Maternal Acetaminophen Use Research Articles

Associations between cord blood acetaminophen biomarkers and childhood asthma with and without allergic comorbidities

BackgroundPrevious studies have linked prenatal acetaminophen use to increased asthma risk in children. However, none have explored this association while differentiating between asthma cases with and without other allergic conditions or by employing objective biomarkers to assess acetaminophen exposure. ObjectiveTo evaluate whether the detection of acetaminophen biomarkers in cord blood is associated with the subgroups of asthma both with and without allergic comorbidities in children. MethodsAcetaminophen biomarkers, including unchanged acetaminophen and acetaminophen glucuronide, were measured in neonatal cord blood samples from the Boston Birth Cohort. Asthma subgroups were defined on the basis of physician diagnoses of asthma and other allergic conditions (atopic dermatitis and allergic rhinitis). Multinomial regressions were used to evaluate the associations between acetaminophen biomarkers and asthma subgroups, adjusting for multiple confounders, including potential indications for maternal acetaminophen use such as maternal fever. ResultsThe study included 142 children with asthma and at least 1 other allergic condition, 55 children with asthma but no other allergic condition, and 613 children free of asthma. Detection of acetaminophen in cord blood, reflecting maternal exposure to acetaminophen shortly before delivery, was associated with 3.73 times the odds of developing asthma without allergic comorbidities (95% CI: 1.79-7.80, P = .0004). In contrast, the detection of acetaminophen in cord blood was not associated with an elevated risk of asthma with allergic comorbidities. Analysis of acetaminophen glucuronide yielded consistent results. ConclusionIn a prospective birth cohort, cord blood acetaminophen biomarkers were associated with an increased risk of childhood asthma without allergic comorbidities, but were not associated with childhood asthma with allergic comorbidities.

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

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.

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

BackgroundAcetaminophen 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.MethodsWe 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.ResultsThere 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).ConclusionsThese 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.

A Systematic Review of the Link Between Autism Spectrum Disorder and Acetaminophen: A Mystery to Resolve.

The purpose of this study is to review the published papers investigating maternal acetaminophen (AP) use during pregnancy and its effect on the offspring's neurodevelopment, particularly autism spectrum disorders (ASD). Acetaminophen is an over-the-counter analgesic and antipyretic considered safe in pregnancy. Recent studies have found an association between acetaminophen and immune system alterations like asthma and adverse neurodevelopmental outcomes. We used online databases (PubMed/Medline/PubMed Central, Science Direct, and Google Scholar) to search the studies relevant to our topic. We screened the papers by titles, abstracts, and then full-text availability. The screened articles were checked for eligibility using relevant quality assessment tools for each study design, extracting and analyzing the data. We finalized 30 studies after the screening; 14 were ineligible. Our final selection included 16 high-quality papers - 13 prospective cohort studies, two review articles, and one meta-analysis.We found a wide range of neurodevelopmental outcomes in our data collection. So, we included autism spectrum disorders, intelligent quotient (IQ), attention-deficit/hyperactivity disorder (ADHD), isolated language, attention and executive function, communication, behavior, and psychomotor development. All studies showed an association between acetaminophen use and listed neurodevelopmental outcomes. Long-term use, increased dose, and frequency were associated with a stronger association. We extracted collective evidence from 16 studies suggesting acetaminophen's role in developing adverse neurodevelopmental outcomes. It is urgent to do more research on this association before pregnant women can be cautioned about the precise use of acetaminophen.

Maternal acetaminophen use and cognitive development at 4 years: the Ontario Birth Study.

BackgroundStudies have suggested a link between prenatal maternal acetaminophen use and adverse developmental outcomes in children. However, there exists a knowledge gap regarding overall cognitive development and use of acetaminophen, especially concerning the timing of use in pregnancy. This study aimed to characterize the relationship between maternal acetaminophen use and cognitive development at 4 years.MethodsThis analysis included data collected throughout pregnancy and delivery from women in the Ontario Birth Study prospective cohort from 2013 to 2019 and from the NIH Toolbox Early Childhood Cognition battery administered to 4-year-old children between 2018 and 2021 (n = 436). The exposure was maternal acetaminophen use and the primary outcome was a cognition composite score. The relationship between exposure and outcome was determined using Poisson regression with a robust error variance.ResultsWe did not observe any association between maternal acetaminophen intake any time before or during pregnancy and low cognition composite score of offspring. The IRR of suboptimal overall cognition was 1.38 (0.78–2.45), 1.22 (0.67–2.22), 0.80 (0.44–1.47), and 1.56 (0.74–3.29) for maternal use of acetaminophen before, in early, late, or overall pregnancy, respectively.ConclusionCurrent data do not provide evidence to support a relationship of maternal acetaminophen use during pregnancy with adverse cognitive effects at 4 years.Impact Acetaminophen use during pregnancy may influence the risk of child neurocognitive disorders, but there is conflicting evidence of its relationship to sub-clinical measures of cognitive development such as executive function.The study design allowed us to examine the role of timing of acetaminophen use in its relationship with cognitive development, based on a validated and standardized tablet-administered instrument for children, instead of a teacher or parent report.We did not observe a clear relationship between maternal acetaminophen use at different timepoints during pregnancy and child cognitive development.

Acetaminophen use during pregnancy and offspring attention deficit hyperactivity disorder - a longitudinal sibling control study.

Maternal acetaminophen use during pregnancy is associated with increased risk of ADHD in the child. This could reflect causal influence of acetaminophen on fetal neurodevelopment or could be due to confounding factors. The aim of the current study was to examine unmeasured familial confounding factors of this association. We used data from 26,613 children from 12,902 families participating in the prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). The MoBa was linked to the Norwegian Medical Birth Register and the Norwegian Patient Registry. Siblings discordant for prenatal acetaminophen exposure were compared regarding risk of having an ADHD diagnosis. Children exposed to acetaminophen up to 28days during pregnancy did not have increased risk of receiving an ADHD diagnosis compared to unexposed children. The adjusted Hazard ratio (aHR) was 0.87 (95% C.I.=0.70-1.08) for exposure 1 to 7days, and 1.13 (95% C.I.=0.82-1.49) for 8-28days. Long-term exposure (29days or more) was associated with a two-fold increase in risk of ADHD diagnosis (aHR=2.02, 95% C.I=1.17-3.25). In the sibling control model, the association between long-term acetaminophen use and ADHD in the child was aHR=2.77 (95% C.I.=1.48-5.05) at the between-family level, and aHR=1.06 (95% C.I.=0.51-2.05) at the within-family level. Both the exposed and the unexposed children of mothers with long-term use of acetaminophen in one of the pregnancies had increased risk of receiving an ADHD diagnosis. This indicates that the observed association between long-term acetaminophen use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors.

Intrauterine Exposure to Acetaminophen and Adverse Developmental Outcomes: Epidemiological Findings and Methodological Issues.

Acetaminophen (or paracetamol) is one of the most commonly used medications during pregnancy. We reviewed recent epidemiological evidence regarding intrauterine exposure to acetaminophen and risk for asthma, neurodevelopment disorders, and reproductive health in childhood. An increasing number of cohort studies have suggested that maternal use of acetaminophen during pregnancy was associated with increased risk for asthma; neurodevelopmental disorders, especially ADHD and behavioral problems; and genital malformations in the offspring. Oxidative stress and inflammation or endocrine effects are plausible shared biological mechanisms for the exposure to influence multiple developmental outcomes. We discussed methodological challenges that can threaten the validity of these observational data, including confounding and measurement errors. Novel statistical methods and research designs that can be used to mitigate these issues were introduced. Given the high prevalence of use, findings regarding intrauterine exposure to acetaminophen on multiple child health outcomes raise concerns. Research on causal and non-causal mechanisms that might explain these associations should be a priority.

Association between maternal acetaminophen use and adverse birth outcomes in a pregnancy and birth cohort.

Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes-preterm birth, low birthweight, and small for gestational age-are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use. Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age. Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen use <once/week was associated with small for gestational age, adjusted relative risk (aRR) = 1.46 (95% CI 1.02, 2.11). Acetaminophen use ≥once/week was associated with both small for gestational age, RR = 1.82 (95% CI 1.12, 2.94), and low birthweight, aRR = 2.16 (95% CI 1.02, 4.54). Acetaminophen use during pregnancy was not associated with the examined outcomes. Prepregnancy acetaminophen use may be associated with higher risk of adverse birth outcomes.

Maternal acetaminophen use during pregnancy and childhood behavioural problems: Discrepancies between mother- and teacher-reported outcomes.

Maternal acetaminophen use during pregnancy is common and has been associated with childhood behavioural problems among offspring, specifically hyperactivity and conduct problems. Assessments of child behaviour in many previous studies have relied on maternal or parent report. Acknowledging that results of behavioural assessments vary between informants, we examined the association between maternal acetaminophen use during pregnancy and behaviour problems in childhood based on mother- and teacher-report. A longitudinal study of 560 mother-child pairs with data on illnesses and medication use during pregnancy and neurodevelopmental assessments during childhood was conducted. Acetaminophen use during pregnancy was captured using a standardised maternal interview, completed 1year after delivery on average. Measures of childhood (6-12years of age) behaviour were obtained via mother- and teacher-report, using the Child Behaviour Checklist and Teacher Report Form. Linear and log-binomial models were used to calculate adjusted mean differences (MD) and risk ratios (RR), respectively and 95% confidence intervals (CI) for internalising, externalising, and total behaviour problems comparing acetaminophen users to non-users. Stabilized inverse probability weights were used to account for loss to follow-up, and adjustments for indication were made. Approximately 60% (n=354) of women reported use of acetaminophen during pregnancy. Acetaminophen use during pregnancy was associated with an increase in total behaviour problem score and risk of clinical behaviour problems according to mother report (MD 2.2, 95% CI 0.3, 4.1 and RR 1.93, 95% CI 0.99, 3.76) but not according to teacher report. Weighting to account for participation did not alter results, while adjustment for indications of acetaminophen use greatly attenuated the associations with mother-reported total behaviour problem score and risk of clinical behaviour problems (MD 0.1, 95% CI -2.1, 2.3 and RR 1.31, 95% CI 0.67, 2.58). Acetaminophen use during pregnancy was weakly associated with mother-reported behaviour problems and not associated with teacher-reported problems.

Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood

Prior studies have raised concern about maternal acetaminophen use during pregnancy and increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in their children; however, most studies have relied on maternal self-report. To examine the prospective associations between cord plasma acetaminophen metabolites and physician-diagnosed ADHD, ASD, both ADHD and ASD, and developmental disabilities (DDs) in childhood. This prospective cohort study analyzed 996 mother-infant dyads, a subset of the Boston Birth Cohort, who were enrolled at birth and followed up prospectively at the Boston Medical Center from October 1, 1998, to June 30, 2018. Three cord acetaminophen metabolites (unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-l-cystein-S-yl]-acetaminophen) were measured in archived cord plasma samples collected at birth. Physician-diagnosed ADHD, ASD, and other DDs as documented in the child's medical records. Of 996 participants (mean [SD] age, 9.8 [3.9] years; 548 [55.0%] male), the final sample included 257 children (25.8%) with ADHD only, 66 (6.6%) with ASD only, 42 (4.2%) with both ADHD and ASD, 304 (30.5%) with other DDs, and 327 (32.8%) who were neurotypical. Unchanged acetaminophen levels were detectable in all cord plasma samples. Compared with being in the first tertile, being in the second and third tertiles of cord acetaminophen burden was associated with higher odds of ADHD diagnosis (odds ratio [OR] for second tertile, 2.26; 95% CI, 1.40-3.69; OR for third tertile, 2.86; 95% CI, 1.77-4.67) and ASD diagnosis (OR for second tertile, 2.14; 95% CI, 0.93-5.13; OR for third tertile, 3.62; 95% CI, 1.62-8.60). Sensitivity analyses and subgroup analyses found consistent associations between acetaminophen buden and ADHD and acetaminophen burden and ASD across strata of potential confounders, including maternal indication, substance use, preterm birth, and child age and sex, for which point estimates for the ORs vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD. Cord biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood ADHD and ASD in a dose-response fashion. Our findings support previous studies regarding the association between prenatal and perinatal acetaminophen exposure and childhood neurodevelopmental risk and warrant additional investigations.

Prenatal Exposure to Acetaminophen and the Risk of Attention-Deficit/Hyperactivity Disorder: A Nationwide Study in Taiwan.

Studies have suggested that a significant association exists between prenatal exposure to acetaminophen and the offspring's attention-deficit/hyperactivity disorder (ADHD) risk. However, this association has largely been unexplored among the Asian population, generally, and the Taiwanese population, specifically. In our study, 950 study pairs (children with ADHD [ICD-9-CM code: 314] and their mothers) and 3,800 control pairs (children without ADHD and their mothers) matched by demographic characteristics were identified between 1998 and 2008 from the Taiwan Longitudinal Health Insurance Database. Maternal use of acetaminophen was assessed in the first trimester, second trimester, and third trimester of pregnancy and over the period from 3 months before pregnancy to the date of last menstrual cycle. Logistic regression analysis with adjustments for demographic data, gestational infections, comorbid perinatal conditions, and maternal mental health disorders indicated that exposure to acetaminophen in the second trimester (odds ratio [OR] = 1.19; 95% CI, 1.00-1.40), both the first and second trimesters (OR = 1.28; 95% CI, 1.00-1.64), or in any trimester (OR = 1.20; 95% CI, 1.01-1.42) was associated with an increased risk of ADHD in offspring. Sensitivity analysis excluding gestational infections and maternal mental health disorders confirmed this association (OR = 1.33; 95% CI, 1.04-1.69). Prenatal exposure to acetaminophen was associated with an increased risk of ADHD in offspring, regardless of gestational infections and maternal mental health disorders. Additional studies are necessary to clarify the underlying mechanisms by which prenatal exposure to acetaminophen leads to neurodevelopmental risks.

Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.

Acetaminophen is considered the safest antipyretic and analgesic medication for pregnant women. However, studies have reported that acetaminophen has endocrine disrupting properties and prenatal exposure has been associated with early life epigenetic changes and later life health outcomes. As the placenta is the central mediator of maternal and fetal interactions, exposure to acetaminophen during pregnancy could manifest as perturbations in the placenta epigenome. Here, we evaluated epigenome-wide cytosine-guanine dinucleotide (CpG) methylation in placental tissue in relation to maternal acetaminophen use during pregnancy in a cohort of 286 newborns born prior to 28 weeks gestation. According to maternal self-report, more than half (166 of 286) of the newborns were exposed to acetaminophen in utero. After adjustment for potential confounders, a total of 42 CpGs were identified to be differentially methylated at a false discovery rate < 0.05, with most displaying increased methylation as it relates to acetaminophen exposure. A notable gene that was significantly associated with acetaminophen is the prostaglandin receptor (PTGDR) which plays an essential role in mediating placental blood flow and fetal growth. Moreover, for 6 of the 42 CpGs, associations of acetaminophen use with methylation were significantly different between male and female placentas; 3 CpG sites were associated with acetaminophen use in the male placenta and 3 different sites were associated with acetaminophen use in the female placenta (Pinteraction < 0.2). These findings highlight a relationship between maternal acetaminophen use during pregnancy and the placental epigenome and suggest that the responses for some CpG sites are sex dependent.

Use of Negative Control Exposure Analysis to Evaluate Confounding: An Example of Acetaminophen Exposure and Attention-Deficit/Hyperactivity Disorder in Nurses' Health Study II.

Frequent maternal use of acetaminophen in pregnancy has been linked to attention-deficit/hyperactivity disorder (ADHD) in children, but concerns regarding uncontrolled confounding remain. In this article, we illustrate use of the negative control exposure (NCE) approach to evaluate uncontrolled confounding bias in observational studies on pregnancy drug safety and explain the causal assumptions behind the method. We conducted an NCE analysis and evaluated the associations between maternal acetaminophen use during different exposure periods and ADHD among 8,856 children born in 1993-2005 to women enrolled in the Nurses' Health Study II cohort. Information on regular maternal acetaminophen use was collected prospectively in biennial questionnaires. A total of 721 children (8.1%) in the cohort had been diagnosed with ADHD as reported by the mothers. Our NCE analysis suggested that only acetaminophen use at the time of pregnancy was associated with childhood ADHD (odds ratio = 1.34, 95% confidence interval: 1.05, 1.72), and the effect estimates for the 2 NCE periods (about 4 years before and 4 years after the pregnancy) were null. Our findings corroborate those of prior reports suggesting that prenatal acetaminophen exposure may influence neurodevelopment. The lack of an association between acetaminophen use in the pre- and postpregnancy exposure periods and ADHD provides assurance that uncontrolled time-invariant factors do not explain this association.

Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis

Acetaminophen is a widely used medication for fever and pain management during pregnancy. However, recent studies have found a possible connection between maternal prenatal acetaminophen use and attention deficit/hyperactivity disorder in children. We aimed to explore the association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring. PubMed, Embase, Web of Science and Cochrane Library were searched from their initial publications through November 2018 for studies. We included all studies that examined the association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring if the authors reported odds ratios, risk ratios, hazard ratios, regression coefficient, standard error and 95% confidence intervals. Two reviewers independently extracted data on the definition of exposure and outcome, exposed, non-exposed and total number of participants in the sample population, adjusted potential confounders and outcome parameters. Study quality was also assessed. Eight cohort studies with a total of 244,940 participants were included. Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25 (95% confidence interval = [1.17, 1.34]). Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder (risk ratio: 1.26; 95% confidence interval = [1.08, 1.47]). In addition, a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio. Children whose mothers used acetaminophen for 28 or more days during gestation had a higher risk of developing attention deficit/hyperactivity disorder (risk ratio: 1.63; 95% confidence interval = [1.23, 2.16]). There is an association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring. The timing and duration of acetaminophen use during pregnancy may have a major effect on the risk of attention deficit/hyperactivity disorder.

Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder.

Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. We sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. This report analyzed 1180 children enrolled at birth and followed prospectively as part of the Boston Birth Cohort, including 188 with ADHD diagnosis based on electronic medical record review. Maternal biomarkers of acetaminophen intake were measured in plasma samples obtained within 1–3 days postpartum. Odds ratios for having ADHD diagnosis or other developmental disorders were estimated using multinomial logistic regression models, adjusting for pertinent covariables. Compared to neurotypical children, we observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose–responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. In the stratified analyses, differential point estimates of the associations were observed across some strata of covariates. However, these differences were not statistically significant. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring. Additional clinical and mechanistic investigations are warranted.

Prenatal Exposure to Acetaminophen and Risk of ADHD.

To estimate the association between maternal use of acetaminophen during 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. Diagnoses were obtained from the Norwegian Patient Registry for 112 973 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. 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] 0.96-1.19), 2 (HR = 1.22; 95% CI 1.07-1.38), and 3 trimesters (HR = 1.27; 95% CI 0.99-1.63). The HR for more than 29 days of maternal acetaminophen use was 2.20 (95% CI 1.50-3.24). Use for <8 days was negatively associated with ADHD (HR = 0.90; 95% CI 0.81-1.00). Acetaminophen use for fever and infections for 22 to 28 days was associated with ADHD (HR = 6.15; 95% CI 1.71-22.05). Paternal and maternal use of acetaminophen were similarly associated with ADHD. 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.

O-32 Prenatal exposure to acetamin-ophen and risk for attention defi-cit disorder (adhd): a systematic review and meta analysis

Background Acetaminophen is the most commonly used analgesic and antipyretic medication during preg-nancy. Recent epidemiological studies have suggested a possible association between acetaminophen exposure in-utero and impaired paediatric neurological develop-ment, including hyperactive attention deficit (ADHD) and related disorders. Methods We conducted a systematic-review and me-ta-analysis to evaluate the risk for ADHD in children of women exposed to acetaminophen during pregnancy. We searched MEDLINE and EMBASE up to January 2017. We used meta-regression analysis to evaluate factors that may moderate this association. Reports of cohorts were pooled using random-effects models. Results Six cohort studies met our inclusion criteria. Among 76 146 mothers who reported acetaminophen use during pregnancy, acetaminophen was associated with an increased risk for ADHD (RR=1.33, 95% CI: 1.19–1.47, I2=77%), hyperactivity symptoms (RR=1.24, 95% CI: 1.02–1.46, I2=95%), and conduct disorders (RR=1.28; 95% CI, 1.05–1.52, I2=93%). Using meta-regression, we found that the association was greater and heterogeneity re-duced as child’s age at diagnosis increased (β=0.045, p=0.035, heterogeneity accounted for (R2)=65.98%). Conclusion This meta-analysis suggests that maternal acetaminophen use during pregnancy is associated with a higher risk for ADHD or related disorders. However, there is evidence of significant heterogeneity in the observed effect, and many of the studies suffer from significant lim-itations. These findings, together with additional recent evidence on teratogenicity of acetaminophen, warrants further investigation and consideration of public health actions. PROSPERO registry-CRD42017055827

Prenatal Use of Acetaminophen and Child IQ: A Danish Cohort Study.

Acetaminophen (paracetamol) is the most commonly used pain and fever medication during pregnancy, and recently has been linked to hyperactivity and behavioral problems in children. We examine whether prenatal use of acetaminophen affects children's intelligence quotient (IQ). We studied 1,491 mothers and children enrolled in the Danish National Birth Cohort (DNBC; 1996-2002). Acetaminophen use in pregnancy was prospectively recorded in three telephone interviews. Child IQ was assessed at age 5 with the Wechsler Primary and Preschool Scales of Intelligence-Revised (WPPSI-R) administered by trained psychologists. We employed linear regression analysis, adjusting for maternal IQ and other confounding factors, and assessed interactions between acetaminophen and indications for use. Both maternal fever in pregnancy and acetaminophen use were associated with child IQ. Children born to mothers using acetaminophen without reporting fever scored on average 3.4 points lower (95% confidence interval [CI]: 0.30 to 6.6 points) on performance IQ compared with offspring of mothers who neither experienced fever nor took acetaminophen. Estimated effects for acetaminophen were stronger for first or second trimester use. Children born to mothers reporting fever without using acetaminophen also scored lower on verbal (2.7 points, 95% CI: -0.19, 5.6) and performance IQ (4.3 points, 95% CI: 0.30, 8.3); IQ scores were not affected if mothers with fever used acetaminophen. Maternal acetaminophen use during pregnancy was associated with lower performance IQ in 5-year olds. However, acetaminophen treatment of maternal fever in pregnancy showed an apparent compensatory association with child IQ scores. (See video abstract at http://links.lww.com/EDE/B87.).

Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study.

Acetaminophen (paracetamol) is the most commonly used pain and fever medication during pregnancy. Previously, a positive ecological correlation between acetaminophen use and autism spectrum disorders (ASD) has been reported but evidence from larger studies based on prospective data is lacking. We followed 64,322 children and mothers enrolled in the Danish National Birth Cohort (DNBC; 1996-2002) for average 12.7 years to investigate whether acetaminophen use in pregnancy is associated with increased risk of ASD in the offspring. Information on acetaminophen use was collected prospectively from three computer-assisted telephone interviews. We used records from the Danish hospital and psychiatric registries to identify diagnoses of ASD. At the end of follow up, 1,027 (1.6%) children were diagnosed with ASD, 345 (0.5%) with infantile autism. We found that 31% of ASD (26% of infantile autism) have also been diagnosed with hyperkinetic disorders. More than 50% women reported ever using acetaminophen in pregnancy. We used Cox proportional hazards model to estimate hazard ratio (HR) and 95% confident interval (CI). Prenatal use of acetaminophen was associated with an increased risk of ASD accompanied by hyperkinetic symptoms (HR = 1.51 95% CI 1.19-1.92), but not with other ASD cases (HR = 1.06 95% CI 0.92-1.24). Longer duration of use (i.e., use for >20 weeks in gestation) increased the risk of ASD or infantile autism with hyperkinetic symptoms almost twofold. Maternal use of acetaminophen in pregnancy was associated with ASD with hyperkinetic symptoms only, suggesting acetaminophen exposure early in fetal life may specifically impact this hyperactive behavioral phenotype. Autism Res 2016, 9: 951-958. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Association of prenatal exposure to acetaminophen and coffee with childhood asthma

Some studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma, and whether such a potential association could be modified by maternal coffee consumption. We included 63,652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards regression model. After adjusting for potential confounders, acetaminophen use during pregnancy was associated with an increased risk of offspring asthma (HR = 1.16, 95% confidence interval (CI): 1.11-1.22). Coffee drinking during pregnancy was associated with a slightly decreased risk (HR = 0.94, 95%CI: 0.90-0.99). But there was no strong evidence of effect measure modification of acetaminophen use on offspring asthma by coffee consumption. Acetaminophen use during pregnancy was associated with a modest increased risk for offspring asthma, which was not modified by coffee consumption.