Search

Intrahepatic cholestasis of pregnancy (ICP) can lead to many adverse pregnancy outcomes, and the influencing factors remain unclear at present. This study retrospectively analyzed clinical data from 1815 pregnant women with ICP and evaluated the relationship between ICP subtypes, gestational age at onset, and pregnancy outcomes. The results of this study show that during pregnancy, the levels of biochemical indicators (TBA, DBIL and ALT) in the serum of pregnant women initially diagnosed with subtypes of ICP were noted to constantly change, and the subtype of ICP and its severity also changed. The incidence of adverse pregnancy outcomes [meconium-stained amniotic fluid (MSAF), NICU transfer, Apgar score ≤ 7 at 1 min, and preterm birth] in patients with ICP1 (icteric type) was significantly higher than for patients with ICP2, ICP3 or ICP4. The preterm birth rate of early-onset ICP was higher than that of late-onset ICP in ICP1 and ICP3 subtypes. In conclusion, the outcome of pregnancy in women with ICP is closely related to the serum TBA level and ICP subtype, which should be recognized in the clinic., (© 2024. The Author(s).)

Background: Thrombotic microangiopathy has been invoked as one of the most important mechanisms of damage in COVID-19 patients. Protease ADAMTS13 is a marker of microangiopathy responsible for controlling von Willebrand multimers size. Von Willebrand factor/ADAMTS13 ratio has been found impaired in COVID-19 patients outside pregnancy., Methods: We prospectively investigated 90 pregnant women admitted to two tertiary academic hospitals in Italy with a laboratory-confirmed diagnosis of SARS-CoV-2 infection. Demographic, clinical information and routine laboratory data were collected at the hospital admission and until discharge. We investigated whether vonWillebrand /ADAMTS13 axis imbalance is a predictor of adverse outcomes. Logistic regression analysis, which controlled for potential confounders, was performed to evaluate the association between laboratory parameters and clinical outcomes., Results: Most women (55.6%) were parae, with median gestational age at admission of 39 weeks. At hospital admission, 63.3% were asymptomatic for COVID-19 and 24.4% showed more than one sign or symptom of infection. Nulliparae with group O showed Willebrand / ADA MTS-13 ratios significantly lower than non-O, whereas in multiparae this difference was not observed. Logistic regression showed that ratio von Willebrand to ADAMTS13 was significantly and independently associated with preterm delivery (OR 1.9, 95%CI 1.1-3.5)., Conclusion: This study shows an imbalance of vonWillebrand /ADAMTS13 axis in pregnant women with COVID-19, leading to a significantly higher and independent risk of preterm delivery. Monitoring these biomarkers might support decision making process to manage and follow-up pregnancies in this setting., (© 2022. The Author(s).)

Women with low n-3 (omega-3) status in pregnancy can reduce their risk of early preterm birth (<34 weeks' gestation) through n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation. As investigators measure fatty acid status in different blood fractions, equations are needed to compare results across studies. Similarly, derived cut-points for defining low and replete n-3 status are needed to assist clinical interpretation during early pregnancy. Our aims were to develop equations to convert the percentage of total n-3 fatty acids, EPA+DHA and DHA between whole blood, plasma and red blood cells (RBC), and to derive cut-points for defining low and replete total n-3 fatty acid status in plasma and RBC from those already established in whole blood. Using blood samples from 457 pregnant women in a multicentre randomised controlled trial, equations for these interconversions were developed using simple linear regression models. Measures of n-3 fatty acid status in whole blood and plasma were strongly related (R 2 > 0.85), while more moderate relationships were observed between measures in whole blood and RBC (R 2 0.55 - 0.71), or plasma and RBC (R 2 0.55 - 0.63). Using the conversion equations, established cut-points for low and replete n-3 status in whole blood (<4.2% and >4.9% of total fatty acids) converted to <3.7% and >4.3% of plasma total fatty acids, and to <7.3% and >8.1% of RBC total fatty acids. Agreement to define low and replete n-3 status was better between whole blood and plasma, rather than between whole blood and RBC. Our data also show that total n-3 fatty acids in plasma and serum are interchangeable. We conclude that either whole blood or plasma total n-3 fatty acids can be used to define low status in pregnancy and identify women who will most benefit from n-3 LCPUFA supplementation to reduce their risk of early birth. Further research is needed to determine the clinical utility of other fatty acid measures in various blood lipid fractions., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Current studies suggest that vitamin D deficiency during pregnancy can produce a certain effect for preterm birth (PTB), but there is no research showing whether vitamin D deficiency has a consistent effect in different pregnancies; thus, we conducted a systematic review and meta-analysis of 24 observational studies, grouping them according to the gestational age at the time of serum sampling, to investigate whether vitamin D deficiency in different periods of gestation has different effects on PTB and to provide an evidence-based basis for pregnant women to measure and supplement vitamin D., Methods: The databases PubMed-Medline, EMBASE, the Cochrane Library, Web of Science, EBSCO, CBM, and CNKI were searched until February 2020. Two researchers independently assessed the eligibility and quality of studies, and STATA 12.0 software was used for meta-analysis., Result: Seven cohort studies, 13 case-control studies, and 4 cross-sectional studies were included from 2500 articles by inclusion and exclusion criteria. After adjusting for age, race, and other confounding factors, meta-analysis results showed that vitamin D deficiency in the first trimester, the second trimester, and the third trimester did not increase the risk of PTB (odds ratio (OR) = 1.01, 95% confidence interval (CI) (0.88, 1.16), P = .867; OR = 1.12, 95%CI (0.92, 1.37), P = .249; OR = 1.05, 95%CI (0.87, 1.27), P = .602). However, there was moderate heterogeneity in the study of vitamin D deficiency in the second trimester, and subgroup analysis suggested that vitamin D deficiency in the second trimester may increase the risk of PTB (OR = 1.33, 95%CI (1.15, 1.54), P = .000). A sensitivity analysis of the second trimester showed that excluding any 1 study did not significantly change the results., Conclusions: Vitamin D deficiency in early and late pregnancy may not be associated with PTB, while vitamin D deficiency in middle pregnancy is likely to have an important effect on PTB. Vitamin D levels should be measured in the second trimester of pregnancy, and vitamin D supplements should be provided if necessary., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Women living with HIV (WLHIV) have a higher prevalence of anemia than women without HIV, possibly related to the effects of HIV and antiretroviral medications., Objectives: To estimate the prevalence of anemia in the third trimester of pregnancy and the effect of anemia on preterm births in WLHIV in the longitudinal, US-based Pediatric HIV/AIDS Cohort Study (PHACS)., Methods: During the third trimester, we obtained up to three 24-hour dietary recalls to estimate daily intakes of nutrients and measured serum concentrations of iron, vitamin B6, vitamin B12, zinc, folate, ferritin, total iron-binding capacity (TIBC), and high sensitivity C-reactive protein. Third trimester anemia was defined as hemoglobin < 11 g/d and iron-deficiency anemia (IDA) was defined as low ferritin, high TIBC, and low transferrin saturation. A preterm birth was defined as birth at < 37 completed weeks of gestation, regardless of etiology. We fit separate modified Poisson regression models for each outcome (anemia, preterm birth) and each main exposure, adjusted for confounders, and report adjusted prevalence ratios (aPR) and 95% CIs., Results: Of the 267 WLHIV, 50% were anemic in the third trimester, of whom 43.5% (n = 57/131) had IDA. On average, women with anemia were younger, were more likely to be black, started antiretroviral medications in the second trimester, had a low CD4 count (<200 cells/mm3) early in pregnancy, and were less likely to meet recommended intakes for iron, B6, and folate. The prevalence of anemia was greater in WLHIV with a low CD4 count (aPR = 1.65; 95% CI: 1.20-2.27) and high HIV viral load (>10,000 copies/mL; aPR = 1.38; 95% CI: 1.02-1.87). In total, 16% of women delivered preterm. Anemia was associated with a 2-fold (aPR = 2.04; 95% CI: 1.12-3.71) higher prevalence of preterm births., Conclusions: Anemia is common in pregnant WLHIV, highlighting the need to address the underlying factors and clinical outcomes of anemia in this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aim: Several studies consider vitamin D deficiency as a modifiable risk factor for adverse pregnancy outcomes. However, there is no specific cut-off point for the serum level of this prohormone to identify high-risk pregnant women. This study aimed to determine the thresholds for the circulating levels of 25-hydroxyvitamin D (25(OH)D), associated with adverse pregnancy outcomes, including preterm labor, preeclampsia (PE), and gestational diabetes mellitus (GDM), using a generalized additive model., Methods: This is a descriptive and analytical cross-sectional study carried out on the data collected from the Khuzestan Vitamin D Deficiency Screening Program in Pregnancy. Of 1800 pregnant women, referred to the health centers of Masjed-Soleyman and Shushtar (Khuzestan Province, Iran), we used the data of 1763 pregnant women, whose serum vitamin D status during the third trimester of pregnancy was available. The datasets were randomly divided into training (70%) and validation (30%) subsets. The cut-off levels of 25(OH)D were identified for the low, moderate, and high risk of adverse pregnancy outcomes, according to generalized additive models (GAM) with smooth functions in the training data set. Then Generalized Linear Model (GLM), with logit link function was applied in the validation dataset to explore the relationships between the optimal vitamin D classification and adverse pregnancy outcomes after adjusting for the potential confounders., Results: The optimal cut-off levels of 25(OH)D for the high, moderate, and low risk of GDM were ≤16, 16-26, and >26 ng/mL, respectively. Also, the optimal cut-off points of 25(OH)D for the high, moderate, and low risk of preterm delivery were ≤15, 15-21, and >21 ng/mL, respectively. Finally, the corresponding values for the high, moderate, and low risk of PE were ≤15, 15-23, and >23 ng/mL, respectively. The models were well-calibrated, based on the Hosmer-Lemeshow test. Results of the adjusted generalized linear model showed a significant increasing trend in the risk of pregnancy outcomes by decreasing 25(OH)D levels., Conclusion: In the preconception period, a 25(OH)D cut-off level of >15 ng/mL is recommended for the prevention of adverse pregnancy outcomes., Competing Interests: Conflicts of Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Understanding of causal biology and predictive biomarkers are lacking for hypertensive disorders of pregnancy (HDP) and preterm birth (PTB). First-trimester serum specimens from 51 cases of HDP, including 18 cases of pre-eclampsia (PE) and 33 cases of gestational hypertension (GH); 53 cases of PTB; and 109 controls were obtained from the Global Alliance to Prevent Prematurity and Stillbirth repository. Metabotyping was conducted using liquid chromatography high resolution mass spectroscopy and nuclear magnetic resonance spectroscopy. Multivariable logistic regression was used to identify signals that differed between groups after controlling for confounders. Signals important to predicting HDP and PTB were matched to an in-house physical standards library and public databases. Pathway analysis was conducted using GeneGo MetaCore. Over 400 signals for endogenous and exogenous metabolites that differentiated cases and controls were identified or annotated, and models that included these signals produced substantial improvements in predictive power beyond models that only included known risk factors. Perturbations of the aminoacyl-tRNA biosynthesis, L-threonine, and renal secretion of organic electrolytes pathways were associated with both HDP and PTB, while pathways related to cholesterol transport and metabolism were associated with HDP. This untargeted metabolomics analysis identified signals and common pathways associated with pregnancy complications.

Adiponectin is an adipocyte-derived hormone that plays a critical role in energy homeostasis, mainly attributed to its insulin-sensitizing properties. Accumulating studies have reported that adiponectin concentrations are decreased during metabolic diseases, such as obesity and type 2 diabetes, with an emerging body of evidence providing support for its use as a biomarker for pregnancy complications. The identification of maternal factors that could predict the outcome of compromised pregnancies could act as valuable tools that allow the early recognition of high-risk pregnancies, facilitating close follow-up and prevention of pregnancy complications in mother and child. In this review we consider the role of adiponectin as a potential biomarker of disorders associated with pregnancy. We discuss common disorders associated with pregnancy (gestational diabetes mellitus, preeclampsia, preterm birth and abnormal intrauterine growth) and highlight studies that have investigated the potential of adiponectin to serve as biomarkers for these disorders. We conclude the review by recommending strategies to consider for future research.

Vitamin D deficiency during pregnancy has been linked to perinatal adverse outcomes. Studies conducted to date have recommended assessing interactions with other vitamin D-related metabolites to clarify this subject. We aimed to evaluate the association of vitamin D deficiency during early pregnancy with preterm birth. Secondary outcomes included low birth weight and small for gestational age. Additionally, we explored the role that parathyroid hormone, calcium and phosphorus could play in the associations. We conducted a prospective cohort study comprising 289 pregnant women in a hospital in Granada, Spain. Participants were followed-up from weeks 10-12 of gestation to postpartum. Serum 25-hydroxyvitamin D, parathyroid hormone, calcium, and phosphorus were measured within the first week after recruitment. Pearson's χ 2 test, Mann-Whitney U test, binary and multivariable logistic regression models were used to explore associations between variables and outcomes. 36.3% of the participants were vitamin D deficient (<20 ng/mL). 25-hydroxyvitamin D concentration was inversely correlated with parathyroid hormone (ρ = -0.146, p = 0.013). Preterm birth was associated with vitamin D deficiency in the multivariable model, being this association stronger amongst women with parathyroid hormone serum levels above the 80th percentile (adjusted odds ratio (aOR) = 6.587, 95% CI (2.049, 21.176), p = 0.002). Calcium and phosphorus were not associated with any studied outcome. Combined measurement of 25-hydroxyvitamin D and parathyroid hormone could be a better estimator of preterm birth than vitamin D in isolation.

Aims: To compare the effects of maternal subclinical hypothyroidism (SCH) diagnosed by the 2011 or 2017 "Guidelines of the American Thyroid Association (ATA) for the diagnosis and management of thyroid disease during pregnancy and the postpartum" during the first trimester on adverse pregnancy outcomes in thyroid peroxidase antibody (TPOAb)-negative pregnant women. Methods: There were 1,556 Chinese singleton pregnant women with negative TPOAb diagnosed with either SCH or euthyroidism who were investigated, and the prevalence and risk of obstetric outcomes were compared between the two groups using 2011 and 2017 ATA standards, respectively. The effects of a mildly elevated thyroid-stimulating hormone (TSH) concentration on adverse pregnancy outcomes were evaluated by binary logistic regression. Results: Maternal SCH identified by the 2011 ATA guidelines correlated with higher rates and risks of pregnancy-induced hypertension (PIH), preeclampsia, and low-birth-weight infants, while maternal SCH diagnosed by the 2017 ATA guidelines was more likely to develop PIH, preeclampsia, cesarean delivery, preterm delivery, placenta previa, and total adverse maternal and neonatal outcomes. Moreover, a mildly elevated TSH level was significantly associated with PIH after adjustment for confounding factors. Conclusions: Compared with the 2011 ATA guidelines, the 2017 ATA guidelines could be more applicable to Chinese pregnant women to screen the effects of SCH on the majority of adverse pregnancy outcomes., (Copyright © 2020 Li, Ma, Feng, Zhu, Yu, Ke, Zhang, Liu and Li.)

African American women have the highest rate of preterm birth (PTB; <37 completed weeks' gestation) of any racial and ethnic group in the United States (14.1%). Depressive symptoms (DS) have been linked to PTB risk of African American women. We hypothesized that maternal lipidomic profiles are related to prenatal DS and gestational age at birth among African American women. Women were enrolled at 9-25 weeks' gestation, completed questionnaires, and provided plasma samples. Lipidomic profiles were determined by "shotgun" Orbitrap high-resolution/accurate mass spectrometry. Data were analyzed using SIMCA P+ software. There was a clear separation in the orthogonal projections to latent structures discriminant analysis score plot between women with Center for Epidemiologic Studies Depression Scale (CES-D) scores ≥23 and women with CES-D scores ≤22. Similarly, a clear separation was observed in the model between PTB and full-term birth. Corresponding S-plot, loading plot, and variable importance in projection plot/list were used to identify the lipids responsible for the groupings. Higher levels of specific triglyceride (TG) species and lower levels of specific phosphatidylcholines (PCs) PC(37:1), PC(41:6), and PC(39:3) were associated with PTB. PC PC(37:1) levels were also lower among women with CES-D scores ≥23, pointing toward a possible connection between DS and PTB. Although overweight pregnant women showed higher levels of TGs, the PTB model showed specific TGs unique to PTB. Lipidomic profiles in pregnant African American women are related to DS, and our data suggest a role for specific TGs and PCs in PTB.

Background: Intrahepatic cholestasis of pregnancy (ICP) increases the risk of adverse pregnancy outcomes. This study aimed to explore the association between serum syndecan-1 and glypican-3 levels and the adverse perinatal outcome as well as the responses to the treatment of ursodeoxycholic acid (UDCA)., Methods: This prospective, case control study included 88 pregnant women (44 women with ICP and 44 healthy controls). The primary end points were the perinatal outcome and the response to UDCA therapy. A logistic regression model was used to identify the independent risk factors of adverse pregnancy outcomes and reduced response to UDCA therapy., Results: Women with ICP had significantly higher serum syndecan-1 (1.27 ± 0.36 ng/mL vs. 0.98 ± 0.50 ng/mL; P = 0.003), glypican-3 (1.78 ± 0.13 ng/mL vs.1.69 ± 0.16 ng/mL; P = 0.004), AST (128.59 ± 1.44 vs. 13.29 ± 1.32 U/L; P < 0.001), and ALT (129.84 ± 1.53 vs. 8.00 ± 3.67 U/L; P < 0.001) levels compared with the controls. The increased levels of syndecan-1 (OR = 4.715, 95% CI: 1.554-14.310; P = 0.006), glypican-3 (OR = 8.465, 95% CI: 3.372-21.248; P = 0.007), ALT (OR = 1.382, 95% CI: 1.131-1.690; P = 0.002), and postprandial bile acid (PBA) (OR = 3.392, 95% CI: 1.003-12.869; P = 0.026) were correlated to ICP. The adverse neonatal outcome was related to increased glypican-3 (OR = 4.275, 95% CI: 2.726-5.635; P = 0.039), and PBA (OR = 3.026, 95% CI: 1.069-13.569; P = 0.037). Increases of syndecan-1 (OR = 7.464, 95% CI: 2.130-26.153, P = 0.017) and glypican-3 (OR = 6.194, 95% CI: 2.951-13.002; P = 0.025) were the risk factors of decreased response to UDCA treatment., Conclusion: Syndecan-1 and glypican-3 might be powerful determinants in predicting adverse perinatal outcome in patients with ICP, and they can be used to predict the response to the UDCA treatment., (Copyright © 2020 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Vitamin D and calcium are essential micronutrients for reproductive success. Vitamin D deficiency during pregnancy is associated with increased risk of pregnancy complications including pre-eclampsia and preterm birth (PTB). However, inconsistencies in the literature reflect uncertainties regarding the true biological importance of vitamin D but may be explained by maternal calcium intakes. We aimed to determine whether low dietary consumption of calcium along with vitamin D deficiency had an additive effect on adverse pregnancy outcome by investigating placental morphogenesis and foetal growth in a mouse model. Female mice were randomly assigned to one of four diets: control-fed (+Ca+VD), reduced vitamin D only (+Ca-VD), reduced calcium only (-Ca+VD) and reduced calcium and vitamin D (-Ca-VD), and sacrificed at gestational day (GD) 18.5. Maternal serum 25-hydroxyvitamin D (25(OH)D 3 ) levels were lower in each reduced diet group when compared with levels in +Ca+VD-fed mice. While the pregnancy rate did not differ between groups, in the -Ca-VD-fed group, 55% (5 out of 9 pregnant of known gestational age) gave birth preterm (

Objective: During pregnancy, inhibin A is mainly derived from the placenta and regulates the implantation and differentiation of embryos. Our aim was to assess whether second trimester serum inhibin A was associated with an increased risk of adverse pregnancy outcomes., Methods: We investigated the serum levels of Inhibin A during the second trimester in pregnancy, and analyzed associations between the Inhibin A and the risk of adverse pregnancy outcome. 12,124 pregnant women were enrolled in this study between January 2017 and July 2019 at the Obstetrics & Gynecology Hospital of Fudan University. Multivariate logistic regression analysis was conducted to estimate the relative risk between Inhibin A and adverse pregnancy outcome., Results: Compared with the group without adverse pregnancy outcome, during the second trimester of pregnancy, age and Inhibin A were risk factors for pre-eclampsia, gestational diabetes mellitus and preterm delivery; Inhibin A was risk factors for low birth weight. Gravidity and Inhibin A were risk factors for macrosomia; while parity was a protective factor against pre-eclampsia, gestational hypertension and low birth weight., Conclusion: Elevated Inhibin A levels in pregnancy are significantly associated with pre-eclampsia, GDM, macrosomia, low birth weight and preterm delivery., Competing Interests: The authors have declared that no competing interests exist.

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

Background: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth., Methods: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134., Findings: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I 2 =59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001)., Interpretation: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery., Funding: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Inflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia., Study Design: A sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios., Results: Higher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia., Conclusions: Among women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth.

Objective: To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia., Study Design: Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC)., Results: Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822-0.959) training; 0.883 (0.804-0.963) testing)., Conclusion: Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia.

The isolated hypothyroxinemia of pregnancy (IHP) has gained specific attention in the specialized literature during the recent years as the possible factor impeding the intellectual development of fetus and increasing the risk of complications related with pregnancy, delivery and perinatal period. Aim of the study was to define the importance of isolated hypothyroxinemia in the development of obstetric and somatic pathologies in outpatient population of pregnant females. The study of prospective design was performed at the base of "David Gagua Clinic" Ltd. Based on hospital referral we selected the pregnant patients who were diagnosed for isolated hypothyroxinemia in the 1st trimester of pregnancy by clinical-laboratory studies. 104 pregnant females with isolated hypothyroxinemia were included in the main group, and 58 pregrant females of reproductive age who were not identified to have thyroid pathology by screening studies were included in the control group,. The questionnaire used in the study process included the retrospective medical history data, demographic findings, information about premorbid background, genetic burden of somatic pathology, social-economical factors (including education level, living conditions, economic income, family environment etc.) and concomitant somatic pathology. In addition, it included the clinical and para-clinical study data and pregnancy follow-up findings. The test studies for thyroid status were performed every trimester and after one month postpartum. The software packages Microsoft Excel (2010) and SPSS/v.12 was used for statistical treatment of data. The digital data is presented by M±STD, where M is the arithmetic mean and STD is the standard deviation of arithmetic mean. To define the confidence interval for the indices and their relation, we calculated 2 and p, whose critical value was defined to be 0.05. Based on analysis of the acquired data, we found out that pregnant females with isolated hypothyroxinemia were more statistically demonstrating asthenia, dry skin, increased hair loss and fragile nails, and from somatic disorders - pregnancy-associated vomiting and anemia. From concomitant diseases, allergic disorders (18.2%), primary dysmenorrhea (27.8%), spontaneous abortions (25%) were taking the highest incidence rate and other obstetric complications (premature delivery, late delivery) were higher in the main group, though statistically significant difference was not demonstrated. It must be noted that isolated hypothyroxinemia in the studied cohort was mostly found in 1st trimester of pregnancy, whereas according to the literature data, the latter is demonstrated more frequently in the second or third trimester. The above mentioned makes us consider that the iodine deficit in the cohort of pregnant females studied by us was probably present before pregnancy as well and maybe with even higher extent. Thus, the isolated hypothyroxinemia developed in the very first trimester of pregnancy still has its negative impact on the pregnancy course and outcome, despite of applied treatment. According to performed studies and their results, for the prevention of obstetric and perinatal complications, its important to administer iodine preparations together with folic acid at pregravid stage in addition to complete elimination of diet abnormalities, plan the pregnancy in stable normothyroxinemia conditions and at positive energetic balance. In addition, its desirable to perform the repeated thyroid status evaluation in the first trimester of pregnancy and timely administration of adequate therapeutic measures in case of finding any pathology.

Context: Overt thyroid disease in pregnancy is a known risk factor for abnormal fetal growth and development. Data on the effects of milder forms of variation in maternal thyroid function on intrauterine growth are less well examined., Objective: We explored these associations using repeated thyroid hormone and ultrasound measurements., Design, Setting, and Participants: Data were obtained from 439 pregnant women without diagnosed thyroid disease who were participants in a case-control study of preterm birth nested within an ongoing prospective birth cohort in Boston, Massachusetts., Main Outcome Measures: Ultrasound and delivery indices of fetal growth were standardized to those measured in a larger population., Results: At median 10, 18, and 26 weeks of gestation, we observed significant inverse associations between free thyroxine (FT4) and birth weight z scores, with the strongest association detected at median 10 weeks, at which time a 10% increase in FT4 was associated with a 0.02 z score decrease (∼8.5 g) in birth weight (β = -0.41 for ln-transformed FT4; 95% confidence interval, -0.64 to -0.18). FT4 was also inversely associated with repeated measurements of estimated fetal weight, head circumference, and abdominal circumference. We observed weaker inverse associations for total T4 and a positive relationship between total triiodothyronine and birth weight z scores. We did not observe any associations for thyroid-stimulating hormone., Conclusion: In pregnant women without overt thyroid disease, subclinical changes in thyroid function parameters may influence fetal growth.

Background: Preterm delivery (PTD) may be characterized by altered interrelationships among angiogenic factors and measures of placental function. We analyzed the longitudinal relationship between maternal serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt1), an important antiangiogenic factor, and uterine artery resistance in pregnancies resulting in preterm and term deliveries., Methods: Data were collected in a longitudinal cohort study involving 278 women monitored at 6 to 10, 10 to 14, 16 to 20, 22 to 26, and 32 to 36 weeks of gestation. Concentrations of maternal serum sFlt1 were determined using solid-phase enzyme-linked immunosorbent assay, and uterine artery resistance indices (RI) were measured by Doppler velocimetry at each interval. Preterm delivery was defined as birth before 37-weeks completed gestation. Data analyses used multivariable repeated measures regression models., Results: Uterine artery RI decreased across gestation. As pregnancy progressed, RI trajectories diverged for term and preterm deliveries; the mean RI was significantly higher in third trimester for pregnancies resulting in PTD ( P = .08). sFlt1 was stable through 21 3/7 weeks of gestation and then increased rapidly; women who delivered preterm had significantly higher sFlt1 levels in the third trimester ( P = .04). The relationship between uterine artery RI and sFlt1 from the prior visit was significantly different between the groups ( P < .0001). For term deliveries, higher sFlt1 concentrations were associated with a smaller RI at the subsequent visit (β = -.08, 95% confidence interval [CI]: -0.14 to -0.02). For PTD, higher sFlt1 concentrations were associated with a larger uterine artery RI (β = .14, 95% CI: 0.06 to 0.22)., Conclusion: PTD is characterized by altered relationships between angiogenic factors and placental vascular blood flow starting in early pregnancy.

Pregnancy is a delicate balance of angiogenic factors. Adverse pregnancy outcomes in the form of placental insufficiency occur when antiangiogenic factors predominate, which manifests as maternal-placental syndrome (MPS). Women with rheumatic disease are at increased risk of MPS. Endothelial damage from circulating antiangiogenic factors and other inflammatory molecules in combination with preexisting maternal vascular risk factors is the likely underlying pathophysiological process for MPS. It is likely that these changes persist, and additional "insults" from ongoing inflammation, medications, and disease damage contribute to the development of accelerated cardiovascular disease seen in young women with rheumatic disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: This study is designed to evaluate predictive value of first-trimester cystatin C levels for long-term pregnancy complications., Methods: The cross-sectional study population consisted of patients who admitted to outpatient clinic of a Maternity Hospital between September 2013 and December 2014. Among the 203 participants who accepted to participate in the study, 174 subjects who continued antenatal follow-up in the same clinic were included in the final analyses. Cystatin C, blood urea nitrogen, Creatinine levels and estimated glomerular filtration rates were evaluated in the first-trimester routine antenatal visit. Mode of delivery and gestational complications were noted., Results: First-trimester cystatin C levels were significantly higher in cases complicated with preterm delivery and premature rupture of membrane (PROM) compared to uncomplicated ones (0.58±0.07 vs. 0.55±0.07, P=0.041, and 0.58±0.07 vs. 0.55±0.07, P=0.036). With a cutoff value of 0.505 mg/L, sensitivity of cystatin C for preterm delivery and PROM was 91.9% and specificity was 27.7% with a negative predictive value of 92.3% and a positive predictive value of 26.6%., Conclusion: Detection of cystatin C levels in the first trimester of pregnancy for the prediction of preterm/PROM seems as a promising preliminary data. The relatively higher first-trimester cystatin C levels in complicated pregnancies are conspicuous. The results imply that in pregnancy cystatin C might be more than a marker for renal function.

Objective: To evaluate whether pregnancy-associated hypertension (preeclampsia or gestational hypertension) among women with varying degrees of glucose intolerance during pregnancy is associated with maternal metabolic syndrome 5-10 years later., Methods: This was an observational cohort study of women previously enrolled in a treatment trial of mild gestational diabetes mellitus or an observational study of lesser degrees of glucose intolerance evaluated 5-10 years after their index pregnancy. At follow-up, women underwent anthropometric and blood pressure measurements and analysis of fasting glucose and serum lipids., Results: A total of 825 women (47% of eligible women from the original study) were included in this analysis and evaluated at a median 7 years after their index pregnancy at a median age of 35 years. Overall, 239 (29%) had subsequent metabolic syndrome. The frequency of metabolic syndrome and its components was highest in the women who had pregnancy-associated hypertension and delivered preterm. After adjusting for confounding factors, pregnancy-associated hypertension in women who delivered preterm was associated with subsequent hypertension (130/85 mm Hg or greater; relative risk 3.06, 95% confidence interval [CI] 1.95-4.80, P<.001), high triglycerides (150 mg/dL or greater; relative risk 1.82, 95% CI 1.06-3.14, P=.03), and metabolic syndrome (per the American Heart Association and National Heart Lung and Blood Institute Scientific Statement; relative risk 1.78, 95% CI 1.14-2.78, P=.01) compared with women who remained normotensive throughout their index pregnancy and were delivered at term., Conclusion: Women with varying degrees of glucose intolerance who experienced pregnancy-associated hypertension and then delivered preterm had a higher frequency of subsequent hypertension, high triglycerides, and metabolic syndrome 5-10 years later.

Objectives: Identify applications and utility of serum markers dosed in the first trimester in predicting, early diagnosis and management of various complications of pregnancy., Methods: Eight hundred and eighty patients were included in this prospective regional study performed in the governorate of Bizerte in northern Tunisia in collaboration between the private and public sectors. Serum markers of the first quarter, PAPP A and βhCG, were measured in the same laboratory. The performance of these markers was studied in the prediction of adverse pregnancy complications., Results: The prevalence of various pregnancy complications was 8.6% for birth prematurely, 9.2% for hypertension or preeclampsia, IUGR 5.8% and 7.3% for loss pregnancy. PAPP A levels were lower in fetal loss group (P=0.005), vascular disease group (P=0.001) and preterm delivery group (P=0.001). In addition, a lower rate of βhCG was associated with the occurrence of placental pathologies such as growth retardation (P=0.037) and hypertension (P=0.034) and appears to have no predictive value in the occurrence of preterm birth (P=0.76) and fetal loss (P=0.189). Logistic regression analysis showed a significant predictive value of these markers., Conclusion: Serum markers of the first trimester appear to have adequate predictive validity of adverse pregnancy complications. A risk predictive model could be designed based on these markers and involving maternal and ultrasound features in order to target prophylactically a high risk population., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A cause is proposed for several forms of reproductive suboptimality (viz foetal loss, preterm birth and low birth weight). The point is illustrated here in the case of miscarriage. I suggest that all these forms of reproductive suboptimality are partially caused by high levels of stress-related maternal adrenal androgens. The argument is supported by both experimental and epidemiological data., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: In early pregnancy, maternal transfer of thyroxine (T4) significantly contributes to the foetal T4 requirements. Interruption of the maternal transfer of T4 may lead to inadequate T4 exposure, potentially leading to neurodevelopmental deficits., Aim: To determine if maternal factors are associated with the thyroid hormone status of extremely premature infants during the first five days of life., Method: This prospective study looked at 117 mothers and their extremely premature babies (born before 28 weeks' gestation). The relationship between neonatal thyroid hormone status and maternal factors (gestation, route of delivery, exogenous maternal glucocorticoid administration, maternal free T4 (FT4), presence or absence of maternal chorioamnionitis, maternal smoking status, maternal body mass index (BMI) index, maternal thyroid peroxidase antibody status (TPO) and maternal haemoglobin levels) were evaluated. Multiple linear regression was used to study independent factors affecting neonatal thyroid function., Results: Mean gestational age was 25(+5) ± 1.3 weeks (range 22(+0) to 27(+6)). Neonatal FT4 strongly correlated with gestation, with a greater severity of hypothyroxinaemia associated with lower gestation (r = 0.6, p < 0.0001). Multiple regression found gestation to be the only independent factors affecting thyroid status (beta coefficient = 0.08, p = 0.01), and no maternal factors were found to be associated with neonatal thyroid status., Conclusion: Neonatal thyroid status in extreme preterm infants is independently affected by gestation and not maternal factors such as route of delivery, exogenous maternal glucocorticoid administration, third trimester maternal FT4, presence or absence of chorioamnionitis, smoking status, BMI, TPO status or haemoglobin levels. The severity of neonatal hypothyroxinaemia increases with lower gestational age.

Objective: The objective of the study was to determine whether pregnancies resulting in early preterm birth (PTB) (<30 weeks) were more likely than term pregnancies to have elevated midtrimester serum tumor necrosis factor alpha (TNF-α) levels combined with lipid patterns suggestive of hyperlipidemia., Study Design: In 2 nested case-control samples drawn from California and Iowa cohorts, we examined the frequency of elevated midpregnancy serum TNF-α levels (in the fourth quartile [4Q]) and lipid patterns suggestive of hyperlipidemia (eg, total cholesterol, low-density-lipoproteins, or triglycerides in the 4Q, high-density lipoproteins in the first quartile) (considered independently and by co-occurrence) in pregnancies resulting in early PTB compared with those resulting in term birth (n = 108 in California and n = 734 in Iowa). Odds ratios (ORs) and 95% confidence intervals (CIs) estimated in logistic regression models were used for comparisons., Results: Early preterm pregnancies were 2-4 times more likely than term pregnancies to have a TNF-α level in the 4Q co-occurring with indicators of hyperlipidemia (37.5% vs 13.9% in the California sample (adjusted OR, 4.0; 95% CI, 1.1-16.3) and 26.3% vs 14.9% in the Iowa sample (adjusted OR, 2.7; 95% CI, 1.1-6.3). No differences between early preterm and term pregnancies were observed when TNF-α or target lipid abnormalities occurred in isolation. Observed differences were not explicable to any maternal or infant characteristics., Conclusion: Pregnancies resulting in early PTB were more likely than term pregnancies to have elevated midpregnancy TNF-α levels in combination with lipid patterns suggestive of hyperlipidemia., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: The aims were to establish a gestational-age specific curve for serum total thyroxine (T4) levels and to compare pregnancy outcomes of euthyroid women with those identified to have subclinical hypothyroidism (SCH) defined by an elevated thyroid-stimulating hormone (TSH) level in conjunction with either total T4 or free T4 determinations., Study Design: Over a 2.5 year period, serum thyroid analytes were measured in all women presenting for prenatal care. After exclusion of women with overt thyroid disorders, the normal distribution of serum total T4 levels were determined by quantile curves for those screened in the first 20 weeks and who were delivered of a singleton infant weighing at least 500 g. Pregnancy outcomes for women with an elevated TSH and normal total T4 concentrations were analyzed and compared with those of women identified to have SCH defined by normal free T4 levels., Results: Of 17,298 women tested, serum total T4 increased into the second trimester and plateaued around 16 weeks. The upper threshold for total T4 ranged from 12.6 to 16.4 μg/dL, and the lower threshold ranged from 5.3 to 8.0 μg/dL. Women identified to have SCH defined by serum free T4, total T4, or both were at risk for preterm delivery (P = .007) and placental abruption (P = .013) when compared with euthyroid women., Conclusion: When combined with elevated TSH levels, free or total T4 determinations are equally sensitive to identify women with SCH who are at increased risk for preterm birth and placental abruption when compared with euthyroid women., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background/objectives: Observational studies relating 25-hydroxyvitamin D (25(OH)D) and pregnancy outcomes have reported conflicting results. The aim was to assess maternal 25(OH)D status and its association with pregnancy outcomes. A prospective observational study was carried out in Guangzhou city (23 ºN), China., Subjects/methods: Pregnant women (n=2960) and healthy controls (n=100) were recruited at a teaching hospital. Maternal 25(OH)D levels were measured at 16-20-week gestation. The pregnant women, if met inclusion and exclusion criteria, were enrolled in further analysis for pregnancy outcomes (n=1953)., Results: Mean serum 25(OH)D in pregnant women was 27.03±7.92 ng/ml. In total, 18.9 and 48.6% of pregnant women had low (25(OH)D less than or equal to 20 ng/ml) and medium level (25(OH)D 21-29 ng/ml) of vitamin D, respectively. 25(OH)D was highest in summer and lowest in winter, which showed a positive correlation with temperature (R=0.942) and calcium (R=0.074). Most maternal outcomes (premature rupture of membranes break, polyhydramnios, oligohydramnios, pre-eclampsia, cesarean section), fetal outcomes (spontaneous abortions, medically induced labor, fetal death, fetal distress, fetal growth restriction) and neonatal outcomes (malformations, birth weight and height, low birth weight, macrosomia, small-for-gestational age, score of Apgar 1',5', asphyxia of newborn) were not significantly different between groups, but prevalence of gestational diabetes (adjusted odds ratio (OR) 1.017; 95% confidence interval (CI) 1.002-1.033) and preterm delivery (adjusted OR 1.038; 95% CI 1.018-1.059) in high level group (25(OH)D ⩾30 ng/ml) was higher than that in low and medium level groups., Conclusions: The prevalence of low level of vitamin D (serum 25OHD ⩽20 ng/ml) was 18.9% among pregnant women in southern China. There were no significant differences in most adverse pregnancy outcomes among pregnant women with different levels of vitamin D at 16-20-week gestation except for higher prevalence of gestational diabetes and preterm delivery in women with high level of vitamin D, possibly related to the older age and higher body mass index of this group.

Background: To assess the association of maternal hyperuricemia with adverse pregnancy outcome and neonatal metabolic, neurologic and respiratory disturbances in normotensive singleton pregnant women., Method: This prospective multicentric cohort study was conducted on 404 normotensive singleton pregnant women who were admitted for delivery in Vali-Asr and Akbar-Abadi teaching hospitals of Tehran University of Medical Sciences, Tehran, Iran. Upon enrollment maternal and umbilical sera were obtained for determining uric acid levels. 1 and 5 minutes Apgar scores, the need for neonatal resuscitation and neonatal intensive care unit (NICU) admission were recorded. In case of NICU admission a neonatal blood sample was drawn for determining uric acid, blood sugar and bilirubin levels. An intracranial ultrasound imaging was also carried out for the admittd neonates for detecting intraventricular hemorrhage., Results: Maternal hyperuricemia (uric acid one standard deviation greater than the appropriate gestational age) was independently associated with preterm birth (odds ratio (OR), 3.17; 95% confidence interval (CI), 2.1 - 4.79), small for gestational age delivery (OR, 1.28; 95% CI, 1.04 - 2.57), NICU admission (OR, 1.65; 95% CI, 1.12 - 2.94) and neonatal IVH (OR, 8.14; 95% CI, 1.11 - 87.1)., Conclusions: Maternal hyperuricemia in normotensive singleton pregnant women is significantly associated with preterm and SGA delivery and the development of neonatal IVH.

Objective: This study aimed to investigate the relationship between maternal serum pregnancy-associated plasma protein-A (PAPP-A) in the first trimester of pregnancy and the development of preeclampsia (PE), early PE, small-for-gestational age (SGA) fetus and preterm delivery (PD)., Method: This is a retrospective study of 12,355 pregnant women that delivered between 2008 and 2011. We define the first, third and fifth percentiles of maternal serum PAPP-A multiples of the median (MoM). The primary outcome measures were the occurrence of PE, early PE (PE requiring delivery before 34 weeks), SGA fetus (birth weight < 5th centile) and PD. The Mann-Whitney U-test and chi-squared test were used to analyze continuous and dichotomous variables, respectively., Results: Maternal serum PAPP-A was significantly lower in women with PE, early PE, SGA fetus and PD (0.91, 0.74, 0.80 and 0.84 MoM, respectively) than in the study population (0.99 MoM) (p < 0.05). The lower the MoM percentile of PAPP-A, the higher are the odds ratio (OR) to develop PE, early PE, SGA fetus and PD., Conclusions: Maternal serum PAPP-A levels are lower in women who develop preeclampsia, those with SGA fetus and those who deliver preterm. However, on its own, maternal serum PAPP-A performs poorly (OR for PE between 1.76 and 2.41 with the lower percentile of PAPP-A) as a screening test for these conditions., (© 2013 John Wiley & Sons, Ltd.)

Elevated levels of homocysteine produce detrimental effects in humans but its role in preterm birth is not known. Here we used a mouse model of hyperhomocysteinemia to examine the relevance of homocysteine to preterm birth. The mouse carries a heterozygous deletion of cystathionine β-synthase (Cbs(+/-)). Gestational period was monitored in wild type and Cbs(+/-) female mice. Mouse uterine and placental tissues, human primary trophoblast cells, and human myometrial and placental cell lines were used to determine the influence of homocysteine on expression of specific genes in vitro. The activity of BKCa channel in the myometrial cell line was monitored using the patch-clamp technique. We found that hyperhomocysteinemia had detrimental effects on pregnancy and induced preterm birth in mice. Homocysteine increased the expression of oxytocin receptor and Cox-2 as well as PGE2 production in uterus and placenta, and initiated premature uterine contraction. A Cox-2 inhibitor reversed these effects. Gpr109a, a receptor for niacin, induced Cox-2 in uterus. Homocysteine upregulated GPR109A and suppressed BKCa channel activity in human myometrial cells. Deletion of Gpr109a in Cbs(+/-) mice reversed premature birth. We conclude that hyperhomocysteinemia causes preterm birth in mice through upregulation of the Gpr109a/Cox-2/PGE2 axis and that pharmacological blockade of Gpr109a may have potential in prevention of preterm birth., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To examine the possible relationship between maternal and fetal characteristics and pregnancy outcomes on fetal and maternal cell-free (cf) DNA in maternal plasma at 11-13 weeks' gestation., Methods: cfDNA was extracted from maternal plasma of 1,949 singleton pregnancies and chromosome-selective sequencing was used to determine the proportion of cfDNA and total cfDNA counts which was of fetal and maternal origin. Multivariate regression analysis was used to determine whether specific maternal and fetal characteristics and pregnancy complications, such as preeclampsia (PE), early spontaneous preterm birth (SPB) and delivery of small for gestational age (SGA) neonates, were significant predictors of fetal and maternal cfDNA in maternal plasma., Results: The fetal and maternal cfDNA plasma concentration increased with serum pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin level, was higher in women of Afro-Caribbean and East-Asian racial origin than in Caucasians, and lower in smokers, but it was not significantly altered in pregnancies complicated by PE, SPB or SGA. The fetal cfDNA level was inversely related to maternal weight and uterine artery pulsatility index, and maternal cfDNA increased with maternal weight., Conclusions: The fetal and maternal cfDNA level in maternal plasma is affected by maternal and fetal characteristics, but it is not altered in pregnancy complications., (Copyright © 2013 S. Karger AG, Basel.)

Objective: To evaluate the effect of connective tissue disease (CTD) diagnosed during the first trimester on uterine arteries (UtA) Doppler velocities and on pregnancy outcomes., Method: Pregnant women were screened for CTDs during the first trimester, using a questionnaire, testing for autoantibodies, rheumatologic examination and UtA Doppler evaluations., Results: Out of 3932 women screened, 491 (12.5%) were screened positive at the questionnaire; of them, 165(33.6%) tested positive for autoantibodies, including 66 eventually diagnosed with undifferentiated connective tissue disease (UCTD), 28 with a definite CTD and 71 with insufficient criteria for a diagnosis. Controls were 326 women screened negative for autoantibodies. In logistic analysis, women diagnosed with either UCTD (OR = 7.9, 95% CI = 2.3-27.3) or overt CTD (OR = 24.9, 95% CI = 6.7-92.4), had increased rates of first trimester bilateral UtA notches compared with controls. The rates of bilateral UtA notches persisting in the second (15/94 vs 0/326, p < 0.001) and third trimesters (7/94 vs 0/326, p < .001) were higher among women with CTDs than in controls. The risk of complications (preeclampsia, fetal growth restriction, prematurity, diabetes, fetal loss) was higher (OR = 7.8, 95% CI = 3.6-17.0) among women with CTDs than in controls., Conclusion: Women with undiagnosed CTDs have higher rates of bilateral UtA Doppler notches throughout pregnancy and increased rates of adverse pregnancy outcomes than controls., (© 2012 John Wiley & Sons, Ltd.)

Objective: Determine whether elevated second trimester maternal serum α-fetoprotein (AFP) is associated with clinical and histopathologic markers of inflammation at preterm delivery., Methods: 105 women <32 weeks' gestation were included. AFP levels were dichotomized at 2.0 multiples of the median (MoM). Rates of neonatal morbidities, clinical chorioamnionitis, cord blood IL-6 level, and placental inflammatory findings were compared., Results: Thirteen (12.4%) had elevated AFP. Fewer women with AFP ≥ 2 MoM had histologic placental or membrane rupture site inflammation, funisitis, or placental culture positive for Mycoplasma and Ureaplasma species, compared to those with normal AFP. Neonatal death was increased in the elevated AFP group (23.1% vs. 2.27%, RR 10.6). Elevated AFP was associated with a nonsignificant increase in indicated birth (54% vs. 35%; p = 0.225). Virtually all inflammatory findings were confined to the spontaneous delivery group., Conclusion: Elevated midtrimester AFP conveyed significant risk of neonatal death, but was negatively associated with clinical or histopathologic inflammation in preterm infants.

Background: Pre-eclampsia, small-for-gestational-age infants, preterm birth and recurrent miscarriage complicate a significant number of pregnancies. The vascular endothelial growth factor (VEGF) family of angiogenic growth factors is implicated in the pathophysiology of these complications. We aimed to elucidate the role of these angiogenic factors in placentation and to evaluate the predictive value of their protein concentrations and genetic variations in pregnancy complications., Methods: We performed a systematic search of PubMed, and retrieved original articles. The search included a combination of terms such as VEGF-A, placental growth factor (PlGF), kinase insert domain receptor, fms-like-tyrosine-kinase receptor 1, soluble fms-like-tyrosine-kinase receptor 1, pre-eclampsia, small-for-gestational-age infants, preterm birth, recurrent miscarriage, placenta, prediction and polymorphisms., Results: This review summarizes the current knowledge of the roles of the VEGF family in early placentation and of the abnormalities in maternal plasma and placental expression of angiogenic proteins in adverse pregnancy outcomes compared with normal pregnancy. PlGF and sFLT-1 in combination with other clinical and biochemical markers in late first or second trimester appear to predict early-onset pre-eclampsia with a high sensitivity and specificity. However, VEGF family proteins do not have sufficient power to accurately predict late-onset pre-eclampsia, small-for-gestational age pregnancies or preterm birth. Functional polymorphisms in these angiogenic genes are implicated in pregnancy complications, but their contribution appears to be minor., Conclusions: Although the VEGF family has important roles in normal and complicated pregnancy, the current predictive value of the VEGF family as biomarkers appears to be limited to early-onset pre-eclampsia.

Objective: To investigate the association between maternal oxidative stress at mid-gestation and subsequent development of pregnancy complications., Study Design: A total of 503 healthy pregnant women provided their blood and urine samples at 24 to 26 weeks of gestation and were prospectively followed through postpartum. These samples were used to assess a variety of oxidative stress markers, including plasma total antioxidant capacity, 8-isoprostane, erythrocyte glutathione peroxidase and superoxide dismutase activity, and urinary 8-hydroxydeoxyguanosine (8-OHdG)., Results: Compared with women with uncomplicated pregnancies, significantly higher plasma 8-isoprostane levels were noted in women who developed preeclampsia (P = .008) and small-for-gestational age infants (P = .002), while higher urinary 8-OHdG concentrations were noted in women who subsequently had low-birth-weight neonates (<2500 g, P = .043)., Conclusion: Increased maternal oxidative stress at mid-gestation was associated with subsequent pregnancy complications.

Background: Spontaneous preterm birth (SPB, before 37 gestational weeks) is a major cause of perinatal mortality and morbidity, but its pathogenesis remains unclear. Studies on SPB have been hampered by the limited availability of markers for SPB in predelivery clinical samples that can be easily compared with gestational age-matched normal controls. We hypothesize that SPB involves aberrant placental RNA expression, and that such RNA transcripts can be detected in predelivery maternal plasma samples, which can be compared with gestational age-matched controls., Principal Findings: Using gene expression microarray to profile essentially all human genes, we observed that 426 probe signals were changed by >2.9-fold in the SPB placentas, compared with the spontaneous term birth (STB) placentas. Among the genes represented by those probes, we observed an over-representation of functions in RNA stabilization, extracellular matrix binding, and acute inflammatory response. Using RT-quantitative PCR, we observed differences in the RNA concentrations of certain genes only between the SPB and STB placentas, but not between the STB and term elective cesarean delivery placentas. Notably, 36 RNA transcripts were observed at placental microarray signals higher than a threshold, which indicated the possibility of their detection in maternal plasma. Among them, the IL1RL1 mRNA was tested in plasma samples taken from 37 women. It was detected in 6 of 10 (60%) plasma samples collected during the presentation of preterm labor (≤32.9 weeks) in women eventually giving SPB, but was detected in only 1 of 27 (4%) samples collected during matched gestational weeks from women with no preterm labor (Fisher exact test, p = 0.00056)., Conclusion: We have identified 36 SPB-associated RNA transcripts, which are possibly detectable in maternal plasma. We have illustrated that the IL1RL1 mRNA was more frequently detected in predelivery maternal plasma samples collected from women resulting in SPB than the gestational-age matched controls.

Background/aims: The aim of this study was to determine the incidence, obstetrical and fetal complication rates of intrahepatic cholestasis of pregnancy in patients managed actively around 38 weeks and evaluate the correlation of these results with liver function tests and bile acids., Material and Methods: In this cohort study 3710 women were booked for delivery, of which 32 pregnant women were diagnosed as intrahepatic cholestasis of pregnancy. All data concerning obstetric- medical history, laboratory results, symptom onset time, pruritus degree, treatment response, and delivery time and infants information were recorded in the study protocol. Statistical analyses were conducted with SPSS 12.0 version and correlations were assessed by Spearman Rank correlation analysis., Results: The incidence of intrahepatic cholestasis of pregnancy was 0.86%. The symptoms appeared around 32 weeks. 16.6% multiparas had a previously affected pregnancy and 21.8% of intrahepatic cholestasis of pregnancy patients had family history of intrahepatic cholestasis of pregnancy. Symptom onset varied according to season (p<0.05). Most patients (69.5%) were diagnosed in winter and the beginning of spring. There were no reported cases of clinical maternal jaundice, bleeding tendency or stillbirth. Pruritus was decreased by ursodeoxycholic acid treatment. Total bile acids tended to be higher in patients with preterm delivery (r=0.409, p=0.038)., Conclusion: Total bile acids are correlated with preterm delivery. An attempt to deliver at around 38 weeks may improve perinatal outcome.

Objective: To analyse the pregnancy outcome by combining plasma homocysteine with uterine artery Doppler velocimetry at 11 to 14 weeks of gestation., Method: A prospective cohort study with 103 healthy pregnant women. Uterine artery Doppler velocimetry was performed at between 11 and 14 weeks of gestation. Abnormal blood flow was defined as average pulsatility index >1.5 and presence of unilateral or bilateral diastolic notch. Doppler scores were calculated by a modified scoring method of uterine artery flow velocity waveforms. Serum for measurement of homocysteine, vitamin B(12) and folate levels were collected when the ultrasonographic measurement was performed., Results: Pre-eclampsia developed in five, gestational hypertension in three, intrauterine growth restriction in two and preterm birth in eight patients. There was a significant difference between mean plasma homocysteine levels at different Doppler scores (p<0.001) and a weak positive correlation between Doppler scores and occurrence of pregnancy complications (r(s) = 0.232, p<0.05). Mean homocysteine level increased with increasing Doppler scores. Any uterine artery abnormality had a sensitivity of 88.9% in predicting obstetric complications. Addition of hyperhomocytenemia to Doppler scores did not change the sensitivity., Conclusion: Maternal serum homocysteine level is increased in 11 to 14 weeks of gestation that is complicated with pre-eclampsia, gestational hypertension, intrauterine growth restriction and preterm birth. Addition of homocysteine determination to uterine artery Doppler in the first trimester does not add any advantage in predicting adverse perinatal outcome., (Copyright © 2011 John Wiley & Sons, Ltd.)

We assessed if first-trimester vitamin D deficiency is more prevalent in women who experienced a spontaneous preterm birth compared with women who delivered at term. We conducted a nested case-control study of pregnant women who had previously given blood for first-trimester combined screening for trisomy 21 and subsequently delivered at a tertiary hospital between November 2004 and July 2009. From an overall cohort of 4225 women, 40 cases of spontaneous preterm birth (≥ 23 (0/7) and ≤ 34 (6/7) weeks) were matched by race/ethnicity with 120 women delivering at term (≥ 37 (0/7) weeks) with uncomplicated pregnancies. Banked maternal serum was used to measure maternal 25-hydroxyvitamin D [25(OH)D]. The prevalence of first-trimester maternal vitamin D deficiency [25(OH)D < 50 nmol/L] was comparable among women who subsequently delivered preterm compared with controls (7.5% versus 6.7%, P  = 0.90). The median 25(OH)D level for all subjects was 89 nmol/L (interquartile range, 73 to 106 nmol/L). Seventy-three percent (117/160) of the cohort had sufficient vitamin D levels [25(OH)D ≥ 75 nmol/L]. In a cohort of pregnant women with mostly sufficient levels of first-trimester serum 25(OH)D, vitamin D deficiency was not associated with spontaneous preterm birth., (© Thieme Medical Publishers.)

Objectives: To evaluate plasma endothelin-1 (ET-1) and fetuin-A concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and to determine whether there is any association between these parameters and fetal asphyxia., Methods: We carried out a prospective case-control study consisting of 32 women with ICP at third trimester of pregnancy and 32 pregnant women without ICP. Blood samples from maternal peripheral venous circulation were collected and ET-1 and fetuin-A levels were determined from the plasma samples. Pulse-wave Doppler and Apgar scores were also recorded., Results: ET-1 concentrations were significantly higher in ICP patients. No difference was observed in fetuin-A levels between the two groups. Six newborns were declared as asphyctic (APGAR score at the 5 min <7). Maternal ET-1 levels did not correlate with the APGAR score at 5 min, total bile acid (TBA) and umbilical artery systolic/diastolic ratio with ICP patients. TBA levels were positively correlated with umbilical artery systolic/diastolic ratio negatively correlated with APGAR score at the 1' and 5'-Apgar score in all subjects. Plasma ET-1 concentration was higher in the preterm neonates of mothers with ICP compared with normal term neonates of mothers., Conclusions: Although these data did not show evidence that maternal ET-1 would be associated with fetal distress, we can speculate that maternal ET-1 may be playing a role in the underlying pathology regarding microvascular dysfunction especially in the preterm neonates of mothers with ICP. Elevated TBA levels may increase the risk of asphyxia whereas fetuin-a (as an anti-inflammation marker) does not seem to have effect in women with ICP.

Background: The purposes of this study were to determine: 1) if periodontal treatment in pregnant women before 21 weeks of gestation alters levels of inflammatory mediators in serum; and 2) if changes in these mediators are associated with birth outcomes., Methods: A total of 823 pregnant women with periodontitis were randomly assigned to receive scaling and root planing before 21 weeks of gestation or after delivery. Serum obtained between 13 and 16 weeks, 6 days (study baseline) and 29 to 32 weeks of gestation was analyzed for C-reactive protein; prostaglandin E(2); matrix metalloproteinase-9; fibrinogen; endotoxin; interleukin (IL)-1 beta, -6, and -8, and tumor necrosis factor-alpha. Cox regression, multiple linear regression, and the t, chi(2), and Fisher exact tests were used to examine associations among the biomarkers, periodontal treatment, and gestational age at delivery and birth weight., Results: A total of 796 women had baseline serum data, and 620 women had baseline and follow-up serum and birth data. Periodontal treatment did not significantly alter the level of any biomarker (P >0.05). Neither baseline levels nor the change from baseline in any biomarker were significantly associated with preterm birth or infant birth weight (P >0.05). In treatment subjects, the change in endotoxin was negatively associated with the change in probing depth (P <0.05)., Conclusions: Non-surgical mechanical periodontal treatment in pregnant women, delivered before 21 weeks of gestation, did not reduce systemic (serum) markers of inflammation. In pregnant women with periodontitis, levels of these markers at 13 to 17 weeks and 29 to 32 weeks of gestation were not associated with infant birth weight or a risk for preterm birth.

Background: To compare procalcitonin (PCT) concentrations between maternal blood and levels in umbilical cord or venous blood of neonates who were born with or without infection., Methods: Forty-six women with singleton pregnancies, complicated by premature rupture of membranes, preterm delivery and/or chorioamnionitis, were enrolled in this study. The study group comprised 15 patients and their infected newborns. The control group consisted of 31 women and their healthy newborns. We compared PCT concentrations between maternal, umbilical cord and neonatal serum, in both study and control groups. Additionally, PCT levels were compared between the corresponding compartments., Results: PCT concentrations in the umbilical cord and venous blood in infected newborns, but not in non-infected neonates, were significantly higher than maternal serum PCT levels. PCT concentrations of mothers who delivered infected newborns were comparable to those in the controls. However, PCT concentrations in the umbilical cord and in the venous blood of the infected newborns were higher than in healthy newborns., Conclusion: Measurement of maternal PCT concentration during labor does not contribute to early prediction of infection in the neonate. However, umbilical cord PCT concentrations, as well as its neonatal venous levels on the second day of life, seem to be related to intrauterine infection, and may be a useful tool in the diagnosis of early neonatal infection.

Objective: The purpose of this study was to determine whether maternal serum levels of pregnancy-associated plasma protein A, free-beta subunit human chorionic gonadotropin, or nuchal translucency size are associated with obstetric complications., Study Design: Data were obtained from the First and Second Trimester Evaluation of Risk trial. Pregnancy-associated plasma protein A and free-beta subunit human chorionic gonadotropin levels were analyzed, and nuchal translucency was measured between 10 weeks 3 days and 13 weeks 6 days of gestation in 34,271 pregnancies., Results: Women with pregnancy-associated plasma protein A of < or =5th percentile were significantly more likely to experience spontaneous fetal loss at < or =24 weeks of gestation, low birth weight, preeclampsia, gestational hypertension, preterm birth ( P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption ( P < .02). Nuchal translucency at > or =99th percentile and free-beta subunit human chorionic gonadotropin at < or =1st percentile were associated with an increased risk of spontaneous loss at < or =24 weeks of gestation (adjusted odds ratios, 3.90, 3.62, respectively; P < .001)., Conclusion: Low pregnancy-associated plasma protein A levels in the first trimester were associated strongly with a number of adverse pregnancy outcomes. Low free-beta subunit human chorionic gonadotropin levels and large nuchal translucency were both associated with early fetal loss.

Objective: The high rate of preterm births is an imposing public health issue in the United States. Past research has suggested that prenatal stress, anxiety, and elevated levels of maternal plasma corticotropin-releasing hormone (CRH) are associated with preterm delivery in humans and animals. Studies to date have not examined all three variables together; that is the objective of this paper., Methods: Data from 282 pregnant women were analyzed to investigate the effect of maternal prenatal anxiety and CRH on the length of gestation. It was hypothesized that at both 18 to 20 weeks (Time 1) and 28 to 30 weeks gestation (Time 2), CRH and maternal prenatal anxiety would be negatively associated with gestational age at delivery. CRH was also expected to mediate the relationship between maternal prenatal anxiety and gestational age at delivery., Results: Findings supported the mediation hypothesis at Time 2, indicating that women with high CRH levels and high maternal prenatal anxiety at 28 to 30 weeks gestation delivered earlier than women with lower CRH levels and maternal prenatal anxiety. Women who delivered preterm had significantly higher rates of CRH at both 18 to 20 weeks gestation and 28 to 30 weeks gestation (p <.001) compared with women who delivered term., Conclusions: These findings are the first to link both psychosocial and neuroendocrine factors to birth outcomes in a prospective design.