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Background & Aims: Dysregulation of iron homeostasis is associated with cardiac alterations in a sex-dependent manner in adults. It is unknown whether iron status during pregnancy has long-term impact on cardiovascular health, and if this association is influenced by sex. Therefore, this study aimed to evaluate sex-specific association between maternal iron status during early pregnancy and cardiac outcomes in children aged 10 years., Methods: In a population-based cohort study among 1972 mother-child pairs, hemoglobin and ferritin were measured in early pregnancy (<18 weeks) and categorized into anemia (hemoglobin<11 g/dL), elevated hemoglobin (hemoglobin≥13.2 g/dL), iron deficiency (ferritin<15 μg/L), and iron overload (ferritin>150 μg/L). At 10 years of age, cardiac MRI was performed to measure right and left cardiac outcomes of function (ventricular end-diastolic volume (RVEDV and LVEDV) and ejection fraction (RVEF and LVEF)), and structure (left ventricular mass (LVM), and left ventricular mass-to-volume ratio (LMVR)). Results are presented for boys and girls separately and models were adjusted for confounders and multiple testing., Results: In boys, one standard deviation score (SDS) increase in maternal hemoglobin was associated with lower RVEDV and LVEDV (difference (95%CI) -0.10 (-0.17, -0.03) SDS and -0.09 (-0.16, -0.03) SDS, respectively). In boys, maternal anemia, as compared to normal hemoglobin levels, was associated with higher LVEDV (difference 0.34 (0.10, 0.59) SDS). No associations were observed for other cardiac outcomes and for ferritin in boys. No associations were observed in girls., Conclusion: In boys, dysregulated iron status during early pregnancy might permanently alter cardiovascular RVEDV and LVEDV function. Underlying mechanisms need further study., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The epidemiologic literature on associations between urinary phenol concentrations and lipid profiles during pregnancy is limited. We examined whether urinary concentrations of phenol and phenol replacement biomarkers were associated with serum lipid levels among pregnant women. This cross-sectional study included 175 women attending the Massachusetts General Hospital Fertility Center who enrolled in the Environment and Reproductive Health (EARTH) Study between 2005 and 2017 and had data available on urinary phenol biomarkers and serum lipids during pregnancy. We used linear regression models to assess the relationship between groups of urinary phenol and phenol replacement biomarkers and serum lipid levels [total cholesterol, high density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, and triglycerides], while adjusting for age at sample collection, pre-pregnancy BMI, education, race, infertility diagnosis, cycle type, number of fetuses, trimester and specific gravity. In adjusted models, pregnant women with urinary propylparaben concentrations in the highest tertile had 10% [22 (95% CI = 5, 40) mg/dL], 12% [19 (95% CI = 2, 36) mg/dL] and 16% [19 (95% CI = 3, 35) mg/dL] higher mean total, non-HDL and LDL cholesterol, respectively, compared to women with concentrations in the lowest tertile. Similar elevations were observed for urinary bisphenol A concentrations. Urinary bisphenol S, benzophenone-3, triclosan, methylparaben, ethylparaben, and butylparaben were unrelated to serum lipids. Among pregnant women, urinary concentrations of bisphenol A and propylparaben were associated with higher serum levels of total, non-HDL and LDL cholesterol., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background/aim: Matrix metalloproteinases (MMPs) are important regulators of uterine remodeling, a critical process for healthy pregnancies, and studies have revealed a link between an imbalance in MMPs and adverse birth outcomes. Toxicological studies have indicated that exposure to heavy metals can alter the levels of inflammatory cytokines, including MMPs. Despite growing evidence, the clear association between heavy metal exposure and MMPs has yet to be explored extensively in human populations. To have a better understanding of the association, in this study, we assessed associations between maternal blood metal levels with MMPs among 617 pregnant women in the Puerto Rico PROTECT birth cohort., Methods: We measured blood concentrations for 11 metals in the first and/or second trimester of pregnancy using ICP-MS. MMPs (MMP1, MMP2, and MMP9) were quantified using a customized Luminex assay. Linear mixed effects models (LMEs) were used to regress MMPs on metals and included random intercepts for study participants to account for correlated repeated outcome measures. Fetal sex effects were estimated using interaction terms between metal exposure variables and fetal sex indicators., Results: We observed significant associations between cesium, manganese, and zinc with all the MMPs that were measured. We also observed differences in metal-MMPs associations by fetal sex. Cobalt was positively associated with MMP1 only in women with male fetuses, and cesium was negatively associated with MMP1 only in women with female fetuses. MMP2 had significant associations with maternal blood metal concentrations only in women with female fetuses., Conclusion: Certain metals were significantly associated with MMPs that are responsible for uterine remodeling and healthy pregnancies. Most of these associations differed by fetal sex. This study highlighted significant metal-MMPs associations that may inform research on new avenues for understanding heavy metal-induced adverse birth outcomes and the development of diagnostic tools., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To determine the trajectories of platelet counts and the prevalence of gestational thrombocytopenia (<150 × 10 9 /L) during normal pregnancies and pregnancies with complications, such as hypertensive disorders of pregnancy (HDP), preeclampsia, and fetal growth restriction (FGR)., Study Design: A multicenter retrospective study was conducted using laboratory data on women who delivered term singletons at 11 primary maternity care units between 2011 and 2018 (n = 35,045), and non-pregnant women who underwent a medical check-up between 2016 and 2019 (n = 61,189). After 1:1 matching, 28,073 pregnant women and 28,073 non-pregnant women were selected for analysis., Main Outcomes Measures: The trajectories of platelet counts and prevalence of gestational thrombocytopenia were evaluated in normal pregnant women, pregnant women with complications, and non-pregnant women., Results: The platelet counts declined throughout pregnancy, with the nadir occurring on postpartum day 1. The platelet counts recovered to the level of the non-pregnant state at postpartum 2-7 days. The mean platelet counts at postpartum day 1 decreased by an estimated 19.8% and 9.7% compared to those in the non-pregnant state and first trimester, respectively. The prevalence of gestational thrombocytopenia in normal pregnant women at 37-41 gestational weeks and in pregnant women with complications of HDP, preeclampsia, and FGR were 6.1%, 7.3%, 17.5%, and 7.7%, respectively., Conclusion: Platelet counts declined throughout pregnancy and recovered to the level of the non-pregnant state in the early postpartum period. Gestational thrombocytopenia is common during normal pregnancy, and its prevalence is significantly higher in women with preeclampsia., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The prenatal environment, including availability of critical nutrients, has a profound impact on offspring development. The present study examined the association between maternal long-chain polyunsaturated fatty acid (LC-PUFA) status during pregnancy and later child behavioral problems at the age of 5-6 years. In light of evidence of autonomic nervous system (ANS) dysregulation in some behavioral problems, study further tested if the above association is statistically mediated by cardiac ANS activity., Methods: Data was collected as part of the Amsterdam Born Children and their Development-study and complete data were available for 1717 mothers and their offspring. Maternal LC-PUFA status was assessed during early pregnancy (mean gestation = 12.7, SD = 2.5 weeks) and quantified as levels of docosahexenoic acid (DHA), arachidonic acid (AA), eicosapentaenoic acid (EPA), as well as the ratio of n-6:n-3 fatty acids. Child emotional problems and peer problems (internalizing problems), as well as conduct problems and inattention/hyperactivity (externalizing problems), were assessed using the Strengths and Difficulties Questionnaire as rated by the mother and teacher at 5-6 years. Child cardiac respiratory sinus arrhythmia (RSA), pre-ejection period (PEP), and heart rate (HR) were utilized as measures of ANS activity at 5-6 years., Results: The results confirmed an association between maternal LC-PUFA status and internalizing behavioral problems as rated by the mother, as shown for DHA (β = -0.11;p < 0.01), EPA (β = -0.22;p < 0.05), and n-6:n-3 LC-PUFA (β = 0.17;p < 0.01). Statistical mediation was only demonstrated for HR. No associations were observed between LC-PUFA status and externalizing behavioral problems., Conclusions: The present results are consistent with a role of maternal LC-PUFA status in internalizing behavioral problems as rated by the mother. These results were not observed when problem behavior was rated by the teacher. Analyses did not yield strong evidence supporting ANS activity as a possible mediator in this relationship., Competing Interests: Conflict of interest The authors (TV, JS, SdR, JB) declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: This study aims to explore the associations of vitamin D (VD) metabolic pathway gene with 25(OH)D level in pregnant women and the interactions of SNP with season and VD supplement., Methods: A total of 2658 pregnant women were selected from Zhoushan Pregnant Women Cohort study. Gestational 25(OH)D level and single nucleotide polymorphism (SNP) of VD metabolic pathway gene were detected. Multilinear regression models were used to estimate associations of SNPs with gestational 25(OH)D levels. Stratified analyses were performed to test the interactions of SNP with season and VD supplements., Results: The mutations of rs2298849 and rs7041 on the GC gene were respectively associated with higher 25(OH)D in the first and third trimester; the mutations of seven SNPs (rs1155563, rs16846876, rs17467825, rs2282679, rs2298850, rs3755967, and rs4588) on the GC gene were respectively associated with lower 25(OH)D both in the first and third trimester, and lower changes in 25(OH)D during late pregnancy. The mutations of above seven SNPs, except for rs1155563, were also respectively associated with lower 25(OH)D in the second trimester, but to a lesser extent; Besides, pregnant women with mutation on CYP24A1-rs2209314 had a higher increment in 25(OH)D than their counterparts in the second trimester. The increasing dose effect of Gc isoform on 25(OH)D was observed. The associations of GC and LRP2 genes with 25(OH)D modified by season and VD supplements., Conclusions: The polymorphisms of VD metabolic pathway gene were associated with gestational 25(OH)D, and the associations differ by seasons and VD supplements. Gc isoform exerted a profound influence on gestational 25(OH)D., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Rotational thromboelastometry (ROTEM®) is a point-of-care coagulation test. Reference ranges in non-labouring women have recently been established from a cohort of women presenting for elective caesarean delivery using the recommended minimum sample size of 120. This study aimed to present baseline parameters for labouring and non-labouring women and to compare the mean values of these ROTEM® parameters., Methods: Ethical approval was granted for an opt-out recruitment approach for labouring women and written consent was obtained from non-labouring women (data published previously). ROTEM® testing was performed in these two cohorts at term gestation. Women with any condition affecting coagulation were excluded. ROTEM® Delta reference ranges were derived by calculating the 2.5 and 97.5 percentiles for INTEM/EXTEM/FIBTEM amplitude at 5 min (A5), coagulation time (CT), maximum clot firmness (MCF) and clot formation time (CFT)., Results: One hundred and twenty-one labouring and 132 non-labouring women met inclusion criteria. The mean values for selected ROTEM® parameters for labouring and non-labouring women respectively were: FIBTEM A5, 21.05 and 19.7 mm (P=0.008); EXTEM A5, 54.8 and 53.2 mm (P=0.025); and EXTEM CT, 52.2 and 53.7 s (P=0.049). Significant differences between the groups were observed in measures of clotting onset and clot firmness., Conclusions: We demonstrated a significant decrease in the mean time-to-clotting onset in labouring women compared with non-labouring women. Mean values for measures of clot firmness were greater in labouring women. In comparison to previously established ROTEM® baseline parameters for non-labouring women, this study provides evidence that there is greater hyper-coagulability in labouring women., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The objective of this study was to determine the association of beta-carotene concentration in plasma at the moment of artificial insemination (AI) on pregnancy/AI in lactating Holstein cows. A total of 399 events from 364 lactating Holstein cows were enrolled in the trial (143 primiparous and 221 multiparous). All cows were assigned to a timed AI protocol based on estradiol and progesterone. Blood samples were collected at the moment of AI and at 24 and 31d post-AI (samples on 31 d post-AI were collected only from cows that were diagnosed pregnant). The BCS were recorded at the time of AI. Plasma beta-carotene was quantified from blood samples taken at the time of AI using a single step denaturation and extraction into a solvent, followed by measurement using a portable spectrophotometer. Pregnancy-associated glycoproteins (PAG) were analyzed in blood samples taken at 24 and 31 d post-AI of pregnant cows. Milk production was collected for the entire experimental period. Pregnancy diagnosis was performed by ultrasound 31 and 60 d post-AI. Data was analyzed using the MIXED and GLIMMIX procedures of SAS. Cows classified as thin (<2.75) tended to have lower concentration of beta-carotene at AI when compared with those classified as Moderate (≥3.00; 3.8 ± 0.1 vs. 4.3 ± 0.1 μg/mL; P = 0.09). Concentration of beta-carotene were greater in multiparous compared with primiparous (P < 0.01). There was no correlation between concentration of beta-carotene and milk production (r = 0.04; P = 0.10). When plasma beta-carotene was categorized in quartiles, cows in the 1st quartile had lower pregnancy/AI and higher pregnancy losses when compared with cows that were in the 2nd, 3rd and 4th quartile (pregnancy/AI = 19.2 ± 4.5, 33.7 ± 4.7, 36.9 ± 5.0 and 39.8 ± 5.4%, respectively; P = 0.05; pregnancy losses = 41.9 ± 4.8, 20.4 ± 3.7, 22.1 ± 4.1, and 15.7 ± 4.2%, respectively; P < 0.05). There was no association between concentrations of beta-carotene at AI and PAG at 24 d post-AI (P = 0.60). Cows with greater concentrations of beta-carotene at AI were more likely to have greater concentrations of PAG at 31 d post-AI (P < 0.01). In conclusion, the concentration of beta-carotene at AI was affected by BCS and parity. Cows with higher concentrations of plasma beta-carotene at AI had greater pregnancy/AI, lower pregnancy losses and greater concentrations of PAG at d 31 post-AI, suggesting it may be associated with placental function in lactating dairy cows., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Hyperglycosylated human chorionic gonadotropin, the predominant human chorionic gonadotropin variant secreted following implantation, is associated with trophoblast invasion., Objective: To determine whether the initial serum hyperglycosylated human chorionic gonadotropin differs between ongoing and failed pregnancies, and to compare it to total serum human chorionic gonadotropin as a predictor of ongoing pregnancy., Materials and Methods: Women undergoing fresh/frozen in vitro fertilization cycles at a university-based infertility clinic with an autologous day 5 single embryo transfer resulting in serum human chorionic gonadotropin >3 mIU/mL (n = 115) were included. Human chorionic gonadotropin was measured 11 days after embryo transfer in a single laboratory (coefficient of variation <6%). Surplus frozen serum (-80 o C) was shipped to Quest Laboratories for measurement of hyperglycosylated human chorionic gonadotropin (coefficient of variation <9.1%). Linear regression analyses adjusted for oocyte age a priori were used to compare human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin in ongoing pregnancies (>8 weeks of gestation) and failed pregnancies (clinical pregnancy loss, biochemical and ectopic pregnancies)., Results: A total of 85 pregnancies (73.9%) were ongoing. Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated (Pearson correlation coefficient 92.14, P < .0001), and mean values of both were positively correlated with blastocyst expansion score (P value test for trend < .0004). Mean human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin were significantly higher in ongoing vs failed pregnancies. Among ongoing pregnancies vs clinical losses, mean hyperglycosylated human chorionic gonadotropin, but not human chorionic gonadotropin, was significantly higher (19.0 vs 12.2 ng/mL, β -8.1, 95% confidence interval -13.0 to -3.2), and hyperglycosylated human chorionic gonadotropin comprised a higher proportion of total human chorionic gonadotropin (4.6% vs 4.1%; risk ratio, 0.79; 95% confidence interval, 0.66-0.94)., Conclusion: Measured 11 days after single blastocyst transfer, hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated, but only mean hyperglycosylated human chorionic gonadotropin and its ratio to total human chorionic gonadotropin were significantly higher in ongoing pregnancies vs clinical pregnancy losses. Further evaluation of hyperglycosylated human chorionic gonadotropin, including in multiple embryo transfers and multiple pregnancy, and using serial measurements, is required., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Human milk oligosaccharides (HMOs) were recently found in serum of normal-weight pregnant women, with concentrations increasing from early to mid- and late pregnancy. Whether HMOs have effects on maternal metabolism is unknown., Objectives: We aimed to study the presence and changes in HMOs throughout pregnancy and assess associations with maternal glucose metabolism throughout pregnancy., Methods: The study was a prospective longitudinal cohort study including 87 overweight or obese women. Blood samples were taken at 15, 24, and 32 wk of pregnancy. In serum, 4 HMOs [2'-fucosyllactose (2'FL), lactodifucotetraose (LDFT), 3'-sialyllactose (3'SL), and 3'-sialyllactosamine (3'SLN)] were measured. In linear regression models, the associations between HMOs and (changes in) maternal metabolic parameters were assessed., Results: All 4 HMOs showed a significant increase from 15 to 32 weeks of gestation. 3'SL and 3'SLN, but not 2'FL or LDFT, at 15 wk were positively associated with (changes in) fasting glucose at 24 and 32 wk. LDFT was positively associated with (changes in) insulin and HOMA-index at 24 but not 32 wk. A model to predict the development of gestational diabetes mellitus (GDM) that included fasting glucose, prepregnancy BMI, gestational weight gain, age, parity, smoking, and history of macrosomia resulted in an area under the curve (AUC) of 0.81 (95% CI: 0.70, 0.92). Adding 3'SL to this model increased the AUC to 0.91 (95% CI: 0.84, 0.97)., Conclusions: The sialylated HMOs 3'SL and 3'SLN were associated with fasting glucose; LDFT was associated with fasting insulin and HOMA-index. Furthermore, 3'SL was more predictive of future GDM diagnoses than was fasting glucose in early pregnancy. Causal relations are unclear and need further investigation., (Copyright © American Society for Nutrition 2019.)

Background: One-carbon metabolism, responsible for purine and thymidylate synthesis and transmethylation reactions, plays a critical role in embryonic and fetal development. Formate is a key player in one-carbon metabolism. In contrast to other one-carbon metabolites, it is not linked to tetrahydrofolate, is present in plasma at appreciable concentrations, and may therefore be distributed to different tissues., Objective: The study was designed to determine the concentration of formate in cord blood in comparison with maternal blood taken earlier in pregnancy and at delivery and to relate formate concentrations to potential precursors and key fetal genotypes., Methods: Formate and amino acids were measured in plasma during early pregnancy (12-16 wk), at delivery (37-42 wk), and in cord blood samples from 215 mothers, of a prospective cohort study. Three fetal genetic variants in one-carbon metabolism were assessed for their association with cord plasma concentrations of formate., Results: The formate concentration was ∼60% higher in the cord blood samples than in mothers' plasma. The maternal formate concentrations did not differ between the early pregnancy samples and those taken at delivery. Plasma concentrations of 4 formate precursors (serine, glycine, tryptophan, and methionine) were increased in cord blood compared with the maternal samples. Cord blood formate was influenced by fetal genotype, being ∼12% higher in infants harboring the MTHFR A1298C (rs1801131) AC or CC genotypes and 10% lower in infants harboring the MTHFD1 G1958A (rs2236225) GA or AA genotypes., Conclusions: The increased formate concentrations in cord blood may support the increased activity of one-carbon metabolism in infants. As such, it would support increased rates of purine and thymidylate synthesis and the provision of methionine for methylation reactions., (Copyright © American Society for Nutrition 2019.)

Background & Aims: Vitamin D status during pregnancy and in newborns has never been studied in France. This study aims at determining the vitamin D status during the first and third trimesters of pregnancy (T1, T3) and in cord blood (CB) in the middle-north of France., Methods: We conducted a prospective cohort study in five French centers (latitude 47.22 to 48.86°N). Serum 25(OH)-vitamin D (25(OH)D) concentrations were measured using a radioimmunoassay during T1, T3 and in CB. According to the French guidelines, pregnant women received cholecalciferol, 100,000 IU, in the seventh month., Results: Between April 2012 and July 2014, 2832 women were included, of whom 2803 were analyzed (mean ± SD age: 31.5 ± 5.0 years; phototypes 5-6: 21.8%). Three and 88.6% of participants received supplementation during the month before inclusion and in the seventh month, respectively. At T1, T3, and CB, mean 25(OH)D concentrations were 21.9 ± 10.4, 31.8 ± 11.5, and 17.0 ± 7.2 ng/mL, respectively, and 25(OH)D was <20 ng/mL in 46.5%, 14.0%, and 68.5%, respectively. At T1, body mass index ≥25 kg/m 2 , dark phototypes, sampling outside summer, and no supplementation before inclusion were independently associated with vitamin D insufficiency (25(OH)D < 20 ng/mL). Women who received cholecalciferol supplementation in month 7 had higher 25(OH)D at T3 than non-supplemented women (32.5 ± 11.4 versus 25.8 ± 11.4 ng/mL, p = <0.001) and marginally higher 25(OH)D in CB (17.2 ± 7.2 versus 15.5 ± 7.1 ng/mL, p = 0.004)., Conclusions: Despite the recommended supplementation, vitamin D insufficiency is frequent during pregnancy and in newborns in France., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: To assess inter-manufacturer automated immunoassays for soluble FMS-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF)., Methods: sFlt-1 and PlGF levels were measured using the AutoDelfia PlGF1-2-3 (PerkinElmer Inc. Turku, Finland), BRAHMS Kryptor sFlt-1, PlGF plus and PlGF-2 (BRAHMS ThermoFisher, Germany) and Cobas e411 Elecsys® sFlt-1 and PLGF (Roche Diagnostics GmbH, Mannheim, Germany) in 965 asymptomatic pregnancies between 20 and 39 weeks of gestation and in in-vitro samples with predefined levels of glycosylated PlGF isomers (1, 2 and 3), sFlt-1 in human male serum. Percentage PlGF isoform recovery and cross-reactivities were determined. Paired Bland-Altman and Passing-Bablok analyses were performed to determine bias, precision and accuracy. Inter-manufacturer sFlt-1:PlGF ratio were compared., Results: PlGF-1 isomer recovery ranged from 36 to 39% for Elecsys® to 52-60% for PlGF plus and PlGF-1-2-3 assays. PlGF-2 and PlGF-3 isoform cross-reactivity was assay dependent, ranging from 10 to 21% and 16-36% respectively. BRAHMS PlGF-2 assay had high cross-reactivity to PlGF-1 (37-41%) and PlGF-3 isomers (48-65%). Elecsys® recovery of sFlt-1 was 13% vs 6% for BRAHMS. Passing-Bablok indicated significant proportional and systematic differences between all paired PlGF assay comparisons. PlGF Bland-Altman percentage biases ranged from 12 to 37% for PlGF and 18% for sFlt-1. A linear relationship existed between log transformed sFlt-1:PlGF ratios. The clinical equivalent of the BRAHMS sFlt-1:PlGF plus to the Elecsys® sFlt-1:PlGF ratios of 38 and 110 are 55 and 188 respectively., Conclusion: Inter-manufacture immunoassay differences are significantly different. sFlt-1:PlGF rule in/rule out criteria are manufacturer specific, not interchangeable and require separate clinical validation., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: During pregnancy lead crosses the placenta freely and can have adverse effects on the fetus, with the potential for lifelong impact on the child. Identification of dietary patterns and food groups in relation to measures of lead status could provide a more useful alternative to nutrient-specific advice to minimize fetal lead exposure., Objectives: The aim of this study was to evaluate whether dietary patterns and food groups are associated with blood lead concentration (B-Pb) in pregnancy., Design: Whole blood samples were collected at a median of 11 wk gestation (IQR 9-13 wk) from women enrolled in the Avon Longitudinal Study of Parents and Children birth cohort study, and analyzed for lead. Dietary pattern scores were derived from principal components analysis of a food-frequency questionnaire (32 wk gestation). Associations of dietary pattern scores (quartiles), and of food groups (frequency of consumption), with the likelihood of B-Pb ≥5 µg/dL identified with adjusted logistic regression (n = 2167 complete cases)., Results: There was a negative association between the "confectionery" dietary pattern and the likelihood of B-Pb ≥5 µg/dL (OR: 0.62; 95% CI: 0.41, 0.94) in an adjusted model. There were no associations with other dietary patterns. There was a positive association between the food group "all leafy green and green vegetables" and the likelihood of B-Pb ≥5 µg/dL (OR 1.45; 95% CI: 1.04, 2.01). Conversely, the food group "cakes and biscuits" was negatively associated (OR 0.63; 95% CI: 0.43, 0.93). After multiple imputation, there was a positive association of the "healthy" diet pattern and no association of the "confectionery" pattern., Conclusions: We found limited evidence of an association between women's typical diet and B-Pb during pregnancy. Our findings do not indicate need to revise dietary guidance for pregnant women, who are advised to adopt a healthy diet in pregnancy, with a variety of foods consumed in moderation., (Copyright © American Society for Nutrition 2019.)

Circulating sFlt-1 increases significantly in pregnancy compared to the non-pregnant state and even more so in the event of preeclampsia. We set out to determine if circulating sFlt-1 is placentally derived in normal pregnancy. Paired uterine and peripheral vein samples were collected at time of caesarean section. A follow up peripheral sample was collected in the postpartum period. There was a significant sFlt-1 gradient between uterine and peripheral veins. sFlt-1 levels dropped significantly when the placenta has been removed, i.e. postnatally. This is in keeping with the placenta being the main site of sFlt-1 production in normal pregnancies., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Which blood-based indicator best reflects the iron status in pregnant women is unclear. Better assessments of iron status in today's multiethnic populations are needed to optimize treatment and clinical recommendations., Objectives: We aimed to determine the prevalence of anemia (hemoglobin <11.0 g/dL in first and <10.5 g/dL in second trimester) and iron deficiency (ID) by the iron indicators serum ferritin <15 µg/L, serum soluble transferrin receptor (sTfR) >4.4 mg/L, and calculated total body iron <0 mg/kg, and their associations with ethnicity., Methods: This was a population-based cross-sectional study from primary antenatal care of 792 healthy women in early pregnancy in Oslo, Norway. We categorized the women into 6 ethnic groups: Western European, South Asian, Middle Eastern, Sub-Saharan African, East Asian, and Eastern European., Results: Anemia was found in 5.9% of women (Western Europeans: 1.8%; non-Western: 0-14%, P < 0.05). ID from ferritin was found in 33% (Western Europeans: 15%; non-Western: 27-55%, P < 0.05). ID from sTfR was found in 6.5% (Western Europeans: 0.3%; non-Western: 0-20%, P < 0.01). Calculated total body iron indicated ID in 11% (Western Europeans: 0.6%, non-Western: 7.0-28%, P < 0.01). The prevalence of ID was significantly higher by all measures in South Asian, Sub-Saharan African, and Middle Eastern than in Western European women, and the ethnic differences persisted after adjusting for confounders. South Asians, Sub-Saharan Africans, and Middle Easterners had lower iron concentrations by all measures for all hemoglobin intervals. Anemia related to ID varied from 35% (sTfR) to 46% (total body iron) and 72% (ferritin) depending on the iron indicator used., Conclusions: Women at the highest risk of ID and anemia were of South Asian, Middle Eastern, and Sub-Saharan African origin. The prevalence of ID differed considerably depending on the iron indicator used., (© 2019 American Society for Nutrition.)

It is well-known that the neuropeptide oxytocin plays a critical role regulating the formation of adult-adult pairbonds in non-human animals, and recent work suggests oxytocin may similarly play an important role in romantic bonding in humans. Specifically, endogenous oxytocin is predictive of a host of relationship-enhancing behaviors, relationship quality, and even relationship survival amongst newly dating couples. This work suggests that oxytocin can buffer romantic relationships, possibly during especially difficult transition periods. One challenge that many couples face is the birth of a child: a joyous event, but one that is recognized as a major life stressor nonetheless. We aimed to investigate whether maternal oxytocin buffers the parent-partner relationship during the perinatal transition period. To test this, we analyzed data from a longitudinal study of child-bearing women (N = 269) in which endogenous oxytocin was measured in blood plasma during the 1st and 3rd trimesters and at 7-9 weeks postpartum; relationship status was assessed at the outset and 2.5 years postpartum. As predicted, lower maternal oxytocin was associated with greater risk for relationship dissolution by the time the child was a toddler (p < .05). These findings directly replicate research showing that endogenous oxytocin predicts relationship survival in dating couples, but in a novel interpersonal context. That said, only a very small number (N = 7) of couples separated; this, of course, is unsurprising given that the perinatal transition period is not a time when couples typically choose to terminate their relationship. Nonetheless, these findings must be considered preliminary until replicated in future research., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Some maternal hormone levels in pregnancy are associated with a higher risk of breast and ovarian cancer. This study systematically assessed the association between blood hormone levels measured in pregnancy and future risk of these cancers., Methods: Two reviewers independently conducted a literature search of MEDLINE and EMBASE databases from January 1970 to August 2017. Studies were included that measured one or more serum hormone levels in pregnancy and later assessed for cancer. Cancer outcomes were considered by cancer type, each in relation to a specific maternal hormone., Results: Eleven studies were included, comprising a total of 57 967 women. The interval between pregnancy and cancer onset varied from 4.1 to 20.5 years. Elevated serum chorionic gonadotropin (two of four studies) and alpha fetoprotein (two of three studies) were each associated with a lower risk of maternal breast cancer, whereas elevated estrone levels suggested a higher risk (one of three studies). Elevated testosterone (one of one study) and androstenedione (one of one study) were each associated with a significantly greater risk of sex-cord stromal ovarian tumours. Higher serum 17-hydroxyprogesterone was associated with an increased risk of sex-cord stromal (one of one study) and epithelial (one of one study) ovarian cancer., Conclusion: Observational studies suggest some degree of association between serum hormones measured in pregnancy and a woman's future risk of breast and ovarian cancer. More data are needed to determine sufficiently whether certain blood hormone levels measured in pregnancy are predictive of future cancer risk., (Copyright © 2019 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Peroxiredoxin 3 (PRX3) is predominantly located in mitochondria and plays a major role in scavenging hydrogen peroxide of mitochondria. In the present study, we detected plasma PRX3 in pregnant women receiving oral glucose tolerance test at 24-28 gestational weeks. Plasma PRX3 was significantly increased about 1 h later than insulin secretion. In vitro detection of PRX3 in mouse islet cells showed up-regulation by more than 2-fold at 1 h and reached its top at 2 h of glucose stimulation, and the PRX3 level in cultured mediums was concomitantly elevated in a glucose concentration-dependent manner. In addition, both fasting plasma insulin and PRX3 were significantly higher in the subjects of term pregnancy as compared to that at 24-28 gestational weeks, and there was a positive correlation between plasma PRX3 and insulin. Our results indicate that PRX3 plays an active role in the response to insulin release. The positive association of plasma PRX3 and insulin suggest PRX3 to be a potential indicator of high insulin resistance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: To explore the relationship between vitamin D pathway genes, gene-environment interactions and vitamin D level among southeast Chinese pregnant women., Methods: 759 participants from Zhoushan Pregnant Women Cohort (ZPWC) study, were enrolled from August 2011 to April 2014 in China. Plasma 25(OH)D levels and genetic variants in vitamin D pathway (NADSYN1/DHCR7, GC, CYP3A4, CYP2R1, CYP27A1, CYP27B1, VDR, CYP24A1, and LRP2) were measured using the blood sample collected at the first trimester. Information on demographics, lifestyle, and health behavior were collected using a questionnaire. Multilinear regression and logistic regression models were performed to estimate the associations between SNPs and 25(OH)D level., Results: Mean plasma 25(OH)D concentrations were 15.6 ng/mL among the pregnant women. Variants of GC rs16846876, rs17467825, rs2282679, rs3755967, rs2298850, rs4588, rs7041 and rs1155563, CYP3A4 rs2242480 and CYP24A1 rs2209314 were significantly associated with both 25(OH)D concentrations and vitamin D deficiency (25(OH)D < 15 ng/mL). Variants of NADSYN1/DHCR7 were significantly associated with 25(OH)D concentrations among pregnant women without vitamin D supplements. Pregnant women with vitamin D binding protein (Gc) Gc-1f (P = 0.02) and Gc-1s (P = 0.005) had higher plasma 25(OH)D levels compared to women with Gc-2. Genotype risk score (GRS) calculated from rs7041, rs2242480 and rs2209314 shown a significantly negative association with 25(OH)D levels. Participants with GRS > 3 had a higher risk for vitamin D deficiency than individuals with GRS ≤ 3 (OR = 1.71, 95% CI = 1.25-2.35). Interactions between seasons and CYP27A1 rs933994, CYP3A4 rs2246709 on plasma 25(OH)D concentrations were also observed. Haplotypes of GC and LRP2 genes shown significant associations with 25(OH)D levels among pregnant women, respectively., Conclusions: Genetic mutants in vitamin D pathway (GC, CYP3A4, CYP24A1, and NADSYN1/DHCR7) had significant associations with 25(OH)D levels among pregnant women in southeast China. Furthermore, their associations were modified by vitamin D supplementation and season., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: High dietary intakes of phytosterols (Phyto), such as those consumed by vegans and vegetarians, are not recommended for cholesterol-lowering in pregnant women (PW) because the safety of their use during pregnancy has not been fully established [1]. Information on Phyto in pregnancy is very limited., Objective: To characterize the maternal-fetal gradient of free and esterified Phyto at the time of delivery in humans., Design: PW who had a term delivery at the Obstetrics and Gynecology Unit of the University Hospital of Padua (Padua, Italy), between November 2016 and March 2017, participated in the study. Fatty acids (FA), cholesterol (Chol), Chol metabolites (7-dehydrocholesterol, 7-DHChol; lathosterol, Latho; 7α-hydroxycholesterol, 7α-OHChol), and Phyto (campesterol, Camp; stigmasterol, Stigma; sitosterol, Sito) were measured in both maternal (MB) and cord blood (CB) at the time of delivery. Non-pregnant adult volunteers (Ref-NA) served as a reference., Results: Thirty-four term PW and 12 Ref-NA signed informed consent and were studied. Plasma total Phyto concentrations in CB were up to 20-fold lower than in MB (p < 0.05). Positive and significant correlations were found between total Phyto of MB-CB pairs (p < 0.01), and between total FA and Camp of MB (p < 0.05). Interestingly, free Chol to Chol ester ratio of CB did not differ from that of MB, and free Phyto to Phyto ester ratios were higher in CB than in MB (p < 0.001). No differences were found between Phyto concentrations of MB and Ref-NA. However, free Chol to Chol ester ratio, and free Phyto to Phyto ester ratios were higher in MB than in Ref-NA (p < 0.05). Chol synthesis, as indicated by 7-DHChol to 7α-OHChol, Latho to 7α-OHChol, and Latho to Sito ratios, was greatest in CB and lowest in Ref-NA., Conclusion: Our data suggest that free Phyto cross the human placenta more easily than Phyto ester. An elevated Stigma to Chol ratio in CB than in MB was also described for the first time. The impact of these findings on the neonatal outcomes remains to be elucidated., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Despite decades of investigation, we cannot predict, prevent, or adequately treat the most common and deadly complications of pregnancy, including pre-eclampsia (pregnancy-induced hypertension). The current working hypothesis for the repeated failures of several multicenter studies that measured a wide variety of biomarkers is common pregnancy complications like pre-eclampsia are most likely heterogeneous syndromes with various etiologies; therefore, no combination of blood-based biomarkers will provide predictive power. Although the clinical syndrome of pre-eclampsia may have various causes, the current dogma is most cases share similar placental pathology, including accelerated chorionic villous maturation and an increased frequency of malperfusion-related infarctions. This pathology is thought to begin in the late first trimester of pregnancy. The challenge has been to develop an approach to monitor placental health in vivo. New contrast-enhanced imaging studies of blood flow to the placenta are providing insights, but rapid liquid-based assays using maternal blood would be more cost-effective. Recently, there has been a growing interest in placental extracellular vesicles (EVs) to determine if these complex lipid-based spheres involved in intercellular communication offer clues to the early pathophysiology of placental damage. Most EVs are nanoscale-sized exosomes (∼60-120 nm) that retain cell-specific plasma membrane surface markers. Their concentration, composition, and relative size distribution may provide clinical predictive power, but more investigation is needed. A major obstacle to advancement in this field has been the lack of EV imaging and isolation assays that can provide both cell- and size-specificity. Nanoscale multiplex high-resolution flow cytometry being developed in a number of laboratories may provide a solution. It is a potential means to quantitate both cell- and size-specific EVs from various cell sources, including the placenta., (Copyright © 2018. Published by Elsevier Inc.)

Exposure to poly- and perfluoroalkyl substances (PFAS), ubiquitous and persistent environmental contaminants, could be associated with adverse health outcomes, but there are limited longitudinal data assessing patterns and predictors of exposure during childhood. We quantified concentrations of eight different PFAS in sera collected from women during pregnancy and children at delivery and ages 3 and 8 years in 367 mother-child pairs enrolled in a prospective cohort from 2003 to 2006. In general, median childhood PFAS concentrations increased from birth to age 3 and then decreased by age 8. Maternal serum PFAS concentrations during pregnancy were strongly correlated with cord serum concentrations (0.76 < r < 0.94), but were weakly correlated with childhood concentrations (0.12 < r < 0.30). Several sociodemographic factors were associated with maternal PFAS concentrations, including income, race, and parity. In children, serum PFAS concentrations were associated with maternal age at delivery, race, parity, and child age. Breastfeeding duration was positively associated with childhood PFAS concentrations at ages 3 and 8 years. In addition, stain repellant use was associated with higher perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations at age 8 years. Serum PFAS concentrations are higher during early childhood, a potentially sensitive period of development, and were highest among breastfed children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: To better understand the immunology of pregnancy, study of female genital tract fluid (FGF) is desirable. However the optimum method of collection of FGF in pregnant women for immunological methods, specifically cytokine measurement, is unknown., Methods: A prospective study of HIV-uninfected pregnant women comparing two methods of FGF collection: polyvinyl acetal sponge collection of cervical fluid (CF) and menstrual cup collection of cervicovaginal fluid (CVF). Samples were collected at 3 time points across the second and third trimesters: 14-21, 22-25 and 26-31 weeks. Multiplex chemi-luminescent assays were used to measure: IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13 and TNF-α. Optimal methodology for cytokine normalisation (sample weight, volume and total protein) was explored., Results: All cytokines were measurable in both fluid types. IL-1β, IL-8 and IL-6 were detected at the highest concentrations (ranking order CF > CVF > plasma). CVF collection was simpler, provided the largest volume of sample (median 0.5 g) with the potential for undiluted usage, and allowed for self-insertion. CF cytokine concentrations were intrinsically associated with sample weight and protein concentration however CVF cytokines were independent of these., Conclusion: Both methods of collection are robust for measurement of FGF cytokines during pregnancy. We recommend CVF collection using a menstrual cup as a viable option in pregnant women for high dimensional biological techniques., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To assess whether serum concentrations of saturated (SFAs), polyunsaturated (PUFAs), and monounsaturated (MUFAs) fatty acids are associated with changes in blood pressure (BP) throughout pregnancy., Study Design: Prospective cohort., Main Outcome Measures: Longitudinal measurements of systolic (SBP) and diastolic (DBP) BP., Methods: Two hundred twenty-three healthy pregnant women were recruited in a public health center in Rio de Janeiro, Brazil between 2009 and 2011. Fasting blood samples and BP measurements were obtained at the 1st (5th-13th weeks), 2nd (20 th -26th) and 3rd trimester (30th-36th). Crude and adjusted (maternal age, education, energy intake, gestational body weight change, leptin concentrations, early pre-pregnancy BMI, leisure time physical activity prior to pregnancy and linear and quadratic gestational weeks) longitudinal linear mixed-effects models were employed., Results: SBP and DBP decreased from the 1st to the 2nd trimester and slightly increased from the 2nd to the 3rd trimester (P < 0.001). In the adjusted model (ß and 95% CI), total SFAs [0.005 (0.001-0.008); P = 0.008], total MUFAs [0.005 (0.001-0.009); P = 0.019] and total n-6 PUFAs [0.005 (0.001-0.009); P = 0.025] were positively associated with SBP throughout pregnancy., Conclusions: Maternal serum concentrations of total SFAs, MUFAs and n-6 PUFAs were positively associated with BP levels in normotensive pregnant women., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable because it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome., Objective: The recent availability of a highly multiplexed platform affording the simultaneous measurement of 1310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns caused by fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins and link such attributes to relevant immunological changes., Study Design: Pregnant women participated in this longitudinal study. In 2 subsequent sets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 weeks), second (15-20 weeks), and third (24-32 weeks) trimesters and 6 weeks postpartum for analysis with a highly multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piecewise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term., Results: An independently validated model consisting of 74 proteins strongly predicted gestational age (P = 3.8 × 10 -14 , R = 0.97). The model could be reduced to 8 proteins without losing its predictive power (P = 1.7 × 10 -3 , R = 0.91). The 3 top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase and signal transducer and activator of transcription pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top-ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with signal transducer and activator of transcription-5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age., Conclusion: Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a proteomic clock. Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a clock is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-related pathologies, and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that chrionic somatomammotropin hormone may critically regulate T-cell function during pregnancy., (Copyright © 2018. Published by Elsevier Inc.)

Selenium (Se) has been positively associated with neurodevelopment in early life. However, its margin of safety is rather narrow, and few prospective studies have evaluated its potential neurotoxic effects at intermediate levels. We aimed to explore the association between maternal Se concentrations and child neuropsychological development, including the genetic effect modification of the Se metabolizing gene INMT. Study subjects were 650 mother-child pairs from the Spanish Childhood and Environment Project (INMA, 2003-2005). Infant neuropsychological development was assessed around 12months of age by the Bayley Scales of Infant Development. Sociodemographic and dietary characteristics were collected by questionnaire at the first and third trimester of gestation. Se was measured in serum samples at the first trimester. The mean serum Se concentration was 79.7 (standard deviation=7.9) μg/L. In multivariate analysis, nonsignificant inverse linear associations were found between Se concentrations and standardized mental and psychomotor development scores (β (95% CI)=-0.13 (-0.29, 0.03) and β (95% CI)=-0.08 (-0.24, 0.07), respectively). Generalized additive models indicated inverted U-shaped relationships between Se concentrations and both scales. Using segmented regression, the turning point for the associations was estimated at 86μg/L for both scales. The association between Se and neuropsychological development was inverted U-shaped for children with the AG+AA genotype for rs6970396 INMT but a descending curve was suggested for the GG genotype. Further studies would be necessary in order to disentangle the complex equilibrium between the toxicity and benefits of Se exposure during the prenatal period., (Copyright © 2017 Elsevier B.V. All rights reserved.)

DHA is important for fetal neurodevelopment. During pregnancy, maternal plasma DHA increases, but the mechanism is not fully understood. Using rats fed a fixed-formula diet (DHA as 0.07% total energy), plasma and liver were collected for fatty acid profiling before pregnancy, at 15 and 20 days of pregnancy, and 7 days postpartum. Phosphatidylethanolamine methyltransferase (PEMT) and enzymes involved in PUFA synthesis were examined in liver. Ad hoc transcriptomic and lipidomic analyses were also performed. With pregnancy, DHA increased in liver and plasma lipids, with a large increase in plasma DHA between day 15 and day 20 that was mainly attributed to an increase in 16:0/DHA phosphatidylcholine (PC) in liver (2.6-fold) and plasma (3.9-fold). Increased protein levels of Δ6 desaturase (FADS2) and PEMT at day 20 and increased Pemt expression and PEMT activity at day 15 suggest that during pregnancy, both DHA synthesis and 16:0/DHA PC synthesis are upregulated. Transcriptomic analysis revealed minor changes in the expression of genes related to phospholipid synthesis, but little insight on DHA metabolism. Hepatic PEMT appears to be the mechanism for increased plasma 16:0/DHA PC, which is supported by increased DHA biosynthesis based on increased FADS2 protein levels., (Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.)

During pregnancy, iron needs to increase substantially to support fetoplacental development and maternal adaptation to pregnancy. To meet these iron requirements, both dietary iron absorption and the mobilization of iron from stores increase, a mechanism that is in large part dependent on the iron-regulatory hormone hepcidin. In healthy human pregnancies, maternal hepcidin concentrations are suppressed in the second and third trimesters, thereby facilitating an increased supply of iron into the circulation. The mechanism of maternal hepcidin suppression in pregnancy is unknown, but hepcidin regulation by the known stimuli (i.e., iron, erythropoietic activity, and inflammation) appears to be preserved during pregnancy. Inappropriately increased maternal hepcidin during pregnancy can compromise the iron availability for placental transfer and impair the efficacy of iron supplementation. The role of fetal hepcidin in the regulation of placental iron transfer still remains to be characterized. This review summarizes the current understanding and addresses the gaps in knowledge about gestational changes in hematologic and iron variables and regulatory aspects of maternal, fetal, and placental iron homeostasis., (© 2017 American Society for Nutrition.)

Pregnant women are particularly vulnerable to iron deficiency due to the high iron demands of pregnancy. To avoid the adverse birth outcomes that are associated with maternal iron deficiency anemia, both Canada and the United States recommend universal iron supplementation for pregnant women. Although the benefits of iron supplementation in anemic women are well recognized, insufficient data are currently available on the maternal and neonatal benefits and harms of universal iron supplementation in developed countries as evidenced by the recent conclusions of the US Preventive Services Task Force on the need for further data that address existing gaps. As part of an effort to evaluate the impact of the current North American prenatal iron supplementation policy, this review highlights the lack of national data on longitudinal changes in iron status in pregnant North American women, emphasizes possible limitations with the original longitudinal hemoglobin data used to inform the current CDC reference hemoglobin values, and presents additional normative data from recent longitudinal research studies of iron status in North American pregnant women. Further longitudinal data in North American pregnant women are needed to help identify those who may benefit most from supplementation as well as to help determine whether there are adverse effects of iron supplementation in iron-replete women., (© 2017 American Society for Nutrition.)

Understanding the iron status in pregnant women in Europe provides a foundation for considering the role of iron screening and supplementation. However, available reports and studies have used different approaches that challenge the devising of overall summaries. Moreover, data on pregnant women are limited, and thus, data on women of reproductive age provide useful background information including baseline iron stores in pregnant women. This review considered data that are available from >15 European countries including national surveys and relevant clinical studies. In European women of reproductive age, median or geometric mean serum ferritin (SF) concentrations were estimated at 26-38 μg/L. Approximately 40-55% of this population had small or depleted iron stores (i.e., SF concentration ≤30 μg/L), and 45-60% of this population had apparently replete iron stores. The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) was 10-32% and 2-5%, respectively, depending on the cutoffs used. Approximately 20-35% of European women of reproductive age had sufficient iron stores (SF concentration >70 μg/L) to complete a pregnancy without supplementary iron. During pregnancy, European women in controlled supplementation trials who were not receiving iron supplements displayed increasing prevalences of ID and IDA during pregnancy, which peaked in the middle to late third trimester. Available evidence has suggested that, in gestational weeks 32-39, the median or geometric mean SF concentrations were 6-21 μg/L, and prevalences of ID and IDA were 28-85% and 21-35%, respectively. Women who were taking iron supplements had higher iron status and lower prevalences of ID and IDA, which were dependent on the dose of iron and compliance. The data suggest that, in Europe, the iron status of reproductive-aged women varies by region and worsens in pregnancy without iron supplementation., (© 2017 American Society for Nutrition.)

Study Objective: The aim of this work was to measure the irisin levels in maternal and umbilical cord serums at cesarean section and vaginal delivery., Study Design: This is a case-control study conducted at the Obstetric Department of the Mansoura University Hospital, Mansoura University, Egypt., Material and Methods: The 150 nulliparous cases were divided into three groups., Main Outcome Measure: Serum irisin concentrations were assayed by enzyme-linked immunosorbent assay (ELISA) method., Statistical Analysis: Unpaired t-test and correlation were done by using the Statistical Package for Social Scientists (SPSS)., Results: The maternal irisin levels in cases with mild preeclampsia were found to be significantly lower than that of the normal cases. In cases with mild preeclampsia, the maternal irisin levels early in labor for vaginal deliveries were significantly higher than that during cesarean section. The maternal irisin levels after vaginal deliveries were significantly higher than the levels early in labor. The maternal serum irisin was a significantly correlated with the duration of the first stage. The umbilical cord serum irisin levels were significantly correlated with the neonatal weight and with the duration of the first stage of labor., Major Conclusion: Labor is a strong stimulus to the release of irisin into the maternal and fetal circulations. Neonatal serum irisin levels are positively correlated with the birth weight and with the duration of the first stage. The neonatal birth weight and the duration of the first stage of labor are positively correlated with the umbilical cord serum irisin levels., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Maternal pre-pregnancy overweight and obese status has been associated with a number of pregnancy complications and adverse offspring outcomes. Mechanisms for observed associations, however, are largely unknown. We investigated associations of pre-pregnancy body mass index with early-mid pregnancy epigenetic biomarkers, circulating microRNAs., Methods: Peripheral blood was collected from participants (16-27 weeks gestation) of two multi-racial pregnancy cohorts, the Omega Study and the Pregnancy Outcomes and Community Health Study. Plasma miRNA expression was characterised using epigenome-wide (319 miRNAs) profiling among 20 pregnant women in each cohort. Cohort-specific linear regression models that included the predictor (pre-pregnancy body mass index), the outcome (microRNA expression), and adjustment factors (maternal age, gestational age at blood collection, and race) were fit., Results: Expression of 27 miRNAs was positively associated with pre-pregnancy body mass index in both cohorts (p-values <0.05). A number of these differentially expressed miRNAs have previously been associated with adipogenesis (e.g. let-7d*, miR-103-2*, -130b, -146b-5-p, -29c, and -26b). Identified miRNAs as well as their experimentally validated targets participate in pathways that involve organismal injury, reproductive system disease, connective tissue disorders, cancer, cellular development, growth and proliferation., Conclusion: Pre-pregnancy body mass index is associated with circulating miRNAs in early-mid pregnancy., (Published by Elsevier Ltd.)

Background: Dichlorodiphenyldichloroethene (p,p´-DDE), the main metabolite of dichlorodiphenyltrichloroethane (DDT), has been associated with changes in human thyroid hormone levels. Maternal thyroid hormones are essential for adequate fetal neurodevelopment during the first half of pregnancy., Objective: To evaluate the association between maternal p,p´-DDE concentration and the maternal thyroid profile during the first half of pregnancy., Materials and Methods: We analyzed the information of 430 pregnant women from a Mexican floriculture area, with a gestational age ≤16 weeks. By questionnaire, we obtained sociodemographic, reproductive, and life-style, information. Serum concentrations of thyroid stimulating hormone (TSH), and total and free T3 and T4 were determined by means of Enzyme-Linked ImmunoSorbent Assay (ELISA). p,p´-DDE was analyzed by Gas Chromatography. The association between p,p´-DDE and thyroid profile was assessed through linear and logistic regression models., Results: Thirty eight percent of women had p,p´-DDE levels below the Limit of Detection and 12.3% below the Limit of Quantification. Within the quantifiable range, median was 53.03ng/g. TSH >2.5 mIU/L was present in 9.3% of women; 47.7% had isolated hypothyroxinemia; 3.5% had subclinical hypothyroidism, and 5.8% had overt hypothyroidism. We observed a significant positive association between quantifiable p,p´-DDE and total T3 serum levels in comparison with those with concentrations below the Limit of Detection (β=0.19; 95% CI=0.06, 0.34). There were no significant associations with other hormones of the thyroid profile or with clinical diagnosis., Conclusions: Our findings suggest that p,p´-DDE exposure, even at low concentrations, could disrupt thyroid homeostasis during pregnancy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The normal range of plasma brain natriuretic peptide (BNP) in pregnant women is still unclear. Moreover, pregnant women experience dynamic body weight changes and suffer from anemia, but effects on maternal BNP have not been investigated. This study aimed to reveal the normal plasma BNP range and examine the effects of physiological changes on BNP among pregnant women., Methods and Results: Plasma BNP, hemoglobin, plasma creatinine and BMI were measured in 58 non-pregnant control women and in 773 normal pregnant women at late pregnancy, early postpartum and 1-month postpartum. Mean plasma BNP (in pg/mL) was 11.8 (95% confidence interval: 0-27.5) in non-pregnant women, 17.9 (0-44.7, p<0.001) at late pregnancy, 42.5 (0-112.6, p<0.001) early postpartum and 16.1 (0-43.9, p=0.001) 1-month postpartum. Multiple regression analysis revealed that pre-delivery BNP levels were negatively correlated with BMI (p<0.001) and hemoglobin (p=0.002) and positively correlated with creatinine (p<0.001). Post-delivery BNP was positively associated with body weight change during pregnancy (p=0.001) and post-delivery creatinine (p=0.010) but negatively associated with body weight loss at delivery (p<0.001) and post-delivery hemoglobin (p=0.004)., Conclusion: Even normal pregnancy affects plasma BNP, particularly in the early postpartum period, indicative of cardiac stress. Plasma BNP levels are affected by BMI, body weight changes, creatinine and hemoglobin levels; therefore, these factors should be considered when analysing cardiac function and the physiological implications of BNP levels in pregnant women., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: There is need to assess the developmental neurotoxicity of fluoride. Our knowledge of prenatal fluoride exposure is challenged as few population-based studies have been conducted and these generally date back several decades, provide incomplete data on sociodemographic variables, and have methodological limitations., Objective: To measure urinary and plasma fluoride levels across three time points in pregnant mothers who were enrolled in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort study., Methods: Fluoride levels were characterized in archived urine and plasma from 872 pregnant mothers sampled from the ELEMENT cohort. Various statistical methods were used to analyze the fluoride data with particular consideration for changes across three stages of pregnancy and against sociodemographic variables., Results: All samples had detectable levels of fluoride. The mean urinary and plasma fluoride levels were 0.91 and 0.0221mg/L respectively, and these were not statistically different across three stages of pregnancy. Fluoride levels correlated across the stages of pregnancy studied, with stronger correlations between neighboring stages. Urinary fluoride changed as pregnancy progressed with levels increasing until ~23 weeks and then decreasing until the end of pregnancy. For plasma fluoride, there was a decreasing trend but this was not of statistical significance. Creatinine-adjusted urinary fluoride levels did not associate consistently with any of the sociodemographic variables studied., Conclusions: This study provides the most extensive characterization to date of fluoride exposure throughout pregnancy. These results provide the foundation to explore exposure-related health outcomes in the ELEMENT cohort and other studies., (Copyright © 2016. Published by Elsevier Inc.)

Background: Rice ingestion is an important dietary exposure pathway for methylmercury. There are few studies concerning prenatal methylmercury exposure through rice ingestion, yet the health risks are greatest to the developing fetus, and thus should be investigated., Objectives: Our main objective was to quantify dietary methylmercury intake through rice and fish/shellfish ingestion among pregnant mothers living in southern China, where rice was a staple food and mercury contamination was considered minimal., Methods: A total of 398 mothers were recruited at parturition, who donated scalp hair and blood samples. Total mercury and/or methylmercury concentrations were measured in biomarkers, in rice samples from each participant's home, and in fish tissue purchased from local markets. Additional fish/shellfish mercury concentrations were obtained from a literature search. Dietary methylmercury intake during the third trimester was equivalent to the ingestion rate for rice (or fish/shellfish)×the respective methylmercury concentration., Results: Dietary methylmercury intake from both rice and fish/shellfish ingestion averaged 1.2±1.8µg/day (median=0.79µg/day, range=0-22µg/day), including on average 71% from rice ingestion (median: 87%, range: 0-100%), and 29% from fish/shellfish consumption (median 13%, range: 0-100%). Median concentrations of hair total mercury, hair methylmercury, and blood total mercury were 0.40µg/g (range: 0.08-1.7µg/g), 0.28µg/g (range: 0.01-1.4µg/g), and 1.2µg/L (range: 0.29-8.6µg/L), respectively, and all three biomarkers were positively correlated with dietary methylmercury intake through rice ingestion (Spearman's rho=0.18-0.21, p≤0.0005), although the correlations were weak. In contrast, biomarkers were not correlated with fish/shellfish methylmercury intake (Spearman's rho=0.04-0.08, p=0.11-0.46)., Conclusions: Among pregnant mothers living in rural inland China, rice ingestion contributed to prenatal methylmercury exposure, more so than fish/shellfish ingestion., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The impact of the reproductive state on vitamin D metabolism and requirements is uncertain in part because of a lack of studies with controlled dietary intakes of vitamin D and related nutrients., Objective: We aimed to quantify the impact of the reproductive state on a panel of vitamin D biomarkers among women of childbearing age consuming equivalent amounts of vitamin D and related nutrients., Methods: Nested within a feeding study providing 2 doses of choline, healthy pregnant (26-29 wk gestation; n = 26), lactating (5 wk postpartum; n = 28), and control (nonpregnant/nonlactating; n = 21) women consumed a single amount of vitamin D (511 ± 48 IU/d: 311 ± 48 IU/d from diet and 200 IU/d as supplemental cholecalciferol) and related nutrients (1.6 ± 0.4 g Ca/d and 1.9 ± 0.3 g P/d) for 10 wk. Vitamin D biomarkers were measured in blood obtained at baseline and study end, and differences in biomarker response among the reproductive groups were assessed with linear mixed models adjusted for influential covariates (e.g., body mass index, season, race/ethnicity)., Results: At study end, pregnant women had higher (P < 0.01) circulating concentrations of 25-hydroxyvitamin D [25(OH)D; 30%], 1,25-dihydroxyvitamin D [1,25(OH)2D; 80%], vitamin D binding protein (67%), and C3 epimer of 25(OH)D3 (100%) than control women. Pregnant women also had higher (P ≤ 0.04) ratios of 25(OH)D to 24,25-dihydroxyvitamin D [24,25(OH)2D; 40%] and 1,25(OH)2D to 25(OH)D (50%) than control women. In contrast, no differences (P ≥ 0.15) in vitamin D biomarkers were detected between the lactating and control groups. Notably, the study vitamin D dose of 511 IU/d achieved vitamin D adequacy in most participants (95%) regardless of their reproductive state., Conclusions: The higher concentrations of vitamin D biomarkers among pregnant women than among control women suggest that metabolic adaptations, likely involving the placenta, transpire to enhance vitamin D supply during pregnancy. The study findings also support the adequacy of the current vitamin D RDA of 600 IU for achieving serum 25(OH)D concentrations ≥50 nmol/L among women differing in their reproductive state. This trial was registered at clinicaltrials.gov as NCT01127022., (© 2016 American Society for Nutrition.)

Background: Alterations in serum adipokines in preeclampsia remain vague. We investigated the roles of leptin, adiponectin and resistin and their relationships with clinical characteristics in normotensive and preeclamptic patients., Methods: A case-control study was carried out in a cohort of 74 preeclampsia(PE) and 79 healthy pregnant women. Serum levels of leptin, adiponectin and resistin were measured by enzyme-linked immunosorbent assay., Results: The mean body mass index(BMI), the serum leptin and resistin levels were significantly higher in the PE group than in the control group (p<0.001). The resistin/creatinine ratio was also higher in the PE group than in the control group (p=0.018). No significant difference was observed in the serum adiponectin level between both groups. Serum leptin levels were positively correlated with BMI (r=0.301, p<0.001) and negatively correlated with newborn birth weight (r=-0.435, p<0.001). Serum resistin levels were also negatively correlated with birth weight (r=-0.229, p=0.005) but were unrelated to BMI. Logistic regression showed that BMI≥28 and serum leptin levels were independent factors of PE. Leptin was a potential mediator between BMI and PE (p<0.001), and the mediating effect accounted for 22.54% of the total effect., Conclusions: Leptin, resistin, and obesity play important roles in the onset of PE. Leptin and resistin may have some impacts on the fetal growth and development., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Late-onset fetal growth restriction (FGR) is often undetected prior to birth, which puts the fetus at increased risk of adverse perinatal outcomes including stillbirth., Objective: Measuring RNA circulating in the maternal blood may provide a noninvasive insight into placental function. We examined whether measuring RNA in the maternal blood at 26-30 weeks' gestation can identify pregnancies at risk of late-onset FGR. We focused on RNA highly expressed in placenta, which we termed "placental-specific genes.", Study Design: This was a case-control study nested within a prospective cohort of 600 women recruited at 26-30 weeks' gestation. The circulating placental transcriptome in maternal blood was compared between women with late-onset FGR (<5th centile at >36+6 weeks) and gestation-matched well-grown controls (20-95th centile) using microarray (n = 12). TaqMan low-density arrays, reverse transcription-polymerase chain reaction (PCR), and digital PCR were used to validate the microarray findings (FGR n = 40, controls n = 80)., Results: Forty women developed late-onset FGR (birthweight 2574 ± 338 g, 2nd centile) and were matched to 80 well-grown controls (birthweight 3415 ± 339 g, 53rd centile, P < .05). Operative delivery and neonatal admission were higher in the FGR cohort (45% vs 23%, P < .05). Messenger RNA coding 137 placental-specific genes was detected in the maternal blood and 37 were differentially expressed in late-onset FGR. Seven were significantly dysregulated with PCR validation (P < .05). Activating transcription factor-3 messenger RNA transcripts were the most promising single biomarker at 26-30 weeks: they were increased in fetuses destined to be born FGR at term (2.1-fold vs well grown at term, P < .001) and correlated with the severity of FGR. Combining biomarkers improved prediction of severe late-onset FGR (area under the curve, 0.88; 95% CI 0.80-0.97). A multimarker gene expression score had a sensitivity of 79%, a specificity of 88%, and a positive likelihood ratio of 6.2 for subsequent delivery of a baby <3rd centile at term., Conclusion: A unique placental transcriptome is detectable in maternal blood at 26-30 weeks' gestation in pregnancies destined to develop late-onset FGR. Circulating placental RNA may therefore be a promising noninvasive test to identify pregnancies at risk of developing FGR at term., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: To study the relationship between 2-dimensional placental ultrasound measurements and maternal serum (MS) levels of biomarkers of placentation and in pregnancies presenting with an isolated abnormally high or low birthweight at term, without evidence of placental insufficiency., Method: We performed a population based cohort study of 306 pregnancies delivered at term including 30 presenting with large-for-gestational age (LGA, birthweight > 90th centile) and 17 small-for-gestational age (SGA; birthweight < 10th centile). Antenatal measurements included placental thickness and 2D-volume and MS levels of pregnancy-associated plasma protein A (PAPP-A) and free-beta human chorionic gonadotrophin (fβhCG) at 11-13(+6) weeks of gestation and mid-trimester MS α-fetoprotein (AFP), unconjugated estriol (uE3) and inhibin A levels., Results: In the subgroup with a normal birthweight (10th-90th centile), there was a significant positive correlation between birthweight and the basal plate surface area (p < 0.001) and 2D placental volume (p < 0.01). In the LGA subgroup, MS PAPP-A was significantly (p < 0.05) higher than in normal controls and there was a significant (p < 0.01) positive correlation with birthweight. There was no significant difference for any of the ultrasound and biomarkers parameters between SGA and the normally grown controls., Discussion: In uncomplicated singleton pregnancies with a normal birthweight, 2D measurements of placentation are related with fetal size but are not related to subsequent excessive or slow fetal growth. LGA at birth is associated with increased MS PAPP-A at 11-14 weeks of gestation supporting the association between PAPP-A synthesis and early placental growth and development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Angiogenic factors, such as placental growth factor (PlGF) and soluble Flt-1 (sFlt-1), are key regulators of placental vascular development. Evidence from in vitro studies indicates that fatty acids can affect angiogenesis. We investigated the associations of maternal fish consumption and fatty acids levels with angiogenic factors during pregnancy, and in cord blood in a large population-based prospective cohort., Methods: First trimester fish consumption was assessed among 3134 pregnant women using a food-frequency questionnaire. Plasma fatty acid levels were measured in second trimester. Plasma PlGF and sFlt-1 were measured in first and second trimester and in cord blood. Associations of fish consumption or fatty acid levels with angiogenic factors were assessed by multivariable linear regression analyses., Results: There were no consistent associations of total fish or lean fish consumption with levels of PlGF, sFlt-1, or sFlt-1/PlGF ratio. Neither fatty fish nor shellfish were associated with angiogenic factors. Plasma omega-3 polyunsaturated fatty acids, which are the main type of fatty acids in fish, were inconsistently associated with angiogenic factors in second trimester and cord blood. Yet, higher levels of arachidonic acid, an omega-6 polyunsaturated fatty acid, were associated with lower levels of PlGF and sFlt-1., Discussion: We found no consistent associations of fish consumption or fatty acids levels with angiogenic factors in a population with low fish consumption. Studies including populations with higher fish consumption are required to fully grasp the potential effects of maternal fish consumption on placental angiogenesis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The challenge in noninvasive prenatal diagnosis for monogenic disorders lies in the detection of low levels of fetal variants in the excess of maternal cell-free plasma DNA. Next-generation sequencing, which is the main method used for noninvasive prenatal testing and diagnosis, can overcome this challenge. However, this method may not be accessible to all genetic laboratories. Moreover, shotgun next-generation sequencing as, for instance, currently applied for noninvasive fetal trisomy screening may not be suitable for the detection of inherited mutations. We have developed a sensitive, mutation-specific, and fast alternative for next-generation sequencing-mediated noninvasive prenatal diagnosis using a PCR-based method. For this proof-of-principle study, noninvasive fetal paternally inherited mutation detection was performed using cell-free DNA from maternal plasma. Preferential amplification of the paternally inherited allele was accomplished through a personalized approach using a blocking probe against maternal sequences in a high-resolution melting curve analysis-based assay. Enhanced detection of the fetal paternally inherited mutation was obtained for both an autosomal dominant and a recessive monogenic disorder by blocking the amplification of maternal sequences in maternal plasma., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

This commentary highlights the article by van den Oever et al that describes a new method of prenatal diagnosis of single-mutation disorders., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Ischemia modified albumin (IMA) is a marker of ischemia elevated in different clinical conditions and its use for hypoxia in perinatology is of current interest. We aimed to investigate the association between maternal and cord blood IMA levels and placental histopathological findings in uncomplicated term deliveries. In this study, placental histopathological evaluation in uncomplicated deliveries that ended with healthy newborns revealed 80.6% vasculopathy. The results support the hypothesis that hypoxia exceeding the placental reserve ends with fetal compromise. Moreover, the presence of maternal vasculopathy in placenta is not correlated with maternal and fetal IMA levels., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies., Study Design: Placental growth factor (PlGF), soluble feline McDonough sarcoma (fms)-like tyrosine kinase (sFlt)-1, and soluble endoglin from healthy pregnant women were quantified at 10, 18, 26, and 35 weeks' gestation (n=91), and during the third trimester (31-39 weeks) and at delivery (33-41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age-adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies., Results: Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 (sFlt-1: 36,916 vs 10,151 pg/mL; P<.0001; sFlt-1/PlGF: 168.4 vs 29.0; P<.0001). Maternal concentrations of soluble endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only (219.2 vs 350.2 pg/mL; P<.0001). Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of pregnancy in both twins and singletons., Conclusion: Higher maternal antiangiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted., (Published by Elsevier Inc.)