Supranutritional Maternal Organic Selenium Supplementation during Different Trimesters of Pregnancy Affects the Muscle Gene Transcriptome of Newborn Beef Calves in a Time-Dependent Manner.

Selenium (Se) is an essential micronutrient for growth and immune function in beef cattle. We previously showed that supranutritional maternal organic Se supplementation during late pregnancy improves immune function in their newborn calves; however, the effects of maternal organic Se-supplementation on fetal programming during different pregnancy stages have yet to be elucidated. Herein, we investigated the effects of supranutritional maternal organic Se-supplementation in different pregnancy trimesters on their beef calf's genome-wide transcriptome profiles. Within 12 to 48 h of birth, whole blood and Longissimus dorsi (LD) muscle biopsies were collected from calves born to 40 crossbred Angus cows that received, except for the control group (CTR), Se-yeast boluses (105 mg of Se/wk) during the first (TR1), second (TR2), or third (TR3) trimester of gestation. Whole-blood Se concentrations of newborn calves increased from CTR, TR1, TR2 to TR3, whereas muscle Se concentrations of newborn calves were only increased in TR3 group. We identified 3048 unique differentially expressed genes (DEGs) across all group comparisons (FDR ≤ 0.05 and |log2FC| ≥ 1.5). Furthermore, we predicted 237 unique transcription factors that putatively regulate the DEGs. Independent of supplementation trimester, supranutritional maternal organic Se supplementation downregulated genes involved in adaptive immunity in all trimesters. Dependent on supplementation trimester, genes involved in muscle development were upregulated by TR3 Se supplementation and downregulated by TR1 Se-supplementation, and genes involved in collagen formation were downregulated by TR2 Se-supplementation. Supranutritional maternal organic Se supplementation in the last trimester of pregnancy resulted in upregulation of myosin and actin filament associated genes, potentially allowing for optimal muscle function and contraction. Our findings suggest a beneficial effect of supranutritional maternal organic Se supplementation during late gestation on Se-status and muscle development and function of newborn calves.

Prediction of Pregnancy-Induced Changes in Secretory and Total Renal Clearance of Drugs Transported by Organic Anion Transporters.

Pregnancy can significantly change the pharmacokinetics of drugs, including those renally secreted by organic anion transporters (OATs). Quantifying these changes in pregnant women is logistically and ethically challenging. Hence, predicting the in vivo plasma renal secretory clearance (CLsec) and renal CL (CLrenal) of OAT drugs in pregnancy is important to design correct dosing regimens of OAT drugs. Here, we first quantified the fold-change in renal OAT activity in pregnant versus nonpregnant individual using available selective OAT probe drug CLrenal data (training dataset; OAT1: tenofovir, OAT2: acyclovir, OAT3: oseltamivir carboxylate). The fold-change in OAT1 activity during the 2nd and 3rd trimester was 2.9 and 1.0 compared with nonpregnant individual, respectively. OAT2 activity increased 3.1-fold during the 3rd trimester. OAT3 activity increased 2.2, 1.7 and 1.3-fold during the 1st, 2nd, and 3rd trimester, respectively. Based on these data, we predicted the CLsec, CLrenal and total clearance ((CLtotal) of drugs in pregnancy, which are secreted by multiple OATs (verification dataset; amoxicillin, pravastatin, cefazolin and ketorolac, R-ketorolac, S-ketorolac). Then, the predicted clearances (CLs) were compared with the observed values. The predicted/observed CLsec, CLrenal, and CLtotal of drugs in pregnancy of all verification drugs were within 0.80-1.25 fold except for CLsec of amoxicillin in the 3rd trimester (0.76-fold) and cefazolin in the 2nd trimester (1.27-fold). Overall, we successfully predicted the CLsec, CLrenal, and CLtotal of drugs in pregnancy that are renally secreted by multiple OATs. This approach could be used in the future to adjust dosing regimens of renally secreted OAT drugs which are administered to pregnant women. SIGNIFICANCE STATEMENT: To the authors' knowledge, this is the first report to successfully predict renal secretory clearance and renal clearance of multiple OAT substrate drugs during pregnancy. The data presented here could be used in the future to adjust dosing regimens of renally secreted OAT drugs in pregnancy. In addition, the mechanistic approach used here could be extended to drugs transported by other renal transporters.

The effects of progesterone treatment on nuchal translucency in women with threatened miscarriage.

This study aims to investigate the effects of progesterone on the possible changes in nuchal translucency (NT) levels for patients diagnosed with threatened miscarriage. The study group was composed of 125 patients diagnosed with threatened miscarriage and taking 400 mg/day micronized orally progesterone at least for two weeks, the control group was composed of 160 healthy pregnant women not taking any progesterone. Crown rump length (CRL) NT thickness, Pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (Beta-HCG) levels of patients were measured for assessment of aneuploidy risk. Both of the groups were divided into four subgroups to determine the relationship between thickness of NT and progesterone use for specific CRL measurements. CRL in the first, second, third and fourth group was 45-55 mm, 55-65 mm, 65-75 mm, 75-84 mm, respectively. The two groups were age and BMI matched. In all groups of CRL there were no significant difference in Mom levels of NT thickness, PAPP-A and free Beta-HCG between the study and control groups. There havent been any relation between NT thickness and progesterone use.IMPACT STATEMENTWhat is already known about this subject? Recently some studies have claimed that progesterone use might have caused atypical blood flow pattern on foetal circulation, which could possibly increase NT. If the NT thickness is affected by the use of progesterone, then the false positive rate of detecting Down Syndrome screening tests would increase.What the results of this study add? In this study we did not found any relation between NT thickness and progesterone use.What the implications are of these findings for clinical practice and/or further research? Using orally progesterone due to threatened miscarriage do not change NT thickness levels. Further studies have to be done with a large number of participants.

Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis.

BACKGROUND: Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. RESULTS: Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. CONCLUSIONS: Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.

Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy.

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine's active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15-25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

Patterns and Variability of Endocrine-disrupting Chemicals During Pregnancy: Implications for Understanding the Exposome of Normal Pregnancy.

BACKGROUND: The exposome is a novel research paradigm offering promise for understanding the complexity of human exposures, including endocrine-disrupting chemicals (EDCs) and pregnancy outcomes. The physiologically active state of pregnancy requires understanding temporal changes in EDCs to better inform the application of the exposome research paradigm and serve as the impetus for study. METHODS: We randomly selected 50 healthy pregnant women with uncomplicated pregnancies from a pregnancy cohort who had available serum/urine samples in each trimester for measuring 144 persistent and 48 nonpersistent EDCs. We used unsupervised machine-learning techniques capable of handling hierarchical clustering of exposures to identify EDC patterns across pregnancy, and linear mixed-effects modeling with false-discovery rate correction to identify those that change over pregnancy trimesters. We estimated the percent variation in chemical concentrations accounted for by time (pregnancy trimester) using Akaike Information Criterion-based R methods. RESULTS: Four chemical clusters comprising 80 compounds, of which six consistently increased, 63 consistently decreased, and 11 reflected inconsistent patterns over pregnancy. Overall, concentrations tended to decrease over pregnancy for persistent EDCs; a reverse pattern was seen for many nonpersistent chemicals. Explained variance was highest for five persistent chemicals: polybrominated diphenyl ethers #191 (51%) and #126 (47%), hexachlorobenzene (46%), p,p'-dichloro-diphenyl-dichloroethylene (46%), and o,p'-dichloro-diphenyl-dichloroethane (36%). CONCLUSIONS: Concentrations of many EDCs are not stable across pregnancy and reflect varying patterns depending on their persistency underscoring the importance of timed biospecimen collection. Analytic techniques are available for assessing temporal patterns of EDCs during pregnancy apart from physiologic changes.

Bayesian varying coefficient kernel machine regression to assess neurodevelopmental trajectories associated with exposure to complex mixtures.

Exposure to environmental mixtures can exert wide-ranging effects on child neurodevelopment. However, there is a lack of statistical methods that can accommodate the complex exposure-response relationship between mixtures and neurodevelopment while simultaneously estimating neurodevelopmental trajectories. We introduce Bayesian varying coefficient kernel machine regression (BVCKMR), a hierarchical model that estimates how mixture exposures at a given time point are associated with health outcome trajectories. The BVCKMR flexibly captures the exposure-response relationship, incorporates prior knowledge, and accounts for potentially nonlinear and nonadditive effects of individual exposures. This model assesses the directionality and relative importance of a mixture component on health outcome trajectories and predicts health effects for unobserved exposure profiles. Using contour plots and cross-sectional plots, BVCKMR also provides information about interactions between complex mixture components. The BVCKMR is applied to a subset of data from PROGRESS, a prospective birth cohort study in Mexico city on exposure to metal mixtures and temporal changes in neurodevelopment. The mixture include metals such as manganese, arsenic, cobalt, chromium, cesium, copper, lead, cadmium, and antimony. Results from a subset of Programming Research in Obesity, Growth, Environment and Social Stressors data provide evidence of significant positive associations between second trimester exposure to copper and Bayley Scales of Infant and Toddler Development cognition score at 24 months, and cognitive trajectories across 6-24 months. We also detect an interaction effect between second trimester copper and lead exposures for cognition at 24 months. In summary, BVCKMR provides a framework for estimating neurodevelopmental trajectories associated with exposure to complex mixtures.

Effects of trimester-specific exposure to vanadium on ultrasound measures of fetal growth and birth size: a longitudinal prospective prenatal cohort study.

BACKGROUND: Identification of windows of heightened vulnerability to environmental factors has substantial public health implications. Prenatal exposure to vanadium has been linked to adverse birth outcomes; however, critical windows for such exposure during fetal growth remain unknown. We aimed to assess trimester-specific associations of vanadium exposure with ultrasound measures of fetal growth and birth size in a Chinese longitudinal cohort. METHODS: The present study was embedded in our ongoing prospective prenatal cohort study at the Wuhan Women and Children Medical Care Center (Wuhan, Hubei, China). Pregnant women were eligible for inclusion if they provided signed informed consent and were less than 16 weeks pregnant with a single gestation, and agreed to take in-person interviews, undergo ultrasound examinations, and provide blood and urine samples. We collected urine samples and measured urinary vanadium concentrations using inductively coupled plasma mass spectrometry. We calculated SD scores for ultrasound-measured biparietal diameter, head circumference, occipitofrontal diameter, abdominal circumference, femur length, and estimated fetal weight at 16, 24, and 31 weeks of gestation. We applied linear regressions with generalised estimating equations to estimate associations of urinary vanadium concentrations in each trimester with ultrasound-measured fetal growth parameters or neonatal size at birth. FINDINGS: As of Oct 12, 2016, we recruited 3075 women who were non-smokers and non-drinkers during pregnancy, provided up to three urine samples during the first, second, and third trimesters, and gave birth to live singletons without birth defects. We excluded women who did not provide information on ultrasound measurements (n=20) or who only had one ultrasound measurement of fetal crown-rump length at the first trimester (n=14). We excluded another 16 women because they had missing values for confounding variables, leaving 3025 women retained in the study. Every doubling of urinary vanadium concentration in the first trimester was associated with a significant increase in femur length (adjusted percentage change 6·4%, 95% CI 0·7 to 12·1) at 16 weeks of gestation and reductions in biparietal diameter (-4·2%, -8·2 to -0·1), head circumference (-6·0%, -10·1 to -1·9), occipitofrontal diameter (-5·7%, -9·9 to -1·5), and abdominal circumference (-5·3%, -9·4 to -1·2) at 31 weeks of gestation. Every doubling of urinary vanadium concentration in the second trimester was significantly associated with reductions in SD scores for head circumference (-7·2%, -14·1 to -0·3) and abdominal circumference (-6·9%, -13·8 to -0·1) at 31 weeks of gestation. The highest quartile of urinary vanadium concentration (>1·18 µg/L) in the first trimester, when compared with the lowest quartile (≤0·60 µg/L), was associated with a mean decrease in birthweight of 12·6 g (95% CI 2·5-22·8; ptrend=0·0055) and a mean decrease in ponderal index of 0·07 kg/m3 (0·01-0·12; ptrend=0·0053). Moreover, newborns with restricted birth size had higher vanadium exposure in the first and third trimesters. INTERPRETATION: Vanadium might be toxic to humans and impair fetal growth. The first, early second, and late third trimesters could be critical windows for heightened vulnerability to vanadium for fetal growth. Our findings require further investigation in other populations. FUNDING: National Key R&D Plan of China, National Natural Science Foundation of China, and Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology.

Drilling and Production Activity Related to Unconventional Gas Development and Severity of Preterm Birth.

BACKGROUND: Studies of unconventional gas development (UGD) and preterm birth (PTB) have not presented risk estimates by well development phase or trimester. OBJECTIVE: We examined phase and trimester-specific associations between UGD activity and PTB. METHODS: We conducted a case-control study of women with singleton births in the Barnett Shale area, Texas, from 30 November 2010 to 29 November 2012. We individually age- and race/ethnicity-matched five controls to each PTB case (n=13,328) and truncated controls' time at risk according to the matched case's gestational age. We created phase-specific UGD-activity metrics: a) inverse squared distance-weighted (IDW) count of wells in the drilling phase ≤0.5 mi (804.7 meters) of the residence and b) IDW sum of natural gas produced ≤0.5 mi of the residence. We also constructed trimester- and gestation-specific metrics. Metrics were categorized as follows: zero wells (reference), first, second, third tertiles of UGD activity. Analyses were repeated by PTB severity: extreme, very, and moderate (<28, 28 to<32, and 32 to<37 completed weeks). Data were analyzed using conditional logistic regression. RESULTS: We found increased odds of PTB in the third tertile of the UGD drilling {odds ratio (OR)=1.20 [95% confidence interval (CI): 1.06, 1.37]} and UGD-production [OR=1.15 (1.05, 1.26)] metrics. Among women in the third tertile of UGD-production, associations were strongest in trimesters one [OR=1.18 (1.02, 1.37)] and two [OR=1.14 (0.99, 1.31). The greatest risk was observed for extremely PTB [third tertile ORs: UGD drilling, 2.00 (1.23, 3.24); UGD production, 1.53 (1.03-2.27)]. CONCLUSIONS: We found evidence of differences in phase- and trimester-specific associations of UGD and PTB and indication of particular risk associated with extremely preterm birth. Future studies should focus on quantifying specific chemical and nonchemical stressors associated with UGD. https://doi.org/10.1289/EHP2622.

Placental Complications Associated With Psychostimulant Use in Pregnancy.

OBJECTIVE: To evaluate whether psychostimulants used to treat attention-deficit/hyperactivity disorder (ADHD) are associated with risk of adverse placental-associated pregnancy outcomes including preeclampsia, placental abruption, growth restriction, and preterm birth. METHODS: We designed a population-based cohort study in which we examined a cohort of pregnant women and their liveborn neonates enrolled in Medicaid from 2000 to 2010. Women who received amphetamine-dextroamphetamine or methylphenidate monotherapy in the first half of pregnancy were compared with unexposed women. We considered atomoxetine, a nonstimulant ADHD medication, as a negative control exposure. To assess whether the risk period extended to the latter half of pregnancy, women who continued stimulant monotherapy after 20 weeks of gestation were compared with those who discontinued. Risk ratios and 95% CIs were estimated with propensity score stratification to control for confounders. RESULTS: Pregnancies exposed to amphetamine-dextroamphetamine (n=3,331), methylphenidate (n=1,515), and atomoxetine (n=453) monotherapy in early pregnancy were compared with 1,461,493 unexposed pregnancies. Among unexposed women, the risks of the outcomes were 3.7% for preeclampsia, 1.4% for placental abruption, 2.9% for small for gestational age, and 11.2% for preterm birth. The adjusted risk ratio for stimulant use was 1.29 for preeclampsia (95% CI 1.11-1.49), 1.13 for placental abruption (0.88-1.44), 0.91 for small for gestational age (0.77-1.07), and 1.06 for preterm birth (0.97-1.16). Compared with discontinuation (n=3,527), the adjusted risk ratio for continuation of stimulant use in the latter half of pregnancy (n=1,319) was 1.26 for preeclampsia (0.94-1.67), 1.08 for placental abruption (0.67-1.74), 1.37 for small for gestational age (0.97-1.93), and 1.30 for preterm birth (1.10-1.55). Atomoxetine was not associated with the outcomes studied. CONCLUSION: Psychostimulant use during pregnancy was associated with a small increased relative risk of preeclampsia and preterm birth. The absolute increases in risks are small and, thus, women with significant ADHD should not be counseled to suspend their ADHD treatment based on these findings.

Prescription drug use during pregnancy in France: a study from the national health insurance permanent sample.

PURPOSE: To provide an up-to-date account of drug prescription during pregnancy in France from 2011 to 2014 using the permanent sample of the French national computerized healthcare database and with a focus on recommended supplementations, fetotoxic drugs and teratogenic drugs. METHODS: All pregnancies identified by the International Classification of Diseases, 10th Revision codes list in the hospitalization database, lasting more than 9 weeks of amenorrhea and whose delivery occurred between 01/01/2011 and 12/31/2014, were included. Drugs delivered between the trimester before and until the end of the pregnancy were included. Drug exposure prevalence was calculated for each year and according to pregnancy trimesters. RESULTS: The study included 28,491 pregnancies with a median number of 9 [5-13] (median [IQ range]) drugs delivered. The most prescribed drug class was antianemia (in 72.5% of exposed). The prescription rate of recommended vitamins (B9 and D) increased over the study period (+10%). Influenza vaccination also increased but remained at a low rate (1%). Exposure to fetotoxic drugs decreased as pregnancy advanced. Exposure to the main teratogenic antiepileptics was stable over the study period. Low-income pregnant women had a higher average drug consumption except for recommended vitamins. CONCLUSION: Pregnant French women are among the largest consumers of prescription medications worldwide. Overall, the dispensation trends observed in this study are in line with the recommendations of the French National College of Gynecologists and Obstetricians. Nevertheless, while being low, exposure to fetotoxic drugs, teratogenic drugs or those under safety alerts still occurred. Supplementations and vaccines in low-income pregnant women should also be increased.

Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: Results from a pregnancy registry in South India.

OBJECTIVE: Kerala Registry of Epilepsy and Pregnancy had been prospectively evaluating the reproductive issues of women with epilepsy since April 1998. This analysis aimed to estimate the relative risk of major congenital malformations (MCM) to the registrants. METHODS: All pregnancies with known outcome in this register until December 2013 were included. Malformation status was evaluated by antenatal ultrasonography, physical examination at birth, echocardiography, and abdomen ultrasonography at 3 months of age and a final review at 1 year of age. RESULTS: There were 1,688 fetuses (singlets 1,643, twins 21, and triplet 1) resulting in 1,622 live births. All were born to women of Asian origin living in South India. The MCM rate for all live births was 6.84% (95% confidence interval [CI] 5.71-8.18) and for all pregnancy outcomes including fetal loss was 7.11% (95% CI 5.98-8.44). The MCM rates (mean with 95% CI) for exposed group were 6.4% (5.03-8.03) for monotherapy and 9.9% (7.37-13.13) for polytherapy; internal control group (women with epilepsy [WWE] not on antiepileptic drugs [AEDs] in first trimester) 5.6% (3.34-9.11), external control group (women without epilepsy or AED exposure in first trimester) 3.45% (1.94-6.07). Valproate monotherapy group had a dose-dependent relative risk for MCM of 2.6 (95% CI 1.30-5.20) compared to the external control group. The preliminary data on MCM rate for the nine total clobazam monotherapy (22.2%; 95% CI 6.2-54.7) signals increased risk that needs further validation on larger sample size. There was no association between MCM rate and maternal socioeconomic status, epilepsy syndrome, or use of folic acid in first trimester. SIGNIFICANCE: This dataset from South India confirms the increased risk of MCM with exposure to AEDs, particularly polytherapy. A dose-dependent increased risk was observed with valproate. The increased risk associated with clobazam monotherapy is an important signal that needs to be confirmed in a larger sample.

Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies.

Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009-2010 (40% of participants received the MIV). We found potential biases in the vaccine-birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases.

Reproductive Safety of Second-Generation Antipsychotics: Current Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

OBJECTIVE: Second-generation antipsychotics are used to treat a spectrum of psychiatric illnesses in reproductive-age women. The National Pregnancy Registry for Atypical Antipsychotics was established to determine the risk of major malformations among infants exposed to second-generation antipsychotics during pregnancy relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity. METHOD: Women were prospectively followed during pregnancy and the postpartum period; obstetric, labor, delivery, and pediatric medical records were obtained. Eligible enrollees were pregnant women ages 18-45. The Registry is based at the Center for Women's Mental Health at Massachusetts General Hospital. Women were recruited through provider referral, self-referral, and the Center's web site. RESULTS: As of December 2014, 487 women were enrolled: 353 who used second-generation antipsychotics and 134 comparison women. Medical records were obtained for 82% of participants. A total of 303 women had completed the study and were eligible for inclusion in the analysis. Of 214 live births with first-trimester exposure to second-generation antipsychotics, three major malformations were confirmed. In the control group (N=89), one major malformation was confirmed. The absolute risk of major malformations was 1.4% for exposed infants and 1.1% for unexposed infants. The odds ratio for major malformations comparing exposed infants with unexposed infants was 1.25 (95% CI=0.13-12.19). CONCLUSIONS: The results suggest that it would be unlikely for second-generation antipsychotics to raise the risk of major malformations more than 10-fold beyond that observed in the general population or among control groups using other psychotropic medications. If the estimate stabilizes around the null with ongoing data collection, findings may be reassuring for both clinicians and women trying to make risk-benefit treatment decisions about using atypical antipsychotics during pregnancy. These findings are timely given the renewed focus of regulatory agencies on reproductive safety.

Iodine status among pregnant women after mandatory salt iodisation.

I is essential for thyroid hormone synthesis and neurological development. Various changes occur in thyroid hormone metabolism during pregnancy and I requirements increase significantly. The purpose of this study was to investigate I status among pregnant women in Trabzon, formerly a severely I-deficient area but shown to have become I sufficient following mandatory iodisation of table salt based on monitoring studies among school-age children (SAC) in the area. A total of 864 healthy pregnant women with a median age of 28 (25th-75th percentile 17-47) years participated in the study. None of them were using I-containing supplement. All of them were screened for use of iodised salt, obstetric history, thyroid function tests and urinary I concentrations (UIC), and thyroid ultrasonography was performed. Median UIC was 102 (25th-75th percentile=62-143) µg/l. Median UIC of the patients according to trimesters were 122 µg/l at the 1st, 97 µg/l at the 2nd and 87 µg/l at the 3rd trimester. UIC in the 1st trimester was higher compared with the 2nd and 3rd trimesters (P<0·017). Nodules were present in 17·7% of women (n 153). The rate of iodised salt usage among pregnant women was 90·7%. Our study demonstrates that, although the I status among SAC has been rectified, I deficiency (ID) is still prevalent among pregnant women. Current knowledge is in favour of I supplementation in this group. Until the effects of maternal I supplementation in mild ID have been clarified by large-scale prospective controlled trials, pregnant women living in borderline defficient and I-sufficient areas, such as Trabzon city, should receive 100-200 µg/d of I-containing supplements in addition to iodised salt.

Association between PM10 air pollution and birth weight after full-term pregnancy in Krakow city 1995-2009--trimester specificity.

INTRODUCTION AND OBJECTIVE: The results of epidemiological studies indicate that the higher maternal exposure to air pollution, especially with particulate matter during pregnancy, the lower the infant's birth weight. The aim of this study was to estimate entire pregnancy and trimester-specific exposure of pregnant women in the city of Krakow, southern Poland, to fine particulate matter [≤10 µg (PM10)], and to assess its effect on the birth weight of boys and girls separately. MATERIAL AND METHODS: The study group consisted of 85,000 singleton, live, full-term births in Krakow city during a 15-year period (data from the birth registry). The mean concentrations of the pollutant for each month of gestation were estimated using continuous municipal monitoring data. RESULTS: Multiple linear regression analyses indicated that the mean PM10 concentration during entire pregnancy was inversely associated with birth weight in girls and the group of boys and girls combined, after adjusting for maternal age, gestational age and year of birth; in boys the relationship was not statistically significant. Maternal exposure to PM10 during the first trimester was negatively associated with birth weight separately in girls and boys, and the group of boys and girls combined. However, the PM10 exposure during the second and third trimester of pregnancy was not associated with birth weight. CONCLUSIONS: PM10 air pollution at levels currently encountered in Krakow city adversely affect infant birth weight; however, the effect seems to be very small. The influence of particulate air pollution on foetal growth in early gestation is one of several possible explanations for the results, but further research is needed to establish possible biological mechanisms explaining the observed relationship.

Effects of all three trimester moderate binge alcohol exposure on the foetal hippocampal formation and olfactory bulb.

OBJECTIVE: Pre-natal alcohol exposure results in injury to the hippocampus and olfactory bulb,but currently there is no consensus on the critical window of vulnerability. This study tested thehypothesis that pre-natal exposure to a moderate dose of alcohol during all three trimesterequivalentsalters development of the hippocampal formation and olfactory bulb in an ovinemodel, where all brain development occurs pre-natally as it does in humans.Research design and methods: Pregnant sheep were divided into saline control and abinge drinking groups (alcohol dose 1.75 g kg(-1); mean peak blood alcohol concentration189 + 19mg dl(-1)). OUTCOME AND RESULTS: The density, volume and total cell number were not different betweengroups for the dentate gyrus, pyramidal cells in the CA1 and CA2/3 fields and mitral cells in theolfactory bulb. CONCLUSIONS: A moderate dose of alcohol administered in a binge pattern throughout gestationdoes not alter cell numbers in the hippocampus or olfactory bulb and exposure during thethird trimester-equivalent is required for hippocampal injury, unless very high doses of alcoholare administered. This has important implications in establishing the sensitivity of imagingmodalities such as MRI in which volumetric measures are being studied as biomarkers forpre-natal alcohol exposure.

Maternal alcohol intake prior to and during pregnancy and risk of adverse birth outcomes: evidence from a British cohort.

BACKGROUND: Evidence is conflicting regarding the relationship between low maternal alcohol consumption and birth outcomes. This paper aimed to investigate the association between alcohol intake before and during pregnancy with birth weight and gestational age and to examine the effect of timing of exposure. METHODS: A prospective cohort in Leeds, UK, of 1303 pregnant women aged 18-45 years. Questionnaires assessed alcohol consumption before pregnancy and for the three trimesters separately. Categories of alcohol consumption were divided into ≤2 units/week and >2 units/week with a non-drinking category as referent. This was related to size at birth and preterm delivery, adjusting for confounders including salivary cotinine as a biomarker of smoking status. RESULTS: Nearly two-thirds of women before pregnancy and over half in the first trimester reported alcohol intakes above the Department of Health (UK) guidelines of ≤2 units/week. Associations with birth outcomes were strongest for intakes >2 units/week before pregnancy and in trimesters 1 and 2 compared to non-drinkers. Even women adhering to the guidelines in the first trimester were at significantly higher risk of having babies with lower birth weight, lower birth centile and preterm birth compared to non-drinkers, after adjusting for confounders (p<0.05). CONCLUSIONS: We found the first trimester to be the period most sensitive to the effect of alcohol on the developing fetus. Women adhering to guidelines in this period were still at increased risk of adverse birth outcomes. Our findings suggest that women should be advised to abstain from alcohol when planning to conceive and throughout pregnancy.

Risk factors for congenital hydrocephalus: a nationwide, register-based, cohort study.

OBJECTIVES: To investigate the associations between isolated congenital hydrocephalus (CHC) and maternal characteristics, maternal medical diseases, and medicine intake during pregnancy as well as birth characteristics of the child in a retrospective, register-based, nationwide cohort study. Furthermore, to identify the risk factors unique for isolated CHC as compared to syndromic CHC. METHODS: We established a cohort of all children born in Denmark between 1978 and 2008. Information on CHC and maternal medical diseases were obtained from the National Patient Discharge Register, maternal intake of medicine during pregnancy from the National Prescription Drug Register, and birth characteristics of the child from the Danish National Birth Register. Rate ratios (RR) of isolated and syndromic CHC with 95% CI were estimated using log-linear Poisson regression. RESULTS: In a cohort of 1928666 live-born children, we observed 1193 cases of isolated CHC (0.062/1000) born children. First-borns had an increased risk of isolated CHC compared to later-borns (1.32 95% CI 1.17 to 1.49) (0.72/1000 born children). First trimester exposure to maternal use of antidepressants was associated with a significantly increased risk of isolated CHC compared to unexposed children (RR 2.52, 95% CI 1.47 to 4.29) (1.5/1000 born children). Risk factors also found for syndromic CHC were: Male gender, multiples and maternal diabetes. CONCLUSIONS: The higher risk for isolated CHC in first-born children as well as behavioural aspects and comorbidities associated with maternal use of antidepressants, should be the targets for future research. Potential biological pathways by which antidepressants may cause hydrocephalus remain to be elucidated.