The association between maternal urinary Bisphenol A levels and neurodevelopment at age 2 years in Chinese boys and girls: A prospective cohort study.

The impact of maternal exposure to Bisphenol A on child cognitive development as well as its sex dimorphism remains uncertain. This study used data of 215 mothers and their children from a birth cohort in Shanghai. Urinary BPA were measured in spot urine samples of mothers at late pregnancy and children at age 2 years. Cognitive development was evaluated by Ages & Stages Questionnaires, Third Edition (ASQ-3) at age 2 years. Urinary BPA was detectable in 98.9% of mothers (geometric mean, GM: 2.6 µg/g. creatinine) and 99.8% children (GM: 3.4 µg/g. creatinine). Relative to the low and medium BPA tertiles, high tertile of maternal urinary BPA concentrations were associated with 4.8 points lower (95% CI: -8.3, -1.2) in gross motor and 3.7 points lower (95% CI: -7.4, -0.1) in problem-solving domain in girls only, with adjustment for maternal age, maternal education, pre-pregnancy BMI, passive smoking during pregnancy, parity, delivery mode, birth-weight for gestational age, child age at ASQ-3 test. This negative association remained with additional adjustment for child urinary BPA concentrations at age 2 years. No association was observed in boys. These results suggested the sex-dimorphism on the associations of maternal BPA exposure with gross motor and problem-solving domains in children at age 2 years. This study also indicated that optimal early child development should start with a healthy BPA-free "in utero" environment.

Large-for-Gestational-Age, Leptin, and Adiponectin in Infancy.

CONTEXT: Fetal overgrowth "programs" an elevated risk of obesity and type 2 diabetes in adulthood. Plausibly, adipokines may be involved in programming metabolic health. OBJECTIVE: This work aimed to evaluate whether large-for-gestational-age (LGA), an indicator of fetal overgrowth, is associated with altered circulating leptin and adiponectin levels in infancy, and assess the determinants. METHODS: In the Canadian 3D birth cohort, we studied 70 LGA (birth weight > 90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) infants matched by maternal ethnicity, smoking, and gestational age at delivery. The primary outcomes were fasting leptin, and total and high-molecular-weight (HMW) adiponectin concentrations at age 2 years. RESULTS: LGA infants had higher body mass index (BMI) than OGA infants. However, there were no significant differences in leptin, and total and HMW adiponectin concentrations. Leptin concentrations were positively associated with female sex, weight (z score) gain 0 to 24 months, current BMI, and the sum of triceps and subscapular skinfold thickness, and negatively associated with maternal age and White ethnicity. Female sex was associated with lower total and HMW adiponectin concentrations. Weight (z score) gain 0 to 24 months and current BMI were positively correlated with total and HMW adiponectin concentrations in LGA infants only. CONCLUSION: This study is the first to demonstrate that LGA does not matter for circulating leptin and adiponectin concentrations in infancy, and there may be LGA-specific positive associations between weight gain or current BMI and adiponectin concentrations in infancy, suggesting dysfunction in establishing the adiposity-adiponectin negative feedback loop in LGA individuals.

Sex Dimorphic Associations of Gestational Diabetes Mellitus With Cord Plasma Fatty Acid Binding Protein 4 and Estradiol.

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

Large birth size, infancy growth pattern, insulin resistance and ß-cell function.

OBJECTIVE: Large birth size programs an elevated risk of type 2 diabetes in adulthood, but data are absent concerning glucose metabolic health impact in infancy. We sought to determine whether the large birth size is associated with insulin resistance and ß-cell function in infancy and evaluate the determinants. DESIGN AND PARTICIPANTS: In the Canadian 3D birth cohort, we conducted a nested matched (1:2) study of 70 large-for-gestational-age (LGA, birth weight >90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) control infants. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß) at age 2-years. RESULTS: HOMA-IR and HOMA-ß were similar in LGA and OGA infants. Adjusting for maternal and infant characteristics, decelerated growth in length during early infancy (0-3 months) was associated with a 25.8% decrease (95% confidence intervals 6.7-41.0%) in HOMA-ß. During mid-infancy (3-12 months), accelerated growth in weight was associated with a 25.5% (0.35-56.9%) increase in HOMA-IR, in length with a 69.3% increase (31.4-118.0%) in HOMA-IR and a 24.5% (0.52-54.3%) increase in HOMA-ß. Decelerated growth in length during late infancy (1-2 years) was associated with a 28.4% (9.5-43.4%) decrease in HOMA-IR and a 21.2% (3.9-35.4%) decrease in HOMA-ß. Female sex was associated with higher HOMA-ß, Caucasian ethnicity with lower HOMA-IR, and maternal smoking with lower HOMA-ß. CONCLUSIONS: This study is the first to demonstrate that large birth size is not associated with insulin resistance and ß-cell function in infancy but infancy growth pattern matters. Decelerated infancy growth may be detrimental to beta-cell function.

Large-for-Gestational-Age May Be Associated With Lower Fetal Insulin Sensitivity and ß-Cell Function Linked to Leptin.

Context: Fetal overgrowth is associated with increased risk for type 2 diabetes in adulthood. It is unclear whether there are alterations in insulin sensitivity and ß-cell function in early life. Objective: To determine whether large-for-gestational-age (LGA) (birth weight > 90th percentile), an indicator of fetal overgrowth, is associated with altered fetal insulin sensitivity and ß-cell function. Study Design, Population, and Outcomes: In the Design, Development, and Discover birth cohort in Canada, we studied 106 pairs of LGA and optimal-for-gestational-age (OGA; birth weight, 25th to 75th percentiles) infants matched by maternal ethnicity, smoking status, and gestational age. Cord plasma glucose-to-insulin ratio was used as an indicator of fetal insulin sensitivity, and proinsulin-to-insulin ratio was used as an indicator of ß-cell function. Cord plasma leptin and high-molecular-weight (HMW) adiponectin concentrations were measured. Results: Comparisons of infants who were born LGA vs OGA, adjusted for maternal and newborn characteristics, showed that cord blood insulin, proinsulin, and leptin concentrations were significantly higher, whereas HWM adiponectin concentrations were similar. Glucose-to-insulin ratios were significantly lower (15.4 ± 28.1 vs 22.0 ± 24.9; P = 0.004), and proinsulin-to-insulin ratios significantly higher (0.73 ± 0.82 vs 0.60 ± 0.78; P = 0.005) in LGA vs OGA newborns, indicating lower insulin sensitivity and ß-cell function in LGA newborns. These significant differences were almost unchanged after further adjustment for cord blood adiponectin levels but disappeared upon additional adjustment for cord blood leptin levels. Conclusions: This study demonstrates that LGA may be associated with decreases in both fetal insulin sensitivity and ß-cell function. The alterations appear to be linked to elevated leptin levels.

Urinary Bisphenol A Concentration and Gestational Diabetes Mellitus in Chinese Women.

BACKGROUND: Bisphenol A (BPA) has been associated with variable metabolic effects in animal models. It is unknown whether BPA exposure affects glucose tolerance in pregnancy. We aimed to investigate whether maternal urinary BPA concentration is associated with gestational diabetes mellitus (GDM). METHODS: This study included 620 pregnant women from Shanghai, China 2012-2013. Maternal urinary BPA concentration was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). GDM (n = 79) was diagnosed according to the criteria of the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Multivariate regressions were used to explore the relationships of urinary BPA with GDM, plasma glucose levels in the 75-g 2-hour oral glucose tolerance test (OGTT), birth weight, and ponder index. RESULTS: The geometric mean of BPA was 1.32 µg/L. After adjustment for maternal age, education, husband smoking status, prepregnancy body mass index (BMI), and urinary creatinine concentration, plasma glucose at 2 hours in the 75-g OGTT was 0.36 mmol/L lower (95% confidence index [CI] = -0.73, 0.01) for women with urine BPA in the high versus the low tertile. For each unit increase in natural log-transformed BPA, the odds of GDM was reduced by 27% (odds ratio (OR) = 0.73; 95% CI = 0.56, 0.97), the birth weight decreased by 25.70 g (95% CI = -54.48, 3.07), and ponder index was decreased by 0.02 (100 g/cm) (95% CI = -0.03, 0.00). CONCLUSIONS: Higher maternal urinary BPA concentrations were associated with reduced risk of GDM and marginally lower birth weight and ponder index.

Polybrominated Diphenyl Ether Concentrations in Human Breast Milk Specimens Worldwide.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants of ubiquitous presence in numerous consumer products. PBDEs may impair neurodevelopment in infants. There is a lack of meta-analysis on PBDE concentrations in human breast milk worldwide. We aimed to summarize global research data on PBDE concentrations in human breast milk specimens in recent years. METHODS: We conducted a systematic review through PubMed search of original studies on PBDE concentrations in human individual breast milk specimens collected in the general population over the recent 15-year period (2000-2015) worldwide. RESULTS: A total of 49 eligible studies (total number of study subjects = 7,502) were identified. The pooled means (95% CI) of total PBDE concentration in breast milk (ng/g lipid) were 66.8 (44.7, 88.9) in North America, 2.6 (2.2, 3.1) in Europe, and 2.8 (2.4, 3.3) in Asia, respectively. The pooled means (95% CI) of median total PBDEs concentration in breast milk (ng/g lipid) were 40.0 (30.8-49.1) in North America, 1.9 (1.4-2.4) in Europe, and 2.2 (1.3-3.2) in Asia. The high concentrations of total PBDEs in breast milk in North America were mainly due to high concentrations of brominated diphenyl ether-47 (BDE-47), BDE-99, BDE-100, and BDE-153. There were too few studies from other continents (Africa, South America, and Oceania) for meaningful meta-analysis. CONCLUSION: Total PBDE concentrations in breast milk in the recent 15-year period were over 20 times higher in North America versus Asia or Europe, and comparable in Europe versus Asia. There is a need for more research data from other continents.

Maternal Smoking and Metabolic Health Biomarkers in Newborns.

BACKGROUND: Maternal smoking has been associated with elevated risk of type 2 diabetes among the offspring in adulthood. The mechanisms underlying this fetal "programming" effect remain unclear. The present study sought to explore whether maternal smoking affects metabolic health biomarkers in fetuses/newborns. METHODS: In a prospective singleton pregnancy cohort (n = 248), we compared metabolic health biomarkers in the newborns of smoking and non-smoking mothers. Outcomes included cord plasma insulin, proinsulin, insulin-like growth factor I (IGF-I), IGF-II, leptin and adiponectin concentrations, glucose-to-insulin ratio (an indicator of insulin sensitivity) and proinsulin-to-insulin ratio (an indicator of ß-cell function). RESULTS: Independent of maternal (glucose tolerance, age, ethnicity, parity, education, body mass index, alcohol use) and infant (sex, gestational age, birth weight z score, mode of delivery, cord blood glucose concentration) characteristics, the newborns of smoking mothers had lower IGF-I concentrations (mean: 6.7 vs. 8.4 nmol/L, adjusted p = 0.006), and marginally higher proinsulin-to-insulin ratios (0.94 vs. 0.72, adjusted p = 0.06) than the newborns of non-smoking mothers. Cord plasma insulin, proinsulin, IGF-II, leptin and adiponectin concentrations and glucose-to-insulin ratios were similar in the newborns of smoking and non-smoking mothers. CONCLUSIONS: Maternal smoking was associated with decreased fetal IGF-I levels, and borderline lower fetal ß-cell function. Larger cohort studies are required to confirm the latter finding. The preliminary findings prompt the hypothesis that these early life metabolic changes may be involved in the impact of maternal smoking on future risk of metabolic syndrome related disorders in the offspring.

Plasma cotinine indicates an increased risk of preeclampsia in previous and passive smokers.

OBJECTIVE: Self-reported tobacco smoking in pregnancy has been consistently associated with a decreased risk of developing preeclampsia, but the evidence has been limited and inconsistent for previous and passive smokers. Misclassifications and inaccuracies of self-reported tobacco exposure may disguise the true relationship. This study aimed to assess the association of gestational hypertension and preeclampsia with maternal smoking status as ascertained by plasma cotinine. STUDY DESIGN: This was a prospective study of 605 pregnant women without chronic hypertension. Maternal smoking status at 24-26 weeks' gestation was defined by plasma cotinine: >3.0 ng/mL "current smokers," 0.20-3.00 ng/mL "previous and passive smokers," and <0.20 ng/mL "nonsmokers." RESULTS: Compared to nonsmokers, the risk of developing preeclampsia did not change significantly for current smokers, but increased significantly (adjusted odds ratio, 6.06; 95% confidence interval, 2.32-15.85; P < .001) for previous and passive smokers. There were no significant differences in the risk of developing gestational hypertension only. CONCLUSION: Previous and passive smoking may increase the risk of preeclampsia. Avoidance of exposure to environmental tobacco smoke in pregnancy may decrease the risk of preeclampsia.

Human papillomavirus infection and the association with abnormal Pap findings in Yukon, Canada.

OBJECTIVE: Certain types of the human papillomavirus (HPV) are highly associated with cervical cancer or dysplasia, but its prevalence is largely unknown in northern Canada where there is significant aboriginal representation and unique barriers to accessing care. This study determined the prevalence of HPV infection and its association with cervical cancer precursor lesions in Yukon, Canada. MATERIALS AND METHODS: This was a cross-sectional study of 1,542 women attending routine Pap smear screening in 14 communities in Yukon, from February 2009 to June 2010. Type-specific HPV infection was detected by an in-house Luminex assay. Cervical Pap cytology was evaluated by pathologists blinded to HPV test results. RESULTS: The overall HPV prevalence rate in Yukon women was higher than those reported in some Canadian provinces and other countries. Human papillomavirus infection prevalence rates were 24.5% for any type, 18.4% for high-risk types, 6.2% for HPV types 16 or 18, 6.7% for HPV α-7 species, and 10.6% for HPV α-9 species. Human papillomavirus infection was strongly associated with single marital status or having 2 or more sexual partners in the past year. Human papillomavirus infection (overall, high-risk types, HPV-16/18, α-7, or α-9 species) was strongly associated with Pap cytological abnormalities (adjusted odds ratios ranged from 8.4 to 44.2). CONCLUSIONS: As in other areas of northern Canada, HPV prevalence for high-risk types and α-7 species is high among women in the Yukon. Sexual behavioral factors strongly influence HPV prevalence rates. The findings may have implications for HPV vaccination and health promotion programs in northern regions.

Maternal plasma 25-hydroxyvitamin D levels, angiogenic factors, and preeclampsia.

OBJECTIVE: The objective of the study was to examine the associations of maternal plasma levels of 25-hydroxyvitamin D [25(OH)D] with angiogenesis and endothelial dysfunction indicators: soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and risk of preeclampsia. STUDY DESIGN: In this prospective cohort study (n = 697), maternal plasma 25(OH)D levels were measured at 12-18 and 24-26 weeks; sFlt-1, PlGF, ICAM-1, and VCAM-1 levels were measured at 24-26 weeks. RESULTS: Maternal PlGF levels were significantly lower in women with 25(OH)D less than 50 nmol/L at 12-18 weeks (median, 449.5 vs 507.9 pg/mL, P = 0.04) and 24-26 weeks (median, 450.4 vs 522.5 pg/mL, P = 0.007). Both maternal 25(OH)D and PlGF levels were inversely associated with the risk of preeclampsia (both P < .05). However, based on a test of interaction, there was no evidence that the association between vitamin D and preeclampsia depended on the level of PlGF. CONCLUSION: Maternal vitamin D deficiency is associated with low PlGF levels and increased preeclampsia risk. However, our data do not support the hypothesis that the association between vitamin D deficiency and preeclampsia is mediated by impaired angiogenesis.

Risks for preeclampsia and small for gestational age: predictive values of placental growth factor, soluble fms-like tyrosine kinase-1, and inhibin A in singleton and multiple-gestation pregnancies.

OBJECTIVE: To determine the accuracy of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and inhibin A in singleton and multiple-gestation pregnancies for predicting preeclampsia (PE) and small for gestational age (SGA). STUDY DESIGN: A prospective cohort nested in a randomized controlled trial of antioxidant supplementation for the prevention of PE. Plasma biomarkers were evaluated at 12 to 18 (visit 1) and 24 to 26 (visit 2) weeks' gestation and expressed as adjusted multiples of the median. RESULTS: Multiple-gestation pregnancy (74/772) had a significant impact on all biomarkers' levels. PlGF was the best predictor of PE and SGA. At a 10% false-positive rate, PlGF at visit 1 had 21% sensitivity for predicting PE in singleton versus 60% in multiple-gestation pregnancies. PlGF at visit 1 had a 31% sensitivity in singleton and 27% in multiple-gestation pregnancies for SGA prediction. CONCLUSION: PlGF level was a good predictor of subsequent PE as early as 12 to 18 weeks in multiple-gestation pregnancies but was not clinically useful enough to be used as a single marker.

Inflammatory cytokines and spontaneous preterm birth in asymptomatic women: a systematic review.

OBJECTIVE: To estimate the association between inflammatory cytokines and the risk of spontaneous preterm birth in asymptomatic women. DATA SOURCES: We searched electronic databases of the human literature in PubMed, EMBASE, and the Cochrane Library up to February 2010 using the following key words: "preterm/pre-term + (birth/delivery)" and "cytokine" or "inflammation/inflammatory + marker/biomarker." METHODS OF STUDY SELECTION: We included observational studies that reported the association between common inflammatory cytokines and spontaneous preterm birth as an outcome in asymptomatic women. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed and random effects models. TABULATION, INTEGRATION, AND RESULTS: Seventeen primary studies comprising 6,270 participants met the inclusion criteria. Spontaneous preterm birth was strongly associated with increased levels of interleukin-6 (IL-6) in midtrimester cervicovaginal fluid (OR 3.05, 95% CI 2.00-4.67) (number needed to treat=7 for identifying an additional preterm delivery) and amniotic fluid (OR 4.52, 95% CI 2.67-7.65) (number needed to treat=7), but there was no association in plasma specimen (OR 1.5, 95% CI 0.7-3.0). Spontaneous preterm birth was strongly associated with increased C-reactive protein (CRP) levels in midtrimester amniotic fluid (OR 7.85, 95% CI 3.88-15.87) (number needed to treat=3), but the association was weak in plasma specimen (OR 1.53, 95% CI 1.22-1.90). There were insufficient data (fewer than three studies) for meta-analysis in other inflammatory cytokines. CONCLUSION: Inflammatory cytokine IL-6 in cervicovaginal fluid and IL-6 and CRP in amniotic fluid but not in plasma are strongly associated with spontaneous preterm birth in asymptomatic women, suggesting that inflammation at the maternal-fetal interface, rather than systemic inflammation, may play a major role in the etiology of such spontaneous preterm births.

Effect on neonatal outcomes in gestational hypertension in twin compared with singleton pregnancies.

OBJECTIVE: We tested the hypothesis that gestational hypertension may have a more benign effect on neonatal outcomes in twin compared with singleton pregnancies, because the elevated blood pressure in twin pregnancies may partly or merely reflect the extra demand for blood supply. METHODS: A retrospective cohort study of 102,988 twin and 5,523,797 singleton live births using the U.S. birth cohort linked birth and infant death data sets, 1998-2000. Main outcomes are relative risks (RRs) of adverse neonatal outcomes: preterm birth, intrauterine growth restriction (less than the third percentile), low 5-minute Apgar score (less than 4), and neonatal death comparing gestational hypertensive with no-event healthy pregnancies for twins and singletons. RESULTS: For singletons, crude RRs (95% confidence intervals) comparing gestational hypertensive with healthy pregnancies were 2.23 (2.20-2.25) for preterm birth (17.4 compared with 7.8%), 2.49 (2.45-2.53) for intrauterine growth restriction (7.4 compared with 3.0%), 1.33 (1.21-1.45) for low 5-minute Apgar score (2.6 compared with 2.0 per 1,000), and 1.07 (0.96-1.19) for neonatal death (1.9 compared with 1.8 per 1,000), respectively. For twins, the corresponding RRs were much lower or showed reversed associations: 1.21 (1.19-1.24) (63.6 compared with 52.4%), 1.04 (0.98-1.11) (16.4 compared with 16.4%), 0.32 (0.23-0.46) (4.1 compared with 12.7 per 1,000), and 0.21 (0.14-0.30) (3.6 compared with 17.2 per 1,000), respectively. The adjusted odds ratios showed a similar risk pattern in twin compared with singleton pregnancies after controlling for maternal race, age, education, marital status, parity, smoking, alcohol use, perinatal care use, and mode of delivery. CONCLUSION: Gestational hypertension has a much more benign effect on neonatal outcomes in twin compared with singleton pregnancies. There might be a need for twin- or multiple fetus-specific recommendations for hypertension management in pregnancy, but further interventional studies are needed to test the hypothesis. LEVEL OF EVIDENCE: II-2.

Telomeric associations of chromosomes in patients with esophageal squamous cell carcinomas.

AIM:To investigate the role of telomeric association in the development of esophageal cancer.METHODS:Using chromosome R banding technique,telomeric association of chromosome in peripheral blood lymphocytes from 16 untreated patients with esophageal squamous cell carcinoma were observed and 16 healthy adults served as controls.RESULTS:The teloemeric association frequencies of cell and chromosomes were significantly higher than those of controls(X(2) = 9.56,P <0.01), but its distribution on the chromosome showed no significant difference (X(2) =1.01, P >0.05) between the two groups.CONCLUSION:Chromosomal instability can be initiated by telomeric associations, and sequential chromosome analysis can aid the understanding of the tumor occurrence and progression.