Early Pregnancy Exposure Research Articles

Antithyroid Drug Use in Pregnancy and Birth Defects: Why Some Studies Find Clear Associations, and Some Studies Report None.

Rare cases of birth defects after the use of methimazole (MMI) or carbimazole to treat hyperthyroidism in early pregnancy have been reported since 1972, whereas propylthiouracil (PTU) has not been considered teratogenic. Recently, two studies reported birth defects after the use of MMI in early pregnancy to affect 2-4% of exposed children, and one study also found birth defects after the use of PTU. On the other hand, some published studies did not find associations between the use of thionamides and birth defects. The methods used in the two positive and the four negative reports are reviewed. The two positive studies included a sufficient number of children exposed to MMI (n = 1231 and 1097) to evaluate the studied outcomes, whereas the four negative studies included a much lower number of exposed children (n = 73, 108, 30, and 124). Considering PTU, the birth defects observed in one study were in general milder and tended to be diagnosed and registered only when they resulted in complications and led to surgery after one year of age. None of the negative studies has investigated outcomes after one year of age. Studies finding no associations between early pregnancy exposure to antithyroid drugs and birth defects were either not sufficiently powered or did not study outcomes at optimal ages.

Pregnancy And Inflammation - The Impact Of Air Pollution On Maternal And Child Health

Pregnancy itself is associated with increased inflammation, largely due to the suppression of the immune system that supports maternal-fetal tolerance. Air pollutants increase inflammation and oxidative stress and can lead to adverse pregnancy outcomes with implications for both maternal and child health over the lifecourse. These effects may not be uniformly distributed across the population and health disparities by race, social class and maternal health conditions, such as asthma or hypertension, merit further attention. Even with the relatively low levels of pollutants experienced in urban areas across the United States, we find acute and chronic exposure effects in a large, contemporary obstetric cohort. Blood pressure at admission to labor/delivery was elevated after exposure in the preceding hours to nitrogen oxides (NOx), sulfur dioxide (SO2) and carbon monoxide (CO) and some effects were stronger for women with gestational hypertension or preeclampsia. Exposures during the week prior to delivery were associated with preterm birth (NOx and CO), premature rupture of membranes (ozone (O3)) and cardiac events at delivery (NOx, SO2, particulate matter ≤10 microns (PM10) and ≤2.5 microns (PM2.5) and CO). Early pregnancy and/or preconception exposures increased risk for gestational diabetes (NOx, SO2), orofacial clefts (CO, PM10, SO2, PM2.5) and preterm birth (NOx, PM10, PM2.5). For preterm birth and preeclampsia, we observed significant interaction between pollutants and maternal asthma, suggesting that women with asthma are particularly vulnerable to the effects of poor air quality. The impact of in utero exposures can be lifelong. Preterm birth and gestational hypertension predict long term morbidity and mortality for mothers. Children born growth-restricted or preterm have higher morbidity and mortality as infants and these effects carry on into adult life. Inflammation is potentially modifiable and a common mechanism underlying many of these effects.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study.

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Nicotine replacement therapy in pregnancy and major congenital anomalies in offspring.

Nicotine replacement therapy (NRT) is now being used as a smoking cessation aid during pregnancy, although little is known about fetal safety. We assessed the relationship between early pregnancy exposure to NRT or smoking with major congenital anomalies (MCA) in offspring. We studied 192,498 children born in the United Kingdom between 2001 and 2012 with linked mother-child primary care records. The absolute risks of MCAs in the NRT group (women prescribed NRT during the first trimester or 1 month before conception [and therefore likely consumed during the first trimester]) and odds ratios (ORs) and 99% confidence intervals (CIs) were compared with those of women who smoked during pregnancy and with a control group (women who neither smoked nor were prescribed NRT); logistic regression models adjusted for maternal morbidities that increase MCA risk were used for analysis. MCA prevalence was 288 per 10,000 live births (5535 children with ≥ 1 MCA). Maternal morbidities were most common in the NRT group (35%) followed by smokers (27%) and the control group (20%). Compared with the control group, adjusted ORs for MCAs in the NRT group and smokers were 1.12 (99% CI: 0.84-1.48) and 1.05 (99% CI: 0.89-1.23), respectively. The OR comparing the NRT group directly with smokers was 1.07 (99% CI: 0.78-1.47). There were no statistically significant associations between maternal NRT and system-specific anomalies except for respiratory anomalies (OR: 4.65 [99% CI: 1.76-12.25]; absolute risk difference: 3 per 1000 births), which was based on 10 exposed cases. For most system-specific MCAs, we found no statistically significant increased risks associated with maternal NRT prescribed during pregnancy, except for respiratory anomalies. Although this study is the largest published to date, NRT use in pregnancy remains rare; thus, the statistical power was limited. Higher morbidities in those women prescribed NRT may also be an explanatory factor. Nevertheless, absolute MCA risks were similar between women who smoked and those prescribed NRT during pregnancy.

Effects of maternal dexamethasone treatment early in pregnancy on glucocorticoid receptors in the ovine placenta.

The effects of endogenous cortisol on binucleate cells (BNCs), which promote fetal growth, may be mediated by glucocorticoid receptors (GRs), and exposure to dexamethasone (DEX) in early pregnancy stages of placental development might modify this response. In this article, we have investigated the expression of GR as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 119) were randomized to control (2 mL saline/ewe) or DEX-treated groups (intramuscular injections of 0.14 mg/kg ewe weight per 12 hours) at 40 to 41 days of gestation (dG). Placental tissue was collected at 50, 100, 125, and 140 dG. Total glucocorticoid receptor protein (GRt) was increased significantly by DEX at 50 and 125 dG in females only, but decreased in males at 125 dG as compared to controls. Glucocorticoid receptor α (GRα) protein was not changed after DEX treatment. Three BNC phenotypes were detected regarding GRα expression (++, +-, --), DEX increased the proportion of (++) and decreased (--) BNC at 140 dG. Effects were sex- and cell type dependent, modifying the responsiveness of the placenta to endogenous cortisol. We speculate that 3 maturational stages of BNCs exist and that the overall activity of BNCs is determined by the distribution of these 3 cell types, which may become altered through early pregnancy exposure to elevated glucocorticoids.

Health & Demographic Surveillance System Profile: The Rufiji Health and Demographic Surveillance System (Rufiji HDSS).

The Rufiji Health and Demographic Surveillance System (HDSS) was established in October 1998 to evaluate the impact on burden of disease of health system reforms based on locally generated data, prioritization, resource allocation and planning for essential health interventions. The Rufiji HDSS collects detailed information on health and survival and provides a framework for population-based health research of relevance to local and national health priorities.In December 2012 the population under surveillance was about 105,503 people, residing in 19,315 households. Monitoring of households and members within households is undertaken in regular 6-month cycles known as 'rounds'. Self reported information is collected on demographic, household, socioeconomic and geographical characteristics. Verbal autopsy is conducted using standardized questionnaires, to determine probable causes of death. In conjunction with core HDSS activities, the ongoing studies in Rufiji HDSS focus on maternal and new-born health, evaluation of safety of artemether-lumefantrine (AL) exposure in early pregnancy and the clinical safety of a fixed dose of dihydroartemisinin-piperaquine (DHA-PQP) in the community. Findings of studies conducted in Rufiji HDSS can be accessed at www.ihi.or.tz/IHI-Digital-Library.

The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: the Norwegian Mother and Child Cohort Study.

BackgroundMaternal smoking during pregnancy (MSDP) is associated with multiple adverse childhood outcomes including externalizing behaviors. However, the association between MSDP and internalizing (anxiety and depressive) behaviors in offspring has received less investigation. We aimed to assess the association between MSDP and childhood internalizing (anxiety and depressive) behaviors in a very large, well-characterized cohort study.MethodsWe assessed the association between MSDP and internalizing behaviors in offspring utilizing information drawn from 90,040 mother-child pairs enrolled in the Norwegian Mother and Child Cohort Study. Mothers reported smoking information, including status and frequency of smoking, twice during pregnancy. Mothers also reported their child’s internalizing behaviors at 18 months, 36 months, and 5 years. Associations between MSDP and childhood internalizing behaviors, including dose-response and timing of smoking in pregnancy, were assessed at each time point.ResultsMSDP was associated with increased internalizing behaviors when offspring were aged 18 months (B = 0.11, P <0.001) and 36 months (B = 0.06, P <0.01), adjusting for numerous potential confounders. Higher rates of smoking (e.g., >20 cigarettes per day) were associated with higher levels of internalizing behaviors. Maternal smoking during early pregnancy appeared to be the critical period for exposure.ConclusionsWe found evidence supporting a potential role for MSDP in increasing internalizing (anxiety and depressive) behaviors in offspring. We also found evidence supportive of a possible causal relationship, including dose-dependency and support for a predominant role of early pregnancy exposure. Further investigation utilizing genetically informed designs are warranted to assess this association.

Congenital Bands with Intestinal Malrotation after Propylthiouracil Exposure in Early Pregnancy.

Exposure to propylthiouracil in early pregnancy may be associated with an increased risk of birth defects. But the spectrum of associated congenital anomalies is not yet well defined. While preliminary reports suggest that most cases of propylthiouracil-associated birth defects are restricted to the preauricular and urinary systems, careful consideration should be given to other possible manifestations of teratogenicity. We propose that congenital bands may potentially represent a rare yet serious complication of propylthiouracil exposure in early pregnancy, possibly arising from an early mesenteric developmental anomaly. We report a case of a 17-day-old girl that presented with acute small bowel obstruction associated with intestinal malrotation arising from several anomalous congenital bands. Her mother was treated for Graves' disease during pregnancy with first trimester exposure to propylthiouracil but remained clinically and biochemically euthyroid at conception and throughout the duration of pregnancy. This case suggests that the use of propylthiouracil in early pregnancy may be associated with congenital bands and intestinal malrotation. More reports are needed to further support this association.

Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis

Background and objectiveWhile paracetamol exposure in pregnancy and early infancy has been associated with asthma, it remains unclear whether this is confounded by respiratory tract infections, which have been suggested...

Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age

Prenatal exposure to pesticides may affect neurodevelopment, while the impact of modern pesticides is unclear. From 1997–2001, women working in greenhouse horticultures were recruited at the beginning of their pregnancy. Based on detailed interview of the women and their employers, those categorized as occupationally exposed to pesticides were moved to unexposed work functions or went on paid leave, while women without any exposure were considered unexposed controls. Of the resulting birth cohort of 203 children, 133 (65%) were examined at age 6 to 11years together with 44 newly recruited children of same age whose mothers were not occupationally exposed to pesticides in pregnancy. All children underwent a standardized examination including a battery of neurodevelopmental tests. Maternal occupational pesticide exposure in early pregnancy was associated with prolonged brainstem auditory evoked potential latencies in the children as a whole and with impaired neuropsychological function in girls, while no effect was apparent in boys. In girls, language and motor speed functions were significantly inversely associated with prenatal exposure, and a non-significant tendency toward decreased function was also seen for other neuropsychological outcomes. A structural equation model that combined all these test results showed an overall impaired neuropsychological function in girls prenatally exposed to pesticides. Thus, our findings suggest an adverse effect of maternal occupational pesticide exposure on their children's neurodevelopment, despite the fact that the exposures occurred solely during early pregnancy and under well regulated working conditions, where special measures to protect pregnant women were applied.

An Effect of Household Environment and Nitrogen Dioxide Pollution on Congenital Malformations

Background: Nitrogen Dioxide (NO2) is a product of fuel combustion originating mainly from industry and transportation. Studies suggest an association between NO2 and congenital malformations (CM). We investigated an independent effect of NO2 on CM by adjusting to individual factors and household environment in Bedouin-Arab pregnant women in southern Israel. This population is characterised by high rates of CMs, frequent consanguineous marriages, paternal smoking, temporary housing and usage of open fire for heat cooking. Methods: We enrolled 1050 women during their admission to the delivery room (2012-2013). Information on pregnancy and risk factors was collected from a hospital registry and an interview. Ambient measurements of 24-hour average NO2 and temperature were obtained from 5 local monitors and assigned to each woman, based on a distance from the closest monitor and limited to women residing within 20km. Exposure was estimated as an average value of NO2 for the first trimester. Log-binomial regression was used for adjustment. As a sensitivity analysis, Generalized Estimating Equations were employed on NO2 daily measurements adjusted to distance from a monitor. Results: Median value of daily NO2 measured in the area was 6.3 ppb (inter-quartile range: 4.3-8.7). CM was diagnosed in 8.1% (85) of offspring. Based on multivariate analysis, maternal NO2 exposure during the 1st trimester was borderline associated with CM (RR=1.50, 95%CI: 0.97-2.32, p=0.066), also confirmed by sensitivity analyses. Mothers to offspring with CM, were more likely to use open fire for cooking (RR=2.70, 95%CI: 1.22-6.11, p=0.013). Maternal age and consanguineous marriages rate was similar between mothers to newborns with and without CM (28±6 years and 47.6% in the whole study population). Conclusions: NO2 exposure in early pregnancy was borderline associated with CM in Bedouin-Arab population. Household factors had a greater impact on CM elevated rates compared to ambient exposure.

World thyroidology news

The article is to overview papers: Effect of vitamin C on the absorption of levothyroxine in patients with hypothyroidism and gastritis. Management of neonates born to women with Graves’ disease: a cohort study. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Graves’ ophthalmopathy. Glucocorticoid regimens for prevention of Graves’ ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Smoking induces overexpression of immediate early genes in active Graves’ ophthalmopathy. Obesity and the risk of papillary thyroid cancer: A pooled analysis of three case-control studies. Differentiation of postpartum Graves’ thyrotoxicosis from postpartum destructive thyrotoxicosis using antithyrotropin receptor antibodies and thyroid blood flow. Follow-up of newborns of mothers with Graves’ disease. Severity of birth defects after propylthiouracil exposure in early pregnancy. The attitude toward hypothyroid- ism during early gestation: time for a change of mind? Effect of iodine restriction on thyroid function in subclinical hypothyroid patients in an iodine-replete area: A long period observa- tion in a large-scale cohort. Subclinical hypothyroidism and risk for incident ischemic stroke among postmenopausal women. Hashimoto’s thyroiditis pathology and risk for thyroid cancer. Anxiety and depression are more prevalent in patients with Graves’ disease than in patients with nodular goitre. The TRHR gene is associated with hypothalamo-pituitary sensitivity to levothyroxine.

79. Does moderate in utero alcohol exposure result in inflammation in the developing brain?

Alcohol exposure during early fetal development can have significant consequences for neural development and function. To determine whether moderate alcohol exposure in early pregnancy can induce pro-inflammatory cytokine and chemokine expression in the fetal brain, pregnant Sprague–Dawley rats were treated with alcohol or water from embryonic days (E) 10 to 16. This treatment regimen (50% ethanol 2X/day) produced a daily blood alcohol concentration of 0.08% for ∼8 h. On E17, the hippocampus-cortex of each pup was collected for the analysis of pro-inflammatory cytokines and chemokines using real-time PCR. Alcohol exposure increased the expression of cytokines in the tumor necrosis factor superfamily, including TNF-α, TNF-SF13, and TNF-SF13B in females but not males. CCL2 and CCL20 revealed opposing expression trends in males and females such that levels decreased in males and increased in females following alcohol treatment. We also found a significant increase in IL-6 and TNF-SF4 in the placenta of both males and females exposed to moderate fetal alcohol levels. In a second experiment, we repeated the experimental paradigm and raised pups to adulthood to measure cytokines and chemokines following a mild lipopolysaccharide challenge. We predict that pups exposed to moderate prenatal alcohol may express a stronger neuroimmune or peripheral immune response to this challenge in adulthood. Future experiments will investigate potential behavioral or cognitive deficits brought on by mild prenatal ethanol exposure. Supported by 5P20GM103653-02.

Severity of birth defects after propylthiouracil exposure in early pregnancy.

Propylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated. Review of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730). Fourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04-11.86) and in the urinary system 2.73 (1.22-6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs). We report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.

Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case-control studies.

We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring. Two case-control studies. HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis. Odds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.

Maternal exposure to methotrexate and birth defects: a population-based study.

Methotrexate is an anti-folate medication that is associated with increased risk of multiple birth defects. Using data from the National Birth Defects Prevention Study, a case-control study of major birth defects in the United States, we examined mothers exposed to methotrexate. The study population included mothers of live-born infants without major birth defects (controls) and mothers of fetuses or infants with a major birth defect (cases), with expected dates of delivery between October 1997 and December 2009. Mothers of cases and controls were asked detailed questions concerning pregnancy history, demographic information, and exposures in a telephone interview. Approximately 0.06% (n = 16/27,623) of case and 0.04% (n = 4/10,113) of control mothers reported exposure to methotrexate between 3 months prior to conception through the end of pregnancy. Of the 16 case infants, 11 (68.8%) had a congenital heart defect (CHD). The observed CHDs included atrial septal defects, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defects (VSDs), and total anomalous pulmonary venous return. One case infant had microtia in addition to a VSD and another had VACTER association. Exposed cases without a CHD had one of the following birth defects: cleft palate, hypospadias, congenital diaphragmatic hernia, or craniosynostosis. Based on a limited number of methotrexate-exposed mothers, our findings support recent case reports suggesting an association between early pregnancy exposure to methotrexate and CHDs. Because of the rarity of maternal periconceptional exposure to methotrexate, long-term, population-based case-control studies are needed to confirm these findings and better evaluate the association between methotrexate and birth defects.

Safety of antimalarial drugs exposure during early pregnancy.

IntroductionInadequately controlled malaria infection in pregnancy is associated with poor maternal and fetal outcomes. However, there are important questions about drug safety for mothers with malaria and their fetuses as, currently, there is limited safety data on many of the medications used. The objective of this review is to determine from published evidence the safety of antimalarial drugs exposure during early pregnancy, focusing on abortions, stillbirths, and congenital abnormalities.MethodsWe searched PubMed, Embase, Cochrane Library, and Malaria in Pregnancy databases from their inception to June 2013, inclusive, for reports published in English only. Data were extracted on exposure to antimalarial drugs during early pregnancy and adverse pregnancy outcomes including congenital abnormalities, stillbirth, and miscarriage.ResultsTwenty-two publications including one abstract with a total of 6,333 early pregnancy exposures to antimalarial agents used for treatment and/or prevention of malaria in pregnancy met the inclusion criteria. More than 40% of the pregnancies were exposed to mefloquine, about 10% to artemisinin based regimens and, 15.2% and 14.7% were exposed to chloroquine and quinine, respectively. A total of 1,199 adverse outcomes including abortions, stillbirths, and congenital abnormalities were reported. The reported absolute risks of adverse outcomes were similar for all the antimalarial exposures, but, in two publications, increased risk of stillbirths was linked to mefloquine exposure. Extensive heterogeneity and variability in the way in which authors assessed, recorded, and reported safety data precluded formal meta-analysis.ConclusionThe absolute estimates of risks obtained in the included studies are difficult to interpret and the clinical significance of any association of adverse outcomes reported with antimalarial exposure in early pregnancy is uncertain. Well planned, executed, and analyzed studies are needed to confirm whether there is increased risk for adverse fetal outcomes attributable to exposure of first trimester pregnancies to antimalarials compared to relevant controls.

Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy

The first trimester of human fetal life, a period of extremely rapid development of physiological systems, represents the most rapid growth phase in human life. Interference in the establishment of organ systems may result in abnormal development that may be manifest immediately or programmed for later abnormal function. Exposure to environmental chemicals may be affecting development at these early stages, and yet there is limited knowledge of the quantities and identities of the chemicals to which the fetus is exposed during early pregnancy. Clearly, opportunities for assessing fetal chemical exposure directly are extremely limited. Hence, this review describes indirect means of assessing fetal exposure in early pregnancy to chemicals that are considered disrupters of development. Consideration is given to such matrices as maternal hair, fingernails, urine, saliva, sweat, breast milk, amniotic fluid and blood, and fetal matrices such as cord blood, cord tissue, meconium, placenta, and fetal liver. More than 150 articles that presented data from chemical analysis of human maternal and fetal tissues and fluids were reviewed. Priority was given to articles where chemical analysis was conducted in more than one matrix. Where correlations between maternal and fetal matrices were determined, these articles were included and are highlighted, as these may provide the basis for future investigations of early fetal exposure. The determination of fetal chemical exposure, at the time of rapid human growth and development, will greatly assist regulatory agencies in risk assessments and establishment of advisories for risk management concerning environmental chemicals.

Balance in Opioid Prescription during Pregnancy

Balance in Opioid Prescription during Pregnancy

Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys.

Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov-Smirnov test, P-value<10-15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (r S -values>-0.62), but in girls only 207 (41%) showed inverse correlation (r S -values>-0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.