[Latest Findings on Prediction and Prevention of Preeclampsia].

Preeclampsia, a progressive disease involving multiple systems, afflicts pregnancy specifically. It contributes to severe maternal and perinatal morbidity and mortality. It has been reported that preeclampsia initiates from a mismatch between the utero-placental supply and demand, which subsequently triggers the release of placental syncytiotrophoblast stress-derived factors and an imbalance of proangiogenic/antiangiogenic factors, eventually causing maternal systemic endothelial lesions and systemic inflammatory response. Currently, treatments available for preeclampsia are very limited in number. Hence, prediction and prevention carry special significance. Herein, we reviewed the current understanding of preeclampsia, especially findings on the prediction and prevention of preeclampsia published within the past 5 years. We discussed the Fetal Medicine Foundation (FMF) screening model based on placental growth factor (PlGF) and the effects of aspirin, calcium, exercise, and termination of pregnancy in preventing preeclampsia. The efficacy and safety of other new preventive measures still need further validation.

Early-Pregnancy Intermediate Hyperglycemia and Adverse Pregnancy Outcomes Among Women Without Gestational Diabetes.

CONTEXT: Universal early-pregnancy screening for overt diabetes reveals intermediate hyperglycemia (fasting plasma glucose [FPG] [5.1-6.9 mM]). OBJECTIVE: We evaluated the association between early-pregnancy intermediate hyperglycemia and adverse pregnancy outcomes among women without gestational diabetes. METHODS: This retrospective cohort study was conducted at the Obstetrics and Gynecology Hospital, Shanghai, China, from 2013 to 2017. All singleton pregnancies with FPG less than or equal to 6.9 mM in early pregnancy and receiving a 75-g oral glucose tolerance test (OGTT) were included. Women with prepregnancy diabetes were excluded. Individuals with normal OGTT were analyzed. Pregnancy outcomes for FPG less than 5.1 mM and intermediate hyperglycemia were evaluated. The primary outcomes were large for gestational age (LGA) and primary cesarean delivery. Multivariate logistic regressions were conducted. Statistical significance was defined as P less than .05. RESULTS: In total, 24 479 deliveries were included, of which 23 450 (95.8%) had normal OGTTs later in pregnancy (NGT). There were 807 (3.4%) women who had an FPG of 5.1 to 6.9 mM in early pregnancy. Compared to the NGT group with an FPG of less than 5.1 mM in early pregnancy (N = 20692), the intermediate hyperglycemia NGT group (N = 693) had a higher age and body mass index (BMI), and significantly higher rates of LGA, primary cesarean delivery, preterm birth, preeclampsia, and neonatal distress. The rates of primary cesarean delivery (adjusted odds ratio [AOR] 1.24; 95% CI, 1.05-1.45), preterm birth (AOR 1.75; 95% CI, 1.29-2.36), and neonatal distress (AOR 3.29; 95% CI, 1.57-6.89) remained statistically significantly higher after adjustments for maternal age, BMI, and other potential confounding factors. CONCLUSION: Women with intermediate hyperglycemia in early pregnancy are at an increased risk for adverse maternal-fetal outcomes, even with normal future OGTTs.

Early Versus Routine Oral Glucose Tolerance Test in Women With Intermediate Hyperglycemia at First Prenatal Visit: A Retrospective Cohort Study in China.

Background and Objectives: Intermediate hyperglycemia in the first half of pregnancy, defined as a fasting plasma glucose level between 5.1- 6.9 mM, increases the risk of gestational diabetes mellitus, but clinical evidence for further management is lacking. We aim to evaluate the effectiveness of an early oral glucose tolerance test (OGTT) followed by the identification of intermediate hyperglycemia on pregnancy outcomes in real world setting. Subjects and Methods: A retrospective cohort study was conducted at the Obstetrics and Gynecology Hospital, Shanghai, China, between 2013 and 2017. Women with intermediate hyperglycemia at the first prenatal visit were identified and underwent an immediate (within one week) or a routine OGTT (24-28 gw) according to their wishes and received nutrition and exercise advice. Women diagnosed of gestational diabetes (GDM) were managed by standard interventions. Primary outcome was larger for gestational age (LGA). Secondary outcomes were primary cesarean delivery, preterm birth, shoulder dystocia or forceps delivery, preeclampsia, neonatal hypoglycemia, hyperbilirubinemia, and low Apgar score. Logistic regressions with or without a further propensity score-matched analysis were performed. Results: Among 42406 women involved, 1104 (2.6%) with intermediate hyperglycemia at the first prenatal visit were identified, of whom 176 (15.9%) underwent an early OGTT and 741 (67.1%) received a routine OGTT. Logistic regression showed that an early OGTT was not significantly associated with an altered risk of LGA (adjusted OR 1.13, 95% CI 0.73-1.75) but was related to an increased odds for neonatal hyperbilirubinemia (adjusted OR 2.89; 95% CI 1.55-5.37). No significant associations were observed for other secondary outcomes. These trends remained consistent in propensity score-matched models. Conclusions: Our data from a real-world setting did not support that an early OGTT among women with intermediate hyperglycemia at the first prenatal visit improved pregnancy outcomes.

Differentially expressed circular RNAs and the competing endogenous RNA network associated with preeclampsia.

INTRODUCTION: Circular RNAs (circRNAs) are non-coding RNAs that are implicated in preeclampsia (PE) pathogenesis; however, their expression and functions in PE remain unclear. In this study, we aimed to investigate the expression of circRNAs in PE and construct a competing endogenous RNA (ceRNA) network, and analyze the associated pathways in PE pathogenesis. METHODS: We performed circRNA sequencing to identify the differential expression profile of circRNAs in PE as compared to normal pregnancy. The circRNA candidates were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Subsequently, we used datasets from the GEO database to generate the interaction network between circRNAs, microRNAs (miRNAs), and mRNAs. GO and KEGG enrichment analyses were performed to understand the functional significance of the differentially expressed circRNAs in PE. RESULTS: We identified 361 differentially expressed circRNAs (252 upregulated and 109 downregulated) in preeclamptic placentas. Within the selected 31 circRNAs, 6 of them were verified by qRT-PCR. GO and KEGG analyses revealed the potential pathways affected by these circRNAs, e.g., T cell receptor signaling and MAP kinase pathways. A total of 134 miRNAs and 199 mRNAs were revealed to be differentially expressed in PE by analyzing datasets from the GEO database. The circRNA-miRNA-mRNA network comprised 206 circRNAs, 50 miRNAs, and 38 mRNAs. KEGG analysis of the 38 mRNAs included pathways involved in AMPK and PI3K-Akt signaling. DISCUSSION: Our results reported the differential expression profile of circRNAs and the circRNA-miRNA-mRNA network in PE, which provides potential therapeutic targets for this disease.

Comparison of Machine Learning Methods and Conventional Logistic Regressions for Predicting Gestational Diabetes Using Routine Clinical Data: A Retrospective Cohort Study.

BACKGROUND: Gestational diabetes mellitus (GDM) contributes to adverse pregnancy and birth outcomes. In recent decades, extensive research has been devoted to the early prediction of GDM by various methods. Machine learning methods are flexible prediction algorithms with potential advantages over conventional regression. OBJECTIVE: The purpose of this study was to use machine learning methods to predict GDM and compare their performance with that of logistic regressions. METHODS: We performed a retrospective, observational study including women who attended their routine first hospital visits during early pregnancy and had Down's syndrome screening at 16-20 gestational weeks in a tertiary maternity hospital in China from 2013.1.1 to 2017.12.31. A total of 22,242 singleton pregnancies were included, and 3182 (14.31%) women developed GDM. Candidate predictors included maternal demographic characteristics and medical history (maternal factors) and laboratory values at early pregnancy. The models were derived from the first 70% of the data and then validated with the next 30%. Variables were trained in different machine learning models and traditional logistic regression models. Eight common machine learning methods (GDBT, AdaBoost, LGB, Logistic, Vote, XGB, Decision Tree, and Random Forest) and two common regressions (stepwise logistic regression and logistic regression with RCS) were implemented to predict the occurrence of GDM. Models were compared on discrimination and calibration metrics. RESULTS: In the validation dataset, the machine learning and logistic regression models performed moderately (AUC 0.59-0.74). Overall, the GBDT model performed best (AUC 0.74, 95% CI 0.71-0.76) among the machine learning methods, with negligible differences between them. Fasting blood glucose, HbA1c, triglycerides, and BMI strongly contributed to GDM. A cutoff point for the predictive value at 0.3 in the GBDT model had a negative predictive value of 74.1% (95% CI 69.5%-78.2%) and a sensitivity of 90% (95% CI 88.0%-91.7%), and the cutoff point at 0.7 had a positive predictive value of 93.2% (95% CI 88.2%-96.1%) and a specificity of 99% (95% CI 98.2%-99.4%). CONCLUSION: In this study, we found that several machine learning methods did not outperform logistic regression in predicting GDM. We developed a model with cutoff points for risk stratification of GDM.

Bisphenol A affects estradiol metabolism by targeting CYP1A1 and CYP19A1 in human placental JEG-3 cells.

Estradiol, in some way or another, plays a critically important physiologic role in the establishment and maintenance of pregnancy. This study was designed to investigate whether BPA affects the estradiol level of human placental JEG-3 cells, which may contribute to insights into the reproductive toxicity and endocrine disruption of BPA. The JEG-3 cells were treated with increasing concentrations of BPA (0.1 to 50 µM). We observed that BPA significantly reduced estradiol level of JEG-3 cells in a dose-dependent manner, which was accompanied by an increase in CYP1A1 protein level and an inhibition of CYP19A1 protein level. Additionally, by lentiviral transduction, we determined that estradiol level of JEG-3 cells over-expressing CYP1A1 gene was notably decreased and the decrease was of 84.9% compared to the control. Meanwhile, estradiol was almost undetectable in CYP19A1 knockdown group. On the contrary, the group with over-expression of CYP19A1 gene increased estradiol level by 8.6 fold while the CYP1A1 knockdown group increased by 5.6 fold. In summary, our research clearly showed that BPA alters JEG-3 estradiol synthesis and catabolism due to its action on CYP1A1 and CYP19A1 protein levels and may interfere with the normal process of placenta formation and embryonic development during early pregnancy.

Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2.

Preeclampsia leads to adverse outcomes for pregnant women. Bisphenol A (BPA) is an environmental endocrine disruptor and has been shown to be positively associated with increased risk of preeclampsia in human studies. We investigated whether BPA exposure causes preeclampsia-like features in pregnant mice and the associated underlying mechanisms. Experiments were performed in animal models and cell cultures. In pregnant mice, BPA-exposed mice exhibited preeclampsia-like features including hypertension, disruption of the circulation, and the placental angiogenesis biomarkers fms-related tyrosine kinase 1 and placenta growth factor, and glomerular atrophy; urinary protein was not affected. These preeclampsia-like features correlated with increased retention of smooth muscle cells and reduced vessel areas at the junctional zone of the placenta. In addition, there were disrupted expression of invasion-related genes including increased tissue inhibitors of metalloproteinases, decreased metalloproteinases, and Wnt family member WNT2/ß-catenin, which correlated with increased DNA methylation in its promoter region and upregulation of DNA methyltransferase (Dnmt)1. BPA exposure impeded the interaction between the human cytotrophoblast cell line, HTR-8/SVneo, and endothelium cells. BPA exposure down-regulated WNT2 expression, and elevated the DNA methylation of WNT2; these results were consistent with in vivo observations. Inhibition of DNMT in HTR-8/SVneo cells resulted in reduced DNA methylation and increased expression of WNT2. Taken together, these data demonstrate that BPA exposure alters trophoblast cell invasion and causes abnormal placental vessel remodeling, both of which lead to the development of preeclampsia-like features in pregnant mice. Our results suggest that this phenomenon involves the epigenetic reprogramming and down-regulation of WNT2 mediated by DNMT1.-Ye, Y., Tang, Y., Xiong, Y., Feng, L., Li, X. Bisphenol A exposure alters placentation and causes preeclampsia-like features in pregnant mice involved in reprogramming of DNA methylation of WNT2.

Maternal serum bisphenol A levels and risk of pre-eclampsia: a nested case-control study.

Background: Although recent studies have indicated the potential adverse effects of maternal bisphenol A (BPA) exposure on pregnancy such as increasing the risk of pre-eclampsia, epidemiological evidence is limited. We aimed to evaluate the relationship between maternal BPA exposure and the risk of pre-eclampsia. Methods: We conducted a nested case-control study among 173 women (74 cases of pre-eclampsia and 99 controls). BPA concentrations were measured using liquid chromatography-mass spectrometry in the maternal serum samples collected during 16-20 gestational weeks. Multivariate logistic models were used to examine the relationship between maternal serum BPA concentrations and the risk of pre-eclampsia. Results: BPA was detectable (>0.1 µg/l) in 78.6% of the maternal serum samples at three levels: low (<2.24 µg/l), medium (2.24-4.44 µg/l), and high (>4.44 µg/l). BPA concentrations were significantly higher in the serum samples collected from the pre-eclampsia cases than those from controls (median: 3.40 vs. 1.50 µg/l, P < 0.01). With adjustment for maternal age, primiparous and BMI, the odds of developing pre-eclampsia were significantly elevated in subjects with high serum BPA levels compared with those with low levels (adjusted OR = 16.46, 95%CI = 5.42-49.85) regardless of subcategories of pre-eclampsia including severity and onset time. Among the pre-eclampsia subjects, the maternal serum concentration of BPA was not different between the early- and late-onset subjects (median: 3.09 vs. 3.50 µg/l, P = 0.57), but surprisingly higher in mild pre-eclampsia subjects compared with severe pre-eclampsia subjects (median: 5.20 vs. 1.80 µg/l, P < 0.01). Conclusions: These results demonstrated that maternal exposure to high level of BPA could be associated with an increased risk of pre-eclampsia.

Hypomethylation of tissue factor pathway inhibitor 2 in human placenta of preeclampsia.

OBJECTIVES: To investigate the expression, DNA methylation status and its regulatory mechanism of tissue factor pathway inhibitor 2 (TFPI-2) in human placenta tissues of preeclampsia (PE). MATERIAL AND METHODS: We studied the mRNA and protein expression and the promoter methylation levels of TFPI-2 in the PE placentas compared with those in the normal pregnant (NP) women. Quantitative real-time polymerase chain reaction, immunohistochemistry, western blot, and Sequenom MassARRAY were used for placenta tissue detection. RESULTS: The expressions of TFPI-2 mRNA and protein were significantly elevated in the PE placentas when compared with those in the NP ones (P<0.05). Hypomethylation of the TFPI-2 promoter was detected both in PE patients and NP women, with a significant decrease in PE placentas (P=0.005). The methylation level was significantly decreased at CpG_6 (-168 to -167), CpG_15 (-98 to -97) and CpG_18.19 (-68 to -65) in PE patients than that in normal placentas (P<0.05). However, the expression of DNMT-1 didn't show significant difference between the two groups (P>0.05). CONCLUSION: Over-expression of TFPI-2 and aberrant promoter mythylation status presented in the PE placentas, suggesting that epigenetic mechanism might contribute to the pathogenesis of PE.