Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Epigenetic modifications, such as DNA methylation, due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a major risk factor for multiple adverse health outcomes in children, but the underlying mechanisms are unclear.
We investigated epigenome-wide methylation in cord blood of newborns in relation to maternal smoking during pregnancy.
We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord blood samples from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip (450K).
We found differential DNA methylation at epigenome-wide statistical significance (p-value
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.
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.
We studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002.
Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth.
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.
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
This study was designed to test the hypothesis that fetal exposure to corticosteroids in the antenatal period is an independent risk factor for the development of asthma in childhood.
A population-based cohort study was conducted of all pregnant women who resided in Nova Scotia, Canada, and gave birth to a singleton fetus between January 1989 and December 1998 and lived to discharge. After exclusions, 79,395 infants were available for analysis. Using linked health care utilization records, incident asthma cases between 36 to 72 months of age were identified. Generalized Estimating Equations were used to estimate the odds ratio of the association between exposure to corticosteroids and asthma while controlling for confounders.
Over the 10 years of the study corticosteroid therapy increased by threefold. Exposure to corticosteroids during pregnancy was associated with a risk of asthma in childhood: adjusted odds ratio of 1.23 (95% confidence interval: 1.06, 1.44).
Antenatal steroid therapy appears to be an independent risk factor for the development of asthma between 36 and 72 months of age. Further research into the smallest possible steroid dose required to achieve the desired post-natal effect is needed to reduce the risk of developing childhood asthma.
This study was undertaken to (1) measure the frequency of AED monotherapy or polytherapy during pregnancy and AED discontinuation prior to pregnancy in a cohort of women with treated epilepsy; and (2) describe the frequency of major congenital malformations according to maternal use of AED during pregnancy.
A cohort of epileptic pregnant women was identified within the Quebec Pregnancy Registry and was divided into three groups based on maternal AED use during pregnancy: AED monotherapy, AED polytherapy and no AED use.
Of the 349 pregnancies meeting eligibility criteria, 79.6% were exposed to AED monotherapy and 5.8% to polytherapy during pregnancy; 14.6% discontinued AED prior to pregnancy. The most commonly used AEDs were carbamazepine (29.9%) and valproic acid (19.7%); the most common AED polytherapy combination was carbamazepine combined with clobazam (2.5%). Of 111 deliveries in the group of women on monotherapy during pregnancy, 9.9% (n=11) were born with major congenital malformations; in the group of women treated with polytherapy, 19.0% (n=8 over 42) of babies had major congenital malformations compared to 20.0% in women who discontinued AEDs prior to pregnancy.
This study demonstrates that the majority of women suffering from epilepsy were treated with monotherapy rather than polytherapy during pregnancy. While most used other agents, an important number of women continued to use valproate in pregnancy despite the long standing evidence of its teratogenicity and increasing evidence of its neuro-toxicity to the fetus.
To compare the risk for congenital malformations in offspring between women with epilepsy being treated with antiepileptic drugs (AEDs) during pregnancy and those who discontinued their antiepileptic medication before pregnancy in a population-based cohort of female patients with epilepsy.
All patients with epilepsy (n = 20,101) eligible for AED reimbursement for the first time during 1985 to 1994 were identified from the Social Insurance Institution of Finland. Information on births during 1991 to 2000 was obtained from the National Medical Birth Registry. Information on AED use during pregnancy and on pregnancy outcomes was abstracted from medical records.
Congenital malformations were more common among offspring of women on antiepileptic medication (65/1,411; 4.6%) than among offspring of untreated patients (26/939; 2.8%) (p = 0.02). The risk of malformations was substantially higher in the offspring of patients using valproate as monotherapy (OR = 4.18; 95% CI: 2.31, 7.57) or valproate as polytherapy (OR = 3.54; 95% CI: 1.42, 8.11) than of untreated patients. Polytherapy without valproate was not associated with increased risk of malformations.
Excess risk was confined to patients using valproate during pregnancy. The risk for malformations was not elevated in offspring of mothers using carbamazepine, oxcarbazepine, or phenytoin (as monotherapy or polytherapy without valproate).
Secondhand smoke is associated with a myriad of adverse health outcomes. Therefore, it is essential for clinicians to ask precise questions about exposures, particularly for children. We present 4 questions that incorporate several locations of exposure and provide a more comprehensive account of children's smoke exposures than maternal smoking alone.
Cites: JAMA. 1994 Feb 23;271(8):621-38301796
Cites: J Pediatr Health Care. 2011 Nov-Dec;25(6):365-7222018427
Congenital cryptorchidism, i.e. failure of the testicular descent to the bottom of the scrotum, is a common birth defect. The evidence from epidemiological, wildlife, and animal studies suggests that exposure to mixtures of endocrine disrupting chemicals during fetal development may play a role in its pathogenesis. We aimed to assess the association between cryptorchidism and prenatal exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), and polybrominated diphenyl ethers (PBDEs).
We conducted a case-control study consisting of 44 cryptorchid cases, and 38 controls operated for inguinal hernia, umbilical hernia, or hydrocele at the Turku University Hospital or Rigshospitalet, Copenhagen in 2002-2006. During the operation a subcutaneous adipose tissue biopsy was taken. Samples were analysed for 37 PCBs, 17 PCDD/Fs and 14 PBDEs by gas chromatography-high-resolution mass spectrometry. Chemical concentrations were adjusted for postnatal variation introduced by differences in duration of breastfeeding, age at the operation, and country of origin with a multiple linear regression. Association between adjusted and unadjusted chemical concentrations and the risk of cryptorchidism were analysed with logistic regression to get an estimate for odds ratio (OR) of cryptorchidism per multiplication of chemical concentrations with ca. 2.71 (Napier's constant).
Total-TEq i.e. the WHO-recommended 2,3,7,8-TCDD equivalent quantity of 17 dioxins and 12 dioxin-like PCBs and sum of PCDD/Fs were positively associated with cryptorchidism [OR 3.21 (95% CI 1.29-9.09), OR 3.69 (95% CI 1.45-10.9), respectively], when adjusting for country of origin, the duration the child was breastfed, and age at operation. The association between the sum of PCBs and cryptorchidism was close to significant [OR 1.92 (95% CI 0.98-4.01)], whereas the association between the sum of PBDEs and cryptorchidism was not [OR 0.86 (95% CI 0.47-1.54)]. There were no associations between unadjusted chemical concentrations and the risk of cryptorchidism.
Prenatal exposure to PCDD/Fs and PCDD/F-like PCBs may be associated with increased risk for cryptorchidism. Our finding does not exclude the possibility of an association between the exposure to PBDEs and cryptorchidism.
Cites: Scand J Work Environ Health. 1996 Aug;22(4):267-738881015
To date, few attempts have been made to examine associations between exposure to maternal epilepsy with or without antiepileptic drug (AED) therapy and pregnancy and perinatal outcomes.
To investigate associations between epilepsy in pregnancy and risks of pregnancy and perinatal outcomes as well as whether use of AEDs influenced risks.
A population-based cohort study was conducted on all singleton births at 22 or more completed gestational weeks in Sweden from 1997 through 2011; of these, 1?424?279 were included in the sample. Information on AED exposure was available in the subset of offspring from July 1, 2005, to December 31, 2011. Data analysis was performed from October 1, 2016, to February 15, 2017.
Pregnancy, delivery, and perinatal outcomes. Multivariable Poisson log-linear regression was used to estimate adjusted risk ratios (aRRs) and 95% CIs, after adjusting for maternal age, country of origin, educational level, cohabitation with a partner, height, early pregnancy body mass index, smoking, year of delivery, maternal pregestational diabetes, hypertension, and psychiatric disorders.
Of the 1?429?652 births included in the sample, 5373 births were in 3586 women with epilepsy; mean (SD) age at first delivery of the epilepsy cohort was 30.54 (5.18) years. Compared with pregnancies of women without epilepsy, women with epilepsy were at increased risks of adverse pregnancy and delivery outcomes, including preeclampsia (aRR 1.24; 95% CI, 1.07-1.43), infection (aRR, 1.85; 95% CI, 1.43-2.29), placental abruption (aRR, 1.68; 95% CI, 1.18-2.38), induction (aRR, 1.31; 95% CI, 1.21-1.40), elective cesarean section (aRR, 1.58; 95% CI, 1.45-1.71), and emergency cesarean section (aRR, 1.09; 95% CI, 1.00-1.20). Infants of mothers with epilepsy were at increased risks of stillbirth (aRR, 1.55; 95% CI, 1.05-2.30), having both medically indicated (aRR, 1.24; 95% CI, 1.08-1.43) and spontaneous (aRR, 1.34; 95% CI, 1.20-1.53) preterm birth, being small for gestational age at birth (aRR, 1.25; 95% CI, 1.13-1.30), and having neonatal infections (aRR, 1.42; 95% CI, 1.17-1.73), any congenital malformation (aRR, 1.48; 95% CI, 1.35-1.62), major malformations (aRR, 1.61; 95% CI, 1.43-1.81), asphyxia-related complications (aRR, 1.75; 95% CI, 1.26-2.42), Apgar score of 4 to 6 at 5 minutes (aRR, 1.34; 95% CI, 1.03-1.76), Apgar score of 0 to 3 at 5 minutes (aRR, 2.42; 95% CI, 1.62-3.61), neonatal hypoglycemia (aRR, 1.53; 95% CI, 1.34-1.75), and respiratory distress syndrome (aRR, 1.48; 95% CI, 1.30-1.68) compared with infants of unaffected women. In women with epilepsy, using AEDs during pregnancy did not increase the risks of pregnancy and perinatal complications, except for a higher rate of induction of labor (aRR, 1.30; 95% CI, 1.10-1.55).
Epilepsy during pregnancy is associated with increased risks of adverse pregnancy and perinatal outcomes. However, AED use during pregnancy is generally not associated with adverse outcomes.
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark (JLT-P, HRA, PG, and TKJ); the Research Unit for Dietary Studies, Institute of Preventive Medicine, Copenhagen University Hospitals, Frederiksberg, Denmark (JLT-P and BLH); the National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark (BLH); the Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical School, Sydney, Australia (BLH); the Department of Occupational Medicine and Public Health, Tórshavn, Faroe Islands (US); and the Department of Environmental Medicine, Faroese Hospital System, Tórshavn, Faroe Islands (PW).
Chemicals with endocrine-disrupting abilities may act as obesogens and interfere with the body's natural weight-control mechanisms, especially if exposure occurs during prenatal life.
We examined the association between prenatal exposure to polychlorinated biphenyls (PCBs) and p,p'-dichlorodiphenyldichloroethylene (DDE) and subsequent obesity at 5 and 7 y of age.
From 1997 to 2000, 656 pregnant Faroese women were recruited. PCB and DDE were measured in maternal serum and breast milk, and children's weight, height, and waist circumference (WC) were measured at clinical examinations at 5 and 7 y of age. The change in body mass index (BMI) from 5 to 7 y of age was calculated. Analyses were performed by using multiple linear regression models for girls and boys separately, taking into account maternal prepregnancy BMI.
For 7-y-old girls who had overweight mothers, PCB was associated with increased BMI (ß = 2.07, P = 0.007), and PCB and DDE were associated with an increased change in BMI from 5 to 7 y of age (PCB: ß = 1.23, P = 0.003; DDE: ß = 1.11, P = 0.008). No association was observed with BMI in girls with normal-weight mothers. PCB was associated with increased WC in girls with overweight mothers (ß = 2.48, P = 0.001) and normal-weight mothers (ß = 1.25, P = 0.04); DDE was associated with increased WC only in girls with overweight mothers (ß = 2.21, P = 0.002). No associations were observed between PCB or DDE and BMI in 5-y-old girls. For boys, no associations were observed.
Results suggest that prenatal exposure to PCB and DDE may play a role for subsequent obesity development. Girls whose mothers have a high prepregnancy BMI seem most affected.
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.