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.

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.

Establishment of pregnancy-specific lipid reference intervals in pregnant women in a single-centre and assessment of the predictive value of early lipids for gestational diabetes mellitus: a prospective cohort study.

INTRODUCTION: This study was aimed at establishing a pregnancy-specific lipid reference interval (RI) in pregnant women in a single-centre in the Beijing area of China, simultaneously exploring the predictive value of lipid levels in early pregnancy for gestational diabetes mellitus (GDM). MATERIAL AND METHODS: From October 2017 to August 2019, Peking University International Hospital established records for 1588 pregnant women, whose lipid profiles were determined during the first and third trimesters. The Hoffmann technique was used to calculate gestation-specific lipid RI. The 95% reference range for gestational lipids was also estimated for 509 healthy pregnant women screened according to the Clinical and Laboratory Standards Institute guideline. Multivariate logistic regression analysis was used to calculate odds ratios (OR) and their 95% confidence interval (CI), and the receiver operating characteristic (ROC) curve was applied to assess the predictive value of lipids in the first trimester for the diagnosis of GDM. RESULTS: Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in the third trimester (p < 0.05). Hoffmann technique RI of the lipid profiles and the 95% reference range of the lipid profiles in healthy pregnant women did not differ statistically (p > 0.05). TC, TG, and LDL-C levels were higher in the GDM group in the first trimester (p < 0.05), and the risk of GDM was 2.1 times higher in women with higher TG (95% CI: 1.13-3.77, p < 0.05). The optimal ROC cut-off for TG to predict GDM was 2.375 mmol / L, and the area under the ROC curve was 0.622 (95% CI: 0.592-0.751), with a sensitivity of 73.7% and a specificity of 59.3%. CONCLUSIONS: This study established pregnancy-specific lipid RI for pregnant women in a single centre in the Beijing area of China. Pregnant women with TG ≥ 2.375 mmol/L in the first trimester were at significantly increased risk for GDM.

First trimester maternal tryptophan metabolism and embryonic and fetal growth: the Rotterdam Periconceptional Cohort (Predict Study).

STUDY QUESTION: What is the association between first trimester maternal tryptophan (TRP) metabolites and embryonic and fetal growth? SUMMARY ANSWER: Higher 5-hydroxytryptophan (5-HTP) concentrations are associated with reduced embryonic growth and fetal growth and with an increased risk of small-for-gestational age (SGA), while higher kynurenine (KYN) concentrations are associated with a reduced risk of SGA. WHAT IS KNOWN ALREADY: The maternal TRP metabolism is involved in many critical processes for embryonic and fetal growth, including immune modulation and regulation of vascular tone. Disturbances in TRP metabolism are associated with adverse maternal and fetal outcomes. STUDY DESIGN, SIZE, DURATION: This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective observational cohort conducted at a tertiary hospital from November 2010 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1115 women were included before 11 weeks of gestation between November 2010 and December 2020. Maternal serum samples were collected between 7 and 11 weeks of gestation, and TRP metabolites (TRP, KYN, 5-HTP, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid) were determined using a validated liquid chromatography (tandem) mass spectrometry method. Serial 3D ultrasound scans were performed at 7, 9, and 11 weeks of gestation to accurately assess features of embryonic growth, including crown-rump length (CRL) and embryonic volume (EV) offline using virtual reality systems. Fetal growth parameters were retrieved from medical records and standardized according to Dutch reference curves. Mixed models were used to assess associations between maternal TRP metabolites and CRL and EV trajectories. Linear and logistic regression models were utilized to investigate associations with estimated fetal weight (EFW) and birthweight, and with SGA, respectively. All analyses were adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal 5-HTP concentrations and the maternal 5-HTP/TRP ratio were inversely associated with embryonic growth (5-HTP, √CRL: ß = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: ß = -0.009, 95% CI = -0.016 to -0.003). An increased maternal 5-HTP/TRP ratio was also associated with lower EFW and birthweight, and with an increased risk of SGA (odds ratio (OR) = 1.006, 95% CI = 1.00-1.013). In contrast, higher maternal KYN concentrations were associated with a reduced risk of SGA in the unadjusted models (OR = 0.548, 95% CI = 0.320-0.921). LIMITATIONS, REASONS FOR CAUTION: Residual confounding cannot be ruled out because of the observational design of this study. Moreover, this study was conducted in a single tertiary hospital, which assures high internal validity but may limit external validity. WIDER IMPLICATIONS OF THE FINDINGS: The novel finding that maternal 5-HTP concentrations are associated with a smaller embryo and fetus implies that disturbances of the maternal serotonin pathway in the first trimester of pregnancy are potentially involved in the pathophysiology of fetal growth restriction. The association between higher maternal KYN concentrations and a reduced risk of SGA substantiate the evidence that the KYN pathway has an important role in fetal growth. More research is needed to delve deeper into the potential role of the maternal TRP metabolism during the periconception period and pregnancy outcome for mother and offspring. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

The role of second trimester uterine artery Doppler in predicting obstetric and neonatal outcomes in abnormal first trimester maternal serum pregnancy-associated plasma protein-A and free ß-human chorionic gonadotropin values.

AIM: This study aims to determine whether second-trimester uterine artery (UtA) Doppler combined with first-trimester abnormal pregnancy-associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-Hcg) levels predicts adverse obstetric and neonatal outcomes. MATERIALS AND METHODS: This study of 289 pregnant women included 196 with normal PAPP-A and free ß-HCG values (control group) and 93 with abnormal values (study group) in the first-trimester screening test. Second-trimester UtA Doppler sonography was done in these pregnancies. The perinatal prediction and screening potential of UtA Doppler pulsatility index (PI) parameters were examined in the study group. RESULTS: UtA PI >95 percentile increased birth before the 37th week by 4.46 times, birth before the 34th week by 7.44 times, preeclampsia risk by 3.25 times, fetal growth restriction (FGR) risk by 4.89 times, and neonatal intensive care unit (NICU) admission rates by 3.66 times in the study group (p < 0.05 for all). UtA PI >95 percentile had 49.2% sensitivity and 82.1% specificity for birth before 37 weeks. For birth before 34 weeks, sensitivity was 80.0% and specificity 65.0%. FGR has 70.5% sensitivity and 67.1% specificity. Screening for preeclampsia has 66.6% sensitivity and 61.9% specificity. CONCLUSION: Adding UtA Doppler in the second trimester to pregnancies with abnormal PAPP-A and/or free ß-Hcg values in the first trimester may be a useful screening method for adverse outcomes.

CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes.

OBJECTIVES: The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM). METHODS: A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results. RESULTS: First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57-0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54-0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66-0.79) (p<0.001). The results were confirmed on a second independent cohort. CONCLUSIONS: CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM.

Serum fatty acid binding protein 4 and Doppler of uterine artery ultrasound in the first trimester for the prediction of preeclampsia.

The objective of this study was to determine the predictive value of serum fatty acid binding protein 4 (FABP4) combined with Doppler of the uterine artery in singleton pregnancy at gestational age (GA) 11-13+6 weeks for prediction of preeclampsia. A prospective observational study included singleton pregnant women at GA 11-13+6 weeks and was conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, between December 2020 and April 2022. Serum FABP4 levels and Doppler of the uterine artery were performed. Pregnancy outcomes were recorded. The predictive values of these combined tests at the optimal cut-off values were determined to predict preeclampsia. A total of 330 participants with 15 cases of preeclampsia (4.5%) and 6 cases of them had preterm preeclampsia (GA < 37 weeks) (1.8%) were analyzed. Women with preeclampsia had significantly higher serum FABP4 levels than normal pregnant women (12.9 ± 6.5 ng/ml vs 10.1 ± 4.8 ng/ml, p = 0.034) but no difference in the mean pulsatility index (PI) of the uterine artery and the presence of an early diastolic notch. When using serum FABP4 levels greater than 1.0 multiple of the median of GA as a cut-off value to predict preeclampsia, combined with abnormal Doppler PI of the uterine artery, the sensitivity, specificity, positive predictive value, and negative predictive value were 73.3%, 47.3%, 6.2%, and 97.4%, respectively. This study demonstrated that serum FABP4 levels combined with Doppler of the uterine artery at GA 11-13+6 weeks were effective in predicting preeclampsia.

Investigating the blood rheology in the first trimester pregnancies with high risk for preeclampsia.

BACKGROUND: Pregnancy is a dynamic process associated with changes in vascular and rheological resistance. Maternal maladaptation to these changes is the leading cause of pregnancy complications such as preeclampsia. OBJECTIVE: This study aimed to assess the hemorheological alterations in pregnancies with a high risk for preeclampsia in the first trimester. METHODS: Ninety-two pregnant women were allocated into the high preeclampsia risk group (37 cases) and control groups (55 cases). Plasma and whole blood viscosity and red blood cell morphodynamic properties, including deformability and aggregation were assessed by Brookfield viscometer and laser-assisted optical rotational cell analyzer (LORRCA) at 11-14 gestational weeks. RESULTS: Whole blood viscosity was significantly higher in the high-risk group at all shear rates. Plasma viscosity and hematologic factors showed no differences between the groups. Hematocrit levels positively correlated with high blood viscosity only in the high-risk group. There were no significant changes in the other deformability and aggregation parameters. CONCLUSIONS: Changes in the whole blood viscosity of pregnant women with high preeclampsia risk refer to impaired microcirculation beginning from the early weeks of gestation. We suggest that the whole blood viscosity is consistent with the preeclampsia risk assessment in the first trimester, and its measurement might be promising for identifying high-preeclampsia-risk pregnancies.

Automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation predicts preterm preeclampsia: a retrospective cohort study.

Our aims were to obtain the gestational-age-specific median of common logarithmic placental growth factor (PlGF) values in the first trimester in women with a singleton pregnancy in order to generate the gestational-age-specific multiple of the median (MoM) of log10PlGF at 9-13 weeks of gestation, to evaluate screening parameters of MoM of log10PlGF at 9-13 weeks of gestation to predict preterm preeclampsia (PE), and to construct an appropriate prediction model for preterm PE using minimum risk factors in multivariable logistic regression analyses in a retrospective sub-cohort study. Preterm PE occurred in 2.9% (20/700), and PE in 5.1% (36/700). Serum PlGF levels were measured using Elecsys PlGF®. MoMs of log10PlGF at 9-13 weeks of gestation in Japanese women with a singleton pregnancy followed a normal distribution. We determined the appropriate cut-off value of MoM of log10PlGF to predict preterm PE at around a10% false-positive rate (0.854). The MoM of log10PlGF < 0.854 yielded sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (95% confidence interval [CI]), and negative likelihood ratio (95% CI) of 55.0%, 91.9%, 17.5%, 98.5%, 6.79 (4.22-10.91), and 0.49 (0.30-0.80), respectively. The combination of MoM of log10PlGF and presence of either chronic hypertension or history of PE/gestational hypertension (GH) yielded sensitivity and specificity of 80.0 and 85.7%, respectively, to predict preterm PE. In conclusion, the automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation may be useful to predict preterm PE.

Glycosylated fibronectin improves first-trimester prediction of pre-eclampsia.

OBJECTIVE: To determine whether maternal serum glycosylated fibronectin (GlyFn) level in the first trimester increases the sensitivity of the Fetal Medicine Foundation (FMF) triple test, which incorporates mean arterial pressure, uterine artery pulsatility index and placental growth factor, when screening for pre-eclampsia (PE) in an Asian population. METHODS: This was a nested case-control study of Chinese women with a singleton pregnancy who were screened for PE at 11-13 weeks' gestation as part of a non-intervention study between December 2016 and June 2018. GlyFn levels were measured retrospectively in archived serum from 1685 pregnancies, including 101 with PE, using an enzyme-linked immunosorbent assay (ELISA), and from 448 pregnancies, including 101 with PE, using a point-of-care (POC) device. Concordance between ELISA and POC tests was assessed using Lin's correlation coefficient and Passing-Bablok and Bland-Altman analyses. GlyFn was transformed into multiples of the median (MoM) to adjust for maternal and pregnancy characteristics. GlyFn MoM was compared between PE and non-PE pregnancies, and the association between GlyFn MoM and gestational age at delivery with PE was assessed. Risk for developing PE was estimated using the FMF competing-risks model. Screening performance for preterm and any-onset PE using different biomarker combinations was quantified by area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% fixed false-positive rate (FPR). Differences in AUC between biomarker combinations were compared using the DeLong test. RESULTS: The concordance correlation coefficient between ELISA and POC measurements was 0.86 (95% CI, 0.83-0.88). Passing-Bablok analysis indicated proportional bias (slope, 1.08 (95% CI, 1.04-1.14)), with POC GlyFn being significantly higher compared with ELISA GlyFn. ELISA GlyFn in non-PE pregnancies was independent of gestational age at screening (P = 0.11), but significantly dependent on maternal age (P < 0.003), weight (P < 0.0002), height (P = 0.001), parity (P < 0.02) and smoking status (P = 0.002). Compared with non-PE pregnancies, median GlyFn MoM using ELISA and POC testing was elevated significantly in those with preterm PE (1.23 vs 1.00; P < 0.0001 and 1.18 vs 1.00; P < 0.0001, respectively) and those with term PE (1.26 vs 1.00; P < 0.0001 and 1.22 vs 1.00; P < 0.0001, respectively). GlyFn MoM was not correlated with gestational age at delivery with PE (P = 0.989). Adding GlyFn to the FMF triple test for preterm PE increased significantly the AUC from 0.859 to 0.896 (P = 0.012) and increased the DR at 10% FPR from 64.9% (95% CI, 48.7-81.1%) to 82.9% (95% CI, 66.4-93.4%). The corresponding DRs at 10% FPR for any-onset PE were 52.5% (95% CI, 42.3-62.5%) and 65.4% (95% CI, 55.2-74.5%), respectively. CONCLUSIONS: Adding GlyFn to the FMF triple test increased the screening sensitivity for both preterm and any-onset PE in an Asian population. Prospective non-intervention studies are needed to confirm these initial findings. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Accuracy of Serum Human Chorionic Gonadotrophin for Estimating Gestational Age in the First Trimester of Pregnancy: Population-Based Study.

This study determined the accuracy of first-trimester serum human chorionic gonadotrophin (hCG) for estimating gestational age (GA). We included 273 584 singleton live births that had a first-trimester ultrasound and measured serum hCG at 4-12 weeks gestation in Ontario from 2012 to 2018. We estimated hCG accuracy compared to known GA, within a boundary of ± 1 week. Between 4 to 8 weeks gestation, sensitivity of hCG was over 88% and specificity over 51%. However, at 9-12 weeks gestation, sensitivity declined from 72% to 0%, and specificity rose from 86% to 100%. At all GA, the positive predictive value was consistently under 42%, while negative predictive values were over 96%. Within epidemiological studies in which GA is otherwise unknown, first-trimester serum hCG may aid somewhat in estimating GA between 4 to 6 weeks gestation, but much less so thereafter. Thus, there remains an ongoing need for an accurate method for estimating missing GA within large datasets.

Maternal serum NGAL in the first trimester of pregnancy is a potential biomarker for the prediction of gestational diabetes mellitus.

Objective: Gestational diabetes mellitus (GDM) has adverse effects on the health of mothers and their offspring. Currently, no known biomarker has been proven to have sufficient validity for the prediction of GDM in the first trimester of pregnancy. The aim of this study was to investigate the potential relationship between serum neutrophil gelatinase-associated lipocalin (NGAL) levels in the first trimester of pregnancy and later GDM risk and to evaluate the performance of serum NGAL as a biomarker for the prediction of GDM. Methods: The study was conducted by recruiting participants at 8-13 weeks of gestation from The First Affiliated Hospital of Chengdu Medical College between January and June 2021; participants were followed up for oral glucose tolerance test (OGTT) screening at 24-28 gestational weeks. We examined the serum NGAL levels of all subjects in the first trimester who met the inclusion and exclusion criteria. Anthropometric, clinical, and laboratory parameters of the study subjects were obtained during the same study period. A logistic regression model was carried out to investigate the potential relationship between serum NGAL levels in the first trimester of pregnancy and later GDM risk. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the discrimination and calibration of serum NGAL as a biomarker for the prediction of GDM in the first trimester of pregnancy. Results: Serum NGAL levels in the first trimester of pregnancy were significantly higher in women who later developed GDM than in those who did not develop GDM. Serum NGAL levels in the first trimester of pregnancy were positively associated with an increased risk of GDM after adjustment for potential confounding factors. The risk prediction model for GDM constructed by using serum NGAL levels in the first trimester of pregnancy achieved excellent performance. Conclusions: Maternal serum NGAL in the first trimester of pregnancy is a potential biomarker for the prediction of GDM, which could help guide the clinical practice of antenatal care.

Higher hemoglobin levels are an independent risk factor for gestational diabetes.

Incidence of gestational diabetes (GDM) has increased rapidly. It poses significant risks for both mother and fetus affecting also negatively their longer-term metabolic heath. We asked whether early pregnancy maternal hemoglobin (Hb) levels, indicative for tissue oxygenation, would affect mother's metabolic health and fetal outcome. We assessed in FinnGeDi, a Finnish multicenter case-control study for GDM (n = 1828), association of maternal 1st trimester Hb levels with metabolic parameters and perinatal outcome. Our data show that mothers with GDM had higher Hb levels compared to controls (mean difference 1.746 g/L). Hb levels associated positively with pre-pregnancy body mass index (BMI), fasting glucose levels and glucose levels in a glucose tolerance test and systolic and diastolic blood pressure (bp) levels. When assessed in quartiles the highest Hb quartile had more chronic and gestational hypertension and the most adverse outcome of the metabolic parameters, dose-dependency seen in bp, BMI and glucose levels. In a multivariable regression analysis Hb levels remained an independently associated parameter for GDM after adjusting for key covariates (OR 1.019, 95% CI [1.007; 1.031]). In conclusion, higher maternal Hb levels within the normal variation are an independent risk factor for GDM in this population but have little effect on perinatal outcome.

The screening of diagnostic biomarker microRNA in first-trimester maternal plasma for Down syndrome: A study protocol.

BACKGROUND: The trisomy of human chromosome 21 causes Down syndrome (DS), sometimes known as congenital folly's syndrome. The survivors show apparent mental impairment, unusual facial traits, growth and development abnormalities, and various deformities, with 60 percent of the infants having miscarriages in the early stages of the fetus. Plasma micRNA (miRNA) is a new diagnostic biomarker for DS; however, its significance in first-trimester maternal plasma is unknown. As a result, the purpose of this study is to assess the diagnostic significance of the biomarker miRNA in first-trimester maternal plasma for DS. MATERIALS AND METHODS: From January 2014 until the present, blood samples were obtained from pregnant women who visited our hospital. This study included 20 eligible DS pregnancies and 20 normal pregnant women. We looked at the differential miRNA expression profile in DS maternal plasma from the first and second trimesters using miRNA microarrays. Bioinformatics technology was used to compare the particular miRNA in DS maternal plasma from the first and second trimesters and screen the miRNA co-expressed in DS maternal plasma. Meanwhile, the expression level of chosen miRNAs was verified using quantitative real-time PCR (qRT-PCR). DISCUSSION: This study aims to see how useful the diagnostic biomarker miRNA in first-trimester maternal plasma is for diagnosing DS. The findings of this investigation will provide clinical evidence for the discovery of a new diagnostic biomarker miRNA in first-trimester maternal plasma for DS diagnosis. OSF REGRESSION NUMBER: DOI 10.17605/OSF.IO/R49FT.

Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy.

BACKGROUND: During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy. METHODS: Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath. RESULTS: A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways. CONCLUSION: We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.

Prospective Evaluation of International Prediction of Pregnancy Complications Collaborative Network Models for Prediction of Preeclampsia: Role of Serum sFlt-1 at 11-13 Weeks' Gestation.

The study aimed to investigate whether serum sFlt-1 (soluble fms-like tyrosine kinase-1) at 11-13 weeks' gestation in pregnancies that subsequently developed preeclampsia was different from those without preeclampsia and compare screening performance of the International Prediction of Pregnancy Complications (IPPIC) reported models, which include various combinations of maternal factors, systolic blood pressure, diastolic blood pressure, PlGF (placental growth factor) and sFlt-1 and the competing risk (CR) models, which include various combinations of maternal factors, mean arterial pressure (MAP) and PlGF for predicting any-onset, early-onset, and late-onset preeclampsia. This was a prospective multicenter study in 7877 singleton pregnancies. The differences of the predictive performance between the IPPIC and CR models were compared. There were 141 women (1.79%) who developed preeclampsia, including 13 cases (0.17%) of early-onset preeclampsia and 128 cases (1.62%) of late-onset preeclampsia. In pregnancies that developed preeclampsia compared to unaffected pregnancies, median serum sFlt-1 levels and its MoMs were not significantly different (p>0.05). There was no significant association between gestational age at delivery and log10 sFlt-1 and log10 sFlt-1 MoM (p>0.05). The areas under the curve of CR models were significantly higher than the IPPIC models for the prediction of any-onset and late-onset preeclampsia but not for early-onset preeclampsia. In conclusion, there are no significant differences in the maternal serum sFlt-1 levels at 11-13 weeks' gestation between women who subsequently develop preeclampsia and those who do not. Moreover, the CR models for the prediction of any-onset and late-onset preeclampsia perform better than the IPPIC reported model.

Decreased Monocyte Count Is Associated With Gestational Diabetes Mellitus Development, Macrosomia, and Inflammation.

CONTEXT: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE: Here, we investigated the potential effect of monocytes in GDM. METHODS: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.

A Prospective Study of Early-pregnancy Thyroid Markers, Lipid Species, and Risk of Gestational Diabetes Mellitus.

CONTEXT: While the associations between thyroid markers and gestational diabetes mellitus (GDM) have been extensively studied, the results are inconclusive and the mechanisms remain unclear. OBJECTIVE: We aimed to investigate the prospective associations of thyroid markers in early gestation with GDM risk, and examine the mediating effects through lipid species. METHODS: This study included 6068 pregnant women from the Tongji-Shuangliu Birth Cohort. Maternal serum thyroid markers (free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibody) were measured before 15 weeks. Deiodinase activity was assessed by fT3/fT4 ratio. Plasma lipidome were quantified in a subset of 883 participants. RESULTS: Mean age of the participants was 26.6 ± 3.7 years, and mean gestational age was 10.3 ± 2.0 weeks. Higher levels of fT4 were associated with a decreased risk of GDM (OR = 0.73 comparing the extreme quartiles; 95% CI 0.54, 0.98, Ptrend = .043), while higher fT3/fT4 ratio was associated with an increased risk of GDM (OR = 1.43 comparing the extreme quartiles; 95% CI 1.06, 1.93, Ptrend = .010) after adjusting for potential confounders. Multiple linear regression suggested that fT3/fT4 ratio was positively associated with alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, sphingomyelin 34:1, and phosphatidylcholine 40:7 (false discovery rate [FDR] adjusted P < .05). Mediation analysis indicated 67.9% of the association between fT3/fT4 ratio and GDM might be mediated through the composite effect of these lipids. CONCLUSION: Lower concentration of serum fT4 or higher fT3/fT4 ratio in early pregnancy was associated with an increased risk of GDM. The association of fT3/fT4 ratio with GDM was largely mediated by specific lipid species.

Association of leukocyte counts in the first trimester with glucose intolerance during pregnancy.

AIMS/INTRODUCTION: We investigated the association between leukocyte counts and glucose challenge test (GCT) level during pregnancy. MATERIALS AND METHODS: We collected prenatal information of women who had their first clinic visit in early pregnancy. Women underwent GCT at 24-28 gestational weeks, and a result of ≥7.8 mmol/L was considered positive. Participants were divided into quartiles of leukocyte counts, and association with GCT results and positive rate were analyzed by logistic regression. RESULTS: Among 20,707 pregnant women, the median of leukocyte counts was higher in the positive group than the normal group (8.5 × 109 /L vs 8.2 × 109 /L, P < 0.01). There was a linear trend in GCT results and positive rate with increasing leukocyte quartiles. Compared with the lowest quartile, the highest leukocyte quartile (>9.70 × 109 /L) was significantly associated with positive GCT results (adjusted odds ratio 1.378, 95% confidence interval 1.246-1.524), and the linear relationship between increased risk of positive result and increasing leukocyte quartiles persisted (P for linear trend <0.01). In multivariable analysis, the risk of a positive result increased by 2.2% with each 1-unit increase in leukocyte counts (adjusted odds ratio 1.022, 95% confidence interval 1.011-1.033). CONCLUSIONS: Elevated leukocyte counts in early pregnancy were independently and linearly associated with the risk of positive GCT levels, indicating that inflammation might play an important role in the development of gestational diabetes mellitus.