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Background: Despite the global standardization of hemoglobin (Hb) testing in early pregnancy, the impact of first trimester Hb concentrations on pregnancy outcomes remains inadequately understood. Also, the early pregnancy Hb concentrations have not been well documented in Western China. Therefore, this study aimed to assess the Hb concentrations during early pregnancy and their associations with adverse pregnancy outcomes in Western China., Methods: This cross-sectional study used data from the Chengdu Maternal and Child Health Information System for pregnant women who delivered between January 1, 2019, and December 31, 2023. A total of 454,815 Chinese females aged 15 to 49 years with available first trimester Hb data, including those with singleton or multiple gestations, were included in the analysis. Multivariable logistic regression models were performed to estimate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between Hb categories and adverse pregnancy outcomes., Results: The average first trimester Hb concentration was 126.0 (SD 10.5) g/L, with 5.8% of pregnant women experiencing anemia during early pregnancy. Multivariable logistic regression analyses revealed significantly increased odds of developing gestational diabetes mellitus (GDM) and gestational hypertensive disorders (GHD) across increasing Hb concentration categories. Compared to Hb concentrations of 110-119 g/L, Hb ≥ 140 g/L was associated with elevated risk of GDM (aOR: 1.57, 95% CI: 1.52, 1.62) and GHD (aOR: 1.87, 95% CI: 1.79, 1.96). Moreover, both Hb ≤ 99 g/L (aOR: 1.15, 95% CI: 1.03, 1.29) and Hb ≥ 140 g/L (aOR: 1.20, 95% CI: 1.13, 1.26) were associated with higher odds of preterm birth compared to Hb concentrations of 110-119 g/L. In addition, the restricted cubic spline demonstrated a U-shaped relationship for cesarean delivery, low birthweight and small for gestational age (p < 0.001). However, no significant associations were found between first trimester Hb concentrations and the odds of stillbirth, Apgar score < 7 at 5 min, or Apgar score < 7 at 10 min (p > 0.05)., Conclusions: Our research findings suggest associations between first trimester Hb concentrations and various adverse pregnancy outcomes. We recommend interventions for early pregnancy anemia, particularly moderate to severe cases, and emphasize monitoring females with high Hb concentrations to reduce adverse outcomes., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of Chengdu Women’s and Children’s Central Hospital (approval number: 202285). Informed consent was waived because of the retrospective study design, and the data analyses used data containing no personally identifiable information. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Prenatal exposure to heavy metals such as Lead (Pb), arsenic (As), cadmium (Cd), and selenium (Se) is associated with various adverse pregnancy outcomes. This study examines the association between early pregnancy maternal blood levels of these metals and adverse pregnancy outcomes, while also addressing the differences between low-risk and high-risk groups based on having a history of preterm birth (PTB). This prospective cohort study recruited parous women during first trimester, categorized into low-risk and high-risk groups. Participants completed a questionnaire, and heavy metal levels were measured in blood samples. Pregnancy outcomes including PTB, low birth weight (LBW), gestational age at delivery, birth weight and head circumference were recorded following delivery. Multivariable analyses were conducted to evaluate the independent associations between heavy metal levels and pregnancy outcomes, while adjusting for maternal age, BMI, employment, smoking, fertility treatments and education. Among 404 participants, the mean (± SD) levels were Pb: 3.12 ± 1.82 µg/L, As: 0.41 ± 0.4 µg/L, Cd: 0.26 ± 0.34 µg/L, and Se: 119.84 ± 21.05 µg/L. Significant differences in Pb, Se, Cd and As levels were observed between the low-risk and high-risk groups, with higher levels in the low-risk group. However, no significant associations were found between heavy metal levels and any of the study outcomes in either univariable comparison or multivariable models. These findings highlight the need for further research to understand the potential impact of these metals on pregnancy, considering population-specific factors and exposure timing., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics declaration The study protocol was approved by the institutional review board (Soroka University Medical Center IRB committee, #0390-20-SOR). The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments (Helsinki Declaration 1975, revision 2013). All participants gave signed informed consent at recruitment., (© 2024. The Author(s).)

Objective (s): Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature., Methods: In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm 3 . The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories., Results: Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development., Conclusion(s): Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval The authors report no conflicts of interest. This research was conducted in accordance with the ethical principles for medical research set out in the Declaration of Helsinki and was approved by the Institutional Review Board of the Erasmus Medical Centre on 2 June 2015 (MEC 2015–494).This study was registered at the Dutch Trial Register: NTR6854., (© 2024. The Author(s).)

Objective: Impaired fasting glucose is a prediabetic condition defined as glucose levels of 100-125 mg/dL and is considered a risk factor for type 2 diabetes. However, this definition does not confer to pregnancy. The significance of first-trimester fasting glucose and future progression to diabetes is not well defined. Therefore, we aimed to evaluate the progression to type 2 diabetes according to first- trimester fasting plasma glucose levels, as compared with gestational diabetes, a well-established risk factor for diabetes, in up to 5-year follow-up postpartum., Methods: A retrospective analysis of 69 001 parturients, evaluating fasting plasma glucose levels measured during the first trimester. The primary outcome was the incidence of type 2 diabetes within 5 years post-delivery. Fasting plasma glucose levels were categorized in 10 mg/dL increments. Receiver operating characteristic-area under the curve (ROC-AUC) statistics and the Youden index were employed to identify the optimal fasting plasma glucose cutoff for progression to type 2 diabetes. Survival analysis was applied to calculate the adjusted hazard ratios (aHRs) for type 2 diabetes progression with further stratification to maternal obesity status., Results: The identified fasting plasma glucose cutoff for progression to type 2 diabetes was 86.5 mg/dL. This cut-off demonstrated superior performance compared with gestational diabetes diagnosis. Stratification by maternal obesity revealed enhanced predictive capabilities for type 2 diabetes, particularly among patients without obesity., Conclusions: Increased first-trimester fasting plasma glucose levels are associated with progression to type 2 diabetes, at least as gestational diabetes. For patients without obesity, first-trimester fasting plasma glucose has a more pronounced impact on progression to diabetes., (© 2024 International Federation of Gynecology and Obstetrics.)

Gestational diabetes mellitus (GDM) is the first spontaneous hyperglycemia during pregnancy. Early diagnosis and intervention are important for the management of the disease. This study compared and analyzed the proteins of total plasma exosomes (T-EXO) and placental-derived exosomes (PLAP-EXO) in pregnant women who subsequently developed GDM (12-16 weeks), GDM patients (24-28 weeks) and their corresponding controls to investigate the pathogenesis and biomarkers of GDM associated with exosomes. The exosomal proteins were extracted and studied by proteomics approach, then bioinformatics analysis was applied to the differentially expressed proteins (DEPs) between the groups. At 12-16 and 24-28 weeks of gestation, 36 and 21 DEPs were identified in T-EXO, while 34 and 20 DEPs were identified in PLAP-EXO between GDM and controls, respectively. These proteins are mainly involved in complement pathways, immunity, inflammation, coagulation and other pathways, most of them have been previously reported as blood or exosomal proteins associated with GDM. The findings suggest that the development of GDM is a progressive process and that early changes promote the development of the disease. Maternal and placental factors play a key role in the pathogenesis of GDM. These proteins especially Hub proteins have the potential to become predictive and diagnostic biomarkers for GDM., (© 2024. The Author(s).)

The association between early pregnancy ultrasound parameters and reproductive hormone levels was investigated through a case-control study. Participants for this retrospective study were recruited from obstetrics and gynecology departments across multiple tertiary care centers over 2 years. Inclusion criteria for the case group included pregnant women in their first trimester with detailed ultrasound data, while the control group comprised nonpregnant women without hormonal disorders. A sample size of 850 was estimated to provide sufficient power for detecting differences in hormone levels. Hormone levels were assayed using enzyme-linked immunosorbent assay, and statistical analysis was performed using Statistical Package for the Social Sciences 26.0. A total of 425 participants in each group were included after accounting for dropouts. For hCG, a strong positive correlation was observed with crown-rump length (R = 0.62, P < .001), gestational sac diameter (R = 0.59, P < .001), and a moderate correlation with yolk sac diameter (R = 0.40, P = .003). Progesterone levels exhibited moderate positive correlations with these ultrasound parameters, and estradiol levels demonstrated strong positive correlations. Conversely, follicle-stimulating hormone levels showed a moderate negative correlation with ultrasound measurements, while luteinizing hormone levels indicated a slight negative correlation. Prolactin levels were positively correlated with all ultrasound parameters in cases. The control group did not show any significant correlations between hormone levels and ultrasound parameters. The study concluded a significant association between early pregnancy ultrasound parameters and reproductive hormone levels in pregnant women, underscoring the potential of these hormones as biomarkers for pregnancy development., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Preeclampsia (PE) is a complex and multifaceted obstetric syndrome characterized by several distinct molecular subtypes. It complicates up to 5% of pregnancies and significantly contributes to maternal and newborn morbidity, thereby diminishing the long-term quality of life for affected women. Due to the widespread dissatisfaction with the effectiveness of existing approaches for assessing PE risk, there is a pressing need for ongoing research to identify newer, more accurate predictors. This study aimed to investigate early changes in the maternal serum proteome and associated signaling pathways. The levels of 125 maternal serum proteins at 11-13 weeks of gestation were quantified using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with the BAK-125 kit. Ten serum proteins emerged as potential early markers for PE: Apolipoprotein M (APOM), Complement C1q subcomponent subunit B (C1QB), Lysozyme (LYZ), Prothrombin (F2), Albumin (ALB), Zinc-alpha-2-glycoprotein (AZGP1), Tenascin-X (TNXB), Alpha-1-antitrypsin (SERPINA1), Attractin (ATRN), and Apolipoprotein A-IV (APOA4). Notably, nine of these proteins have previously been associated with PE in prior research, underscoring the consistency and reliability of our findings. These proteins play key roles in critical molecular processes, including complement and coagulation cascades, platelet activation, and insulin-like growth factor pathways. To improve the early prediction of PE, a highly effective Support Vector Machine (SVM) model was developed, analyzing 19 maternal serum proteins from the first trimester. This model achieved an area under the curve (AUC) of 0.91, with 87% sensitivity and 95% specificity, and a hazard ratio (HR) of 13.5 (4.6-40.8) with p < 0.001. These findings demonstrate that serum protein-based SVM models possess significantly higher predictive power compared to the routine first-trimester screening test, highlighting their superior utility in the early detection and risk stratification of PE.

Objective: To identify the relationship between white blood cell indices in missed miscarriage compared to ongoing pregnancy in the first trimester., Methods: The diagnostic accuracy study was conducted at the Department of Maternity, Al-Yarmouk Hospital, Baghdad, Iraq, from January to October 2021,and comprised healthy first-trimester pregnant women in group A and those with missed miscarriage after 7-13 weeks of gestation in group B. Ultrasound findings and the last menstrual period were noted for all the subjects. Total and differential leukocyte counts, neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were compared between the groups. Data was analysed using SPSS 22., Results: Of the 167 women, 81(48.5%) were in group A and 86(51.5%) were in group B. Demographic and obstetrics data was not significantly different between the groups (p>0.05). Mean white blood cell, neutrophil and monocyte counts showed no significant difference between the groups (p>0.05), while lymphocyte count, neutrophil-tolymphocyte ratio and monocyte-to-lymphocyte ratio were significantly different between the groups (p<0.05). With respect to gestational age, neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio had a fair ability to predict missed miscarriage at various time points within the first trimester (p<0.05)., Conclusions: There was no significant correlation between WBC count and gestational age. Reduced MLR and NLR levels can be utilised to forecast miscarriages in a cost-effective manner.

Objective: The aim of this study was to evaluate the potential of immunonutritional markers, specifically the hemoglobin, albumin, lymphocyte, and platelet (HALP) score and the prognostic nutritional index (PNI), in predicting late-onset fetal growth restriction (LO-FGR) during the first trimester., Materials and Methods: This retrospective study was conducted at a tertiary care center between October 2022 and August 2023. The study included a total of 213 singleton pregnancies, with 99 women in the LO-FGR group and 114 in the healthy control group, matched by maternal age and gestational age at delivery. All blood samples were collected between 11 and 14 weeks of gestation (during the first-trimester screening test). We analyzed first-trimester laboratory parameters, specifically focusing on hemoglobin levels, white blood cells (WBCs), lymphocytes, platelets, and albumin levels. Afterwards, we calculated the HALP score and PNI, and then compared the values of both groups., Results: Both HALP score (3.58 ± 1.31 vs. 4.19 ± 1.8, p = 0.012) and PNI (36.75 ± 2.9 vs. 39.37 ± 3.96, p < 0.001) were significantly lower in the FGR group than in the control group. The HALP score cut-off value of < 3.43 in predicting FGR had a sensitivity of 62.3% and specificity of 54.5% (AUC = 0.600, 95% CI: 0.528-0.672, p = 0.012). The PNI cut-off value of < 37.9 in predicting FGR had a sensitivity of 65.8% and specificity of 62.9% (AUC = 0.707, 95% CI: 0.632-0.778, p < 0.001). While the HALP score was not a significant predictor of composite adverse neonatal outcomes in the FGR group, PNI showed a cut-off value of < 37.7 with a sensitivity of 60.9% and specificity of 59.7% (AUC = 0.657, 95% CI: 0.581-0.733, p < 0.001)., Conclusion: The HALP score and PNI are valuable prognostic tools for predicting the risk of FGR in the first trimester. Low PNI values are also associated with composite adverse neonatal outcomes in pregnancies complicated by FGR., (© 2024. The Author(s).)

Introduction: Preterm delivery (PTD) is the leading cause of death in children under 5 years of age. Cervical shortening detected by ultrasound can be used to predict PTD, but prediction is not perfect, and complementary diagnostic markers are needed. Recently, specific plasma microribonucleic acid (miRNAs) detected in early second trimester were shown to be associated with spontaneous PTD in high-risk women with a singleton pregnancy. The aim of this study was to explore to what extent these miRNAs are associated with spontaneous PTD and cervical length in a general population., Material and Methods: This study is a nested case-control study within the CERVIX study. The CERVIX study evaluated the ability of cervical length screening with transvaginal ultrasound to identify women at risk of PTD. In the present study, women who delivered spontaneously <34 weeks (n = 61) were compared with a control group of women who delivered at full term (39 + 0 to 40 + 6 gestational weeks, n = 205). Archived serum samples were analyzed with RT-qPCR for miRNA expression levels of let-7a-5p, miR-150-5p, miR-15b-5p, miR-185-5p, miR-191-5p, miR-19b-3p, miR-23a-3p, miR-374a-5p, and miR-93-5p. The mean relative expression was compared between the groups. Sub-analyses were performed for women delivering <32, <30, and <28 weeks vs the full-term group., Results: The analyzed miRNAs were not significantly differentially expressed in women delivering <34 weeks compared to those delivering at full term. MiR-191-5p and miR-93-5p were significantly overexpressed in women who delivered <32 weeks, and further increase in fold change was observed with decreasing gestational age at delivery. The level of miR-15b-5p was significantly higher in women delivering at <30 weeks compared to those delivering at full term., Conclusions: Our study shows that overexpression of miR-93-5p, miR-15b-5p, and miR-191-5p in serum at early gestation is associated with spontaneous PTD in a general population. Further research is needed to evaluate the potential of these miRNAs as future biomarkers for spontaneous PTD, as well as their pathophysiological role in spontaneous PTD., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To evaluate the associations of plasma polybrominated diphenyl ether (PBDE) concentrations in early pregnancy with gestational weight gain (GWG)., Design: Prospective cohort study., Setting: US-based, multicentre cohort of pregnant women., Population: We used data from 2052 women without obesity and 397 women with obesity participating in the NICHD Fetal Growth Studies - Singleton Cohort, with first-trimester plasma PBDE concentrations and weight measurements throughout pregnancy., Methods: We applied generalised linear models and Bayesian kernel machine regression (BKMR) to evaluate both the individual and joint associations of PBDEs with measures of GWG, adjusting for potential confounders., Main Outcome Measures: Total GWG (kg), total and trimester-specific GWG velocities (kg/week), and GWG categories and trajectory groups., Results: Mean pre-pregnancy BMIs were 23.6 and 34.5 kg/m 2 for women without and with obesity, respectively. Among women without obesity, there were no associations of PBDEs with any GWG measure. Among women with obesity, one standard deviation increase in log-transformed PBDE 47 was associated with a 1.87 kg higher total GWG (95% CI 0.39-3.35) and a 0.05 kg/week higher total GWG velocity (95% CI 0.01-0.09). Similar associations were found for PBDE 47 in BKMR among women with obesity, and PBDE 47, 99 and 100 were associated with lower odds of being in the low GWG trajectory group., Conclusions: PBDEs were not associated with GWG among individuals without obesity. Among those with obesity, only PBDE 47 showed consistent positive associations with GWG measures across multiple statistical methods. Further research is needed to validate this association and explore potential mechanisms., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Subclinical hypothyroidism (SCH) in pregnancy is associated with adverse foetomaternal outcomes. The literature is scarce with respect to maternal and perinatal outcomes in women with mild SCH (TSH levels between 2.5-4 mIU/L)., Objectives: The primary objective of the study was to compare the pregnancy outcome between SCH and euthyroid women. The secondary objectives were to find out the proportion of women with SCH having thyroid peroxidase antibodies (TPOAb) and to see the effect of TPOAb positivity on foetomaternal outcomes., Materials and Methods: A total of 178 pregnant women were recruited in the first trimester, and those with TSH between 0.1 and 2.4 mIU/L were considered as euthyroid and 2.5-4mIU/L were labelled as SCH. Women with SCH underwent testing for TPOAb. All women were followed until delivery, and foetomaternal outcomes were assessed., Results: Amongst SCH group, there was a significantly higher proportion of overweight and obese women (76/91 (83.51%) vs 59/87 (68%), p = 0.031). The neonatal intensive care unit (NICU) admission was higher with adjusted odds ratio of 3.24 (1.41-7.43) in women with SCH as compared to euthyroid women. Otherwise, there was no difference in foetomaternal outcomes between the two groups. The proportion of gestational diabetes mellitus, intrauterine growth retardation and still birth were higher in SCH women with TPOAb as compared to euthyroid. Amongst SCH women, the proportion of induced labour was lower (aOR:0.27 (0.08-0.93) whereas the proportion of stillbirth and low APGAR scores were higher in TPOAb-positive women with a statistically significant difference and adjusted odds ratio (aOR:20.18 (1.84-220.83)) and (aOR:4.77 (1.06-21.3)), respectively, when compared to TPOAb-negative women., Conclusion: There appears to be no difference in pregnancy outcomes between women with SCH and euthyroid women except higher NICU admission in SCH group. Future multi-centre large prospective studies are required to understand better about the pregnancy outcomes in these women., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pregnant women are advised to take folic acid (FA) supplements before conception and during the first trimester of pregnancy. Many women continue FA supplementation throughout pregnancy, and concerns have been raised about associations between excessive FA intake and adverse maternal and child health outcomes. Unmetabolized folic acid (UMFA) is found in serum after high FA intakes and is proposed as a biomarker for excessive FA intake. We aimed to determine if removing FA from prenatal micronutrient supplements after 12 weeks of pregnancy reduces serum UMFA concentrations at 36 weeks gestation. In this double-blind, randomized controlled trial conducted in South Australia, 103 women with a singleton pregnancy were randomly assigned at 12-16 weeks gestation to take a micronutrient supplement containing no FA or 800 µg/day FA from enrollment until 36 weeks gestation. Ninety women (0 µg/day FA n = 46; 800 µg/day FA n = 44) completed the study. Mean, UMFA concentration was lower in the women randomized to the 0 µg/day group compared to the 800 µg/day FA group, 0.6 ± 0.7 and 1.4 ± 2.7 nmol/L, respectively. The adjusted mean difference (95% CI) in UMFA between the groups was [-0.85 (-1.62, -0.08) nmol/L, p = 0.03]. Maternal serum and red blood cell folate concentrations were lower in the 0 µg/day FA group than in the 800 µg/day group (median 23.2 vs. 49.3 and 1335 vs. 1914 nmol/L, respectively; p < 0.001). Removing FA at 12-16 weeks gestation from prenatal micronutrient supplements reduced the concentration of UMFA at 36 weeks gestation., (© 2024 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 μg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB., (© 2024 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Preterm birth (PTB) remains a significant public health concern, and prediction is an important objective, particularly in the early stages of pregnancy. Many studies have relied on cervical characteristics in the mid-trimester, with limited results. It is therefore crucial to identify novel biomarkers to enhance the ability to identify women at risk. The complement pathway is implicated in the process of placentation, and recent proteomics studies have highlighted the potential roles of some complement proteins in the pathophysiology of PTB. To determine the association between the occurrence of spontaneous preterm birth (sPTB) and the concentration of complement C3, factor B, and factor H in the blood of pregnant women during the first trimester. This prospective cohort study included women with singleton pregnancies, both with and without a history of sPTB, from two health institutions in Bucaramanga, Colombia. The outcome was sPTB before 37 weeks. A blood sample was obtained between 11 + 0 to 13 + 6 weeks. ELISA immunoassay was performed to quantify the levels of C3, factor B, and factor H. A total of 355 patients were analyzed, with a rate of sPTB of 7.6% (27/355). The median plasma concentration for C3, factor B, and factor H were 488.3 μg/mL, 352.6 μg/mL, and 413.2 μg/mL, respectively. The median concentration of factor H was found to be significantly lower in patients who delivered preterm compared to patients who delivered at term (382 μg/mL vs. 415 μg/mL; p = 0.034). This study identified a significant association between low first-trimester levels of factor H and sPTB before 37 weeks. These results provide relevant information about a new possible early biomarker for sPTB. However, the results must be confirmed in different settings, and the predictive value must be examined.

Objective: The aim of this study was to investigate the role of systemic immune-inflammation index, neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratios calculated in the first trimester as inflammatory markers in predicting gestational diabetes mellitus diagnosis., Methods: This study was conducted retrospectively at a tertiary center between January 2020 and June 2023. A total of 111 pregnant women with gestational diabetes and 378 pregnant women in the control group were included in the study. Systemic immune-inflammation index, neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratios values were compared between the gestational diabetes mellitus group patients and the healthy group. Receiver operating characteristic analysis curve was used for predicting gestational diabetes mellitus using systemic immune-inflammation index and lymphocyte-monocyte ratio., Results: In pregnant women in the first trimester, systemic immune-inflammation index and lymphocyte-monocyte ratio values based on routine complete blood count parameters were found to be statistically significantly higher in gestational diabetes mellitus patients compared to healthy patients, while neutrophil-lymphocyte ratio and platelet-lymphocyte ratios values were found to be similar (p=0.033, p=0.005, p=0.211, and p=0.989). For predicting gestational diabetes mellitus, a cut-off value of 655.75 for systemic immune-inflammation index resulted in 80.2% sensitivity and 34.4% specificity, and a cut-off value of 3.62 for lymphocyte-monocyte ratio resulted in 56.8% sensitivity and 63.2% specificity, indicating good discriminatory ability., Conclusion: We believe that systemic immune-inflammation index and lymphocyte-monocyte ratio values measured in the first-trimester complete blood count parameters are effective in predicting gestational diabetes mellitus but are not effective in determining insulin requirement.

Exposure to mercury has been associated with adverse effects on pregnancy outcomes. However, there is limited literature on mercury exposure and pregnancy outcomes in Chinese pregnant women. Our study was to investigate the possible association between maternal mercury exposure and spontaneous preterm birth and birth weight. This study was a nested case-control study. The association between blood mercury concentration and both spontaneous preterm birth and birth weight was analyzed using conditional logistic regression and linear regression adjusted for the potential confounding factors, respectively. The dose-response relationship between mercury concentration and birth outcomes was estimated using restricted cubic spline regression. The mean concentration of mercury was 2.8 ± 2.2 µg/L. A positive relationship was observed between maternal blood mercury concentration and SPB when analyzed as a continuous variable. However, it was not found to be statistically significant (adjusted OR = 1.10, 95% CI = 0.95-1.26, P = 0.202). Moderate mercury exposure was associated with a higher risk of SPB (Q3 vs. Q1: crude OR = 2.50, 95% CI = 1.16-5.41, P = 0.02; adjusted OR = 3.49, 95% CI = 1.33-9.11, P = 0.011). After considering the combined effects of chemicals other than mercury exposure (including lead, selenium, and cadmium), the results remained consistent. There was no statistically significant association between blood mercury levels and birth weight (adjusted coefficient = 18.64, P-value = 0.075). There were no statistically significant dose-response associations between mercury concentration and birth outcomes (SPB: P = 0.076; birth weight: P = 0.885). Public health policies should focus on reducing environmental releases of mercury, improving food safety standards, and providing education to pregnant women about the risks of mercury exposure and preventive measures., (© 2024. The Author(s).)

To assess how effective macrophage stimulating protein α-chain (MSP-α) combined with uterine artery Doppler is in predicting preeclampsia in singleton pregnancies during 11-13 +6  weeks of gestation. This prospective observational study included singleton pregnant women who attended antenatal care at King Chulalongkorn Memorial Hospital, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University between December 2021 and April 2023, during 11-13 +6  weeks of gestation. Serum MSP-α levels were collected and uterine artery Doppler ultrasound was performed. Pregnancy outcomes were recorded, and the predictive values of these tests were determined to predict preeclampsia. A total of 365 patients, with 21 cases of preeclampsia (5.8%), were analyzed. Serum MSP-α levels were higher in pregnant women who developed preeclampsia than those who did not (899.7 ± 550.1 ng/ml vs 642.5 ± 466.1 ng/ml, p = 0.016). The mean pulsatility index of the uterine artery and the presence of diastolic notching were not significantly different between the groups. As a cut-off value for predicting preeclampsia, using serum MSP-α levels higher than 1.0 multiple of median for gestational age, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 71.4%, 50.3%, 8.1%, and 96.7%, respectively. Additionally, when abnormal serum MSP-α levels were combined with a uterine artery Doppler pulsatility index above the 95th percentile and bilateral notching as predictive values for preeclampsia, the sensitivity was 85.7%, specificity was 18.3%, PPV was 6.0%, and NPV was 95.5%. Serum MSP-α alone at 11-13 +6  weeks of gestation was effective in predicting preeclampsia. However, the use of serum MSP-α in combination with uterine artery Doppler increased sensitivity but reduced specificity for the prediction of preeclampsia., (© 2024. The Author(s).)

Background: It remains unclear which early gestational biomarkers can be used in predicting later development of gestational diabetes mellitus (GDM). We sought to identify the optimal combination of early gestational biomarkers in predicting GDM in machine learning (ML) models., Methods: This was a nested case-control study including 100 pairs of GDM and euglycemic (control) pregnancies in the Early Life Plan cohort in Shanghai, China. High sensitivity C reactive protein, sex hormone binding globulin, insulin-like growth factor I, IGF binding protein 2 (IGFBP-2), total and high molecular weight adiponectin and glycosylated fibronectin concentrations were measured in serum samples at 11-14 weeks of gestation. Routine first-trimester blood test biomarkers included fasting plasma glucose (FPG), serum lipids and thyroid hormones. Five ML models [stepwise logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, support vector machine and k-nearest neighbor] were employed to predict GDM. The study subjects were randomly split into two sets for model development (training set, n = 70 GDM/control pairs) and validation (testing set: n = 30 GDM/control pairs). Model performance was evaluated by the area under the curve (AUC) in receiver operating characteristics., Results: FPG and IGFBP-2 were consistently selected as predictors of GDM in all ML models. The random forest model including FPG and IGFBP-2 performed the best (AUC 0.80, accuracy 0.72, sensitivity 0.87, specificity 0.57). Adding more predictors did not improve the discriminant power., Conclusion: The combination of FPG and IGFBP-2 at early gestation (11-14 weeks) could predict later development of GDM with moderate discriminant power. Further validation studies are warranted to assess the utility of this simple combination model in other independent cohorts., (© 2024. The Author(s).)

Background: Accumulating evidence shows that free fatty acids (FFA) are associated with gestational diabetes mellitus (GDM). However, most of the studies focus on a few specific types of FFA, such as α-linolenic acid (C18:3n3) and Arachidonic acid (C20:4n6) or a total level of FFA., Objective: This study aimed to test the association between a variety of FFAs during the first trimester and the risk of GDM., Methods: The participants came from the Zhoushan Pregnant Women Cohort (ZWPC). A 1:2 nested case-control study was conducted: fifty mothers with GDM were matched with 100 mothers without GDM by age, pre-pregnancy body mass index (BMI), month of oral glucose tolerance test (OGTT) and parity. Thirty-seven FFAs (including 17 saturated fatty acids (SFA), 8 monounsaturated fatty acids (MUFA), 10 polyunsaturated fatty acids (PUFA) and 2 trans fatty acids (TFA)) in maternal plasma during the first trimester were tested by Gas Chromatography-Mass Spectrometry (GC-MS). Conditional logistic regression models were performed to assess the associations of FFA with the risk of GDM., Results: Nine FFAs were respectively associated with an increased risk of GDM (P < 0.05), and four FFAs were respectively associated with a decreased risk of GDM (P < 0.05). SFA risk score was associated with a greater risk of GDM (OR = 1.34, 95% CI: 1.12-1.60), as well as UFA risk score (OR = 1.26, 95% CI: 1.11-1.44), MUFA risk score (OR = 1.70, 95%CI: 1.27-2.26), PUFA risk score (OR = 1.32, 95%CI: 1.09-1.59) and TFA risk score (OR = 2.51, 95%CI: 1.23-5.13). Moreover, joint effects between different types of FFA risk scores on GDM were detected. For instance, compared with those with low risk scores of SFA and UFA, women with high risk scores of SFA and UFA had the highest risk of GDM (OR = 8.53, 95%CI: 2.41-30.24), while the Odds ratio in those with a low risk score of SFA and high risk score of UFA and those with a high risk score of SFA and low risk score of UFA was 6.37 (95%CI:1.33- 30.53) and 4.25 (95%CI: 0.97-18.70), respectively., Conclusion: Maternal FFAs during the first trimester were positively associated with the risk of GDM. Additionally, there were joint effects between FFAs on GDM risk., Condensation: Elevated FFA levels in the first trimester increased the risk of GDM., (© 2024. The Author(s).)

Background: Maternal gestational diabetes (GDM), small (SGA) and large (LGA) for gestational age neonates are associated with increased morbidity in both mother and child. We studied how different levels of first trimester pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (fβ-hCG) were associated with SGA and LGA in GDM pregnancies and controls., Methods: Altogether 23 482 women with singleton pregnancies participated in first trimester combined screening and delivered between 2014 and 2018 in Northern Finland and were included in this retrospective case-control study. Women with GDM (n = 4697) and controls without GDM (n = 18 492) were divided into groups below 5th and 10th or above 90th and 95th percentile (pc) PAPP-A and fβ-hCG MoM levels. SGA was defined as a birthweight more than two standard deviations (SD) below and LGA more than two SDs above the sex-specific and gestational age-specific reference mean. Odds ratios were adjusted (aOR) for maternal age, BMI, ethnicity, IVF/ICSI, parity and smoking., Results: In pregnancies with GDM the proportion of SGA was 2.6% and LGA 4.5%, compared to 3.3% (p = 0.011) and 1.8% (p < 0.001) in the control group, respectively. In ≤ 5th and ≤ 10th pc PAPP-A groups, aORs for SGA were 2.7 (95% CI 1.5-4.7) and 2.2 (95% CI 1.4-3.5) in the GDM group and 3.8 (95% CI 3.0-4.9) and 2.8 (95% CI 2.3-3.5) in the reference group, respectively. When considering LGA, there was no difference in aORs in any high PAPP-A groups. In the low ≤ 5 percentile fβ-hCG MoM group, aORs for SGA was 2.3 (95% CI 1.8-3.1) in the control group. In fβ-hCG groups with GDM there was no association with SGA and the only significant difference was ≥ 90 percentile group, aOR 1.6 (95% CI 1.1-2.5) for LGA., Conclusion: Association with low PAPP-A and SGA seems to be present despite GDM status. High PAPP-A levels are not associated with increased LGA risk in women with or without GDM. Low fβ-hCG levels are associated with SGA only in non-GDM pregnancies., (© 2024. The Author(s).)

Introduction: Capillary blood collection, a technique traditionally used in diabetes care, shows promise for many applications including pregnancy monitoring. Serial measurement of serum human Chorionic Gonadotrophin (hCG) is frequently necessary for managing early pregnancy, including molar pregnancy, requiring multiple visits to a maternity hospital for blood collection by venepuncture. This proof-of-concept study aimed to assess the clinical performance and user acceptability of capillary blood samples collected remotely, as an alternative to venous blood for hCG measurement., Methods: Women attending the early pregnancy unit who required serum hCG measurement, were invited to participate. Following informed written consent, participants were shown how to collect capillary blood samples using the Mini-Collect® collection device. Matched venous and capillary blood samples were collected in clinic for hCG comparison purposes. Participants were also supplied with a home collection kit in a prepaid return envelope. They were asked to perform a finger-prick blood collection at home using the instructions provided and to return the capillary blood sample by post within 24 h of collection, along with a completed user-satisfaction questionnaire. Statistical analysis was performed using Analyse-it® software., Results: The study enrolled 71 participants and over a third of these women collected a capillary blood sample at home. The median age of participants was 33 years (range 29-36). Passing-Bablok linear regression (y = -0.037 + 1.04x) and Spearman correlation (r = 0.999, p < 0.0001), demonstrated good agreement and strong correlation between venous and capillary samples, over a broad range of hCG values (1.2 to 224,0000 IU/L). The majority of capillary samples collected remotely (39%, 27/69) had sufficient blood volume for analysis (74%, 20/27). Respondents (77%, 18/25) found the collection device easy to use and expressed willingness to use a future service if available (80%, 20/25) CONCLUSION: The study demonstrated excellent agreement between the hCG results obtained from both collection methods, suggesting that capillary blood can serve as a reliable alternative for venous hCG measurement, particularly in clinical settings requiring frequent hCG monitoring. Feedback from the study questionnaire indicates a preference for this type of follow-up among women, indicating potential improvements in compliance for blood based diagnostic tests., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Caroline M Joyce reports financial support was provided by Irish Research Council.]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate combinations of candidate biomarkers to develop a multiplexed prediction model for identifying the viability and location of an early pregnancy. In this study, we assessed 24 biomarkers with multiple machine learning-based methodologies to assess if multiplexed biomarkers may improve the diagnosis of normal and abnormal early pregnancies., Design: A nested case-control design evaluated the predictive ability and discrimination of biomarkers in patients at risk of early pregnancy failure in the first trimester to classify viability and location., Setting: Three university hospitals., Patients: A total of 218 individuals with pain and/or bleeding in early pregnancy: 75 had an ongoing intrauterine gestation; 68 had ectopic pregnancies (EPs); and 75 had miscarriages., Interventions: Serum levels of 24 biomarkers were assessed in the same patients. Multiple machine learning-based methodologies to evaluate combinations of these top candidates to develop a multiplexed prediction model for the identification of a nonviable pregnancy (ongoing intrauterine pregnancy vs. miscarriage or EP) and an EP (EP vs. ongoing intrauterine pregnancy or miscarriage)., Main Outcome Measures: The predicted classification using each model was compared with the actual diagnosis, and sensitivity, specificity, positive predictive value, negative predictive value, conclusive classification, and accuracy were calculated., Results: Models using classification regression tree analysis using 3 (pregnancy-specific beta-1-glycoprotein 3 [PSG3], chorionic gonadotropin-alpha subunit, and pregnancy-associated plasma protein-A) biomarkers were able to predict a maximum sensitivity of 93.3% and a maximum specificity of 98.6%. The model with the highest accuracy was 97.4% (with 70.2% receiving classification). Models using an overlapping group of 3 (soluble fms-like tyrosine kinase-1, PSG3, and tissue factor pathway inhibitor 2) biomarkers achieved a maximum sensitivity of 98.5% and a maximum specificity of 95.3%. The model with the highest accuracy was 94.4% (with 65.6% receiving classification). When the models were used simultaneously, the conclusive classification increased to 72.7% with an accuracy of 95.9%. The predictive ability of the biomarkers in the random forest produced similar test characteristics when using 11 predictive biomarkers., Conclusion: We have demonstrated a pool of biomarkers from divergent biological pathways that can be used to classify individuals with potential early pregnancy loss. The biomarkers choriogonadotropin alpha, pregnancy-associated plasma protein-A, and PSG3 can be used to predict viability, and soluble fms-like tyrosine kinase-1, tissue factor pathway inhibitor 2, and PSG3 can be used to predict pregnancy location., Competing Interests: Declaration of Interests K.T.B. reports funding from NIH R01HD076279 and NIH ROI HD 110448 for the submitted work; funding from NIH ROI HD 110448 and NIH R01HD076279; patent pending outside the submitted work. K.J.B. has nothing to disclose. S.S. reports funding from National Institutes of Health, AbbVie, and Burroughs Wellcome Fund; Society for Assisted Reproductive Technology Research Committee Chair; Oncofertility Consortium Practice Committee outside the submitted work. P.T. reports funding from NIH ROI HD 110448 for the submitted work. J.C.R. has nothing to disclose. D.J.H. has nothing to disclose. L.A.B. has nothing to disclose. R.F.S. has nothing to disclose. N.C.K. has nothing to disclose. D.W.S. has nothing to disclose. J.C. has nothing to disclose. J.B. has nothing to disclose. Z.W. has nothing to disclose. Y.F. has nothing to disclose. M.K. reports funding from National research foundation of Korea; honorarium from Catholic university of Korea. S.M. reports funding from National Institutes of Health (UG3-OD035537) and PCORI (BPS-2022C3-30268); travel support from Society for Epidemiologic Research; Society for Epidemiologic Research Member at Large of the Executive Committee outside the submitted work. L.S. reports funding from R01 HD110448 for the submitted work; funding from IIS 1837964 RF1 AG063481 R01 LM013463 U01 AG068057 R01 AG058854 R01 AG071470 RF1 AG068191 U01 AG066833 R01 AG066833 P30 AG073105 R01 LM011176 - 09 R01 LM011176 - 09S1 R01 LM011176 - 09S2 R00 HG010905 R01 HD110448 U19 AG074879 LillyLRAP P30AG073105-03S2 outside the submitted work. P.G. has nothing to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Research Question: Is low serum 25-hydroxyvitamin D (25(OH)D) associated with an increased risk of miscarriage in women who presented with threatened miscarriage to the Early Pregnancy Assessment Clinic (EPAC)?, Design: This was a secondary retrospective analysis using archived serum samples from a randomized, double-blind, placebo-controlled trial. Stored serum samples from 371 women presenting to the EPAC with threatened miscarriage during the first trimester were assayed for 25(OH)D by liquid chromatography-mass spectrometry., Results: The overall miscarriage rate was 45/371 (12.1%) in the whole cohort. After grouping vitamin D insufficiency and vitamin D sufficiency together into a 'non-deficient' group and excluding participants who underwent termination of pregnancy, there was no difference in the miscarriage rate between those who were vitamin D deficient compared with those who were not (25/205, 12.2% versus 20/157, 12.7%, P= 0.877, odds ratio 0.951, 95% CI 0.507-1.784). When analysed according to the number of gestational weeks, the miscarriage rate was significantly higher in the vitamin D non-deficient group than the vitamin D-deficient group in women who presented at 6 gestational weeks or earlier (13/33 [39.4%] versus 10/58 [17.2%], P= 0.019), but there were no statistically significant differences between the two groups presenting at later gestations. There was no difference in the vitamin D level in women who had a miscarriage compared with those who had a live birth (48 [37-57] versus 47 [37-58] nmol/l, P= 0.725 median [25th-75th percentile])., Conclusions: A low serum vitamin D concentration was not associated with an increased risk of miscarriage in women with threatened miscarriage presenting to the EPAC., (Copyright © 2024 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: To evaluate the role of aspartate aminotransferase to platelet ratio index (APRI) in the prediction of superimposed preeclampsia in chronic hypertensive pregnancy group in the first trimester., Methods: The present retrospective case-control study was conducted on 258 pregnant women, including 75 patients in the isolated chronic hypertension group, 92 in the superimposed preeclampsia group, and 91 low-risk pregnant women in the control group. APRI1 was calculated from routine blood test results in the first antenatal visit, and APRI2 was calculated from prelabor routine blood test results. APRI indices and other blood count parameters were evaluated and compared between groups and with the literature., Results: APRI1 was lower in the superimposed preeclampsia group than in the control and chronic hypertension groups, with p-values < 0.001. In the first trimester, platelet counts were higher in the superimposed preeclampsia group than in the hypertension and control groups. APRI2 was increased in the superimposed preeclampsia group compared to the control and chronic hypertension groups, with p-values 0.001 and 0.002, respectively. The optimal cut-off value for APRI1 was 0.036 (sensitivity 65.2 %, specificity 83.7 %), and for APRI2, it was found to be 0.057 (sensitivity 67.4 %, specificity 52.0 %) to predict superimposed preeclampsia., Discussion: To the best of our knowledge, this was the first study evaluating APRI in predicting superimposed preeclampsia in the first trimester. Increased platelet counts and lower APRI were found to be valuable indices for predicting superimposed preeclampsia. Further studies are needed to determine the utility of APRI in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Importance: There is no consensus regarding the best method for prediction of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia., Objective: To determine predictive ability in early pregnancy of large-scale proteomics for prediction of HDP., Design, Setting, and Participants: This was a nested case-control study, conducted in 2022 to 2023, using clinical data and plasma samples collected between 2010 and 2013 during the first trimester, with follow-up until pregnancy outcome. This multicenter observational study took place at 8 academic medical centers in the US. Nulliparous individuals during first-trimester clinical visits were included. Participants with HDP were selected as cases; controls were selected from those who delivered at or after 37 weeks without any HDP, preterm birth, or small-for-gestational-age infant. Age, self-reported race and ethnicity, body mass index, diabetes, health insurance, and fetal sex were available covariates., Exposures: Proteomics using an aptamer-based assay that included 6481 unique human proteins was performed on stored plasma. Covariates were used in predictive models., Main Outcomes and Measures: Prediction models were developed using the elastic net, and analyses were performed on a randomly partitioned training dataset comprising 80% of study participants, with the remaining 20% used as an independent testing dataset. Primary measure of predictive performance was area under the receiver operating characteristic curve (AUC)., Results: This study included 753 HDP cases and 1097 controls with a mean (SD) age of 26.9 (5.5) years. Maternal race and ethnicity were 51 Asian (2.8%), 275 non-Hispanic Black (14.9%), 275 Hispanic (14.9%), 1161 non-Hispanic White (62.8% ), and 88 recorded as other (4.8%), which included those who did not identify according to these designations. The elastic net model, allowing for forced inclusion of prespecified covariates, was used to adjust protein-based models for clinical and demographic variables. Under this approach, no proteins were selected to augment the clinical and demographic covariates. The predictive performance of the resulting model was modest, with a training set AUC of 0.64 (95% CI, 0.61-0.67) and a test set AUC of 0.62 (95% CI, 0.56-0.68). Further adjustment for study site yielded only minimal changes in AUCs., Conclusions and Relevance: In this case-control study with detailed clinical data and stored plasma samples available in the first trimester, an aptamer-based proteomics panel did not meaningfully add to predictive utility over and above clinical and demographic factors that are routinely available.

Objective: Maternal postpartum depressive and anxiety symptoms are risk factors for subsequent maternal and child mental health problems. Little is known about the potential role of antepartum vitamin D and C-reactive protein (CRP) in the etiology of maternal postpartum affective symptoms. We investigated associations between antepartum vitamin D status and postpartum depressive and anxiety symptoms and whether antepartum CRP mediated these associations., Methods: In 2483 participants of the Amsterdam Born Children and their Development prospective cohort, maternal serum vitamin D and CRP were measured at a median of 13 weeks' gestation. Vitamin D status was defined as deficient (≤29.9 nM), insufficient (30-49.9 nM), sufficient (50-79.9 nM), or normal (≥80 nM). Maternal depressive symptoms (Center for Epidemiologic Studies-Depression) and anxiety (State-Trait Anxiety Inventory) were assessed 3 months postpartum., Results: After adjustments for confounders, vitamin D deficiency was only associated with increased postpartum anxiety symptoms ( B = 0.17, 95% confidence interval [CI] = 0.03-0.30, p = .017) compared to normal vitamin D levels (≥80 nM). In women not taking vitamin D supplementation ( n = 2303), vitamin D deficiency was associated with increased postpartum depressive and anxiety symptoms ( B = 0.14, 95% CI = 0.03-0.28, p = .045; and B = 0.17, 95% CI = 0.03-0.32, p = .015). Antepartum CRP did not mediate these links., Conclusions: We found some evidence that antepartum vitamin D deficiency was associated with increased postpartum affective symptoms, especially in women not taking vitamin D supplementation. Clinical trials should determine whether vitamin D supplementation can reduce the risk for postpartum affective disorders., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Objective: To investigate the association between thyroid peroxidase antibody (TPOAb) positivity in the first trimester and maternal metabolic syndrome in pregnancy., Methods: The study retrospectively reviewed the medical records for 787 pregnant women. Serum-free thyroid hormone, thyroid stimulating hormone, and TPOAb levels were measured in early pregnancy (<13 weeks gestation). Baseline demographics, clinical characteristics, thyroid function, and pregnancy outcomes were compared between women who were TPOAb positive or TPOAb negative in the first trimester. Associations between TPOAb positivity in the first trimester and the occurrence of gestational diabetes mellitus, hypertensive disorders complicating pregnancy (HDCP), maternal metabolic syndrome in pregnancy, and adverse pregnancy outcomes were explored., Results: Data for 787 women with a singleton pregnancy were included in the analyses. In women who were TPOAb positive compared to TPOAb negative in the first trimester, baseline HDL-C was significantly lower (1.51 [1.33, 1.81] vs. 1.62 [1.40, 1.87], p =  0.028), and there was a significantly higher incidence of HDCP (15.8% vs. 6%, p  < 0.0001), maternal metabolic syndrome in pregnancy (18.8% vs 6.4%, p  < 0.0001) or preeclampsia (7% vs, 2.5%, p  = 0.024). There was a significant nonlinear association between TPOAb levels in the first trimester and the incidence of HDCP or maternal metabolic syndrome in pregnancy (both p  < 0.001). The logit of the probability of having HDCP or maternal metabolic syndrome in pregnancy increased rapidly at TPOAb (log 10 ) ≤ 1.5 (TPOAb (log 10 ) = 1.07 as reference). After adjusting for confounders (maternal age, pre-pregnancy BMI, gravidity, parity and history of adverse events during pregnancy), there was a significantly higher risk of HDCP (odds ratio [OR], 3.029; 95% confidence interval [CI], 1.586, 5.622, p  = 0.001), maternal metabolic syndrome in pregnancy (OR, 2.841; 95% CI, 1.473-5.260, p  = 0.001), or preeclampsia (OR 3.315, 95% CI 1.305-7.788, p  = 0.008) in women who were TPOAb positive compared to TPOAb negative in the first trimester., Conclusion: TPOAb positivity in the first trimester may increase the risk of HDCP, maternal metabolic syndrome in pregnancy, and preeclampsia, emphasizing the need for universal screening for thyroid disorders and better diagnostic criteria and management strategies for metabolic disorders during pregnancy.

Background: To explore the relationship between maternal glycaemic control and fetal abdominal circumference in pregnancies complicated by T1D., Methods: This is a retrospective cohort study of 81 pregnant women with T1D using CGM. Inclusion criteria were T1D, CGM use, ≥2 in-house ultrasounds, and the birth of a live singleton neonate between 1st December 2019 and 1st December 2022. Linear regression analysis was used to assess the cross-sectional relationships between estimated fetal abdominal circumference (AC) on ultrasound and time in range (TIR) at matched time-points in the third trimester of pregnancy. Linear regression analysis was also used to examine whether first trimester TIR and HbA1c predicts third trimester fetal AC., Results: At baseline, the mean ± standard deviation (SD) of the first trimester HbA1c was 7.0 ± 1.4% and mean ± SD total daily dose (TDD) insulin was 46.6 ± 21.0 units. The mean ± SD birthweight was 3367.0 ± 861.3 grams. There was no cross-sectional relationship between TIR and fetal AC at 28-, 32- or 36-week' gestation. The results of the regression analysis indicate a significant relationship between first trimester TIR (independent predictor) and fetal AC (dependent variable) at 32- and 36-weeks' gestation while controlling for maternal age, BMI, pump use, and TDD insulin (Adj β= -0.42, 95%CI -0.80 to -0.03 and Adj β = - 0.57, 95%CI -1.02 to -0.12 at 32- and 36-weeks respectively). Although there was a significant relationship between first trimester HbA1c and fetal AC at 32-weeks' gestation ( β =  3.81, 95%CI 0.29 to 7.33), the relationship was not significant after adjustment for confounders., Conclusions: There was no cross-sectional relationship between TIR and fetal AC in the third trimester of pregnancy but first trimester TIR did predict fetal AC in late pregnancy.

Objective: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder. Late-onset (Lo)-PE can cause serious complications in both the mother and child. This study aimed to explore biomarkers for elucidating the mechanisms underlying Lo-PE, via a metabolomic analysis of first-trimester maternal serum., Methods: This study was conducted at Fukushima Regional Center as an adjunct to Japan Environment and Children Study and included 12 patients with Lo-PE matched to 12 women with healthy pregnancies. Capillary electrophoresis-mass spectrometry-based quantitative analyses of charged metabolites were performed on first-trimester maternal serum samples., Results: Overall, 183 charged metabolites were identified. The peak area of glucosamine was significantly higher for the first-trimester sera of patients with Lo-PE than that for controls. Conversely, the peak area of serotonin was significantly decreased in the sera of patients with Lo-PE., Conclusions: During early pregnancy, glucosamine and serotonin levels in maternal serum may serve as early biomarkers for Lo-PE. As part of preconception care, pre-pregnancy dietary habits and mental health could potentially prevent Lo-PE onset.

Objective: Studies have shown that members of the salusin family regulate the migration and proliferation of arterial smooth muscle cells and increase the tendency to atherosclerosis through fibrosis and calcification in the vascular wall. However, the effect of salusins on the uterine artery has not yet been investigated. This study was conducted to investigate whether serum salusin alpha and beta concentrations in the first trimester are associated with diastolic notching in uterine artery Doppler., Methods: This non-interventional cohort study was conducted on 88 pregnant women, 44 of whom had diastolic notching on unilateral or bilateral uterine artery Doppler, and 44 of whom did not have diastolic notching on uterine artery Doppler. The uterine artery notch positive and negative groups were compared in terms of serum salusin alpha and beta concentrations., Results: The two groups were similar in terms of demographic characteristics ( p  < 0.05). The median salusin alpha concentration was found to be 689.4 pg/ml in the uterine artery notch positive group, while it was 734.6 pg/ml in the uterine artery notch negative group ( p  = 0.608). The median salusin beta concentration was found to be 674.5 pg/ml in the uterine artery notch positive group, while it was 693.8 pg/ml in the uterine artery notch negative group ( p  = 0.453).Participants were regrouped into normal and high uterine artery resistance and compared in terms of serum salusin alpha and beta concentrations. The median salusin alpha concentration was found to be 994.5 pg/ml in the high uterine artery PI group, while it was 685.2 pg/ml in the normal uterine artery PI group ( p  = 0.698). The median salusin beta concentration was found to be 1,100.8 pg/ml in the high uterine artery PI group, while it was 669.1 pg/ml in the normal uterine artery PI group ( p  = 0.584)., Conclusion: Although the sample size was too small to draw a definitive conclusion, our results indicate that uterine artery diastolic notching or increased resistance in the uterine artery does not appear to be associated with serum salusin alpha or beta concentrations.

Objective: To screen plasma metabolic markers in patients with unexplained recurrent spontaneous abortion (URSA) by non-target metabolomics approach. Methods: From September 2022 to May 2023, the plasma of 23 URSA pregnant women with threatened abortion who visited the outpatient clinic of Gansu Provincial Maternity and Child-care Hospital in the first trimester (URSA group) was collected, and the plasma of 22 healthy pregnant women in the first trimester who underwent prenatal examination during the same period (normal control group) was collected. Plasma metabolomics was analyzed by ultra performance liquid chromatography (UPLC) coupled with mass spectrometry (MS), fold change analysis, principal component analysis and partial least square discriminant analysis were applied to screen for differential metabolites, and the metabolites and their pathways associated with URSA were screened using receiver operating characteristic (ROC) curve and pathway enrichment analysis. Results: There were no significant differences in age, body mass index and gestational weeks between URSA and normal control group(all P <0.05). Metabolomics analysis using UPLC-MS showed that a total of 526 metabolites were detected from plasma, of which 33 were found to be differential metabolites associated with URSA based on the screening standards. Six potential metabolites with large area under the curve (AUC) were identified by ROC curve analysis, including phosphatidylethanolamine (AUC=0.972, 95% CI : 0.920-1.000), santene hydrate (AUC=0.902, 95% CI : 0.786-0.982), L-leucine (AUC=0.884, 95% CI : 0.772-0.960), cembrene (AUC=0.881, 95% CI : 0.758-0.956), caffeine (AUC=0.875, 95% CI : 0.756-0.962), and 4-hydroxybenzoic acid propyl ester (AUC=0.864, 95% CI : 0.732-0.946). The AUC for the combined diagnosis of URSA by the six metabolites was 0.983 (95% CI : 0.929-1.000). Pathway enrichment analysis of the differential metabolites showed that the pathogenesis of URSA was associated with a variety of metabolic pathways including caffeine metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis. Conclusion: The plasma metabolic profiles of pregnant women with normal pregnancies versus URSA differ in early pregnancy, and six potential metabolites such as phosphatidylethanolamine, santene hydrate, L-leucine, cembrene, caffeine, 4-hydroxybenzoic acid propyl ester, and their metabolic pathways may be involved in the pathogenesis of URSA.

Background: The congenital ventricular outflow tract malformations (CVOTMs) is a major congenital heart diseases (CHDs) subtype, and its pathogenesis is complex and unclear. Lipid metabolic plays a crucial role in embryonic cardiovascular development. However, due to the limited types of detectable metabolites in previous studies, findings on lipid metabolic and CHDs are still inconsistent, and the possible mechanism of CHDs remains unclear., Methods: The nest case-control study obtained subjects from the multicenter China Teratology Birth Cohort (CTBC), and maternal serum from the pregnant women enrolled during the first trimester was utilized. The subjects were divided into a discovery set and a validation set. The metabolomics of CVOTMs and normal fetuses were analyzed by targeted lipid metabolomics. Differential comparison, random forest and lasso regression were used to screen metabolic biomarkers., Results: The lipid metabolites were distributed differentially between the cases and controls. Setting the selection criteria of P value < 0.05, and fold change (FC) > 1.2 or < 0.833, we screened 70 differential metabolites. Within the prediction model by random forest and lasso regression, DG (14:0&#95;18:0), DG (20:0&#95;18:0), Cer (d18:2/20:0), Cer (d18:1/20:0) and LPC (0:0/18:1) showed good prediction effects in discovery and validation sets. Differential metabolites were mainly concentrated in glycerolipid and glycerophospholipids metabolism, insulin resistance and lipid & atherosclerosis pathways, which may be related to the occurrence and development of CVOTMs., Conclusion: Findings in this study provide a new metabolite data source for the research on CHDs. The differential metabolites and involved metabolic pathways may suggest new ideas for further mechanistic exploration of CHDs, and the selected biomarkers may provide some new clues for detection of COVTMs., (© 2024. The Author(s).)

Background: Remnant cholesterol (RC) reportedly contributes to the development of diabetes mellitus. However, evidence on the relationship between maternal RC and the risk of developing gestational diabetes mellitus (GDM) during pregnancy is limited. This study aimed to assess the relationship between maternal RC and GDM risk during early pregnancy, and explore the potential pathways involved in the relationship between RC levels and GDM risk., Methods: From 2018 to 2021, a prospective birth cohort study was designed and carried out in China. The associations of maternal RC and other lipid parameters with GDM risk were estimated using logistic regression models and restricted cubic splines. Subgroup analyses were performed stratified by prepregnancy body mass index (pre-BMI), maternal age and gravidity. Mediation analyses were conducted to explore the mediating effect of some related factors on the relationship between RC levels and the risk of GDM., Results: A total of 33,018 pregnant women were included. The median RC level was 0.47 ± 0.20 mmol/L. The prevalence of GDM was 15.19%. As RC quartiles increased, the incidence of GDM increased substantially, reaching 19.24% for the highest quartile of RC (P < 0.001). Maternal RC in the first trimester was positively correlated with GDM risk (OR: 2.254, 95% CI: 1.943-2.615). Compared to the lowest RC quartile, higher RC quartiles were correlated with an increased risk of GDM, and the ORs (95% CIs) for Q3 and Q4 were 1.208 (1.101-1.325) and 1.489 (1.364-1.626), respectively. Moreover, a linear dose-response relationship was found for this association (P for all < 0.001, P for nonlinearity > 0.05) and was consistent across subgroups with different pre-BMIs, maternal ages and gravidities (all P values for interactions > 0.05). Furthermore, the correlation between RC level and GDM risk was partially mediated by pre-BMI (9.20%) and blood glucose level (-11.1%)., Conclusions: Higher maternal RC levels in the early stage of pregnancy was positively associated with an increased risk of developing GDM. This association was partially mediated by pre- BMI and blood glucose levels., (© 2024. The Author(s).)

Background: Gestational diabetes mellitus (GDM) can result in adverse maternal and neonatal outcomes. Predicting those at high risk of GDM and early interventions can reduce the development of GDM. The aim of this study was to examine the associations between first-trimester prenatal screening biomarkers and maternal characteristics in relation to GDM in Chinese women., Methods: We conducted a retrospective cohort study of singleton pregnant women who received first-trimester aneuploidy and preeclampsia screening between January 2019 and May 2021. First-trimester prenatal screening biomarkers, including pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotropin, and placental growth factor (PLGF), along with maternal characteristics, were collected for analysis in relation to GDM. Receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate variables associated with GDM., Results: Of the 1452 pregnant women enrolled, 96 developed GDM. PAPP-A (5.01 vs. 5.73 IU/L, P < 0.001) and PLGF (39.88 vs. 41.81 pg/mL, P = 0.044) were significantly lower in the GDM group than in the non-GDM group. The area under the ROC curve of combined maternal characteristics and biomarkers was 0.73 (95% confidence interval [CI] 0.68-0.79, P < 0.001). The formula for predicting GDM was as follows: P = 1/[1 + exp (-8.148 + 0.057 x age + 0.011 x pregestational body mass index + 1.752 x previous GDM history + 0.95 x previous preeclampsia history + 0.756 x family history of diabetes + 0.025 x chronic hypertension + 0.036 x mean arterial pressure - 0.09 x PAPP-A - 0.001 x PLGF)]. Logistic regression analysis revealed that higher pregestational body mass index (adjusted odds ratio [aOR] 1.03, 95% CI 1.01 - 1.06, P = 0.012), previous GDM history (aOR 9.97, 95% CI 3.92 - 25.37, P < 0.001), family history of diabetes (aOR 2.36, 95% CI 1.39 - 4.02, P = 0.001), higher mean arterial pressure (aOR 1.17, 95% CI 1.07 - 1.27, P < 0.001), and lower PAPP-A level (aOR 0.91, 95% CI 0.83 - 1.00, P  = 0.040) were independently associated with the development of GDM. The Hosmer-Lemeshow test demonstrated that the model exhibited an excellent discrimination ability (chi-square = 3.089, df = 8, P = 0.929)., Conclusion: Downregulation of first-trimester PAPP-A and PLGF was associated with the development of GDM. Combining first-trimester biomarkers with maternal characteristics could be valuable for predicting the risk of GDM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Chen, Sun, Chen, Wang and Chen.)

Background: Gestational diabetes mellitus (GDM) significantly impacts maternal and infant health both immediately and over the long term, yet effective early diagnostic biomarkers are currently lacking. Thus, it is essential to identify early diagnostic biomarkers for GDM risk screening. Extrachromosomal circular DNA (eccDNA), being more stable than linear DNA and involved in disease pathologies, is a viable biomarker candidate for diverse conditions. In this study, eccDNA biomarkers identified for early diagnosis and assessment of GDM risk were explored., Methods: Using Circle-seq, we identified plasma eccDNA profiles in five pregnant women who later developed GDM and five matched healthy controls at 11-13 weeks of gestation. These profiles were subsequently analyzed through bioinformatics and validated through outward PCR combined with Sanger sequencing. Furthermore, candidate eccDNA was validated by quantitative PCR (qPCR) in a larger cohort of 70 women who developed GDM and 70 normal glucose-tolerant (NGT) subjects. A ROC curve assessed the eccDNA's diagnostic potential for GDM., Results: 2217 eccDNAs were differentially detected between future GDM patients and controls, with 1289 increased and 928 decreased in abundance. KEGG analysis linked eccDNA genes mainly to GDM-related pathways such as Rap1, MAPK, and PI3K-Akt, and Insulin resistance, among others. Validation confirmed a significant decrease in eccDNA PRDM16 circle in the plasma of 70 women who developed GDM compared to 70 NGT women, consistent with the eccDNA-seq results. PRDM16 circle showed significant diagnostic value in 11-13 weeks of gestation (AUC = 0.941, p < 0.001)., Conclusions: Our study first demonstrats that eccDNAs are aberrantly produced in women who develop GDM, including PRDM16 circle , which can predict GDM at an early stage of pregnancy, indicating its potential as a biomarker., Trial Registration: ChiCTR2300075971, http://www.chictr.org.cn . Registered 20 September 2023., (© 2024. The Author(s).)

Purpose: To examine the effects of first-trimester HbA1c (HbA1c-FT) ≥ 37 mmol/mol on preterm birth (PTB) and large-for-gestational-age (LGA) babies in a retrospective cohort of South Asian pregnant women with gestational diabetes (GDM)., Methods: The cohort (n = 686) was separated into two groups based on HbA1c-FT values: Group A (n = 97) and Group B (n = 589), with values of 37-46 mmol/mol (5.5-6.4%) and < 37 mmol/mol (5.5%), respectively. HbA1c-FT's independent influence on PTB and LGA babies was examined using multivariable logistic regression in groups A and B women. The reference group (Group C) included 2031 non-GDM women with HbA1c-FT < 37 mmol/mol (< 5.5%). The effects of HbA1c-FT on PTB and LGA babies in obese women in Groups A, B, and C (designated as A-ob, B-ob, and C-ob, respectively) were re-analyzed using multivariable logistic regression., Results: Group A GDM women with greater HbA1c-FT had a higher risk for PTB (aOR:1.86, 95% CI:1.10-3.14) but not LGA babies (aOR:1.13, 95%: 0.70-1.83). The risk of PTB was higher for obese women in Group A-ob: aOR 3.28 [95% CI 1.68-6.39]. However, GDM women with normal HbA1c-FT exhibited no elevated risk for PTB: Groups B and B-ob had aORs of 1.30 (95% CI 0.86-1.98) and 1.28 (95% CI 0.88-1.85) respectively., Conclusions: South Asian GDM women with prediabetic HbA1c FT; 37-46 mmol/mol (5.5-6.4%) are more likely to deliver preterm babies despite treatment, while the risk for LGA babies was the same as non-GDM women., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aimed to evaluate the association between maternal liver biomarkers in early pregnancy and the risk of hypertensive disorders of pregnancy (HDP), as well as to evaluate interaction between liver enzymes and BMI on the development of HDP. Pregnant women in our study were recruited from the Zhoushan Pregnant Women Cohort. Participants who had their first prenatal follow-up and the blood pressure follow-up records, and measured liver biomarkers in the first trimester were eligible for inclusion in the study. A total of 10,610 pregnant women were included in the analysis, and 305 (2.87%) developed the HDP. There were positive associations between AST, GGT, ALP, HSI and SBP, as well as between ALT, GGT, ALP, HSI and DBP. In addition, AST/ALT level was negatively associated with DBP. The highest quartile of GGT, ALP, AST/ALT and HSI were significantly associated with 1.71-fold (95% Cl: 1.23-2.41), 1.53-fold (95% Cl: 1.10-2.14), 0.62-fold (95% Cl: 0.43-0.90) and 1.67-fold (95% Cl: 1.05-2.67) increased risk of HDP, respectively. There was no significant association between ALT, AST and HDP. These associations remained consistent in pregnant women with liver enzymes within the clinical reference range. Besides, we found an interaction between GGT and BMI (P interaction  = 0.013) in the development of HDP. In summary, the level of GGT, ALP, AST/ALT and HSI were associated with the subsequent risk of HDP, even within the clinical reference range. And there was an interaction between liver biomarkers and BMI in the development of HDP. Our study showed the level of GGT, ALP, AST/ALT and HSI were associated with the subsequent risk of HDP. And there was an interaction between GGT and BMI in the risk of HDP., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Understanding the prenatal origins of children's psychopathology is a fundamental goal in developmental and clinical science. Recent research suggests that inflammation during pregnancy can trigger a cascade of fetal programming changes that contribute to vulnerability for the emergence of psychopathology. Most studies, however, have focused on a handful of proinflammatory cytokines and have not explored a range of prenatal biological pathways that may be involved in increasing postnatal risk for emotional and behavioral difficulties., Methods: Using extreme gradient boosted machine learning models, we explored large-scale proteomics, considering over 1,000 proteins from first trimester blood samples, to predict behavior in early childhood. Mothers reported on their 3- to 5-year-old children's (N = 89, 51% female) temperament (Child Behavior Questionnaire) and psychopathology (Child Behavior Checklist)., Results: We found that machine learning models of prenatal proteomics predict 5%-10% of the variance in children's sadness, perceptual sensitivity, attention problems, and emotional reactivity. Enrichment analyses identified immune function, nervous system development, and cell signaling pathways as being particularly important in predicting children's outcomes., Conclusions: Our findings, though exploratory, suggest processes in early pregnancy that are related to functioning in early childhood. Predictive features included far more proteins than have been considered in prior work. Specifically, proteins implicated in inflammation, in the development of the central nervous system, and in key cell-signaling pathways were enriched in relation to child temperament and psychopathology measures., (© 2024 Association for Child and Adolescent Mental Health.)

Objectives: Placental abruption (PA) is associated with adverse maternal and neonatal outcomes and has an etiological mechanism that is not yet fully understood. The prediction of PA, which has been the subject of numerous studies, remains a challenge. In particular, there is evidence that PA can be considered a chronic process. So, this study aimed to show inflammatory biomarkers based on complete blood count parameters may be used to predict PA., Study Design: A sample of 110 cases (pregnant women with PA) and 110 controls (healthy pregnant women with spontaneous labor) were required the study. The present case-control study included a total of 220 pregnant women. Inflammatory makers were used to evaluate the PA prediction RESULTS: Increases in body mass index, mean corpuscular volume and paletelet lymphocyte ratio are considered protective factors, while increases in neutrophil, the systemic inflammatory response index, neutrophil lymphocyte ratio and the pan-immune inflammation score are considered risk factors. Each 1 unit increase in neutrophil count increases the risk of a PA diagnosis by 1.81 times., Conclusion: Recent studies indicate a strong heterogeneity of clinical courses leading to PA in premature and term births. In the present study, our results showed that, inflammation is associated with PA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study aimed to investigate the effects of the presence of subchorionic hematoma (SH) in early pregnancies with threatened miscarriage (TM) on levels of first-trimester maternal serum markers, pregnancy-associated plasma protein-A (PAPP-A), and free β-human chorionic gonadotropin (β-hCG) levels., Methods: The data of TM cases with SH in the first trimester between 2015 and 2021 were evaluated retrospectively. The data of age and gestational age-matched TM cases without SH were also assessed to constitute a control group. Demographic characteristics, obstetric histories, ultrasonographic findings, and free β-hCG and PAPP-A levels of the groups were compared., Results: There were 119 cases in the study group and 153 cases in the control group. The median vertical and longitudinal lengths of the SH were 31 mm and 16 mm. The median age of both groups was similar (p=0.422). The MoM value of PAPP-A was 0.088 (.93) in the study group and 0.9 (0.63) in the control group (p=0.519). Similarly, the MoM value of free β-hCG was 1.04 (0.78) in the study group and 0.99 (0.86) in the control group (p=0.66). No significant relationship was found in the multivariate analysis between free β-hCG MoM, PAPP-A MoM, age, gravida, and vertical and longitudinal lengths of the hematoma (p>0.05)., Conclusion: The level of PAPP-A and free β-hCG were not affected by the SH. Therefore, these markers can be used reliably in TM cases with SH for the first-trimester fetal aneuploidy screening test., Competing Interests: Conflicts to interest: none to declare.

Background: In order to identify and possibly offer prophylactic treatment to women at risk for preterm birth (PTB), novel prediction models for PTB are needed. Our objective was to utilize high-sensitive plasma protein profiling to investigate whether early prediction of spontaneous PTB (sPTB) before 34 gestational weeks (gw) was possible in a low-risk population., Methods: A case-control study was conducted on 46 women with sPTB before 34 gw and 46 women with normal pregnancies and term deliveries. Prospectively collected plasma sampled at gw 11 (range 7-16) and gw 25 (range 23-30) was analyzed with a high-sensitivity Proximity Extension Assay for levels of 177 inflammation-associated proteins, and statistically processed with multivariate logistic regression analysis., Results: In the first trimester, higher levels of hepatocyte growth factor (HGF) were associated with sPTB <34 gw (OR 1.49 (1.03-2.15)). In the second trimester, higher levels of interleukin (IL)-10 (OR 2.15 (1.18-3.92)), IL-6 (OR 2.59 (1.34-4.99)), and the receptor activator of nuclear factor κB (RANK) (OR 2.18 (1.26-3.77)) were associated with sPTB <34 gw. The area under the curve for the prediction models including these proteins was 0.653 (0.534-0.759) in the first trimester and 0.854 (0.754-0.925) in the second trimester., Conclusion: A combination of inflammation-associated plasma proteins from the second trimester of pregnancy showed a good predictive ability regarding sPTB before 34 gw, suggesting it could be a valuable supplement for the assessment of the clinical risk of sPTB. However, although a high number (n=177) of plasma proteins were analyzed with a high-sensitivity method, the prediction of sPTB in the first trimester remains elusive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Svenvik, Raffetseder, Brudin, Berg, Hellberg, Blomberg, Jenmalm and Ernerudh.)

Background: A role for prenatal steroid hormones in the etiology of autism has been proposed, but evidence is conflicting., Methods: Here, we examined serum levels of maternal estradiol, testosterone, 17-hydroxyprogesterone (OHP), and cortisol from the first trimester of gestation (mean = 10.1 weeks) in relation to the odds of diagnosed autism with and without co-occurring intellectual disability (ID) in the offspring (n = 118 autism with ID, n = 249 autism without ID, n = 477 control). Levels of maternal hormones were measured using highly sensitive liquid chromatography tandem mass spectrometry, standardized according to gestational timing of sample collection, and analyzed with restricted cubic spline logistic regression models adjusting for child's sex and maternal health, demographic, and socioeconomic factors., Results: We observed significant nonlinear associations between maternal estradiol, 17-OHP, and cortisol with autism, which varied with the presence of co-occurring ID. Compared to mean levels, lower levels of estradiol were associated with higher odds of autism with ID (odds ratio for concentrations 1 SD below the mean = 1.66; 95% CI, 1.24-2.11), while higher cortisol levels were associated with lower odds (odds ratio for 1 SD above the mean = 0.55; 95% CI, 0.36-0.88). In contrast, higher 17-OHP was associated with increased odds of autism without ID (odds ratio for 1 SD above the mean = 1.49; 95% CI, 1.11-1.99). We observed no evidence for interaction with sex of the child., Conclusions: These findings support the notion that the maternal steroid hormonal environment in early pregnancy may contribute to autism, but also emphasize the complex relationship between early-life steroid exposure and autism., (Copyright © 2024. Published by Elsevier Inc.)

In this investigation, we explored the correlation between first-trimester biochemical markers and the incidence of preterm birth (PTB), irrespective of the cause, spontaneous preterm birth (sPTB), and preterm premature rupture of membranes (pPROM) within a cohort comprising 1164 patients. It was discovered that diminished levels of Pregnancy-Associated Plasma Protein-A (PAPP-A) between 11 and 13 + 6 weeks of gestation significantly contributed to the risk of preterm deliveries both before 35 and 37 weeks, as well as to pPROM instances. Furthermore, women experiencing sPTB before the 37th week of gestation also exhibited lower concentrations of PAPP-A. Moreover, reduced first-trimester concentrations of free beta-human chorionic gonadotropin (fb-HCG) were identified as a risk factor for deliveries preceding 37 weeks, pPROM, and sPTB before 35 weeks of gestation. Despite these correlations, the area under the curve for these biochemical markers did not surpass 0.7, indicating their limited diagnostic potential. The most significant discriminatory capability was noted for PAPP-A levels, with a threshold of < 0.71 multiples of the median (MoM) predicting PTB before 37 weeks, yielding an odds ratio of 3.11 (95% Confidence Interval [CI] 1.97-4.92). For sPTB, the greatest discriminatory potential was observed for PAPP-A < 0.688, providing an OR of 2.66 (95% CI 1.51-4.66). The cut-off points corresponded to accuracies of 76.05% and 79.1%, respectively. In regression analyses, the combined predictive models exhibited low explanatory power with R 2 values of 9.2% for PTB and 7.7% for sPTB below 35 weeks of gestation. In conclusion, while certain biochemical markers demonstrated associations with outcomes of preterm birth, their individual and collective predictive efficacies for foreseeing such events were found to be suboptimal., (© 2024. The Author(s).)

Background: Vitamin D deficiency is associated with several obstetric complications in singleton pregnancy. The aim of this study was to assess whether vitamin D levels affect the outcomes of twin pregnancy and if targeted supplementation can improve perinatal outcomes., Methods: The serum vitamin D levels of 143 women with twin pregnancies were measured during their first trimester. Those with insufficient (10-30 ng/mL; IL group) or severely deficient (<10 ng/mL, DL group) vitamin D levels were supplemented. In the third trimester, vitamin D levels were reassessed. Perinatal outcomes of the IL and DL groups were compared with those of patients with sufficient levels (>30 ng/mL, SL group) since the beginning of pregnancy., Results: Women in the IL and DL groups had a higher incidence of hypertensive disorders of pregnancy (HDP) compared to the SL group (24.8% and 27.8% vs. 12.5%, p = 0.045): OR = 1.58 for the IL group and 1.94 for the DL group compared to the SL group. In patients whose vitamin D levels were restored after supplementation, HDP incidence was lower than in patients who remained in the IL or DL groups (23.4% vs. 27.3%) but higher than those who were always in the SL group (12.5%)., Conclusions: Insufficient or severely deficient levels of vitamin D in the first trimester are associated with an increased risk of HDP in twin pregnancy. The beneficial effect of targeted vitamin D supplementation in reducing HDP seems limited.

Non-invasive prenatal testing (NIPT) is usually performed beyond 10 weeks of gestation, because earlier in pregnancy, the fetal fraction is low, resulting in failure to obtain reliable results. This study aimed to evaluate the clinical performance of NIPT earlier in pregnancy using a method for cell-free DNA (cfDNA) analysis that eliminates the need for polymerase chain reaction (PCR), DNA sequencing, or microarrays (Vanadis ® system, PerkinElmer, Waltham, MA, USA). Cell-free DNA was extracted from the maternal plasma of 30 singleton pregnancies at 6-9 weeks of gestation (group 1) and at 11-14 weeks of gestation of the same patients (group 2). The mean crown-rump length (CRL) and gestational age in group A was 16.12 mm and that in group B was 61.45 mm. In group A, results were obtained in all, but one, cases (97%). From the remaining pregnancies, one miscarried at 8 weeks and, therefore, the follow-up NIPT at 12 weeks could not be performed. The fetal sex was diagnosed correctly in the 28 cases that had a successful early test, and the results were in accordance with the examination at 12 weeks. There were no cases of aneuploidies and disomy was diagnosed correctly in all. The "Vanadis" prenatal NIPT assay can successfully be used early during the first trimester at 6-9 weeks of gestation (early NIPT) to identify the fetal sex. Further studies are needed to explore the diagnostic potential for aneuploidies.

Objective: This study aimed to investigate the association of maternal first-trimester vitamin D levels and vitamin D supplementation during pregnancy with infant atopic dermatitis (AD) and to determine the effect of variables such as mode of conception on the association., Methods: This study was based on the Shanghai sub-cohort of the International Birth Cohort of China. A total of 4051 woman-infant pairs with singleton pregnancies were recruited. Vitamin D deficiency and insufficiency were defined as serum 25-hydroxyvitamin D concentrations of 25 and 50 nmol/L, respectively. AD in infants was assessed during the first six months using a standardized questionnaire based on the British Working Party criteria. Modified Poisson regression estimated the association between maternal vitamin D status and infant AD., Results: The risk of AD in infants was higher in women with deficient 25-hydroxyvitamin D levels in the first trimester (RR: 1.77, 95% CI: 1.41-2.23). This increased risk was seen in naturally conceived pregnancies, but not in those conceived using assisted reproductive technology (ART). The incidence of AD decreased in infants of mothers who took multi-vitamin (RR: 0.79, 95% CI: 0.67-1.98) and vitamin D supplements (RR: 0.51, 95% CI: 0.37-0.71) compared to those whose mothers did not take any supplements. Maternal vitamin D deficiency had varying effects on AD risk based on passive smoking exposure and breastfeeding patterns., Conclusions: Our findings highlight the importance of monitoring and supplementing vitamin D during pregnancy, especially in specific maternal populations, to reduce the risk of AD in offspring.

Purpose: Preeclampsia (PE) is one of the most common and serious complications of pregnancy, and novel methods for the early prediction of PE are needed for clinical application., Methods: In this study, a circulating cell-free RNA (cfRNA) panel of target genes for PE prediction was designed and validated in a case-control cohort and a nested case-control cohort. The QPCR was applied to quantify the copy number of cfRNA, and the data were normalized as multiples of the median. Ratios of serum placental growth factor (PIGF) and soluble fms-like tyrosine kinase 1 (sFLT-1) were also measured, and transabdominal ultrasonography was conducted for subjects in the prospective cohort. Binary logistic regression models for PE prediction were constructed and tested., Results: Our results revealed that the women with PE showed significant alterations in serum cfRNA profiles from early pregnancy onward and before the onset of PE symptoms. Compared with PIGF/sFLT-1 measurement and ultrasonographic imaging, cfRNA test can detect PE at a very early stage of pregnancy. The predictive model exhibited the best performance at gestation week 32, with a detection rate of 100%. At 12 weeks of gestation, the model still manifested an area under curve (AUC) of 0.9144, and sensitivity of 1.0000. If combined with clinical parameters and ultrasonographic indicators, the model can achieve the highest AUC for PE prediction at early gestation., Conclusion: Measurement of cfRNA can be used to effectively predict PE with high performance, providing an additional method for monitoring PE throughout the course of pregnancy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to determine the association of first-trimester maternal serum biomarkers with preterm birth (PTB), fetal growth restriction (FGR) and hypertensive disorders of pregnancy (HDP) in twin pregnancies., Methods: This is a retrospective cohort study of twin pregnancies followed at Maternidade Dr. Alfredo da Costa, Lisbon, Portugal, between January 2010 and December 2022. We included women who completed first-trimester screening in our unit and had ongoing pregnancies with two live fetuses, and delivered after 24 weeks. Maternal characteristics, pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-hCG) levels were analyzed for different outcomes: small for gestational age (SGA), gestational hypertension (GH), early and late-onset pre-eclampsia (PE), as well as the composite outcome of PTB associated with FGR and/or HDP. Univariable, multivariable logistic regression analyses and receiver-operating characteristic curve were used., Results: 466 twin pregnancies met the inclusion criteria. Overall, 185 (39.7%) pregnancies were affected by SGA < 5th percentile and/or HDP. PAPP-A demonstrated a linear association with gestational age at birth and mean birth weight. PAPP-A proved to be an independent risk factor for SGA and PTB (< 34 and < 36 weeks) related to FGR and/or HDP. None of the women with PAPP-A MoM > 90th percentile developed early-onset PE or PTB < 34 weeks., Conclusion: A high serum PAPP-A (> 90th percentile) ruled out early-onset PE and PTB < 34 weeks. Unless other major risk factors for hypertensive disorders are present, these women should not be considered candidates for aspirin prophylaxis. Nevertheless, close monitoring of all TwP for adverse obstetric outcomes is still recommended., (© 2024. The Author(s).)