Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals used in consumer and industrial products, and have been linked with adverse pregnancy outcomes, including altered fetal growth. Few studies, however, have investigated associations between PFAS and longitudinal measures of fetal growth. Examine associations between prenatal PFAS and ultrasound measures [femur length (FL), head circumference (HC), abdominal circumference (AC)], and birthweight outcomes in the LIFECODES birth cohort. This study included 1220 participants from nested case-control studies within the LIFECODES cohort. We used generalized estimating equations to evaluate associations between six PFAS and repeated fetal growth measurements converted to gestational age (GA)-specific Z-scores, while multivariable linear and logistic regression models assessed associations with birthweight and size-for-GA [small-for-GA (SGA) and large-for-GA (LGA)], respectively. The effect of PFAS mixture was examined using quantile-based g-computation (qgcomp). All models were adjusted for maternal age, race/ethnicity, educational attainment, health insurance status, pre-pregnancy body mass index, parity, enrollment year, fetal sex, and aspects of study design. An interquartile range increase in perfluorooctanoic acid (PFOA) was associated with a 0.10 standard deviation (SD) increase in FL Z-score (95% CI: 0.02, 0.18). Positive associations with FL were more pronounced among African American participants [SD change: 0.26 (95% CI: -0.01, 0.53)] and male fetuses [SD change: 0.16 (95% CI: 0.05, 0.28)]. Qgcomp analyses showed similar positive associations with FL. Associations with birthweight outcomes were generally inconsistent, with certain PFAS associated with increased odds of LGA among females, while some PFAS were linked to lower odds of SGA across sexes. Prenatal PFAS exposure was modestly associated with increased FL, with some variations by fetal sex or maternal race. Future research should examine underlying biological mechanisms, clinical implications, and the influence of modifying factors such as psychosocial stress and maternal diet on the observed associations.

Associations of per- and polyfluoroalkyl substances (PFAS) exposure and thyroid hormone concentration during pregnancy in the LIFECODES cohort.

SARS-CoV-2 infection disrupts iron homeostasis in organs such as the lung. Emerging evidence suggests similar dysregulation in the placenta may impair function and fetal growth. Ferroptosis, an iron-dependent form of cell death, is driven by the accumulation of labile ferrous iron, catalyzing the peroxidation of polyunsaturated fatty acids in the absence of sufficient iron storage or antioxidant defenses. This pathway has been implicated in SARS-CoV-2-related tissue damage in other organs and may contribute to placental dysfunction during pregnancy. However, the influence of infection timing, symptom severity, and fetal sex on placental iron regulation remains unexamined. We analyzed placental samples from a cohort of SARS-CoV-2-exposed pregnancies in the first (n=6), second (n=14), or third trimester (n=30), classified by symptom severity (asymptomatic n=23, symptomatic n=27) and fetal sex, alongside unexposed controls (n=47). We assessed placental iron deposition, lipid peroxidation, and mRNA and protein expression of ferroptosis markers. Publicly available RNA-sequencing datasets from human placenta tissue, exposed or not to SARS-CoV-2, were analyzed to assess ferroptosis-related gene expression. SARS-CoV-2 infection, particularly in symptomatic cases, was associated with reduced placental weight and birth weight. Asymptomatic cases showed increased placental iron deposition, which correlated with lower birthweight and was accompanied by elevated expression of nuclear receptor coactivator 4, a cytosolic adaptor protein that mediates the selective autophagic degradation of ferritin (ferritinophagy) and iron release. Placentas from symptomatic patients exhibited evidence of altered iron transport and sex-specific down-regulation of antioxidant defenses. Transcriptomic analyses further suggested widespread disruption of ferroptosis pathways in placentas from infected patients. Our findings reveal that SARS-CoV-2 infection alters placental iron homeostasis and is associated with ferroptosis-related changes, with distinct molecular responses based on timing of infection, symptom severity, and fetal sex.

Vaginal bleeding in early pregnancy is associated with adverse pregnancy outcomes. Excess folic acid ingestion has shown potential adverse effects on pregnancy outcomes. However, little is known about the fetal sex-specific influence of excess folic acid supplementation on vaginal bleeding. We aimed to determine whether increasing folic acid supplementation is associated with vaginal bleeding in early pregnancy with respect to fetal sex. Two prospective cohorts of nulliparous pregnant women were accessed: prior to (SCOPE, n = 1164) and post (STOP, n = 1300) folic acid food fortification in Australia. Logistic regression was used to examine the relationship between folic acid supplementation and vaginal bleeding severity with fetal sex, as well as the relationship between vaginal bleeding and pregnancy outcomes, after adjusting for confounders. Reported spotting and mild vaginal bleeding was more common in STOP, compared with SCOPE. Women from the two cohorts who experienced spotting and mild vaginal bleeding in pregnancy were more likely to have supplemented with ≥ 800μg folic acid daily and had higher serum folate concentration, compared with no folic acid supplementation. Women who supplemented with ≥ 800μg folic acid per day, and with a male bearing pregnancy, had > twofold greater odds [adjOR 2.14, (95% CI) 1.15-3.99, SCOPE and STOP] of vaginal bleeding in early pregnancy which was more likely to be more severe compared to those who did not supplement. This association was stronger (adjOR 2.85, 95%CI 1.23-6.57) in the STOP cohort. Furthermore, vaginal bleeding was associated with spontaneous preterm birth (sPTB) without premature rupture of membranes, placental abruption and small for gestational age (SGA) and lower gestational age at birth, the latter of which showed a male-fetus dependence, based on total cases in the two cohorts combined. This study reveals a novel association between fetal sex and vaginal bleeding during early pregnancy, which is influenced by high folic acid intake. Our data suggest < 800μg/day folic acid supplementation post food fortification may be safer, especially in male-bearing pregnancy, consistent with guidelines that recommend 400μg/day folic acid to prevent neural tube defects. Vaginal bleeding in early pregnancy needs more clinical attention as it may be an indicator for later pregnancy adverse outcomes. SCOPE and STOP studies were registered with Australian New Zealand Clinical Trial Registry (ACTRN12607000551493; Registration date 26th October 2007 and ACTRN12614000985684; Registration date 12th September 2014, respectively).

Impacts of ambient temperature on pregnant women's cardiovascular function and variations related to fetal sex.

Low-dose aspirin is recommended to pregnant individuals at increased risk of preeclampsia to improve outcomes. We recently showed that low-dose aspirin improves uterine artery function in a rat model of excessive hypercholesterolemia (eHC) in pregnancy, a known risk factor for preeclampsia. However, its effects on placentas from male and female offspring remain unclear. Here, we examined how low-dose aspirin affects various placental inflammatory and angiogenic markers, as well as the maternal soluble fms-like tyrosine kinase receptor-1 (sFlt-1)/placental growth factor (PlGF) ratio, in eHC pregnancies. We hypothesized that low-dose aspirin reduces placental inflammation, leading to angiogenic balance in these pregnancies. Sprague Dawley rats were fed a control diet or a high cholesterol diet (to model eHC) from gestational day (GD)6 to 20, with placebo or low-dose aspirin administered from GD10 to 20. On GD20, placentas were collected and separated based on the fetal sex. eHC in pregnancy elevated maternal plasma sFlt-1 without altering PlGF, resulting in an increased sFlt-1/PlGF ratio; that did not occur with low-dose aspirin treatment. Moreover, placental sFlt-1 was increased in male, but not female, fetuses; and was reduced by low-dose aspirin. Placental PlGF was reduced in males, but increased in females, of eHC pregnancies; low-dose aspirin restored placental PlGF in only the female placentas. NLRP3 (a major placental inflammatory pathway) levels were increased in only eHC male placentas, and normalized by low-dose aspirin. These findings reveal that low-dose aspirin restores the maternal plasma sFlt-1/PlGF ratio and suppresses placental inflammation through sex-specific mechanisms in eHC pregnancies.

This longitudinal, prospective, multicenter observational cohort study investigates the associations between maternal nutritional status-assessed using the first trimester SIMPLE score and pregestational BMI-and fetal growth trajectories and velocity, as proxies for intrauterine development. Healthy women with singleton pregnancies undergoing first trimester screening were enrolled. Adherence to a healthy lifestyle was evaluated using the SIMPLE score, categorizing participants into low (<6) and high (≥6) adherence groups. Fetal growth parameters - including biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), estimated fetal weight (EFW)- were assessed during second and third trimester ultrasounds, and birth outcomes were recorded. Multi-adjusted linear mixed models examined associations between SIMPLE score groups, individual score items, pregestational BMI, and fetal growth, with analyses stratified by fetal sex. Out of 938 enrolled women, 109 (11.6%) were classified as the low adherence group. Multi-adjusted linear mixed models showed that low adherence was associated with decreased EFW acceleration from the second to the third trimester. Stratification by fetal sex confirmed the association only among male fetuses. Analysis of pregestational BMI and individual SIMPLE score items revealed significant positive associations between pregestational BMI, AC, and EFW growth velocity, and a negative association between first trimester hemoglobin [>110 g/l] and EFW growth velocity. Overall, these findings confirm the clinical utility of the SIMPLE score, demonstrating significant associations with intrauterine growth trajectories and velocity, independent of other markers of nutritional status (e.g., pregestational BMI).

To assess whether lifestyle interventions based on Mediterranean diet or stress reduction during pregnancy are associated with differences in fetal brain development detectable by two-dimensional magnetic resonance imaging (MRI) in a high-risk population for small-for-gestational-age neonates. This was a secondary analysis of the randomized controlled clinical trial, Improving Mothers for a better PrenAtal Care Trial BarCeloNa (IMPACT BCN), which enrolled 1221 singleton pregnancies at high-risk for a small-for-gestational-age neonate between February 2017 and March 2020. At midgestation, participants were randomly allocated into three groups: a Mediterranean diet intervention; a stress-reduction program; or usual care. A randomly selected subgroup (n = 124) underwent fetal brain MRI between 36.1 and 39.1 weeks' gestation and were analyzed offline. Offline analysis included measurements of biparietal diameter, occipitofrontal diameter, cortical sulci depth, corpus callosum length, vermis height and cerebellar transverse diameter. Differences in brain measurement between groups were analyzed by regression models adjusted for baseline maternal characteristics, gestational age at MRI assessment, fetal sex, fetal head size and MRI scanner model. Fetuses in the Mediterranean-diet group (n = 36) showed a significantly deeper right insula (mean ± SD, 28.78 ± 1.16 mm vs 27.88 ± 1.23 mm; P = 0.03), a deeper left insula (mean ± SD, 28.60 ± 1.21 mm vs 27.49 ± 1.26 mm; P = 0.01) and a longer corpus callosum (mean ± SD, 42.24 ± 2.50 mm vs 40.61 ± 2.13 mm; P < 0.01) compared with fetuses in the usual-care group (n = 44). Fetuses in the stress-reduction group (n = 44) also had a deeper left insula (mean ± SD, 28.39 ± 1.13 mm vs 27.49 ± 1.26 mm; P = 0.04) compared with those in the usual-care group. Structured maternal lifestyle interventions during pregnancy may influence fetal neurodevelopment. Although the effect sizes were submillimetric, these effects were detectable using two-dimensional MRI, which highlights its potential as a sensitive tool for detecting subtle brain changes during fetal life. Future studies are warranted to truly reveal the clinical meaning of these findings. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.

Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, is a major public health concern with long-term health consequences. Risk factors for (spontaneous) PTB (sPTB) include medical, lifestyle, demographic, environmental, and obstetric factors. Low socioeconomic status (SES) and late initiation of antenatal care (ANC) are known contributors, but their municipal-level impact remains understudied. This study explores the distribution of sPTB across Dutch provinces and municipalities and assesses the role of SES and ANC in regional disparities to inform targeted, place-based interventions. Data from the Netherlands Perinatal Registry (PERINED) on 952,262 singleton pregnancies (2016-2021) were analyzed. Incidence rates of PTB and sPTB were calculated per province and municipality. Logistic regression was used to calculate crude and adjusted sPTB odds ratios across 12 provinces and 364 municipalities. Adjustments were made for SES, late ANC, and risk factors including parity, maternal age, ethnicity, fetal sex and urbanisation level. The incidence of sPTB was 3.6%, with substantial variation across provinces and municipalities (range 2.1-6.6%). Regional differences were partly influenced by SES, late initiation of ANC, and maternal and pregnancy-related characteristics, but persisted after adjustment. Additional adjustment for urbanisation attenuated these regional disparities. There are marked geographic disparities in PTB and sPTB odds across the Netherlands, not fully explained by SES or late ANC. Further research into local environmental or contextual factors is needed to inform targeted strategies for improving perinatal health outcomes.

Acephate, a broadly applied insecticide with endocrine-disrupting properties, has in utero effects that are still not fully elucidated. We hypothesized that maternal exposure to a low dose of acephate alters placental function and induces sex-specific offspring changes. Wistar rat dams received water (control) or acephate (4.5mg/kg/day) by gavage from gestation day (GD) 6.5-18.5, and the placentas and fetuses were collected on GD 18.5. Acephate exposure caused intrauterine growth restriction (IUGR) in both sexes, while placental efficiency (g fetus/g placenta) was reduced in males and increased in females. Placental transcriptomics revealed no significant differential expression in placentas bearing male fetuses. In contrast, 135 downregulated genes and 171 upregulated genes enriched for growth and nutrient transport were identified in placentas bearing female fetuses. A reduction in the profile of proinflammatory cytokines in the amniotic fluid was detected in the fetuses of both sexes, especially in males, whereas the plasma concentration of MCP-1 increased in dams. Taken together, these findings reveal that the response to acephate differs according to fetal sex, suggesting a nontranscriptional mechanism of placental failure in placentas bearing male fetuses, as well as a complex, adaptive transcriptional response in those bearing female fetuses.

Fetal calf serum concentration and sex did not affect the differentiation of human primary osteoblasts, in contrast to dexamethasone.

Early identification of pregnancies at risk for gestational hypertension (gHTN) and preeclampsia (PE) remains a major clinical challenge. We investigated whether early‑pregnancy serum metabolomic profiles differentiate gHTN and PE prior to clinical onset. High-resolution metabolomics (HRM) analysis was performed on 126 early-pregnancy serum samples collected at ≤ 20weeks' gestation from 97 pregnant women enrolled in the Placental Assessment in Response to Environmental Pollution study (PARENTs) cohort at UCLA. Metabolic profiles were compared among pregnancies that later developed gestational hypertension (gHTN; n = 14 mothers, 20 samples), preeclampsia (PE; n = 9 mothers, 11 samples), and pregnancies without ischemic placental disease (non-IPD; n = 74 mothers, 95 samples). Untargeted metabolome-wide association studies (MWAS) and pathway enrichment analyses were conducted. Multivariable linear regression models adjusted for key maternal and pregnancy characteristics such as maternal age, race/ethnicity, early-pregnancy BMI, fetal sex, and parity were used to evaluate associations. Distinct metabolic profiles differentiated gHTN and PE from non-IPD pregnancies. Alterations in the tryptophan metabolism pathway were observed in both gHTN and PE, with a significant dose-response relationship across groups (non-IPD > gHTN > PE, p = 0.008). Key metabolites, including tryptophan and its derivatives, were progressively depleted in association with increasing disease severity. Additionally, urea cycle metabolism was altered in gHTN, with higher levels of arginine and citrulline linked to nitric oxide production and vascular tone regulation. Comparisons between PE and gHTN revealed additional differences, including lower concentration of phenylalanine and pantothenic acid in PE, suggesting distinct metabolic alteration. Early‑pregnancy metabolomic signatures reveal both shared and condition‑specific metabolic pathways underlying gHTN and PE, with tryptophan metabolism showing a dose-response relationship indicative of disease severity. These early gestational alterations may serve as biomarkers for hypertensive disorders of pregnancy (HDP), enabling closer monitoring and stratification in high-risk pregnancies. Further studies in larger cohorts are needed to validate these findings and explore therapeutic implications.

Fetal growth restriction (FGR) caused by placental insufficiency is characterized by fetal hypoxemia and elevated catecholamines. We hypothesized that the catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) would be elevated in a sheep model of placental insufficiency and FGR. We measured HVA and VMA in fetal arterial plasma and amniotic fluid and analyzed their relationships with fetal weight, sex, and concentrations of fetal arterial norepinephrine (NE), oxygen, insulin, and IGF-1. Compared to controls, FGR fetuses had higher arterial plasma concentrations of HVA (39%), VMA (53%), and NE (369%), and lower arterial blood oxygen (26%) and plasma insulin (62%) and IGF-1 (59%). Fetal arterial HVA and VMA were positively correlated with NE and inversely correlated with fetal oxygen and IGF-1 concentrations and fetal weight. Amniotic fluid concentrations of HVA and VMA were also elevated in FGR fetuses. These findings support HVA and VMA as biochemical markers of chronically elevated fetal catecholamine concentrations, with potential utility for identifying fetuses with chronic hypoxemia. The presence of these metabolites in amniotic fluid also suggests the feasibility of non-invasive assessment at the time of or shortly after birth. This manuscript identifies homovanillic acid (HVA) and vanillylmandelic acid (VMA) as biochemical markers of chronic fetal hypoxemia in a sheep model of FGR and are elevated in both plasma and amniotic fluid of FGR fetuses. These data demonstrate strong correlations between HVA/VMA and fetal NE, oxygen content, IGF-1, and fetal weight. This work supports future studies assessing HVA/VMA as potential non-invasive biomarkers in amniotic fluid sampled at delivery to improve newborn risk stratification beyond size-based criteria.

Development and validation of two prediction models for obstetric anal sphincter injury (OASI). Population-based cohort study. Nationwide (the Netherlands). Data from the Netherlands Perinatal Registry, describing nulliparous women who delivered a singleton live born infant in cephalic presentation at term from 2016 to 2020, with spontaneous (SVD) or operative vaginal delivery (OVD). Based on literature and clinical expertise, a set of potential predictors was defined and derived from the national perinatal registry. A predictive model was constructed, and accessible nomograms provided. Internal and temporal external validation was performed. OASI rate. The risk of OASI in 171 046 women with SVD was 4.1%. After logistic regression with step-wise backward selection using Akaike Information Criterion (AIC), ten predictors were retained. These were: mediolateral episiotomy (MLE), expected fetal birth weight, duration of the 2nd stage, occipitoposterior presentation, induction of labour, epidural analgesia, Asian ethnicity, maternal age, gestational age and fetal sex. The final model had a moderate discriminative ability (AUC 0.67, 95% CI 0.67-0.68) and excellent calibration (Brier score 0.039). The average risk of OASI in 37 547 women with OVD was 3.5%. Seven predictors were retained in the model: MLE, expected fetal birth weight, duration 2nd stage of labour, occipitoposterior fetal presentation, epidural analgesia, Asian ethnicity and gestational age. The final model had moderate discrimination (AUC 0.68, 95% CI 0.67-0.70) and excellent calibration (Brier score 0.032). A prediction model for OASI was developed and validated for both nulliparous women with spontaneous vaginal delivery and with operative vaginal delivery. These models can form a basis to identify women with a high risk of OASI.

Although providers may view the use of the noninvasive prenatal testing (NIPT) screen as an opportunity for patients to learn more about potential chromosomal variants of a fetus, research suggests that patients may view the genetic screening test primarily as an opportunity to learn about their fetus's sex chromosomes and may not understand the implications of a screening test, as compared with a diagnostic test. This study critically evaluates the informational quality of TikTok content related to NIPT, with a specific focus on the use and conflation of sex and gender terminology. A total of 83 TikTok videos met our inclusion criteria. Two team members systematically coded the videos using a modified DISCERN instrument and content-specific codes to assess reliability and informational quality across 3 content creator categories: patients/nonexperts, health care professionals, and organizations. Many codes focused specifically on the use of gendered language in the videos. Patient-generated content exhibited the highest engagement metrics but frequently misrepresented NIPT as a confirmatory test and conflated sex with gender. Health care provider and organizational videos demonstrated higher informational reliability but were not immune to deterministic language around sex and gender and promotional framing. The findings underscore the influence of social media as a health information source and reveal significant gaps in public understanding of NIPT, particularly regarding its screening nature and limitations. Additionally, these results highlight the need for clinical protocols that address patient misconceptions and suggest that health care professionals should actively engage with digital platforms to familiarize themselves with what patients are seeing and hearing online. Recommendations include avoiding gendered mirroring, asking questions about patient knowledge, and leveraging social media for public health education.

Animal models remain essential for understanding developmental toxicology, providing insights into how in utero exposures affect fetal and placental outcomes. Litter-bearing species are widely used due to their efficiency and reproducibility, but conventional approaches often summarize outcomes at the litter level, masking meaningful within-litter variability. This review highlights three primary sources of intralitter variability: litter size, uterine implantation location, and fetal sex, and their influence on fetal and placental growth, mortality, and malformations. Larger litters restrict fetal growth through intrauterine competition, while toxicant-induced changes in litter size can obscure or exaggerate effects. Implantation location within uterine horns influences perfusion, nutrient delivery, and local exposure to hormones or toxicants, introducing spatially dependent vulnerability. Fetal sex further modifies responses, as male and female fetuses and placentas differ in growth trajectories, gene expression, and adaptive capacity, leading to sex-specific susceptibility to toxicants. Ignoring these sources of variability risks overlooking subtle effects and vulnerable subpopulations, misinterpreting outcomes, and reducing the translational value of animal studies. We argue that incorporating intralitter variables into experimental design and statistical analyses enhances the accuracy, reproducibility, and interpretability of developmental toxicology research. By refining the use of animal models in line with the 3Rs framework, researchers can maximize the information gained per pregnancy and improve risk assessment for human maternal-fetal health.

Maternal prenatal depression and anxiety (PDA) have been associated with increased risks of adverse birth and neurodevelopmental outcomes in children. While fetal exposure to too high or low levels of steroid hormones has been proposed as a potential biological mechanism underlying these effects, few studies have directly investigated this hypothesis using fetal tissue samples, and the existing studies have been limited to examining cortisol, cortisone or testosterone. We studied associations between PDA and steroid hormones in amniotic fluid by measuring a panel of 17 steroid hormones - including progestogens, mineralocorticoids, glucocorticoids, androgens and estrogens - and their substrate-to-product ratios in 173 women with singleton pregnancies undergoing amniocentesis during second trimester. The fetuses had no chromosomal abnormalities. We defined any PDA as meeting at least one of the following criteria: reported symptoms above clinical cut off (CES-D ≥20 or STAI state or trait anxiety ≥40) during pregnancy, lifetime diagnosis (ICD-10 codes F31-33, F41-43), and/or lifetime medication purchases (ATC-codes N06A, N05B). Elastic net regression identified two glucocorticoid metabolites, 20α-dihydrocortisol and 5β-tetrahydrocortisol, with lower amniotic fluid levels in fetuses of mothers with PDA compared to those without PDA (unadjusted mean difference -0.37 SD units, 95 % CI: [-0.68, -0.07]; and -0.40 SD units, 95 % CI: [-0.70, -0.10], respectively). The model with both steroids remained significant after adjusting for maternal age, body mass index, education, smoking during pregnancy, parity, gestational age at amniocentesis and fetal sex, and in sensitivity analyses excluding mothers with diabetes and hypertensive disorders (p-values<.05) and was not moderated by fetal sex (p-value>.40). PDA was not significantly associated with any substrate-to-product ratios of the steroids, used as proxies of steroid hormone metabolizing enzymes, after correction for multiple testing. This study provides support for the prenatal programming hypothesis of PDA influencing fetal environment through suboptimal levels of steroid hormones and highlights the need to expand to a comprehensive panel of steroid metabolism.

This study evaluated the efficacy of transrectal ultrasonography for early fetal sex determination in dromedary camels by identifying the location of the genital tubercle (GT) relative to the tail head and the abdominal insertion of the umbilical cord. A total of 473 examinations were performed between 55 and 85 days of gestation on 159 female dromedary camels. Overall feasibility of visualising the GT was 86.5%, with a diagnostic accuracy of 90% for feasible cases. Gestational age was the most significant factor affecting accuracy, with significantly lower accuracy before 65 days. The optimal window for reliable determination was between 65 and 80 days, with accuracy peaking at 96.9% between 70 and 74 days of gestation. Dam parity and breed had no significant effect on accuracy. The findings confirm that transrectal ultrasonography is a highly accurate and practical tool for fetal sexing in camels in the first trimester, offering valuable information for commercial herd management when performed within the defined optimal timeframe.

In Austria, more than a third of all births are performed with the assistance of vacuum extraction or a caesarean section. Consistent with the male disadvantage hypothesis, many indications for obstetric intervention, including cephalopelvic disproportion or placental abruption, affect male fetuses more frequently than female ones. Thus, we hypothesized that male fetuses show a higher rate of obstetric intervention than female fetuses. This retrospective, single-center study was based on 11749 singleton live births taking place in Vienna, Austria between 2010 and 2020. Maternal (age, body height, weight, parity, nicotine use), obstetric (fetal presentation, gestational length, delivery mode), and neonatal parameters (sex, birthweight, birth length, head circumference) were included in the analysis. Both instrumental vaginal delivery (6.8% vs. 4.8%) and emergency cesarean section (9.4% vs. 8.2%) occurred significantly more often in males than females (p < 0.001). This association between fetal sex and delivery mode persisted despite controlling for confounding factors such as head circumference, with males having a 1.51 resp. 1.22 increased risk of instrumental vaginal delivery (p < 0.001) resp. emergency cesarean section (p = 0.006) compared to females. Male sex is a major risk factor of birth complications and consequently higher rates of instrumental vaginal delivery and emergency cesarean section.

Placental corticotropin-releasing hormone (pCRH) is a peptide essential for fetal development and birth timing. Prenatal programming frameworks position maternal pCRH as a primary neuroendocrine mediator underlying the intergenerational transmission of stress, but empirical evidence is sparse. Using rigorous methodology, we conducted the first investigation of associations between pCRH and multi-informant indicators of offspring internalizing psychopathology during middle childhood. This study used the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) sample of socioeconomically diverse mother-child dyads (n=838) followed prospectively from pregnancy. We estimated pCRH rate of rise and level at delivery using maternal 2nd and 3rd trimester blood plasma. We operationalized child internalizing psychopathology and related behavioral phenotypes at age eight with maternal report of internalizing problems, child report of depression and anxiety, and task-based indicators of threat sensitivity. Covariate-adjusted regression models estimated associations between pCRH and offspring outcomes and whether fetal sex moderated associations. Neither rate of rise nor cumulative exposure were associated with any of the six multi-method, multi-informant child outcomes tested (e.g., child-reported depression and anxiety symptoms, maternal-reported internalizing problems, task-based indicators of threat sensitivity (ps range from .16-.83). Fetal sex did not moderate associations. Contrasting theory and findings in smaller samples at younger ages, evidence from this study did not support pCRH as a plausible maternal neuroendocrine mediator for the intergenerational transmission of stress effects on offspring internalizing psychopathology during middle childhood. Future research exploring potential for waning associations across early childhood or other potential mechanisms is warranted.