Zeyan Liew

Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders

IMPORTANCE Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. OBJECTIVE To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children. DESIGN, SETTING, AND PARTICIPANTS We studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002. EXPOSURES Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth. MAIN OUTCOMES AND MEASURES To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen. RESULTS More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mothers mental health problems, or other potential confounders we evaluated. CONCLUSIONS AND RELEVANCE Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.

Parental Smoking During Pregnancy and ADHD in Children: The Danish National Birth Cohort

BACKGROUND: Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. METHODS: We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. RESULTS: Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. CONCLUSIONS: Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.

Household organophosphorus pesticide use and Parkinson’s disease

BACKGROUND Household pesticide use is widespread in the USA. Since the 1970s, organophosphorus chemicals (OPs) have been common active ingredients in these products. Parkinsons disease (PD) has been linked to pesticide exposures but little is known about the contributions of chronic exposures to household pesticides. Here we investigate whether long-term use of household pesticides, especially those containing OPs, increases the odds of PD. METHODS In a population-based case-control study, we assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Using logistic regression we estimated the effects of household pesticide use. RESULTS Frequent use of any household pesticide increased the odds of PD by 47% [odds ratio (OR)=1.47, (95% confidence interval (CI): 1.13, 1.92)]; frequent use of products containing OPs increased the odds of PD more strongly by 71% [OR=1.71, (95% CI: 1.21, 2.41)] and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs. CONCLUSIONS We provide evidence that household use of OP pesticides is associated with an increased risk of developing PD.

Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case-control study in the Danish National Birth Cohort.

Background: Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited. Objectives: We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children. Methods: Among 83,389 mother–child pairs enrolled in the Danish National Birth Cohort during 1996–2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child’s sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights. Results: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother’s PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise. Conclusions: In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children. Citation: Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei CY, Bossi R, Henriksen TB, Bonefeld-Jørgensen EC, Olsen J. 2015. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case–control study in the Danish National Birth Cohort. Environ Health Perspect 123:367–373; http://dx.doi.org/10.1289/ehp.1408412

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.

Job exposure matrix (JEM)-derived estimates of lifetime occupational pesticide exposure and the risk of Parkinson's disease.

ABSTRACT Studies that report an association between Parkinsons disease (PD) and occupational pesticide exposure often use self-reported exposure and none adjust for concomitant ambient pesticide exposure. For a population-based case-control study of PD conducted in Californias heavily agricultural region, the authors developed a comprehensive job exposure matrix (JEM) to assess occupational exposure to pesticides. Relying on 357 incident cases and 750 population controls enrolled between 2001 and 2011, the authors estimated more than a 2-fold risk increase for PD among men classified as highly occupationally exposed. The authors also observed an exposure-response pattern and farming tasks with direct and intense pesticide exposures such as spraying and handling of pesticides resulted in greater risks than indirect bystander exposures. Results did not change after adjustment for ambient pesticide exposure. The authors provide further evidence that occupational pesticide exposure increases the risk of PD.

Prenatal Exposure to Perfluoroalkyl Substances and the Risk of Congenital Cerebral Palsy in Children

Perfluoroalkyl substances (PFASs) are persistent pollutants and endocrine disruptors that may affect fetal brain development. We investigated whether prenatal exposure to PFASs increases the risk of congenital cerebral palsy (CP). The source population for this study includes 83,389 liveborn singletons and mothers enrolled in the Danish National Birth Cohort during 1996-2002. We identified 156 CP cases by linking the cohort to the Danish National Cerebral Palsy Register, and we randomly selected 550 controls using a case-cohort design. We measured 16 PFASs in maternal plasma collected in early or midpregnancy, and 6 PFASs were quantifiable in more than 90% of the samples. We found a higher risk of CP in boys with higher maternal PFAS levels; per 1-unit (natural-log ng/mL) increase, the risk ratios were 1.7 (95% confidence interval: 1.0, 2.8) for perfluorooctane sulfonate and 2.1 (95% confidence interval: 1.2, 3.6) for perfluorooctanoic acid. We also observed a dose-response pattern of CP risk in boys per quartile of maternal level of perfluorooctane sulfonate and perfluorooctanoic acid (P for trend < 0.01). PFASs were associated with both unilateral and bilateral spastic CP subphenotypes. No association between PFASs and CP was found in girls. Prenatal exposures to PFASs may increase the risk of CP in boys, but the finding is novel and replication is needed.

Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders

Objective: To evaluate whether early folic acid supplementation during pregnancy prevents diagnosis of autism spectrum disorders in offspring. Methods: Information on autism spectrum disorder diagnosis was obtained from the National Hospital Register and the Central Psychiatric Register. We estimated risk ratios for autism spectrum disorders for children whose mothers took folate or multivitamin supplements from 4 weeks prior from the last menstrual period through to 8 weeks after the last menstrual period (−4 to 8 weeks) by three 4-week periods. Results: We did not find an association between early folate or multivitamin intake for autism spectrum disorder (folic acid—adjusted risk ratio: 1.06, 95% confidence interval: 0.82–1.36; multivitamin—adjusted risk ratio: 1.00, 95% confidence interval: 0.82–1.22), autistic disorder (folic acid—adjusted risk ratio: 1.18, 95% confidence interval: 0.76–1.84; multivitamin—adjusted risk ratio: 1.22, 95% confidence interval: 0.87–1.69), Asperger’s syndrome (folic acid—adjusted risk ratio: 0.85, 95% confidence interval: 0.46–1.53; multivitamin—adjusted risk ratio: 0.95, 95% confidence interval: 0.62–1.46), or pervasive developmental disorder–not otherwise specified (folic acid—adjusted risk ratio: 1.07, 95% confidence interval: 0.75–1.54; multivitamin: adjusted risk ratio: 0.87, 95% confidence interval: 0.65–1.17) compared with women reporting no supplement use in the same period. Conclusion: We did not find any evidence to corroborate previous reports of a reduced risk for autism spectrum disorders in offspring of women using folic acid supplements in early pregnancy.

Genetic Variability in ABCB1, Occupational Pesticide Exposure, and Parkinson’s Disease

BACKGROUND Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinsons Disease (PD) risk. OBJECTIVES To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk. METHODS In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD. RESULTS For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions. CONCLUSIONS This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.

Fetal growth and air pollution - A study on ultrasound and birth measures

Abstract Air pollution has been suggested to affect fetal growth, but more data is needed to assess the timing of exposure effects by using ultrasound measures. It is also important to study effects in low exposure areas to assess eventual thresholds of effects. The MAPSS (Maternal Air Pollution in Southern Sweden) cohort consists of linked registry data for around 48,000 pregnancies from an ultrasound database, birth registry and exposure data based on residential addresses. Measures of air pollution exposure were obtained through dispersion modelling with input data from an emissions database (NOx) with high resolution (100–500 m grids). Air pollution effects were assessed with linear regressions for the following endpoints; biparietal diameter, femur length, abdominal diameter and estimated fetal weight measured in late pregnancy and birth weight and head circumference measured at birth. We estimated negative effects for NOx; in the adjusted analyses the decrease of abdominal diameter and femur length were −0.10 (−0.17, −0.03) and −0.13 (−0.17, −0.01) mm, respectively, per 10 &mgr;g/m3 increment of NOx. We also estimated an effect of NOx‐exposures on birth weight by reducing birth weight by 9 g per 10 &mgr;g/m3 increment of NOx. We estimated small but statistically significant effects of air pollution on late fetal and birth size and reduced fetal growth late in pregnancy in a geographic area with levels below current WHO air quality guidelines. HighlightsLargest study on ultrasound measures and air pollution to date.Individual data on potential confounders (also SES) and nitrogen oxides.Area with levels below current WHO air quality guidelines.Birth weight was reduced by 9 g per 10 &mgr;g/m3 increment of NOx.Small but statistically significant effects of air pollution on late fetal size.