Butyrate and iso-butyrate: a new perspective on nutrition prevention of gestational diabetes mellitus.

BACKGROUND: Dietary imbalance, such as a lower proportion of complex carbohydrates and a higher protein diet, may contribute to gestational diabetes mellitus (GDM) risks through their metabolisms. However, there is a lack of knowledge regarding the association between butyrate, iso-butyrate, and GDM, which are metabolisms of the two primary nutrients above. This study aimed to clarify the association of butyrate and iso-butyrate with GDM. METHODS: A nested case-control study was conducted based on the Beijing Birth Cohort Study (BBCS) from 2017 to 2018. Totally, 99 singleton women were involved (GDM: n = 49, control: n = 50). All participants provided blood samples twice (in their first and second trimesters). Gas chromatography-mass spectrometry (GC-MS) was used for butyrate and iso-butyrate detection. Unconditional logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis. RESULTS: The results showed that butyrate in the first trimester was negatively correlated with GDM (odds ratio (OR): 0.00, 95% confidential interval (CI): 0.00-0.21, P = 0.008), and iso-butyrate in the second trimester was positively related to GDM (OR: 627.68, 95% CI: 40.51-9724.56, P < 0.001). The ratio (butyrate/iso-butyrate) was negatively associated with GDM, both in the first trimester (OR: 0.00, 95%CI: 0.00-0.05, P < 0.001) and in the second trimester (OR: 0.52, 95% CI: 0.34-0.80, P = 0.003). The area under the curve (AUC) using the ratio in the first trimester combined with clinical risk factors achieved 0.89 (95% CI: 0.83-0.95). Iso-butyrate in the second trimester combined with clinical risk factors achieved an AUC of 0.97 (95% CI: 0.92-1.00). CONCLUSIONS: High iso-butyrate and low butyrate levels may be associated with an increased risk of GDM. As they are produced through dietary nutrient formation by gut microbiota, further studies on the association of dietary intake and butyrate or iso-butyrate concentration in plasma may help find a novel approach to nutritional intervention for GDM.

First trimester plasma PER- AND Polyfluoroalkyl Substances (PFAS) and blood pressure trajectories across the second and third trimesters of pregnanacy.

BACKGROUND: Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. OBJECTIVES: To estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. METHODS: In 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters - adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. RESULTS: We collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity - compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. CONCLUSION: Early pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.

Non-esterified fatty acids as biomarkers of diet and glucose homeostasis in pregnancy: The impact of fatty acid reporting methods: NEFA reporting methods affect dietary and cardiometabolic endpoints.

BACKGROUND: Sparse data exists on the utility of individual serum non-esterified fatty acids (NEFAs) as clinical and dietary biomarkers and how reporting methods could affect these associations. We investigated the associations of 19 serum NEFAs expressed as µM or mol%, with self-reported dietary intake data, and cardiometabolic health indicators in pregnant women. METHODS: In this cross-sectional study, 273 pregnant women in their second trimester each completed a semi-quantitative food-frequency questionnaire and provided fasting serum samples. Comprehensive serum NEFA analysis was performed by multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry. We evaluated the associations of NEFAs using two different reporting methods, with diet quality, specific foods intake, and measures of adiposity and glucose homeostasis. RESULTS: Consistently stronger dietary correlations were observed when expressed as mol%. Serum ω-3 NEFAs were associated with diet quality and fish/fish oil daily servings (DHA mol%, r= 0.37; p = 4.8e-10), and odd-chain NEFAs were associated with full-fat dairy intake (15:0 mol%, r = 0.23; p = 9.0e-5). Glucose intolerance was positively associated with odd chain NEFAs as expressed in µM (r = 0.21; p= 0.001) but inversely associated when expressed as mol% (r = -0.31; p= 2.2e-7). In contrast, monounsaturated NEFAs (µM and mol%) had robust positive associations with pre-pregnancy BMI, second trimester skin-fold thickness, glycated hemoglobin, fasting glucose, and glucose intolerance. CONCLUSIONS: This study demonstrates the utility of specific NEFAs and their sub-classes as viable dietary and clinical biomarkers when reported as their relative proportions. More research is needed to investigate inconsistencies between absolute concentrations and relative proportions when reporting fatty acids.

Maternal Body Mass Index, Early-Pregnancy Metabolite Profile, and Birthweight.

CONTEXT: Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. OBJECTIVE: First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. DESIGN, SETTING, AND PARTICIPANTS: Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. MAIN OUTCOME MEASURES: Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. RESULTS: A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values < 0.05). Using penalized regression models, a metabolite profile was selected including 15 metabolites and 4 metabolite ratios based on its association with birthweight in addition to prepregnancy BMI. The adjusted R2 of birthweight was 6.1% for prepregnancy BMI alone, 6.2% after addition of glucose and lipid concentrations, and 12.9% after addition of the metabolite profile. CONCLUSIONS: A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Second trimester prediction of gestational diabetes: maternal analytes as an additional screening tool.

OBJECTIVES: Early diagnosis of gestational diabetes can lead to greater optimization of glucose control. We evaluated associations between maternal serum analytes (alpha-fetoprotein [AFP], free beta-human chorionic gonadotropin [beta-hCG], inhibin, and estriol) and the development of gestational diabetes mellitus (GDM). METHODS: This retrospective cohort study identified single-ton pregnancies with available second trimester serum analytes between 2009 and 2017. GDM was identified by ICD-9 and -10 codes. We examined the associations between analyte levels and GDM and to adjust for potential confounders routinely collected during genetic serum screening (maternal age, BMI, and race) using logistic regression. Optimal logistic regression predictive modeling for GDM was then performed using the analyte levels and the above mentioned potential confounders. The performance of the model was assessed by receiver operator curves. RESULTS: Out of 5,709 patients, 660 (11.6%) were diagnosed with GDM. Increasing AFP and estriol were associated with decreasing risk of GDM, aOR 0.76 [95% CI 0.60-0.95] and aOR 0.67 [95% CI 0.50-0.89] respectively. Increasing beta-hCG was associated with a decreasing risk for GDM(aOR 0.84 [95% CI 0.73-0.97]). There was no association with inhibin. The most predictive GDM predictive model included beta-hCG and estriol in addition to the clinical variables of age, BMI, and race (area under the curve (AUC 0.75), buy this was not statistically different than using clinical variables alone (AUC 0.74) (p=0.26). CONCLUSIONS: Increasing second trimester AFP, beta-hCG, and estriol are associated with decreasing risks of GDM, though do not improve the predictive ability for GDM when added to clinical risk factors of age, BMI, and race.

Evaluating pentraxin-3 and hypersensitivity CRP expression in obese pregnancies.

OBJECTIVE: This study was designed to evaluate the correlation between serum pentraxin-3 (PTX3)/hypersensitivity CRP (hs-CRP) expression and obesity during pregnancy and their application as inflammatory biomarkers in obese pregnant women. MATERIALS AND METHODS: Pregnant women scheduled to experience a single-birth at our hospital between 2016 and 2017 were selected for this nested case-control study. These patients were evaluated for age and gestational age in the first trimester (11-14 weeks), had their body mass index (BMI) calculated and were subjected to an OGTT between Week 24 and 28 of pregnancy. Obese patients with normal OGTT and a BMI of ≥30 kg/m2 in the second trimester were selected as the obese group (OBE, n = 80), and non-obese pregnant women with normal OGTT with a BMI of <30 kg/m2 were selected as the control group (CON, n = 80). ELISA was used to detect the expression of PTX3 and hs-CRP. RESULTS: The expression of both PTX3 and hs-CRP increased in both groups, with increasing gestational age (P < 0.05). However, hs-CRP level in Group OBE was increased, compared to that in the healthy control (P < 0.01), during the second trimester. PTX3 expression was also significantly higher in OBE samples than in the control (P < 0.05), during the third trimester; correlation analysis demonstrated that PTX3 was positively correlated with hs-CRP, BMI, fasting plasma glucose and HOMA-IR. CONCLUSIONS: The expression levels of both PTX3 and hs-CRP increased with increasing gestational age, and PTX3 expression was related to BMI, which serves to confirm the inflammatory response in these patients.

Early postpartum abnormal glucose metabolism subtype differs according to mid-trimester lipid profile in women with gestational diabetes mellitus.

BACKGROUND: It is unknown whether early postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) is related to their mid-trimester lipid profile. The aim of this study was to characterize the mid-trimester lipid profile of women who experienced GDM and developed into different pathophysiologic subtypes of early postpartum AGM. METHODS: A retrospective cohort study of 498 women with history of GDM was conducted. A 75-g oral glucose tolerance test (OGTT) and plasma lipid measurements were performed at 24-28 weeks of gestation and 6-12 weeks of postpartum. Insulin secretion and sensitivity were estimated using early postpartum OGTT-based indices. RESULTS: Women in the mid-trimester dyslipidemia group had higher postpartum 30-min and 2-h plasma glucose, higher postpartum 2-h plasma insulin, higher postpartum triglyceride (TG), higher postpartum low density lipoprotein cholesterol (LDL-c) concentrations, lower postpartum 30-min insulinogenic index (IGI30), lower postpartum insulin sensitivity index (ISI), and lower postpartum disposition index than those in the normal lipid group (all P < 0.05). Abnormal mid-trimester TG and LDL-c concentrations were associated with postpartum AGM (adjusted odds ratio [OR] = 1.786, 95 % confidence interval [CI] = 1.142-2.425; and adjusted OR = 1.621, 95 % CI = 1.323-2.051, respectively; both P < 0.05). AGM women with low IGI30 and low ISI had higher mid-trimester total cholesterol and LDL-c concentrations, and AGM women with low ISI had higher mid-trimester TG concentrations than women with NGT or other subtypes of AGM (all P < 0.05). CONCLUSIONS: GDM women with abnormal mid-trimester TG and LDL-c were predisposed to early postpartum AGM. Postpartum AGM women who experienced GDM had heterogeneous mid-trimester lipid profile when classified according to their pathophysiologic subtype.

Maternal vascular endothelial growth factor receptor and interleukin levels in pregnant women with twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) is an unusual and serious condition that occurs in twin pregnancies when identical twins share a placenta but develop discordant amniotic fluid volumes. TTTS is associated with an increased risk of fetal death and birth defects if untreated. This study investigated the soluble levels of biomarkers including growth factors and interleukins in pregnant women with and without TTTS during pregnancy. We quantified plasma levels of VEGF-R1, VEGF-R2, IL-1ß, IL-6 and IL-8 in twin pregnant women with (n=53) and without TTTS (n=72) and in women with single pregnancy (n=30) by ELISA and analyzed the association of maternal circulating biomarker levels with TTTS. Our results showed that maternal VEGF-R1 levels were significantly higher in twins compared to single pregnancy (P<0.05) and were decreased in the second trimester compared to the first trimester (P = 0.065, 0.019 and 0.072 for twins with and without TTTS and single pregnancy, respectively). VEGF-R2 levels had a trend to be lower in twins compared to single pregnancy. In addition, soluble VEGF-R1 and VEGF-R2 levels were significantly decreased while IL-6 levels were increased after surgical treatment with laser in twin pregnant women with TTTS (P = 0.016, 0.041 and 0.04, respectively). These results suggest that IL-6, VEGF-R1 and VEGF-R2 are involved in vascular regulation and stabilization in twin pregnancies and may contribute to the pathogenesis of TTTS and thus play a prognostic role in the surgical treatment of TTTS.

Second trimester maternal serum biomarkers and the risk of cerebral palsy.

AIMS: To investigate whether second trimester maternal serum screening (2TMSS) biomarkers are associated with cerebral palsy (CP) and identify CP characteristics associated with abnormal biomarker levels. METHOD: In this retrospective case-control data linkage study, we linked mothers of 129 singleton CP cases from a population register to their 2TMSS records and selected 10 singleton pregnancy controls per case (n = 1290). We compared mean and abnormal levels of alpha-fetoprotein (AFP), beta subunit of human chorionic gonadotrophin (ß-hCG), unconjugated estriol (uE3), and inhibin between cases and controls and within CP subgroups. RESULTS: Compared to control pregnancies, CP pregnancies had higher mean levels of AFP (1.10 vs. 1.01 multiple of the population median [MoM], p = 0.01) and inhibin (1.10 vs. 0.98 MoM, p ≤ 0.01). CP pregnancies were 2.5 times more likely to be associated with high levels of AFP (OR 2.52 [95% confidence interval [CI] 1.30, 4.65]; p < 0.01) and 2.6 times for inhibin (OR 2.63 [95% CI 1.37, 4.77]; p < 0.01), and 6.8 times when AFP and inhibin were both elevated (OR 6.75 [95% CI 2.41, 18.94]; p < 0.01). In CP cases, high AFP and high inhibin levels were associated with preterm birth and low birthweight. INTERPRETATION: Abnormal second-trimester biomarker levels suggest abnormal placentation plays a role in the causal pathway of some CP cases.

Maternal circulating SPINT1 is reduced in small-for-gestational age pregnancies at 26 weeks: Growing up in Singapore towards health outcomes (GUSTO) cohort study.

Fetal growth restriction arising from placental insufficiency is a leading cause of stillbirth. We recently identified low maternal circulating SPINT1 concentrations as a novel biomarker of poor fetal growth. Here we measured SPINT1 in a prospective cohort in Singapore. Circulating SPINT1 concentrations were significantly lower among 141 pregnant women destined to deliver small-for-gestational age infants (birthweight <10th centile), compared to 772 controls (p < 0.01) at as early as 26 weeks' gestation. There were no correlations between infant body composition and circulating SPINT1 concentrations at 26 weeks. This provides validation that low maternal SPINT1 concentration is associated with poor fetal growth.

Continuous glucose monitoring in obese pregnant women with no hyperglycemia on glucose tolerance test.

OBJECTIVE: The objective of the present study was to compare 24-hour glycemic levels between obese pregnant women with normal glucose tolerance and non-obese pregnant women. METHODS: In the present observational, longitudinal study, continuous glucose monitoring was performed in obese pregnant women with normal oral glucose tolerance test with 75 g of glucose between the 24th and the 28th gestational weeks. The control group (CG) consisted of pregnant women with normal weight who were selected by matching the maternal age and parity with the same characteristics of the obese group (OG). Glucose measurements were obtained during 72 hours. RESULTS: Both the groups were balanced in terms of baseline characteristics (age: 33.5 [28.7-36.0] vs. 32.0 [26.0-34.5] years, p = 0.5 and length of pregnancy: 25.0 [24.0-25.0] vs. 25.5 [24.0-28.0] weeks, p = 0.6 in the CG and in the OG, respectively). Pre-breakfast glycemic levels were 77.77 ± 10.55 mg/dL in the CG and 82.02 ± 11.06 mg/dL in the OG (p<0.01). Glycemic levels at 2 hours after breakfast were 87.31 ± 13.10 mg/dL in the CG and 93.48 ± 18.74 mg/dL in the OG (p<0.001). Daytime blood glucose levels were 87.6 ± 15.4 vs. 93.1 ± 18.3 mg/dL (p<0.001) and nighttime blood glucose levels were 79.3 ± 15.8 vs. 84.7 ± 16.3 mg/dL (p<0.001) in the CG and in the OG, respectively. The 24-hour, daytime, and nighttime values of the area under the curve were higher in the OG when compared with the CG (85.1 ± 0.16 vs. 87.9 ± 0.12, 65.6 ± 0.14 vs. 67.5 ± 0.10, 19.5 ± 0.07 vs. 20.4 ± 0.05, respectively; p<0.001). CONCLUSION: The results of the present study showed that obesity in pregnancy was associated with higher glycemic levels even in the presence of normal findings on glucose tolerance test.

Adverse obstetric outcomes in early-diagnosed gestational diabetes mellitus: The Japan Environment and Children's Study.

AIMS/INTRODUCTION: To examine adverse outcomes in women with early-diagnosed gestational diabetes mellitus using data from a large birth cohort study in Japan. MATERIALS AND METHODS: This study analyzed data from singleton pregnancies in the Japan Environment and Children's Study including births during 2011-2014. Mothers with an HbA1c level ≥6.5% in the first trimester, a history of diabetes mellitus, or steroid use during pregnancy were excluded. The participants were divided into three groups: control (without gestational diabetes mellitus), early-diagnosed gestational diabetes mellitus (diagnosed before gestational week 24), and late-diagnosed gestational diabetes mellitus (diagnosed after gestational week 24). Multiple logistic regression analysis was performed to calculate the risk of early-diagnosed and late-diagnosed gestational diabetes mellitus for adverse obstetrics outcomes. RESULTS: In total, 100,376 eligible participants were included in this study. The number of individuals in control cases, early-diagnosed gestational diabetes mellitus cases, and late-diagnosed gestational diabetes mellitus cases was 98,090 (97.7%), 751 (0.7%), and 1,535 (1.5%), respectively. When control cases were used as reference, multiple logistic regression analysis revealed that early-diagnosed gestational diabetes mellitus increased the risk of hypertensive disorders of pregnancy (adjusted odds ratio: 2.08, 95% confidence interval: 1.51-2.86), early-onset hypertensive disorders of pregnancy (adjusted odds ratio: 1.91, 95% confidence interval: 1.01-3.65), and late-onset hypertensive disorders of pregnancy (adjusted odds ratio: 1.92, 95% confidence interval: 1.29-2.86). CONCLUSION: Early-diagnosed gestational diabetes mellitus is associated with serious obstetric complications. Our findings indicate the necessity of further investigations to validate the benefit of early screening for gestational diabetes mellitus in pregnant women.

Maternal Midpregnancy Leptin and Adiponectin Levels as Predictors of Autism Spectrum Disorders: A Prenatal Cohort Study.

CONTEXT: Autism spectrum disorders (ASDs) are a group of conditions characterized by impaired social function and repetitive behaviors. Their etiology is largely unknown. OBJECTIVE: This work aims to examine the associations of maternal second-trimester and cord blood leptin and adiponectin levels with ASDs in offspring. METHODS: We used data from 1164 mother-child pairs enrolled in Project Viva, a prospective prebirth cohort. We used logistic regression analysis to examine the associations of leptin and adiponectin levels in maternal second-trimester blood and cord blood obtained at birth with ASDs. Additionally, we examined the association of maternal prepregnancy body mass index (BMI) as an exposure. Main outcome measures included doctor-diagnosed ASDs reported by mothers using questionnaires in midchildhood and early adolescence. RESULTS: The cumulative incidence of ASDs was 3.4%. Maternal prepregnancy BMI (per 5 points) was positively associated with ASDs in a logistic regression model adjusted for maternal race/ethnicity, education, smoking status and child sex (adjusted odds ratio [OR] 1.38; 95% CI, 1.06-1.79). Higher second-trimester adiponectin was associated with lower odds of ASD in offspring (unadjusted OR 0.49; 95% CI, 0.30-0.78; and OR 0.54; 95% CI, 0.32-0.91 after adjusting for maternal race/ethnicity, education, child sex, OR 0.55; 95% CI, 0.33-0.93 after adjusting for BMI, gestational weight gain, gestational diabetes, and smoking status). Maternal leptin and cord blood leptin and adiponectin levels were not associated with ASDs. CONCLUSION: Prepregnancy BMI and adiponectin during pregnancy may be useful as a tool to monitor the risk of autism. Increasing adiponectin levels prenatally may play a role in the prevention of ASDs.

A prospective cohort study of postpartum glucose metabolic disorders in early versus standard diagnosed gestational diabetes mellitus.

Early gestational diabetes mellitus (eGDM) is diagnosed when fasting plasma glucose before 24 weeks of gestation (WG) is ≥ 5.1 mmol/L, whilst standard GDM is diagnosed between 24 and 28 WG by oral glucose tolerance test (OGTT). eGDM seems to have worse obstetric outcomes than standard GDM. We compared the rates of postpartum glucose metabolism disorders between women with early versus standard GDM in this prospective study on women with GDM from three university hospitals between 2014 and 2016. Patients were included if they were < 24 WG with at least one risk factor for GDM and excluded if they had type 2 diabetes. Patients were assigned to Group 1 (G1) for eGDM according to IADPSG: fasting blood glucose < 24 WG between 5.1 and 7 mmol/L. Group 2 (G2) consisted of patients presenting a standard GDM at 24-28 WG on OGTT results according to IADPSG: T0 ≥ 5.1 mmol/L or T60 ≥ 10.0 mmol g/L or T120 ≥ 8.5 mmol/L. The primary outcome was postpartum OGTT result. Five hundred patients were analysed, with 273 patients undergoing OGTT at 4-18 weeks postpartum: 192 patients in G1 (early) and 81 in G2 (standard). Patients in G1 experienced more insulin therapy during pregnancy than G2 (52.2% versus 32.5%, p < 0.001), but no patients were taking insulin postpartum in either group. G1 patients experienced less preterm labour (2.6% versus 9.1%, p = 0.043), more induced deliveries (38% versus 25%, p = 0.049) and reduced foetal complications (29.2% versus 42.0%, p = 0.048). There was no significant difference in the rate of postpartum glucose metabolism disorders (type 2 diabetes, impaired glucose tolerance, impaired fasting glycaemia) between groups: 48/192 (25%) in G1 and 17/81 (21%) in G2, p = 0.58. Thus the frequency of early postpartum glucose metabolism disorders is high, without difference between eGDM and standard GDM. This supports measurement of fasting plasma glucose before 24 WG and the threshold of 5.1 mmol/L seems appropriate until verification in future studies.Trial registration: NCT01839448, ClinicalTrials.gov on 22/04/2013.

Establishment of assay method- and trimester-specific reference intervals for thyroid hormones during pregnancy in Chengdu, China.

BACKGROUND: The reference intervals of thyroid hormone will change at different stages of pregnancy because of physiological alterations. On the other hand, the reference intervals of thyroid hormone will also change in different detection systems due to the manufacturer's methodology as well as a different race. The objective of this study was to establish the assay method- and trimester-specific reference intervals for thyroid-stimulating hormone, free thyroxine and free triiodothyronine for pregnant women in Chengdu. METHODS: A prospective, population-based cohort study involved 23,701 reference samples of pregnant women during the three trimesters and 8646 non-pregnant women with pre-pregnancy clinical and laboratory tests. The 2.5th and 97.5th percentiles were calculated as the reference intervals for thyroid-stimulating hormone, free thyroxine and free triiodothyronine at each trimester of pregnant women according to ATA Guidelines. RESULTS: The reference interval of thyroid-stimulating hormone in the 2.5th and 97.5th percentiles has a significant increasing trend from the first trimester, to second trimester and to third trimester, which was 0.08-3.79 mIU/L for the first trimester, and 0.12-3.95 mIU/L for the second trimester and 0.38-4.18 mIU/L for the third trimester, respectively (p < 0.001). However, the reference intervals of free thyroxine and free triiodothyronine in the 2.5th and 97.5th percentiles have significant decreasing trends from the first trimester, to second trimester and to third trimester, which were 11.87-18.83 pmol/L and 3.77-5.50 pmol/L for the first trimester, and 11.22-18.19 pmol/L and 3.60-5.41 pmol/L for the second trimester, and 10.19-17.42 pmol/L and 3.37-4.79 pmol/L for the third trimester, respectively (both p < 0.001). CONCLUSION: It is necessary to establish assay method- and trimester-specific reference intervals for thyroid-stimulating hormone, free thyroxine, and free triiodothyronine because the reference intervals of these thyroid hormones are significantly different at different stages of pregnancy.

Early pregnancy prediction of spontaneous preterm birth before 32 completed weeks of pregnancy using plasma RNA: transcriptome discovery and initial validation of an RNA panel of markers.

OBJECTIVE: To compare the second-trimester plasma cell-free (PCF) transcriptome of women who delivered at term with that of women with spontaneous preterm birth (sPTB) at or before 32 weeks of gestation and identify/validate PCF RNA markers present by 16 weeks of gestation. DESIGN: Prospective case-control study. SETTING: Academic tertiary care centre. POPULATION: Pregnant women with known outcomes prospectively sampled. METHODS: PCF RNAs extracted from women at 22-24 weeks of gestation (five sPTB up to 32 weeks and five at term) were hybridised to gene expression arrays. Differentially regulated RNAs for sPTB up to 32 weeks were initially selected based on P value compared with control (P < 0.01) and fold change (≥1.5×). Potential markers were then reordered by narrowness of distribution. Final marker selection was made by searching the Metacore™ database to determine whether the PCF RNAs interacted with a reported set of myometrial Preterm Initiator genes. RNAs were confirmed by quantitative reverse transcription polymerase chain reaction and tested in a second group of 40 women: 20 with sPTB up to 32 weeks (mean gestation 26.5 weeks, standard deviation ±2.6 weeks), 20 with spontaneous term delivery (40.1 ± 0.9 weeks) sampled at 16-19+5  weeks of gestation. MAIN OUTCOME MEASURE: Identification of PCF RNAs predictive of sPTB up to 32 weeks. RESULTS: Two hundred and ninety-seven PCR RNAs were differentially expressed in sPTB up to 32 weeks of gestation. Further selection retained 99 RNAs (86 mRNAs and 13 microRNAs) and five of these interacted in silica with seven Preterm Initiator genes. Four of five RNAs were confirmed and tested on the validation group. The expression of each confirmed PCF RNA was significantly higher in sPTB up to 32 weeks of gestation. In vitro study of the four mRNAs revealed higher expression in placentas of women with sPTB up to 32 weeks and the potential to interfere with myometrial quiescence. CONCLUSIONS: The PCF RNA markers are highly associated with sPTB up to 32 weeks by 16 weeks of gestation. TWEETABLE ABSTRACT: Women destined for spontaneous preterm birth can be identified by 16 weeks of gestation with a panel of maternal plasma RNAs.

The association between COVID-19 pandemic and maternal isolated hypothyroxinemia in first and second trimesters.

BACKGROUND: The outbreak of COVID-19 epidemic has induced entire cities in China placed under 'mass quarantine'. The majority of pregnant women have to be confined at home may be more vulnerable to stressors. In our study, we aimed to explore the effects of the epidemic on maternal thyroid function, so as to provide evidence for prevention and intervention of sustained maternal and offspring's health impairment produced by thyroid dysfunction. METHODS: The subjects were selected from an ongoing prospective cohort study. we included the pregnant women who receive a thyroid function test during the COVID-19 epidemic and those receiving the test during the corresponding lunar period of 2019. A total of 7148 pregnant women with complete information were included in the final analysis. Multivariate linear and logistic regression models were used for analyzing the association of COVID-19 pandemic with FT4 levels and isolated hypothyroxinemia. RESULTS: We found a decreased maternal FT4 level during the period of the COVID-19 pandemic in first and second trimesters (ß = -0. 131, 95%CI = -0.257,-0.006，p = 0.040) and in first trimester (ß = -0. 0.176, 95%CI = -0.326,-0.026，p = 0.022) when adjusting for 25 (OH) vitamin D, vitamin B12, folate and ferritin and gestational days, maternal socio-demographic characteristics and health conditions. The status of pandemic increased the risks of isolated hypothyroxinemia in first and second trimesters (OR = 1.547, 95%CI = 1.251,1.913, p < 0.001) and first trimester (OR = 1.651, 95%CI = 1.289,2.114, p < 0.001) when adjusting for the covariates. However, these associations disappeared in the women with positive TPOAb (p > 0.05). Additionally, we found associations between daily reported new case of COVID-19 and maternal FT4 for single-day lag1, lag3 and multi-day lag01 and lag04 when adjusting for the covariates (each p < 0.05). CONCLUSIONS: Mass confinement as a primary community control strategy may have a significant cost to public health resources. Access to health service systems and adequate medical resources should be improved for pregnant women during the COVID-19 pandemic.

Changes of Serum Sex Hormone-Binding Globulin, Homocysteine, and Hypersensitive CRP Levels during Pregnancy and Their Relationship with Gestational Diabetes Mellitus.

BACKGROUND: Inflammatory response state is related to the pathogenesis of gestational diabetes mellitus (GDM). OBJECTIVE: To investigate the changes of serum sex hormone-binding globulin (SHBG), homocysteine (Hcy), and hypersensitive CRP (hs-CRP) levels during pregnancy and their relationship with GDM. METHODS: The nested case-control study method was used. Sixty nonobese single pregnant women diagnosed with GDM were divided into the GDM group (GDM, n = 60), together with another 60 pregnant women with normal glucose tolerance who were matched in the same period and divided into the control group (control, n = 60). The serum Hcy, hs-CRP, and SHBG levels were measured. RESULTS: The serum levels of Hcy and hs-CRP were significantly higher in the GDM group compared with the control group, and serum levels of SHBG was significantly lower in the GDM group compared with the control group at different stages of pregnancy. The serum levels of Hcy and hs-CRP in pregnant women increased with the increase of gestational age, and serum levels of SHBG decreased with the increase of gestational age. Increased Hcy and hs-CRP levels in the second trimester and decreased SHBG levels in the first trimester were related to GDM. The odds ratio (OR) and 95% confidence interval (CI) were as follows: OR: 4.5, 95% CI: 1.5-13.0; OR: 4.2, 95% CI: 1.5-10.1; and OR: 0.4, 95% CI: 0.3-0.7, respectively. CONCLUSION: Increased Hcy and hs-CRP in the second trimester and decreased SHBG in the first trimester were independent predictors of GDM, which provides a new idea for early prevention and treatment of GDM.

Effect of Maternal Nutritional Status and Mode of Delivery on Zinc and Iron Stores at Birth.

Zinc and iron deficiencies among infants aged under 6 months may be related with nutrient store at birth. This study aimed to investigate the association between zinc and iron stores at birth with maternal nutritional status and intakes during pregnancy. 117 pregnant women were enrolled at the end of second trimester and followed until delivery. Clinical data during pregnancy, including pre-pregnancy body mass index (BMI) and at parturition were collected from medical record. Zinc and iron intakes were estimated from a food frequency questionnaire. Serum zinc and ferritin were determined in maternal blood at enrollment and cord blood. Mean cord blood zinc and ferritin were 10.8 ± 2.6 µmol/L and 176 ± 75.6 µg/L, respectively. Cord blood zinc was associated with pre-pregnancy BMI (adj. ß 0.150; p = 0.023) and serum zinc (adj. ß 0.115; p = 0.023). Cord blood ferritin was associated with pre-pregnancy BMI (adj. ß -5.231; p = 0.009). Cord blood zinc and ferritin were significantly higher among those having vaginal delivery compared to cesarean delivery (adj. ß 1.376; p = 0.007 and 32.959; p = 0.028, respectively). Maternal nutritional status and mode of delivery were significantly associated with zinc and iron stores at birth. Nutrition during preconception and pregnancy should be ensured to build adequate stores of nutrients for infants.

Serum complement proteomics reveal biomarkers for hypertension disorder of pregnancy and the potential role of Clusterin.

INTRODUCTION: Hypertension disorder of pregnancy (HDP) is one of the leading causes of maternal and foetal illness. The aim of the current study was to identify and verify novel serum markers for HDP. METHODS: A label-free LC-MS/MS method was used to establish the serum proteomic profiles of 12 pre-HDP (before clinical diagnosis of HDP) pregnancies and verify prioritized candidates in the verification set of 48 pre-HDP pregnancies. These biomarkers were revalidated by ELISA in an independent cohort of 88 pre-HDP pregnancies. Subsequently, the candidate biomarkers were histologically analysed by immunohistochemistry, and function was evaluated in TEV-1 cells. RESULTS: We identified 33 proteins with significantly increased abundance and 14 with decreased abundance (peptide FDR ≤ 1%, P < 0.05). Complement was one of the top enriched components in the pre-HDP group compared with the control group. Three complement factors (CLU, CFHR5, and CRP) were significantly increased in the three sets, of which CLU was a critical factor for the development of HDP (OR = 1.22, P < 0.001). When these three factors and body weight were combined, the AUC was 0.74, with a sensitivity of 0.67 and specificity of 0.68 for HDP prediction compared with normal pregnancy. In addition, inflammation-induced CLU could inhibit the invasion of TEV-1 cells. CONCLUSIONS: Complement proteins may play an essential role in the occurrence of HDP by acting on trophoblast cells. CLU may be a high-risk factor for HDP, and the models combining candidates show reasonable screening efficiency of HDP in the first half of pregnancy.