national education system test results; b) 6 of mathematical abilities including tests of arithmetic and mathematical reasoning, and c) 1 of scientific understanding. Multiple regression was used, adjusting for 15 different exposures including reasons for taking the medication as well as demographic features.Results: Almost all unadjusted and adjusted mean differences were negative (i.e., those exposed to maternal intake of paracetamol did less well), but negative associations for exposures between 18 and 32 weeks of gestation were much more evident than for exposures earlier in pregnancy. Of the later exposures, after adjustment, 12 of the 23 scholastic tests were associated with prenatal exposure to paracetamol at p < 0.05. These negative effects were found in the girls (12 tests at p < 0.05) but not boys (0 tests at p < 0.05).Conclusion: Evidence from this longitudinal study suggests that maternal exposure to paracetamol is associated with disadvantages to the offspring in scholastic abilities such as mathematics and reading at secondary school ages. This raises the question as to whether there are longer-lasting effects on educational attainment from age 15 years onwards, including at university level. Clearly these results should be tested in other settings, but meanwhile they add to a growing accumulation of known adverse effects of exposure to paracetamol in pregnancy.

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Paracetamol use in pregnancy — caution over causal inference from available data

Cited by 15 publications

References 10 publications

Maternal use of acetaminophen during pregnancy and neurobehavioral problems in offspring at 3 years: A prospective cohort study

Maternal use of acetaminophen during pregnancy and neurobehavioral problems in offspring at 3 years: A prospective cohort study

Association of maternal personality traits with medication use during pregnancy to appraise unmeasured confounding in long-term pharmacoepidemiological safety studies

Maternal prenatal paracetamol ingestion and scholastic attainments of the offspring

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