Maternal Urinary Fluoride and Child Neurobehavior at Age 36 Months.

Importance: Recent studies in Canadian and Mexican populations suggest an association of higher prenatal fluoride exposure with poorer neurobehavioral development, but whether this association holds for US-based populations is unknown. Objective: To examine associations of third trimester maternal urinary fluoride (MUF) with child neurobehavior at age 3 years in the US. Design, Setting, and Participants: This prospective cohort study utilized urine samples archived from 2017 to 2020 and neurobehavioral data assessed from 2020 to 2023 from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort, which consisted of predominately Hispanic women residing in Los Angeles, California. Cohort eligibility criteria at recruitment included being 18 years of age or older, less than 30 weeks' gestation, and a fluent English or Spanish speaker. Exclusion criteria included having a disability preventing participation or provision of informed consent, being HIV positive or incarcerated, and having a multiple gestation pregnancy. There were 263 mother-child pairs who completed the 3-year study visit. In this analysis, women who reported prenatal smoking were excluded. Data analysis was conducted from October 2022 to March 2024. Exposure: Specific gravity-adjusted MUF (MUFSG), a biomarker of prenatal fluoride exposure. Main Outcomes and Measures: Neurobehavior was quantified using the Preschool Child Behavior Checklist (CBCL), which included composite scores for Total Problems, Internalizing Problems, and Externalizing Problems. CBCL composite T scores range from 28 to 100. T scores from 60 to 63 are in the borderline clinical range, whereas scores above 63 are in the clinical range. Linear and logistic regression models adjusted for covariates were conducted. Results: A total of 229 mother-child pairs (mean [SD] maternal age, 29.45 [5.67] years; 116 female children [50.7%] and 113 male children [49.3%]) who had MUFSG measured were included in the study. Median (IQR) MUFSG was 0.76 (0.51-1.19) mg/L, and 32 participants (14.0%) had a Total Problems T score in the borderline clinical or clinical range. A 1-IQR (0.68 mg/L) increase in MUFSG was associated with nearly double the odds of the Total Problems T score being in the borderline clinical or clinical range (odds ratio, 1.83; 95% CI, 1.17-2.86; P = .008), as well as with a 2.29-point increase in T score for the Internalizing Problems composite (B = 2.29; 95% CI, 0.47-4.11; P = .01) and a 2.14-point increase in T score for the Total Problems composite (B = 2.14; 95% CI, 0.29-3.98; P = .02). Conclusions and Relevance: In this prospective cohort study of mother-child pairs in Los Angeles, California, prenatal fluoride exposure was associated with increased neurobehavioral problems. These findings suggest that there may be a need to establish recommendations for limiting fluoride exposure during the prenatal period.

Iodine Intake Based on a Survey from a Cohort of Women at Their Third Trimester of Pregnancy from the Bosque County Chile.

Adequate iodine nutrition is fundamental for all humans and is critical during pregnancy and lactation due to iodine forms part of the structure of thyroid hormones (THs) and it is required for THs function. Iodine is a scarce micronutrient that must be obtained from the diet. Sufficient iodine can be found in the nature from seafood and given it is not frequently consumed by Chileans, public health policies state that table salt in Chile must be iodized. Health plans must be monitored to determine if the intake of iodine is being appropriated and the population has not fallen in deficiency or excess. The aim of this work was to evaluate iodine intake in 26 women at the third trimester of pregnancy. Pregnant women are resident from El Bosque a low-income County located in Santiago de Chile. These Chilean pregnant women were recruited by nutritionist at the Centros de Salud familiar (CESFAM). A 24 h dietary recall (24 h-DR) was applied to them to evaluate iodine intake. Samples of urine and blood were taken by health professionals to analyze parameters of thyroid function and to measure urine iodine concentration (UIC). The survey analysis showed that the iodine consumption in these pregnant women derived mainly from salt, bread and milk and not from seafood. The survey analysis indicated that iodine intake was above the requirements for pregnant women. However, the average UIC indicated that iodine intake was adequate, suggesting the need to find a better parameter to determine iodine intake in pregnant women.

Inorganic Phosphate in the Pathogenesis of Pregnancy-Related Complications.

Inorganic phosphate (Pi) is an essential nutrient that fulfills critical roles in human health. It enables skeletal ossification, supports cellular structure and organelle function, and serves key biochemical roles in energetics and molecular signaling. Pi homeostasis is modulated through diet, intestinal uptake, renal reabsorption, and mobilization of stores in bone and extracellular compartments. Disrupted Pi homeostasis is associated with phosphate wasting, mineral and bone disorders, and vascular calcification. Mechanisms of Pi homeostasis in pregnancy remain incompletely understood. The study presented herein examined biological fluid Pi characteristics over the course of gestation. Correlations with gestation age, pregnancy number, preterm birth, preeclampsia, diabetes mellitus, and placental calcification were evaluated during the last trimester. The results support that maternal urinary Pi levels increased during the third trimester of pregnancy. Reduced levels were observed with previous pregnancy. Amniotic fluid Pi levels decreased with gestation while low second trimester levels associated with preterm birth. No significant difference in urinary Pi levels was observed between preeclampsia and controls (8.50 ± 2.74 vs. 11.52 ± 2.90 mmol/L). Moreover, increased maternal urinary Pi was associated with preexisting diabetes mellitus in preeclampsia. Potential confounding factors in this study are maternal age at delivery and body mass index (BMI)-information which we do not have access to for this cohort. In conclusion, Pi levels provide clinical information regarding the pathogenesis of pregnancy-related complications, supporting that phosphate should be examined more closely and in larger populations.

Study on the Potential Biomarkers of Maternal Urine Metabolomics for Fetus with Congenital Heart Diseases Based on Modified Gas Chromatograph-Mass Spectrometer.

BACKGROUND: There has been significant research on the genetic and environmental factors of congenital heart defects (CHDs), but few causes of teratogenicity, especially teratogenic mechanisms, can be clearly identified. Metabolomics has a potential advantage in researching the relationship between external factors and CHD. OBJECTIVE: To find and identify the urinary potential biomarkers of pregnancy (including in the second and third trimesters) for fetuses with CHD based on modified gas chromatograph-mass spectrometer (GC-MS), which could reveal the possibility of high-risk factors for CHD and lay the foundation for early intervention, treatment, and prevention. METHODS: Using a case-control design, we measured the urinary potential biomarkers of maternal urine metabolomics based on GC-MS in a population-based sample of women whose infants were diagnosed with CHD (70 case subjects) or were healthy (70 control subjects). SIMCA-P 13.0 software, principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), Wilcoxon-Mann-Whitney test, and logistics regression were used to find significant potential biomarkers. RESULT: The 3D score graph of the OPLS-DA showed that the CHD and control groups were fully separated. The fitting parameters were R2x=0.78 and R2y=0.69, and the forecast rate was Q2=0.61, indicating a high forecast ability. According to the ranking of VIPs from the OPLS-DA models, we found 34 potential metabolic markers with a VIP > 1, and after two pairwise rank sum tests, we found 20 significant potential biomarkers, which were further used in multifactor logistic regressions. Significant substances, including 4-hydroxybenzeneacetic acid (OR=4.74, 95% CI: 1.06-21.06), 5-trimethylsilyloxy-n-valeric acid (OR=15.78, 95% CI: 2.33-106.67), propanedioic acid (OR=5.37, 95% CI: 1.87-15.45), hydracrylic acid (OR=6.23, 95% CI: 1.07-36.21), and uric acid (OR=5.23, 95% CI: 1.23-22.32), were associated with CHD. CONCLUSION: The major potential biomarkers in maternal urine associated with CHD were 4-hydroxybenzeneacetic acid, 5-trimethylsilyloxy-n-valeric acid, propanedioic acid, hydracrylic acid, and uric acid, respectively. These results indicated that the short chain fatty acids (SCFAs) and aromatic amino acid metabolism may be relevant with CHD.

Maternal urinary phthalate metabolites in relation to gestational diabetes and glucose intolerance during pregnancy.

BACKGROUND: Phthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM). OBJECTIVE: We evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest. STUDY DESIGN: We used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) ("T1T3avg") phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing. RESULTS: In our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ±â€¯27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35). CONCLUSION: In alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT.

Urinary oxidative stress biomarkers and accelerated time to spontaneous delivery.

BACKGROUND: Oxidative stress has been implicated in numerous birth outcomes, including spontaneous preterm birth. However, the relationship with presentation at delivery has been less well studied. We assessed the relationship between oxidative stress biomarkers and gestational duration with a focus on spontaneous presentation for delivery. METHODS: Our sample included 740 women from a multi-center prospective cohort study, recruited from 2010 to 2012. Resultant measures of oxidative stress in pregnancy prostaglandin F2α (PGF2α), 8-iso-prostaglandin F2α (8-iso-PGF2α), and the primary 8-iso-PGF2α metabolite were measured in third trimester urine samples. Information on presentation for delivery was abstracted from medical records. We examined associations with preterm birth using adjusted logistic models. Time to event (overall delivery and spontaneous delivery) was examined using adjusted accelerated failure time models. RESULTS: The 8-iso-PGF2α metabolite was associated with increased odds of overall preterm birth (OR: 1.44 [95% CI: 1.00, 2.06]), and the association with spontaneous preterm birth was similar in magnitude but not statistically significant (OR: 1.45 [95% CI: 0.96, 2.20]). We did not detect associations between other biomarkers and preterm birth, or between biomarkers and timing of overall or spontaneous delivery in accelerated failure time models. CONCLUSIONS: Our data suggest that increased oxidative stress, as indicated by the 8-iso-PGF2α metabolite, may be associated with preterm birth. In contrast to previous studies, associations were similar among individuals with spontaneous versus non-spontaneous presentation for delivery.

Pregnancy-Induced Increases in the Nicotine Metabolite Ratio: Examining Changes During Antepartum and Postpartum.

INTRODUCTION: Pregnancy-induced increases in nicotine metabolism may contribute to difficulties in quitting smoking during pregnancy. However, the time course of changes in nicotine metabolism during early and late pregnancy is unclear. This study investigated how pregnancy alters the nicotine metabolite ratio (NMR), a common biomarker of nicotine metabolism among nonpregnant smokers. METHODS: Urinary NMR (trans-3'-hydroxycotinine [3HC]/cotinine [COT]) was assessed using total (free + glucuronide) and free compounds among women (N = 47) from a randomized controlled trial for smoking cessation who self-reported smoking and provided a urine sample during early pregnancy (M ± SD = 12.5 ± 4.5 weeks' gestation), late pregnancy (28.9 ± 2.0 weeks' gestation), and 6 months postpartum (24.7 ± 1.2 weeks since childbirth). Urine samples were analyzed using liquid chromatography-tandem mass spectrometry and NMR were calculated as Total 3HC/Free COT, Free 3HC/Free COT, and Total 3HC/Total COT. RESULTS: NMR was significantly higher during early and late pregnancy compared to postpartum and significantly increased from early to late pregnancy as measured by Total 3HC/Free COT (0.76, 0.89, 0.60; all p's < .05) and Free 3HC/Free COT (0.68, 0.80, 0.51; all p's < .05). Total 3HC/Total COT did not vary over time (p = .81). CONCLUSIONS: Total 3HC/Free COT and Free 3HC/Free COT increased in the first trimester and continued to increase throughout pregnancy, suggesting a considerable increase in nicotine metabolism over gestation. Future analyses are needed to interpret the changes in NMR in the context of nicotine pharmacokinetics, as well as its impact on changes in smoking behavior and cessation outcomes. IMPLICATIONS: We observed that the NMR was significantly higher as early as 12 weeks' gestation and increased further as a function of gestational age. Among nonpregnant smokers, elevated NMR is associated with smoking phenotypes such as smoking more cigarettes per day and poorer response to nicotine patch; therefore, pregnancy-induced increases in the NMR may contribute to smoking during the first trimester of pregnancy and reducing or quitting smoking may become more challenging as the rate of nicotine metabolism accelerates over the course of pregnancy.

Prenatal exposure to phthalates and autism spectrum disorder in the MARBLES study.

BACKGROUND: Evidence from experimental and observational studies suggests that prenatal phthalate exposures may be associated with autism spectrum disorder (ASD). We examined whether prenatal phthalate exposures were associated with an increased risk of ASD. METHODS: We quantified 14 metabolites of eight phthalates in 636 multiple maternal urine samples collected during 2nd and 3rd trimesters of pregnancy from 201 mother-child pairs in MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a high-risk ASD longitudinal cohort. At 3 years old, children were clinically assessed for ASD and classified into three diagnostic categories: ASD (n = 46), non-typical development (Non-TD, n = 55), and typical development (TD, n = 100). We used multinomial logistic regression to evaluate the association of phthalate metabolite concentrations with ASD and Non-TD. RESULTS: Most associations of phthalate biomarkers with both ASD and Non-TD were null, with the exception that monoethyl phthalate (MEP) was significantly associated with an increased risk of Non-TD (per 2.72-fold relative increase in concentration: Relative risk ratio (RRR) = 1.38; 95% confidence interval (CI): 1.01, 1.90). When stratified by prenatal vitamin use during the first month of pregnancy, among mothers who took vitamins, ASD risk was inversely associated with mono-isobutyl phthalate (MiBP, RRR = 0.44; 95% CI: 0.21, 0.88), mono(3-carboxypropyl) phthalate (MCPP, RRR = 0.41; 95% CI: 0.20, 0.83) and mono-carboxyisooctyl phthalate (MCOP, RRR = 0.49; 95% CI: 0.27, 0.88), but among mothers who did not take prenatal vitamins, Non-TD risk was positively associated with MCPP (RRR = 5.09; 95% CI: 2.05, 12.6), MCOP (RRR = 1.86; 95% CI: 1.01, 3.39), and mono-carboxyisononyl phthalate (MCNP, RRR = 3.67; 95% CI: 1.80, 7.48). When stratified by sex, among boys, MEP, monobenzyl phthalate, MCPP, MCNP, and sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP) were positively associated with Non-TD risk, but associations with ASD were null. Among girls, associations with both ASD and Non-TD were null. CONCLUSIONS: Our study showed that phthalate exposures in mid- to late pregnancy were not associated with ASD in children from this high-risk ASD cohort. Further studies should be conducted in the general population without high-risk genes to confirm our findings.

Iodine status during pregnancy and lactation: a pilot study in the Netherlands.

BACKGROUND: Iodine deficiency occurs in West European countries. Iodine is important for brain development of the foetus and infant. The current iodine status of pregnant and lactating Dutch women is unknown. METHODS: In a pilot study we examined the iodine status of 36 women. From 20 gestational weeks (GW) until 4 weeks postpartum, they ingested 150 µg iodine/day in the form of a multivitamin supplement for pregnant and lactating women. Twenty-four hour urine samples were collected at 20 and 36 GW and at 4 weeks postpartum. A breast milk sample was collected at 4 weeks postpartum. Iodine concentrations were analysed by inductively coupled plasma-mass spectrometry. Cut-off values for the urinary iodine concentration (UIC) for pregnant and lactating women are 150 and 100 µg/l, respectively. Adequate intakes (AI) of iodine for infants aged 0-6 months are 1.1 µmol/l (Institute of Medicine recommendations) or 0.5 µmol/l (Nordic Councilrecommendations). RESULTS: The median UICs (percentages below cut-off) were 102 µg/l (83%) at 20 GW, 144 µg/l (56%) at 36 GW and 112 µg/l (40%) at 4 weeks postpartum. The median breast milk iodine concentration was 1.2 µmol/l (range 0.5-3.0); 33% and 0% of the infants had estimated iodine intakes below the IOM-AI and Nordic-AI, respectively. CONCLUSION: This pilot study suggested a high prevalence of iodine deficiency during pregnancy. Daily supplementation of 150 µg iodine from 20 GW might be insufficient to reach maternal iodine adequacy. The median breast milk iodine concentration seems adequate. Further studies, using a representative sample of the Dutch population, are needed to establish the current Dutch iodine status of pregnant and lactating women.

Urinary metal concentrations among mothers and children in a Mexico City birth cohort study.

Personal care product use is a potential source of metals exposure among children, but studies have been limited. We measured urinary concentrations of 10 metals (aluminum, arsenic [As], barium [Ba], cadmium, cobalt [Co], lead [Pb], manganese [Mn], molybdenum [Mo], nickel, and zinc [Zn]) in third trimester pregnant women (n = 212) and their children at 8-14 years of age (n = 250). Demographic factors (child sex, age, socioeconomic status, and maternal education), body mass index (BMI) z-score, and child personal care product use in the 24 h prior to urine collection were examined as predictors of urinary metal concentrations. Metals were detected in 80-100% of urine samples, with significant differences in maternal versus childhood levels. However, metal concentrations were not strongly correlated within or between time points. In linear regression models including all demographic characteristics, BMI z-score, and specific gravity, age was associated with higher Co (6% [95% CI: 2, 10]), while BMI z-score was associated with lower Mo (-6% [95% CI: -11, -1). In addition, significantly higher metal concentrations were observed among users of colored cosmetics (Mo: 42% [95% CI: 1, 99]), deodorant (Ba: 28% [3, 58]), hair spray/hair gel (Mn: 22% [3, 45]), and other toiletries (As: 50% [9, 108]), as well as with an increasing number of personal care products used (As: 7% [3, 11]) after adjustment for child sex, age, total number of products used, and specific gravity. However, significantly lower metal concentrations were noted for users of hair cream (As and Zn: -20% [-36, -2] and -21% [-35, -2], respectively), shampoo (Pb: -40% [-62, -7]), and other hair products (Pb: -44% [-65, -9]). We found that personal care product use may be a predictor of exposure to multiple metals among children. Further research is recommended to inform product-specific exposure source identification and related child health risk assessment efforts.

The effectiveness of iodine supplementation during pregnancies in geographical areas of high prevalence of iodine insufficiency.

The objective of this study was to determine the effectiveness of routine iodine supplementation among pregnant women in areas of high prevalence of an iodine insufficiency, using WHO criteria to determine the iodine status. A longitudinal study was conducted on pregnant women attending antenatal care at a tertiary hospital. The urine iodine concentration was measured in the first trimester and after 150 µg of iodine supplementation in the third trimester. A total of 327 pregnant women met the inclusion criteria with a complete follow-up. The prevalence of an iodine insufficiency was significantly lower in the third trimester, when compared to the first trimester (21.41% vs 55.35%, p < .001). However, 21.4% of cases still had an iodine insufficiency and 35.17% had an 'above-requirement' in the third trimester. In the areas of high prevalence of iodine insufficiency, an iodine supplementation significantly reduces the number of women with insufficiency; however, it was associated with unnecessarily high UICs, leading to the risk of excess iodine. Impact statement What is already known on this subject: Iodine insufficiency is highly prevalent in many geographical areas. Half of the pregnant women in the northern part of Thailand had an iodine insufficiency in the first trimester. What do the results of this study add: Iodine supplementation (daily 150-mcg of potassium iodide) could significantly reduce the number of women with the insufficiency. About one-fifth of women still had an iodine insufficiency in spite of iodine supplementation. Universal supplementation could be associated with unnecessarily high UICs, potentially at risk of iodine excess. What are the implications of these findings for clinical practice and/or further research: Physicians should guard against the occurrence of adverse effect from an iodine excess when there is routine iodine supplementation for pregnant women. Further study is required to establish the best strategy for an iodine supplementation in pregnancy.

New insights into early and late onset subgroups of preeclampsia from longitudinal versus cross-sectional analysis of urinary inositol-phosphoglycan P-Type.

Most pre-eclampsia (PE) studies have used cross-sectional data to derive conclusions regarding the pathophysiology of the condition. This has led to the concept that there exists early (<34 weeks) and late-onset (>34 weeks) disease according to gestational age at diagnosis. Survival time models have predicted that if the pregnancy was to continue indefinitely, all women would develop PE. In this study we have performed a longitudinal analysis of the urinary biomarker, inositol phosphoglycan (IPG), in a cohort of women giving birth in Mauritius (n-920). We have analysed the PE data in the traditional cross-sectional manner for n = 77 women who developed PE and also then looked at the longitudinal data for 71/77 of the same women. The data allows us to use longitudinal values to calculate a date of onset (first presence of biomarker in urine) and compare that to date of clinical diagnosis (cross sectional). We find two populations for both analysis consistent with an early and late stage subgroup. The calculated date of onset had subgroups (early and late) at 28.4 ±â€¯0.41 weeks and 35.37 ±â€¯0.26 weeks and for clinical date of diagnosis, 32.3 ±â€¯0.59 weeks and 37.04 ±â€¯0.62 weeks, respectively. The presence of the same biomarker in both subgroups and its ability to predict clinical onset 2-4 weeks prior to clinical diagnosis suggest that both groups may have similar aetiology.

Perinatal Biochemical Confirmation of Smoking Status by Trimester.

INTRODUCTION: Tobacco use during pregnancy is the most modifiable risk factor associated with poor pregnancy outcomes. Self-reported tobacco use has been demonstrated to have high misclassification rates. The aims were to examine misclassification rates of perinatal tobacco use during each trimester of pregnancy and 8 weeks postpartum, and to evaluate characteristics associated with misclassification of tobacco use status. METHODS: This is secondary analysis of a prospective, multicenter trial of pregnant women, and it includes participants who were biochemically identified as tobacco users during their first trimester (N = 103). Each trimester and once postpartum, tobacco use was assessed via self-report and validated using a cutoff of 100 ng/mL for urine cotinine via NicAlert test strips to indicate current use. Those who self-reported as nonusers but were identified as users via urine cotinine were considered misclassified; misclassification rates were determined for each time period. Logistic regression assessed maternal factors associated with misclassification status. RESULTS: Misclassification rates declined from 35.0% at first trimester to 31.9% and 26.6% at the second and third; the postpartum rate was 30.4%. These rates did not differ significantly from each other at the 0.05 level. Race/ethnicity was associated with misclassification status; white/non-Hispanic women were 87% less likely to be misclassified (p < .001). CONCLUSION: Misclassification of prenatal smoking status decreases as pregnancy progresses, though the observed rate change was not significant. Minority women may be at particular risk for non-disclosure of tobacco use. Biochemical validation should be considered when assessing perinatal tobacco use via self-report, given high misclassification rates throughout the perinatal period. IMPLICATIONS: These results demonstrate that regardless of trimester, more than one-quarter of tobacco-using pregnant women may not disclose tobacco use throughout pregnancy and early postpartum. Although the rate of misclassification decreased from first to third trimester and then increased in the immediate postpartum, these changes in misclassification rates were not significant. Minority groups may be at particular risk of misclassification compared with white/non-Hispanic women. Biochemical validation is warranted throughout pregnancy to encourage cessation as tobacco use is one of the most easily-modified risk factors for poor birth outcomes.

Evaluation of the risk of perchlorate exposure in a population of late-gestation pregnant women in the United States: Application of probabilistic biologically-based dose response modeling.

The risk of ubiquitous perchlorate exposure and the dose-response on thyroid hormone levels in pregnant women in the United States (U.S.) have yet to be characterized. In the current work, we integrated a previously developed perchlorate submodel into a recently developed population-based pregnancy model to predict reductions in maternal serum free thyroxine (fT4) levels for late-gestation pregnant women in the U.S. Our findings indicated no significant difference in geometric mean estimates of fT4 when perchlorate exposure from food only was compared to no perchlorate exposure. The reduction in maternal fT4 levels reached statistical significance when an added contribution from drinking water (i.e., 15µg/L, 20µg/L, or 24.5µg/L) was assumed in addition to the 90th percentile of food intake for pregnant women (0.198µg/kg/day). We determined that a daily intake of 0.45 to 0.50µg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. Adjusting for this food intake dose, the relative source contribution of perchlorate from drinking water (or other non-dietary sources) was estimated to range from 0.25-0.3µg/kg/day. Assuming a drinking water intake rate of 0.033L/kg/day, the drinking water concentration allowance for perchlorate equates to 7.6-9.2µg/L. In summary, we have demonstrated the utility of a probabilistic biologically-based dose-response model for perchlorate risk assessment in a sensitive life-stage at a population level; however, there is a need for continued monitoring in regions of the U.S. where perchlorate exposure may be higher.

[A cohort study on association between the first trimester phthalates exposure and fasting blood glucose level in the third trimester].

Objective: To examine the association between the phthalate exposure in the first trimester and fasting blood glucose level or gestational diabetes mellitus (GDM) in the third trimester in pregnant women. Methods: A total of 3 474 pregnant women, receiving their prenatal examination in Ma' anshan Maternal and Child Health-Care Hospital of Anhui province, were selected from May 2013 to September 2014. Questionnaires were used to collect the information about their socio-demographic characteristics, clinical characteristics and GDM diagnostic results in the first, second and third trimesters. Urine samples and fasting venous blood samples were collected. Concentrations of 7 kinds of phthalate metabolites in urine samples were detected by solid phase extraction-high performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS), and multiple linear regression model was used for statistical analyses. Logistic regression analysis on the risk of the first trimester phthalate exposure for GDM in the third trimester was conducted. Results: The prevalence of GDM in this study was 12.8%, monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEHHP) exposure levels were positively correlated with the fasting blood glucose level in the third trimester (P<0.05), but mono-(2-ethylhexyl) phthalate (MEHP) and mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEOHP) exposure levels were negatively correlated with the fasting blood glucose level in the third trimester (P<0.05). Stratified analysis showed a positive correlation between MEHHP exposure and the third trimester fasting blood glucose level in both normal group and GDM group. However, MMP, MEP, MBP, MBzP, MEHP and MEOHP exposure levels had influences on the third trimester fasting blood glucose level in normal group but not in GDM group. MMP and MBP exposure might increase the risk of GDM, but MEOHP exposure might reduce the risk of GDM. Conclusion: The phthalate exposure in the first trimester might be associated with the fasting blood glucose level in the third trimester, MMP, MEP, MBP, MBzP and MEHHP concentrations were positively associated with the third trimester blood glucose level, MEHP and MEOHP concentrations were negatively associated with the third trimester blood glucose level. Moreover, the effects of different kinds of phthalates might be different.

The Level of Serum and Urinary Nephrin in Normal Pregnancy and Pregnancy with Subsequent Preeclampsia.

PURPOSE: The aim of this study was to evaluate serum and urinary nephrin levels of normal pregnancy to establish a standard reference value and to compare them with patients who subsequently developed preeclampsia (PE). MATERIALS AND METHODS: In this prospective study, 117 healthy singleton pregnancies were enrolled between 6 to 20 weeks of gestation at 2 participating medical centers during October 2010 to March 2012. Urine and serum samples were collected at the time of enrollment, each trimester, and at 4 to 6 weeks postpartum. Enzyme-linked immunosorbent assay for nephrin was performed and samples from patients who subsequently developed PE were compared to the normal patients. RESULTS: Of 117 patients initially enrolled, 99 patients delivered at the study centers and of those patients, 12 (12.1%) developed PE at a median gestational age of 34⁺4 weeks (range 29⁺5-36⁺6). In the normal patients (n=68), serum nephrin level decreased and urinary nephrin level increased during the latter of pregnancy. In 12 patients who subsequently developed PE, a significant rise in the 3rd trimester serum and urinary nephrin levels, compared to the controls, was observed (p<0.001), and this increase occurred 9 days prior to the onset of clinical disease. CONCLUSION: As the onset of PE was preceded by the rise in the serum and urinary nephrin in comparison to normal pregnancy, serum and urinary nephrin may be a useful predictive marker of PE.

sFlt-1, PlGF, sFlt-1/PlGF ratio and uterine artery Doppler for preeclampsia diagnostics.

BACKGROUND AND OBJECTIVE: Angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) play a key role in the pathogenesis of preeclampsia. Uterine artery (UA) blood flow is important for preeclamptic pregnancy outcome, but small amount of evidence suggests UA dopplerometry for preeclampsia diagnostics and management. The aim of our study was to compare the value of angiogenic factors and UA dopplerometry in preeclampsia diagnosis and determine cut-off values to obtain the highest sensitivity and specificity of the parameter. MATERIALS AND METHODS: We performed a case controlled study of 72 pregnant women with preeclampsia and 72 healthy matched controls. SFlt-1 and PlGF were measured in serum samples, the sFlt-1/PlGF ratio was calculated and UA pulsatility (PI) and resistance (RI) indexes were registered. RESULTS: Significantly higher levels of sFlt-1, sFlt-1/PlGF ratio and mean UAPI and UARI and lower levels of PlGF were found in preeclampsia group when compared to controls. The highest sensitivity and specificity for preeclampsia had SFlt-1/PlGF and PlGF with the cut-off values of ≥35 (sensitivity of 95.8% and specificity of 96.2%, respectively) and ≤138.6pg/mL (sensitivity of 95.8% and specificity of 93.7%, respectively). For diagnostics of early-onset preeclampsia, all factors sFlt-1, PlGF and sFlt-1/PlGF had equal significance with the cut-off values of ≥7572pg/mL (specificity of 97.5%, sensitivity 92.3%), ≤100.5pg/mL (specificity 96.2%, sensitivity of 100%) and ≥54.6 (specificity 97.5%, sensitivity 97.5%) respectively. CONCLUSIONS: The sFlt-1/PlGF ratio and PlGF are superior to sFlt-1, UAPI and UARI for preeclampsia diagnosis. For early-onset preeclampsia diagnostics either sFlt-1 or PlGF is sufficient.

Self-reported and laboratory evaluation of late pregnancy nicotine exposure and drugs of abuse.

OBJECTIVE: The objective of this study was to evaluate the prevalence of late pregnancy nicotine exposures, including secondhand smoke exposures, and to evaluate the associated risk of exposure to drugs of abuse. STUDY DESIGN: The study was a retrospective single-center cohort analysis of more than 18 months. We compared self-reported smoking status from vital birth records with mass spectrometry laboratory results of maternal urine using a chi-square test. Logistic regression estimated adjusted odds for detection of drugs of abuse based on nicotine detection. RESULTS: Compared with 8.6% self-reporting cigarette use, mass spectrometry detected high-level nicotine exposures for 16.5% of 708 women (P<0.001) and an additional 7.5% with low-level exposures. We identified an increased likelihood of exposure to drugs of abuse, presented as adjusted odds ratios, (95% confidence interval (CI), for both low-level (5.69, CI: 2.09 to 15.46) and high-level (13.93, CI: 7.06 to 27.49) nicotine exposures. CONCLUSION: Improved measurement tactics are critically needed to capture late pregnancy primary and passive nicotine exposures from all potential sources.

Arsenic exposure and hepatitis E virus infection during pregnancy.

BACKGROUND: Arsenic has immunomodulatory properties and may have the potential to alter susceptibility to infection in humans. OBJECTIVES: We aimed to assess the relation of arsenic exposure during pregnancy with immune function and hepatitis E virus (HEV) infection, defined as seroconversion during pregnancy and postpartum. METHODS: We assessed IgG seroconversion to HEV between 1st and 3rd trimester (TM) and 3 months postpartum (PP) among 1100 pregnancies in a multiple micronutrient supplementation trial in rural Bangladesh. Forty women seroconverted to HEV and were matched with 40 non-seroconverting women (controls) by age, parity and intervention. We assessed urinary inorganic arsenic plus methylated species (∑As) (µg/L) at 1st and 3rd TM and plasma cytokines (pg/mL) at 1st and 3rd TM and 3 months PP. RESULTS: HEV seroconverters' urinary ∑As was elevated throughout pregnancy. Non-seroconverters' urinary ∑As was similar to HEV seroconverters at 1st TM but declined at 3rd TM. The adjusted odds ratio (95% confidence interval) of HEV seroconversion was 2.17 (1.07, 4.39) per interquartile range (IQR) increase in average-pregnancy urinary ∑As. Increased urinary ∑As was associated with increased concentrations of IL-2 during the 1st and 3rd TM and 3 months PP among HEV seroconverters but not non-seroconverters. CONCLUSIONS: The relation of urinary arsenic during pregnancy with incident HEV seroconversion and with IL-2 levels among HEV-seroconverting pregnant women suggests arsenic exposure during pregnancy may enhance susceptibility to HEV infection.

Prenatal exposure to phthalates and neuropsychological development during childhood.

There is inconsistent evidence regarding the effects of prenatal phthalate exposure on children's neuropsychological development. We evaluate the association between prenatal phthalate exposure and the cognitive, psychomotor and behavioral development of 367 children at repeated ages in a prospective birth cohort study. We measured phthalate metabolites (sum of four DEHP metabolites - Σ4DEHP, MBzP, MEP, MiBP and MnBP) in urine samples collected during the 1st and 3rd trimesters of pregnancy in women participating in the INMA-Sabadell birth cohort study. We assessed cognitive and psychomotor development of their children at 1 and 4 years, and social competence, ADHD symptoms and other behavioral problems at 4 and 7 years. No associations were observed between prenatal phthalate exposure and cognitive and psychomotor scores at the age of 1 year and at the age of 4 years, except for an association between MBzP and lower psychomotor scores (ß=-1.49 [95% confidence interval (CI)=-2.78, -0.21]). Σ4DEHP concentrations were associated with increased social competence scores at 4 years and with reduced ADHD symptoms at age 4 and 7 years. Increasing MEP concentrations were associated with a reduced risk of inattention symptoms at 4 years. No associations were observed for MBzP, MiBP or MnBP in relation to behavioral problems. This study, with multiple phthalate exposure measurements and measures of neuropsychological domains at different ages, suggest that prenatal phthalate exposure does not adversely affect children's cognitive, psychomotor or behavioral development.