Sex-specific difference in placental inflammatory transcriptional biomarkers of maternal phthalate exposure: a prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to birth outcomes in a sex-specific manner. These outcomes may be mediated by placental inflammation, which is the proposed biological mechanism. This is the first study to address the relationship between phthalate exposure and gene expression in placental inflammation in a sex-specific manner. We performed quantitative PCR to measure placental inflammatory mRNAs (CRP, TNF-α, IL-1ß, IL-6, IL-10, MCP-1, IL-8, CD68, and CD206) in 2469 placentae that were sampled at birth. We estimated the associations between mRNA and urinary phthalate monoesters using multiple linear regression models. Mono-n-butyl phthalate (MBP) was correlated with higher IL-1ß, IL-6, and CRP expression in placentae of male fetuses and with higher IL-6, CRP, MCP-1, IL-8, IL-10, and CD68 expression in placentae of female fetuses. Mono benzyl phthalate (MBzP) increased the expression of TNF-α, MCP-1, and CD68 only in placentae of male fetuses. Mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with CRP, MCP-1, and CD68 in placentae of female fetuses. Maternal phthalate exposure was associated with inflammatory variations in placental tissues. The associations were stronger in placentae of male than of female fetuses. Compared with the other metabolites, MBP plays a strong role in these associations. The placenta is worth being further investigated as a potential mediator of maternal exposure-induced disease risk in children.

Urinary concentrations of phthalate metabolites during gestation and intrahepatic cholestasis of pregnancy: a population-based birth cohort study.

Phthalates, a class of widely used endocrine-disrupting chemicals (EDCs), are toxic to various organ systems in animals and humans. Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver dysfunction causing cholestasis in late pregnancy. Evidence on the associations between exposure to phthalates and ICP is still lacking. In the present study, we investigated the relationships between urinary concentrations of phthalate metabolites and the risk of ICP in a Chinese population-based birth cohort. Pregnant women participated in the Ma'anshan Birth Cohort (MABC) study in China. Seven phthalate metabolites were detected in a urine sample in early pregnancy. Chemical concentrations were grouped by quartiles, and associations with outcomes were examined using logistic regression with adjustment for urine creatinine, race, education, poverty status, smoking status, alcohol consumption, maternal age, prepregnancy body mass index (BMI), parity, twin pregnancy, and pregnancy-related liver complications. Of 3474 women recruited into the Ma'anshan Birth Cohort, 2760 met the inclusion criteria and contributed to further analysis and biomonitoring data. Elevated odds ratios (ORs) of ICP were observed in the highest quartiles of monomethyl phthalate (MMP) exposure (OR = 1.59, 95% confidence intervals (CI) = 1.01-2.51) and monobutyl phthalate (MBP) exposure (OR = 1.82, 95% CI = 1.16-2.85) in the adjusted analyses. Our findings add to the evidence that supports the role of maternal phthalate exposure in the first trimester of gestation as a risk factor for ICP.

Maternal intelligence quotient and motor development in early childhood: The mediating role of mother's education.

AIM: To examine the association between maternal intelligence quotient (IQ) and early childhood motor development and whether maternal education mediates this relationship. METHODS: Data were collected prospectively in the Ma'anshan Birth Cohort study. Maternal IQ was assessed using the Wechsler Adult Intelligence Scale-Revised by China (WAIS-RC). Information on baseline characteristics and maternal education was obtained from questionnaires and medical records. The study outcome was motor development evaluated at 18 months by the Third Edition of Ages and Stages Questionnaire. Logistic regression analyses and mediation analyses were used. RESULTS: Of 2739 valid subjects (84% follow-up), the rate of developmental delay was 3.1% in the gross motor domain and 6.2% in the fine motor domain. The mean value for maternal IQ was 96.2 (standard deviation 10.6). About 40.3% of the mothers had secondary education or less, while 59.7% had a college education. Mothers with higher IQ had a significantly higher educational level and had children with better motor development. Maternal education significantly mediated the association between maternal IQ and fine motor development. There was a direct effect of maternal IQ on gross motor development, but the mediation effect of maternal education was not found. CONCLUSIONS: Maternal IQ was associated with motor development. Maternal education played an important role in reducing the disparities in fine motor development among children of different maternal IQs.

Impact of maternal thyroid autoantibodies positivity on the risk of early term birth: Ma'anshan Birth Cohort Study.

PURPOSE: We aim to investigate associations of maternal serum anti-thyroperoxidase autoantibody (TPOAb) with duration of gestation. We aim to investigate whether maternal TPOAb positivity is associated with the risk of premature or early term birth. METHODS: This was a prospective birth cohort study performed in an iodine sufficient area of China. Serum samples were collected from 2931 women at both the first and second trimesters of pregnancy. Thyrotropin (TSH), free thyroxine (FT4), and TPOAb levels were measured. Data on gestational age at birth was obtained from delivery records. RESULTS: The prevalence of early term birth was 23.8%, while the prevalence of premature birth was 4.2%. The prevalence of TPOAb positivity was 12.1% in the first trimester and was 7.2% in the second trimester. Gestational age at birth was inversely associated with lgTPOAb both in the first trimester (ß, -0.283, 95% CI -0.408, -0.158; P < 0.001) and in the second trimester (ß, -0.174, 95% CI -0.319, -0.030; P = 0.018), after adjustment for potential confounding factors. There was a positive association of TPOAb positivity with the risk of early term birth both in the first (OR = 1.691, 95% CI 1.302, 2.197) and second trimesters (OR = 1.644, 95% CI 1.193, 2.264), after adjustment for potential confounding factors. TPOAb positivity in the second trimester was associated with a 1.863-fold higher risk of premature birth (OR = 1.863, 95% CI 1.009, 3.441), after adjustment for potential confounding factors. CONCLUSIONS: Our results show that TPOAb is associated with shorter duration of gestation and with higher risk of premature and early term birth.

Thyroid autoantibodies in pregnancy are associated with hypertensive disorders of pregnancy: Ma'anshan Birth Cohort Study.

OBJECTIVE: Hypertensive disorders of pregnancy (HDP) have been associated with adverse health outcomes for both mothers and children. Previous studies examining associations of maternal thyroid autoantibodies with HDP indicate conflicting results. The objective of this study was to examine associations of maternal thyroid autoantibody positivity in the first and the second trimesters with the risk of HDP. DESIGN, PARTICIPANTS AND MEASUREMENTS: In the Ma'anshan Birth Cohort study, a population-based prospective study in China, a total of 3474 pregnant women were enrolled between May 2013 and September 2014. Thyroid autoantibodies, including antithyroperoxidase autoantibody (TPOAb) and antithyroglobulin autoantibody (TgAb), as well as thyroid function tests, were measured in both the first and the second trimesters in 2893 pregnant women. Multivariate logistic regression analyses were conducted to calculate the odds ratio (OR) and 95% confidence interval (CI) for the associations between thyroid autoantibodies and HDP. RESULTS: Multivariate logistic regression analyses showed that TPOAb positivity in the first trimester was associated with a 1.80 (95% CI = 1.17-2.78) increased odds of HDP after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR = 1.93, 95% CI = 1.17-3.18). In addition, TgAb positivity in the first trimester was associated with a higher risk of HDP (OR = 1.78, 95% CI = 1.16-2.73) after adjustment for confounders, which was mainly due to an increased risk of gestational hypertension (OR = 1.89, 95% CI = 1.15-3.11). These associations were also seen among euthyroid women. Women with positive TPOAb in the second trimester seemed to have a higher risk of gestational hypertension (OR = 1.87, 95% CI = 1.02-3.43) after adjustment for confounders. However, among euthyroid women, TPOAb positivity in the second trimester was not associated with HDP. The TgAb status in the second trimester was not associated with HDP. CONCLUSIONS: Our results show that TPOAb positivity and TgAb positivity in the first trimester are associated with an increased risk of HDP. These data demonstrate that these associations are even seen among euthyroid women.

Effects of the phthalate exposure during three gestation periods on birth weight and their gender differences: A birth cohort study in China.

Phthalate has been widely used as a type of plasticiser in various consuming products in daily life. Recent studies have suggested that prenatal phthalate exposure may have adverse effects on fetal development. We aimed to identify the effects of in utero phthalate exposure on birth weight (BW). We evaluated a birth cohort comprising 3474 pregnant women and their single infants; 3103, 2975 and 2838 urine samples were collected in the first, second and third trimesters, respectively. Phthalate metabolites included monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEHHP), and mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEOHP), which were analysed in the urine by using high performance liquid chromatography-tandem mass spectrometry. Mixed linear model was used in the statistical analysis. Generally, MMP and MEP exposure during pregnancy was associated with decreased birth weight of infants (MMP, ß=-12.192, p=0.009; MEP, ß=-11.876, p=0.014). Hierarchical analysis found that MMP and MEOHP exposure was associated with decreased infants' birth weight only in low birth weight groups (MMP, ß=-42.538, p=0.005; MEOHP, ß=-63.224, p=0.008); MEHP and MEHHP exposure was associated with decreased infants' birth weight in both low birth weight group (MEHP, ß=-42.348, p=0.035; MEHHP, ß=-50.485, p=0.006) and high birth weight group (MEHP, ß=-16.580, p=0.034; MEHHP, ß=-18.009, p=0.040), MBP and MEHP exposure were associated with increased infants' birth weight in male NBW group (MBP, ß=10.438, p=0.039; MEHP, ß=13.223, p=0.017). Moreover, the effect has sex difference. The reduction of birth weight associated with MEHP and MEOHP exposure was stronger in male infants, while MMP and MEP exposure was more significant in female infants.

Prenatal phthalate exposure and placental size and shape at birth: A birth cohort study.

OBJECTIVE: There is concern over the potential placental effects of prenatal phthalate exposure, and the potential adverse effects of prenatal phthalate exposure require further study; however, few data are available in humans. We investigated the associations between phthalate exposure in each trimester and both placental size and shape at birth. METHODS: We measured the urinary concentrations of phthalate metabolites among 2725 pregnant women in the Ma'anshan Birth Cohort. Before collecting urine samples from each of the three trimesters, the pregnant women were interviewed via questionnaires. Placental information was obtained from hospital records. We estimated the sex-specific associations between urinary phthalate concentrations in each trimester and both placental size and shape at birth using adjusted multiple regression. A linear mixed model was used for the repeated measures analysis with subject-specific random intercepts and slopes for gestational age at sample collection to test the effect of phthalate levels on placental size and shape and to estimate the effect sizes. RESULTS: Overall, placental breadth increased by 0.148cm (95% CI: 0.078, 0.218) with each 1 ln-concentration increase in MBP in the first trimester. The difference between placental length and breadth (length-breadth) decreased by 0.086cm (95% CI: -0.159, -0.012) and 0.149cm (95% CI: -0.221, -0.076) with each 1 ln-concentration increase in MMP and MBP, respectively, in the first trimester. In the second trimester, placental thickness increased by 0.017cm (95% CI: 0.006, 0.027), 0.020cm (95% CI: 0.004, 0.036), 0.028cm (95% CI: 0.007, 0.048), and 0.035cm (95% CI: 0.018, 0.053) with each 1 ln-concentration increase in MMP, MBP, MEOHP, and MEHHP, respectively. In the third trimester, placental thickness increased by 0.037cm (95% CI: 0.019, 0.056) and 0.019cm (95% CI: 0, 0.037) with each 1 ln-concentration increase in MBP and MEHP, respectively. Multiple linear regression for each offspring sex indicated that prenatal phthalate exposure increased placental thickness in both the first and second trimesters in males, whereas the corresponding relationship was close to null in females. Linear mixed models (LMMs) yielded similar results. CONCLUSION: Our results suggest the presence of associations between prenatal phthalate exposure and placental size and shape. Exposure to certain phthalates may cause the placenta to become thicker and more circular. Associations appeared stronger for the subsample representing male offspring than those for the subsample representing female offspring. Given the few studies on this topic, additional research is warranted.

Urinary concentrations of phthalate metabolites in early pregnancy associated with clinical pregnancy loss in Chinese women.

Limited evidence revealed conflicting results on relationship between phthalate exposure and clinical pregnancy loss (gestational weeks >6). A prospective cohort study in Chinese pregnant women (n = 3220) was conducted to investigate the association between urinary phthalate metabolites and clinical pregnancy loss (gestational weeks 6 to 27; n = 109). Morning urine samples during gestational weeks 5 to 14 (mean 10.42) were collected to measure monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). The concentrations of low- and high-molecular weight phthalate metabolites (ΣLMWP <250 Da and ΣHMWP >250 Da) were calculated. Adjusted logistic regression models showed increased risks of clinical pregnancy loss in women with higher creatinine- normalized concentrations of MEP, MBP, MEOHP, MEHHP, ΣLMWP and ΣHMWP. Stratified analysis by gestational weeks (10 weeks) of miscarriage indicated positive associations of MEP, MEOHP, MEHHP and ΣHMWP with embryonic loss (during gestational weeks 6 to 10). The only association of foetal loss (during gestational weeks 11 to 27) was observed with MEHHP. Our findings suggested that Chinese women who were exposed to phthalates during early pregnancy had an increased risk of clinical pregnancy loss, especially embryonic loss.

Maternal Continuing Folic Acid Supplementation after the First Trimester of Pregnancy Increased the Risk of Large-for-Gestational-Age Birth: A Population-Based Birth Cohort Study.

Supplementation with folic acid (FA) was proven to prevent neural tube defects (NTDs) and was recommended worldwide before and during early pregnancy. However, much less is known regarding the role of FA after the 12th gestational week (GW). This study aimed to investigate the related effects of continued FA supplementation after the first trimester of pregnancy on fetal growth. The study subjects came from the Ma'anshan-Anhui Birth Cohort Study (MABC) that recruited 3474 pregnant women from the city of Ma'anshan in Anhui Province in China during the period of May 2013 to September 2014. The information on use of vitamin and mineral supplements was recorded in different periods (the first/second/third trimester of pregnancy). Small-for-gestational-age (SGA) births were live-born infants that were <10th percentile of birth weight, and large-for-gestational-age (LGA) births were live-born infants that were ≥90th percentile of birth weight according to nomograms based on gender and gestational age from the latest standards. We used multivariable logistic regression to evaluate the effects of FA supplement consumption in the second/third trimester of pregnancy on the risk of LGA and SGA. In addition, propensity score analysis was also performed to examine the effects. In this prospective birth cohort study conducted in Chinese women who had taken FA in the first trimester of pregnancy, we found that continued FA supplementation with 400 micrograms/day in the second and third trimesters of pregnancy significantly increased the risk of LGA (RR = 1.98 (1.29, 3.04)). This relation was strong or monotonic after adjusting for maternal age, newborn's gender, maternal pre-pregnancy BMI, maternal education level, smoking, alcohol consumption and calcium supplementation. We did not observe that continuing FA supplementation after the first trimester of pregnancy remarkably decreased the risk of SGA. The propensity score analysis showed similar results. To confirm these findings, additional investigations or trials with a large sample and the tracking of folate status throughout pregnancy are recommended.

Maternal Snoring May Predict Adverse Pregnancy Outcomes: A Cohort Study in China.

OBJECTIVE: To examine the prevalence of snoring during pregnancy and its effects on key pregnancy outcomes. METHODS: Pregnant women were consecutively recruited in their first trimester. Habitual snoring was screened by using a questionnaire in the 1st and 3rd trimester, respectively. According to the time of snoring, participants were divided into pregnancy onset snorers, chronic snorers and non-snorers. Logistic regressions were performed to examine the associations between snoring and pregnancy outcomes. RESULTS: Of 3 079 pregnant women, 16.6% were habitual snorers, with 11.7% were pregnancy onset snorers and 4.9% were chronic snorers. After adjusting for potential confounders, chronic snorers were independently associated with gestational diabetes mellitus (GDM) (RR 1.66, 95%CI 1.09-2.53). Both pregnancy onset and chronic snorers were independently associated with placental adhesion (RR 1.96, 95%CI 1.17-3.27, and RR 2.33, 95%CI 1.22-4.46, respectively). Pregnancy onset snorers were at higher risk of caesarean delivery (RR 1.37, 95%CI 1.09-1.73) and having macrosomia (RR 1.54, 95%CI 1.05-2.27) and large for gestational age (LGA) (RR 1.71, 95%CI 1.31-2.24) infants. In addition, being overweight or obese before pregnancy plays an important role in mediating snoring and adverse pregnancy outcomes. CONCLUSIONS: Maternal snoring may increase the risk of adverse pregnancy outcomes, and being overweight or obese before pregnancy with snoring is remarkable for researchers. Further studies are still needed to confirm our results.

[Mid-gestational glucose levels and newborn birth weight: birth cohort study].

OBJECTIVE: To understand the association between the blood glucose levels of pregnant women in second trimester detected by 75 gram oral glucose tolerance test (OGTT) and the birth weight of neonates. METHODS: Demographic information collection and OGTT were conducted for 3 081 pregnant women at ≤14 gestational weeks and 24-28 gestational weeks respectively. Multiple logistic regression analysis was done to identify the factors associated with the birth weight and the risks of large for gestational age (LGA) in three levels (FPG, OGTT-1 h and OGTT-2 h) of OGTT percentile group, multiple linear regression analysis was used to evaluate the relationships between maternal glucose levels and neonate birth weight. RESULTS: Pre-pregnancy obesity (24.0 kg/m2≤BMI<28.0 kg/m2) (OR=1.4, 95%CI:1.0-2.0, P=0.029) and gestational diabetes mellitus (OR=2.4,95% CI: 1.8-3.2, P<0.001) were the risk factors. Pre-pregnancy underweight (BMI<18.5 kg/m2) (OR=1.6, 95%CI: 1.2-2.2, P=0.003), preeclampsia (OR=4.0, 95%CI: 1.9-8.4, P<0.001) increased the risk for small for gestational age (SGA). Multiple linear regression analysis showed neonate birth weight was positive correlated with maternal glucose levels (ß were 91.99, 33.60, 32.00, respectively, P<0.001). Percentile groups of each OGTT level was linearly positive associated with increased mean value of neonate birth weight, and so with the risk of LGA. CONCLUSIONS: There were positive correlations between maternal glucose levels and neonate birth weight. The risk of LGA increased with the maternal glucose levels, but there was no statistical association between SGA and maternal glucose levels. FPG level is one of the predictors of LGA. Active surveillance and control of maternal glucose level can effectively reduce the risk of LGA.

[Course and risk factors of maternal pregnancy-related anxiety across pregnancy in Ma' anshan city].

OBJECTIVE: To explore the prevalence, trends and related influencing factors of pregnancy-related anxiety throughout pregnancy. METHODS: A total of 990 pregnant women at the maternal and child health centers of Ma' anshan participated in all three surveys. Data on demographic characteristic and exposure factors during pregnancy were collected. The Pregnancy-related Anxiety Questionnaire was used to assess the anxiety symptoms. Generalized estimating equations (GEE) was used to evaluate the related influencing factors of pregnancy-related anxiety. RESULTS: The mean score of the pregnancy-related anxiety were 20.3 ± 4.9, 19.6 ± 4.6, 18.9 ± 4.4 for the first, second and third trimester, respectively. Pregnancy-related anxiety showed a significant difference among the three trimesters ( F = 63.10, P < 0.001). Prevalence of pregnancy-related anxiety were 21.0%, 17.7% and 13.6%, respectively, at the first, second and third trimester. Results from GEE analysis indicated that maternal education of senior high school( OR = 1.36, 95% CI 1.05 - 1.75), lower family monthly income (OR =1.33, 95%, CI 1.01 - 1.75), unplanned pregnancy (OR = 2.60, 95% CI 2.05 - 3.29), history of miscarriage (OR = 1.30, 95% CI 1.06 - 1.60), vaginal bleeding (OR = 1.61, 95% CI 1.22 - 2.12), fever ( OR = 1.69, 95% CI 1.17 - 2.46) and use of nutritional supplementation during pregnancy ( OR = 1.43, 95% CI 1.08 - 1. 88 ) significantly increased the risk of pregnancy-related anxiety. CONCLUSION: Pregnancy-related anxiety appeared a decrease from the first to third trimester. Maternal education, economic situation, unplanned pregnancy, history of miscarriage, and adverse physiological symptoms such as vaginal bleeding and fever were associated with the risk of pregnancy-related anxiety.

[Pregestational body mass index, weight gain during first half of pregnancy and gestational diabetes mellitus: a prospective cohort study].

OBJECTIVE: To evaluate the associations between pregestational body mass index (BMI), weight gain during first half of pregnancy and the risk for gestational diabetes mellitus (GDM). METHODS: A prospective cohort study was conducted among 1,914 local pregnant women, receiving the first prenatal examination during the first 14 weeks of gestation, in Ma'anshan of Anhui province from May 2013 to September 2014. The body weight and height were measured for these pregnant women and questionnaire surveys were conducted among them at enrollment, middle gestation and late gestation, respectively. During 24-28 week of gestation, 75 g oral glucose tolerance test was conducted for them. The independent and joint associations between pregestational BMI/weight gain and the risk of GDM were examined by using logistic regression model. RESULTS: The prevalence of GDM was 14.73%. There was significant negative correlation between pregestational BMI and weight gain during the first half of pregnancy (r=-0.085, P<0.01), meanwhile the weight gain of GDM women was significantly higher than that of women without GDM. The women with pregestational overweight or obesity had increased risks of GDM. The results from the logistic regression analysis showed that the risk factors included age≥35 years (OR=3.06, 95% CI: 1.68-5.58), fasting plasma glucose level during early pregnancy (OR=2.17, 95% CI: 1.57-3.00), pregestational overweight (OR=2.08, 95% CI: 1.38-3.13), pregestational obesity (OR=3.73, 95% CI: 1.84-7.56). CONCLUSION: Pregestational overweight or obesity and body weight gain during pregnancy were associated with increased risk of GDM.