Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

Preterm Birth and Metal Mixture Exposure among Pregnant Women from the Navajo Birth Cohort Study.

BACKGROUND: Preterm birth (PTB), defined as birth before 37 wk gestation, is associated with hypertension, diabetes, inadequate prenatal care, unemployment or poverty, and metal exposure. Indigenous individuals are more likely to have maternal risk factors associated with PTB compared with other populations in the United States; however, the role of environmental metals on PTB among pregnant Indigenous women remains uncertain. Previous research identified associations between PTB and individual metals, but there is limited investigation on metal mixtures and this birth outcome. OBJECTIVES: We used a mixtures analysis framework to investigate the association between metal mixtures and PTB among pregnant Indigenous women from the Navajo Birth Cohort Study (NBCS). METHODS: Maternal urine and blood samples were collected at the time of study enrollment and analyzed for metals by inductively coupled plasma dynamic reaction cell mass spectrometry. Bayesian Profile Regression was used to identify subgroups (clusters) of individuals with similar patterns of coexposure and to model association with PTB. RESULTS: Results indicated six subgroups of maternal participants with distinct exposure profiles, including one group with low exposure to all metals and one group with total arsenic, cadmium, lead, and uranium concentrations exceeding representative concentrations calculated from the National Health and Nutrition Examination Survey (NHANES). Compared with the reference group (i.e., the lowest exposure subgroup), the subgroup with the highest overall exposure had a relative risk of PTB of 2.9 times (95% credible interval: 1.1, 6.1). Exposures in this subgroup were also higher overall than NHANES median values for women 14-45 years of age. DISCUSSION: Given the wide range of exposures and elevated PTB risk for the most exposed subgroups in a relatively small study, follow-up investigation is recommended to evaluate associations between metal mixture profiles and other birth outcomes and to test hypothesized mechanisms of action for PTB and oxidative stress caused by environmental metals. https://doi.org/10.1289/EHP10361.

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States.

BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Preconception and periconception interventions to prevent low birth weight, small for gestational age and preterm birth: a systematic review and meta-analysis.

BACKGROUND: Low birth weight (LBW), including preterm birth (PTB) and small for gestational age (SGA), contributes a significant global health burden. We aimed to summarise current evidence on the effect of preconception and periconception interventions on LBW, SGA and PTB. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library and WHO Global Index Medicus for randomised controlled trials and quasi-experimental studies published by 28 November 2020, which assessed interventions delivered in preconception and periconception or preconception and pregnancy. Primary outcomes were LBW, SGA and PTB. Studies were categorised by intervention type and delivery during preconception and periconception or during preconception and pregnancy. Estimates were pooled using fixed-effects or random-effects restricted maximum likelihood method meta-analyses. Quality of evidence for primary outcomes was assessed using the Grades of Recommendations, Assessment, Development and Evaluation approach. RESULTS: We included 58 studies. Twenty-eight studies examined nutrition interventions (primarily micronutrient or food supplementation). Thirty studies (including one reporting a nutrition intervention) provided health interventions (general preconception health, early adverse pregnancy outcome prevention, non-communicable disease and infectious disease prevention and management). One study assessed a social intervention (reproductive planning). Studies varied in terms of specific interventions, including delivery across preconception or pregnancy, resulting in few studies for any single comparison. Overall, the evidence was generally very uncertain regarding the impact of any intervention on LBW, SGA and PTB. Additionally, preconception and periconception nutritional supplementation containing folic acid was associated with reduced risk of birth defects (10 studies, N=3 13 312, risk ratio: 0.37 (95% CI: 0.24 to 0.55), I2: 74.33%). CONCLUSION: We found a paucity of evidence regarding the impact of preconception and periconception interventions on LBW, SGA and PTB. Further research on a wider range of interventions is required to clearly ascertain their potential effectiveness. TRIAL REGISTRATION NUMBER: This review was prospectively registered with PROSPERO (CRD42020220915).

Effects of Benzo[a]pyrene-DNA adducts, dietary vitamins, folate, and carotene intakes on preterm birth: a nested case-control study from the birth cohort in China.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and its DNA adducts has been suggested to increase the risk of preterm birth (PB). Yet, few studies have been conducted to investigate this association, and the role of dietary nutrients intakes including vitamins, folate, and carotene during pre- and post-conception on this association has not been studied. METHODS: Building upon a birth cohort in Taiyuan China, we conducted a nested case control study including 83 PB and 82 term births. Benzo[a]pyrene (BaP)-DNA adducts were measured by an improved LC-MC/MC analytic method. Dietary nutrient intakes were estimated from food frequency questionnaire using the Chinese Standard Tables of Food Consumption. Multivariable logistic regression model was used to examine the associations. RESULTS: Increased risk of PB was observed as per interquartile increase in maternal BaP-DNA adduct level (OR = 1.27, 95%CI 0.95-1.67). Compared to low level (below mean) of maternal adducts, high level (above mean) of adducts was associated with the risk of PB (OR = 2.05, 95%CI 1.05-4.01). After stratified by dietary nutrients intakes, high adducts levels were associated with approximately 2-fourfold times increases in risk of PB among women with low vitamin A, C, E, folate, and carotene intakes during pre- and/or post-conception. Stronger stratified associations were consistently seen during preconception. Similar patterns were observed after additional adjustment for supplementation. CONCLUSIONS: Our study supports the hypothesis that high level of maternal PAHs exposure was significantly associated with increased risk of PB, and provides the first evidence that dietary vitamins, carotene, and folate intake levels may modify this association during different pregnancy windows. Our findings are relevant to identify recommendation for environment management and prenatal nutrition regarding pregnant women and newborns. Further investigation in other populations is warranted.

Folic Acid and Risk of Preterm Birth, Preeclampsia, and Fetal Growth Restriction Among Women With Epilepsy: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Women with epilepsy treated with antiseizure medication (ASM) have increased risk of pregnancy complications including preterm birth, fetal growth restriction, and preeclampsia. We aimed to investigate whether folic acid supplementation is associated with these pregnancy complications in women with epilepsy using ASM. METHODS: Singleton pregnancies in the prospective Norwegian Mother and Child Cohort Study (MoBa) (1999-2008) were included. Information on maternal epilepsy, ASM, folic acid supplementation, and pregnancy outcomes was obtained from the MoBa questionnaires and the Norwegian Medical Birth Registry. The main exposure, periconceptional folic acid supplementation, was defined as intake between 4 weeks before pregnancy and 12 weeks into pregnancy, retrospectively collected by recall of the mothers in weeks 17-19. The primary outcomes were preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia. RESULTS: The study included 100,105 pregnancies: 99,431 without maternal epilepsy, 316 with maternal epilepsy and ASM exposure in pregnancy, and 358 with untreated maternal epilepsy. Among ASM-treated women with epilepsy, the risk of preterm birth was higher in those who did not use periconceptional folic acid (n = 64) compared with those who did (n = 245, the reference) (adjusted odds ratio [aOR] 3.3, 95% CI 1.2-9.2), while the risk of preterm birth among the reference was similar to the risk among women without epilepsy using folic acid periconceptionally (aOR 0.9, 95% CI 0.5-1.6). ASM-treated women with epilepsy starting folic acid after the first trimester had a higher risk compared with women without epilepsy with similar timing of folic acid (aOR 2.6, 95% CI 1.1-6.5), and even higher if not using folic acid (aOR 9.4, 95% CI 2.6-34.8). Folic acid was not associated with risk of preterm birth among women with epilepsy without ASM or among women without epilepsy. Folic acid was not associated with risk of preeclampsia or SGA among women with epilepsy. DISCUSSION: In women with epilepsy using ASM, periconceptional folic acid was associated with a lower risk of preterm birth. This finding supports the recommendation that ASM-treated women with epilepsy of childbearing potential should use folic acid supplementation on a regular basis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with epilepsy using ASM, periconceptional folic acid supplementation decreases the risk of preterm birth.

Four kinds of tocolytic therapy for preterm delivery: Systematic review and network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Premature birth affects more than 15 million infants, as well as mothers and families around the world. With the relaxation of the two-child policy, the problem of premature birth has become relatively prominent in China. According to statistics, China had a birth population of 15.23 million in 2018, with a considerably large number of premature births. This study aims to evaluate the efficacy and safety of tocolysis in the treatment of preterm delivery, provide clinical evidence for medical staff and promote the self-management of patients with premature births. METHODS: Four English databases (PubMed, Embase, Cochrane Library and Web of Science) were retrieved by computer, the retrieval time was from the establishment of each database to November 2021, and the randomized controlled trials for the treatment of preterm delivery were screened according to the pre-set natriuretic exclusion criteria. After literature screening, data selection and risk of bias evaluation were independently conducted by two researchers. R 4.1.1 and Stata 17.0 software were used for statistical analysis. RESULTS AND DISCUSSION: A total of 44 RCTs were included, including 6939 patients. The results of network meta-analysis reveal that in terms of effectiveness, indomethacin was the most effective intervention measure, followed by nifedipine, and the difference was statistically significant; regarding safety, nifedipine was the safest intervention measure, followed by indomethacin, and the difference was statistically significant; and in respect of adverse reactions, ritodrine had the highest probability, and the difference was statistically significant. WHAT IS NEW AND CONCLUSION: Nifedipine may be better for delayed delivery and less likely to produce adverse pregnancy outcomes, followed by indomethacin. Limited by the number and quality of recipient studies, the aforementioned conclusions need to be verified through more high-quality studies. At the same time, the focus should be on patients with twin pregnancy and patients with clinical manifestations of extreme preterm delivery.

Potential occupational exposure of parents to endocrine disrupting chemicals, adverse birth outcomes, and the modification effects of multi-vitamins supplement and infant sex.

BACKGROUND: Maternal occupational exposure to endocrine disrupting chemicals (EDCs) may have adverse effect on birth outcomes. However, little is known about paternal EDCs exposure and the combined effect of parental exposure on birth outcomes. OBJECTIVES: To assess the effects of both maternal and paternal occupational EDCs exposure on adverse birth outcomes, and further explore if multi-vitamins supplement and infant sex modify the association. METHODS: We conducted a prospective cohort study of 5421 mother-father-newborn groups in Guangzhou, China. A questionnaire informed by a job exposure matrix (JEM) was applied to collect parental occupational EDCs exposure based on the type of work performed. We used logistic regression to estimate association between parental EDCs exposure and birth outcomes (including preterm birth (PTB), low birth weight (LBW), birth defects and congenital heart defects (CHD)). Stratified analyses and Cochran Q tests were performed to assess the modifying effect of maternal multi-vitamins supplement use and infant sex. RESULTS: Compared with mothers unexposed, we found that mothers those exposed to EDCs were associated with increased odds of birth defects (aOR=1.70, 95% confidence interval (CI): 1.10-2.62), especially for those exposed for > 1.5 years (aOR= 3.00, 95% CIs: 1.78-5.03), or those with directly occupational exposed to EDCs (aOR= 2.94, 95% CIs: 1.72-5.04). Maternal exposure for > 1.5 years and direct exposure increased the risk of CHD, with aORs of 2.47 (1.21-5.02) and 2.79 (1.37-5.69), respectively. Stronger adverse effects were also observed when mothers and fathers were both exposed to EDCs. Paternal occupational EDCs exposure and exposure ≤ 1.5 years was associated with increased odds of LBW, with aORs of 2.14 (1.63-2.79) and 1.54 (1.10-2.15), respectively. When stratified by multi-vitamins supplement and infant sex, we observed slightly stronger effects for maternal exposure on birth defects/CHD as well as paternal EDCs exposure on PTB and LBW, among those without multi-vitamins supplement and among male babies, although the modification effects were not significant. CONCLUSION: Maternal exposure to EDCs was associated with greater odds of birth defects and CHD, while paternal exposure was mainly associated with greater odds of LBW. These effects tend to be stronger among mothers without multi-vitamins supplement and among male babies.

Verbascoside-Rich Abeliophyllum distichum Nakai Leaf Extracts Prevent LPS-Induced Preterm Birth Through Inhibiting the Expression of Proinflammatory Cytokines from Macrophages and the Cell Death of Trophoblasts Induced by TNF-α.

Background: Preterm birth is a known leading cause of neonatal mortality and morbidity. The underlying causes of pregnancy-associated complications are numerous, but infection and inflammation are the essential high-risk factors. However, there are no safe and effective preventive drugs that can be applied to pregnant women. Objective: The objectives of the study were to investigate a natural product, Abeliophyllum distichum leaf (ADL) extract, to examine the possibility of preventing preterm birth caused by inflammation. Methods: We used a mouse preterm birth model by intraperitoneally injecting lipopolysaccharides (LPS). ELISA, Western blot, real-time PCR and immunofluorescence staining analyses were performed to confirm the anti-inflammatory efficacy and related mechanisms of the ADL extracts. Cytotoxicity and cell death were measured using Cell Counting Kit-8 (CCK-8) analysis and flow cytometer. Results: A daily administration of ADL extract significantly reduced preterm birth, fetal loss, and fetal growth restriction after an intraperitoneal injection of LPS in mice. The ADL extract prevented the LPS-induced expression of TNF-α in maternal serum and amniotic fluid and attenuated the LPS-induced upregulation of placental proinflammatory genes, including IL-1ß, IL-6, IL-12p40, and TNF-α and the chemokine gene CXCL-1, CCL-2, CCL3, and CCL-4. LPS-treated THP-1 cell-conditioned medium accelerated trophoblast cell death, and TNF-α played an essential role in this effect. The ADL extract reduced LPS-treated THP-1 cell-conditioned medium-induced trophoblast cell death by inhibiting MAPKs and the NF-κB pathway in macrophages. ADL extract prevented exogenous TNF-α-induced increased trophoblast cell death and decreased cell viability. Conclusions: We have demonstrated that the inhibition of LPS-induced inflammation by ADL extract can prevent preterm birth, fetal loss, and fetal growth restriction.

Does Maternal Exposure to Secondhand Tobacco Smoke During Pregnancy Increase the Risk for Preterm or Small-for-Gestational Age Birth?

Introduction While associations between active smoking and various adverse birth outcomes (ABOs) have been reported in the literature, less is known about the impact of secondhand smoke (SHS) on many pregnancy outcomes. Methods We examined the relationship between maternal exposure to SHS during pregnancy and preterm (< 37 weeks gestation) and small-for-gestational age (SGA; assessed using sex-, race/ethnic-, and parity-specific growth curves) singleton births using non-smoking controls from the National Birth Defects Prevention Study (1997-2011). Multivariable logistic regression models for household, workplace/school, and combined SHS exposure-controlled for maternal education, race/ethnicity, pre-pregnancy body mass index, and high blood pressure-were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Interaction was assessed for maternal folic acid supplementation, alcohol use, age at delivery, and infant sex. Results Infants of 8855 mothers were examined in the preterm birth analysis with 666 (7.5%) categorized as preterm, 574 moderately preterm (32-36 weeks), and 92 very preterm (< 32 weeks). For the SGA analysis, infants of 8684 mothers were examined with 670 (7.7%) categorized as SGA. The aORs for mothers reporting both household and workplace/school SHS were elevated for preterm (aOR 1.99; 95% CI 1.13-3.50) and moderately preterm birth (32-36 weeks) (aOR 2.17; 95% CI 1.22-3.88). No results for the SGA analysis achieved significance, nor was evidence of interaction evident. Conclusion The findings suggest an association between SHS from multiple exposure sources and preterm birth, but no evidence for association with SGA births. Continued study of SHS and ABOs is needed to best inform public health prevention programs.

Opium use during pregnancy and risk of preterm delivery: A population-based cohort study.

BACKGROUND: Use of narcotic or "recreational" drugs has been associated with adverse pregnancy outcomes such as preterm delivery. However, the associations might be confounded by other factors related to high-risk behaviours. This is the first study to investigate the association between traditional opium use during pregnancy and risk of preterm delivery. METHOD AND FINDINGS: We performed a population-based cohort study in the rural areas of the Golestan province, Iran between 2008 and 2010. We randomly selected 920 women who used (usually smoked) opium during pregnancy and 920 women who did not. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the opium use during pregnancy and preterm delivery and adjustment was made for potential confounding factors. This study shows compared with non-use of opium and tobacco, use of only opium during pregnancy was associated with an increased risk of preterm delivery (OR = 1.56; 95% CI 1.05-2.32), and the risk was more than two-fold increased among dual users of opium and tobacco (OR = 2.31; 95% CI 1.37-3.90). We observed that opium use only was associated with a doubled risk for preterm caesarean delivery (OR = 2.05; 95% CI 1.10-3.82) but not for preterm vaginal delivery (OR = 1.25; 95% CI 0.75-2.07). Dual use of opium and tobacco was associated with a substantially increased risk of vaginal preterm delivery (OR = 2.58; 95% CI 1.41-4.71). CONCLUSIONS: Opium use during pregnancy among non-tobacco smokers is associated with an increased risk of preterm caesarean delivery, indicating an increased risk of a compromised foetus before or during labour. Women who use both opium and smoked during pregnancy have an increased risk of preterm vaginal delivery, indicating an increased risk of spontaneous preterm delivery.

High Adherence to Iron/Folic Acid Supplementation during Pregnancy Time among Antenatal and Postnatal Care Attendant Mothers in Governmental Health Centers in Akaki Kality Sub City, Addis Ababa, Ethiopia: Hierarchical Negative Binomial Poisson Regression.

BACKGROUND: Iron deficiency during pregnancy is a risk factor for anemia, preterm delivery, and low birth weight. Iron/Folic Acid supplementation with optimal adherence can effectively prevent anemia in pregnancy. However, studies that address this area of adherence are very limited. Therefore, the current study was conducted to assess the adherence and to identify factors associated with a number of Iron/Folic Acid uptake during pregnancy time among mothers attending antenatal and postnatal care follow up in Akaki kality sub city. METHODS: Institutional based cross-sectional study was conducted on a sample of 557 pregnant women attending antenatal and postnatal care service. Systematic random sampling was used to select study subjects. The mothers were interviewed and the collected data was cleaned and entered into Epi Info 3.5.1 and analyzed by R version 3.2.0. Hierarchical Negative Binomial Poisson Regression Model was fitted to identify the factors associated with a number of Iron/Folic Acid uptake. Adjusted Incidence rate ratio (IRR) with 95% confidence interval (CI) was computed to assess the strength and significance of the association. RESULT: More than 90% of the mothers were supplemented with at least one Iron/Folic Acid supplement from pill per week during their pregnancy time. Sixty percent of the mothers adhered (took four or more tablets per week) (95%CI, 56%-64.1%). Higher IRR of Iron/Folic Acid supplementation was observed among women: who received health education; which were privately employed; who achieved secondary education; and who believed that Iron/Folic Acid supplements increase blood, whereas mothers who reported a side effect, who were from families with relatively better monthly income, and who took the supplement when sick were more likely to adhere. CONCLUSION: Adherence to Iron/Folic Acid supplement during their pregnancy time among mothers attending antenatal and postnatal care was found to be high. Activities that would address the above mentioned factors were highly recommended to ensure the sustainability of mothers' adherence to the supplement.

Hypericum perforatum use during pregnancy and pregnancy outcome.

Hypericum perforatum (HP; also known as St. John's Wort) is one of the most commonly used herbal therapies in the management of depressive illness. The aim of this study was to evaluate the potential side effects of HP during pregnancy on pregnancy outcome. Using data from the Danish National Birth Cohort (DNBC), we investigated outcomes among 38 HP exposed pregnancies compared to a group of 90,128 women. Associations between HP use and gestational age, preterm birth, birth weight, malformations and Apgar scores were investigated. Preterm birth did not differ across the groups. While the prevalence of malformations in the HP exposed group was slightly higher (8.1%) than observed in the control groups (3.3%; p=0.13), this was based on only three cases and was not of any specific pattern.

Tea consumption in pregnancy as a predictor of pesticide exposure and adverse birth outcomes: The MIREC Study.

INTRODUCTION: Pesticide residues in tea may contribute to exposure during pregnancy; however, the impact on maternal and infant health is not well understood. The aim of this study was to determine whether tea intake in the first trimester was associated with elevated concentrations of various pesticides in maternal blood or urine. Further, we examined the relationship between tea consumption and adverse birth outcomes. METHODS: Data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canada pregnancy cohort, were used. All singleton, live births (n=1898) with available biomarkers were included in the analyses. Descriptive statistics were used to characterize the population. The geometric means (GM) of organochlorine (OC) pesticide constituents or metabolites in maternal plasma (lipid adjusted) and organophosphate (OP) pesticide metabolites (adjusted for specific gravity) in maternal urine were calculated for participants who drank regular, green or herbal tea in the first trimester and for those who did not. Differences between groups were examined using chi-square or t-tests. Associations between frequency of drinking tea and adverse birth outcomes were examined using logistic regression (preterm birth and small-for-gestational-age) or generalized linear models (birthweight decile and head circumference). RESULTS: The GM of the OC pesticide constituent trans-nonachlor was 2.74 mg/g lipid, and for metabolites oxychlordane and p,p'-DDE this was 1.94 ng/g lipid and 55.8 ng/g lipid, respectively. OP pesticide metabolite concentrations adjusted for specific gravity, were dimethylphosphate (GM: 3.19 µg/L), dimethylthiophosphate (GM: 3.29 µg/L), dimethyldithiophosphate (GM: 0.48 µg/L), diethlphosphate (GM: 2.46), and diethylthiophosphate (GM: 0.67 µg/L). There was no significant difference in mean concentrations for these OC or OP pesticide constituents or metabolites between tea drinkers - of any type - and non-tea drinkers. Further, no association was found between tea intake and adverse birth outcomes. CONCLUSIONS: Pesticide concentrations did not differ by tea intake. Further, tea intake in the first trimester was not associated with adverse birth outcomes. In this study population, there was no evidence for concern about tea intake being a source of the OP or OC pesticide metabolites measured or adversely affecting birth outcomes; however, tea intake was lower than national Canadian data for women of reproductive age.

Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births.

BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.

Folic acid protects against lipopolysaccharide-induced preterm delivery and intrauterine growth restriction through its anti-inflammatory effect in mice.

Increasing evidence demonstrates that maternal folic acid (FA) supplementation during pregnancy reduces the risk of neural tube defects, but whether FA prevents preterm delivery and intrauterine growth restriction (IUGR) remains obscure. Previous studies showed that maternal lipopolysaccharide (LPS) exposure induces preterm delivery, fetal death and IUGR in rodent animals. The aim of this study was to investigate the effects of FA on LPS-induced preterm delivery, fetal death and IUGR in mice. Some pregnant mice were orally administered with FA (0.6, 3 or 15 mg/kg) 1 h before LPS injection. As expected, a high dose of LPS (300 µg/kg, i.p.) on gestational day 15 (GD15) caused 100% of dams to deliver before GD18 and 89.3% of fetuses dead. A low dose of LPS (75 µg/kg, i.p.) daily from GD15 to GD17 resulted in IUGR. Interestingly, pretreatment with FA prevented LPS-induced preterm delivery and fetal death. In addition, FA significantly attenuated LPS-induced IUGR. Further experiments showed that FA inhibited LPS-induced activation of nuclear factor kappa B (NF-κB) in mouse placentas. Moreover, FA suppressed LPS-induced NF-κB activation in human trophoblast cell line JEG-3. Correspondingly, FA significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 in mouse placentas. In addition, FA significantly reduced the levels of interleukin (IL)-6 and keratinocyte-derived cytokine (KC) in amniotic fluid of LPS-treated mice. Collectively, maternal FA supplementation during pregnancy protects against LPS-induced preterm delivery, fetal death and IUGR through its anti-inflammatory effects.

Genistein upregulates placental corticotropin-releasing hormone expression in lipopolysaccharide-sensitized mice.

Genistein is a phytoestrogen isolated from soya beans. Although soy products are staple food of Asian, the potential effect of genistein on reproduction has not been fully addressed. Lipopolysaccharide (LPS) is an endotoxin found in the cell membrane of gram-negative bacteria. It may cause inflammation and other immune responses. Previous study has shown that LPS may induce pre-mature birth in rodents. In the present study, effect of genistein on LPS-induced preterm birth was investigated. Pregnant ICR mice were gavaged with genistein at 40, 200 and 400 mg/kg body weight/day during E13 to E16. LPS was injected i.p. on E16.5 and the animals were sacrificed at E17. Compared to the control group, an increased incidence of early delivery was observed in the pooled mice under LPS treatment. A rising trend of incidence was also demonstrated dose-dependently with genistein co-treatment. Real-time RT-PCR indicated that the placental crh expression was highly induced by the co-administration of 400 mg/kg genistein and LPS. By contrast, neither genistein nor LPS alone could alter the expression. Increased plasma CRH concentration was also seen in the co-treatment groups. In addition, the mRNA expression of placental CRH-binding protein and plasma progesterone concentration were reduced in these groups. These results indicated that genistein might exacerbate the undesirable effect of LPS on pregnant mice by altering hormonal regulations.

Periconceptional intake of folic acid and food folate and risks of preterm delivery.

We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

Preconception omega-3 fatty acid supplementation of adult male mice with a history of developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure prevents preterm birth in unexposed female partners.

We have recently reported that adult male C57BL/6 mice exposed in utero to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) confer an increased risk of preterm birth (PTB) to unexposed females. Risk of PTB was coincident with decreased placental progesterone receptor (Pgr) mRNA expression and increased toll-like receptor 4 (Tlr4) mRNA expression, suggesting that toxicant exposure induced a heightened inflammatory response at the maternal-fetal interface. Since omega-3 fatty acids exhibit anti-inflammatory activity, in this study, we provided TCDD-exposed males a fish oil-enriched diet prior to mating. Although PTB was common in control females mated to TCDD-exposed males on the standard diet, fish oil supplementation of TCDD-exposed males eliminated PTB in unexposed partners. We also determined the influence of preconception, paternal fish oil supplementation on the placental inflammatory response in late pregnancy (E18.5) by examining the expression of Pgr and Tlr4 mRNA as well as the expression of 15-hydroxyprostaglandin dehydrogenase (PGDH). PGDH catabolizes the inflammatory PGE2 to an inactive form; thus, reduced expression of this enzyme would promote tissue inflammation. Compared with control pregnancies, examination of E18.5 placentas arising from TCDD-exposed males on the standard diet revealed a significant increase in Tlr4 mRNA expression corresponding to a reduction in Pgr mRNA and PGDH protein expression. In contrast, fish oil supplementation of toxicant-exposed males led to normalization of placental expression of both Pgr and Tlr4 mRNA and a marked increase in PGDH expression. These studies suggest that a paternal preconception diet that includes omega-3 fatty acids prevents the toxicant-associated increase in the placental inflammatory response at late gestation, preventing PTB.

Does lack of multinutrient supplementation during early pregnancy increase vulnerability to alcohol-related preterm or small-for-gestational-age births?

The objective of this study was to assess whether women who do not take multinutrient supplements during early pregnancy are more susceptible to the effects of low-to-moderate alcohol consumption on preterm birth and small-for-gestational-age birth (SGA) compared to women who do take multinutrients. This analysis included 800 singleton live births to mothers from a cohort of pregnant women recruited for a population-based cohort study conducted in the Kaiser Permanente Medical Care Program in Northern California. Participants were recruited in their first trimester of pregnancy and information about their alcohol use and supplement intake during pregnancy was collected. Preterm birth (n=53, 7%) was defined as a delivery prior to 37 completed weeks of gestation and SGA birth (n=124, 16%) was defined as birth weight less than the 10th percentile for the infant's gestational age and sex compared to US singleton live births. A twofold increase in the odds of SGA birth attributed to low-to-moderate alcohol intake was found among multinutrient supplement non-users (95% CI: 1.1, 5.3). Yet, among multinutrient supplement users, there was no increased risk of an SGA birth for women who drank low-to-moderately compared to women who abstained (aOR: 0.97, 95% CI: 0.6, 1.6). Similar results emerged for preterm birth. Our findings provide marginal evidence that multinutrient supplementation during early pregnancy may modify the risk of SGA births and preterm birth associated with alcohol consumption during pregnancy and may have important implications for pregnant women and women of child-bearing age. However, future research needs to be conducted.