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OBJECTIVES: To estimate the association between maternal use of acetaminophen during abstract
pregnancy and of paternal use before pregnancy with attention-deficit/hyperactivity
disorder (ADHD) in offspring while adjusting for familial risk for ADHD and indications of
acetaminophen use.
METHODS: Diagnoses were obtained from the Norwegian Patient Registry for 112973
offspring from the Norwegian Mother and Child Cohort Study, including 2246 with ADHD.
We estimated hazard ratios (HRs) for an ADHD diagnosis by using Cox proportional hazard
models.
RESULTS: After adjusting for maternal use of acetaminophen before pregnancy, familial
risk for ADHD, and indications of acetaminophen use, we observed a modest association
between any prenatal maternal use of acetaminophen in 1 (HR = 1.07; 95% confidence
interval [CI] 0.961.19), 2 (HR = 1.22; 95% CI 1.071.38), and 3 trimesters (HR = 1.27; 95%
CI 0.991.63). The HR for more than 29 days of maternal acetaminophen use was 2.20 (95%
CI 1.503.24). Use for <8 days was negatively associated with ADHD (HR = 0.90; 95% CI
0.811.00). Acetaminophen use for fever and infections for 22 to 28 days was associated
with ADHD (HR = 6.15; 95% CI 1.7122.05). Paternal and maternal use of acetaminophen
were similarly associated with ADHD.
CONCLUSIONS: Short-term maternal use of acetaminophen during pregnancy was negatively
associated with ADHD in offspring. Long-term maternal use of acetaminophen during
pregnancy was substantially associated with ADHD even after adjusting for indications of
use, familial risk of ADHD, and other potential confounders.
NIH
aNorwegian Institute of Public Health, Oslo, Norway; bSection of Health, Developmental, and Personality Whats Known on This Subject: In previous
Psychology, Department of Psychology, cPharmacoEpidemiology and Drug Safety Research Group, School studies, researchers have identified an association
of Pharmacy, and dFaculty of Medicine, University of Oslo, Oslo, Norway; eMailman School of Public Health, between acetaminophen use during pregnancy
Columbia University, New York, New York; fNew York State Psychiatric Institute, New York, New York; gMedical
Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; and hDepartment
and attention-deficit/hyperactivity disorder (ADHD)
of Global Public Health and Primary Care, University of Bergen, Bergen, Norway in offspring. Maternal use of acetaminophen is
associated with impulsivity; hence, it is unknown
Dr Ystrom designed the study, conducted analyses, and drafted the initial manuscript; Drs if the association is due to indications of use or
Gustavson, Brandlistuen, Susser, Davey Smith, Stoltenberg, Surn, Hberg, Hornig, Lipkin,
familial risk for ADHD.
Nordeng, and Reichborn-Kjennerud contributed substantially to the conception and design of
the study and critically reviewed the manuscript for important intellectual content; Dr Knudsen What This Study Adds: After adjusting for familial
contributed substantially in the acquisition of data by coordinating the registry linkage and risk for ADHD, indications of use, and acetaminophen
critically reviewed the manuscript for important intellectual content; Dr Magnus contributed use before pregnancy, long-term acetaminophen use
substantially in the acquisition of data by leading the data collection of the Norwegian Mother during pregnancy is related to more than a twofold
and Child Cohort study and critically reviewed the manuscript for important intellectual content;
increase in risk for offspring ADHD.
and all authors approved the final manuscript as submitted and agree to be accountable for all
aspects of the work in ensuring that questions related to the accuracy or integrity of any part of
the work are appropriately investigated and resolved.
DOI: https://doi.org/10.1542/peds.2016-3840
To cite: Ystrom E, Gustavson K, Brandlistuen RE, et al.
Prenatal Exposure to Acetaminophen and Risk of ADHD.
Pediatrics. 2017;140(5):e20163840
Results
The study population included
112973 children, of whom 2246 had
been diagnosed with ADHD. In Fig 1,
we present the estimated cumulative
number of expected ADHD events
across age. We estimated that 4% of
children in MoBa will have an ADHD
diagnosis at the age of 13 (Fig 1).
Fifty-two thousand seven-hundred
and seven (46.7%) women used
acetaminophen during pregnancy
FIGURE 1
(Table 1). Twenty-seven percent The figure depicts the Nelson-Aalen cumulative hazard estimate and the estimated proportion of
used acetaminophen in 1 trimester, children receiving an ADHD diagnosis by age after birth.
16% in 2 trimesters, and 3.3% in all 3
trimesters. Maternal preconceptional use of acetaminophen, had no associated with ADHD (HR = 1.10;
use and use in the first trimester was effect on offspring ADHD. Paternal 95% CI 0.921.30); paternal use
approximately equally associated preconceptional use had no weaker for 29 days or more was as
(r = 0.49) with use in the first and effect than maternal use during strongly associated with ADHD
second trimester (r = 0.56) and use pregnancy (Table 1). (HR = 2.06; 95% CI 1.363.13) as the
in the second and third trimester corresponding maternal prenatal use.
In Table 2, we present the HRs for
(r = 0.49) (Supplemental Table 4).
offspring ADHD by number of days
Paternal use was associated with
of prenatal acetaminophen exposure,
maternal preconceptional use and Discussion
adjusted for each indication of use
use during pregnancy (r = 0.180.10)
by stratification. We found that We found maternal prenatal
(Supplemental Table 4).
use of acetaminophen <7 days was acetaminophen use to be associated
Offspring prenatally exposed to negatively associated with offspring with a higher hazard rate for
acetaminophen had an increased ADHD. For use >7 days, the HR for offspring ADHD, supporting the
unadjusted hazard rate of ADHD of offspring ADHD increased with the findings of Liew et al13 based on
17%, 39%, and 46% after 1, 2, and 3 number of days exposed. Prenatal Danish registry data. Liew et al13
trimesters of exposure, respectively use of acetaminophen for 29 or did not, however, control for the
(Table 1). These associations were more days was associated with a indications for use or ADHD-
not attenuated when we adjusted substantially increased hazard rate of related familial factors. In our
for maternal and paternal use ADHD (HR = 2.20; 95% CI 1.503.24), study, the association persisted
before pregnancy (model 1), but they even after adjusting for indications of after adjusting for acetaminophen
were slightly lower after we adjusted use by stratification (Supplemental use before pregnancy and for
for parental symptoms of ADHD Table 6). The associations with parental symptoms of ADHD.
(model 2). In model 3, we adjusted use of 29 days or more did not differ We had the advantage of having
for a range of potential confounders across groups of indications medication data separately for each
Supplemental Table 5), (HR = 2.132.56). Acetaminophen indication, allowing us to account for
and the hazard ratios (HRs) for the use for fever and infections for 22 confounding by each indication in a
associations between 1, 2, and 3 to 28 days was strongly associated stratified model. Offspring prenatally
trimesters of prenatal acetaminophen with ADHD (HR = 6.15; 95% CI exposed to acetaminophen for 29
exposure were 1.07 (95% confidence 1.7122.05). Associations between days or more had a twofold HR for
interval [CI] 0.961.19), 1.22 (95% CI paternal preconceptional use of receiving a clinical diagnosis of ADHD
1.071.38), and 1.27 (95% CI 0.99 acetaminophen and ADHD are from specialist health services. This
1.63), respectively. The negative presented in Table 3. Short-term estimate was the same regardless of
control, maternal preconceptual paternal use was not negatively indication (ie, fever and infections
also found small associations for
5
6
TABLE 2 HRs for Offspring ADHD by Number of Days of Maternal Acetaminophen Use During Pregnancy
All Indications Groups of Indications for Acetaminophen Use
Fever and Infections Pain Conditions Indication Not Specified
No. of Mothers Adjusted HRa (95% No. of Mothers Adjusted HRa (95% CI) No. of Mothers Adjusted HRa (95% No. of Mothers Adjusted HRa (95%
Reporting Each CI) Reporting Each Reporting Each CI) Reporting Each CI)
Exposure Duration Exposure Duration Exposure Duration Exposure Duration
/ / / /
Overall No. of Overall No. of Overall No. of Overall No. of
Observations of Observations of Observations of Use per Observations of Use per
Use per Exposure Use per Exposure Exposure Duration Exposure Duration
Duration Duration
No use 103017 1.00 84304 1.00 75019 1.00 4606 1.00
1153338 Reference 216206 Reference 180288 Reference 4639 Reference
17 d 36899 0.90 (0.811.00) 8752 0.90 (0.751.09) 10335 0.89 (0.761.04) 19154 1.30 (0.981.73)
53667 10864 12064 21796
814 d 6434 1.18 (0.981.42) 1021 1.02 (0.551.89) 2653 1.12 (0.831.50) 1949 1.96 (1.362.82)
7923 1185 2925 2020
1521 d 2003 1.35 (1.001.81) 185 0.98 (0.243.95) 1045 1.43 (0.962.14) 441 1.79 (0.953.35)
2369 200 1147 447
2228 d 253 1.60 (0.703.69) 16 6.15 (1.7122.05) 133 1.08 (0.343.39) 61
283 17 138 62
29 or more d 1034 2.20 (1.503.24) 72 2.40 (0.3416.78) 609 2.56 (1.544.25) 200 2.13 (0.885.15)
1395 75 772 212
, not applicable.
a Adjusted for year of birth, maternal age, parity, comedication within each indication of use, acetaminophen use first 6 months before pregnancy within each indication of use (only reports on first trimester are adjusted), and acetaminophen use
in the first 6 months postpartum within each indication of use (only reports on last trimester are adjusted). Two thousand two hundred and forty six children were diagnosed with ADHD by December 31, 2014.
death.4,40
brain development.5,15, 36
formation of synapses.33 35
2 trimesters. This supports
39
effect of maternal postnatal
exposure to acetaminophen
indications but are related to
Third,
between maternal acetaminophen
to male germ-line epigenetic effects
Second,
pregnancy are unclear. It may be due
Ystrom et al
oxidative stress, leading to neuronal
TABLE 3 HRs for Offspring ADHD by Number of Days of Paternal Acetaminophen Use 6 Months Before during pregnancy was associated
Pregnancy with ADHD. However, given that
No. of Fathers Reporting Each Category HRa 95% CI paternal use of acetaminophen is also
No use 64348 1.00 Reference associated with ADHD, the causal
17 d 8887 1.10 (0.921.30) role of acetaminophen in the etiology
828 d 1079 1.81 (1.262.60) of ADHD can be questioned. We do
29 or more d 657 2.06 (1.363.13) not provide definitive evidence for
a Adjusted for year of birth, paternal age, and parity. or against a causal relation between
maternal use of acetaminophen and
ADHD.
Our finding that acetaminophen use may limit generalization of results
for <8 days is negatively associated to all children. It has, however,
with offspring ADHD indicates previously been shown that although Acknowledgments
that the antipyretic effect could estimates of frequencies and means We thank Ragna Bugge Askeland for
be beneficial with regard to fetal were biased because of selective assisting in the registry linkage and
development.11,12
participation, selected exposure- Ragnhild Eskeland for interpretation
We address 3 limitations that outcome associations did not differ of the paternal effects. We are
could have biased the results. First, between MoBa participants and the grateful to all the participating
although we were able to stratify on general Norwegian population.43 45
families in Norway who take part in
each indication of use, long-term use this ongoing cohort study.
within each indication is likely to
represent a more severe form of the Conclusions
disorder. We were not able to adjust Long-term maternal use of
for the severity of each condition acetaminophen during pregnancy is Abbreviations
indicative of acetaminophen use. associated with ADHD in offspring.
ADHD:attention-deficit/hyperac-
Second, the ADHD diagnosis was not This holds true even after adjusting
tivity disorder
validated in a research clinic but was for potential confounders, including
CI:confidence interval
based on a diagnosis registered by parental symptoms of ADHD and
HR:hazard ratio
a specialist in the Norwegian health indications of acetaminophen use.
MoBa:Norwegian Mother and
care system. Finally, young parents Although maternal preconceptional
Child Cohort Study
and parents who were smokers are use was substantially correlated
NPR:Norwegian Patient Registry
underrepresented in MoBa,43 which with use during pregnancy, only use
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.