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Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist—including insulin and lifestyle interventions—there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.

Background Gestational diabetes mellitus (GDM) has been associated with several fetal complications, such as macrosomia and fetal growth restriction (FGR). Infants from GDM associated FGR are at increased risk for adult-onset obesity and associated metabolic disorders. However, the underlying mechanisms of GDM associated FGR remain to be explored. Methods We analyzed placentas from GDM patients with FGR for ferroptosis markers and GLUT1 expression. High glucose conditions were established by adding different concentrations of D-Glucose to the 1640 cell culture medium. RSL3 were used to test ferroptosis sensitivity in trophoblast cells. GLUT1 was inhibited using siRNA or its inhibitor WZB117 to assess its impact on ferroptosis inhibition in HTR8/SVneo cell line. Mechanistic studies explored the effects of GLUT1 on AMPK and ACC phosphorylation, which in turn impacted lipid metabolism and ferroptosis. In mouse models, streptozotocin (STZ)-induced GDM was treated with WZB117 and the ferroptosis inhibitor liproxstatin-1 (Lip-1). Finally, AMPK and ACC phosphorylation levels were evaluated in GDM patient samples. Results In this study, placentas from GDM patients with FGR showed signs of ferroptosis and upregulation of GLUT1. In cell models, high glucose conditions sensitized trophoblast cells to ferroptosis and induced GLUT1 expression. Interestingly, GLUT1 inhibition significantly suppressed ferroptosis in trophoblast cells under high glucose conditions. Mechanistically, elevated GLUT1 inhibited AMPK phosphorylation and reduced ACC phosphorylation, thereby promoting lipid synthesis and facilitating ferroptosis. In pregnant mice, STZ-induced hyperglycemia led to FGR, and treatment with either the GLUT1 inhibitor WZB117 or the ferroptosis inhibitor Lip-1 alleviated the FGR phenotype. Moreover, in vivo elevation of GLUT1 increased ferroptosis markers, decreased AMPK/ACC phosphorylation, and resulted in altered lipid metabolism, which likely contributed to the observed phenotype. Finally, placental samples from GDM patients showed reduced AMPK and ACC phosphorylation. Conclusions Our findings suggest a potential role of ferroptosis in GDM associated FGR and indicate that the dysregulated GLUT1-AMPK-ACC axis may be involved in the pathogenesis of GDM associated FGR in clinicals.

Background Pregnant women expecting twins are more likely to experience stress, which can lead to anxiety and depression. Our aim was to investigate the prevalence of prenatal anxiety and depressive symptoms in women with twin pregnancies and the associated factors. Methods In a cross-sectional survey, 210 women with twin pregnancies who satisfied the inclusion and exclusion criteria in two tertiary centers in Southwestern China were asked to complete a basic information form, the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). To compare statistics with normal distribution in distinct characteristic groups, a paired t-test, and one-way ANOVA were utilized. Binary logistic step regression was used to analyze the associated factors of antenatal anxiety and depressive symptoms. Results The 210 women with twin pregnancies (age = 30.8 ± 4.2 years) were between 7 and 37 gestational weeks (29.2 ± 1.2 weeks), were typically well-educated (72.4% had a post-high-school degree), and reasonably affluent (88.1% were above the low-income cutoff). Among them, 34.8% had symptoms associated with clinical levels of anxiety, and 37.1% had symptoms indicating possible depression. The prevalence of co-morbid anxiety and depressive symptoms was 24.3%. Binary stepwise logistic regression analysis showed that previous health status and sleep disturbance during pregnancy were the associated factors of anxiety symptoms in women with twin pregnancies ( P  < 0.05), whereas age, previous health status, negative life events, and physical activity during pregnancy were the associated factors of depressive symptoms in women with twin pregnancies ( P  < 0.05). Conclusion About one-third of women with twin pregnancies had symptoms of anxiety or depression; these were most strongly predicted by some modifiable factors, suggesting that early preventive mind-body interventions may be a promising strategy to protect against mental health issues for women with twin pregnancies.

Gestational diabetes mellitus (GDM) represents a prevalent pregnancy complication with long-term health implications for offspring. While metabolic outcomes have been extensively studied, sex-specific effects on neurodevelopment remain poorly understood. Here we investigated the sex-dependent impact of maternal GDM on offspring brain development and behavior using a high-fat diet and low-dose streptozotocin induced mouse model. We found that adult female offspring exposed to maternal GDM exhibited depressive-like behaviors and sustained impairments in hippocampal neurogenesis across multiple developmental stages (embryonic, weaning and adult), characterized by reduced neural stem cell proliferation and altered differentiation. By contrast, male offspring displayed substantial metabolic dysfunction but no sustained neurogenic deficits beyond the embryonic period. Metabolomic analysis revealed persistent downregulation of myo-inositol in female offspring hippocampus, associated with disruptions in neurogenic signaling pathways. In vitro experiments with female-derived neural stem cells confirmed that hyperglycemic conditions directly impaired proliferation and differentiation, partly through oxidative stress mechanisms. These findings establish a sex-specific vulnerability to GDM-induced neurodevelopmental alterations and identify myo-inositol metabolism as a potential therapeutic target for preventing long-term neuropsychiatric consequences in female offspring. Maternal GDM induces sex-specific effects on offspring neurodevelopment, with females exhibiting persistent hippocampal neurogenesis deficits and depressive-like behaviors, while males show neurogenic resilience. The identification of myo-inositol depletion and oxidative stress as potential contributors to female-specific neurogenic impairments provides new insights into sex-specific vulnerability to maternal metabolic disturbances and suggests potential targets for intervention. HFD, High fat diet; STZ, Streptozotocin; GCL, Granule cell layer; SGZ, Subgranular zone; NSCs, Neural stem cells. Figure created with BioRender.com. Sex-specific effects of GDM on offspring neurogenesis Gestational diabetes mellitus (GDM), a condition of glucose intolerance first identified during pregnancy, affects about 15% of pregnant women globally, posing risks to both maternal and offspring health. This study explores how GDM impacts neurodevelopment, particularly focusing on depressive- and anxiety-like behaviors in offspring. Using a GDM mouse model, researchers tracked hippocampal neurogenesis and examined neurometabolic changes and oxidative stress. The results showed that GDM selectively induces depressive-like behaviors in female offspring, linked to impaired neurogenesis and reduced synaptic plasticity in the hippocampus. Notably, female offspring exhibited decreased dendritic complexity and reduced levels of neurotransmitters such as serotonin and dopamine. These findings highlight the sex-specific impact of GDM on neurodevelopment, with potential implications for understanding the developmental origins of neuropsychiatric disorders. Future research could explore therapeutic interventions targeting metabolic-neural pathways to mitigate these effects. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Advanced maternal age (AMA) pregnancies are rapidly increasing and are associated with aberrant trophoblast cell function, poor placentation, and unfavorable pregnancy outcomes, presumably due to premature placental senescence. SIRT1 is an NAD+‐dependent deacetylase with well‐known antiaging effects, but its connection with placental senescence is unreported. In this study, human term placentas and first‐trimester villi were collected from AMA and normal pregnancies, and a mouse AMA model was established by cross breeding young and aged male and female C57 mice. SIRT1 expression and activity in HTR8/SVneo cells were genetically or pharmacologically manipulated. Trophoblast‐specific Sirt1‐knockout (KO) mouse placentas were generated by mating Elf5‐Cre and Sirt1fl/fl mice. Trophoblast cell mobility was assessed with transwell invasion and wound‐healing assays. SIRT1‐binding proteins in HTR8/SVneo cells and human placental tissue were identified by mass spectrometry. We identified SIRT1 as the only differentially expressed sirtuin between AMA and normal placentas. It is downregulated in AMA placentas early in the placental life cycle and is barely impacted by paternal age. SIRT1 loss upregulates P53 acetylation and P21 expression and impairs trophoblast invasion and migration. Sirt1‐KO mouse placentas exhibit senescence markers and morphological disruption, along with decreased fetal weight. In trophoblasts, SIRT1 interacts with vimentin, regulating its acetylation. In conclusion, SIRT1 promotes trophoblast epithelial−mesenchymal transition (EMT) to enhance invasiveness by modulating vimentin acetylation. AMA placentas are associated with premature senescence during placentation due to SIRT1 loss. Therefore, SIRT1 may be an antiaging therapeutic target for improving placental development and perinatal outcomes in AMA pregnancies. Both the first‐trimester villi and full‐term placentas from pregnancies of advanced maternal age (AMA) are associated with the significant downregulation of SIRT1 and accumulation of P53, P21, and β‐galactosidase in trophoblasts, where SIRT1 directly interacts with vimentin and modulates the acetylation status of vimentin, thus affecting the EMT process and ultimately influencing the invasiveness and mobility of trophoblasts. Both P53–P21 axis‐dependent cellular senescence and vimentin acetylation‐induced EMT suppression may orchestrate premature placental senescence and eventually lead to a variety of adverse pregnancy outcomes.

Preeclampsia causes substantial maternal and perinatal morbidity and mortality and significant societal economic impact. Effective screening would facilitate timely and appropriate prevention and management of preeclampsia. To develop an early cost-effectiveness analysis to assess both costs and health outcomes of a new screening test for preeclampsia from a healthcare payer perspective, in the United Kingdom (UK), Ireland, the Netherlands and Sweden. A decision tree over a 9-month time horizon was developed to explore the cost-effectiveness of the new screening test for preeclampsia compared to the current screening strategy. The new test strategy is being developed so that it can stratify healthy low risk nulliparous women early in pregnancy to either a high-risk group with a risk of 1 in 6 or more of developing preeclampsia, or a low-risk group with a risk of 1 in 100 or less. The model simulated 25 plausible scenarios in a hypothetical cohort of 100,000 pregnant women, in which the sensitivity and specificity of the new test were varied to set a benchmark for the minimum test performance that is needed for the test to become cost-effective. The input parameters and costs were mainly derived from published literature. The main outcome was incremental costs per preeclampsia case averted, expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty. Base case results showed that the new test strategy would be more effective and less costly compared to the current situation in the UK. In the Netherlands, the majority of scenarios would be cost-effective from a threshold of €50,000 per preeclampsia case averted, while in Ireland and Sweden, the vast majority of scenarios would be considered cost-effective only when a threshold of €100,000 was used. In the best case analyses, ICERs were more favourable in all four participating countries. Aspirin effectiveness, prevalence of preeclampsia, accuracy of the new screening test and cost of regular antenatal care were identified as driving factors for the cost-effectiveness of screening for preeclampsia. The results indicate that the new screening test for preeclampsia has potential to be cost-effective. Further studies based on proven accuracy of the test will confirm whether the new screening test is a cost-effective additional option to the current situation.

Vitamin D insufficiency and deficiency have been associated with an increased risk of adverse pregnancy outcomes. Controversy remains as findings have been inconsistent between disparate populations. The aim of this study was to investigate the relationship between vitamin D status and pregnancy outcomes in a large, prospective pregnancy cohort. 25-Hydroxyvitamin D concentration was analysed in serum samples collected at 15 weeks of gestation from 1710 New Zealand women participating in a large, observational study. Associations between vitamin D status and pre-eclampsia, preterm birth, small for gestational age (SGA) and gestational diabetes were investigated. The mean 25-hydroxyvitamin D concentration was 72·9 nmol/l. In all, 23 % had 25-hydroxyvitamin D concentrations <50 nmol/l, and 5 % of participants had concentrations <25 nmol/l. Women with 25-hydroxyvitamin D concentrations <75 nmol/l at 15 weeks of gestation were more likely to develop gestational diabetes mellitus than those with concentrations >75 nmol/l (OR 2·3; 95 % CI 1·1, 5·1). However, this effect was not significant when adjustments were made for BMI and ethnicity (OR 1·8; 95 % CI 0·8, 4·2). 25-Hydroxyvitamin D concentration at 15 weeks was not associated with development of pre-eclampsia, spontaneous preterm birth or SGA infants. Pregnancy complications were low in this largely vitamin D-replete population.

Background A growing number of studies have found that breech presentation is related to preexisting diseases and may affect future fetal development. This study aimed to compare the differences between breech presentation and cephalic presentation and explore the underlying mechanisms of adverse outcomes caused by fetal station itself. Methods ‘PubMed’, ‘Embase’ and ‘Cochrane Library’ were searched from inception to October 21, 2022. Comparative studies containing ‘prelabor CS’ or ‘elective CS’ of cephalic and breech presentation were included. A total of 585 studies were included, and 5 studies were eligible for final research. Review Manager 5.4.1 was used for data synthesis. Results The mortality of breech group is not different from that of cephalic group (RR 0.69, 95% CI 0.09–5.13, p  = 0.71). No differences in infant (< 1 year) and neonatal (0–27 days) mortality were found between the breech and cephalic presentations (RR 1.56, 95% CI 0.86–2.82, p  = 0.14). However, breech group was found to have lower birth weight ( p  < 0.002), umbilical coiling index( p  < 0.0001), and bone SOS ( p  = 0.03 )than cephalic group. Conclusions The breech presentation itself may not be related to adverse pregnancy outcomes, and more attention is needed for further exploration. Graphical Abstract

Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. Accurate prediction of preeclampsia risk would enable more effective, risk-based prenatal care pathways. Current risk assessment algorithms depend on clinical risk factors largely unavailable for first-time pregnant women. Delivering accurate preeclampsia risk assessment to this cohort of women, therefore requires for novel biomarkers. Here, we evaluated the relevance of metabolite biomarker candidates for their selection into a prototype rapid, quantitative Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) based clinical screening assay. First, a library of targeted LC-MS/MS assays for metabolite biomarker candidates was developed, using a medium-throughput translational metabolomics workflow, to verify biomarker potential in the Screening-for-Pregnancy-Endpoints (SCOPE, European branch) study. A variable pre-selection step was followed by the development of multivariable prediction models for pre-defined clinical use cases, i.e., prediction of preterm preeclampsia risk and of any preeclampsia risk. Within a large set of metabolite biomarker candidates, we confirmed the potential of dilinoleoyl-glycerol and heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine to effectively complement Placental Growth Factor, an established preeclampsia biomarker, for the prediction of preeclampsia risk in first-time pregnancies without overt risk factors. These metabolites will be considered for integration in a prototype rapid, quantitative LC-MS/MS assay, and subsequent validation in an independent cohort.

Caesarean section (CS) rates are increasing globally and exceed 50% in some countries. Childhood obesity has been linked to CS via lack of exposure to vaginal microflora although the literature is inconsistent. We investigated the association between CS birth and the risk of childhood obesity using the nationally representative Growing-Up-in-Ireland (GUI) cohort. The GUI study recruited randomly 11134 infants. The exposure was categorised into normal vaginal birth (VD) [reference], assisted VD, elective (planned) CS and emergency (unplanned) CS. The primary outcome measure was obesity defined according to the International Obesity Taskforce criteria. Statistical analysis included multinomial logistic regression with adjustment for potential confounders. Infants delivered by elective CS had an adjusted relative risk ratio (aRRR) = 1.32; [95% confidence interval (CI) 1.01–1.74] of being obese at age three years. This association was attenuated when macrosomic children were excluded (aRRR = 0.99; [95% CI 0.67–1.45]). Infants delivered by emergency CS had an increased risk of obesity aRRR = 1.56; [95% CI 1.20–2.03]; this association remained after excluding macrosomic children. We found insufficient evidence to support a causal relationship between elective CS and childhood obesity. An increased risk of obesity in children born by emergency CS, but not elective, suggests that there is no causal effect due to vaginal microflora.