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Micronutrients, as essential components of prenatal care, are important to reduce the risk for maternal and child morbidity and mortality by lowering pregnancy-related complications. The present study aimed to investigate the status of the trace elements, i.e., selenium, zinc, and manganese in pregnant and non-pregnant women from a developing country and to evaluate its relationship with maternal and child complications. Selenium, zinc, and manganese concentrations were measured in the blood serum of 80 pregnant women and compared with 40 non-pregnant healthy controls. The quantitative analyses of trace elements were performed by using the inductively coupled plasma-optical emission spectrometry (ICP-OES) method. The information about the dietary habits of the study participants was recorded by using a food frequency questionnaire. The results showed significant lower selenium and zinc levels in pregnant women as compared to the controls (2.26 ± 1.09 vs. 2.76 ± 1.15 µmol/L, p = 0.031; 21.86 ± 7.21 vs. 29.54 ± 7.62 µmol/L, p < 0.001) respectively, with no difference in manganese concentrations (1.40 ± 0.09 vs.1.38 ± 0.09 log 10 nmol/L, p = 0.365). Regarding maternal and child complications, higher manganese levels were associated with an increased odds ratio for maternal complications (OR = 3.175, CI (95%) 1.631-6.181; p = 0.038). Consumption of dairy products was associated with lower selenium and manganese values. Pregnant women showed a lower serum selenium and zinc status, and in addition elevated serum manganese concentrations, which might be associated with a higher risk for maternal pregnancy/birth complications, although more studies are necessary to evaluate this association.

Background: A positive pregnancy test in acute or chronically ill patients has implications for the use of potentially mutagenic or teratogenic products in urgent medical therapies such as the use of chemotherapies or therapies with immunosuppressants, for anesthesia, and for time-sensitive indications like urgent surgery or organ Transplantation. Despite a lack of evidence, it is currently believed that human chorionic gonadotropin serum concentrations are always elevated in female dialysis patients even without pregnancy. It is also believed that human chorionic gonadotropin cannot be used to confirm or exclude pregnancy., Methods: Human chorionic gonadotropin was examined in female dialysis patients (18-50 years of age), and was classified as positive above 5 mlU/ml. In addition, fertility status was determined. For an enhanced index test, the cut-off of 5 mIU/ml was used for potentially fertile patients and 14 mIU/ml for infertile patients to calculate diagnostic test accuracy. The ideal cut-off for human chorionic gonadotropin was estimated using Liu's method with bootstrapped 95% confidence intervals. Predictors of human chorionic gonadotropin increase were analyzed using multivariable linear regression., Results: Among 71 women, two (2.8%) were pregnant, 46 (64.8%) potentially fertile, and 23 (32.4%) infertile. We observed human chorionic gonadotropin concentrations > 5 mIU/ml in 10 patients, which had a sensitivity of 100% (95% confidence interval: 100 to 100), a specificity of 86% (95% confidence interval: 77 to 94), a positive predictive value of 17% (95% confidence interval: 8 to 25) and a negative predictive value of 100% (95% confidence interval: 100 to 100) for the diagnosis of pregnancy. Using a cut-off > 14 mIU/ml for infertile patients or the exclusion of infertile patients increased specificity to 93% or 98%, respectively. The ideal cut-off was 25 mIU/ml (95% confidence interval: 17 to 33). Pregnancy and potential fertility, but not age, were independent predictors of human chorionic gonadotropin., Conclusion: Human chorionic gonadotropin is elevated > 5mIU/ml in 14.5% of non-pregnant dialysis patients of child-bearing age. In potentially fertile women, this cut-off can be used to exclude pregnancy. In case of an unknown fertility status, the ideal human chorionic gonadotropin cut-off was 25 mIU/ml.

Environmental contamination by chlorotriazines has been evidenced in mother-child cohort suggesting more detailed risk assessment of these compounds in drinking water. Exposure of rodents to atrazine (ATZ) has been associated with alterations of endocrine and reproductive functions by disrupting neuroendocrine control at hypothalamus level. Perinatal exposure to low doses of ATZ has been associated with reproductive dysfunction, and to behavioral abnormalities in adult exposed during embryogenesis. The objectives of the current investigation were to (1) evaluate the influence of physicochemical properties of chlorotriazines on tissue distribution in pregnant rats and in fetuses and (2) gain a better understanding of fetal distribution of chlorotriazines in specific tissues, particularly in brain. Serial blood samples were obtained from pregnant rats after administration of ATZ, propazine (PRO), and simazine (SIM) via oral route at a dose of 10 mg/kg from day 15 to day 19. Maternal and fetal tissues were harvested at day 20, 24 h after the last dosing. The metabolic extraction ratio was estimated to 87% suggesting a significant first-pass effect explaining the low oral bioavailability. Blood exposure to parent compounds (ATZ, PRO, and SIM) was negligible (lower than 5%) compared with metabolite exposure. The main metabolite exposure involved diamino-s-chlorotriazine, ranging from 60% to 90% depending on the molecules administered. A correlation between tissue-to-blood ratio and physicochemical descriptors was observed for fat and mammary gland tissues but not for brain in adult rats. A more pronounced distribution in fetal brain was observed for ATZ and PRO, the 2 most lipophilic compounds., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Embryo implantation is a complex process which involves biochemical and physiological interactions between an implantation-competent blastocyst and a receptive uterus. However, the exact biochemical changes of uterine fluid, uterus, and plasma during peri-implantation remain unclear. This study aims to characterize the biochemical and metabolic changes that occur during the peri-implantation period of early pregnancy, using mice as an animal model. Gas chromatography-mass spectrometry was used to analyze the metabolite profiles of the uterus, uterine fluid, and maternal plasma at pre-implantation and implantation. The multivariate analyses, ANOVA and Tukey's HSD test, were applied to detect significant changes in metabolites and metabolic pathways. The metabolic networks were reconstructed in silico based on the identified metabolites and KEGG metabolic framework. Between pre-implantation day 1 and day 4, dramatic metabolic changes were observed in the uterine fluid that could be important for blastocyst development and protection against the harsh uterine environment. Palmitoleic acid, fumaric acid, and glutaric acid changed levels at day 4 in the uterus, suggesting that they may be associated with endometrial receptivity. Both the uterus and maternal plasma showed profound changes in cellular metabolism at the early implantation period, including upregulation of branched-chain amino acids and intermediates of one-carbon metabolism, an upregulation of glyoxylate and dicarboxylate metabolism, and downregulation of aerobic respiration; all of which could be involved in the regulation of the maternal-fetal interface, alternative nutrient utilization, and energy preservation for implantation as well as later placentation and fetal development to ensure successful embryo implantation.

Problem: The complement system plays a key role in normal placentation, and delicate regulation of complement system activation is critical for successful pregnancy. Therefore, establishing a normal range of complement components during pregnancy is important for clinical evaluation and research., Methods: We performed a prospective study to investigate the normal range of complement components in circulation during different stages of pregnancy. Plasma concentrations of complement factor B (CFB), C1q, complement factor H (CFH), C3, C3c, and C4 were measured using an immunoturbidimetric assay; mannan-binding lectin (MBL), C3a, C5a, and soluble C5b-9 (sC5b-9) levels at different time points of pregnancy were determined by enzyme-linked immunosorbent assay (ELISA)., Results: A total of 733 plasma samples were collected from 362 women with a normal pregnancy and 65 samples from non-pregnant women. In the first trimester of pregnancy, the levels of CFB, CFH, MBL, C3c, C4, and C3a were 414.5 ± 85.9 mg/L (95% CI for mean: 402.4-426.6 mg/L), 381.0 ± 89.0 mg/L (95% CI for mean: 368.5-393.6 mg/L), 4274.5 ± 2752 ng/mL (95% CI for mean: 3881.1-4656.4 ng/mL), 1346.9 ± 419.8 mg/L (95% CI for mean: 1287.7-1406.0 mg/L), 357.4 ± 101.8 mg/L (95% CI for mean: 343.0-371.7 mg/L), and 182.5 ± 150.0 ng/mL (95% CI for mean: 186.9-229.1 ng/mL), respectively. The levels of C3 and C4 increased gradually throughout pregnancy. The levels of C1q, C5a, and sC5b-9 in the first and second trimesters were nearly the same as those in non-pregnant women., Conclusion: The results of this study show that pregnancy itself may influence the plasma levels of complement system components., (© 2019 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Pregnancy is associated with physiological changes that may impact drug pharmacokinetics (PK). The goals of this study were to build maternal-fetal physiologically based pharmacokinetic (PBPK) models for acyclovir and emtricitabine, 2 anti(retro)viral drugs with active renal net secretion, and to (1) evaluate the predicted maternal PK at different stages of pregnancy; (2) predict the changes in PK target parameters following the current dosing regimen of these drugs throughout pregnancy; (3) evaluate the predicted concentrations of these drugs in the umbilical vein at delivery; (4) compare the model performance for predicting maternal PK of emtricitabine in the third trimester with that of previously published PBPK models; and (5) compare different previously published approaches for estimating the placental permeability of these 2 drugs. Results showed that the pregnancy PBPK model for acyclovir predicted all maternal concentrations within a 2-fold error range, whereas the model for emtricitabine predicted 79% of the maternal concentrations values within that range. Extrapolation of these models to earlier stages of pregnancy indicated that the change in the median PK target parameters remained well above the target threshold. Concentrations of acyclovir and emtricitabine in the umbilical vein were overall adequately predicted. The comparison of different emtricitabine PBPK models suggested an overall similar predictive performance in the third trimester, but the comparison of different approaches for estimating placental drug permeability revealed large differences. These models can enhance the understanding of the PK behavior of renally excreted drugs, which may ultimately inform pharmacotherapeutic decision making in pregnant women and their fetuses., (© 2019, The American College of Clinical Pharmacology.)

In 575 women with 1-2 prior pregnancy losses; total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated preconception and throughout pregnancy to evaluate whether previously observed associations between third trimester maternal lipid profile and birthweight outcomes are driven by preconception lipids or lipid changes during pregnancy. Lipid trajectories were compared by pre-pregnancy body mass index (BMI) <25 or ≥25 kg/m 2 ; logistic regression models evaluated preconception lipid concentration and change from preconception to 28 weeks with adjusted odds of large- or small-for-gestational age (LGA or SGA) neonate by BMI group. Preconception lipid concentrations and gestational lipid trajectories varied by BMI group (P < 0.001). Preconception lipids were not associated with LGA or SGA in either group. A 10 mg/dL increase in HDL-C change from preconception to 28 weeks was associated with decreased odds of LGA (odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.46, 0.86) and 10 mg/dL increase in TG change associated with increased odds of LGA (OR = 1.05, 95% CI: 1.01, 1.1) overall. For ≥25 BMI only, 10 mg/dL increase in HDL-C change was associated with decreased SGA odds (OR = 0.35, 95% CI: 0.19, 0.64). Gestational lipid trajectories differed by BMI group and were differentially associated with birthweight outcomes, with HDL-C more strongly associated with healthy birthweight in women with BMI ≥25.

Background: Breast cancer rates in Asia are much lower than in Europe and North America. Within Asia, rates are lower in Mongolia than in neighboring countries. Variation in pregnancy exposure to endogenous hormone concentrations may explain the differences, but data are lacking., Methods: We measured maternal serum progesterone, prolactin, estradiol and estrone concentrations in the second half of pregnancy in a cross-sectional study of urban ( n = 143-194 depending on the analyte) and rural ( n = 150-193) Mongolian women, and U.S. women from Boston ( n = 66-204). Medical records provided information on maternal and perinatal factors. Geometric mean hormones were estimated from standard linear models with the log-hormone as the dependent variable and country as the independent variable adjusted for maternal and gestational age at blood draw., Results: Mean concentrations of prolactin (5722 vs. 4648 uIU/mL; p < 0.0001) and estradiol (17.7 vs. 13.6 ng/mL; p < 0.0001) were greater in Mongolian than U.S. women, while progesterone (147 vs. 201 ng/mL; p < 0.0001) was lower. Mean hormone concentrations were similar in rural and urban Mongolian women. Results were generally similar, with additional adjustment for gravidity, parity, height, body mass index at blood draw, education and alcohol use during pregnancy, and when stratified by offspring sex or parity., Conclusions: Mongolian women had greater concentrations of prolactin and estrogen and lower concentrations of progesterone than U.S. women, while hormone concentrations were similar in rural and urban Mongolian pregnancies., Impact: These data do not support the hypothesis that estrogen concentrations in pregnant women are lower in Mongolian compared with Caucasian women.

Maternal glucocorticoids critically rise during pregnancy reaching up to a 20-fold increase of mid-pregnancy concentrations. Concurrently, another steroid hormone, progesterone, increases. Progesterone, which shows structural similarities to glucocorticoids, can bind the intracellular glucocorticoid receptor, although with lower affinity. Progesterone is essential for the establishment and continuation of pregnancy and it is generally acknowledged to promote maternal immune tolerance to fetal alloantigens through a wealth of immunomodulatory mechanisms. Despite the potent immunomodulatory capacity of glucocorticoids, little is known about their role during pregnancy. Here we aim to compare general aspects of glucocorticoids and progesterone during pregnancy, including shared common steroidogenic pathways, plasma transporters, regulatory pathways, expression of receptors, and mechanisms of action in immune cells. It was recently acknowledged that progesterone receptors are not ubiquitously expressed on immune cells and that pivotal features of progesterone induced- maternal immune adaptations to pregnancy are mediated via the glucocorticoid receptor, including e.g., T regulatory cells expansion. We hypothesize that a tight equilibrium between progesterone and glucocorticoids is critically required and recapitulate evidence supporting that their disequilibrium underlie pregnancy complications. Such a disequilibrium can occur, e.g., after maternal stress perception, which triggers the release of glucocorticoids and impair progesterone secretion, resulting in intrauterine inflammation. These endocrine misbalance might be interconnected, as increase in glucocorticoid synthesis, e.g., upon stress, may occur in detriment of progesterone steroidogenesis, by depleting the common precursor pregnenolone. Abundant literature supports that progesterone deficiency underlies pregnancy complications in which immune tolerance is challenged. In these settings, it is largely yet undefined if and how glucocorticoids are affected. However, although progesterone immunomodulation during pregnancy appear to be chiefly mediated glucocorticoid receptors, excess glucocorticoids cannot compensate by progesterone deficiency, indicating that additional und still undercover mechanisms are at play., (Copyright © 2020 Solano and Arck.)

Background: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis., Methods: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B 9 ) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation., Results: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22-2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D 3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring., Conclusions: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

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.)

Objectives: The objective of this study was to analyze indications for amniocentesis in cases of patients with normal fetal ultrasound results between 11+0 and 13+6 weeks of gestation., Material and Methods: The results of first-trimester screening tests performed between 2014 and 2018 on 6,863 patients of the Prenatal Testing Outpatient Clinic at the Clinical Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland, were analyzed. The inclusion criteria were a singleton pregnancy and normal results of fetal ultrasound between 11+0- and 13+6-weeks' gestation. Depending on the calculated risk of fetal trisomy 21, the patients were divided into three groups (group A = RS > 1:300, group B = RS 1:300 - 1:999, group C = RS ≤ 1:1000). Subsequently, values such as PAPP-A and fβ-hCG protein levels and maternal age were analyzed for each of the groups., Results: The patients, 6,310 (91.94%) met the inclusion criteria. A high risk of fetal trisomy 21 was identified for 514 women (8.15%). Group B had 733 (11.62%) and group C 5,063 (80.23%) patients. In group A, an fβ-hCG level of ≥ 2.000 MoM was shown for 50.97% of the women. A PAPP-A level ranging from 0.001 to 0.499 MoM was observed for 38.72% of group A patients. The mean maternal age in groups A, B and C was 36.45, 36.08 and 31.64 years, respectively., Conclusions: In the first-trimester, patients with normal ultrasound results obtained during prenatal screening tests, the main cause of an increased risk of trisomy 21 was elevated PAPP-A and fβ-hCG concentrations. According to this paper's authors, in these cases extension of diagnosis to include other gestational complications, e.g. preeclampsia, should be considered.

Handedness ontogenesis is still under debate in science. This systematic review analyzed articles regarding the theories and basis of handedness formation, highlighting the historical knowledge path that this literature underwent. Cochrane Library, LILACS, Web of Sciences, Science Direct and PubMed databases were searched. This review included review studies with handedness as the main topic. Only papers written in English with analyses exclusively in neurotypical humans (any age range) were included. Different approaches (genetic, neural, social, and behavioural) were reviewed in light of growing evidence, summarizing the current state of the art. Genetic and environmental/social impacts are common points in most of the reviews, each given more or less importance, depending on the author and theory proposed. Multifactorial, developmental approaches to handedness formation seem to be the most up to date view of the phenomenon. Different control mechanisms between hemisphere and neural asymmetries are also contributing factors to handedness formation.

Objective: Studies of maternal serum uric acid (UA) in pregnancy focus primarily on high levels of UA, however, both low and high UA levels can be markers of oxidative stress, a biological state potentially linked to fetal growth. We therefore aimed to test whether low and high maternal serum UA levels during pregnancy are associated with atypical fetal growth (unusually small or large) measured as birthweight (BW) for gestational age. Methods: The Pregnancy Outcomes and Community Health Study enrolled 3019 pregnant women between their 16th-27th week of pregnancy from 52 clinics in five Michigan communities (1998-2004). Maternal UA levels were measured in blood collected at enrollment among a subcohort of 1291 participants. Infant BW and gestational age were used to calculate gestational age-specific BW Z -score. Infants were grouped as small (SGA = BW < 10th percentile), appropriate (AGA = BW 10th-90th percentile), or large (LGA) = BW > 90th percentile) for their gestational age. Analyses considered multiple potential confounders. Linear spline or multiple linear regression models were applied to evaluate the relationship between maternal UA levels and BW Z -score overall and within SGA, AGA, and LGA groups. Model robustness was tested through bootstrap, sensitivity analysis, and cross-validation techniques. Results: The relation between maternal UA levels and BW Z -score varied by infant group. Among SGA infants, the relation was nonlinear (J-shape): both extremes of UA had lower BW Z -score with a breakpoint of 0.267 mmol/L UA (adjusted regression coefficient β  = 2.32, p  = .01 for lower UA; adjusted β  = -37.38, p  < .01 for higher UA). Among AGA infants, there was no significant association, and among LGA infants, the relation was linear (adjusted β  = 2.86, p  = .03). Conclusions: Future research on maternal UA levels in pregnancy may benefit from considering both very low and high levels, and identifying in utero conditions associated with the two extremes.

Objectives: To analyze the association of sedentary time and physical activity (PA) intensity levels with immunometabolic markers during early pregnancy; and to examine if meeting the PA recommendations is associated with the immunometabolic profile of pregnant women., Methods: Fifty Caucasian pregnant women (age: 32.8 ± 4.7 years old, body mass index: 24.2 ± 4.1kg/m 2 , gestational age: 17 ± 1.5weeks) participated in this cross-sectional study (from September 2015 through May 2016). Sedentary time and PA intensity levels were objectively measured with triaxial accelerometer (seven consecutive valid days). Fasting serum glucose, total cholesterol, phospholipids, and triglycerides were assessed with standard methods. Serum pro-inflammatory and anti-inflammatory cytokines (fractalkine, interleukin-1β, interleukin-6, interleukin-8, interleukin-10, interferon-γ, and tumor necrosis factor-α) were measured using Luminex xMAP technology., Results: Sedentary time and PA were not correlated with any glycemic or lipid marker (P > .05). After adjusting for the potential confounders, vigorous PA showed a positive non-significant association with interleukin-6 (P = .06), and bouts of moderate-vigorous PA was inversely associated with interleukin-1β and interferon-γ (P = .02 and P = .04, respectively). Meeting the PA guidelines was inversely associated with interleukin-1β and positively associated with interleukin-8 (P = .01 and P = .04, respectively). These associations disappeared after controlling for multiplicity., Conclusions: Increasing the time spent in moderate-vigorous PA, or meeting the PA recommendations, is associated with the cytokine profile of women without metabolic disruptions in early pregnancy. However, sedentary time and PA do not seem to be associated with glucose or lipid levels. These results should be interpreted cautiously in view of the discrepancies after adjusting for multiple comparisons. Future studies in this novel field of research are warranted before reaching any conclusion., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate serum levels of vitamin A and E in pregnant women in Huai&apos;an and evaluate their nutritional status., Methods: Totally 2824 cases of pregnant women were chosen from the Huai&apos;an Maternal and Child Health-Care Center during January 2017 to May 2018. The serum level of vitamin A and vitamin E in the blood was detected by high performance liquid chromatography(HPLC)., Results: The serum level of vitamin A was(0. 39±0. 08) mg/L, the overall abnormal rate was 12. 3%. The serum level of vitamin E was(13. 28±4. 67) mg/L, the overall abnormal rate was 3. 7%. Vitamin A level were positively correlated with age and dysarteriotony. Vitamin E level were also positively correlated age, dysarteriotony and appetite., Conclusion: The abnormal of vitamin A is mainly lack, the abnormal of vitamin E is mainly excessive.

The objectives of this study were to explore reference intervals of ratios of concentrations of urinary iodine to creatinine (UIC/UCr) in pregnant women, to determine specific reference intervals for thyroid hormone concentrations (FT 3 , FT 4 , TSH) in the first trimester of pregnancy, and provide a comprehensive evaluation of iodine nutritional status and thyroid function. Cross-sectional data analysis, including questionnaires and thyroid ultrasonograms, were used to exclude subjects who had a history of thyroid disease, a family history of thyroid disease, or thyroid morphological abnormalities. Tests of thyroid hormone were evaluated together with urinary iodine concentration (UIC), urinary creatinine concentration (UCr), and salt iodine concentration in pregnant women. For the sample of pregnant women eligible for inclusion, the 95% reference intervals of the bilateral limits of UIC/UCr and thyroid hormone concentrations in pregnant women were determined by the percentile method. Pregnant women were recruited in Harbin, Heilongjiang Province, a particular geographical area of China, where iodine nutrition is adequate. The median UIC was 141.47 μg/L, while the median UIC/UCr was 141.12 μg/g. The reference intervals of thyroid hormone concentrations in the first trimester were FT 3 3.63-6.12 pmol/L, FT 4 11.89-22.91 pmol/L, and TSH 0.013-3.814 mIU/L. The reference intervals of UIC/UCr were 52.47 to 532.09 μg/g (first trimester 47.25-353.91 μg/g, second trimester 57.95-639.08 μg/g, third trimester 46.98-494.73 μg/g).The established UIC/UCr medical reference intervals and thyroid hormone concentration reference intervals may be used for iodine nutritional assessment and thyroid disease screening in pregnant women.

Background : Biotin is a water-soluble vitamin that plays various biological roles through histone modification, such as immune functions and fetal growth. Mammalian maternal biotin deficiency during gestation induces fetal growth restriction. Preterm infants are known to be marginal biotin deficiency. However, studies on the biotin status of pregnant women under various conditions are lacking. Method : This was a retrospective case control study to analyze serum biotin concentration during pregnancy and cord blood in normal pregnancy, preterm delivery and small-for-gestational-age (SGA). Results : Twenty pregnant women with normal term delivery, 35 with preterm delivery, 24 with SGA, and 10 non-pregnant adult women were enrolled. Serum biotin concentrations of pregnant women remained low from first to third trimester. The levels of serum biotin in cord blood showed a significant positive correlation with gestational age, and that of pregnant women showed a weak positive correlation with gestational age. The maternal serum biotin levels during second and third trimester of SGA group were significantly lower than those of normal term delivery. Conclusion : This study suggests that maternal biotin deficiency during pregnancy might be the risk of preterm labor or fetal growth restriction. Further studies are required to clarify the roles of biotin in perinatal medicine. J. Med. Invest. 67 : 170-173, February, 2020.

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.)

Pregnancy represents a unique immunological state in which the mother adapts to tolerate the semi-allogenic conceptus; yet, the cellular dynamics in the maternal circulation are poorly understood. Using exon-level expression profiling of up to six longitudinal whole blood samples from 49 pregnant women, we undertook a systems biology analysis of the cellular transcriptome dynamics and its correlation with the plasma proteome. We found that: (1) chromosome 14 was the most enriched in transcripts differentially expressed throughout normal pregnancy; (2) the strongest expression changes followed three distinct longitudinal patterns, with genes related to host immune response (e.g., MMP8, DEFA1B, DEFA4 , and LTF ) showing a steady increase in expression from 10 to 40 weeks of gestation; (3) multiple biological processes and pathways related to immunity and inflammation were modulated during gestation; (4) genes changing with gestation were among those specific to T cells, B cells, CD71+ erythroid cells, natural killer cells, and endothelial cells, as defined based on the GNF Gene Expression Atlas; (5) the average expression of mRNA signatures of T cells, B cells, and erythroid cells followed unique patterns during gestation; (6) the correlation between mRNA and protein abundance was higher for mRNAs that were differentially expressed throughout gestation than for those that were not, and significant mRNA-protein correlations were observed for genes part of the T-cell signature. In summary, unique changes in immune-related genes were discovered by longitudinally assessing the cellular transcriptome in the maternal circulation throughout normal pregnancy, and positive correlations were noted between the cellular transcriptome and plasma proteome for specific genes/proteins. These findings provide insights into the immunobiology of normal pregnancy., (Copyright © 2019 Gomez-Lopez, Romero, Hassan, Bhatti, Berry, Kusanovic, Pacora and Tarca.)

Equine chromosome 24 microRNA cluster (C24MC), the ortholog of human C14MC, is a pregnancy-related miRNA cluster. This cluster is believed to be implicated in embryonic, fetal, and placental development. The current study aimed to characterize the expression profile of this cluster in maternal circulation throughout equine gestation. The expression profile of miRNAs belonging to this cluster was analyzed in the serum of non-pregnant (diestrus), pregnant (25 d, 45 d, 4 mo, 6 mo, 10 mo), and postpartum mares. Among the miRNAs examined, 11 miRNAs were differentially expressed across the analyzed time-points. Four of these miRNAs ( eca-miR-1247-3p , eca-miR-134-5p , eca-miR-382-5p, and eca-miR-433-3p ) were found to be enriched in the serum of pregnant mares at Day 25 relative to non-pregnant mares. To further assess the accuracy of these miRNAs in differentiating pregnant (25 d) from non-pregnant mares, receiver operating characteristic (ROC) analysis was performed for each of these miRNAs, revealing that eca-miR-1247-3p and eca-miR-134-5p had the highest accuracy (AUC ROC = 0.92 and 0.91, respectively; p < 0.05). Moreover, eca-miR-1247-3p , eca-miR-134-5p , eca-miR-409-3p, and eca-miR-379-5p were enriched in the serum of Day 45 pregnant mares. Among those miRNAs, eca-miR-1247-3p and eca-miR-409-3p retained the highest accuracy as shown by ROC analysis. GO analysis revealed that these miRNAs are mainly implicated in nervous system development as well as organ development. Using in situ hybridization, we localized eca-miR-409-3p in the developing embryo (25 d) and extra-embryonic membranes (25 and 45 d). In conclusion, the present study is the first to elucidate the circulating maternal profile of C24MC-associated miRNAs throughout pregnancy and to suggest that serum eca-miR-1247-3p , eca-miR-134-5p , and eca-miR-409-3p could be used as pregnancy-specific markers during early gestation (25 and 45 d). Overall, the high abundance of these embryo-derived miRNAs in the maternal circulation suggests an embryo-maternal communication during the equine early pregnancy.

Aims: In current clinical practice, prenatal alcohol exposure is usually assessed by interviewing the pregnant woman by applying questionnaires. An alternative method for detecting alcohol use is to measure the biomarker carbohydrate-deficient transferrin (CDT). However, few studies measure CDT during pregnancy. This study examines the utility of CDT biomarker in the screening of alcohol exposure during early pregnancy., Methods: A cohort of 91, first-trimester pregnant women assigned to a public reference maternity hospital, was screened using the Green Page (GP) questionnaire, an environmental exposure tool. CDT levels and other biomarkers of alcohol use were measured and compared with questionnaire data., Results: About 70% of the mothers in the study consumed alcohol during early pregnancy and 22% met high-risk criteria for prenatal exposure to alcohol. CDT measurement showed a statistically significant area under the receiver operating characteristic curve with a value of 0.70. For a value of 0.95% of CDT, a specificity of 93% was observed. The most significant predictors of CDT were the number of binge drinking episodes, women's body mass index and European white race., Conclusion: Pregnant women with a CDT value >0.95% would be good candidates for the performance of the GP questionnaire during early pregnancy in order to detect potential high-risk pregnancy due to alcohol exposure., (© The Author(s) 2019. Published by Oxford University Press on behalf of All rights reserved.)

Objective: To determine the circulating levels of insulin, Nε-carboxymethyllysine (CML), soluble receptor for advanced glycation end products (sRAGE), and markers of inflammation and oxidative stress (OS) in maternal and umbilical cord blood in a cohort of healthy women with normal pregnancy. Methods: We conducted an observational longitudinal study in a group of women ( n  = 31; age range 18-39 years) with healthy pregnancy starting at 30 weeks of gestation and finishing at the time of delivery. We collected weight and height in the participants and their neonates and calculated body mass index (BMI). Blood from each patient was collected at 30th week of pregnancy and at delivery when a sample of cord blood was also obtained. Glucose, lipid profile, CML, sRAGE, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), highly sensitivity C-reactive protein (hsPCR), and insulin were determined. The study was approved by the University of Guanajuato Institutional Ethics Committee. Results: All pregnancies reached term (mean gestational time 38.9 ± 0.83 weeks) and there were no maternal complications. Mean age was 27.6 years. Lipid profile values were higher in the group compared with our values in nonpregnant women. During pregnancy, levels of insulin increased ( p  < .0006), CML ( p  < .0001) and sRAGE ( p  < .01) decreased, levels of MDA did not change, while those of TNF-α and hsPCR tended to increase. In the neonates, we found lower levels of CML ( p  < .003), hsPCR ( p  < .004), and insulin ( p  < .004) and higher levels of sRAGE ( p  < .013) and TNF-α ( p  < .022) compared to their mothers at delivery. In the total group, we found association of CML of the mother at baseline with the CML ( p  < .0006) and MDA ( p  < .002) in neonates, while maternal sRAGE at the end of pregnancy was associated with CML ( p  < .004) of their neonates. Conclusions: Our study confirms that normal pregnancy is accompanied by insulin resistance (IR) and significant increase in lipid profile, and demonstrates that circulating levels of CML and sRAGE decreased significantly at the end of pregnancy. The lack of association between the course of insulin levels and those of CML probably results from the predominant role of placental factors in the pathogenesis of IR in pregnancy. sRAGE levels in the neonates are markedly increased compared to their mothers suggesting a placental origin of this compound which may have a protective effect on the fetus since sRAGE restricts Advanced glycation end product (AGE) effects and may exert anti-inflammatory effects.

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.)

Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder of fertile-aged women. Several adverse pregnancy outcomes and abnormalities of the placenta have been associated with PCOS. By using quantitative label-free proteomics we investigated whether changes in the plasma proteome of pregnant women with PCOS could elucidate the mechanisms behind the pathologies observed in PCOS pregnancies. A total of 169 proteins with ≥2 unique peptides were detected to be differentially expressed between women with PCOS (n = 7) and matched controls (n = 20) at term of pregnancy, out of which 35 were significant (p-value < 0.05). A pathway analysis revealed that networks related to humoral immune responses, inflammatory responses, cardiovascular disease and cellular growth and proliferation were affected by PCOS. Classification of cases and controls was carried out using principal component analysis, orthogonal projections on latent structure-discriminant analysis (OPLS-DA), hierarchical clustering, self-organising maps and ROC-curve analysis. The most significantly enriched proteins in PCOS were properdin and insulin-like growth factor II. In the dataset, properdin had the best predictive accuracy for PCOS (AUC = 1). Additionally, properdin abundances correlated with AMH levels in pregnant women.

Background: In comparison to the non-pregnant state, the first trimester of pregnancy is characterized by systemic adaptation of the mother. The extent to which these adaptive processes are reflected in the maternal blood metabolome is not well characterized., Objective: To determine the differences between the plasma metabolome of non-pregnant and pregnant women before 16 weeks gestation., Study Design: This study included plasma samples from 21 non-pregnant women and 50 women with a normal pregnancy (8-16 weeks of gestation). Combined measurements by ultrahigh performance liquid chromatography/tandem mass spectrometry and by gas chromatography/mass spectrometry generated molecular abundance measurements for each sample. Molecular species detected in at least 10 samples were included in the analysis. Differential abundance was inferred based on false discovery adjusted p-values (FDR) from Mann-Whitney-Wilcoxon U tests <0.1 and a minimum median abundance ratio (fold change) of 1.5. Alternatively, metabolic data were quantile normalized to remove sample-to-sample differences in the overall metabolite abundance (adjusted analysis)., Results: Overall, 637 small molecules met the inclusion criteria and were tested for association with pregnancy; 44% (281/637) of small molecules had significantly different abundance, of which 81% (229/281) were less abundant in pregnant than in non-pregnant women. Eight percent (14/169) of the metabolites that remained significant in the adjusted analysis also changed as a function of gestational age. A pathway analysis revealed enrichment in steroid metabolites related to sex hormones, caffeine metabolites, lysolipids, dipeptides, and polypeptide bradykinin derivatives (all, FDR < 0.1)., Conclusions: This high-throughput mass spectrometry study identified: 1) differences between pregnant vs. non-pregnant women in the abundance of 44% of the profiled plasma metabolites, including known and novel molecules and pathways; and 2) specific metabolites that changed with gestational age., Competing Interests: BI is employed by Metabolon Inc., who provided the metabolomics profiling on a pay for service basis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Hepcidin production is normally upregulated by iron stores, and in obesity has been shown to be overexpressed and correlated with low iron status. The increased hepcidin may restrain the iron release from the cells by affecting the expression of ferroportin, which probably associates with the development of diabetes complication. First, we investigate the difference of serum hepcidin and iron parameters between obese and non-obese pregnant women; second, we examine the correlation between serum hepcidin and adverse maternal and neonatal outcomes in pregnant women., Methods and Analysis: This is a mono-centre, prospective cohort study with a study (obese) and a control group (non-obese women). In the first trimester, 188 singleton pregnancies will be recruited. Thereof, we expect 75 with a body mass index (BMI) ≥30 kg/m 2 and 113 with a BMI 18.5-30 kg/m 2 . Serum hepcidin, iron and haematological parameters will be measured at 11-14, 24-28, 32-36 weeks of gestation and at time of delivery. Blood pressure, weight, BMI and smoking status will be examined at all visits. We will assess the composite endpoints adverse maternal outcomes (including pre-eclampsia, gestational hypertension, gestational diabetes mellitus, haemorrhage, placenta abruption) and adverse neonatal outcomes (preterm birth, intrauterine growth restriction, preterm premature rupture of membranes, Apgar score <7 at 5 min, stillbirth, neonatal death).Recruitment has started in April 2019., Ethics and Dissemination: This study received ethical approval from the ethics committee in Basel. The results of the study will be published in a peer-reviewed journal, and presented at national scientific conferences., Trial Registration Number: NCT03792464., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The exposome is a novel research paradigm offering promise for understanding the complexity of human exposures, including endocrine-disrupting chemicals (EDCs) and pregnancy outcomes. The physiologically active state of pregnancy requires understanding temporal changes in EDCs to better inform the application of the exposome research paradigm and serve as the impetus for study., Methods: We randomly selected 50 healthy pregnant women with uncomplicated pregnancies from a pregnancy cohort who had available serum/urine samples in each trimester for measuring 144 persistent and 48 nonpersistent EDCs. We used unsupervised machine-learning techniques capable of handling hierarchical clustering of exposures to identify EDC patterns across pregnancy, and linear mixed-effects modeling with false-discovery rate correction to identify those that change over pregnancy trimesters. We estimated the percent variation in chemical concentrations accounted for by time (pregnancy trimester) using Akaike Information Criterion-based R methods., Results: Four chemical clusters comprising 80 compounds, of which six consistently increased, 63 consistently decreased, and 11 reflected inconsistent patterns over pregnancy. Overall, concentrations tended to decrease over pregnancy for persistent EDCs; a reverse pattern was seen for many nonpersistent chemicals. Explained variance was highest for five persistent chemicals: polybrominated diphenyl ethers #191 (51%) and #126 (47%), hexachlorobenzene (46%), p,p'-dichloro-diphenyl-dichloroethylene (46%), and o,p'-dichloro-diphenyl-dichloroethane (36%)., Conclusions: Concentrations of many EDCs are not stable across pregnancy and reflect varying patterns depending on their persistency underscoring the importance of timed biospecimen collection. Analytic techniques are available for assessing temporal patterns of EDCs during pregnancy apart from physiologic changes.

In this study, we measured plasma concentrations of progesterone, pregnenolone, estradiol, estrone, estrone sulfate, and cortisol and analyzed the correlations between these hormones during gestation in 13 Suffolk ewes, the main breed in Japan. Progesterone increased during gestation and decreased a few days before parturition; however, this pattern was different in samples with high progesterone concentrations (P4 spike samples). This P4 spike was associated with a high pregnenolone concentration. Apart from the P4 spike, the progesterone change was similar to that in other sheep breeds. Pregnenolone increased during gestation and decreased after parturition. A significant correlation between progesterone and pregnenolone was observed a few days before parturition. Estrone sulfate and estradiol concentrations increased during gestation, but estrone did not. They increased shortly before parturition, and then decreased immediately after parturition. At parturition, the correlation between estrone and estrone sulfate was significantly stronger. Moreover, a strong correlation between estrone sulfate and estradiol was observed after parturition. Cortisol did not change during gestation and increased shortly before parturition. The results showed steroid hormone dynamics in normal pregnant Suffolk ewes, which were mostly in line with those of other sheep breeds. It should be noted that high progesterone concentrations altered the typical patterns., (© 2019 Japanese Society of Animal Science.)

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 and Objectives: This study aimed to describe how haemoglobin trajectories in pregnant Australian women were associated with subsequent postpartum haemorrhage, blood transfusion and other outcomes., Materials and Methods: The study was conducted in two tertiary public hospitals in Australia, using routinely collected maternity and hospital data on singleton pregnancies (2011-2015). Latent class growth modelling defined trajectories among those with at least one haemoglobin in each of three antenatal time periods (0-15, 16-30 and 31+ weeks; n = 7104). Observed over expected ratios were calculated after predicting expected outcomes with adjusted logistic regression., Results: The mean minimum haemoglobin levels across the three periods were 127·9, 116·5 and 119·3 g/l. We identified seven groups of women with similar haemoglobin trajectories: five with parallel U-shaped trajectories, one with increasing and one with decreasing trajectory. Thirty-eight women (0.5%) had very low haemoglobin across the pregnancy and the highest adverse outcomes, including higher than expected blood transfusion risk. One hundred thirteen women (1.6%) with a progressively decreasing trajectory also had higher risk of transfusion. Women with high haemoglobin across the antenatal period had higher than expected risk of preterm birth, small for gestational age and infants transferred to higher care., Conclusions: Haemoglobin trajectories across pregnancy can predict women at higher risk of requiring transfusion around birth. Women who maintain high haemoglobins across the pregnancy are worthy of increased surveillance as they carry increased risks of newborn morbidity., (© 2019 International Society of Blood Transfusion.)

Background: Paleolithic diet has recently gained popularity due to its presumed health benefits. The favorable metabolic effects of this diet were assessed in non-pregnant population but its impact during pregnancy remains to be evaluated., Study Design: A retrospective cohort study comparing two groups. Group A comprised of women with singleton low-risk pregnancy adherent to paleolithic diet throughout gestation (n = 37). Group B comprised low risk pregnant women on a regular diet (n = 39). Women were excluded if they had low adherence to diet, started paleolithic diet during pregnancy, and had pre-gestational diabetes mellitus or other types of metabolic syndrome such as pre gestational hyperlipidemia, hypertension or BMI > 35. Blood indices such as Glucose challenge test scores, hemoglobin, ferritin, and TSH levels were compared. Other pregnancy factors such as maternal weight gain, rest days during gestation and pregnancy complications such as IUGR, GDM or preeclampsia were compared. Lastly, obstetrical outcomes such as mode of delivery and complications such as high-grade tears, as well as neonatal factors such as birth weight and pH were compared between the two groups., Results: General maternal characteristics such as age, BMI and parity were comparable between the two groups. Women who maintained a paleolithic diet had a significant decrease in glucose challenge test scores (95.8 mg/dL vs. 123.1 mg/dL, p < 0.01) and increase in hemoglobin levels (12.1 g/dL vs. 11.05 g/dL p < 0.01) and Ferritin (32.1 vs 21.3 mg/mL, p = 0.03) compared to women maintaining regular diet. Maternal pregnancy weight gain was also slightly decreased in group A (9.3Kg vs. 10.8 kg, p = 0.03). Birthweights were lower in group A (3098 g Vs.3275 g, p = 0.046) with no difference in adverse neonatal outcomes. We found no differences in other pregnancy complications or labor outcomes such as mode of delivery, shoulder dystocia or high grade perineal tears., Conclusion: Paleolithic diet maintained during pregnancy may have a beneficial effect on the glucose tolerance. It also may increase iron stores and hemoglobin levels. Neonates of women maintaining paleolithic diet are slightly lighter but appropriate for gestational age with no difference in neonatal outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype-decreased fetal growth-previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings., Methods: Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review., Results: Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring., Conclusions: Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia., (Copyright © 2019. Published by Elsevier B.V.)

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.)

Introduction: Pregnancy is characterized by increased innate immune response, with low-grade systemic inflammation. The specific role of MPO during normal pregnancy remains not well understood. Therefore, the aim of this study was to evaluate plasma levels of MPO, hs-CRP, total leukocyte, absolute neutrophil and monocyte counts, in all trimesters of normal human pregnancy compared with non-pregnant controls. In addition, possible fluctuations of MPO according to different inflammatory conditions in the normal gestation were studied., Materials and Methods: Case-control study (n=84) developed with 63 normal pregnant women and 21 healthy non-pregnant women. Total leukocyte, absolute neutrophils and absolute monocytes count, hs-CRP and MPO were measured in non-pregnant women and normal human pregnancy. They were evaluated according to the 3 trimesters of pregnancy and systemic low grade inflammatory status, which was identified through increased hs-CRP levels., Results: MPO levels in the normal pregnant women were not elevated in every 3 trimesters of pregnancy (P=0.456) or in systemic inflammation (P=0.446). The hs-CRP levels, total leukocyte, absolute neutrophil and monocyte counts are present in higher concentrations in normal pregnant women in relation to non-pregnant women., Conclusions: The MPO did not show fluctuations in plasma levels during the 3 trimesters of gestation or in relation to different inflammation conditions. Considering MPO and hs-CRP levels are changed in high cardiovascular risk conditions and MPO levels (unlike hs-CRP) didn't increase during non complicated pregnancy, MPO could be a better biomarker than hs-CRP to monitor these patients., Competing Interests: No conflict of interest has been declared by the authors., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To explore the characteristics of serum D-dimer level before and after delivery in women with advanced maternal age (VTE), and to assess the value of the characteristics for the diagnosis of venous thromboembolic disease. Methods: The objects were 785 puerperae with advanced maternal age (AMA) who experienced delivery in Women's Hospital, Zhejiang University School of Medicine during 1(st) Jan 2017 to 31(st) Dec 2017, and 327 puerperae with appropriate maternal age as controls were randomly selected from puerperae who gave birth in the same period. Their serum D-dimer levels before and after delivery were evaluated, and AMAs with high-level postnatal serum D-dimer were specially observed for the prognosis. Besides, puerperae complicated with VTE were retrieved from the medical database during 2014-2018, and their clinical characteristics and dynamic variation of serum D-dimer levels were analyzed. Result: The significant difference of D-dimer levels neither before nor after delivery was not observed between AMAs and controls (antenatal: 1.64(1.19, 2.29) mg/L vs 1.53(1.04, 2.23) mg/L, and postnatal: 2.70(1.71, 2.97) mg/L vs 2.63(1.17, 4.13) mg/L, P< 0.05 for both; None of AMAs with high-level serum D-dimer after delivery were complicated with VTE, and most of their serum D-dimer levels decreasedsharply with in four postnatal days (the average decrease was 9.2(7.69,12.74) mg/L, and 96.2% of the sepuerperae's decrease was more than 50%). Eight puerperae complicated with VTE were found in the database from 2014 to 2018, among which five were AMAs. The eight puerperae all received a B ultrasound because of the discomfort of lower limbs or abnormal variation of serum D-dimer levels (a slow decrease or an increase trend), so that a diagnosis of VTE was established; besides, the diagnosis or symptoms all emerged in the 3(rd) to 5(th) day after caesarean. Conclusions: The factor of advanced maternal age has little influence on the serum D-dimer level before or after delivery among pregnant women. It is not a single detection for serum D-dimer level, but the intensive monitoring of clinical symptoms and dynamic change of serum D-dimer level, that helps early diagnosis of VTE.

Background: The incidence of Cesarean has increased in recent years. The purpose of this study is to evaluate the effect of cesarean section on ovarian reserve. This is a prospective cohort study from January 2016 to November 2017. Inclusion criteria included singleton primigravid pregnant women whose gestational age was above 37 weeks. Exclusion criteria included history of infertility, pelvic surgery, underlying chronic diseases, any adverse pregnancy outcome and postpartum complication in current pregnancy and hormonal medication within six months of delivery. Anti-Mullerian hormone was measured at the admission time for delivery. The type of delivery was determined based on obstetrics indications. Six months after delivery, antral follicle count was performed and anti-Mullerian hormone was measured again., Result(s): First blood sample was taken from 730 women. After excluding 550 women, the second blood sample was taken from 180 participants. The mean of first anti-Mullerian hormone in women with cesarean and vaginal delivery were 1.01 ng/mL (95% CI 0.82 to 1.18) and 1.18 ng/mL (95% CI 0.96 to 1.40) respectively (P = 0.211). The mean of second anti-Mullerian hormone in women with cesarean and vaginal delivery were 4.77 ng/mL (95% CI:3.91 to 5.63) and 4.92 ng/mL (95% CI: 4.01 to 5.82) respectively (P = 0.818). No statistically significant difference existed in total AFC between cesarean and vaginal delivery groups (MD: 0.41, 95% CI: - 1.05 to 1.89, P = 0.576)., Conclusion: Antral follicle count and anti-Mullerian hormone, six month after delivery, are not affected by delivery mode even after adjusting for women's age, baseline Anti-Mullerian hormone, body mass index, gestational age at delivery, breastfeeding, postpartum menstruation, neonatal sex and weight. Based on our best knowledge, this is the first report that investigates the effects of delivery mode on ovarian reserve. Decreased fertility following cesarean has been shown in some previous studies but most of them had assessed this association based on the incidence of subsequent pregnancy. Since subsequent pregnancy can be influenced by several confounding factors, we investigated the effect of cesarean on fertility using its impact on anti-Mullerian hormone levels and antral follicle count. We hope that this study will be a beginning of more detailed studies in this field. We believe that this link is yet to be studied.

Background: The prenatal period is a period of vulnerability during which neurotoxic exposures exert persistent changes in brain development and behavior. Polybrominated diphenyl ethers (PBDEs), used as flame retardants in commercial products, are known to be developmental neurotoxicants. PBDEs were phased out of use in the United States a decade ago, but exposure remains widespread due to their release from existing products and biopersistence. Despite consistent animal and epidemiological evidence of developmental neurotoxicity, the neural substrates linking prenatal PBDE serum concentrations to impaired neurodevelopment are poorly understood., Methods: In the present study, we used resting state functional magnetic resonance imaging (fMRI) to examine associations between prenatal PBDE concentrations measured in maternal serum and intrinsic functional network organization (i.e., global and local efficiency; estimated using a graph-theoretical approach) in 5-year-old children (n = 34). We explored whether PBDE serum concentrations were associated with executive functioning (EF) assessed using a parent-report questionnaire (BRIEF-P) (n = 106) and whether changes in intrinsic functional network organization linked the association between prenatal PBDE serum concentrations and EF problems., Results: Children with higher prenatal PBDE serum concentrations showed: (a) increased global efficiency of brain areas involved in visual attention (e.g., inferior occipital gyrus) (β's = .01, FDR-corrected p's ≤ .05); (b) more reported EF problems (β's = .001, FDR-corrected p's ≤ .05). Higher global efficiency of brain areas involved in visual attention was associated with more EF problems (β's = .01, FDR-corrected p's < .05)., Conclusions: Intrinsic functional network organization of visual attention brain areas linked prenatal PBDE concentrations to EF problems in childhood. Visual attention may contribute to the development of higher-order cognitive functions, such as EF, which could be explored in future studies., (© 2019 Association for Child and Adolescent Mental Health.)

Background: Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies., Methods: An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects., Results: Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin., Conclusions: Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Background: Adequate thyroid hormone availability during pregnancy is necessary for optimal fetal brain development. During the first 18-20 weeks of gestation, fetal thyroid hormone availability largely depends on the placental transfer of maternal thyroxine. Although various studies have shown that maternal thyroid dysfunction is associated with suboptimal child neurodevelopmental outcomes, the most vulnerable time window remains to be identified. The aim of this study is to examine the association of maternal thyroid function with child brain morphology and to study whether any association depends on the timing of thyroid assessment., Methods: This prospective cohort study was part of the Generation R Study in Rotterdam, Netherlands, with a prospective population-based birth cohort. Pregnant women living in Rotterdam with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible. Other inclusion criteria were maternal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT 4 ) measurement in early or mid-pregnancy (≤18 weeks) and available brain MRI data for child at age 10 years. Exclusion criteria were pre-existing thyroid disorder, thyroid disorder treatment, twin pregnancy, in-vitro fertilisation-induced pregnancy, and suboptimal-quality MRI data or major incidental finding on MRI. The main outcome was the association between maternal TSH and FT 4 concentrations with brain MRI outcomes of children. Regression analyses accounted for gestational age at blood sampling, maternal age, ethnicity, education level, smoking, thyroid peroxidase antibody positivity, child sex, age at MRI, and total intracranial volume. Effect modification by gestational age at blood sampling was also investigated., Findings: Between Dec 1, 2001, and June 30, 2005, 7069 women were enrolled during early or mid-pregnancy (≤18 weeks of gestation), of whom 5088 were not included because they did not have available data on maternal serum TSH or FT 4 concentrations (n=1175), their child did not have brain MRI done (n=3377), or they met exclusion criteria (n=536). Thus, 1981 mother-child pairs were included in the study, with TSH and FT 4 concentrations measured during pregnancy at a median of 13·1 weeks of gestation (IQR 12·1-14·5) and offspring brain morphology assessed by MRI at a median age of 9·9 years (9·7-10·2). Maternal TSH had an inverted U-shaped association with offspring total grey matter volume (p=0·007) and with cortical grey matter volume (p=0·022). The association of maternal TSH with child total grey matter volume (p interaction =0·053) and cortical volume (p interaction =0·086) differed by the duration of gestation. Analyses stratified for gestational age at blood sampling showed an inverted U-shaped association of maternal TSH with child total grey matter volume and cortical grey matter volume, which was most evident at 8 weeks gestation. After about 14 weeks of gestation, TSH was no longer associated with child brain morphology. Maternal FT 4 concentrations were not associated with child total grey matter volume after adjusting for total intracranial volume (p=0·75)., Interpretation: Here, we show that both low and high maternal thyroid function are associated with smaller child total grey matter and cortical volume. To the best of our knowledge, this study is the first to show that an association with a neurodevelopmental outcome is most evident when maternal thyroid function is measured early in pregnancy. These novel findings suggest that embryonic brain development is particularly vulnerable to altered maternal thyroid function., Funding: Netherlands Organisation for Health Research and Development and the Sophia Children's Hospital Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Anemia is one of the common complications of pregnancy. Hemoglobin concentration, Hematocrit, and Red cell count are laboratory tests used to diagnose anemia. In are source poor setting, there is a practice of using three-fold converted Hematocrit. This study is designed to assess the association and acceptability of three-fold converted Hematocrit as compared to the standard Micro-hematocrit method, in pregnant women., Method: The cross-sectional study conducted from May 18 to June 12, 2018 involved 200 pregnant women who visited the Laboratory for a Hematocrit test. Three milliliter of venous blood was collected with EDTA tube to determine Hematocrit by the Micro-hematocrit method and Hemoglobin concentration measured by a HemoCue Hemoglobin B analyzer. A scatter plot, correlation coefficient, Bland and Altman plot, and Area under curve were employed to assess the agreement and acceptability of the calculated Hematocrit as compared to the standard Micro-hematocrit., Result: The correlation coefficient, Intraclass correlation coefficient and concordance correlation coefficient were 0.91, 0.94, and 0.89, respectively. The Bland and Altman plot showed a mean difference of 0.94 with the limit of agreement ranges from 0.6 to 1.3. The area under the receiver operating characteristics with cut-off point of Hematocrit <33% was 0.86. The sensitivity and specificity of the calculated method was 95.5% and 71.4%, respectively., Conclusion: Generally there is excellent association between the two methods. The two methods were identical within inherent imprecision of both methods. Hence, the Hematocrit value, threefold calculated from the Hemoglobin was found to be acceptable to diagnose anemia in pregnant women., Competing Interests: The authors have declared that no competing interest exist.

Objective: Women with prediabetes are identified from screening for overt diabetes in early pregnancy, but the clinical significance of prediabetes in pregnancy is unclear. We examined whether prediabetes in early pregnancy was associated with risks of adverse outcomes., Study Design: We conducted a retrospective cohort study of pregnant women enrolled in Kaiser Permanente Washington from 2011 to 2014. Early pregnancy hemoglobin A1C (A1C) values, covariates, and outcomes were ascertained from electronic medical records and state birth certificates. Women with prediabetes (A1C of 5.7-6.4%) were compared with those with normal A1C levels (<5.7%) for risk of gestational diabetes mellitus (GDM) and other outcomes including preeclampsia, primary cesarean delivery, induction of labor, large/small for gestational age, preterm birth, and macrosomia. We used modified Poisson's regression to calculate adjusted relative risks (RRs) and 95% confidence intervals (CIs)., Results: Of 7,020 women, 239 (3.4%) had prediabetes. GDM developed in 48% of prediabetic women compared with 11% of women with normal A1C levels (adjusted RR: 2.8, 95% CI: 2.4-3.3). Prediabetes was not associated with all other adverse maternal and neonatal outcomes., Conclusion: Prediabetes in early pregnancy is a risk factor for GDM. Future research is needed to elucidate whether early intervention may reduce this risk., Competing Interests: O.Y. received funding as a biostatistician from a research grant awarded to the Kaiser Permanente Washington Health Research Institute (KPWHRI) from Bayer. S.M.S. has worked on grants awarded to KPWHRI by Pfizer and also serves as a co-investigator on grants awarded to KPWHRI from Syneos Health, who is representing a consortium of pharmaceutical companies carrying out FDA-mandated studies regarding the safety of extended-release opioids. All other authors report no potential conflict of interest relevant to this article., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Maternal anemia is a well-recognized global health problem; however, there remain questions on specific hemoglobin (Hb) thresholds that predict health risk or protection for mother and child. We conducted a systematic review and meta-analysis to examine the associations of maternal Hb concentrations with a range of maternal and infant health outcomes, accounting for the timing of measurement (preconception, and first, second, and third trimesters), etiology of anemia, and cutoff category. The systematic review included 272 studies and the meta-analysis included 95 studies. Low maternal Hb (<110 g/L) was associated with poor birth outcomes (low birth weight, preterm birth, small-for-gestational-age (SGA), stillbirth, and perinatal and neonatal mortality) and adverse maternal outcomes (postpartum hemorrhage, preeclampsia, and blood transfusion). High maternal Hb (>130 g/L) was associated with increased odds of SGA, stillbirth, preeclampsia, and gestational diabetes. Relationships varied by the timing of measurement and cutoff category (stronger associations with lower cutoffs); limited data were available on anemia etiology. There were insufficient data for other maternal outcomes and long-term child health outcomes. Current data are insufficient for determining if revisions to current Hb cutoffs are required. Pooled high-quality individual-level data analyses, as well as prospective cohort studies, would be valuable to inform the reevaluation of Hb cutoffs., (© 2019 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

Preterm birth (PTB) is defined as birth before the 37th week of pregnancy and results in 15 million early deliveries worldwide every year. Presently, there is no clinical test to determine PTB risk; however, a panel of nine biomarkers found in maternal blood serum has predictive power for a subsequent PTB. A significant step in creating a clinical diagnostic for PTB is designing an automated method to extract and purify these biomarkers from blood serum. Here, microfluidic devices with 45 μm × 50 μm cross-section channels were 3D printed with a built-in polymerization window to allow a glycidyl methacrylate monolith to be site-specifically polymerized within the channel. This monolith was then used as a solid support to attach antibodies for PTB biomarker extraction. Using these functionalized monoliths, it was possible to selectively extract a PTB biomarker, ferritin, from buffer and a human blood serum matrix. This is the first demonstration of monolith formation in a 3D printed microfluidic device for immunoaffinity extraction. Notably, this work is a crucial first step toward developing a 3D printed microfluidic clinical diagnostic for PTB risk.

High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk., (Copyright © 2019. Published by Elsevier Inc.)

Objective: This article systematically reviews the literature to establish the normal range of lactic acid in healthy pregnant women., Study Design: Ovid MEDLINE, Embase.com, and Clinicaltrials.gov were searched to identify studies that reported maternal lactic acid in healthy pregnant women. Pooled aggregate means and two standard deviations for each time period were computed using the inverse variance weighting technique. Analyses were performed separately for 1st, 2nd, and 3rd trimesters, scheduled cesarean delivery, early labor, active labor, 2nd stage of labor, and delivery., Results: Overall, 22 studies met the inclusion criteria. There were 1,193 patients, and 2,008 observations identified. All time periods had maternal venous lactic acid aggregate means and two-standard-deviation ranges less than 4 mmol/L. Outside of labor, all ranges were less than 2 mmol/L. All labor periods had a range higher than 2 mmol/L. While the pooled ranges were less than 4 mmol/L, many individual studies reported ranges > 4 mmol/L during labor., Conclusion: This meta-analysis suggests that venous lactic acid levels can be used as a screening tool in pregnant women just as the test would be used in nonpregnant women, except that elevations may be seen during labor, especially later in labor when there is maximal skeletal muscle contraction., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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.)

Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia., (© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)