Search Results (185)

The Barker hypothesis links intrauterine conditions, mainly low birth weight, subject to poor nutrition with paradoxically improved standards of living and nutrition after World War II in Western countries, to adult disease, mainly coronary heart disease. The limitations of his hypothesis include the fact that it is based only on human epidemiological data and animal studies, and also that it is difficult to isolate the effect of the intrauterine environment from postnatal conditions, familial and genetic background. In the last 20 years, the introduction of ultrasound and Doppler techniques in the assessment of fetal and maternal vascularity added a major contribution to the evaluation of the intrauterine environment. Studies based on ultrasound and Doppler assist in differentiating between prematurity and fetal growth restriction (FGR), mainly in those with placental insufficiency, and postnatal morbidity and even mortality. In addition, the Pedersen hypothesis regarding fetuses with overgrowth, mainly with diabetic mothers, states that they are also prone to postnatal morbidity. However, most of the studies on the issue do not emphasize the effects of the intrauterine environment on fetal organs, such as the brain, heart, liver, kidneys and pancreas in FGR and fetal overgrowth, that may impose a different prognosis in later life. This narrative review aims to summarize current evidence from animal and human studies regarding the impact of intrauterine undernutrition and overnutrition on fetal organ development, and to evaluate how ultrasound and Doppler findings may contribute to understanding the link between the intrauterine environment and postnatal morbidity. Full article

Background: Experimental studies indicated that maternal choline and betaine status have the potential to alter fetal growth, but epidemiological data remain sparse. Objective: We aimed to investigate the association of maternal and cord blood choline and betaine concentrations with birthweight outcomes. Methods: This prospective cohort study involved 988 mother–infant dyads from Hebei and Shandong provinces. Plasma concentrations of choline and betaine in maternal late pregnancy and cord blood were quantified using ultra-performance liquid chromatography–mass spectrometry. Multivariable linear or logistic regression was performed to examine their association with continuous or binary birthweight outcomes. Results: Maternal plasma choline and betaine concentrations in late pregnancy (median [interquartile range]; 12.34 [10.13, 14.78] and 14.99 [12.01, 18.36] μmol/L) were significantly lower than those in cord blood (29.98 [24.74, 35.93] and 31.14 [25.56, 37.28] μmol/L). Each 1 μmol/L increase of late-pregnancy and cord blood betaine concentrations were associated with 9.87 g (95% confidence interval [CI]: −16.08, −3.66 g) and 5.29 g (95% CI: −8.52, −2.06 g) lower birthweight, respectively. Compared with the lowest quintile, the highest quintiles of late-pregnancy and cord blood betaine concentrations were associated with lower risks of large-for-gestational-age (adjusted odds ratios [ORs] = 0.47 [95% CI: 0.24, 0.90] and 0.31 [95% CI: 0.17, 0.56]) and macrosomia (adjusted ORs = 0.12 [95% CI: 0.03, 0.43] and 0.15 [95% CI: 0.05, 0.40]). These associations, particularly for cord blood, persisted and appeared more pronounced in pregnancies with maternal overweight/obesity or gestational diabetes mellitus (GDM), but the interaction effect did not reach statistical significance. No significant associations were observed for choline in any periods. Conclusions: Higher plasma concentrations of betaine in maternal late-pregnancy and cord blood were associated with lower birthweight. These findings emphasize the importance of sufficient betaine status during pregnancy, especially among mothers with obesity or GDM. Full article

Obesity in women of reproductive age is a major issue. It is associated with reduced fertility and an increased risk of obstetric and perinatal complications. Bariatric surgery is the most effective treatment for severe obesity, leading to substantial weight reduction, improvement of metabolic disorders, and enhanced fertility. Consequently, an increasing number of women are becoming pregnant after undergoing bariatric surgery. The aim of this paper is to review current recommendations and research data regarding the care of women after bariatric surgery in the periconceptional and perinatal periods, as well as throughout pregnancy, delivery, and the postpartum period. Research suggests that pregnancy after bariatric surgery is associated with a lower risk of gestational diabetes, hypertension, preeclampsia, and fetal macrosomia compared with pregnancies in women with similar baseline BMI (body mass index) who have not undergone surgical treatment. At the same time, an increased risk is observed for low birth weight, maternal micro- and macronutrient deficiencies, and complications characteristic of bariatric procedures, such as dumping syndrome or intra-abdominal hernias. Most scientific societies recommend postponing pregnancy planning for 12–18 months after surgery and using effective contraception, preferably methods that do not require gastrointestinal absorption. Regular monitoring of laboratory parameters, individually tailored supplementation, and interdisciplinary care are essential for the safe management of pregnancy after bariatric surgery. In particular, care should include achieving a stable body weight before conception, monitoring of nutritional status, verifying proper weight gain during pregnancy, and considering alternative methods for gestational diabetes screening (e.g., glycaemic monitoring instead of oral glucose tolerance testing) due to the risk of dumping syndrome. Appropriate preparation for pregnancy and proper management throughout its course allow for reducing the risk of perinatal complications. Bariatric surgery itself is not a contraindication to vaginal delivery. Full article

Objective: The study aimed to assess the accuracy of two distinct methods for estimating blood loss (EBL) and to identify potential factors contributing to early-onset postpartum hemorrhage (PPH) following a vaginal delivery (VD). Methods: Women in singleton pregnancies undergoing spontaneous/induced VD were recruited for this prospective observational cohort study. Methods of EBL included: (1) visual assessment by an attending obstetrician (sEBL) and (2) implementation of a mathematical formula (fEBL). Early PPH was defined as a cumulative blood loss exceeding 500 mL within the first 24 h after delivery as reflected by clinical assessment. Results: During the study period, 485 women delivered vaginally, and early PPH was diagnosed in 29 cases (5.97%). Among patients with PPH, a significant increase in the duration of the 2nd (61 min. vs. 33.5 min., p < 0.05) and 3rd (13 min. vs. 7 min., p < 0.001) stages of labor, as well as in the application of a dinoprostone insert (31% vs. 10.5%, p < 0.01) was noted. Additionally, in the same cohort, uterine atony (41.4% vs. 1.5%, p < 0.001), 3rd/4th degree perineal rupture (6.9% vs. 0%, p < 0.01), fetal macrosomia (17.2% vs. 4.8%, p < 0.05) and stillbirth (6.9% vs. 0.2%, p < 0.05) occurred significantly more frequently. In both groups visual estimation of blood loss was significantly lower compared to fEBL: (PPH sEBL: 800 mL vs. fEBL 1439.6 mL, p < 0.001; control sEBL: 250 mL vs. fEBL 621.8 mL, p < 0.001). In the multivariate analysis, factors such as third stage of delivery time ≥ 30 min. (OR 11.6; 95% CI: 4.18–32.33), FBW ≥ 4000 g (OR 6.37; 95% CI: 1.54–26.3), and dinoprostone insert application (OR 4.33; 95%CI: 1.63–11.48) were selected as independent predictors of the PPH. Conclusions: Compared to mathematical formula, visual estimation of blood loss by an attending obstetrician is significantly decreased. Prolonged third stage of delivery, fetal macrosomia, and application of a dinoprostone insert are the strongest contributors to early PPH following a VD. Full article

Aims: This study aimed to examine the associations between both birth weight (BW) and body mass index (BMI)/waist circumference (WC) measured at ages 7–10 years, and adolescent overweight (OW)/obesity (OB), and central OB at ages 11–13 years. Methods: Longitudinal data were collected from children’s and parents’ questionnaires. Anthropometric data were obtained from health check-ups. BW (kg) was categorized into three groups: <3.0, 3.0–3.9 and ≥4.0 (macrosomia). Underweight (UW)/normal weight (NW), OW and OB were defined based on sex- and age-specific reference values for Chinese children. Central OB was identified using the sex-specific waist-to-height ratio (WHtR) cutoffs. Results: Of the 1204 children, 14.5% had a BW < 3.0 and 15.6% had macrosomia. The rates of OB and central OB were 10.13% and 28.32%, respectively, among children aged 7–10 years and 6.23% and 23.34%, respectively, among those aged 11–13 years. An increasing BW z-score was associated with higher odds of OW/OB in girls aged 11–13 years. Childhood BMI and WC z-scores were associated with higher odds of OW/OB and central OB, respectively, at ages 11–13 years. Childhood OW/OB and central OB were associated with a higher risk of OW/OB and central OB, respectively, at ages 11–13 years. Conclusions: BW was modestly associated with OW/OB in girls. Childhood BMI was the strongest predictor of OW/OB, while childhood WC was a strong and significant predictor of central OB in early adolescence. These findings highlight that early school age is a critical period for risk identification and the implementation of future preventive strategies. Full article

The role of amino acid disturbances in the mother–fetus system remains poorly understood, despite their critical involvement in gestational diabetes mellitus (GDM), fetal macrosomia (FM) and offspring metabolic programming. This study included 62 mother–newborn dyads stratified by GDM and FM status. An analysis of the association of amino acids with clinical parameters was performed using the Spearman test. Amino acid markers of GDM were identified using the mutual information index and the Mann–Whitney test. A random forest method was used to identify amino acid markers, with the SHAP value used to estimate the contribution of each amino acid. In maternal serum, GDM was associated with significantly lower levels of glycine, 1-methylhistidine, γ-aminobutyric acid, lysine, and tryptophan. Umbilical cord serum from GDM pregnancies showed reduced concentrations of glutamine, glycine, asparagine, methionine, and proline. In amniotic fluid, GDM with FM was characterized by elevated lysine and 1-methylhistidine. Cord blood exhibited increased lysine, proline, leucine, and allo-isoleucine, while amniotic fluid showed low homocitrulline, asparagine, and lysine, together with high histidine. Fetal weight correlated directory with lysine and isoleucine and inversely with homocitrulline. Pathway analysis linked maternal serum markers to disturbances in biotin, glutamate, and carnitine metabolism, whereas cord blood markers involved broader alterations in amino acid, purine, and amino sugar metabolism. In amniotic fluid from GDM with FM, the methylhistidine pathway was specifically enriched, suggesting changes in neonatal muscle protein turnover. GDM induces distinct alterations in the amino acid profiles of all three compartments, and the combination with FM yields unique metabolic signatures. These findings identify candidate biomarkers for prediction of GDM and its complications and point to potential targets for metabolic intervention. Full article

Background/Objectives: Maternal diet during pregnancy may influence neonatal outcomes, but dietary behaviours are socially patterned and were measured differently across cohorts. We therefore evaluated whether cohort-specific, partially harmonized maternal dietary patterns were associated with adverse birth outcomes after accounting for maternal and socioeconomic characteristics in two Italian birth cohorts. Methods: We analyzed 3234 mother–infant dyads from Piccolipiù (2011–2015) and 1564 from MAMI-MED (2020–ongoing). Maternal diet was captured by cohort-specific food questionnaires and grouped into food categories. Principal component analysis identified dietary patterns; pattern scores were categorized into tertiles and combined into five joint-adherence profiles. Logistic regression estimated odds ratios (OR) for preterm birth (PTB, <37 weeks), low birth weight (LBW, ≤2500 g), macrosomia (≥4000 g), and small/large for gestational age (SGA/LGA), with progressive adjustment for maternal age, pre-pregnancy body mass index (BMI), education, employment, and (Piccolipiù) income. Results: Two comparable patterns emerged in both cohorts: Western (processed foods, fried items, snacks/sweets, sugar-sweetened beverages) and Prudent (fruit, vegetables, fish, whole grains/yogurt). Western adherence was more common among younger women and those with disadvantage, whereas Prudent adherence tracked higher education, employment and income. After full adjustment, dietary profiles were not consistently associated with PTB, SGA or LGA in either cohort. In Piccolipiù, preferential Prudent adherence was associated with lower odds of LBW (OR 0.49; 95% CI 0.24–0.92) and higher odds of macrosomia (OR 1.56; 95% CI 1.06–2.30). Across cohorts, higher pre-pregnancy BMI predicted macrosomia/LGA, while lower education increased the probability of PTB and LBW. Conclusions: Across two Italian birth cohorts, maternal dietary patterns were socially stratified, whereas pre-pregnancy BMI and maternal education were more consistently associated with birth outcomes than dietary-pattern adherence per se. Full article

Background/Objectives: To construct and compare multivariable prediction models for the early prediction of large-for-gestational-age (LGA) neonates, using ultrasound biometry and maternal characteristics. Methods: This retrospective cohort study analyzed data from singleton pregnancies that underwent routine ultrasound examinations at 30⁺⁰–34⁺⁰ weeks of gestation. Ultrasound parameters included fetal abdominal circumference (AC), head circumference (HC), femur length (FL), HC-to-AC ratio, mean uterine artery pulsatility index (mUtA-PI), and presence of polyhydramnios. LGA neonates were defined as those having a birthweight > 90th percentile. Logistic regression was used to evaluate associations between ultrasound markers and LGA after adjusting for the following maternal and pregnancy-related covariates: maternal age, body mass index, parity, gestational diabetes mellitus (GDM), pre-existing diabetes, previous cesarean section (PCS), assisted reproductive technology (ART) use, smoking, hypothyroidism, and chronic hypertension. Associations were expressed as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Three prognostic models were developed utilizing the following predictors: (i) biometric ultrasound measurements including AC, HC-to-AC ratio, FL, UtA-PI, and polyhydramnios (Model 1), (ii) a combination of biometric ultrasound measurements and clinical–maternal data (Model 2), and (iii) only the estimated fetal weight (EFW) (Model 3). Results: In total, 3808 singleton pregnancies were included in the analyses. The multivariable analysis revealed that AC (aOR 1.07, 95% CI [1.06, 1.08]), HC to AC (aOR 1.01, 95% CI [1.006, 1.01]), FL (aOR 1.01, 95% CI [1.009, 1.01]), and the presence of polyhydramnios (aOR 4.97, 95% CI [0.7, 58.8]) were associated with an increased risk of LGA, while a higher mUtA-PI was associated with a reduced risk (aOR 0.98, 95% CI [0.98, 0.99]). Maternal parameters, such as GDM, pre-existing diabetes, elevated pre-pregnancy BMI, absence of uterine artery notching, mUtA-PI, and multiparity, were significantly higher in the LGA group. Both models 1 and 2 showed similar performance (AUCs: 84.7% and 85.3%, respectively) and outperformed model 3 (AUC: 77.5%). Bootstrap and temporal validation indicated minimal overfitting and stable model performance, while decision curve analysis supported potential clinical utility. Conclusions: Models using biometric and Doppler ultrasound at 30–34 weeks demonstrated good discriminative ability for predicting LGA neonates, with an AUC up to 84.7%. Adding maternal characteristics did not significantly improve performance, while the biometric model performed better than EFW alone. Sensitivity at conventional thresholds was low but increased substantially when lower probability cut-offs were applied, illustrating the model’s threshold-dependent flexibility for early risk stratification in different clinical screening needs. Although decision curve analysis was performed to explore potential clinical utility, external validation and prospective assessment in clinical settings are still needed to confirm generalizability and to determine optimal decision thresholds for clinical application. Full article

Background: Folic acid supplementation (FAS) before and in early pregnancy prevents neural tube defects, but the benefits of extending FAS to late pregnancy on pregnancy outcomes remain unclear. We aimed to investigate the associations between duration of FAS and a spectrum of pregnancy outcomes, and to determine whether the associations were modified by maternal age or pre-pregnancy body mass index (BMI). Methods: This prospective multicenter study included 15,694 singleton pregnancies. We used mixed-effects log-binomial regression models to estimate the adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for gestational diabetes mellitus (GDM), gestational hypertensive disorders (GHDs), pre-eclampsia, preterm birth, macrosomia, small (SGA) and large for gestational age (LGA), and the interaction effects of advanced maternal age and pre-pregnancy BMI. Results: Of 15,694 women, 4523 (28.8%) did not take FAS before or during pregnancy, 2854 (18.2%) took FAS only during peri-pregnancy, 921 (5.9%) took FAS from peri- to mid-pregnancy, and 7396 (47.1%) took it through late pregnancy. Compared with women without FAS, those supplemented until mid-pregnancy were associated with lower risks of GHDs (aRR 0.84, 95% CI 0.74, 0.96) and pre-eclampsia (aRR 0.81, 95% CI 0.67, 0.97). Supplementation until late pregnancy was associated with lower risks of preterm birth (aRR 0.67, 95% CI 0.59, 0.76), SGA (aRR 0.74, 95% CI 0.63, 0.87), and LGA (aRR 0.88, 95% CI 0.79, 0.97). Among women of advanced maternal age or with overweight/obesity, supplementation until mid-pregnancy was associated with higher risk of GDM. Conclusions: Extending FAS until mid-pregnancy is associated with lower risks of GHDs and preeclampsia, and extending it until late pregnancy is associated with lower risks of preterm birth, SGA, and LGA. However, women of advanced maternal age or with overweight/obesity should be cautious about prolonging FAS. Full article

Background and Objectives: Gestational diabetes mellitus (GDM) is a complex pregnancy condition that carries substantial risks for adverse pregnancy outcomes. Following the implementation of universal diagnostic criteria in our clinical practice, this study was undertaken to assess their applicability and to determine whether locally conducted clinical studies are beneficial before adopting globally applicable criteria. By retrospectively analyzing parameters relevant to GDM from medical records, we aimed to determine the suitability of existing diagnostic criteria for our population, taking into account distinct socioeconomic, demographic, and genetic factors, and to assess the validity of alternative criteria. Materials and Methods: We used data from 2183 pregnant women who underwent 75 g-OGTT between 24 and 28 weeks of pregnancy. Results of the plasma glucose (PG) measurements were used to assign women into four diagnostic groups: diagnosed and treated by IADPSG criteria, diabetes mellitus in pregnancy identified according to WHO-2006 criteria, identified according to CDA-2013 criteria, and identified according to Tomic et al. criteria, based on a study on our population. Pregnancy outcomes were extracted from medical records. Results: The prevalence of GDM was 18.7% by IADPSG criteria, comparable to published data. Adverse pregnancy outcomes were consistently more frequent in GDM groups across all diagnostic systems (46.6–80% versus 33.9–35.9% in non-GDM). Maternal BMI ≥ 25 kg/m² was also associated with having large-for-gestational-age (LGA) neonates, contributing to the influence of hyperglycemia. Excessive gestational weight gain was a predictor of complications such as macrosomia and cesarean delivery. Conclusions: Before adopting universal GDM diagnostic criteria, population-specific studies are valuable to balance detection rates and clinical accuracy. Full article

Background: Gestational weight gain (GWG) is commonly used as an indicator of nutritional adequacy during pregnancy and a marker for pregnancy outcomes. This study aims to report the prevalence and extent of GWG inadequacy among Saudi women and to examine the effects of GWG inadequacy on pregnancy outcomes. Methods: This study was conducted as part of the Riyadh Mother and Baby Multicenter Cohort Study; it included 6984 women with singleton pregnancies. Adverse pregnancy outcomes—including hypertension, gestational diabetes (GDM), cesarean section (CS), low birth weight (LBW), Neonatal Intensive Care Unit admission (NICU), and macrosomia—were compared between women with adequate and inadequate GWG, based on the Institute of Medicine (IOM) guidelines. Results: Of the participants, 2221 women (31.8%) had adequate GWG for prepregnancy BMI, 2959 (42.4%) had inadequate GWG, and 1804 (25.8%) had excessive GWG. Women with normal prepregnancy BMI and inadequate GWG had significantly increased odds of delivering LBW infants (adjusted odds ratio (AOR) = 1.61, 95% CI: 1.17–2.20). Inadequate GWG also decreased the odds of emergency cesarean delivery among women with obesity (AOR = 0.75, 95% CI: 0.56–0.97) and lowered the likelihood of NICU admission for infants of obese women (AOR = 0.59, 95% CI: 0.36–0.97). Women with prepregnancy obesity experienced the highest rate of adverse outcomes; however, the prevalence of all adverse outcomes decreased as the degree of weight gain inadequacy increased. Conversely, underweight women had the highest percentage of LBW, with this percentage increasing as weight gain inadequacy increased. Conclusions: The effects of inadequate GWG vary depending on maternal prepregnancy BMI and the specific outcome assessed. For women with obesity, reduced weight gain during pregnancy may be beneficial. In contrast, inadequate GWG is associated with a higher incidence of LBW in women with normal prepregnancy BMI and underweight women. Full article

Gestational diabetes mellitus (GDM) and macrosomia are crucial for improving maternal and neonatal outcomes. Molecular dysregulations can manifest long before clinical symptoms appear. This study aimed to leverage first-trimester serum lipidomic signatures to build early predictive models for these complications. A case–control study was conducted using serum samples from 119 women during first-trimester screening: 40 cases and 79 controls for GDM prediction and 45 cases and 74 controls for macrosomia prediction (newborn weight more than 90 percentile). Lipidomic profiling was performed using shotgun mass spectrometry in both positive and negative electrospray ionization modes. After feature selection based on Shapley values, machine learning models—including Random Forest and XGBoost—were constructed and evaluated via 10-fold cross-validation. For GDM, potential early biomarkers included elevated levels of triacylglycerol (TG) 55:7 and decreased levels of 13-Docosenamide, plasmenyl-phosphatidylcholine (PC P)-36:2, and phosphatidylcholine (PC) 42:7. For macrosomia, phosphatidylglycerol (PG) (i-, a- 29:0), 4-Hydroxybutyric acid, and Pantothenol were significantly altered. The model for GDM prediction achieved a sensitivity of 87% and specificity of 89%. For macrosomia, the model demonstrated a sensitivity of 87% and specificity of 93%. The Random Forest and XGBoost models demonstrated comparable performance metrics on average. The risk ratio between the high- and low-risk groups defined by the models was 11.9 for GDM and 11.1 for macrosomia. Our findings demonstrate that first-trimester serum lipidomic profiles, combined with clinical data and interpreted by advanced machine learning, can accurately identify patients at high risk for GDM and macrosomia. This integrated approach holds significant promise for developing a clinical tool for timely intervention and personalized pregnancy management. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) is associated with altered maternal gut microbiota and increased risk of large-for-gestational age (LGA) births. The contribution of gut microbiota to fetal overgrowth in GDM, independent of glycemic control, remains unclear. Methods: In this pilot longitudinal study, the gut microbiota of 18 women with GDM was followed from the second (2T) to the third trimester (3T). Maternal fecal samples were analyzed by 16S rRNA gene sequencing, and associations between microbial profiles and infant birth weight were examined. In addition, these associations were adjusted for pre-pregnancy body mass index (BMI) and gestational weight gain (GWG). Results: Maternal gut microbiota of LGA infants exhibited consistently lower microbial diversity, a reduced Bacillota/Bacteroidota ratio, and enrichment of pro-inflammatory taxa including Prevotella, Sutterella, and Bilophila. Short-chain fatty acids (SCFAs)-producing genera such as Acinetobacter, Odoribacter, Faecalibacterium, and Lachnoclostridium were depleted. Although Bilophila was identified as a third-trimester biomarker with LEfSE approach, its association with LGA disappeared after adjusting for BMI and GWG. Conversely, Nitrospirota, Polaromonas, Acinetobacter, and Aeromonas correlated negatively with LGA even after BMI and GWG adjustment. Conclusions: These findings suggest that specific maternal microbiota signatures, together with pre-pregnancy adiposity, influence fetal overgrowth in GDM and may serve as early biomarkers or targets for preventive interventions. Full article

Objectives: Gestational diabetes mellitus (GDM), particularly when combined with overweight or obesity, is associated with adverse neonatal outcomes such as high birth weight and increased adiposity. We determined the effect of a preconception lifestyle intervention initiated before and continued throughout pregnancy on neonatal, birth-related, and body composition outcomes at birth and 6–8 weeks of age in children of participants in the BEFORE THE BEGINNING randomized controlled trial. Methods: People (N = 167) at increased risk of GDM and planning pregnancy were randomly allocated 1:1 to intervention or control. The intervention included time-restricted eating and exercise training. Time-restricted eating involved consuming all energy within ≤10 h/day, ≥5 days per week, and the amount of exercise was set using a heart rate-based physical activity metric (Personal Activity Intelligence, PAI), with the goal of ≥100 weekly PAI points. The main outcome of interest in this report was the proportion of infants with birth weight > 4.0 kg. Results: Among 106 live births, 21% (11/53) of infants in the intervention group and 28% (15/53) in the control group had birth weight > 4 kg (p = 0.367). Mean birth weight did not differ significantly between groups (mean difference −159.3 g, 95% confidence interval −375.7 to 57.2, p = 0.148). No significant between-group differences were found for additional neonatal, birth-related, or early postnatal body composition outcomes. Conclusions: In this secondary analysis, we found no evidence of effects of a preconception lifestyle intervention on the risk of macrosomia or neonatal body composition. Full article

Weaver syndrome is a rare congenital overgrowth disorder caused by pathogenic EZH2 variants. This study reports a novel EZH2 variant associated with atypical manifestations, including severe bilateral camptodactyly and complex brain malformations. A 4-year-old Taiwanese female exhibited classical Weaver syndrome features including macrosomia, macrocephaly, hypertelorism, and developmental delay, plus atypical findings of severe bilateral camptodactyly and complex brain malformations. Neuroimaging revealed corpus callosum dysgenesis with rostral agenesis and genu hypoplasia, bilateral frontal lobe hypoplasia, and an arachnoid cyst. The patient demonstrated global developmental delay with marked motor impairment but less severely affected speech and cognition, consistent with mild intellectual disability. Whole-exome sequencing identified a novel de novo pathogenic variant in EZH2: c.449T>C (p.Ile150Thr), affecting a highly conserved amino acid within the SANT domain. This case broadens the clinical spectrum of Weaver syndrome by highlighting severe camptodactyly and complex brain malformations as possible EZH2-related manifestations. The corpus callosum dysgenesis suggests a wider role of EZH2 in neurodevelopment than previously recognized. The novel SANT domain variant may explain the severe phenotypic presentation. The novel EZH2 variant c.449T>C (p.Ile150Thr) expands the molecular and phenotypic spectrum of Weaver syndrome. These findings underscore the importance of comprehensive neuroimaging and molecular genetic testing in suspected cases, particularly atypical presentations. Full article