Prenatal Acetaminophen Exposure Research Articles

Retraction Note: Impact of Prenatal Acetaminophen Exposure for Hippocampal Development Disorder on Mice.

Retraction Note: Impact of Prenatal Acetaminophen Exposure for Hippocampal Development Disorder on Mice.

Prenatal acetaminophen exposure and the developing ovary: Time, dose, and course consequences for fetal mice

Acetaminophen is an emerging endocrine disrupting chemical and has been detected in various natural matrices. Numerous studies have documented developmental toxicity associated with prenatal acetaminophen exposure (PAcE). In this study, we established a PAcE Kunming mouse model at different time (middle pregnancy and third trimester), doses (low, middle, high) and courses (single or multi-) to systematically investigate their effects on fetal ovarian development. The findings indicated PAcE affected ovarian development, reduced fetal ovarian oocyte number and inhibited cell proliferation. A reduction in mRNA expression was observed for genes associated with oocyte markers (NOBOX and Figlα), follicular development markers (BMP15 and GDF9), and pre-granulosa cell steroid synthase (SF1 and StAR). Notably, exposure in middle pregnancy, high dose, multi-course resulted in the most pronounced inhibition of oocyte development; exposure in third trimester, high dose and multi-course led to the most pronounced inhibition of follicular development; and in third trimester, low dose and single course, the inhibition of pre-granulosa cell function was most pronounced. Mechanistic investigations revealed that PAcE had the most pronounced suppression of the ovarian Notch signaling pathway. Overall, PAcE caused fetal ovarian multicellular toxicity and inhibited follicular development with time, dose and course differences.

The relationship of prenatal acetaminophen exposure and attention-related behavior in early childhood

Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be related to poorer neurodevelopmental outcomes. Multiple studies have suggested that it may be associated with attention problems, but few have examined this association by trimester of exposure. The Illinois Kids Development Study is a prospective birth cohort located in east-central Illinois. Exposure data were collected between December 2013 and March 2020, and 535 newborns were enrolled during that period. Mothers reported the number of times they took acetaminophen at six time points across pregnancy. When children were 2, 3, and 4 years of age, caregivers completed the Child Behavior Checklist for ages 1.5–5 years (CBCL). Associations of acetaminophen use during pregnancy with scores on the Attention Problems and ADHD Problems syndrome scales, the Internalizing and Externalizing Behavior composite scales, and the Total Problems score were evaluated. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher Attention Problems, ADHD Problems, Externalizing Behavior, and Total Problems scores at ages 2 and 3. Higher second trimester exposure was only associated with higher Externalizing Behavior and Total Problems scores at 4 years. Higher cumulative exposure across pregnancy was associated with higher Attention Problems and ADHD Problems scores at ages 2 and 3. Findings suggest that prenatal acetaminophen exposure, especially during the second trimester, may be related to problems with attention in early childhood.

Postnatal acetaminophen exposure and neurodevelopmental outcomes at 18-21 months corrected gestational age in preterm infants

Studies have reported prenatal acetaminophen exposure is associated with abnormal neurodevelopment. There is limited and conflicting data on neurodevelopmental outcomes following postnatal acetaminophen exposure. Our objective was to investigate the neurodevelopmental outcomes of preterm infants < 29 weeks gestation postnatally exposed to acetaminophen. Retrospective cohort study of infants born between 2008 and 2017 at a tertiary care perinatal center. Exclusion criteria included chromosomal disorders, major congenital abnormalities, and congenital infections. The primary outcome was a composite score of <85 on the cognitive, language, or motor components of the Bayley Scales of Infant and Toddler Development, 3rd edition, assessed at 18 to 21 months corrected gestational age. Multivariate logistic regression was used to assess confounders. Of the 945 infants included in the study, 120 were in the acetaminophen group. There was no difference in any of Bayley-III cognitive, language or motor composite scores of < 85 between the two groups for postnatal acetaminophen exposure, adjusted odds ratios (aORs) 1.03, 95% CI 0.60-1.78, or days of acetaminophen use, aORs 1.10, 95% CI 0.93-1.29. There was no difference in neurodevelopmental outcome between the acetaminophen exposed and non-exposed groups. Our results need validation in larger cohorts. Animal research and cohort studies have suggested that prenatal acetaminophen exposure may be associated with an elevated risk of neurobehavioral abnormalities. However, there is limited and conflicting research on the impact of postnatal acetaminophen on neurodevelopment. The results of this study suggest that postnatal acetaminophen does not negatively impact neurodevelopment at 18 to 21 months in preterm infants born at <29 weeks gestational age. While these results need validation in larger and more longitudinal studies, this study provides reassurance for the use of postnatal acetaminophen in extremely preterm infants.

Prenatal exposure to acetaminophen at different doses, courses and time causes testicular dysplasia in offspring mice and its mechanism

Epidemiological investigation suggested that the use of acetaminophen during pregnancy may cause offspring testicular dysplasia, but no systematic study has been conducted. In this study, Kunming mice were given acetaminophen at different doses (100/200/400 mg/kg.d), courses (single/multiple), time (second/third trimester) during pregnancy. Fetal blood and testes were collected on gestaional day 18 for detection. The results indicated abnormal testicular development in the PAcE (prenatal acetaminophen exposure) groups. The maximum diameter/cross-sectional area decreased, the interstitial space widened, and decreased proliferation/increased apoptosis were observed, especially in the high-dose, multi-course and second-trimester groups. Meanwhile, the serum testosterone level decreased in PAcE groups, and the steroid synthesis function in Leydig cells, Sertoli and spermatogenic cell function were inhibited, it was more significant in high-dose, multi-course and second-trimester groups. Furthermore, Wnt signal pathway was activated but Notch signal pathway was inhibited in the PAcE groups. Finally, in vitro experiment, acetaminophen could inhibit spermatogonial cell proliferation, enhance apoptosis, and change Wnt/Notch signal pathway. In conclusion, this study confirmed that PAcE can change fetal testicular development in a dose, course and time-dependent manner, and found that multicellular function impaired. This study provides theoretical and experimental basis for systematically elucidating the developmental toxicity of acetaminophen in testis.

Effects of prenatal acetaminophen exposure at different stages, doses and courses on articular cartilage of offspring mice.

Previous studies showed that chondrodysplasia has intrauterine origin. Although prenatal acetaminophen exposure (PAcE) can cause nervous and reproductive abnormalities in offspring, its effect on cartilage is uninvestigated. Herein, mice were treated with different doses and courses of acetaminophen at various gestational stages (100 or 400mg/kg∙d on gestational days 10-12 (GD10-12), 400mg/kg∙d on GD12 or GD15-17) based on clinical administration and conversion between humans and mice. Fetal knee joints were harvested on GD18 to analyze cartilage morphology, chondrocyte proliferation and apoptosis, and matrix content, synthesis and degradation. Results showed that 400mg/kg∙d acetaminophen exposure during GD10-12 decreased chondrocyte numbers, safranin O staining, proliferation and matrix synthesis, without elevating matrix degradation and apoptosis. Low-dose, single-course, or late-pregnancy exposure had no effect on above indexes. Moreover, Tgfβ pathway was inhibited, showing a positive correlation with the expression of Col2a1, Acan, Ki67, and Pcna. Overall, clinical doses of PAcE can inhibit chondrocyte proliferation and matrix synthesis, causing fetal mice chondrodysplasia, especially after multi-course exposure of 400mg/kg∙d acetaminophen during GD10-12, the mechanism of which might involve Tgfβ pathway inhibition. This study provides an experimental basis for assessing fetal developmental toxicity and standardizing the clinical use of acetaminophen during pregnancy.

Course-, dose-, and stage-dependent toxic effects of prenatal acetaminophen exposure on fetal long bone development

Acetaminophen is a common analgesic and fever reduction medicine for pregnant women. Epidemiological studies suggest that prenatal acetaminophen exposure (PAcE) affects offspring health and development. However, the effects of PAcE on fetal long bone development and its potential mechanisms have not been elucidated. Based on clinical dosing characteristics, fetal mouse femurs were obtained for detection after oral gavage of acetaminophen at different doses (0, 100 or 400 mg/kg d), courses (single or multiple times) or stages (mid- or late pregnancy) during pregnancy in Kunming mice. The results showed that compared with the control group, PAcE reduced the length of total femur and the primary ossification center (POC), delayed the mineralization of POC and the ossification of epiphyseal region, and down-regulated the mRNA expression of osteogenic function markers (such as Runx2, Bsp, Ocn , Col1a1) in fetal femur, particularly in the high dose, multiple courses, and mid-pregnancy group. Meanwhile, the osteoclast and angiogenic function were also inhibited by PAcE at high dose, multiple courses, and mid-pregnancy, but the inhibition level was less than osteogenic function. Moreover, the alteration of canonical Wnt signalling pathway in PAcE fetal bone were consistent with its osteogenesis function changes. In conclusion, PAcE caused development toxicity and multi-cellular function inhibition in fetal long bone, particularly in the high dose, multiple treatments and mid-pregnancy group, and the alteration of canonical Wnt signalling pathway may be its potential mechanism.

Impact of Prenatal Acetaminophen Exposure for Hippocampal Development Disorder on Mice.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic agents. They have been detected in various environmental matrices. The degradation of environmental contaminants and the long-term adverse effects have become a major public concern. Prenatal exposure to acetaminophen can cause damage to the developing hippocampus. However, the molecular mechanisms behind hippocampal damage following prenatal acetaminophen exposure (PAcE) remain unclear. The present study shows an increased risk of adverse neurodevelopmental outcomes in offspring following exposure to acetaminophen during pregnancy on mice. The results revealed that different doses, timings, and duration of exposure to acetaminophen during pregnancy were associated with dose-dependent changes in the hippocampus of the offspring. Furthermore, exposure to high doses, multiple-treatment courses, and late pregnancy induced pathological changes, such as wrinkling and vacuolation, inhibited hippocampal proliferation and increased apoptosis. In addition, PAcE significantly decreased the expression of genes related to synaptic development in fetal hippocampal neurons and hippocampal astrocyte and microglia were also damaged to varying degrees. The significant reduction either in SOX2, an essential gene in regulating neural progenitor cell proliferation, and reduction of genes related to the SOX2/Notch pathway may suggest that the role of SOX2/Notch pathway in impaired hippocampal development in the offspring due to PAcE. In general, PAcE at high doses, multiple-treatment courses, and mid- and late gestation were associated with neurodevelopmental toxicity to the offspring.

Prenatal exposure to acetaminophen and adolescent assessment of behavior: Discrepancies by age and reporter.

Acetaminophen, which is one of the most commonly used medications during pregnancy, has been linked to adverse neurodevelopmental outcomes among offspring during childhood. Less is known about associations with outcomes occurring later in adolescence. Methods: We conducted a follow-up study of children born between 1996 and 2002. Data on illnesses and medications, including acetaminophen, during pregnancy were collected through a standardized interview after delivery. Behavioral assessments were conducted at two subsequent time points, childhood (ages 5-10) and adolescence (ages 11-17). Outcomes examined included internalizing, externalizing, and total behavior problems based on the parent-completed Child Behavior Checklist (CBCL), the teacher-completed Teacher Report Form (TRF), and the youth-completed Youth Self Report (YSR, adolescent follow-up only). Adjusted linear regression models were used to calculate mean differences (MD) and 95% confidence intervals (95% CI) in T-scores comparing those with prenatal acetaminophen exposure to those without. Stabilized inverse probability weights were used to account for attrition. Results: Among the 216 mother-child dyads with completed parent and teacher behavioral assessments at both childhood and adolescence, prenatal acetaminophen exposure was not associated with behavioral problems according to either parent or teacher assessments. Modest increases in externalizing and total behavior problems were observed according to youth report (MD: 1.9). Compared to associations observed during the childhood follow-up, associations at adolescence were attenuated according to parent-report. Conclusion: Reported associations between prenatal acetaminophen exposure and behavioral outcomes were not consistent over time nor between reporters.

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.

In Utero Exposure to Caffeine and Acetaminophen, the Gut Microbiome, and Neurodevelopmental Outcomes: A Prospective Birth Cohort Study.

Pregnant individuals are exposed to acetaminophen and caffeine, but it is unknown how these exposures interact with the developing gut microbiome. We aimed to determine whether acetaminophen and/or caffeine relate to the childhood gut microbiome and whether features of the gut microbiome alter the relationship between acetaminophen/caffeine and neurodevelopment. Forty-nine and 85 participants provided meconium and stool samples at 6–7, respectively, for exposure and microbiome assessment. Fecal acetaminophen and caffeine concentrations were quantified, and fecal DNA underwent metagenomic sequencing. Caregivers and study staff assessed the participants’ motor and cognitive development using standardized scales. Prenatal exposures had stronger associations with the childhood microbiome than concurrent exposures. Prenatal acetaminophen exposure was associated with a trend of lower gut bacterial diversity in childhood [β = −0.17 Shannon Index, 95% CI: (−0.31, −0.04)] and was marginally associated with differences in the relative abundances of features of the gut microbiome at the phylum (Firmicutes, Actinobacteria) and gene pathway levels. Among the participants with a higher relative abundance of Proteobacteria, prenatal exposure to acetaminophen and caffeine was associated with lower scores on WISC-IV subscales. Acetaminophen during bacterial colonization of the naïve gut is associated with lasting alterations in childhood microbiome composition. Future studies may inform our understanding of downstream health effects.

Association of Prenatal Acetaminophen Exposure Measured in Meconium With Adverse Birth Outcomes in a Canadian Birth Cohort.

BackgroundThe small number of studies examining the association of prenatal acetaminophen with birth outcomes have all relied on maternal self-report. It remains unknown whether prenatal acetaminophen exposure measured in a biological specimen is associated with birth outcomes.ObjectivesTo investigate the association of acetaminophen measured in meconium with birthweight, gestational age, preterm birth, size for gestational age, gestational diabetes, preeclampsia, and high blood pressure.MethodsThis birth cohort from Sherbrooke, QC, Canada, included 773 live births. Mothers with no thyroid disease enrolled at their first prenatal care visit or delivery. Acetaminophen was measured in meconium for 393 children at delivery. We tested associations of prenatal acetaminophen with birthweight, preterm birth, gestational age, small and large for gestational age, gestational diabetes, preeclampsia, and high blood pressure. We imputed missing data via multiple imputation and used inverse probability weighting to account for confounding and selection bias.ResultsAcetaminophen was detected in 222 meconium samples (56.5%). Prenatal acetaminophen exposure was associated with decreased birthweight by 136 g (β = −136; 95% CI [−229, −43]), 20% increased weekly hazard of delivery (hazard ratio = 1.20; 95% CI [1.00, 1.43]), and over 60% decreased odds of being born large for gestational age (odds ratio = 0.38; 95% CI [0.20, 0.75]). Prenatal acetaminophen was not associated with small for gestational age, preterm birth, or any pregnancy complications.ConclusionPrenatal acetaminophen was associated with adverse birth outcomes. Although unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.

18.2 ASSOCIATION OF PRENATAL ACETAMINOPHEN WITH CHILD ADHD IS MEDIATED BY FUNCTIONAL BRAIN CONNECTIVITY BUT NOT BIRTH OUTCOMES

This presentation aims to evaluate associations of prenatal acetaminophen exposure measured in meconium with child ADHD, and to test birth outcomes and functional brain connectivity as potential mediators. Mothers were enrolled into this birth cohort study in Sherbrooke, Québec, Canada at their first prenatal care visit or delivery. Acetaminophen was measured in the meconium. A physician diagnosis of ADHD was determined at follow-up when children were 6 to 7 years old or from medical records. When children were 9 to 11 years old, resting-state brain connectivity was assessed with MRI, and attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between the meconium, acetaminophen, and outcomes were estimated with linear, logistic, and cox proportional hazards models. Birth outcomes and resting-state brain connectivity were tested as mediators of the association between prenatal acetaminophen exposure and ADHD. Among 345 children included in the analysis, acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Detection of acetaminophen in meconium was associated with increased odds of ADHD (OR = 2.43; 95% CI, 1.41-4.21). Prenatal acetaminophen was associated with negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14% mediation; 95% CI, 1-26). Although prenatal acetaminophen exposure was associated with decreased birthweight by 128 grams (β = –128; 95% CI, –221 to –36), and 22% increased weekly hazard of delivery (hazard ratio = 1.22; 95% CI, 1.06-1.40), birth outcomes did not mediate an effect on ADHD. Although unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.

ADHD: NEUROBIOLOGICAL AND PSYCHOSOCIAL APPROACHES TO PREVENTION AND TREATMENT

ADHD is one of the most common mental health disorders affecting youth. While existing treatments are effective in controlling symptoms of the disorder over the short term, longer-term effects of ADHD remain an area of significant concern, highlighting the importance of advancing new preventive efforts and novel treatments. Here, we present 4 studies aimed at advancing neurobiological and psychosocial approaches to better prevention and treatment of ADHD. The first presentation describes a longitudinal birth cohort study aimed at identifying a prenatal exposure associated with ADHD in school-age children. The second presentation leverages a longitudinal, probability-based sample of Puerto Rican children to study the association between ADHD and adverse childhood experiences (ACEs). The third presentation describes a mechanistic study of psychostimulants’ therapeutic effects by coupling neuroimaging with an RCT. The fourth presentation describes a novel psychosocial treatment for ADHD. The first presentation demonstrates an association between prenatal acetaminophen exposure measured from fetal meconium and the subsequent development of ADHD in childhood. In the second presentation, we show that the diagnosis of ADHD prospectively increases risk of children experiencing adversity. The third presentation highlights the importance of a novel measurement of brain connectivity in understanding the mechanisms by which psychostimulants reduce ADHD symptoms. In the last presentation, we offer initial support for a novel mindfulness-based intervention as a feasible and efficacious approach to treating ADHD. ADHD is a chronic disorder and is associated with a host of long-term negative outcomes. In these 4 presentations, we describe new insights that may advance prevention strategies as well as novel treatment development, with the goal of limiting the negative effects of this highly common and impairing condition.

Prenatal Exposure to Acetaminophen and Childhood Asthmatic Symptoms in a Population-Based Cohort in Los Angeles, California.

Acetaminophen is the most common over-the-counter pain and fever medication used by pregnant women. While European studies suggest acetaminophen exposure in pregnancy could affect childhood asthma development, findings are less consistent in other populations. We evaluated whether maternal prenatal acetaminophen use is associated with childhood asthmatic symptoms (asthma diagnosis, wheeze, dry cough) in a Los Angeles cohort of 1201 singleton births. We estimated risk ratio (RR) and 95% confidence interval (CI) for childhood asthmatic outcomes according to prenatal acetaminophen exposure. Effect modification by maternal race/ethnicity and psychosocial stress during pregnancy was evaluated. The risks for asthma diagnosis (RR = 1.39, 95% CI 0.96, 2.00), wheezing (RR = 1.25, 95% CI 1.01, 1.54) and dry cough (RR =1.35, 95% CI 1.06, 1.73) were higher in children born to mothers who ever used acetaminophen during pregnancy compared with non-users. Black/African American and Asian/Pacific Islander children showed a greater than two-fold risk for asthma diagnosis and wheezing associated with the exposure. High maternal psychosocial stress also modified the exposure-outcome relationships. Acetaminophen exposure during pregnancy was associated with childhood asthmatic symptoms among vulnerable subgroups in this cohort. A larger study that assessed prenatal acetaminophen exposure with other social/environmental stressors and clinically confirmed outcomes is needed.

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.

22566 Identifying metabolic mechanisms linking prenatal acetaminophen exposure to childhood attention-deficit hyperactivity disorder

ABSTRACT IMPACT: This study has implications for understanding early developmental mechanisms of ADHD and for guidelines regarding safe use of acetaminophen during pregnancy. OBJECTIVES/GOALS: Prenatal acetaminophen exposure has been associated with childhood attention-deficit hyperactivity disorder (ADHD), but the underlying mechanism is unknown. This prospective birth cohort study aims to identify linkages between specific metabolites in umbilical cord plasma and the association of prenatal acetaminophen exposure and ADHD. METHODS/STUDY POPULATION: The sample was a subset of the Boston Birth Cohort that included 583 mother-newborn dyads followed at Boston Medical Center from 1998 to 2018. Metabolites were measured from cord plasma collected at birth. Based on existing literature, the analyses focused on candidate metabolites involved in neuroendocrine, inflammation, and oxidative stress pathways. The outcome was physician-diagnosed ADHD between the ages of 3 and 16 years. Exploratory analyses and multiple logistic regressions were used to examine the association of these candidate metabolites with both unmetabolized cord plasma acetaminophen levels and with incident risk of ADHD, adjusting for covariates of maternal and child characteristics. RESULTS/ANTICIPATED RESULTS: Of the 583 children, 257 had ADHD and 326 had neurotypical development. Two promising results have been found thus far. 5-methoxytryptophol (5-MTX), a neuroendocrine molecule which also has antioxidant and immunomodulatory properties, was inversely associated with acetaminophen and ADHD risk. For children below the median cord 5-MTX level, the odds of ADHD were 3.29 (95% CI [1.56, 7.16], p=0.002) for the third tertile of acetaminophen compared to the first tertile. This association attenuated among those above the median 5-MTX level: 2.23 (95% CI [0.98, 5.21], p=0.059), suggesting a protective effect. Tryptophan, an essential amino acid and precursor of serotonin, was positively associated with acetaminophen and ADHD. Next steps include mediation analysis with tryptophan and analyses for other metabolites. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study identifies cord plasma metabolites as possible modifiers or mediators linking prenatal acetaminophen exposure and childhood ADHD, which may offer insight into a mechanistic pathway. The study findings have implications for FDA, clinical, and public health guidelines regarding safe use of acetaminophen during pregnancy.

Acetaminophen Attenuates invasion and alters the expression of extracellular matrix enzymes and vascular factors in human first trimester trophoblast cells

Acetaminophen is one of the most common medications taken during pregnancy, considered safe for maternal health and fetal development. However, recent epidemiological studies have associated prenatal acetaminophen use with several developmental disorders in offspring. As acetaminophen can freely cross into and through the placenta, epidemiological associations with prenatal acetaminophen use may reflect direct actions on the fetus and/or the impact of altered placental functions. In the absence of rigorous mechanistic studies, our understanding of how prenatal acetaminophen exposure can cause long-term effects in offspring is limited. The objective of this study was to determine whether acetaminophen can alter key functions of a major placental cell type by utilizing immortalized human first trimester trophoblast cells. This study employed a comparative analysis with the nonsteroidal, anti-inflammatory drug aspirin, which has established effects in first trimester trophoblast cells. We report that immortalized trophoblast cells express the target proteins of acetaminophen and aspirin: cyclooxygenase (COX) −1 and −2. Unlike aspirin, acetaminophen significantly repressed the expression of angiogenesis and vascular remodeling genes in HTR-8/SVneo cells. Moreover, acetaminophen impaired trophoblast invasion by over 80%, while aspirin had no effect on invasion. Acetaminophen exposure reduced the expression of matrix metalloproteinase (MMP)-2 and −9 and increased the expression of tissue inhibitors of matrix metalloproteinases 2, leading to an imbalance in the ratio of proteolytic enzymes. Finally, a bioinformatic approach identified novel acetaminophen-responsive gene networks associated with key trophoblast functions and disease. Together these results suggest that prenatal acetaminophen use may interfere with critical trophoblast functions early in gestation, which may subsequently impact fetal development.

Association of Prenatal Acetaminophen Measured in Meconium with Attention-Deficit Hyperactivity Disorder

Background Multiple studies have shown an association between prenatal acetaminophen exposure and attention-deficit hyperactivity disorder (ADHD), but questions remain due to a paucity of quantifiable dose-response estimates and poor understanding of fetal exposure to acetaminophen and its toxic metabolites. To address this gap, we examined the association between prenatal acetaminophen concentrations measured in meconium and ADHD diagnosis in children aged 6-7 years. Methods Acetaminophen was measured in meconium with ultraperformance liquid chromatography mass spectrometry and ADHD diagnosis was determined at a scheduled cohort follow-up when children were 6-7 years old or from medical records for 345 children in the Gestation and the Environment prospective observational pregnancy cohort in Sherbrooke, Quebec, Canada. We modeled the associations of both binary (detected versus not detected) and continuous meconium acetaminophen with ADHD using logistic regressions. We compared continuous linear and non-linear models with a likelihood ratio test. We employed inverse probability weighting with propensity scores to account for potential confounders, including child sex, familial income, and maternal age, education, pre-pregnancy BMI, smoking during pregnancy, alcohol during pregnancy, and maternal self-reported ADHD. Results Acetaminophen was detected in 199 meconium samples (58%) and ADHD was diagnosed in 33 children (10%). Compared to no acetaminophen, detection of acetaminophen in meconium was associated with more than double the odds of ADHD (odds ratio = 2.44 [1.41, 4.22]). There was a linear dose response relationship: each doubling of exposure increased the odds of ADHD by 10% (OR = 1.10 [1.02, 1.19]). Conclusions and Relevance Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.

Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity

Despite evidence of an association between prenatal acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD) in offspring, the drug is not contraindicated during pregnancy, possibly because prior studies have relied on maternal self-report, failed to quantify acetaminophen dose, and lacked mechanistic insight. To examine the association between prenatal acetaminophen exposure measured in meconium (hereinafter referred to as meconium acetaminophen) and ADHD in children aged 6 to 7 years, along with the potential for mediation by functional brain connectivity. This prospective birth cohort study from the Centre Hospitalier Université de Sherbrooke in Sherbrooke, Québec, Canada, included 394 eligible children, of whom 345 had meconium samples collected at delivery and information on ADHD diagnosis. Mothers were enrolled from September 25, 2007, to September 10, 2009, at their first prenatal care visit or delivery and were followed up when children were aged 6 to 7 years. When children were aged 9 to 11 years, resting-state brain connectivity was assessed with magnetic resonance imaging. Data for the present study were collected from September 25, 2007, to January 18, 2020, and analyzed from January 7, 2019, to January 22, 2020. Acetaminophen levels measured in meconium. Physician diagnosis of ADHD was determined at follow-up when children were aged 6 to 7 years or from medical records. Resting-state brain connectivity was assessed with magnetic resonance imaging; attention problems and hyperactivity were assessed with the Behavioral Assessment System for Children Parent Report Scale. Associations between meconium acetaminophen levels and outcomes were estimated with linear and logistic regressions weighted on the inverse probability of treatment to account for potential confounders. Causal mediation analysis was used to test for mediation of the association between prenatal acetaminophen exposure and hyperactivity by resting-state brain connectivity. Among the 345 children included in the analysis (177 boys [51.3%]; mean [SD] age, 6.58 [0.54] years), acetaminophen was detected in 199 meconium samples (57.7%), and ADHD was diagnosed in 33 children (9.6%). Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21). A dose-response association was detected; each doubling of exposure increased the odds of ADHD by 10% (OR, 1.10; 95% CI, 1.02-1.19). Children with acetaminophen detected in meconium showed increased negative connectivity between frontoparietal and default mode network nodes to clusters in the sensorimotor cortices, which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%). Together with the multitude of other cohort studies showing adverse neurodevelopment associated with prenatal acetaminophen exposure, this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.