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Maternal hyperglycemia contributes to abnormal fetal development; yet, how it affects fetal metabolism is poorly understood. Perez-Ramirez and colleagues recently provided a comprehensive metabolic atlas of fetal organs isolated from normal and diabetic pregnant mice, identifying novel metabolites and alterations in tissue glucose utilization throughout mid-to-late gestation by maternal hyperglycemia.

BackgroundWidespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results.ObjectivesWe conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex.MethodsWe included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as log2-transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex.ResultsThree OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in >85% of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per doubling=1.07; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. nondetect=1.25; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age z-scores (β for detect vs. nondetect=0.04-0.07); other chemicals showed null associations.DiscussionIn the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.

Background: Early pregnancy Zika virus (ZIKV) infection is associated with major brain damage in fetuses, leading to microcephaly in 0.6–5.0% of cases, but the underlying mechanisms remain largely unknown. Methods: To understand the kinetics of ZIKV infection during fetal development in a nonhuman primate model, four cynomolgus macaque fetuses were exposed in utero through echo-guided intramuscular inoculation with 103 PFU of ZIKV at 70–80 days of gestation, 2 controls were mock inoculated. Clinical, immuno-virological and ultrasound imaging follow-ups of the mother/fetus pairs were performed until autopsy after cesarean section 1 or 2 months after exposure (n = 3 per group). Results: ZIKV was transmitted from the fetus to the mother and then replicate in the peripheral blood of the mother from week 1 to 4 postexposure. Infected fetal brains tended to be smaller than those of controls, but not the femur lengths. High level of viral RNA ws found after the first month in brain tissues and placenta. Thereafter, there was partial control of the virus in the fetus, resulting in a decreased number of infected tissue sections and a decreased viral load. Immune cellular and humoral responses were effectively induced. Conclusions: ZIKV infection during the second trimester of gestation induces short-term brain injury, and although viral genomes persist in tissues, most of the virus is cleared before delivery. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions Labor induction exhibits considerable variations in protocols and medication regimens. Limited studies compare vaginal dinoprostone inserts with different oral misoprostol dosages, considering parity influence. This study explores the distinctions among 10 mg vaginal dinoprostone inserts and oral misoprostol 25 μg every 2 and every 4 h for labor induction, stratified by parity.This retrospective cohort study involved 607 participants across two hospitals. The primary outcome, time from induction to delivery, and secondary outcomes, including mode of delivery and maternal and fetal safety, were assessed.Patient characteristics revealed differences in indication for labor induction, with the dinoprostone cohort having fewer post‐term and premature rupture of membranes cases but more intrauterine growth restriction/small‐for‐gestational age. Both oral misoprostol regimens showed a shorter time to delivery interval compared to the dinoprostone cohort (median: 1380 min [IQR 1381.0] and 1127.0 min [IQR 1214.0] versus 1631.5 [IQR 1736.2], p < 0.001 and p = 0.014). Only the difference between oral misoprostol q2h and vaginal dinoprostone remained significant for nulliparous but not multiparous women, losing significance over all the population after adjusting for confounding factors. The proportion of women giving birth within 24 h did not significantly differ between misoprostol q2h and dinoprostone after adjusting for confounders. When comparing misoprostol q4h with dinoprostone after confounder adjustment, an increased time to delivery interval for misoprostol q4h was found (p = 0.001). Both oral misoprostol regimens exhibited fewer meconium‐stained liquor (miso q4h: OR 0.44, miso q2h: OR 0.34) and cesarean sections (miso q4h: OR 0.48, miso q2h: OR 0.53) compared to dinoprostone, even after adjustment for confounders.Our study suggests that oral misoprostol 25 μg q4h is less effective than 10 mg vaginal dinoprostone for labor induction if parity and indication for induction are adjusted for, particularly in multiparous women. In terms of side effects, oral misoprostol regimens seem superior to vaginal dinoprostone. Our data support the individualized use of different agents for labor induction according to parity, indication for induction, bishop score, and women's preference. [ABSTRACT FROM AUTHOR]

Objective: The phosphoinositide 3-kinase (PI3K) pathway is an important signaling mechanism for cell proliferation and metabolism. Mutations that activate PIK3CA may make cells p110α dependent, but when phosphatase tensin homolog (PTEN) is lost, the p110β isoform of PI3Ks becomes more important. However, the exact mechanism underlying the prevalence of p110s remains unclear. In this study, our aim was to elucidate the processes behind PI3K isoform dependency in a cellular model of embryonic development. Material and Methods: In order to understand PI3K isoform prevalence, mouse embryonic fibroblasts (MEFs) were used and p110β, PTEN and Rac1 activity was modulated using retroviral plasmids. Expression levels and cellular growth were assessed by performing immunoblots and crystal violet assays. Results: The levels of PTEN had only a partial effect on the prevalence of PI3K isoforms in MEFs. The dependency on p110α diminished when PTEN was depleted. Of note, when PTEN expression was repressed, there was no full transition in dependency from one PI3K isoform to the other. Interestingly, the viability of PTEN-depleted MEFs became less dependent on p110α and more dependent on p110β when p110β was overexpressed. Nevertheless, the overexpression of p110β in conjunction with PTEN knock-downs did not result in a complete shift of isoforms in PI3Ks. Finally, we investigated Rac1 activation with a mutant allele and determined a more potent increase in p110β prominence in MEFs. Conclusion: These findings suggest that multiple cellular parameters, including PTEN status, PI3K isoform levels, and Rac1 activity, combine to influence PI3K isoform prevalence, rather than a single determinant. [ABSTRACT FROM AUTHOR]

Objective: To investigate the trimester‐specific associations between maternal total physical activity level vs moderate‐to‐vigorous exercise and fetal growth disorders. Methods: We analyzed 2062 mother–neonate pairs participating in the longitudinal China Medical University Birth Cohort Study. The Pregnancy Physical Activity Questionnaire was used to assess the physical activity level of women during the three trimesters. A higher level of total physical activity was defined as meeting or exceeding the cohort‐specific 75th percentile, and a higher level of exercise was defined according to the Physical Activity Guidelines for Americans. Fetal growth disorder was defined as small‐for‐gestational age (SGA) or large‐for‐gestational age (LGA) at birth. Results: Of the neonates included in this study, 7.1% were SGA and 15.5% were LGA. A higher level of total physical activity during the first trimester (adjusted relative risk (aRR), 0.62 (95% CI, 0.42–0.91)) and second trimester (aRR, 0.62 (95% CI, 0.41–0.95)) was associated with a lower risk of SGA, and a higher level of total physical activity during the third trimester was associated with a lower risk of LGA (aRR, 0.73 (95% CI, 0.54–0.97)). When analyzing physical activity by subtype, a higher level of occupational physical activity during the first and second trimesters was associated negatively with SGA risk, and higher levels of occupational and low‐intensity physical activity during the first trimester were associated negatively with LGA risk. No significant association was found between maternal adherence to the Physical Activity Guidelines for Americans and risk of fetal growth disorders. Conclusions: A higher total physical activity level during the first and second trimesters was associated with a decreased risk of SGA, whereas a higher total physical activity level in the third trimester was associated with a decreased risk of LGA. Pregnant women should be advised to increase their total physical activity levels instead of focusing on engaging in only moderate‐to‐vigorous exercise. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Introduction: Maternal smoking during pregnancy and gestational diabetes mellitus (GDM) have opposite effects on fetal growth during pregnancy. The aim of the study was to evaluate the interaction of smoking during pregnancy and gestational diabetes mellitus on head circumference and birthweight of newborns. Material and Methods: The study included all primiparous women with singleton pregnancies (n = 290 602) without previously diagnosed diabetes or hypertension in Finland between 2006 and 2018. The information on gestational diabetes mellitus, newborn birthweight and head circumference, and maternal smoking and backgrounds was derived from the Finnish Medical Birth Register. Linear regression models were used in the analyses. Results: In total 8.0% of parturients quit smoking during the first trimester and 9.9% continued smoking thereafter. The prevalence of GDM was 8.9% (n = 25 948). Newborns of women who continued smoking had a smaller head circumference (b = −0.24, SE = 0.01, p < 0.0001) and birthweight (b = −0.28, SE = 0.01, p < 0.0001) compared to newborns of women who did not smoke. Head circumference and birthweight were greater in newborns of women with GDM (b = 0.09, SE = 0.01, p < 0.0001 and b = 0.16, SE = 0.01, p < 0.0001, respectively) compared to newborns of women without GDM. In the interaction analyses, head circumference (b = −0.13, SE = 0.01, p < 0.0001) was smaller and birthweight (b = −0.13, SE = 0.02, p < 0.0001) was lower in newborns of women with GDM who continued smoking compared to newborns of women without GDM who did not smoke. Conclusions: Although smoking and GDM have opposite effects on fetal growth, the negative effects of exposure to smoking are also seen in newborns of women with GDM. Compared to smoking after the first trimester of pregnancy, cessation of smoking during the first trimester was associated with greater head circumference and birthweight in newborns. [ABSTRACT FROM AUTHOR]

Ectogenesis technology would make it possible to support the complete gestational development of a human being outside the female body. Proponents argue that this technology offers a welcome opportunity to expand reproductive options for those unable or unwilling to gestate. However, by completely bypassing pregnancy, the use of ectogenesis prevents the formation of gestational family ties. Consequently, it has faced criticism for perpetuating a patriarchal view of the family that undermines the moral significance of gestation. The concern is that the introduction of this technology might result in the loss of reproductive autonomy for those who desire to experience pregnancy, as they face pressures to opt for ectogenesis instead. Existing accounts of family values define parents' rights to rear a child, but they fail to establish a right to gestate that can protect an individual's interest in bearing a child. To provide a more comprehensive account of family values, I argue that pregnancy involves a unique quality of intimacy and can make distinct contributions to one's flourishing. Based on this premise, I defend a fundamental moral right to gestate that can help safeguard the option of pregnancy for those who desire it. In conclusion, I consider how a prospective gestator need not provide optimal conditions for fetal development in the way that ectogenesis promises in order for their choice of pregnancy to be justified. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a life-threatening multisystem disorder of pregnancy which has been observed in 2%–10% of pregnancies. The prevalence of Vitamin D deficiency ranges from 15% to 80%. Deficiency of Vitamin D is associated with the development of preeclampsia. This study was done to find out the prevalence of Vitamin D deficiency among preeclamptic/eclamptic and normal pregnant females, to establish Vitamin D deficiency as a causal factor of preeclampsia, and to elucidate the relation between 25 (OH) Vitamin D status and the severe preeclampsia. Materials and Methods: Blood samples were collected from 50 normotensives (controls) and 50 hypertensive pregnant females with preeclampsia/eclampsia (cases), and 25 (OH) Vitamin D level was measured by chemiluminescence Immunoassay. Results: Among the preeclamptic/eclamptic group, 32 (64%) were noted with Vitamin D deficiency and 18 (36%) with Vitamin D insufficiency. In the control group, 30 (60%) pregnant women showed Vitamin D deficiency, 19 (38%) with Vitamin D insufficiency, and a sufficient level of Vitamin D was observed in one woman (2%). Conclusion: Although it is difficult to demonstrate the correlation between Vitamin D levels and preeclampsia, there is a widespread global prevalence of Vitamin D deficiency during pregnancy. Hence, Vitamin D supplementation can be included routinely in the antenatal care program in India. [ABSTRACT FROM AUTHOR]

Introduction: An optimal fetal supply of docosahexaenoic acid (DHA) is critical for normal brain development. The relationship between maternal DHA intake and DHA delivery to the fetus is complex and is dependent on placental handling of DHA. Little data exist on placental DHA levels in pregnancies supplemented with the recommended dose of 200 mg/d. Our objective was to determine how prenatal DHA at the recommended 200 mg/d impacts maternal, placental, and fetal DHA status in both normal-weight and high-BMI women compared to women taking no supplements. Methods: Maternal blood, placenta, and cord blood were collected from 30 healthy pregnant women (BMI 18.9–43.26 kg/m2) giving birth at term. Red blood cells (RBCs) and villous tissue were isolated, and lipids were extracted to determine DHA content by LC-MS/MS. Data were analyzed by supplement group (0 vs. 200 mg/d) and maternal BMI (normal weight or high BMI) using two-way ANOVA. We measured maternal choline levels in maternal and cord plasma samples. Results: Supplementation with 200 mg/d DHA significantly increased (p < 0.05) maternal and cord RBC DHA content only in pregnancies complicated by high BMI. We did not find any impact of choline levels on maternal or cord RBC phospholipids. There were no significant differences in total placental DHA content by supplementation or maternal BMI (p > 0.05). Placental levels of phosphatidylinositol (PI) and phosphatidic acid containing DHA species were higher (p < 0.05) in high-BMI women without DHA supplementation compared to both normal-BMI and high-BMI women taking DHA supplements. Conclusion: Maternal DHA supplementation at recommended doses cord increased RBC DHA content only in pregnancies complicated by higher BMI. Surprisingly, we found that obesity was related to an increase in placental PI and phosphatidic acid species, which was ameliorated by DHA supplementation. Phosphatidic acid activates placental mTOR, which regulates amino acid transport and may explain previous findings of the impact of DHA on placental function. Current recommendations for DHA supplementation may not be achieving the goal of improving fetal DHA levels in normal-weight women. [ABSTRACT FROM AUTHOR]

Background The 3Rs (Reduction, Refinement, Replacement) principle is driving the need for alternative methods in animal testing. Despite advancements in in vitro testing, complex systemic toxicity tests still necessitate in vivo approaches. The aim of this study was to develop a developmental toxicity test protocol using the Iberian ribbed newt (Pleurodeles waltl) as a model organism, integrating AI image analysis for embryo selection to improve test accuracy and reproducibility. Methods We established a developmental toxicity test protocol based on the zebrafish test. Gonadotropin was administered to induce ovulation, and in vitro fertilization was performed. Embryos were imaged at 5-6 and 6-7 h post-fertilization. AI image analysis was utilized to assess embryo viability. The test chemical was administered 24-48 h post-fertilization, and morphological changes were observed daily until day 8. Additionally, a time-lapse photography system was constructed to monitor embryonic development. Results Out of 24 cultured embryos, 75% developed normally to the late tail bud stage or initial hatching stage, whereas 25% experienced developmental arrest or death. AI image analysis achieved high accuracy in classifying embryos, with overall accuracies of 92.0% and 92.9% for two learning models. The AI system demonstrated higher precision in the selection of viable embryos compared to visual inspection. Conclusion The Iberian ribbed newt presents a viable alternative model for developmental toxicity testing, adhering to the 3Rs principles. The integration of AI image analysis substantially enhances the accuracy and reproducibility of embryo selection, providing a reliable method for evaluating developmental toxicity in pharmaceuticals. [ABSTRACT FROM AUTHOR]

Developing embryos have traditionally been viewed as passive agents in the evolution of family conflicts, with maternal substances within the uterus or eggs as main factors modulating later expression of offspring solicitation behaviors. Yet, parent-offspring conflict theory predicts that offspring might also rely on alternative cues to adjust demand in response to prenatal cues of parental capacity for resource provisioning. Here, we show how embryonic experience with vocalizations carried out by parents during nest-relief displays at incubation adaptively shapes avian offspring development, providing lasting benefits to offspring. Genetic siblings prenatally exposed to different levels of parent-parent communication showed differences in epigenetic patterns, adrenocortical responsiveness, development, and food solicitation behavior. The correspondence between prenatal acoustic experience and parental context positively influenced the nutritional status and growth rate of offspring reared by communicative parents. Offspring can thus retain strong control over their own development by gathering prenatal acoustic information about parental generosity. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) and thyroid disorders during pregnancy pose significant health concerns, impacting a substantial number of mothers globally. Globally, about 14% of pregnant women develop GDM, while thyroid disorders impact approximately 2%–3%. Both conditions contribute to adverse outcomes, including gestational hypertension, excessive fetal growth, and heightened perinatal morbidity. The central focus of this literature review is to examine the relationship between vitamin A, a crucial fat-soluble micronutrient in fetal development, and the occurrence of GDM and thyroid disorders during pregnancy. The primary research question investigates the association between vitamin A, GDM, and thyroid disorders, analyzing their combined impact on maternal, fetal, and neonatal outcomes. The review underscores the potential of vitamin A to modulate the risk and outcomes of GDM and thyroid disorders during gestation, emphasizing its role in GDM development and resolution and its influence on thyroid function in pregnancy. [ABSTRACT FROM AUTHOR]

Developing prenatal coparenting is important for preparing couples for parenting immediately after childbirth, but knowledge of prenatal coparenting remains limited. Adult attachment style has been shown to be one of the factors during pregnancy that predict coparenting after childbirth, as well as a significant factor in the developmental process of the coparenting relationship. The present study mainly examines the relationship between prenatal coparenting as perceived by pregnant women and their attachment style. A cross-sectional survey was conducted at a tertiary emergency medical facility in Japan. Data from 181 pregnant women at 22–36 weeks' gestation who completed a self-reported questionnaire consisting of the Prenatal Coparenting Scale (PCS), relationship-specific attachment styles, and characteristics were subjected to analysis. The mean age of the women in this study was 33.1 years (standard deviation = 5.2), 80 (44.2%) were expecting their first child, and 101 (55.8%) were expecting their second or subsequent child. Women's attachment avoidance toward their mother (r = –.26), father (r = –.23), and partner (r = –.60) and attachment anxiety toward their partner (r = –.33) were significantly negatively correlated with PCS scores. When classified into two groups by fetal birth order, attachment avoidance and attachment anxiety toward the partner were significantly negatively correlated with PCS scores, regardless of fetal birth order. Unlike attachment style toward the partner, attachment avoidance toward the mother (r = –.33) and father (r = –.32) was significantly negatively correlated with PCS scores in the group of women expecting their second or subsequent child only. These results provide valuable insights into the relationship between prenatal coparenting and adult attachment style and deepen the understanding of prenatal coparenting. Future studies using longitudinal surveys and multivariate analyses could present relevant suggestions for specific types of support that promote the development of prenatal coparenting. [ABSTRACT FROM AUTHOR]

Background: The endometrium holds a crucial role in reproduction by supporting blastocyst adhesion, cytotrophoblast invasion and fetal development. Among the various uterine disorders, endometritis, particularly chronic endometritis (CE), has gained attention due to its association with adverse reproductive outcomes (recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and infertility). The association between CE and adverse reproductive outcomes stresses the necessity for comprehensive diagnostic and therapeutic strategies to optimize fertility outcomes and support individuals in their journey towards parenthood. Aim: To explore the relationship between CE and reproductive disorders. Methods: Following PRISMA guidelines, a systematic review and meta-analysis using published data from 1990 to 2024 were carried out. Results: A population of 1,038 women was included. Regarding CE-infertility association, a positive correlation was found, with 19.46% CE rate in infertile women compared to 7.7% in controls (OR: 2.96, 95% CI 1.53-5.72, p 0.001). No significant association was observed between RIF and CE (OR: 1.10, 95% CI 0.26- 4.61, p 0.90), CE rates in both groups were relatively comparable, with 6.35% in women with RIF and 5.8% in controls. On the opposite, a strong association between CE and RPL was found, reporting a CE rate of 37.6% in RPL cases compared to 16.4% in controls (OR: 3.59, 95% CI 2.46-5.24, p < 0.00001). Conclusions: CE appears to be associated to infertility and RPL, while no significant association was noted in cases of RIF. [ABSTRACT FROM AUTHOR]

Background: Women's knowledge of the nutritional guidelines during pregnancy can affect the health and nutritional status of both mother and child. Having good nutritional information related to maternal dietary intake and healthy lifestyles is therefore of great importance. However, there is limited published research that demonstrates pregnant women's knowledge of the nutritional guidelines during pregnancy in Lebanon. Objective: To assess the knowledge on food sources and energy recommendations as well as food safety practices and diet–health relationship among women during pregnancy in Lebanon. Design: A cross-sectional study. Methods: The study was conducted at prenatal care clinics in Lebanon, and all pregnant women present, regardless of nationality, were invited to complete the self-administered nutrition knowledge questionnaire. The study assessed five different nutrition knowledge domains (food sources of nutrients, dietary behaviors, food safety knowledge, micronutrients for fetal development, and energy requirements and weight gain) and the demographic characteristics of pregnant women who completed a multidimensional online survey based on validated and existing measures. Results: Four-hundred and ten responses were obtained. Approximately half of respondents (47%) held a university degree, for 42% of women this was their first pregnancy, and 71% had a planned pregnancy. Among the different nutrition knowledge domains, the highest levels of knowledge were for the behaviors that can minimize the effect of nausea/vomiting, heartburn, and constipation during pregnancy (63.9%) and the lowest levels of knowledge was for the importance of iodine and omega-3 fatty acids in pregnancy (28.4%). Most of females knew about food safety practices during pregnancy (72.9%) but less than half were knowledgeable about listeriosis contamination (45.9%), and the types of fish that are the safest to select during pregnancy (47.8%). Conclusion: Despite the fact that pregnant women had an adequate level of knowledge in different nutrition-related areas, there was inadequate level of awareness related to critical nutrients and behaviors that can have adverse effects on mother and/or baby. Therefore, there is a need to focus on specific maternal nutrition aspects such as iron-rich foods, listeriosis food contamination, and nutrients that aid in fetal brain and retina development. Plain Language Summary: Nutrition knowledge among pregnant women in Lebanon Women who adopt healthy dietary patterns during pregnancy are more likely to prevent adverse birth outcomes. Pregnant women from the Middle East have limited knowledge of the dietary guidelines for healthy eating during pregnancy. Yet there are no studies on nutritional knowledge of pregnant women residing in the Middle East. This study aimed to investigate the nutrition knowledge of pregnant women in Lebanon, which includes food sources of nutrients, diet–health relationships, food safety, and energy requirements during pregnancy. The highest levels of nutrition knowledge were for the behaviors that can reduce the effect of nausea and vomiting, heartburn, and constipation during pregnancy and the lowest levels of knowledge were for the importance of iodine and omega-3 fatty acids in pregnancy. The level of awareness related to critical nutrients and behaviors that can have adverse effects on mother and/or baby is inadequate. Lebanese women need to obtain their information from reliable sources such as their healthcare providers. Collaboration between healthcare providers and dietitians is essential to ensure that pregnant women receive comprehensive and accurate nutritional advice throughout their pregnancy journey. [ABSTRACT FROM AUTHOR]

Background: Gestational DNA methylation age (GAmAge) has been developed and validated in European ancestry samples. Its applicability to other ethnicities and associations with fetal stress and newborn phenotypes such as inflammation markers are still to be determined. This study aims to examine the applicability of GAmAge developed from cord blood samples of European decedents to a racially diverse birth cohort, and associations with newborn phenotypes. Methods: GAmAge based on 176 CpGs (Haftorn GAmAge) was calculated for 940 children from a US predominantly urban, low-income, multiethnic birth cohort. Cord blood DNA methylation was profiled by Illumina EPIC array. Newborn phenotypes included anthropometric measurements and, for a subset of newborns (N = 194), twenty-seven cord blood inflammatory markers (sandwich immunoassays). Results: GAmAge had a stronger correlation with GEAA in boys (r = 0.89, 95% confidence interval (CI) [0.87,0.91]) compared with girls (r = 0.83, 95% CI [0.80,0.86]), and was stronger among extremely preterm to very preterm babies (r = 0.91, 95% CI [0.81,0.96]), compared with moderate (r = 0.48, 95% CI [0.34,0.60]) and term babies (r = 0.58, 95% CI [0.53,0.63]). Among White newborns (N = 51), the correlation between GAmAge vs. GEAA was slightly stronger (r = 0.89, 95% CI [0.82,0.94]) compared with Black/African American newborns (N = 668; r = 0.87, 95% CI [0.85,0.89]) or Hispanic (N = 221; r = 0.79, 95% CI [0.74,0.84]). Adjusting for GEAA and sex, GAmAge was associated with anthropometric measurements, cord blood brain-derived neurotrophic factor (BDNF), and monocyte chemoattractant protein-1 (MCP-1) (p < 0.05 for all). Conclusions: GAmAge estimation is robust across different populations and racial/ethnic subgroups. GAmAge may be utilized as a proxy for GEAA and for assessing fetus development, indicated by inflammatory state and birth outcomes. [ABSTRACT FROM AUTHOR]

During pregnancy, two fetomaternal interfaces, the placenta–decidua basalis and the fetal membrane–decidua parietals, allow for fetal growth and maturation and fetal–maternal crosstalk, and protect the fetus from infectious and inflammatory signaling that could lead to adverse pregnancy outcomes. While the placenta has been studied extensively, the fetal membranes have been understudied, even though they play critical roles in pregnancy maintenance and the initiation of term or preterm parturition. Fetal membrane dysfunction has been associated with spontaneous preterm birth (PTB, < 37 weeks gestation) and preterm prelabor rupture of the membranes (PPROM), which is a disease of the fetal membranes. However, it is unknown how the individual layers of the fetal membrane decidual interface (the amnion epithelium [AEC], the amnion mesenchyme [AMC], the chorion [CTC], and the decidua [DEC]) contribute to these pregnancy outcomes. In this study, we used a single-cell transcriptomics approach to unravel the transcriptomics network at spatial levels to discern the contributions of each layer of the fetal membranes and the adjoining maternal decidua during the following conditions: scheduled caesarian section (term not in labor [TNIL]; n = 4), vaginal term in labor (TIL; n = 3), preterm labor with and without rupture of membranes (PPROM; n = 3; and PTB; n = 3). The data included 18,815 genes from 13 patients (including TIL, PTB, PPROM, and TNIL) expressed across the four layers. After quality control, there were 11,921 genes and 44 samples. The data were processed by two pipelines: one by hierarchical clustering the combined cases and the other to evaluate heterogeneity within the cases. Our visual analytical approach revealed spatially recognized differentially expressed genes that aligned with four gene clusters. Cluster 1 genes were present predominantly in DECs and Cluster 3 centered around CTC genes in all labor phenotypes. Cluster 2 genes were predominantly found in AECs in PPROM and PTB, while Cluster 4 contained AMC and CTC genes identified in term labor cases. We identified the top 10 differentially expressed genes and their connected pathways (kinase activation, NF-κB, inflammation, cytoskeletal remodeling, and hormone regulation) per cluster in each tissue layer. An in-depth understanding of the involvement of each system and cell layer may help provide targeted and tailored interventions to reduce the risk of PTB. [ABSTRACT FROM AUTHOR]

Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods. [ABSTRACT FROM AUTHOR]

US populations have seen dramatic increases in the prevalence of chronic disease over the past three generations. Rapid increases in type 2 diabetes and obesity have occurred in all the states but have been particularly striking in the Deep South. These increases have contributed to decreases in life expectancy and to painful elevations in health care costs. The causes of worsening population health are complex and incompletely understood. However, there is strong evidence that vulnerability to chronic conditions is determined in early life. Most chronic diseases are developmentally driven. There are specific stressors experienced in early life that influence epigenetic and structural changes during development. These include malnutrition, severe levels of social stress, toxic chemicals, and low oxygen levels. Most US populations have experienced a decrease in the quality of the food they consume as industrial foods have replaced garden-grown foods. Thus, the consumption of too few nutrients before and during pregnancy and during lactation influences the growth of the placenta and fetal organs and their level of resilience when faced with stresses in postnatal life and particularly as adults. Animal studies have shown that the effects of poor nutrition can be passed on to future generations. The most powerful way that the current epidemics of obesity and insulin resistance can be reversed is by providing key nutrients to prospective mothers and those already pregnant. [ABSTRACT FROM AUTHOR]

Introduction: Androgens play a pivotal role in shaping male sexual characteristics, with testosterone being an essential hormone in orchestrating various developmental processes. Testosterone biosynthesis involves a series of enzymatic reactions, among which the 17ß-hydroxysteroid dehydrogenase type 3 (HSD17B3) holds significance. While its role in adult Leydig cells is well established, its localization and importance during the fetal period remain less known, especially in humans. This study aims to delineate the dynamics of HSD17B3 expression in human fetal testes to clarify the contribution of specific cell types to testosterone biosynthesis. Methods: Using immunofluorescence staining, we investigated the expression pattern of HSD17B3 in human fetal and adult testicular tissues. Results and discussion: The findings of this study revealed a distinct temporal and cellular expression pattern of HSD17B3 protein in the fetal period. We detected its expression exclusively in Sertoli cells, the highest during the second trimester. This unique localization suggests the inclusion of fetal Sertoli cells in testosterone production during the critical masculinization-programming window. Furthermore, we demonstrated a shift in HSD17B3 expression from Sertoli cells to Leydig cells in adulthood, corroborating findings from rodent studies. This study sheds light on the intricate, still underexplored regulation of steroidogenesis during fetal development, whose disturbance might lead to testicular dysgenesis. Further research is warranted to elucidate the regulatory pathways governing the expression of HSD17B3 and its transition between Sertoli and Leydig cells, potentially paving the way for novel therapeutic interventions in disorders of sexual development. [ABSTRACT FROM AUTHOR]

More than 13 million children are born preterm annually. Prematurity-related mortality accounts for 0.9 million deaths worldwide. The majority of those affected are Extremely Preterm Infants (gestational age less than 28 weeks). Immaturity causes organ failure and specific morbidities like germinal matrix hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. Artificial womb and placenta technologies address these issues. As a bridge-to-life technology, they provide a liquid environment to allow organ maturation under more physiological conditions. The proposed artificial womb can adapt to fetal growth. Volume adjustment is achieved by removing fluid from the interspace between an inner and outer chamber. Results of the in vitro tests showed a temperature constancy of 36.8℃ ± 0.3℃ without pressure loss over 7 days. The volume of the inner sac was variable between 3.6 and 7.0 L. We designed a filtration and disinfection system for this particular purpose. This system has proven strong disinfection capabilities, effective filtering of metabolic waste, and the ability to avoid phospholipid washout. The presented artificial womb has sufficient volume variability to adapt to the physiologic growth of an extremely preterm neonate over a 4-week period. We regard this as an important step in the development of this bridge-to-life technology. [ABSTRACT FROM AUTHOR]

The long and very long chain polyunsaturated fatty acids (LC-PUFAs) are preferentially transported by the mother to the fetus. Failure to supply LC-PUFAs is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting imperfectly understood interactions between dietary fatty acid intake and the molecular mechanisms of maternal supply. Here we employ a comprehensive approach combining untargeted and targeted lipidomics with transcriptional profiling of maternal and fetal tissues in mouse pregnancy. Comparison of wild-type mice with genetic models of impaired lipid metabolism allows us to describe maternal hepatic adaptations required to provide LC-PUFAs to the developing fetus. A late pregnancy-specific, selective activation of the Liver X Receptor signalling pathway dramatically increases maternal supply of LC-PUFAs within circulating phospholipids. Crucially, genetic ablation of this pathway in the mother reduces LC-PUFA accumulation by the fetus, specifically of docosahexaenoic acid (DHA), a critical nutrient for brain development. Fetal brain development is dependent on the maternal supply of long chain polyunsaturated fatty acids (LC-PUFAs). Here, the authors show that pregnancy-induced liver-X-receptor (LXR) signaling in the maternal liver promotes the synthesis of LC-PUFA-containing phospholipids for export to the fetus. [ABSTRACT FROM AUTHOR]

Spironolactone, a potassium-sparing diuretic, is used to treat hypertension, heart failure, and certain hyperandrogenic disorders. Its use during pregnancy is not recommended due to the risk of feminizing male fetuses, primarily because of its antiandrogenic activity. However, human data remain scarce and largely inconclusive. Here, we present the first case of a 25-year-old pregnant woman, at 16 weeks of gestation, who was inadvertently exposed to spironolactone (240 mg/day) for 1 week due to a pharmacy dispensing error. The patient subsequently delivered a healthy male infant with normal genitalia at 38 weeks of gestation following vaginal delivery. Current follow-up shows that the infant is healthy and developing normally. This article summarizes the potential causes of spironolactone-induced anomalous genital development and explores the safety of new-generation mineralocorticoid receptor antagonists (MRAs) during pregnancy. The mechanisms behind spironolactone-induced anomalous genital development in male fetuses have not been fully elucidated. Spironolactone competes with dihydrotestosterone for binding to androgen receptors and inhibits enzymes involved in androgen biosynthesis, which may partly explain its antiandrogenic effects. Recent advancements in MRAs have led to the development of compounds with higher selectivity for the mineralocorticoid receptor, thereby reducing the incidence of antiandrogen side effects. These new-generation MRAs may be effective alternatives during pregnancy, but more data are needed to establish their safety in pregnant women. This case contributes to the limited but growing body of literature on the safety profile of spironolactone in pregnancy, providing insights into its effects during a critical period of fetal development. [ABSTRACT FROM AUTHOR]

Background: Extensive research has been conducted on embryonic developmental disorders linked to Polycystic Ovary Syndrome (PCOS), a pathological condition that affects 5−10% of women and is characterized by irregularities in the menstrual cycle and infertility. By employing RNA sequencing (RNA-seq), we performed an in-depth investigation of PCOS-related changes in gene expression patterns at the mouse blastocyst stage. Methods: The zygotes of female B6D2 mice were obtained and then differentiated into blastocysts in K + Simplex Optimised Medium (KSOM) cultures containing exo-NC (negative control for exosomes) or exo-LIPE-AS1 (a novel exosomal marker of PCOS). Subsequently, blastocysts were collected for RNA-seq. The bioinformatics was performed to analyze and compare the differences of gene expression profile between blastocysts of control and PCOS group. Results: There were 1150 differentially expressed genes (DEGs) between the two groups of mouse blastocysts; 243 genes were upregulated and 907 downregulated in the blastocysts of the exo-LIPE-AS1 group compared to those of the exo-NC group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the genes involved in amino acid synthesis and glutathione metabolic pathways were down-regulated in exo-LIPE-AS1 group. Conclusion: This study has revealed that blastocyst developmental retardation may be associated with the downregulation of amino acid synthesis and glutathione metabolism, which may affect energy metabolism, biosynthesis, cellular osmotic pressure, antioxidant synthesis, ROS clearance or mitochondrial function, and ultimately cause blastocyst cell development abnormalities. Our research offers encouraging data on the mechanisms underlying aberrant embryonic development in patients with PCOS as well as potential treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The hypothalamic–pituitary–adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. Methods: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. Results: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. Conclusions: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development. Highlights: This study is the first to analyze HPA and HPG axes receptors, peptides, and enzyme mRNA expression levels in the brains of fetuses in the wild. Higher HPA and HPG axes receptors mRNA expression levels in females hint towards alternative sex-specific mechanisms that regulate endocrine axes during fetal development. Coordination of HPA and HPG axes components' expression levels is different between males and females at different stages of gestation. Plain language summary: In litter-bearing mammals, the positioning of a fetus in the uterus relative to other fetuses of the same or opposite sex has been shown to directly influence fetal morphology and physiology, and later behavior, reproductive success, and survival in adults. In this study, we sought to understand the mechanisms by which the location in the uterus influences two major neuroendocrine pathways in fetal brains. We quantified expression of multiple receptors and an enzyme (referred to as 'components') of the endocrine axes in three different brain regions in fetal free-ranging nutrias. Our results showed higher expression in females than in males for some endocrine axes components. The location inside the uterus was also related to the expression of some components. Lastly, coordination between the axes was higher earlier on in gestation, and females were more coordinated than males in the second trimester, whereas males were more coordinated than females in the third trimester. The results of this study point to the mechanisms by which the sexes regulate key neuroendocrine pathways during fetal development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Phenols and parabens are two classes of high production volume chemicals that are used widely in consumer and personal care products and have been associated with reproductive harm and pregnancy complications, such as preeclampsia and gestational diabetes. However, studies examining their influence on maternal blood pressure and gestational hypertension are limited. OBJECTIVES: We investigated associations between individual phenols, parabens, and their mixture on maternal blood pressure measurements, including systolic and diastolic blood pressure (SBP and DBP) and hypertension during pregnancy (defined as stage 1 or 2 hypertension), among 푁 = 1,433 Puerto Rico PROTECT study participants. METHODS: We examined these relationships cross-sectionally at two time points during pregnancy (16–20 and 24–28 wks gestation) and longitudinally using linear mixed models (LMMs). Finally, we used quantile g-computation to examine the mixture effect on continuous (SBP, DBP) and binary (hypertension during pregnancy) blood pressure outcomes. RESULTS: We observed a trend of higher odds of hypertension during pregnancy with exposure to multiple analytes and the overall mixture [including bisphenol A (BPA), bisphenol S (BPS), triclocarbon (TCC), triclosan (TCS), benzophenone-3 (BP-3), 2,4-dichlorophenol (2,4-DCP), 2,5-dichlorophenol (2,5-DCP), methyl paraben (M-PB), propyl paraben (P-PB), butyl paraben (B-PB), and ethyl paraben (E-PB)], especially at 24-28 wk gestation, with an adjusted mixture odds?ratio(OR)=1.57 (95% CI: 1.03, 2.38). Lower SBP and higher DBP were also associated with individual analytes, with results from LMMs most consistent for methyl paraben (M-PB) or propyl paraben (P-PB) and increased DBP across pregnancy [adjusted M-PB β=0.78 (95% CI: 0.17, 1.38) and adjusted P-PB β=0.85 (95% CI: 0.19, 1.51)] and for BPA, which was associated with decreased SBP (adjusted β=-0.57; 95% CI: -1.09, -0.05). Consistent with other literature, we also found evidence of effect modification by fetal sex, with a strong inverse association observed between the overall exposure mixture and SBP at visit 1 among participants carrying female fetuses only. CONCLUSIONS: Our findings indicate that phenol and paraben exposure may collectively increase the risk of stage 1 or 2 hypertension during pregnancy, which has important implications for fetal and maternal health. [ABSTRACT FROM AUTHOR]

The RNA exosome is an evolutionarily conserved complex required for both precise RNA processing and decay. Pathogenic variants in EXOSC genes, which encode structural subunits of this complex, are linked to several autosomal recessive disorders. Here, we describe a missense allele of the EXOSC4 gene that causes a collection of clinical features in two affected siblings. This missense variant (NM_019037.3: exon3:c.560T>C) changes a leucine residue within a conserved region of EXOSC4 to proline (p.Leu187Pro). The two affected individuals show prenatal growth restriction, failure to thrive, global developmental delay, intracerebral and basal ganglia calcifications, and kidney failure. Homozygosity for the damaging variant was identified by exome sequencing with Sanger sequencing to confirm segregation. To explore the functional consequences of this amino acid change, we modeled EXOSC4-L187P in the corresponding budding yeast protein, Rrp41 (Rrp41-L187P). Cells that express Rrp41-L187P as the sole copy of the essential Rrp41 protein show growth defects. Steady-state levels of both Rrp41-L187P and EXOSC4- L187P are decreased compared to controls, and EXOSC4- L187P shows decreased copurification with other RNA exosome subunits. RNA exosome target transcripts accumulate in rrp41-L187P cells, including the 7S precursor of 5.8S rRNA. Polysome profiles show a decrease in actively translating ribosomes in rrp41-L187P cells as compared to control cells with the incorporation of 7S pre-rRNA into polysomes. This work adds EXOSC4 to the structural subunits of the RNA exosome that have been linked to human disease and defines foundational molecular defects that could contribute to the adverse phenotypes caused by EXOSC pathogenic variants. [ABSTRACT FROM AUTHOR]

Simple Summary: Fetal macrosomia is when a baby's weight at birth is equal to or greater than 4000 g or 4500 g. The rising incidence of macrosomia poses a significant challenge in obstetrics, as it can have serious health consequences for both mothers and babies. The maternal gut microbiome can influence the health of pregnant women and their babies, with potential effects on birth weight. However, research on the link between the microbiome and birth weight, especially macrosomia, is limited; further investigation is needed. Here, we discovered a connection between the maternal gut microbiome and macrosomia. Our findings present novel opportunities for preventing macrosomia by manipulating the composition of the intestinal microbiota. Early prediction models using gut microbiota and clinical indicators can predict macrosomia. Fetal macrosomia is defined as a birthweight ≥4000 g and causes harm to pregnant women and fetuses. Studies reported that the maternal intestinal microbiome plays a key role in the establishment, growth, and development of the fetal intestinal microbiome. However, whether there is a relationship between maternal gut microbiota and macrosomia remains unclear. Our study aimed to identify gut microbiota that may be related to the occurrence of macrosomia, explore the possible mechanisms by which it causes macrosomia, and establish a prediction model to determine the feasibility of predicting macrosomia by early maternal gut microbiota. We conducted a nested case-control study based on an early pregnancy cohort (ChiCTR1900020652) in the Maternity and Child Health Hospital of Hunan Province on fecal samples of 93 women (31 delivered macrosomia as the case group and 62 delivered normal birth weight newborns as the control group) collected and included in this study. We performed metagenomic analysis to compare the composition and function of the gut microbiome between cases and controls. Correlation analysis was used to explore the association of differential species and differential functional pathways. A random forest model was used to construct an early pregnancy prediction model for macrosomia. At the species level, there were more Bacteroides salyersiae, Bacteroides plebeius, Ruminococcus lactaris, and Bacteroides ovatus in the intestinal microbiome of macrosomias' mothers compared with mothers bearing fetuses that had normal birth weight. Functional pathways of the gut microbiome including gondoate biosynthesis, L-histidine degradation III, cis-vaccenate biosynthesis, L-arginine biosynthesis III, tRNA processing, and mannitol cycle, which were more abundant in the macrosomia group. Significant correlations were found between species and functional pathways. Bacteroides plebeius was significantly associated with the pathway of cis-vaccenate biosynthesis (r = 0.28, p = 0.005) and gondoate biosynthesis (r = 0.28, p < 0.001) and Bacteroides ovatus was positively associated with the pathway of cis-vaccenate biosynthesis (r = 0.29, p = 0.005) and gondoate biosynthesis (r = 0.32, p = 0.002). Bacteroides salyersiae was significantly associated with the pathway of cis-vaccenate biosynthesis (r = 0.24, p = 0.018), gondoate biosynthesis (r = 0.31, p = 0.003), and L–histidine degradation III (r = 0.22, p = 0.291). Finally, four differential species and four clinical indicators were included in the random forest model for predicting macrosomia. The areas under the working characteristic curves of the training and validation sets were 0.935 (95% CI: 0.851~0.979) and 0.909 (95% CI: 0.679~0.992), respectively. Maternal gut microbiota in early pregnancy may play an important role in the development of macrosomia and can be used as potential predictors to prevent macrosomia. [ABSTRACT FROM AUTHOR]

Background/Aim. To date, most of the scientific attention has been aimed at the morphometric analysis of the nephrogenic zone (NZ) of the fetal renal cortex, while the quantification and analysis of the maturation zone (MZ) and other indicators of renal maturity were missing. The aim of the study was to examine the characteristics of fetal kidney cortex maturation, as well as to propose the development of a new cortical maturity index (CMI). Methods. The study included 42 paraffin molds of the fetal kidney, divided into three groups according to gestational age (GA). After hematoxylin and eosin staining, tissue sections were analyzed through the following parameters: the thickness of the NZ and MZ, the renal corpuscles area (RCa) and the glomerular capillary tuft area (GCTa), and the maturation stages of the glomeruli. In addition, a new parameter, CMI, was formed as a ratio of NZ and MZ thickness. The collected data were statistically processed. Results. Changes in NZ and MZ thickness were statistically significant, and they correlated with GA. A value of CMI higher than 0.2 was recorded in the kidney samples of fetuses younger than the 20th gestational week (GW), while a value lower than 0.1 was recorded in the samples older than the 30th GW. With an increase in GA in all zones of the renal cortex, RCa and GCTa decreased. A statistically significant reduction of GCTa was observed in the oldest group in the juxtamedullary and intermediate zones of the cortex (p < 0.01). Glomeruli located in the deeper parts of the cortex were more mature than the superficial ones. Conclusion. The measured parameters can serve as a starting point for future studies that would analyze the histomorphological characteristics of the fetal kidney cortex. In the absence of clinical data, a newly formed parameter CMI can represent assistance with the determination of GA, as it significantly correlates with GA (p < 0.01). [ABSTRACT FROM AUTHOR]

Objective: In this study, we examined the HOXA1 expression in the placentas of women diagnosed with fetal growth restriction (IUGR) by immunoexpression and in silico analysis. Methods: Placenta samples from 40 control (healthy) and 40 pregnant women diagnosed with IUGR were included in the study. The samples were fixed in zinc-formal and embedded in paraffin. Demographic information of the patients was recorded. Sections taken from paraffin blocks were analyzed by Hematoxylin-Eosin and HOXA1 immunostaining. The protein-protein interaction network of HOXA1 was constructed using the STRING database and analyzed with Cytoscape. The route description was made with the DAVID web tool. Results: In histopathological examination, intense fibrin accumulation, structural degeneration of placental components, congestion, dilatation and increased syncytial nodes were observed in the IUGR group compared to the control group. HOXA1 gene expression was significantly increased in the IUGR group. The HOXA1 PPI network contained 201 nodes and 3876 edges. MCODE analysis identified 8 modules, the highest scoring module was related to the “Systemic lupus erythematosus”, “Alcoholism” and “Neutrophil extracellular trap formation” pathways. Conclusion: With immunoexpression and in silico analysis, we showed HOXA1 is a player of immune pathways, tissue development, and placental regulation, suggesting potential research avenues in understanding IUGR mechanisms. [ABSTRACT FROM AUTHOR]

Objectives: Fetuses with late‐onset growth restriction (FGR) have a higher risk of suboptimal neurocognitive performance after birth. Previous studies have reported that impaired brain and cortical development can start in utero. The primary aim of this study was to report midline structure growth and cortical development in fetuses with late‐onset FGR according to its severity; the secondary aim was to elucidate whether the severity of FGR, as defined by the presence of abnormal Doppler findings, plays a role in affecting brain growth and maturation. Methods: This was a prospective observational study that included fetuses with late‐onset FGR (defined according to the Delphi FGR criteria) undergoing neurosonography between 32 and 34 weeks' gestation. Midline structure (corpus callosum (CC) and cerebellar vermis (CV)) length and cortical development, including the depth of the Sylvian (SF), parieto‐occipital (POF) and calcarine (CF) fissures, were compared between late‐onset FGR, small‐for‐gestational‐age (SGA) and appropriate‐for‐gestational‐age (AGA) fetuses. Subgroup analysis according to the severity of FGR (normal vs abnormal fetal Doppler) was also performed. Univariate analysis was used to analyze the data. Results: A total of 52 late‐onset FGR fetuses with normal Doppler findings, 60 late‐onset FGR fetuses with abnormal Doppler findings, 64 SGA fetuses and 100 AGA fetuses were included in the analysis. When comparing AGA controls with SGA fetuses, late‐onset FGR fetuses with normal Doppler findings and late‐onset FGR fetuses with abnormal Doppler findings, there was a progressive and significant reduction in the absolute values of the following parameters: CC length (median (interquartile range (IQR)), 43.5 (28.9–56.1) mm vs 41.9 (27.8–51.8) mm vs 38.5 (29.1–50.5) mm vs 31.7 (23.8–40.2) mm; K = 26.68; P < 0.0001), SF depth (median (IQR), 14.5 (10.7–16.8) mm vs 12.7 (9.8–15.1) mm vs 11.9 (9.1–13.4) mm vs 8.3 (6.7–10.3) mm; K = 75.82; P < 0.0001), POF depth (median (IQR), 8.6 (6.3–11.1) mm vs 8.1 (5.6–10.4) mm vs 7.8 (6.1–9.3) mm vs 6.6 (4.2–8.0) mm; K = 45.06; P < 0.0001) and CF depth (median (IQR), 9.3 (6.7–11.5) mm vs 8.2 (5.7–10.7) mm vs 7.7 (5.2–9.4) mm vs 6.3 (4.5–7.2) mm; K = 46.14; P < 0.0001). Absolute CV length was significantly higher in AGA fetuses compared with all other groups, although the same progressive pattern was not noted (median (IQR), 24.9 (17.6–29.2) mm vs 21.6 (15.2–26.1) mm vs 19.1 (13.8–25.9) mm vs 21.0 (13.5–25.8) mm; K = 16.72; P = 0.0008). When the neurosonographic variables were corrected for fetal head circumference, a significant difference in the CC length and SF, POF and CF depths, but not CV length, was observed only in late‐onset FGR fetuses with abnormal Doppler findings when compared with AGA and SGA fetuses. Conclusions: Fetuses with late‐onset FGR had shorter CC length and delayed cortical development when compared with AGA fetuses. After controlling for fetal head circumference, these differences remained significant only in late‐onset FGR fetuses with abnormal Doppler. These findings support the existence of a link between brain development and impaired placental function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This paper investigates the effects of immigration from a developing country to a developed country during pregnancy on offspring outcomes. We focus on intermediate- and long-term outcomes, using quasi-experimental variation created by the immigration of Ethiopian Jews to Israel in May 1991. Individuals conceived before immigration experienced dramatic changes in their environmental conditions at different stages of prenatal development depending on their gestational age at migration. We find that females whose mothers immigrated at an earlier gestational age have better educational outcomes. They also tend to work more as adults. In contrast, we do not find any effect among males. [ABSTRACT FROM AUTHOR]

Per- and poly-fluoroalkyl substances (PFAS) are a broad class of synthetic compounds widely used in commercial applications. The persistent nature of PFAS in the environment has earned them the epithet "forever chemicals." Concerns arise from widespread exposure to PFAS from occupational, household, and environmental sources. This widespread use of PFAS is particularly concerning, as emerging epidemiological evidence highlights their adverse effects on lung health. Such adverse impacts include impaired fetal lung development, reduced immune function in children, and potential links to lung cancer. Both in vivo and in vitro studies illuminate potential mechanisms underlying such adverse health outcomes subsequent to PFAS inhalation exposure, which may include immunomodulation, oxidative stress, and disruptions to epithelial barriers. However, evidence-based information focusing on the mechanisms of PFAS-mediated lung injury is lacking. Additionally, the discrepancies between data collected from animal and epidemiological studies highlight the need for improved approaches to better understand the toxicity results of PFAS exposure. To address these gaps, we recommend leveraging route-to-route extrapolation for risk assessment, prioritizing research on understudied PFAS, and adopting physiologically relevant, high-throughput approaches. These strategies are aimed at enhancing our understanding of PFAS inhalation effects, aiding in more informed risk management decisions. In this review, we summarize the current literature on PFAS exposure, emphasizing its adverse effects on lung health, particularly through inhalation. We then discuss the current knowledge on mechanisms underlying tissue- and cellular-level adverse outcomes caused by PFAS. [ABSTRACT FROM AUTHOR]

The placenta is crucial for fetal development, yet the impact of environmental stressors such as arsenic exposure remains poorly understood. We apply single-cell RNA sequencing to analyze the response of the mouse placenta to arsenic, revealing cell-type-specific gene expression, function, and pathological changes. Notably, the Prap1 gene, which encodes proline-rich acidic protein 1 (PRAP1), is significantly upregulated in 26 placental cell types including various trophoblast cells. Our study shows a female-biased increase in PRAP1 in response to arsenic and localizes it in the placenta. In vitro and ex vivo experiments confirm PRAP1 upregulation following arsenic treatment and demonstrate that recombinant PRAP1 protein reduces arsenic-induced cytotoxicity and downregulates cell cycle pathways in human trophoblast cells. Moreover, PRAP1 knockdown differentially affects cell cycle processes, proliferation, and cell death depending on the presence of arsenic. Our findings provide insights into the placental response to environmental stress, offering potential preventative and therapeutic approaches for environment-related adverse outcomes in mothers and children. Environmental stressors have been associated with placental dysfunction and pregnancy complications. Here, the authors reveal gene expression changes in the mouse placenta exposed to arsenic at single-cell resolution and identify a potential therapeutic target to mitigate its harmful effects on pregnancy and fetal development. [ABSTRACT FROM AUTHOR]

Simple Summary: Assisted reproduction technologies (ARTs) are usually safe; however, recent evidence suggests we need to look at potential risks in adulthood for better safety. ART techniques, like embryo vitrification, differ from natural conditions, which can potentially impact foetal development and life after birth. This study examined whether hepatic changes previously described after birth are already present in foetal livers at the end of gestation. We performed a comparison of phenotype and hepatic genome-wide mRNA expression via RNA sequencing between fresh and vitrified transferred rabbit embryos. As a result, we found phenotypic differences at 24 days of gestation, with vitrified embryos having lower foetal and liver weights and shorter body lengths. Moreover, offspring derived from vitrified embryos tended to be heavier, indicating a growth spurt in the last week of gestation. Additionally, only a total of 12 differentially expressed genes (DEGs) were detected among foetus groups, some of which are known for their role in lipid metabolism and the stress and immune response. Therefore, our results suggest that vitrification and embryo transfer manipulation induce an adaptive response in embryos and foetuses, which is apparent in the hepatic tissue at the end of the gestation period. Assisted reproduction technologies (ARTs) are generally considered safe; however, emerging evidence highlights the need to evaluate potential risks in adulthood to improve safety further. ART procedures like rederivation of embryos by vitrification differ from natural conditions, causing significant disparities between in vitro and in vivo embryos, affecting foetal physiology and postnatal life. This study aims to investigate whether hepatic transcriptome and metabolome changes observed postnatally are already present in foetal livers at the end of gestation. This study compared fresh and vitrified rabbit embryos, finding differences between foetuses obtained by the transfer of fresh and vitrified embryos at 24 days of gestation. Rederived embryos had reduced foetal and liver weights and crown-rump length. However, the offspring of vitrified embryos tended to be born with higher weight, showing compensatory growth in the final week of gestation (59.2 vs. 49.8 g). RNA-Seq analysis revealed 43 differentially expressed genes (DEGs) in the foetal liver of vitrified embryos compared to the fresh group. Notably, downregulated genes included BRAT1, CYP4A7, CYP2B4, RPL23, RPL22L1, PPILAL1, A1BG, IFGGC1, LRRC57, DIPP2, UGT2B14, IRGM1, NUTF2, MPST, and PPP1R1B, while upregulated genes included ACOT8, ERICH3, UBXN2A, METTL9, ALDH3A2, DERPC-like, NR5A2-like, AP-1, COG8, INHBE, and PLA2G4C. Overall, a functional annotation of these DEGs indicated an involvement in lipid metabolism and the stress and inflammatory process or immune response. Thus, our results suggest that vitrification and embryo transfer manipulation induce an adaptive response that can be observed in the liver during the last week of gestation. [ABSTRACT FROM AUTHOR]

In a previous Space Shuttle/Spacelab experiment (STS-42), we observed direct responses of isolated fetal mouse long bones to near weightlessness. This paper aimed to verify those results and study the effects of daily 1×g exposure during microgravity on the growth and mineralization of these bones. Two experiments were conducted: one on an American Space Shuttle mission (IML-2 on STS-65) and another on a Russian Bio-Cosmos flight (Bion-10 on Cosmos-2229). Despite differences in hardware, both used 17-day-old fetal mouse metatarsals cultured for 4 days. Results showed reduced proteoglycan content under microgravity compared to 1×g conditions, with no main differences in other cellular structures. While the overall metatarsal length was unaffected, the length increase of the mineralized diaphysis was significantly reduced under microgravity. Daily 1×g exposure for at least 6 h abolished the microgravity-induced reduction in cartilage mineralization, indicating the need for long-duration exposure to 1×g as an in-flight countermeasure using artificial gravity. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions The IMPACT BCN trial—a parallel‐group randomized clinical trial where 1221 pregnant women at high risk for small‐for‐gestational age (SGA) newborns were randomly allocated at 19‐ to 23‐week gestation into three groups: Mediterranean diet, Mindfulness‐based Stress reduction or non‐intervention—has demonstrated a positive effect of Mediterranean diet and Stress reduction in the prevention of SGA. However, the mechanism of action of these interventions remains still unclear. The aim of this study is to investigate the effect of Mediterranean diet and Stress reduction on placental volume and perfusion.Participants in the Mediterranean diet group received monthly individual and group educational sessions, and free provision of extra‐virgin olive oil and walnuts. Women in the Stress reduction group underwent an 8‐week Stress reduction program adapted for pregnancy, consisting of weekly 2.5‐h and one full‐day sessions. Non‐intervention group was based on usual care. Placental volume and perfusion were assessed in a subgroup of randomly selected women (n = 165) using magnetic resonance (MR) at 36‐week gestation. Small placental volume was defined as MR estimated volume <10th centile. Perfusion was assessed by intravoxel incoherent motion.While mean MR placental volume was similar among the study groups, both interventions were associated with a lower prevalence of small placental volume (3.9% Mediterranean diet and 5% stress reduction vs. 17% non‐intervention; p = 0.03 and p = 0.04, respectively). Logistic regression showed that small placental volume was significantly associated with higher risk of SGA in both study groups (OR 7.48 [1.99–28.09] in Mediterranean diet and 20.44 [5.13–81.4] in Stress reduction). Mediation analysis showed that the effect of Mediterranean diet on SGA can be decomposed by a direct effect and an indirect effect (56.6%) mediated by a small placental volume. Similarly, the effect of Stress reduction on SGA is partially mediated (45.3%) by a small placental volume. Results on placental intravoxel incoherent motion perfusion fraction and diffusion coefficient were similar among the study groups.Structured interventions during pregnancy based on Mediterranean diet or Stress reduction are associated with a lower proportion of small placentas, which is consistent with the previously observed beneficial effects of these interventions on fetal growth. [ABSTRACT FROM AUTHOR]

Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population. [ABSTRACT FROM AUTHOR]

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the interwired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and postmortem fetal brains, the in utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in utero dMRI data from human fetuses of both sexes between 26 and 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intrahemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for Wernicke’s area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development. [ABSTRACT FROM AUTHOR]

Successful human pregnancy needs several highly controlled steps to guarantee an oocyte's fertilization, the embryo's pre-implantation development, and its subsequent implantation into the uterine wall. The subsequent placenta development ensures adequate fetal nutrition and oxygenation, with the trophoblast being the first cell lineage to differentiate during this process. The placenta sustains the growth of the fetus by providing it with oxygen and nutrients and removing waste products. It is not surprising that issues with the early development of the placenta can lead to common pregnancy disorders, such as recurrent miscarriage, fetal growth restriction, pre-eclampsia, and stillbirth. Understanding the normal development of the human placenta is essential for recognizing and contextualizing any pathological aberrations that may occur. The effects of these issues may not become apparent until later in pregnancy, during the mid or advanced stages. This review discusses the process of the embryo implantation phase, the molecular mechanisms involved, and the abnormalities in those mechanisms that are thought to contribute to the development of pre-eclampsia. The review also covers the histological hallmarks of pre-eclampsia as found during the examination of placental tissue from pre-eclampsia patients. [ABSTRACT FROM AUTHOR]

Background: This study aims to evaluate pregnant women's knowledge of antenatal ultrasound in Saudi Arabia and its correlation with demographic factors like age and education to enhance prenatal care. Methods: A cross-sectional study was conducted in six Saudi Arabian hospitals, involving 22 questions split between sociodemographic information and knowledge of antenatal ultrasound. Descriptive statistics were used to characterize the participants' demographics and responses. Additionally, inferential statistics were employed to analyze the relationships and differences among the study variables. Results: Among the 531 pregnant women in the study, most demonstrated a good understanding of antenatal ultrasound, identifying its various uses. Specifically, they recognized its roles in evaluating fetal growth (82.5%), placental location (81.7%), amniotic fluid volume (67%), and fetal morphology (65%), predicting the delivery date (79%), and determining the baby's sex (89%). A majority viewed ultrasound as important (89.3%), safe (82.3%), and tolerable (76.3%) for prenatal care. Additionally, 66.7% felt adequately informed, mainly through clinical staff and doctors. Younger age, lower education, lack of prior ultrasound experience, and first pregnancy were linked to lower knowledge. Approximately 65% were uncertain about the nonionizing radiation properties of ultrasound. Conclusions: The study found that while most pregnant women in Saudi Arabia understand the objectives of antenatal ultrasonography, there are gaps in their knowledge about its nonionizing properties. Younger age, lower education, lack of prior ultrasound experience, and first pregnancy contribute to lower knowledge. [ABSTRACT FROM AUTHOR]

Background: Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent–offspring trios and proband only analysis. Methods: We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation. Results: Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications. Conclusion: CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to investigate the co-culture effects of human endometrial mesenchymal stem cells (EnMSCs) with mouse oocytes to enhance their maturation and development by using the hanging drop and sodium alginate hydrogel methods. Materials and Methods: In this experimental study, we prepared human EnMSCs (2.5x105 cells/mL) and co-cultured them with partially denuded mouse oocytes by the hanging drop (n=120) and sodium alginate hydrogel (n=120) methods. Control oocytes (n=230, total) were cultured in both systems in the absence of human EnMSCs for 18 hours. Both survival and maturation rates of the oocytes were analysed morphologically. After insemination with capacitated sperm, the fertiliza tion and development of the embryos up to the blastocyst stage were assessed and compared statistically for all of the study groups via one-way ANOVA and the t tests. Results: Oocytes cultured in the hanging drop method had a significantly higher survival rate than their control group (92.60 ± 4.36% vs. 84.20 ± 3.12%, P=0.018). There were no significant differences between the two experimental groups in terms of survival. The mean percent of oocytes that reached the metaphase II (MII) stage was 64.35 ± 3.19% and fertilised was 62.25 ± 4.43% in the hanging drop method; these rates were 63.43 ± 1.92% and 58.14 ± 4.14 in sodium alginate hydrogel method, respectively. These rates were higher than their controls (P<0.050), but there were no statistical differences between the two experimental groups (P>0.050). Among the studied groups, the highest significant blastocyst rate (32.55 ± 2.18%) was observed in the hanging drop experimental group (P=0.0017). Conclusion: The results of this study show that human EnMSCs improve the survival, maturation, and development rates of oocytes and they could have future clinical applications. [ABSTRACT FROM AUTHOR]

Third-trimester ultrasound has low sensitivity to small for gestational age (SGA) and adverse perinatal outcomes (APOs). The objective of this study was to compare, in terms of cost-effectiveness, two routine third-trimester surveillance protocols for the detection of SGA and evaluate the added value of a Doppler study for the prediction of APO. This was a retrospective observational study of low-risk pregnancies that were followed by a two growth scans protocol (P2) at 32 and 38 weeks or by a single growth scan at 36 weeks (P1). Ultrasound scans included an estimated fetal weight (EFW) in all cases and a Doppler evaluation in most cases. A total of 1011 pregnancies were collected, 528 with the P2 protocol and 483 with the P1 protocol. While the two models presented no differences for the detection of SGA in terms of sensitivity (47.89% vs. 50% p = 0.85) or specificity (94.97 vs. 95.86% p = 0.63), routine performance of two growth scans (P2) led to a 35% cost increase. The accuracy of EFW for the detection of SGA showed a noteworthy improvement when reducing the interval to labor, and the only parameter with predictive capacity of APO was the cerebroplacental ratio at 38 weeks. In low-risk pregnancies, the higher costs of a two-scan growth surveillance protocol at the third trimester are not justified by an increase in diagnostic effectivity. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR), or intrauterine growth restriction (IUGR), is still the second most common cause of perinatal mortality. The factors that contribute to fetal growth restriction can be categorized into three distinct groups: placental, fetal, and maternal. The prenatal application of various diagnostic methods can, in many cases, detect the deterioration of the fetal condition in time because the nature of the above disorder is thoroughly investigated by applying a combination of biophysical and biochemical methods, which determine the state of the embryo–placenta unit and assess the possible increased risk of perinatal failure outcome and potential for many later health problems. When considering the potential for therapeutic intervention, the key question is whether it can be utilized during pregnancy. Currently, there are no known treatment interventions that effectively enhance placental function and promote fetal weight development. Nevertheless, in cases with fetuses diagnosed with fetal growth restriction, immediate termination of pregnancy may have advantages not only in terms of minimizing perinatal mortality but primarily in terms of reducing long-term morbidity during childhood and maturity. [ABSTRACT FROM AUTHOR]

Background: Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a form of monogenic diabetes that is caused by heterozygous inactivating mutations in GCK gene. The management of GCK-MODY during pregnancy is challenging, as pharmacological treatment dose could not alter glycaemia in GCK-MODY in longitudinal studies and noninvasive antenatal fetal GCK genotyping is unavailable. Case presentation: Here, we report a case of GCK-MODY with pregnancy. The patient was 41 years old. She was diagnosed with GCK-MODY at 10 weeks of gestation. At 22 weeks and 6 days of gestation, she underwent amniocentesis due to her advanced age and genetic testing confirmed that the fetus was a heterozygous mutation carrier. We described the characteristics of blood glucose fluctuation, insulin responsiveness, hypoglycemic risk, fetal development, and pregnancy outcome before and after fetus genetic testing during her entire pregnancy. Until now, there were no studies describing insulin titration and blood glucose fluctuations during pregnancy in patients with GCK-MODY. Conclusion: Our case indicted that insulin therapy during pregnancy is effective in GCK-MODY. Careful dietary modifications, individualized insulin titration and specialized diabetes education can reduce the risk of hypoglycemia and improve gestational outcome in GCK-MODY with pregnancy. [ABSTRACT FROM AUTHOR]

This review summarizes the results of a series of studies performed by our group with the aim to define the expression levels of thymosin β4 and thymosin β10 over time, starting from fetal development to different ages after birth, in different human organs and tissues. The first section describes the proteomics investigations performed on whole saliva from preterm newborns and gingival crevicular fluid, which revealed to us the importance of these acidic peptides and their multiple functions. These findings inspired us to start an in-depth investigation mainly based on immunochemistry to establish the distribution of thymosin β4 and thymosin β10 in different organs from adults and fetuses at different ages (after autopsy), and therefore to obtain suggestions on the functions of β-thymosins in health and disease. The functions of β-thymosins emerging from these studies, for instance, those performed during carcinogenesis, add significant details that could help to resolve the nowadays so-called "β-thymosin enigma", i.e., the potential molecular role played by these two pleiotropic peptides during human development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. METHODS: In the LIFECODES Fetal Growth Study (2008–2018), an enriched case–cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. RESULTS: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng/mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger 푧-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng/mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). CONCLUSIONS: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. [ABSTRACT FROM AUTHOR]

Background: CircRNA‐encoded proteins (CEPs) are emerging as new players in health and disease, and function as baits for the common partners of their cognate linear‐spliced RNA encoded proteins (LEPs). However, their prevalence across human tissues and biological roles remain largely unexplored. The placenta is an ideal model for identifying CEPs due to its considerable protein diversity that is required to sustain fetal development during pregnancy. The aim of this study was to evaluate circRNA translation in the human placenta, and the potential roles of the CEPs in placental development and dysfunction. Methods: Multiomics approaches, including RNA sequencing, ribosome profiling, and LC‐MS/MS analysis, were utilised to identify novel translational events of circRNAs in human placentas. Bioinformatics methods and the protein bait hypothesis were employed to evaluate the roles of these newly discovered CEPs in placentation and associated disorders. The pathogenic role of a recently identified CEP circPRKCB119aa in preeclampsia was investigated through qRT‐PCR, Western blotting, immunofluorescence imaging and phenotypic analyses. Results: We found that 528 placental circRNAs bound to ribosomes with active translational elongation, and 139 were translated to proteins. The CEPs showed considerable structural homology with their cognate LEPs, but are more stable, hydrophobic and have a lower molecular‐weight than the latter, all of which are conducive to their function as baits. On this basis, CEPs are deduced to be closely involved in placental function. Furthermore, we focused on a novel CEP circPRKCB119aa, and illuminated its pathogenic role in preeclampsia; it enhanced trophoblast autophagy by acting as a bait to inhibit phosphorylation of the cognate linear isoform PKCβ. Conclusions: We discovered a hidden circRNA‐encoded proteome in the human placenta, which offers new insights into the mechanisms underlying placental development, as well as placental disorders such as preeclampsia. Key points: A hidden circRNA‐encoded proteome in the human placenta was extensively identified and systematically characterised.The circRNA‐encoded proteins (CEPs) are potentially related to placental development and associated disorders.A novel conserved CEP circPRKCB119aa enhanced trophoblast autophagy by inhibiting phosphorylation of its cognate linear‐spliced isoform protein kinase C (PKC) β in preeclampsia. [ABSTRACT FROM AUTHOR]