Search Results (109)

Background/Objectives: Antepartum computerized cardiotocography (cCTG) represents an essential tool for assessing fetal well-being. This study aimed to comparatively evaluate antepartum cCTG-derived indices across high-risk pregnancies to identify distinctive fetal autonomic and reactivity profiles. Methods: A comparative analysis of antepartum cCTG parameters was conducted. The cohort included pregnancies beyond 28 weeks of pregnancy, 169 cases of hypertensive disorders of pregnancy (HDP), 146 of gestational diabetes mellitus (GDM), 86 of intrahepatic cholestasis (ICP), and 87 low-risk pregnancies as controls. Results: Baseline FHR remained within the physiological range across all groups (110–160 bpm; p > 0.05). Dynamic cCTG parameters exhibited clear pathology-dependent alterations. Short-term variability (STV) showed a stepwise decline from controls to ICP and GDM, reaching its lowest values in HDP (mean 1.08 bpm; p < 0.00001), accompanied by an increased proportion of epochs with STV < 1 bpm. Long-term variability suppression (LTV < 5 bpm) was significantly higher in GDM and HDP (p = 0.0077). Acceleration frequency decreased across all pathological groups, with the most pronounced reduction observed in HDP, whereas fetal movements were paradoxically elevated in both GDM and HDP. Total decelerations were more frequent in ICP and HDP; however, repetitive, late, prolonged, and >5 min decelerations remained rare and did not differ significantly between groups. Conclusions: HDP showed the most unfavorable cCTG profiles, consistent with impaired fetal autonomic regulation and chronic subclinical hypoxemia. GDM and ICP had moderate changes, suggesting milder adaptive responses. These findings emphasize the value of quantitative cCTG in differentiating fetal autonomic patterns in high-risk pregnancies and the importance of tailored surveillance strategies. Full article

Background: Progressive familial intrahepatic cholestasis (PFIC) describes a group of genetically heterogeneous disorders. Several mutations in the ATP-Binding Cassette Subfamily B Member 4 (ABCB4) gene have been confirmed to cause reduced phosphatidylcholine levels in bile, leading to a deficiency of biliary vesicles and instability of mixed in micelles. The disease spectrum ranges from PFIC type 3 (PFIC3) to milder conditions. Herein, we present a rare case of PFIC3 in a young woman, emphasizing the importance of early detection and management. Methods: The patient was diagnosed using next-generation sequencing, with genetic testing and analysis performed by the Chengdu Hua Chuang Testing Institute. Variant pathogenicity was evaluated according to the American College of Medical Genetics and Genomics guidelines and classified into five categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. Nomenclature was assigned following the Human Genome Variation Society standards. Results: Contrast-enhanced abdominal computed tomography demonstrated liver cirrhosis with marked splenomegaly. Histological examination of liver biopsy specimens using hematoxylin and eosin and Masson staining further confirmed cirrhotic changes. Genetic testing was subsequently performed and revealed a likely pathogenic variant, c.2757T > A (p. Tyr919Ter), in exon 22 of the ABCB4 gene, which was also detected in the patient’s mother but absent in her father. Finally, PFIC3 was diagnosed. Following initiation of ursodeoxycholic acid therapy, the patient showed moderate improvement in liver function tests, underscoring a clinical case with therapeutic implications. Conclusions: Molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3. Clinicians should consider cholestatic liver diseases, particularly PFIC, as a differential diagnosis in cases of liver cirrhosis with unknown etiology, especially in young patients who lack prior symptoms or a family history of liver disease. Full article

Variants of the MYO5B gene, which encodes the molecular motor protein myosin-Vb, have gained prominence as a causative factor in familial intrahepatic cholestasis (FIC). Understanding the disease mechanism is pivotal for therapy development and clinical decision-making. The prevailing theory for the mechanism underlying MYO5B-associated cholestasis implicates faulty trafficking of the ABCB11-encoded bile salt export pump (BSEP) in hepatocytes due to dysfunctional myosin-Vb. This is supported by cell and mouse studies. However, while BSEP localization was abnormal in some patients’ liver biopsies, BSEP appeared normally localized in others, raising questions with regard to the role of BSEP in MYO5B-associated FIC. We present a focused systematic narrative review of all cases of MYO5B variant-associated isolated FIC reported in the MEDLINE database. We assembled a comprehensive patient dataset and assessed clinical features of MYO5B-associated FIC, their relationship with MYO5B genotype, the clinical value and significance of BSEP abnormalities, and the relationship of MYO5B-associated FIC to ABCB11 variant-associated FIC. Our review revealed that aberrant BSEP localization correlated with the absence of one MYO5B allele carrying a truncating nonsense or frameshift variant. Notably, biochemical and clinical parameters including treatment outcome were indistinguishable between patients presenting with normal and aberrant BSEP localization. Further, myosin-Vb and BSEP deficiency-associated FIC patient cohorts showed distinct biochemical and clinical phenotypes, indicating different underlying mechanisms. This suggests that whether or not BSEP localization was abnormal depended on the MYO5B genotype without a predictable effect on clinical parameters and treatment response. Treatment decisions should be guided by clinical parameters rather than by genotype or immunohistochemistry findings. Full article

Rare genetic diseases (RGDs) affect individuals, families, and healthcare systems worldwide. Population-scale genomic data remain largely restricted to Western cohorts with an estimated 10,000 RGDs. South Asian populations remain underrepresented in molecular, clinical, and genomic databases. This study presents the first preliminary molecular genetic characterization of RGDs in the Punjabi population of Pakistan. Data were collected from the provincial RGD registry at the Punjab Thalassemia and Other Genetic Disorders Prevention and Research Institute (PTGDPRI), Lahore. Families diagnosed using next-generation sequencing (NGS) between 2021 and 2023 were enrolled. Structured questionnaires captured clinical, demographic, and socioeconomic information, and statistical and genetic analyses were performed to assess allele frequencies, and disease distribution. The registry included 167 families with 72 distinct RGDs, with a mean burden of 0.81 ± 0.24 affected children per family. Niemann–Pick disease (NP), progressive familial intrahepatic cholestasis (PFIC), and mucopolysaccharidosis (MPS) were the most common diseases. Consanguinity was observed in 89% of families, 77% of which involved first-cousin marriages, and was significantly associated with RGD incidence. Most families belonged to low-income groups despite high literacy rates, underscoring inequity in healthcare. The primary and secondary variants included 131 variants, including copy number variants (CNVs) and single nucleotide variants (SNVs), annotated as pathogenic, likely pathogenic, or variants of unknown significance (VUS) across 109 genes, including 24 South Asian-enriched variants. This study provides the first genomic and epidemiological overview of RGDs in the Punjabi population. The findings reveal how genetic, socioeconomic, and cultural factors converge to amplify the RGD burden and highlight the need for affordable molecular diagnostics, inclusive genomic databases, and regional genomic surveillance initiatives in South Asia. Full article

Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse perinatal outcomes. However, its metabolic consequences on newborns remain inadequately characterized. This study investigated amino acid, carnitine, and acylcarnitine profiles in neonates born to mothers with ICP. Methods: This retrospective study encompassed 299 neonates born to mothers with ICP. For comparative analysis, term infants without additional complications (ICP-term, n = 150) were compared with term controls (n = 150). Capillary blood samples collected at 24–48 h of life as part of newborn screening were analyzed using LC–MS/MS for acylcarnitine and amino acid profiles. Results: The ICP cohort exhibited a high preterm delivery rate (46.2%), with maternal bile acids negatively correlating with gestational age (r = −0.266, p < 0.001). No inborn errors of metabolism were observed. Elevated levels of amino acids (alanine, leucine/isoleucine, valine, tyrosine, arginine, glycine, and ornithine) and specific acylcarnitines (C5, C5-OH, C10:1, and C18:2), along with decreased levels of amino acids (argininosuccinic acid and glutamic acid) and specific acylcarnitines (C3, C5-DC, C6-DC, C14, C14:1, C16, C16:1, and C18:1-OH), were observed in ICP-term neonates (p < 0.05). Receiver operating characteristic curve analysis identified ornithine (area under the curve [AUC] = 0.74) and leucine/isoleucine (AUC = 0.73) as strong discriminators. A multivariable model integrating multiple metabolites achieved high accuracy (AUC = 0.86 ± 0.03). Conclusions: This first comprehensive characterization of neonatal metabolic alterations in ICP reveals amino acid metabolism, fatty acid oxidation, and mitochondrial function disruptions, suggesting fetal adaptation to a cholestatic intrauterine environment. Metabolomic profiling may improve understanding of maternal–fetal interactions and inform strategies for risk stratification and long-term monitoring. Full article

Acute liver injury during pregnancy is rare and predominantly associated with pregnancy-related conditions including acute fatty liver of pregnancy; Hemolysis, Elevated Liver Enzymes and Low Platelets syndrome; intrahepatic cholestasis of pregnancy; and preeclampsia. Drug-induced liver injury (DILI) is a less common and often overlooked cause of acute liver injury in pregnant patients. A literature search on acute liver injury during pregnancy and therapeutic plasma exchange was conducted, revealing the most common causative factors and syndromes. A 39-year-old woman was diagnosed with acute liver injury in the 23rd week of her third pregnancy and, upon extensive differential diagnoses, a suspicion of DILI occurred after the use of methyldopa. Methyldopa, the drug of choice for the treatment of hypertensive disorders of pregnancy, has a high safety profile for the developing fetus and is well tolerated by pregnant women, yet, in susceptible individuals, a hepatotoxic effect may occur. The drug was discontinued and symptomatic treatment with ursodeoxycholic acid and prednisone was implemented with marginal effect. Upon a multidisciplinary joint consultation, plasmapheresis procedures were introduced, granting a significant improvement in the patient’s liver function and enabling the continuation of the pregnancy. Plasmapheresis treatment was safely and effectively used for the first time in the therapeutic process in a pregnant patient with DILI. Interdisciplinary cooperation of specialists with gastroenterology, nephrology, and obstetrics expertise is crucial to achieving a timely diagnosis and begin effective treatment for pregnant patients with acute liver injury. Full article

Background/Objectives: The management of high-risk pregnancies remains a major clinical challenge, particularly regarding the optimal timing of delivery, which has significant implications for both perinatal outcomes and healthcare costs. In this context, computerized cardiotocography (cCTG) offers an objective, non-invasive and cost-effective method for fetal surveillance, providing quantitative measures of heart rate dynamics that reflect autonomic regulation and oxygenation status. This study aimed to develop and validate regression-based machine learning models capable of predicting the duration of neonatal hospitalization—an objective and quantifiable indicator of neonatal well-being—using cCTG parameters obtained outside of labor, binary clinical variables describing the presence or absence of pregnancy pathologies, and gestational age at monitoring and at delivery. Methods: A total of 694 singleton high-risk pregnancies complicated by gestational diabetes, preexisting diabetes, intrahepatic cholestasis of pregnancy, pregnancy-induced or preexisting hypertension, or fetal growth restriction were enrolled. Twenty clinically relevant features derived from cCTG recordings and perinatal data were used to train and evaluate four regression algorithms: Random Forest, CatBoost, XGBoost, and LightGBM against a linear regression model with Ridge regularization serving as a benchmark. Results: Random Forest achieved the highest generalization performance (test R² = 0.8226; RMSE = 3.41 days; MAE = 2.02 days), outperforming CatBoost (R² = 0.7059), XGBoost (R² = 0.6911), LightGBM (R² = 0.6851) and the linear regression benchmark with Ridge regularization (R² = 0.5699) while showing a consistent train–validation–test profile (0.9428 → 0.8042 → 0.8226). The error magnitude (≈2 days on average) is clinically interpretable for neonatal resource planning, supporting the model’s practical utility. These findings justify selecting Random Forest as the final predictor and its integration into a clinician-facing application for real-time length-of-stay estimation. Conclusions: Machine learning models integrating cCTG features with maternal clinical factors can accurately predict neonatal hospitalization duration in pregnancies complicated by maternal or fetal disease. This approach provides a clinically interpretable and non-invasive decision support tool that may enhance delivery planning, optimize neonatal resource allocation, and improve perinatal care outcomes. Full article

Background: Gestational diabetes mellitus (GDM) is associated with subclinical alterations in fetal cardiac morphology and function. Ursodeoxycholic acid (UDCA), widely used in pregnancy for intrahepatic cholestasis, has demonstrated cardioprotective properties in experimental fetal models, preventing conduction abnormalities and improving myocardial function. Whether UDCA modifies fetal or neonatal cardiac adaptation in GDM pregnancies has not been previously investigated. The objective was to evaluate the effect of ursodeoxycholic acid (UDCA) on fetal and neonatal cardiac function in pregnancies complicated by gestational diabetes mellitus (GDM). Methods: In this randomized, placebo-controlled study, 113 women with GDM were enrolled, of whom 56 received UDCA and 57 the placebo. After measurement of maternal blood UDCA concentrations, 43 participants in the treatment group had levels ≥0.5 µmol/L and were included in the per-protocol analysis. Echocardiographic and Doppler-derived cardiac indices were assessed at baseline, 36 weeks’ gestation, and postpartum. Comparisons were performed using univariable tests and mixed-effects multivariable models accounting for time and treatment. Results: In the treatment group, compared to the placebo group, there were no significant differences in cardiac indices at 36 weeks’ gestation or postpartum when assessed individually. However, in the mixed-effects longitudinal analysis, a significant treatment-by-time interaction was observed. Specifically, in the postpartum period, mitral A-wave velocity (MV-A) was higher in the treatment group compared to that under the placebo (9.58, 95% CI 2.29–16.87; p = 0.010), reflecting a more pronounced increase in the atrial contribution to left ventricular filling over time. Similarly, aortic peak velocity (Ao_Vmáx) was significantly higher in the treatment group compared to that under the placebo in the postpartum period (7.97, 95% CI 0.19–15.75; p = 0.045), indicating a greater augmentation in left ventricular outflow dynamics. Conclusions: In pregnancies complicated by GDM, UDCA did not lead to significant cross-sectional differences in fetal or neonatal cardiac indices at 36 weeks or postpartum. However, longitudinal modeling indicated that UDCA was associated with a greater increase in the atrial contribution to ventricular filling (MV-A) and aortic peak velocity (Ao_Vmáx) in the postpartum period compared to that under the placebo. These findings suggest that while UDCA does not broadly alter cardiac function, it may modulate specific aspects of diastolic filling and systolic outflow dynamics during late gestation and early neonatal adaptation. Full article

Background: Intrahepatic cholestasis of pregnancy (ICP) is the most common reversible liver disorder linked to pregnancy, characterised by pruritus and elevated serum bile acids (BAs). Condition severity correlates with increased maternal and neonatal complications, and recent evidence highlights a significantly elevated risk of adverse perinatal outcomes, including stillbirth, when BA > 100 µmol/L. Methods: This retrospective study, conducted at a tertiary perinatology centre between 2019 and 2023, was performed in two phases. In the first phase, baseline group characteristics and pregnancy outcomes were compared between ICP and non-ICP (control) groups. In the second phase, outcomes were analysed across three ICP severity subgroups: mild (BA < 40 µmol/L), moderate (BA 40–99 µmol/L), and severe (BA ≥ 100 µmol/L). Results: A total of 210 patients diagnosed with ICP and 24,177 controls were included in the analysis. After multivariable regression, the results indicated that patients with severe ICP (BA ≥ 100 µmol/L) experienced significantly worse perinatal outcomes compared to those with mild or moderate disease: spontaneous preterm birth occurred in 26.7% of cases (p = 0.002), iatrogenic preterm birth in 36.7% (p < 0.001), meconium-stained amniotic fluid in 43.3% (p = 0.001), and neonatal intensive care unit (NICU) admission in 23.3% (p = 0.006). This subgroup also had the lowest mean birth weight (2830 g, p < 0.001). Notably, no stillbirths were recorded in any of the subgroups. Compared to controls, no major differences in maternal characteristics were noted, except in pregnancies conceived via in vitro fertilisation (IVF, p = 0.012) and those complicated by gestational diabetes (p = 0.040), both showing elevated risk for ICP development. Conclusions: This study confirms an association between ICP and increased perinatal complications, with severity of disease correlating with poorer outcomes. The findings highlight the need for standardised BA testing and improved strategies for perinatal management. Full article

Sickle cell disease (SCD) is a hereditary hemoglobin disorder characterized by chronic hemolysis and recurrent vaso-occlusive crises, leading to a wide spectrum of complications. While common SCD manifestations have well-established management protocols, rare and atypical complications pose significant diagnostic and therapeutic challenges. A critical barrier is diagnostic overshadowing, where common SCD symptoms (pain, fever, respiratory distress) mask infrequent but life-threatening conditions, resulting in delayed recognition and suboptimal outcomes. This narrative review synthesizes the literature from 2000–2025 on rare SCD complications, including atypical neurological events (e.g., spontaneous epidural or subdural hematoma, central retinal artery occlusion, cerebral arteriovenous malformations, posterior reversible encephalopathy syndrome), uncommon hematologic syndromes (acute leukemia, extramedullary hematopoiesis in unusual sites, hemophagocytic lymphohistiocytosis), severe cardiopulmonary emergencies (acute multiorgan failure and fat embolism syndromes), unusual hepatic crises (acute hepatic sequestration, intrahepatic cholestasis), and others (e.g., compartment syndrome). Key insights underscore the need for high clinical suspicion and prompt use of advanced diagnostics (e.g., MRI, specialized laboratory tests) when patients present with atypical or disproportionate symptoms. Clinical implications: Heightening clinician awareness of these rare complications and implementing structured diagnostic strategies can facilitate earlier intervention, improving outcomes and reducing the high morbidity and mortality associated with these infrequent but severe events. Full article

Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent hepatobiliary disorder unique to gestation, characterized by maternal pruritus and elevated serum bile acids. While maternal prognosis is favorable, mounting evidence links ICP to a range of neonatal complications. This narrative review aims to synthesize the current knowledge on the pathophysiological mechanisms, clinical impact and management strategies related to neonatal outcomes in ICP. Methods: A narrative review approach was employed, drawing on recent clinical guidelines, observational studies, mechanistic investigations and meta-analyses. Emphasis was placed on evidence exploring the relationship between maternal bile acid concentrations and neonatal morbidity, as well as on established and emerging therapeutic interventions. No systematic search strategy or formal quality appraisal was undertaken. Results: ICP is associated with an increased risk of adverse neonatal outcomes, including spontaneous and iatrogenic preterm birth, meconium-stained amniotic fluid, respiratory distress syndrome and stillbirth, particularly when bile acid concentrations exceed 100 μmol/L. Proposed mechanisms include placental vasoconstriction, arrhythmogenic effects and surfactant inhibition. Ursodeoxycholic acid remains the most widely used pharmacologic agent for maternal symptom relief, although evidence supporting neonatal benefit is inconclusive. Delivery by 36–37 weeks is generally recommended in cases of severe cholestasis to mitigate fetal risk. Conclusions: Severe ICP confers substantial neonatal risk, requiring individualized, bile-acid-guided management. While current therapies offer symptomatic maternal benefit, optimization of fetal outcomes requires timely diagnosis, vigilant surveillance and evidence-based delivery planning. Further research is warranted to refine therapeutic targets and standardize clinical practice. Full article

Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterized by progressive destruction of the small intrahepatic bile ducts, leading to cholestasis, inflammation, and ultimately fibrosis and cirrhosis. This review emphasizes the central role of bile acids in PBC pathogenesis, exploring how disruptions in their synthesis, transport, and detoxification contribute to cholangiocyte damage and disease progression. In addition to discussing the autoimmune features of PBC, including the presence of specific autoantibodies and cellular immune responses, we examine how bile acid dysregulation exacerbates cholestasis and promotes lipid metabolic disturbances. Particular attention is given to the “bicarbonate umbrella” hypothesis, which describes a protective mechanism by which cholangiocytes resist bile acid–induced injury—an essential factor disrupted in PBC. The aim of this review is to summarize current knowledge gaps in the pathophysiology of PBC, with a focus on the role of bile acids not only as key drivers of disease mechanisms, but also as potential biomarkers of disease progression and treatment response. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) play a crucial role in trophoblast invasion, immune tolerance, and placental angiogenesis. To delineate their diagnostic and pathological significance, we critically evaluated the evidence for correlations between circulating or placental lncRNA profiles with pregnancy complications. Methods: Five databases were searched from inception through September 2024. We included only the studies that assessed the expression of the lncRNA-complicated pregnancies versus a control group. Results: Three single-center case–control studies fulfilled the inclusion criteria. Eight serum lncRNAs that present <20 weeks of gestation were elevated in subsequent pregnancy-induced hypertension or preeclampsia. The three lncRNAs in intrahepatic cholestasis of pregnancy were consistently decreased with a negative correlation with bile acids. Gestational diabetes was characterized by the elevation of MALAT1. Conclusions: Different lncRNAs showed a potential for use as non-invasive markers as well as for risk stratification for pregnancy-induced hypertension or preeclampsia, metabolic, and hepatobiliary pregnancy complications. There is a need for large-scale, multi-ethnic, prospective cohorts to include lncRNA as screening or therapeutic targeting in obstetric practice. Full article

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy, typically presenting in the third trimester. It is characterized by pruritus, elevated serum bile acids, and abnormal liver function tests. While maternal symptoms resolve postpartum, ICP poses significant risks to fetal health, including spontaneous preterm labor, meconium-stained amniotic fluid, and stillbirth. This review aims to synthesize current knowledge on the pathogenesis, diagnosis, and management and highlight emerging research and possible therapy directions in ICP. A comprehensive review of recent literature was conducted, focusing on molecular mechanisms, clinical management guidelines, fetal outcomes, and novel therapeutics under investigation. Ursodeoxycholic acid (UDCA) remains the primary pharmacologic treatment of intrahepatic cholestasis of pregnancy; however, its effect on perinatal outcomes is debated. Investigational therapies—including Volixibat, FXR agonists, 4-phenylbutyrate, and NorUDCA—are under exploration. These emerging therapies hold the potential to improve both maternal symptoms and perinatal outcomes by addressing the underlying pathophysiology of ICP more effectively than current standard treatment. Additionally, emerging biomarkers and machine-learning tools hold promise for improved diagnosis and personalized care. ICP continues to pose diagnostic and therapeutic challenges. While maternal outcomes are generally favorable, optimizing fetal safety requires timely diagnosis, stratified risk assessment, and evidence-based delivery planning. Future research should prioritize identifying predictive biomarkers, refining treatment algorithms, and assessing long-term outcomes for both mothers and offspring. Special attention should also be given to the investigation of novel therapeutic targets. Full article

Background/Objectives: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder with a multifactorial pathogenesis and a well-established genetic component. While pathogenic variants in genes such as ABCB4 and ABCB11 are implicated in a subset of cases, many remain genetically unexplained. This study aimed to investigate the genetic background of ICP in a multi-generational family with recurrent hepatobiliary disease. Methods: Whole-exome sequencing was performed on the proband and five female relatives. Variant filtering prioritized rare, exonic or splice-site variants predicted to undergo damage by in silico tools and which were present in all affected family members. Identified variants were assessed using population databases and compared with a control group of 433 unrelated women with uncomplicated pregnancies. Variant confirmation was performed using Sanger sequencing and high-resolution melting analysis. Results: No pathogenic variants were identified in known ICP-associated genes. However, a rare heterozygous missense variant in ABCB5 (c.1610G>A; p.Arg537His; rs779950110) was found in all affected individuals and two younger female relatives. This variant is exceedingly rare in population databases, absent in controls, and predicted to be pathogenic by multiple algorithms. ABCB5, although not previously linked to ICP, is an ATP-binding cassette transporter expressed in various tissues, including liver compartments. Conclusions: This study reports a novel ABCB5 variant segregating with ICP and early-onset hepatobiliary disease in a family. These findings suggest ABCB5 as a potential new susceptibility gene in ICP, warranting further functional investigation. Full article