The human (h) growth hormone (GH)/placental lactogen (PL) gene family has served as an important model to study tissue-specific expression. The two GH genes (hGH-N/GH1 and GH-V/GH2) and three PL or chorionic somatomammotropin hormone (CSH) genes (hPL-L/CSL1, hPL-A/CSH1 and hPL-B/CSH2) are clustered together at a single locus. Although they share >90% sequence similarity, hGH-N is expressed by somatotrophs of the anterior pituitary while the remaining four hGH/PL genes are expressed by the villous syncytiotrophoblast of the placenta. Efficient pituitary expression depends on a locus control region (LCR) that includes nuclease hypersensitive sites I-V (HS I-V). For activation, data indicate that HS III facilitates the initial access of pituitary-specific transcription factor Pit-1 to the locus, where it is required to bind Pit-1 sites at HS I/II and the hGH-N promoter. This is associated with histone acetylation and tri-methylation modifications that are consistent with active chromatin. However, all five hGH/PL genes share similar nuclease sensitivity in human pituitary chromatin, suggesting similar levels of accessibility and thus potential for transcription. Furthermore, hPL-A and hPL-B promoters contain Pit-1 binding sites, and the hPL-A promoter, like hGH-N, will support expression in transfected pituitary tumor GC cells in culture. These observations suggest the possibility of a transcriptional repressor mechanism that prevents hPL gene expression in the pituitary. P sequences were identified as a candidate. They are located upstream of all four placental hGH/PL genes but not hGH-N, repress hPL-A promoter activity in transfected pituitary GC cells, and bind a forkhead box A1/nuclear factor-1 transcription, which is proposed to act as a repressor complex in human pituitary chromatin. In spite of this, the inability to limit hGH-N expression when tested in transgenic mice brought the role of P sequences in pituitary repression into question. These observations are re-examined here in light of new evidence that the LCR (HS III) interacts with P sequences in the human pituitary.

Placental villi include an outer syncytiotrophoblast (STB) layer and an inner layer of cytotrophoblasts (CTBs) that fuse to generate the STB layer in pregnancy. While activation of the locus containing the human (h) placental lactogen (hPL) genes (hPL-A/CSH1 and hPL-B/CSH2) begins in the CTBs, their expression in the STB requires epigenetic modifications and interactions between locus control region (LCR) and gene regulatory sequences. No factor that limits or facilitates hPL LCR/gene interactions for locus activation is reported. The paternally-expressed gene 3 (PEG3/PW1) transcription factor was pursued as a candidate. PEG3 is expressed by villous CTBs but not the STB and putative binding sites were identified in hPL-related sequences.

PEG3 expression was assessed in multiple cell types including in CTB-like JEG-3 cells. PEG3 binding was also assessed in JEG-3 cells and term placenta samples from women with or without maternal obesity, where chromosomal architecture of the hPL gene locus was also examined.

In JEG-3 cells, PEG3 was found to bind to hypersensitive site (HS III-V) sequences within the LCR. Knockdown of PEG3 in these cells resulted in increased hPL gene expression. In term placenta, PEG3 binding at placenta-specific HS IV was increased with maternal obesity, where a decrease in hPL RNA levels is seen, while PEG3 binding was reduced in women with obesity who develop insulin-treated gestational diabetes mellitus (O/GDM + Ins), where increased hPL gene expression is observed. Chromatin conformation capture revealed distinct hPL gene domain interactions that are modified with maternal obesity but largely reversed in O/GDM + Ins, correlating with PEG3 binding.

Decreased PEG3 binding may be required for hPL domain generation and expression during CTB to STB transition.

Pregnancy alters the systemic exposure and clearance of many hepatically cleared drugs that are commonly used by obstetric patients. Understanding the molecular mechanisms underlying the changes in factors that affect hepatic drug clearance (blood flow, protein binding, and intrinsic clearance) is essential to more precisely predict systemic drug exposure and dose requirements in obstetric patients.

This review (1) summarizes the anatomic, physiologic, and biochemical changes in maternal hepatic, cardiovascular, endocrine, and renal systems relevant to hepatic drug clearance and (2) reviews the molecular mechanisms underlying the altered hepatic metabolism and intrinsic clearance of drugs during pregnancy via a comprehensive PubMed search. It also identifies knowledge gaps in the molecular mechanisms and factors that modulate hepatic drug clearance during pregnancy.

Pharmacokinetic studies have shown that pregnancy alters systemic exposure, protein binding, and clearance of many drugs during gestation in part due to pregnancy-associated decreases in plasma albumin, increases in organ blood flow, and changes in the activity of drug-metabolizing enzymes (DMEs) and transporters. The changes in the activity of certain DMEs and transporters during pregnancy are likely driven by hormonal-changes that inhibit their activity or alter the expression of these proteins through activation of transcription factors.

This study investigated the association between maternal age and early and late gestational diabetes mellitus (GDM).

In total, 72,270 pregnant women were included in this prospective birth cohort study. Associations between maternal age and early GDM (diagnosed at <24 gestational weeks) and late GDM (diagnosed at ≥24 gestational weeks) were evaluated using a multinomial logistic regression model with possible confounding factors. The reference category was maternal age of 30-34.9 years.

Higher maternal age was associated with higher odds of early and late GDM (P-value for trend <0.0001 and <0.0001, respectively). The adjusted odds ratios (aORs) for early GDM with maternal age of 35-39.9 years and ≥40 were 1.399 (95% confidence interval [CI]: 1.134-1.725) and 2.494 (95% CI: 1.828-3.402), respectively. The aORs for late GDM with maternal age of 35-39 years and ≥40 were 1.603 (95% CI: 1.384-1.857) and 2.276 (95% CI: 1.798-2.881), respectively.

Higher maternal age was associated with an increased risk of GDM regardless of when GDM was diagnosed. The association between maternal age and early GDM was similar to that between maternal age and late GDM.

In higher primates, unlike other mammals, the GH gene locus is complex, comprising several GH-like genes, resulting from gene duplication and divergent evolution, expressed in pituitary and placenta. There are 5 genes in this GH gene cluster in human and 5 to 7 in apes and most Old-World monkeys, but in macaques the cluster has expanded further. Here the nature and evolution of the GH locus in this important primate genus is explored. Analysis of genomic data for Macaca fascicularis (crab-eating macaque) revealed that the GH gene cluster in this species is variable, with at least 5 different haplotypes, comprising 11 to 14 GH-like genes. Gene-number heterozygosity was also detected in Macaca mulatta (rhesus macaque) with 9 to 13 genes. Analysis of genomic data for other macaque species revealed GH gene clusters containing 8 to 14 GH-like genes, but gene-number heterozygosity was not detected. Expression of GH-like genes in pituitary and placenta was examined for Macaca fascicularis. This analysis has established that the complexity of the GH gene cluster increased during the evolution of macaques, by gene duplication and divergent evolution, and that these processes continue within at least 2 extant species. Analysis of rate of sequence change, and distribution of substitutions within the 3D structure, shows that for at least 1 GH-like gene (GH2), the changes reflect positive selection, implying adaptive biological change. Whether this involves changes in physiological (endocrine) function or response to viral or other pathogenic challenge is not yet clear.

Maternal metabolic intensity significantly increases during late gestation and lactation, placing significant stress on cells and tissues. This heightened metabolic demand can lead to inflammatory responses and metabolic disorders, adversely affecting the health of both the mother and her offspring. Diet plays a key role in modulating host health by influencing the gastrointestinal microbiome. This study examined the impact of two roughage sources, corn straw (CS), and alfalfa hay (AH), on ewes and their offspring during late gestation and lactation, with a focus on metabolism, immunity, and the microbiome. Thirty-six multiparous Inner Mongolia cashmere goats, approximately 60 days pregnant, were assigned to CS and AH groups. Samples were collected from the ewes on day 140 of gestation (G140) and day 28 of lactation (L28) for analysis. The results showed that ewes fed AH had reduced body weight loss during lactation (p < 0.05), and increased serum metabolic factors levels (p < 0.05). Additionally, ewes in the AH group exhibited a reduced inflammatory response during both gestation and lactation compared to those in the CS group, as evidenced by a significant decrease in TNF-α and LPS levels and a notable increase in IL-10 (p < 0.05). The rumen microbiomes of ewes in the AH and CS groups exhibited stark differences, with specific microbial markers identified at G140 and L28. Correlation analysis revealed associations between microbiome, volatile fatty acids, cytokines, and metabolic markers. The analysis of the lambs demonstrated that their immune status and microbial composition were significantly influenced by the immune health and microbial community structure of the ewe. Moreover, microbial and immune-related components from the ewes were transmitted to the lambs, further shaping their immune development and rumen microbiota. Overall, different roughage sources during late gestation and lactation had minimal impact on the growth performance of ewes and lambs, given that both diets were iso-nitrogen and iso-energetic. However, ewes fed AH exhibited significant improvements in immune function and overall health for both them and their lambs.

Cytochrome P450 (CYP) 3A4 is an essential drug-metabolizing enzyme in humans, which shows substantial interindividual variation in response to various intrinsic and extrinsic factors such as sex and pregnancy. In humans, higher CYP3A4 metabolism has been observed in females compared with that in males and in pregnant compared with that in nonpregnant individuals, which has been linked to increased CYP3A4 expression in liver. However, sex differences and pregnancy-mediated changes in hepatic CYP3A4 expression and activity in vivo are not fully understood. In this study, we investigated the utility of a genetically engineered humanized mouse model that carries human CYP3A4/7, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (huPXR/CAR/CYP3A4/7) to recapitulate sex-associated and pregnancy-associated differences in the hepatic CYP3A4 expression and metabolism observed in humans. We found that female huPXR/CAR/CYP3A4/7 mice exhibited higher basal CYP3A4 mRNA levels and CYP3A4 absolute protein concentrations in liver, and higher 1-hydroxymidazolam formation in liver microsomes, compared with male humanized mice. In contrast, pregnant huPXR/CAR/CYP3A4/7 mice exhibited lower CYP3A4 mRNA levels, CYP3A4 absolute protein concentrations, and 1-hydroxymidazolam formation compared with nonpregnant and postpartum humanized mice. Expression of CAR and Cyp2b10 (a CAR responsive gene) were also higher in females and decreased during pregnancy and were positively correlated with hepatic CYP3A4 mRNA levels. Overall, the huPXR/CAR/CYP3A4/7 mouse model demonstrated utility to study higher basal hepatic CYP3A4 metabolism in females compared with that in males in vivo; however, this humanized mouse model did not demonstrate utility to study pregnancy-mediated increases in CYP3A4 drug substrate metabolism and clearance observed in humans. SIGNIFICANCE STATEMENT: This study assessed the impact of sex and pregnancy on hepatic CYP3A4 protein concentrations and metabolism in humanized PXR/CAR/CYP3A4 mice. Consistent with humans, female mice demonstrated higher hepatic CYP3A4 expression and activity than male mice. In contrast, pregnant mice showed decreased CYP3A4 expression and metabolism compared with nonpregnant mice. The humanized mouse model appeared useful to evaluate sex differences in basal hepatic CYP3A4 metabolism in vivo, but not to study the pregnancy-mediated increase in CYP3A4 metabolism observed during human pregnancy.

This study examined associations between mitochondrial markers-circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)-with maternal distress and pregnancy outcomes.

Participants were drawn from two pregnancy studies, EPI (N=187, USA) and BABIP (N=198, Turkey). Plasma cf-mtDNA and GDF15 levels were quantified using qPCR and ELISA assays.

Plasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p=0.035) and gestational age (p=0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (p<0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (p<0.05).

This study reveals distinct plasma cf-mtDNA and GDF15 patterns during the perinatal period, linking mitochondrial markers to maternal distress and pregnancy outcomes.

Understanding environmental risk factors for gestational diabetes (GD) is crucial for developing preventive strategies and improving pregnancy outcomes.

To examine the association of county-level radon exposure with GD risk in pregnant individuals.

This multicenter, population-based cohort study used data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) cohort, which recruited nulliparous pregnant participants from 8 US clinical centers between October 2010 and September 2013. Participants who had pregestational diabetes or were missing data on GD or county-level radon measurements were excluded from the current study. Data were analyzed from September 2023 to January 2024.

County-level radon data were created by the Lawrence Berkeley National Laboratory based on the Environmental Protection Agency's short- and long-term indoor home radon assessments. Radon exposure was categorized into 3 groups: less than 1, 1 to less than 2, and 2 or more picocuries (pCi)/L (to convert to becquerels per cubic meter, multiply by 37). Because radon, smoking, and fine particulate matter air pollutants (PM2.5) may share similar biological pathways, participants were categorized by joint classifications of radon level (<2 and ≥2 pCi/L) with smoking status (never smokers and ever smokers) and radon level with PM2.5 level (above or below the median).

The main outcome was GD, identified based on glucose tolerance testing and information from medical record abstraction. Multiple logistic regression models were used to assess the association between radon exposure and GD.

Among the 9107 participants, mean (SD) age was 27.0 (5.6) years; 3782 of 9101 (41.6%) had ever used tobacco. The mean (SD) county-level radon concentration was 1.6 (0.9) pCi/L, and 382 participants (4.2%) had GD recorded. After adjusting for potential confounders, individuals living in counties with the highest radon level (≥2 pCi/L) had higher odds of developing GD compared with those living in counties with the lowest radon level (<1 pCi/L) (odds ratio [OR], 1.37; 95% CI, 1.02-1.84); after additional adjustment for PM2.5, the OR was 1.36 (95% CI, 1.00-1.86). Elevated odds of GD were also observed in ever smokers living in counties with a higher (≥2 pCi/L) radon level (OR, 2.09; 95% CI, 1.41-3.11) and participants living in counties with higher radon and PM2.5 levels (OR, 1.93; 95% CI, 1.31-2.83), though no statistically significant interactions were observed.

This cohort study suggests that higher radon exposure is associated with greater odds of GD in nulliparous pregnant individuals. Further studies are needed to confirm the results and elucidate the underlying mechanisms, especially with individual-level residential radon exposure assessment.

The 'Developmental Origins of Health and Disease' (DOHaD) hypothesis postulates that exposures during critical periods of development and growth, including maternal hyperglycemia, can have significant consequences for short- and long-term health in offspring. The influence of fetal status on maternal (patho)physiology is less well understood but gaining attention. Fetal sex specifically may be an independent risk factor for a range of adverse pregnancy outcomes, including increased gestational diabetes mellitus (GDM) frequency with male fetuses in multi-ethnic populations. Fetal sex has been thought to modulate maternal glucose metabolism, including insulin dynamics, through complex genetic and hormonal interactions. Mechanisms have not been fully elucidated, however, but may relate to sexual dimorphism in maternal-fetal-placental interactions. We review current evidence on the potential influence of fetal sex on maternal glucose and insulin dynamics, and fetal outcomes.

Radon is a colorless, odorless radioactive gas that is naturally occurring in the environment, originating from the decay of uranium that exists in the earth's crust. In addition to lung cancer, radon exposure has recently been associated with hypertension and cardiovascular disease. However, little consideration has been given to radon exposure during pregnancy, even though pregnant people are a more vulnerable population and ionizing radiation is a known risk factor for adverse maternal and fetal outcomes. There is also greater recognition of the potential effect of ambient particle radioactivity. The radioactivity of ambient particles is primarily due to the decay of radon progeny, and thus another source of exposure to radiation due to radon decay. We systematically searched and evaluated the literature and summarized the current evidence on radon and particle radioactivity exposure during pregnancy. While the literature is sparse, we identified eight human studies that address this topic. The accumulated evidence suggests that radon and particle radioactivity may be associated with a range of adverse pregnancy outcomes, including gestational diabetes and hypertension and fetal development. Additionally, we highlight several potential biological pathways by which radon may affect maternal and fetal health. The ubiquity of radon and ambient particle radioactivity exposure, biological plausibility and results of early studies all suggest radon exposure during pregnancy is an important topic that merits further investigation.

Prediabetes (PD) is associated with intermediate hyperglycaemia, dyslipidaemia, reduced nitric oxide (NO) bioavailability and moderate hypertension. All these factors are risk factor for preeclampsia (PE). However, the effects of the PD on placental function have not been shown. Accordingly, this study sought to investigate a possible link between maternal PD and the risk of developing PE.

Pregnant female Sprague-Dawley rats (N = 18) were divided into normal, preeclamptic and prediabetic groups (n = 6 in each group) to study the effects of maternal PD on placenta function over the period of 19 days. Blood glucose and blood pressure were measured on gestational day (GND) 0, 9 and 18. Placental vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) mRNA expression were measured terminally. Data were analysed using ANOVA followed by the Tukey-Kramer post hoc test. Values of p < .05 were used to indicate statistical significance.

Maternal PD and PE significantly increased blood glucose, decrease NO concentration and increase in MAP by comparison to the normal pregnant control group. Maternal PD significantly decreased VEGF, PlGF mRNA expression with a slight increase in sFlt-1 mRNA expression comparison to the normal pregnant control group.

Maternal PD is associated with placental dysfunction due to impaired glucose handling, endothelial dysfunction and an imbalance in angiogenic and antiangiogenic factors. Therefore, maternal PD is a risk factor of PE.

Gestational diabetes (GD) is associated with a variety of numerous metabolic changes. Discovering related biomarkers by the metabolomic studies can provide a better understanding of the pathological processes involved in the development and progression of GD.

Blood samples were taken from 400 naturally conceived healthy women aged 25-40 years old in the first trimester of pregnancy. Participants were followed up again at 28 weeks of gestation and reevaluated for GD based on American Diabetes Association (ADA) criteria. After identifying 32 women with GD as the case group, 32 healthy matched women selected as the control group. Plasma samples in the first and third trimester, were sent for nuclear magnetic resonance (NMR) testing. Altered biochemical pathways were identified in MetaboAnalyst 4.0 using Human Metabolism Database (HMDB). The comparison of altered metabolomes in two groups was assessed using multivariate logistic regression analysis in SPSS 23 software.

In the first trimester, the amount of increase in steroid hormones level was greater in women who progressed to GD (Impact = 0.344). In the third trimester, although we had lower levels of steroid hormones, prostaglandins and bile acids in the diabetic group vs healthy subjects, however the level of glycine conjugated bile acid was higher in affected women by GD (P = 0.016).

For the first time, we reported new disrupted pathways such as steroid hormone pathways and their related altered metabolites in a group of Iranian population with GD. This may provide a better and faster way to predict, diagnose and prevent GDM in the future. Surely, further studies are required for the validation of the results.

Women with intrahepatic cholestasis of pregnancy (ICP) have hypercholanemia alongside an increased risk of dyslipidemia. We investigated how cholic acid (CA) supplementation in murine pregnancy impacts adipose tissue function. Mice were fed normal or 0.5% CA-supplemented chow from identification of copulatory plug until gestational day 14 or 15 (n = 10-11/group) and were matched experimentally with nonpregnant mice (n = 7/group). Tissue weights were measured alongside plasma bile acids, glucose, lipids, reactive oxygen metabolites (ROM), and adipokines. Subcutaneous and gonadal adipocyte mRNA expression was evaluated. CA supplementation inhibited pregnancy-associated adipose tissue expansion and decreased fetal weight. CA diet in pregnancy increased LDL-cholesterol and reduced HDL-cholesterol. Pregnancy and CA diet reduced lipid metabolism transcript expression in adipocytes. CA supplementation during pregnancy increased plasma ROM by 1.24-fold and suppressed inflammatory-modulating pentraxin-2/3 and insulin-like growth factor 1 (IGF-1) levels by >50% and >80%, respectively. Together, we show that hypercholanemia disturbs pregnancy-associated adipose tissue expansion and mRNA expression in late gestation concomitant with reduced IGF-1, altered lipid availability and increased inflammation and oxidation, which could impact fetal growth. This work highlights the need to better understand adipose tissue and redox stress changes in ICP pregnancies and the potential implications for fetal health.

Gestational Diabetes Mellitus (GDM) is the most frequent pregnancy-related medical issue and presents significant risks to both maternal and foetal health, requiring monitoring and management during pregnancy. The prevalence of GDM has surged globally in recent years, mirroring the rise in diabetes and obesity rates. Estimated to affect from 5% to 25% of pregnancies, GDM impacts approximately 21 million live births annually, according to the International Diabetes Federation (IDF). However, consensus on diagnostic approaches remains elusive, with varying recommendations from international organizations, which makes the comparison between research complicated. Compounding concerns are the short-term and long-term complications stemming from GDM for mothers and offspring. Maternal outcomes include heightened cardiovascular risks and a notable 70% risk of developing Type 2 Diabetes Mellitus (T2DM) within a decade postpartum. Despite this, research into the metabolic profiles associated with a previous GDM predisposing women to T2D remains limited. While genetic biomarkers have been identified, indicating the multifaceted nature of GDM involving hormonal changes, insulin resistance, and impaired insulin secretion, there remains a dearth of exploration into the enduring health implications for both mothers and their children. Furthermore, offspring born to mothers with GDM have been shown to face an increased risk of obesity and metabolic syndrome during childhood and adolescence, with studies indicating a heightened risk ranging from 20% to 50%. This comprehensive review aims to critically assess the current landscape of Gestational Diabetes Mellitus (GDM) research, focusing on its prevalence, diagnostic challenges, and health impacts on mothers and offspring. By examining state-of-the-art knowledge and identifying key knowledge gaps in the scientific literature, this review aims to highlight the multifaceted factors that have hindered a deeper understanding of GDM and its long-term consequences. Ultimately, this scholarly exploration seeks to promote further investigation into this critical area, improving health outcomes for mothers and their children.

Gestational diabetes mellitus (GDM) is a common complication during pregnancy with an increasing prevalence worldwide. Early prediction of GDM and its associated adverse outcomes is crucial for timely intervention and improved maternal and fetal health. The objective of this review is to provide a comprehensive summary of contemporary evidence on biomarkers, focusing on their potential to predict the development of GDM and serve as predictors of maternal, fetal, and neonatal outcomes in women with GDM. A literature search was conducted in the PubMed database using relevant terms. Original research articles published in English between 1 January 2015, and 30 June 2024, were included. A two-stage screening process was employed to identify studies on biomarkers for GDM diagnosis and prognosis and to evaluate the evidence for each biomarker's diagnostic performance and its potential prognostic correlation with GDM. Various biochemical markers, including adipokines, inflammatory markers, insulin resistance markers, glycemic markers, lipid profile markers, placenta-derived markers, and other related markers, have shown promise in identifying women at risk of developing GDM and predicting adverse pregnancy outcomes. Several promising markers with high predictive performance were identified. However, no single biomarker has demonstrated sufficient accuracy to replace the current diagnostic criteria for GDM. The complexity of multiple pathways in GDM pathogenesis highlights the need for a multi-marker approach to improve risk stratification and guide personalized management strategies. While significant progress has been made in GDM biomarker research, further studies are required to refine and validate these markers for clinical use and to develop a comprehensive, evidence-based approach to GDM prediction and management that can improve maternal and child health outcomes.

Offspring growth requires establishing maternal behavior associated with the maternal endocrine profile. Placentae support the adaptations of the mother, producing bioactive molecules that affect maternal organs. We recently reported that placentae produce superoxide dismutase 3 (SOD3) that exerts sustained effects on the offspring liver via epigenetic modifications. Here, we demonstrate that placenta-specific Sod3 knockout (Sod3-/-) dams exhibited impaired maternal behavior and decreased prolactin levels. Most fibroblast growth factor (FGF)-regulated pathways were downregulated in the pituitary tissues from Sod3-/- dams. FGF1-, FGF2-, and FGF4-induced prolactin expression and signaling via the phosphoinositide 3-kinase (PI3K)-phospholipase C-γ1 (PLCγ1)-protein kinase-Cδ (PKC)δ axis were reduced in primary pituitary cells from Sod3-/- dams. Mechanistically, FGF1/FGF receptor (FGFR)2 expressions were inhibited by the suppression of the ten-eleven translocation (TET)/isocitrate dehydrogenase (IDH)/α-ketoglutarate pathway and DNA demethylation levels at the zinc finger and BTB domain containing 18 (ZBTB18)-targeted promoters of Fgf1/Fgfr2. Importantly, offspring from Sod3-/- dams also showed impaired nurturing behavior to their grandoffspring. Collectively, placenta-derived SOD3 promotes maternal behavior via epigenetic programming of the FGF/FGFR-prolactin axis.

Preeclampsia is a heterogeneous syndrome of diverse etiologies and molecular pathways leading to distinct clinical subtypes. Herein, we aimed to characterize the extracellular vesicle (EV)-associated and soluble fractions of the maternal plasma proteome in patients with preeclampsia and to assess their value for disease prediction.

This case-control study included 24 women with term preeclampsia, 23 women with preterm preeclampsia, and 94 healthy pregnant controls. Blood samples were collected from cases on average 7 weeks before the diagnosis of preeclampsia and were matched to control samples. Soluble and EV fractions were separated from maternal plasma; EVs were confirmed by cryo-EM, NanoSight, and flow cytometry; and 82 proteins were analyzed with bead-based, multiplexed immunoassays. Quantile regression analysis and random forest models were implemented to evaluate protein concentration differences and their predictive accuracy. Preeclampsia subgroups defined by molecular profiles were identified by hierarchical cluster analysis. Significance was set at p < 0.05 or false discovery rate-adjusted q < 0.1.

In preterm preeclampsia, PlGF, PTX3, and VEGFR-1 displayed differential abundance in both soluble and EV fractions, whereas angiogenin, CD40L, endoglin, galectin-1, IL-27, CCL19, and TIMP1 were changed only in the soluble fraction (q < 0.1). The direction of changes in the EV fraction was consistent with that in the soluble fraction for nine proteins. In term preeclampsia, CCL3 had increased abundance in both fractions (q < 0.1). The combined EV and soluble fraction proteomic profiles predicted preterm and term preeclampsia with an AUC of 78% (95% CI, 66%-90%) and 68% (95% CI, 56%-80%), respectively. Three clusters of preeclampsia featuring distinct clinical characteristics and placental pathology were identified based on combined protein data.

Our findings reveal distinct alterations of the maternal EV-associated and soluble plasma proteome in preterm and term preeclampsia and identify molecular subgroups of patients with distinct clinical and placental histopathologic features.

Early nutritional and growth experiences can impact development, metabolic function, and reproductive outcomes in adulthood, influencing health trajectories in the next generation. The insulin-like growth factor (IGF) axis regulates growth, metabolism, and energetic investment, but whether it plays a role in the pathway linking maternal experience with offspring prenatal development is unclear. To test this, we investigated patterns of maternal developmental weight gain (a proxy of early nutrition), young adult energy stores, age, and parity as predictors of biomarkers of the pregnancy IGF axis (n = 36) using data from the Cebu Longitudinal Health and Nutrition Survey in Metro Cebu, Philippines. We analyzed maternal conditional weight measures at 2, 8, and 22 years of age and leptin at age 22 (a marker of body fat/energy stores) in relation to free IGF-1 and IGFBP-3 in mid/late pregnancy (mean age = 27). Maternal IGF axis measures were also assessed as predictors of offspring fetal growth. Maternal age, parity, and age 22 leptin were associated with pregnancy free IGF-1, offspring birth weight, and offspring skinfold thickness. We find that free IGF-1 levels in pregnancy are more closely related to nutritional status in early adulthood than to preadult developmental nutrition and demonstrate significant effects of young adult leptin on offspring fetal fat mass deposition. We suggest that the previously documented finding that maternal developmental nutrition predicts offspring birth size likely operates through pathways other than the maternal IGF axis, which reflects more recent energy status.

Reproductive factors play significantly important roles in determining the breast cancer (BC) risk. The impact of pregnancy, abortion, and birth control methods on tumor development remains unclear. It has been found that early full-term pregnancies in young women can lower their lifetime risk of developing the type of cancer in question. However, having a first full-term pregnancy at an older age can increase this risk. The relationship between pregnancy and breast cancer (BC) is, however, much more complicated. Both induced and spontaneous abortions lead to sudden changes in hormonal balance, which could cause different effects on sensitive breast epithelial cells, making abortion a potential risk factor for breast cancer. The influence of hormonal contraception on carcinogenesis is not comprehensively understood, and therefore, more exhaustive analysis of existing data and further investigation is needed. This review explores how the mentioned reproductive factors affect the risk of breast cancer (BC), focusing on the molecular mechanisms that contribute to its complexity. By comprehending this intricate network of relationships, we can develop new strategies for predicting and treating the disease.

Dermatological conditions in pregnancy pose unique challenges due to concerns for maternal and fetal health. We present a case of a 32-year-old primigravida who, at 36 weeks of gestation, exhibited melanotic papules and neoplasms on her neck, chest, and breasts. Seeking evaluation for potential effects on her unborn child and breastfeeding, she presented to our dermatological outpatient facility. Physical examination revealed varied pigmented papules and verrucous proliferations. Laboratory tests and imaging were unremarkable, with histological analysis confirming fibromas and pityriasis versicolor. The patient declined treatment during pregnancy, and postpartum, spontaneous regression of lesions occurred, with complete resolution within 1 year. The child exhibited normal development, with no recurrence observed at the 2-year follow-up. This case underscores the importance of multidisciplinary care and long-term monitoring in managing dermatological manifestations during pregnancy.

Dietary nutrition plays a crucial role in determining pregnancy outcomes, with poor diet being a major contributor to pregnancy metabolic syndrome and metabolic disorders in offspring. While carbohydrates are essential for fetal development, the excessive consumption of low-quality carbohydrates can increase the risk of pregnancy complications and have lasting negative effects on offspring development. Recent studies not only highlighted the link between carbohydrate intake during pregnancy, maternal health, and offspring well-being, but also suggested that the quality of carbohydrate foods consumed is more critical. This article reviews the impacts of low-carbohydrate and high-carbohydrate diets on pregnancy complications and offspring health, introduces the varied physiological effects of different types of carbohydrate consumption during pregnancy, and emphasizes the importance of both the quantity and quality of carbohydrates in nutritional interventions during pregnancy. These findings may offer valuable insights for guiding dietary interventions during pregnancy and shaping the future development of carbohydrate-rich foods.

The remodelling of gut mycobiome (ie, fungi) during pregnancy and its potential influence on host metabolism and pregnancy health remains largely unexplored. Here, we aim to examine the characteristics of gut fungi in pregnant women, and reveal the associations between gut mycobiome, host metabolome and pregnancy health.

Based on a prospective birth cohort in central China (2017 to 2020): Tongji-Huaxi-Shuangliu Birth Cohort, we included 4800 participants who had available ITS2 sequencing data, dietary information and clinical records during their pregnancy. Additionally, we established a subcohort of 1059 participants, which included 514 women who gave birth to preterm, low birthweight or macrosomia infants, as well as 545 randomly selected controls. In this subcohort, a total of 750, 748 and 709 participants had ITS2 sequencing data, 16S sequencing data and serum metabolome data available, respectively, across all trimesters.

The composition of gut fungi changes dramatically from early to late pregnancy, exhibiting a greater degree of variability and individuality compared with changes observed in gut bacteria. The multiomics data provide a landscape of the networks among gut mycobiome, biological functionality, serum metabolites and pregnancy health, pinpointing the link between Mucor and adverse pregnancy outcomes. The prepregnancy overweight status is a key factor influencing both gut mycobiome compositional alteration and the pattern of metabolic remodelling during pregnancy.

This study provides a landscape of gut mycobiome dynamics during pregnancy and its relationship with host metabolism and pregnancy health, which lays the foundation of the future gut mycobiome investigation for healthy pregnancy.

Maternal obesity is a serious health concern because it increases risks of neurological disorders, including anxiety and peripartum depression. In mice, a high fat diet (HFD) in pregnancy can negatively affect placental structure and function as well as maternal behavior reflected by impaired nest building and pup-retrieval. In humans, maternal obesity in pregnancy is associated with reduced placental lactogen (PL) gene expression, which has been linked to a higher risk of depression. PL acting predominantly through the prolactin receptor maintains energy homeostasis and is a marker of placenta villous trophoblast differentiation during pregnancy. Impaired neurogenesis and low serum levels of brain-derived neurotrophic factor (BDNF) have also been implicated in depression. Augmented neurogenesis in brain during pregnancy was reported in the subventricular zone (SVZ) of mice at gestation day 7 and linked to increased prolactin receptor signaling. Here, we used transgenic CD-1 mice that express human (h) PL during pregnancy to investigate whether the negative effects of diet on maternal behavior are mitigated in these (CD-1[hGH/PL]) mice. Specifically, we examined the effect of a HFD on nest building prepartum and pup retrieval postpartum, as well as on brain BDNF levels and neurogenesis. In contrast to wild-type CD-1[WT]mice, CD-1[hGH/PL] mice displayed significantly less anxiety-like behavior, and showed no impairment in prepartum nest building or postpartum pup-retrieval when fed a HFD. Furthermore, the HFD decreased prepartum and increased postpartum BDNF levels in CD-1[WT] but not CD-1[hGH/PL] mice. Finally, neurogenesis in the SVZ as well as phosphorylated mitogen-activated protein kinase, indicative of lactogenic signaling, appeared unaffected by pregnancy and diet at gestation day 7 in CD-1[hGH/PL] mice. These observations indicate that CD-1[hGH/PL] mice are resistant to the negative effects of HFD reported for CD-1[WT] mice, including effects on maternal behaviors and BDNF levels, and potentially, neurogenesis. This difference probably reflects a direct or indirect effect of the products of the hGH/PL transgene.

Obesity and metabolic-associated fatty liver disease (MAFLD) during pregnancy constitute significant problems for routine antenatal care, with increasing prevalence globally. Similar to obesity, MAFLD is associated with a higher risk for maternal complications (e.g. pre-eclampsia and gestational diabetes) and long-term adverse health outcomes for the offspring. However, MAFLD during pregnancy is often under-recognized, with limited management/treatment options.

PubMed/MEDLINE, EMBASE, and Scopus were searched based on a search strategy for obesity and/or MAFLD in pregnancy to identify relevant papers up to 2024. This review summarizes the pertinent evidence on the relationship between maternal obesity and MAFLD during pregnancy. Key mechanisms implicated in the underlying pathophysiology linking obesity and MAFLD during pregnancy (e.g. insulin resistance and dysregulated adipokine secretion) are highlighted. Moreover, a diagnostic approach for MAFLD diagnosis during pregnancy and its complications are presented. Finally, promising relevant areas for future research are covered.

Research progress regarding maternal obesity, MAFLD, and their impact on maternal and fetal/offspring health is expected to improve the relevant diagnostic methods and lead to novel treatments. Thus, routine practice could apply more personalized management strategies, incorporating individualized algorithms with genetic and/or multi-biomarker profiling to guide prevention, early diagnosis, and treatment.

Gestational diabetes mellitus (GDM) is associated with increased postpartum risk for metabolic dysfunction-associated steatotic liver disease (MASLD). GDM-related MASLD predisposes to advanced liver disease, necessitating a better understanding of its development in GDM. This preclinical study evaluated the MASLD development in a lean GDM mouse model with impaired insulin secretion capacity. Lean GDM was induced by short-term 60% high-fat diet and low-dose streptozotocin injections (60 mg/kg for 3 days) before mating in C57BL/6N mice. The control dams received only high-fat diet or low-fat diet. Glucose homeostasis was assessed during pregnancy and postpartum, whereas MASLD was assessed on postpartum day 30 (PP30). GDM dams exhibited a transient hyperglycemic phenotype during pregnancy, with hyperglycaemia reappearing after lactation. Lower insulin levels and impaired glucose-induced insulin response were observed in GDM mice during pregnancy and postpartum. At PP30, GDM dams displayed higher hepatic triglyceride content compared controls, along with increased MAS (MASLD) activity scores, indicating lipid accumulation, inflammation, and cell turnover indices. Additionally, at PP30, GDM dams showed elevated plasma liver injury markers. Given the absence of obesity in this double-hit GDM model, the results clearly indicate that impaired insulin secretion driven pregnancy hyperglycaemia has a distinct contribution to the development of postpartum MASLD.

Dietary fiber (DF) consumption was reported to improve insulin sensitivity, change the tryptophan metabolism, and alter the gut microbiota. Herein, this study aimed to investigate the effects of DF consumption on insulin sensitivity, tryptophan metabolism, and gut microbiota composition in sows during late pregnancy, and explore the relationship between tryptophan metabolites and insulin sensitivity regulated by DF supplementation.

Twelve sows were randomly assigned to two dietary treatment groups (six/group): the low-fiber (LF) group, which was fed a basal diet, and the high-fiber (HF) group, which was fed the basal diet supplemented with 22.60 g/kg inulin and 181.60 g/kg cellulose. During late pregnancy, meal test, glucose tolerance test, and insulin challenge test were used to investigate the insulin sensitivity of sows, using the percutaneous brachiocephalic vein catheterization technique. High DF consumption resulted in improved insulin sensitivity, especially during the second and third trimesters, and promoted serotonin production from tryptophan. Additionally, plasma serotonin concentration was positively correlated with the insulin sensitivity index during late pregnancy. Moreover, DF consumption elevated fecal short-chain fatty acid (SCFA) concentrations, altered fecal microbial diversity, and increased the abundances of Rikenellaceae_RC9_gut_group, Alloprevotella, Parabacteroides, Roseburia, and Sphaerochaeta, which were positively correlated to plasma serotonin concentration.

DF consumption improved insulin sensitivity during late pregnancy in sows, which improved microbial diversity in fecal samples and increased fecal SCFA concentrations, resulting in a positive correlation with plasma serotonin level.

Some recent observational studies have shown that gut microbiota composition is associated with puerperal sepsis (PS) and no causal effect have been attributed to this. The aim of this study was to determine a causal association between gut microbiota and PS by using a two-sample Mendelian randomization (MR) analysis.

This study performed MR analysis on the publicly accessible genome-wide association study (GWAS) summary level data in order to explore the causal effects between gut microbiota and PS. Gut microbiota GWAS (n = 18,340) were obtained from the MiBioGen study and GWAS-summary-level data for PS were obtained from the UK Biobank (PS, 3,940 cases; controls, 202,267 cases). Identification of single nucleotide polymorphisms associated with each feature were identified based on a significance threshold of p < 1.0 × 10-5. The inverse variance weighted (IVW) parameter was used as the primary method for MR and it was supplemented by other methods. Additionally, a set of sensitivity analytical methods, including the MR-Egger intercept, Mendelian randomized polymorphism residual and outlier, Cochran's Q and the leave-one-out tests were carried out to assess the robustness of our findings.

Our study found 3 species of gut microbiota, Lachnospiraceae FCS020, Lachnospiraceae NK4A136, and Ruminococcaceae NK4A214, to be associated with PS. The IVW method indicated an approximately 19% decreased risk of PS per standard deviation increase with Lachnospiraceae FCS020 (OR = 0.81; 95% CI 0.66-1.00, p = 0.047). A similar trend was also found with Lachnospiraceae NK4A136 (OR = 0.80; 95% CI 0.66-0.97, p = 0.024). However, Ruminococcaceae NK4A214 was positively associated with the risk of PS (OR = 1.33, 95% CI: 1.07-1.67, p = 0.011).

This two-sample MR study firstly found suggestive evidence of beneficial and detrimental causal associations of gut microbiota on the risk of PS. This may provide valuable insights into the pathogenesis of microbiota-mediated PS and potential strategies for its prevention and treatment.

Prolactin (PRL) is a pituitary hormone promoting lactation in response to the suckling reflex. Beyond its well-known effects, novel tissue-specific and metabolic functions of PRL are emerging.

To dissect PRL as a critical mediator of whole-body gluco-insulinemic sensitivity.

PubMed-based search with the following terms 'prolactin', 'glucose metabolism', 'type 2 diabetes mellitus', 'type 1 diabetes mellitus', 'gestational diabetes mellitus' was performed.

The identification of the PRL-glucose metabolism network poses the basis for unprecedented avenues of research in the pathogenesis of diabetes mellitus type 1 or 2, as well as of gestational diabetes. In this regard, it is of timely relevance to define properly the homeostatic PRL serum levels since glucose metabolism could be influenced by the circulating amount of the hormone.

This review underscores the basic mechanisms of regulation of pancreatic β-cell functions by PRL and provides a revision of articles which have investigated the connection between PRL unbalancing and diabetes mellitus. Future studies are needed to elucidate the burden and the role of PRL in the regulation of glucose metabolism and determine the specific PRL threshold that may impact the management of diabetes.

A careful evaluation and context-driven interpretation of PRL levels (e.g., pregnancy, PRL-secreting pituitary adenomas, drug-related hyper- and hypoprolactinemia) could be critical for the correct screening and management of glucometabolic disorders, such as type 1 or 2 as well as gestational diabetes mellitus.

High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.

This study aimed to investigate the effects of the dietary fiber pectin on the gut microbiota and health of parturient sows. A total of 30 parity 5-7, multiparous gestation sows (Large White × Landrace) were randomly assigned to two treatment groups after mating: Con (control, basic diet) and Pec (pectin, 3%). The sows received the two diets during gestation, and all sows were fed the same standard basic diet during lactation. The results of β-diversity showed that the composition of the gut microbiota was different in the Con and Pec groups. Compared with the sows in the Con group, the Pec sows showed a higher abundance of the gut bacteria Clostridium and Romboutsia and a lower abundance of harmful bacteria (Micrococcaceae, Coriobacteriaceae, Dorea, Actinomyces). On the other hand, the SCFA plasma concentration was increased in the Pec group, while pro-inflammatory cytokine (IL-6, IL-1β, and TNF-α) concentrations were decreased. In conclusion, the soluble dietary fiber pectin could improve the reproductive performance and health of sows by increasing the abundance of some commensal bacteria enhancing the metabolite SCFA levels and reducing the pro-inflammatory cytokine plasma levels.

Pituitary gland height reflects secretory activity of the hypothalamo-pituitary axis.

To assess the cumulative impact of fetal growth and sex on pituitary gland height in premature twins, dissociated from prematurity.

A retrospective study was conducted, assessing the pituitary gland height in 63 pairs of preterm twins, measured from T1-weighted magnetic resonance imaging (MRI). Auxological parameters, including body weight, body length, and head circumference, at birth and at the time of MRI, were used as proxies for fetal and postnatal growth, respectively. The study population was divided into two groups, using corrected age at around term equivalent as the cutoff point. Statistical analysis was performed using mixed-effects linear regression models.

When pituitary gland height was evaluated at around term equivalent, a greater pituitary gland height, suggesting a more immature hypothamo-pituitary axis, was associated with the twin exhibiting lower auxological data at birth. The same association was observed when body weight and length at MRI were used as covariants. In the group evaluated after term equivalent, a smaller pituitary gland height, suggesting a more mature hypothamo-pituitary axis, was associated with male sex. This difference was observed in twin pairs with higher average body weight at birth, and in babies exhibiting higher auxological data at MRI.

After isolating the effect of prematurity, at around term equivalent, pituitary gland height reflects the cumulative impact of fetal growth on the hypothalamo-pituitary axis. Subsequently, pituitary gland height shows effects of sex and of fetal and postnatal growth.

Nausea and vomiting in pregnancy (NVP) is heritable, common and aversive, and its extreme, hyperemesis gravidarum (HG), can be highly deleterious to the mother and fetus. Recent influential studies have demonstrated that HG is caused predominantly by high levels of Growth-Differentiation Factor 15 (GDF15), a hormone produced by the placenta in substantial amounts. This work has led to calls for therapeutic modulation of this hormone to reduce GDF15 levels and ameliorate HG risk. I describe three main lines of evidence relevant to the hypothesis that GDF15 production is typically adaptive for the fetus, in the context of enhanced placental invasion, reduced rates of miscarriage and preterm birth and higher birth weight. These considerations highlight the medical implications of maternal-fetal conflict, in the context of tradeoffs between aversive symptoms during gestation, rare disorders of pregnancy with major adverse effects and moderate fitness-enhancing benefits to fetuses.

The Yangtze finless porpoises (Neophocaena asiaeorientalis a.) are an endemic and critically endangered species in China. Intensive captive breeding is essential for understanding the biology of critically endangered species, especially their pregnancy characteristics, knowledge of which is crucial for effective breeding management. Urine metabolomics can reveal metabolic differences, arising from physiological changes across pregnancy stages. Therefore, we used the urinary metabolomic technology, to explore urinary metabolite changes in pregnant Yangtze finless porpoises. A total of 2281 metabolites were identified in all samples, which including organic acids and derivatives (24.45%), organoheterocyclic compounds (20.23%), benzenoids (18.05%), organic oxygen compounds (7.73%), and phenylpropanoids and polyketides (6.48%). There were 164, 387, and 522 metabolites demonstrating differential abundance during early pregnancy, mid pregnancy, and late pregnancy, respectively, from the levels observed in nonpregnancy. The levels of pregnenolone, 17α-hydroxyprogesterone, and tetrahydrocortisone were significantly higher during all pregnancy stages, indicating their important roles in fetal development. The differential metabolites between nonpregnancy and pregnancy were mainly associated with amino acid and carbohydrate metabolism. Moreover, metabolic activity varied across pregnancy stages; steroid hormone biosynthesis was predominant in early pregnancy, and amino acid biosynthesis and carbohydrate metabolism were predominant in mid pregnancy and late pregnancy, respectively. Our results provide new insights into metabolic characteristics in the Yangtze finless porpoises' urine during pregnancy, and indicate that the differential levels of urine metabolites can determine pregnancy in Yangtze finless porpoises, providing valuable information for the husbandry and management of pregnant Yangtze finless porpoises in captivity.

Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.

Maternal experiences before pregnancy predict birth outcomes, a key indicator of health trajectories, but the timing and pathways for these effects are poorly understood. Here we test the hypothesis that maternal pre-adult growth patterns predict pregnancy glucose and offspring fetal growth in Cebu, Philippines.

Using multiple regression and path analysis, gestational age-adjusted birthweight and variables reflecting infancy, childhood, and post-childhood/adolescent weight gain (conditional weights) were used to predict pregnancy HbA1c and offspring birth outcomes among participants in the Cebu Longitudinal Health and Nutrition Survey.

Maternal early/mid-childhood weight gain predicted birth weight, length, and head circumference in female offspring. Late-childhood/adolescent weight gain predicted birth length, birth weight, skinfold thickness, and head circumference in female offspring, and head circumference in male offspring. Pregnancy HbA1c did not mediate relationships between maternal growth and birth size parameters.

In Cebu, maternal growth patterns throughout infancy, childhood, and adolescence predict fetal growth via a pathway independent of circulating glucose, with stronger impacts on female than male offspring, consistent with a role of developmental nutrition on offspring fetal growth. Notably, the strength of relationships followed a pattern opposite to what occurs in response to acute pregnancy stress, with strongest effects on head circumference and birth length and weakest on skinfolds. We speculate that developmental sensitivities are reversed for stable, long-term nutritional cues that reflect average local environments. These findings are relevant to public health and life-history theory as further evidence of developmental influences on health and resource allocation across the life course.

Gestational diabetes mellitus (GDM) is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development. As a bridge between the mother and the fetus, the placenta has nutrient transport functions, endocrine functions, etc., and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status. Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus. There are many reports on the placental pathophysiological changes associated with GDM, the impacts of GDM on the growth and development of offspring, and the prevalence of GDM in offspring after birth. Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases. This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.