Search Results (238)

Background: Fetal programming, conceptualized within the Developmental Origins of Health and Disease framework, describes how intrauterine exposures may shape long-term offspring physiology and disease susceptibility. Metformin is increasingly used during pregnancy for gestational diabetes mellitus, type 2 diabetes mellitus, and selected cases of polycystic ovary syndrome. Its developmental interpretation is complex because the drug improves the maternal metabolic environment but also crosses the placenta and directly exposes the fetus. Methods: This focused narrative review used iterative, targeted searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify pharmacological, placental, mechanistic, clinical, guideline-based, and offspring follow-up evidence. The literature search covered publications available through 31 May 2026. The manuscript was subsequently revised during the editorial submission and peer-review process, and the evidence synthesis was re-evaluated against this final literature cut-off date. Earlier landmark studies were retained where necessary for historical, pharmacological, or methodological context. Results: Metformin reduces hepatic glucose production and maternal insulin resistance and may limit gestational weight gain, insulin requirements, neonatal hypoglycemia, and excessive fetal growth in selected pregnancies. Placental transfer creates biological plausibility for direct effects on AMPK, mitochondrial, mTOR, nutrient-sensing, and epigenetic pathways. Long-term studies are broadly reassuring regarding neurodevelopment and major metabolic disease, but findings on growth trajectory, adiposity, and small-for-gestational-age risk remain heterogeneous and indication-dependent. Conclusions: Metformin should be interpreted neither as uniformly beneficial nor as developmentally neutral. Its use should be individualized according to maternal phenotype, indication, glycemic benefit, placental function, fetal growth, dose, timing, and the limitations of long-term offspring evidence. Full article

Background and Clinical Significance: Budd–Chiari syndrome (BCS) is a rare disorder characterized by hepatic venous outflow obstruction, often associated with underlying hypercoagulable states. Pregnancy represents a physiologic prothrombotic condition that may precipitate disease onset. Case Presentation: We report a case of de novo BCS diagnosed in the second trimester in a previously healthy 36-year-old multiparous patient. Evaluation revealed cirrhotic liver morphology, portal hypertension, and bleeding esophageal varices requiring emergent treatment. The patient’s course included a transjugular intrahepatic portosystemic shunt (TIPS) procedure with complications, anticoagulation, multidisciplinary care, and a work-up revealing a JAK2 mutation consistent with an underlying myeloproliferative disorder. Despite apparent maternal stabilization and reassuring fetal growth, the pregnancy resulted in intrauterine fetal demise at 34 weeks’ due to placental abruption, followed by postpartum hemorrhage. Conclusions: This case highlights the diagnostic and therapeutic challenges of BCS in pregnancy, and demonstrates that favorable maternal stabilization does not preclude severe obstetric complications. Full article

Hepatobiliary disorders during pregnancy represent a significant cause of maternal and fetal morbidity, requiring careful differentiation between physiological adaptations of pregnancy and true hepatic pathology. This narrative review provides a comprehensive overview of three major hepatobiliary conditions encountered during pregnancy: gallstone disease, intrahepatic cholestasis of pregnancy (ICP), and viral hepatitis (HAV, HBV, HCV, HDV, and HEV). Pregnancy-induced hormonal and immunological changes influence disease pathogenesis, clinical presentation, diagnostic interpretation, and therapeutic decision-making. Gallstone disease remains the most common non-obstetric surgical condition in pregnancy, with contemporary evidence supporting timely laparoscopic intervention when indicated. ICP is characterized by pruritus and elevated serum bile acids and is associated with increased risks of preterm birth, fetal distress, and stillbirth, necessitating close surveillance and individualized delivery planning. Viral hepatitis poses unique challenges because of the potential for vertical transmission, maternal complications, and adverse neonatal outcomes. Universal antenatal screening for hepatitis B and C is increasingly recognized as a cornerstone of care. For HBV, maternal antiviral prophylaxis combined with neonatal immunoprophylaxis has reduced mother-to-child transmission to below 1%, whereas the role of direct-acting antivirals for HCV during pregnancy continues to evolve. HEV remains the most severe viral hepatitis in pregnancy, carrying disproportionately high maternal mortality in endemic regions. Across all conditions, multidisciplinary management involving hepatologists, gastroenterologists, obstetricians, maternal–fetal medicine specialists, surgeons, and neonatologists is essential to optimize outcomes. This review synthesizes current evidence, highlights pregnancy-specific diagnostic and therapeutic considerations, and identifies emerging areas of research that may further improve maternal and neonatal outcomes. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to systemic cardiometabolic dysfunction. Resting heart rate (RHR), a marker of autonomic and metabolic stress, has been associated with metabolic syndrome and cardiovascular disease, though its relationship with MASLD remains incompletely characterized. We evaluated the association between RHR and liver-related outcomes in a nationally representative U.S. cohort. Materials and Methods: We analyzed adults aged 20–79 years from NHANES 2017–2020 with valid vibration-controlled transient elastography (VCTE) measurements. Participants with significant alcohol use, viral hepatitis, pregnancy, use of heart rate-modifying medications, or missing key data were excluded. Liver outcomes included elevated alanine aminotransferase (ALT), advanced steatosis (CAP ≥ 290 dB/m), FIB-4 fibrosis category, and VCTE-defined fibrosis. Multivariable regression models adjusted for demographic and metabolic covariates were used to evaluate associations between RHR and liver-related outcomes. Results: A total of 3532 adults were included. Each 1 beat-per-minute increase in RHR was independently associated with elevated ALT (OR 1.025, 95% CI 1.002–1.050, p = 0.043) and advanced steatosis (OR 1.036, 95% CI 1.001–1.073, p = 0.048). No significant association was observed between RHR and higher FIB-4 category (OR 1.025, 95% CI 0.992–1.060, p = 0.169) or VCTE-defined fibrosis (OR 0.990, 95% CI 0.961–1.021, p = 0.481). Associations with ALT and steatosis were attenuated after adjustment for glycemic and lipid parameters. Conclusions: Higher RHR was associated with steatosis-related and metabolic liver outcomes, but not fibrosis, in a nationally representative cohort. These findings suggest that RHR may reflect underlying autonomic and metabolic dysfunction relevant to early MASLD pathogenesis rather than advanced fibrotic disease. Full article

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder unique to pregnancy, closely associated with severe adverse maternal and fetal outcomes such as preterm birth and intrauterine fetal death. Its pathogenesis involves a complex interplay of genetic, hormonal, metabolic, and environmental factors, with a higher risk observed in southern China and among individuals co-infected with hepatitis B virus. Substantial evidence demonstrates a significant dose–response relationship between serum total bile acid (TBA) levels and perinatal outcomes, with TBA ≥ 40 μmol/L commonly used as a criterion for severe ICP. However, most existing prediction models are based on single-center, retrospective studies with small sample sizes and insufficient external validation, limiting their clinical generalizability. In recent years, nomograms and machine learning methods have demonstrated advantages in the early prediction and risk stratification of ICP. Deep learning models and multi-omics integration strategies have further enhanced predictive accuracy. Nevertheless, challenges remain regarding model interpretability, data standardization, and cross-population applicability. Future research should leverage large-scale, multi-center prospective cohorts, integrating multi-omics technologies, including genomics, metabolomics, gut microbiome profiling with artificial intelligence to develop clinically actionable and interpretable risk prediction tools. Integrating these tools into electronic health record systems and mobile platforms may facilitate the early identification and individualized management of ICP, ultimately improving maternal and neonatal outcomes. Full article

(1) Background: Hepatitis E remains a major public health challenge in India. (2) Methods: In August 2025, the recombinant HEV 239 vaccine was approved in India for adults aged 18 to 65 years. To establish clinical guidelines tailored to the Indian setting, an expert panel consensus was conducted using a modified Delphi process in accordance with the ACCORD reporting guidelines. (3) Results: A steering committee put forth 18 statements covering vaccine safety, efficacy, and clinical indications, which were independently evaluated by 33 senior Indian hepatologists and epidemiologists. Consensus was assessed using the GRADE framework for level of evidence, balance of benefits and harms, and strength of recommendations. Of the 18 statements, 12 reached the 70% consensus threshold. The panel concluded that the vaccine, which is administered on a standard three-dose schedule, is safe and highly effective in healthy adults, providing protection for up to 10 years. Targeted vaccination was recommended for five high-risk populations: outbreak-affected groups, hyperendemic pockets, women of childbearing age, patients with CLD, and solid organ transplant recipients. Although derived from HEV genotype 1, the vaccine demonstrated cross-protective efficacy against HEV genotype 4. (4) Conclusions: This consensus report provides a framework for deploying the HEV vaccine to mitigate disease burden in India while emphasizing the need for real-world effectiveness and safety data from India. Full article

Background/Objectives: Vitamin D deficiency (VDD) is a major global health concern. Although maternal VDD during pregnancy may influence metabolic health in offspring, previous studies have focused predominantly on male offspring, leaving its effects in females insufficiently characterized. This study aimed to comprehensively assess hepatic metabolic profiles in female offspring exposed to maternal VDD during gestation. Methods: Pregnant 129/Sv mice were fed either a control diet or a vitamin D-deficient diet throughout pregnancy. After weaning, female offspring were maintained on a normal diet and analyzed at 12 weeks of age following a 16 h fast. Hepatic metabolomic profiling was conducted using GC–MS/MS, followed by multivariate analysis. To evaluate the potential contribution of fasting, publicly available liver RNA-seq data from ad libitum-fed and 16 h-fasted mice (GSE130127) were also analyzed. Results: No overt metabolic abnormalities were detected between the groups. However, principal component analysis revealed differences in hepatic metabolic profiles between the Control and VDD groups. Levels of 4-aminobutyric acid and proline were significantly elevated in the VDD group. Pathway analysis revealed significant alterations in arginine and proline metabolism and purine metabolism, along with changes in pathways associated with amino acid and energy metabolism. Comparison with fasting-associated liver RNA-seq data revealed minimal overlap, although the potential influence of fasting cannot be completely excluded. Conclusions: Maternal VDD during pregnancy was associated with altered hepatic metabolic profiles in female offspring despite the absence of overt metabolic abnormalities. These findings suggest that maternal VDD may influence hepatic metabolism in female offspring and indicate that the potential long-term effects of maternal VDD on offspring metabolism warrant further investigation. Full article

Background: Congenital infections included in the TORCH complex remain an important cause of fetal and neonatal morbidity and mortality, being associated with miscarriage, intrauterine growth restriction, congenital malformations, neurological impairment, and long-term developmental sequelae. Prenatal serological screening may contribute to the early identification of maternal infections and facilitate preventive and therapeutic interventions. However, data regarding the utilization of TORCH screening and associated socio-demographic determinants in Romania remain limited. Objective: This study aimed to evaluate the self-reported uptake of prenatal serological testing for one or more infections included in the TORCH complex, particularly Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus (HSV), and syphilis, and to identify socio-demographic, obstetrical, and prenatal care-related factors associated with TORCH testing among pregnant women in Romania. Materials and Methods: A cross-sectional observational study was conducted using an online self-administered questionnaire completed by 1301 pregnant women from Romania. Data collection was performed between August 2022 and March 2023 through digital platforms, including social media and pregnancy-related forums. The primary outcome was self-reported performance of serological testing for at least one TORCH-related infection during pregnancy. Associations between explanatory variables and TORCH testing were evaluated using chi-square tests and multivariable binary logistic regression models. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results: Overall, 75.6% of participants reported undergoing serological testing for at least one infection included in the TORCH complex during pregnancy, while 49.3% reported a complete TORCH panel. The most frequently reported investigations were for Toxoplasma gondii (92.8%) and rubella virus (89.9%), whereas HSV testing was less commonly reported (42.5%). Lower educational level was the strongest independent factor associated with reduced likelihood of TORCH testing (adjusted OR = 0.08; 95% CI: 0.03–0.19; p < 0.001) (adjusted OR—aOR). Unemployment status (aOR = 0.70; 95% CI: 0.50–0.99; p = 0.045) and multiparity (aOR = 0.62; 95% CI: 0.49–0.77; p < 0.001) were also associated with lower testing uptake. In contrast, participation in prenatal education programs was associated with increased likelihood of TORCH testing (aOR = 1.37; 95% CI: 1.04–1.80; p = 0.024). The number of prenatal consultations was not independently associated with testing uptake. Conclusions: The uptake of prenatal serological screening for congenital infections (assessed using an expanded Romanian panel that includes hepatitis B and HIV in addition to the classical TORCH agents) in Romania appears to be influenced predominantly by socio-educational and behavioral factors rather than by the quantitative utilization of prenatal care services alone. Given the online recruitment strategy and the predominantly urban and highly educated sample, the reported uptake rates may overestimate population-level coverage. Significant inequalities in access to preventive prenatal investigations were observed, particularly among women with lower educational and socio-economic status. Strengthening prenatal education programs and improving equitable access to standardized prenatal screening may contribute to optimizing congenital infection prevention and maternal–fetal health outcomes. Full article

Pregnancy is a physiological state of transient, reversible insulin resistance accompanied by major adaptations in glucose and lipid metabolism. Although placental hormones are key drivers of gestational insulin resistance, the mechanisms underlying the rapid restoration of insulin sensitivity after delivery remain incompletely understood. This review proposes a conceptual framework in which fibroblast growth factor 21 (FGF21) and sex hormone-binding globulin (SHBG) are considered as complementary hepatic signals potentially involved in maternal metabolic adaptation. During late pregnancy, FGF21 may function as a metabolic stress-response factor associated with fatty acid oxidation, lipid handling, and mitochondrial adaptation through AMPK–PPARα-related pathways. Reduced SHBG, in contrast, may reflect hepatic insulin resistance and altered hepatic metabolic regulation. After delivery, changes in FGF21 and SHBG levels may be associated with recovery of hepatic metabolic homeostasis and insulin sensitivity, while persistent adaptive FGF21 signaling facilitate metabolic reprogramming may contribute to ongoing metabolic adaptation. Postpartum metabolic recovery may therefore represent an active and dynamic process rather than a purely passive consequence of placental hormone withdrawal. Disruption of FGF21- and SHBG-mediated pathways may contribute to persistent insulin resistance and increased cardiometabolic risk after gestational diabetes. Understanding hepatokine-mediated regulation of maternal metabolic flexibility may provide further insight into postpartum metabolic recovery and may support future development of risk stratification strategies, biomarker-based approaches, and preventive interventions aimed at reducing the risk of type 2 diabetes after pregnancy. Full article

Background/Objectives: Globally, coverage of the hepatitis B vaccine within 24 h of birth is 45 percent, far below the WHO target of 90 percent by 2030. For newborns delivered in out-of-facility settings, delayed contact with health workers, transportation barriers, and cold chain constraints can impede timely vaccination. This review explores strategies and facilitators for delivering birth dose vaccines to infants born outside of health facilities in low- and middle-income countries. Methods: A rapid scoping review was conducted, searching PubMed and targeted websites for peer-reviewed and gray literature published between 2005 and 2025. Data were charted using a standardized extraction tool. Frequency and thematic analyses were conducted. Results: After screening 315 studies, 26 eligible sources were identified. Delivery strategies consisted of three components: identifying and tracking home births; supporting caregiver uptake through education, reminders, or incentives; and delivering the vaccine through home-based administration or referral to facilities. Sub-components included pregnancy and birth notification systems, postnatal home visits, mobile reminders, incentives, and home-based vaccination by facility or community providers. The feasibility of these strategies was shaped by factors across system levels, such as national policies and financing; health system infrastructure; cold chain capacity; health workforce configuration; caregiver awareness; and community social norms. In several contexts, flexible cold chain approaches and vaccine administration by community-based cadres enabled timely vaccination of infants born at home. Conclusions: Vaccination programs can learn from existing out-of-facility vaccine delivery approaches to strengthen hepatitis B birth dose vaccination programs for timely and equitable coverage. Full article

Background/Objectives: Automated insulin delivery (AID) systems have improved the management of type 1 diabetes (T1D), but exercise and nutrition remain challenging because they rapidly alter glucose flux, substrate oxidation, hepatic glucose output, insulin requirements, and fuel availability. This narrative review aimed to synthesize current evidence on the interaction between AID systems, physical activity, and nutritional strategies from a metabolism-oriented perspective. Methods: A narrative bibliographic approach was used to integrate evidence from clinical trials, observational studies, technical studies, consensus statements, and reviews involving people with T1D across different life stages, including pediatric, adolescent, adult, and pregnancy-related contexts, when available. The review focused on AID systems, exercise physiology, nutritional strategies, meal announcement, bolus adjustment, dual-hormone systems, metabolic biomarkers, and emerging metabolomic approaches. Results: AID systems generally improve time in range and reduce hypoglycemia across several user groups, although most exercise- and nutrition-specific evidence comes from adult and pediatric/adolescent cohorts rather than pregnancy-specific exercise studies. Exercise-related glucose responses remain highly dependent on user input, exercise modality, insulin on board, meal timing, and metabolic state. Planned exercise announcement, prandial bolus reduction before postprandial activity, and individualized carbohydrate intake remain key strategies. Biomarkers such as lactate, ketone bodies, non-esterified fatty acids, and counter-regulatory hormones may help explain interindividual variability and support future personalization. Conclusions: Nutrition and exercise management in AID users should be interpreted as a dynamic metabolic interface among exogenous insulin, endogenous counter-regulation, substrate availability, and algorithmic control. Emerging approaches, including activity sensors, adaptive algorithms, dual-hormone systems, digital twins, and metabolomics-informed personalization, may improve safety and reduce user burden, but several remain exploratory and require further validation in diverse free-living conditions. Full article

Insulin resistance (IR) is a significant risk factor for various diseases, particularly during pregnancy. Dietary patterns have been reported to influence IR susceptibility. High-protein (HP) diet has gained popularity for its role in weight management. However, whether trimethylamine N-oxide (TMAO), which is produced in the liver from gut microbiota-derived metabolites of dietary protein, influences IR remains uncertain. In this study, we established a pregnant mouse model to examine the effect of an HP diet on IR, assess its impact on liver function, and investigate associated signaling pathways. The role of gut microbiota was also evaluated. We found that the HP diet induced liver injury in pregnant mice following significantly decreased body weight. The HP diet also elevated plasma TMAO levels and upregulated hepatic FMO₃ expression. Transcriptomic analysis revealed enrichment of insulin-related signaling pathways in the HP group, with notable downregulation of the Insrr gene. IR was induced through the IRS-1/PI3K/Akt signal pathway. Gut microbiota composition was disrupted in HP group, characterized by an increased Firmicutes/Bacteroidetes ratio and a higher abundance of the TMA-producing genus Coprococcus, indicating an elevated potential for TMA generation. Furthermore, several amino acid metabolism pathways closely linked to IR were also enriched in the HP group. In conclusion, our study demonstrates that HP diet induces liver injury and increases IR risk during pregnancy. Gut microbiota contributes to this process, in part through an enhanced capacity for TMA production. These findings highlight the need for greater attention to dietary patterns in pregnancy to mitigate metabolic risks. Full article

Background: Ectopic pregnancy remains a significant cause of maternal morbidity in early pregnancy. While most ectopic pregnancies happen within the fallopian tube, implantation may rarely occur in atypical locations such as the ovary or abdominal cavity. These rare forms often present with nonspecific clinical findings and may represent a considerable diagnostic challenge. Methods: We report a case series of three rare ectopic pregnancies managed at a tertiary referral center. Two cases involved ovarian pregnancy, and one case represented an exceptionally rare hepatic ectopic pregnancy. Clinical presentation, diagnostic pathway, surgical management, and outcomes were analyzed and compared with available literature. Results: In the first two cases, ovarian pregnancy was confirmed intraoperatively and treated surgically, with ovarian preservation in one patient and adnexectomy in the other due to active bleeding. The third case had an unusual course: initial surgery was performed for hemoperitoneum caused by a ruptured corpus luteum cyst, while persistent β-hCG elevation later led to identification of hepatic ectopic pregnancy, confirmed by imaging and surgery. All patients recovered favorably, with complete β-hCG negativization. Conclusions: Rare ectopic implantation sites may mimic acute abdominal conditions and remain difficult to diagnose preoperatively. High clinical suspicion, serial β-hCG monitoring, and appropriate imaging are essential. Surgical management remains central, particularly in life-threatening bleeding. Standard algorithms for tubal ectopic pregnancy may not be fully applicable and should be adapted to the clinical context. Full article

Hepatitis E is a liver inflammation caused by the hepatitis E virus (HEV). In pregnant women, the infection significantly increases the risk of acute liver failure, fetal loss, and maternal death. According to the World Health Organization, infection by HEV during the third trimester of pregnancy may increase the risk of maternal mortality in 20–25% of cases. In Tunisia, little is known about HEV infection and its outcome, especially in pregnant women. This study aims to evaluate the prevalence of HEV infection in a large cohort of pregnant women in Tunisia. A total of 891 women who attended the Centre of Maternity and Neonatology of Tunis during 2021–2023 were included. Serum samples were screened to detect HEV-antibodies and RNA using commercial ELISA tests and molecular assays, respectively. Statistical analyses were conducted using SPSS 21.0 software and the EPISTAT package version 7.2.6. Seroprevalence of HEV infection was 3.82%, based on the detection of anti-HEV IgG. The distribution of the seroprevalence according to age was statistically significant (p < 0.05), showing a higher seroprevalence among women over 30 years. Among the 51 women with composite outcomes, viral RNA was detected in one case by real-time RT-PCR. Our findings indicate a low HEV prevalence among pregnant women in Tunisia. Expanding the study to other cohorts and to environmental surveillance would improve understanding of HEV burden in Tunisia and support hepatitis elimination efforts. Full article

(1) Background: Diclofenac sodium is a drug with reported developmental toxicity in several non-mammalian and mammalian models. This study aims to evaluate the stage-dependent embryolethality of diclofenac sodium according to developmental stage using the chicken (Gallus gallus domesticus) embryo in ovo model, a system widely used in veterinary and avian developmental toxicology screening. The study focuses specifically on quantitatively determining the “critical sensitivity windows” between the early (day 7) and late (day 14) embryonic stages. (2) Methods: Fertilized chicken eggs (Gallus gallus domesticus) were exposed to different doses (3.125–50 mg/kg) of diclofenac sodium, and mortality rates were analyzed. (3) Results: The data indicated that diclofenac toxicity is highly dependent on the developmental stage (p = 0.002). While the LD50 value for the early stage (day 7) was calculated as 20.67 mg/kg, (95% CI 6.79–860.87 mg/kg; wide interval reflecting low precision and steep response), embryos at the late stage (day 14) were found to be more resistant, with an LD50 value of 32.16 mg/kg (95% CI 27.77–37.90 mg/kg). The calculated Potency Ratio of 1.55 indicates that 7-day-old embryos are more sensitive to diclofenac. (4) Conclusions: This study provides model-specific preliminary quantitative data on the stage-dependent embryo mortality profile of diclofenac sodium in chicken embryos. The higher mortality observed on day 7 is consistent with a window of susceptibility during early organogenesis that may be associated with immature detoxification pathways (e.g., hepatic CYP450) and active organic anion transport (e.g., Oatp1d1) reported in other developmental models. However, these mechanisms were not directly measured here. These findings contribute to comparative developmental toxicology and the One Health-focused assessment of NSAID exposure in animal species, emphasizing the importance of considering “timing of exposure” in developmental toxicity assessments. Furthermore, no extrapolation to mammalian pregnancy or human clinical guidelines is implied. Full article