Malaria in pregnancy constitutes a principal factor in the enduring prevalence of significant maternal and foetal illness and fatality. This study investigated the potential of Syzygium cumini (L.) Skeels (Myrtaceae) fruit fraction in modulating TNF-α, preserving placental spiral artery integrity, and improving foetal outcomes in Plasmodium berghei-infected pregnant mice. A true experimental design was conducted using second-trimester pregnant mice (n = 5 per group), which were infected with the P. berghei ANKA strain. Each mouse was administered an intraperitoneal dose of 0.2 mL phosphate-buffered saline comprising roughly 1 × 10⁶ parasitized red blood cells obtained from donor mice with 20–30% parasitaemia. The animals were categorized into six groups: normal control (K1), infected untreated (K2), drug control treated with dihydroartemisinin–piperaquine (5 mg/kg body weight, oral), and three treatment groups receiving Syzygium cumini fruit (SCF) fraction at doses of 600 mg/kg (P1), 800 mg/kg (P2), and 1200 mg/kg (P3). Placental TNF-α levels were significantly reduced in all treatment groups compared with the infected control (K2), with the greatest reduction observed at 1200 mg/kg (P3, p < 0.05). Histological analysis revealed that P2 and P3 significantly improved spiral artery diameter and wall thickness, while P1 produced moderate changes. Foetal body length increased significantly in all treatment groups (p < 0.05), and foetal weight in P3 approached the normal control (K1). The (SCF) fraction demonstrated anti-inflammatory properties and improved placental function and supported foetal growth. These findings demonstrate its potential as a complementary natural therapeutic agent for managing malaria-associated complications during pregnancy.

Preeclampsia, a serious hypertensive disorder of pregnancy, is associated with increased long-term risk of cardiovascular disease in adult offspring, particularly stroke. Although low-dose aspirin (LDA) is used prophylactically to prevent preeclampsia, its impact on offspring is unclear. This study investigated the effect of maternal LDA treatment during experimental preeclampsia (ePE) on adult first-generation (F1) offspring, including stroke outcome. ePE was induced in pregnant Sprague-Dawley rats via a high-cholesterol diet starting on gestational day 7 and treated with LDA (1.5 mg/kg) or vehicle. Offspring were weaned and fed standard chow until transient middle cerebral artery occlusion at 12 to 18 weeks (3-hour ischemia and 1-hour reperfusion). Fetal and juvenile weights were taken at gestational day 20 and from weeks 10 to 13. Infarct and edema were quantified using 2,3,5-triphenyltetrazolium chloride staining. Multisite laser Doppler was used to measure cerebral hemodynamics, including cerebral blood flow autoregulation and collateral flow. Circulating proinflammatory and anti-inflammatory factors were measured via multiplex immunoassay. Male offspring from ePE dams (ePE-F1) had larger infarction and edema versus male offspring from normal pregnant dams (NormP-F1, 48%±6 versus 11%±4; P<0.01) and all female offspring. Maternal treatment with LDA was protective of male offspring (ePE+Asp-F1) that had reduced infarct and edema. Increased infarction in ePE-F1 males was associated with greater collateral perfusion deficit and elevated levels of TNF-α (tumor necrosis factor-alpha) and IL (interleukin)-1β that were prevented by maternal LDA treatment. There were no differences in infarct, edema, or perfusion deficit in female offspring. Prenatal exposure to ePE worsened stroke severity and inflammation in male but not female offspring, which was largely mitigated by maternal LDA treatment, potentially due to an improved intrauterine environment. These findings highlight a sex-specific impact of prenatal preeclampsia exposure on long-term cerebrovascular health and suggest that maternal LDA may confer long-lasting protection to the offspring in addition to the mother.

The impact of early amniotomy on delivery outcomes in pregnancies with fetal macrosomia.

This study aims to evaluate the therapeutic efficacy of hip muscle training combined with pelvic floor biofeedback electrical stimulation (BES) in postpartum patients with stress urinary incontinence (SUI) and identify predictors of treatment outcomes. A total of 142 SUI patients were randomly allocated to a control group [n = 71, pelvic floor muscle training (PFMT) + BES] or an observation group (n = 71, PFMT + BES + hip muscle training). Outcomes included therapeutic efficacy, pelvic floor muscle strength (GRRUG criteria), and incontinence symptoms (International Consultation on Incontinence Questionnaire-Short Form, ICI-Q-SF). Univariate and multivariate logistic regression analyses were performed to identify predictors of treatment success. The observation group exhibited a significantly higher total efficacy rate (94.4% vs. 74.6%, P = 0.001) and a greater proportion of grade III or higher pelvic floor muscle strength (88.7% vs. 70.4%, P = 0.007). Post-intervention, the observation group demonstrated superior improvements in leakage frequency, urine volume, and quality of life impact (all P < 0.001). Univariate analysis identified parity, delivery mode, gestational weight gain, fetal weight, episiotomy, bladder neck mobility, SUI severity, and intervention type as significant predictors (P < 0.05). Multivariate analysis confirmed gestational weight gain < 17.5 kg, absence of episiotomy, reduced bladder neck mobility, mild SUI, and combined therapy as independent protective factors (all P < 0.05). The integration of hip muscle training with pelvic floor BES significantly improves SUI symptoms and pelvic floor function. This biomechanically synergistic approach provides a novel framework for personalized postpartum rehabilitation.

Comparative accuracy of mid-thigh soft tissue thickness and the hadlock formula in fetal weight estimation during the third trimester: A prospective cross-sectional study.

Maternal obesity is known to adversely affect fetal development, with placental transcriptional dysregulation being one of the key mechanisms. However, the effect of a maternal high-fat diet (HFD) on dynamic placental gene expression, particularly in the context of obesity propensity, remains poorly understood. This study aimed to investigate the impact of a maternal HFD on time-dependent placental transcriptome alterations, with a focus on identifying key dysregulated pathways during mid-to-late gestation in rats. Female Sprague-Dawley rats were fed either a high-fat diet (HFD) or control chow (CC) diet before and during pregnancy. HFD-treated rats were categorized into obese-prone (OP) and obese-resistant (OR) groups based on pre-pregnancy weight. Maternal and fetal characteristics, as well as fetal outcomes, were recorded at gestational days (GD) 14.5, 17.5, and 19.5. Plasma cytokine levels were also measured. RNA sequencing (RNA-seq) was used to compare the transcriptomes of the three groups at GD 14.5, GD 17.5, and GD 19.5. At GD 14.5, OP and OR groups showed significantly lower fetal body weight, placental weight, and efficiency compared to the CC group, with these measures increasing significantly by GD 17.5. Concurrently, RNA-seq time-series analysis revealed a significant dysregulation of the spliceosome pathway in the OR group and the parathyroid hormone synthesis pathway in the OP group during mid-to-late gestation. Specifically, 19 out of 229 annotated spliceosome genes were differentially expressed in the OR group. These transcriptomic findings were robustly validated by qPCR, which confirmed the upregulation of Sf3a1 and Sart1 in both the OR and OP groups at GD 14.5, while Sf3a2, Sf3b4, and Rbm22 were specifically elevated in the OP group. Maternal high-fat diet disrupts placental transcriptome dynamics during mid-to-late gestation, particularly affecting spliceosome pathways, regardless of maternal obesity phenotype, contributing to placental dysfunction and adverse fetal outcomes. The observed time-dependent divergences highlight the need for phenotype- and gestational stage-specific interventions to mitigate developmental risks associated with maternal HFD.

Tetralogy of Fallot (ToF) shows variability in neonatal outcomes, and identifying reliable prenatal predictors is essential for optimizing perinatal management. The aim of this study was to determine the prognostic value of feto-placental data and prenatal echocardiography in the third trimester in ToF and to compare these findings with a matched control population. Multicenter prospective cohort study (2011-2023) at two referral centers (BCNatal and University Hospital of Gießen and Marburg). The cohort included 63 fetuses with isolated ToF and 66 healthy controls. All fetuses underwent a third trimester ultrasound and comprehensive echocardiography with 2D speckle tracking. Severe small-for-gestational age (SGA) was defined as estimated fetal weight (EFW) below the third percentile. Adverse composite outcomes were defined as the need for prostaglandin infusion, surgery or ductal stenting, corrective surgery before 3 months, and/or neonatal intensive care unit stay ≥7 days. The association of feto-placental and cardiac data with adverse composite outcome was evaluated. Compared with controls, ToF fetuses showed higher rates of severe SGA (19% vs. 0%, p < 0.001). Cardiac findings showed mild biventricular concentric hypertrophy (relative wall thickness ToF 0.7 [0.5-0.9] vs. controls 0.5 [0.5-0.6], p = 0.001), and reduced deformation (right and left ventricular global longitudinal strain: ToF -17.3% ± 3.8 vs. controls -19.3% ± 3.1, p = 0.001; ToF -18.0% ± 3.8 vs. controls -20.9% ± 3.45, p < 0.001), regardless of placental dysfunction. The adverse composite outcome occurred in 29.3% of ToF cases with pulmonary stenosis. Within this group, EFW <3rd centile (adjusted OR 9.17) and PV peak systolic velocity (aOR 1.03) showed the strongest association with adverse outcomes. Their combined performance yielded an AUC of 0.734, with a predictive value of 71.4% at a 20% false-positive rate. Assessed individually, the AUC was 0.650 for PV peak systolic velocity and 0.639 for estimated fetal weight. Optimal PV Doppler cutoff values were >70 cm/s when EFW was <3rd centile, and >144 cm/s when EFW was above the 3rd centile. Combining EFW with PV artery Doppler may allow identification of a high-risk subgroup of ToF-PS fetuses who may benefit from closer prenatal monitoring and prompt neonatal care.

Fetal intrauterine growth restriction (IUGR) is a common pregnancy complication that significantly impacts fetal health and long-term outcomes. Prenatal nicotine exposure (PNE) is a major environmental risk factor for IUGR, with abnormal placental angiogenesis, leading to insufficient placental perfusion, which represents a key pathological process. Electroacupuncture (EA), a non-pharmacologic traditional Chinese medicine therapy, is known to regulate qi and blood flow and improve circulation. This study investigated whether EA could reverse PNE-induced IUGR by enhancing placental angiogenesis and explored the underlying mechanisms. In a PNE-induced IUGR rat model, daily EA treatment was applied at bilateral “ST36” acupoints. On gestational day 20, fetal and placental growth parameters, along with placental perfusion, were assessed. Placental RNA sequencing (RNA-seq) was performed to identify relevant biological pathways, with key pathway molecules validated by qRT-PCR and Western blot. EA significantly restored fetal weight and length and increased placental weight and diameter. It also reduced the umbilical artery resistance index and improved placental perfusion. Furthermore, EA increased placental vascular density. Bulk RNA-seq revealed EA induced substantial changes in placental gene expression, including significant upregulation of the key angiogenic factor placental growth factor (PGF). Gene Ontology (GO) enrichment analysis indicated that differentially expressed genes were primarily involved in stress response regulation and cell surface receptor-mediated signal transduction, with notable enrichment in the PI3K/AKT signaling pathway. These transcriptomic findings were validated by qRT-PCR and Western blot, which confirmed that EA upregulated the mRNA expression of PGF, VEGFR-1, PI3K, and AKT, and increased the protein levels of PGF, VEGFR-1, and the phosphorylation of PI3K/AKT (p-PI3K, p-AKT). This integrated evidence suggests that maternal EA treatment may promote placental angiogenesis via activation of the PGF/VEGFR-1/PI3K/AKT pathway, thereby protecting against PNE-induced IUGR.

Pseudoamniotic band sequence (PABS) is a rare but serious complication following fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). We aim to explore associations between perioperative factors and PABS in monochorionic, diamniotic twins undergoing FLP for TTTS. A secondary analysis was conducted using a prospective cohort of 816 FLP procedures performed between 2011 and 2024 at a single fetal therapy center. All cases had confirmed absence of PABS prior to FLP via ultrasound and fetoscopic evaluation. PABS was diagnosed postnatally or suspected after FLP and confirmed after birth. Clinical and perioperative variables were compared between cases with and without PABS using appropriate two-sample tests, with statistical significance set at p<0.01 to minimize type I error in a smaller cohort. PABS occurred in 11 cases (1.3%), with only 3 (27.3%) identified prenatally and treated with in utero band lysis. Digital amputation occurred in 3 undiagnosed cases. There were no differences in maternal characteristics between groups. Estimated fetal weight discordance (p=0.003), GA at FLP (p=0.0004), and chorion-amnion separation (CAS, p<0.0001) differed significantly between cases with and without PABS. Observed associations with perioperative factors, particularly with CAS, may inform detailed post-FLP evaluation for PABS. Early detection of PABS may facilitate prenatal intervention and reduce adverse neonatal outcomes.

We aimed to develop a machine learning model for first-trimester prediction of gestational diabetes mellitus (GDM) in twin pregnancies using a prospective international, multi-center cohort and identify useful predictive markers. Pregnant women with two live fetuses were enrolled at 11 + 0 to 13 + 6 weeks' gestation and followed until delivery. GDM was diagnosed at 24-28 weeks' gestation using the two-stage GCT and OGTT tests. Biochemical, biophysical, and blood assessments were conducted at three periods during pregnancy. Multiple machine learning models evaluated demographic, clinical, and laboratory parameters, including maternal factors (BMI, age, medical history), sonographic markers (crown rump length, estimated fetal weight, uterine artery pulsatility index), and blood and biochemical markers (placental growth factors, blood glucose, cell counts). LightGBM, XGBoost, and logistic regression models were compared using area under the curve (AUC) analysis. Among 596 women, 99 (16.6%) developed GDM. LightGBM demonstrated superior performance (AUC = 0.72, 95% CI 0.69-0.75). First-trimester high BMI was the strongest predictor, followed by elevated white blood cell counts and platelet levels. Detection rates (DR)were 28% and 42% at 10% and 20% falsepositive rates(FPR), respectively. Previous GDM was associated with an increased risk for GDM. GDM in twins is associated with certain characteristics of thefirst-trimester. Information from later trimesters has a limited impact. The GDM probability risk score increased with the severity of the treatment. An app to predict this score is available at: twin-pe.math.biu.ac.il.

Gestational diabetes mellitus (GDM) causes adverse effects on both mothers and offspring. This study investigated the effects of a polyherbal formulation combining Pandanus amaryllifolius root and Tectona grandis leaf extracts on maternal and fetal outcomes in streptozotocin (STZ)-induced GDM rats, compared with metformin. Pregnant rats were assigned to a non-diabetic reference group and diabetic groups, including an untreated diabetic group (negative control), a metformin-treated group (positive control), and diabetic groups treated with low, medium, or high doses of the pandan–teak formulation from gestation day 7 to 21. Medium and high doses significantly increased maternal body weight and pancreatic mass index (p < 0.05) without altering maternal glycemia or insulin levels. Fetal weight increased at medium and high doses, whereas crown–rump length increased only at the high dose. Placental index and fetal glucose levels decreased in a dose-dependent manner (p < 0.05), with no significant change in implantation loss. These findings suggest that the pandan–teak formulation may exert complementary actions that support placental–fetal glucose regulation and fetal growth while maintaining maternal glycemic stability, indicating its potential as a plant-based adjunct approach for gestational diabetes focused on fetal protection.

Preeclampsia induces adverse cardiovascular outcomes for both mother and offspring. We established a novel leptin-induced mouse model of preeclampsia that induces hypertension, endothelial dysfunction, and fetal growth restriction, which are collectively ablated by endothelial cell mineralocorticoid receptor (MR) deletion. However, literature lacks preclinical evidence to use MR antagonism for preeclamptic patients. We hypothesize eplerenone improves blood pressure, vascular function, and fetal outcomes in leptin-infused pregnant mice. We infused timed-pregnant Balb/c mice with saline (sham) or leptin via s.c. osmotic minipump and administered vehicle or eplerenone from gestation day (GD)11-18 and GD15-18. We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in 2nd order mesenteric arteries by wire myography, and pup/placental weights on GD18. Eplerenone from GD11-18 ablated leptin-induced increases in BP but independently decreased fetal weight and placental efficiency. Eplerenone increased vascular contractility to phenylephrine and increased mRNA expression of NADPH oxidase (NOX) 1 and 2 in the placentas of pregnant mice in the GD11-18 cohort. We observed in our GD15-18 cohort that eplerenone no longer decreased fetal weight nor placental efficiency and there was no increase in contractility to phenylephrine. In conclusion, our data suggest that although eplerenone improves leptin-induced hypertension in pregnant mice, eplerenone reduces fetal weight when administered at mid-, but not late-, gestation in pregnant mice.

Pregnancy-induced hypertension (PIH) is a condition marked by elevated blood pressure during pregnancy, posing serious risks to both maternal and perinatal health, including increased mortality. Due to the safety concerns and side effects of current treatments for PIH, the search for new therapeutic agents is urgently needed. This study aimed to develop a β-cyclodextrin-functionalized sodium alginate (β-CD/SA) nanocarrier co-encapsulated with Naringenin (NR) to enhance its therapeutic potential. The β-CD/SA@NR nanocarriers were synthesized using ionic gelation and characterized by FTIR, XRD, and SEM, revealing a mean particle size of 142.6 ± 8.3nm and an encapsulation efficiency of 68.4 ± 3.1%. A total of sixty pregnant mice were randomly assigned to five groups, with seven mice in each group (n = 7): control, PIH model, NR, β-CD/SA, and β-CD/SA@NR nanocarrier. Treatment with β-CD/SA@NR significantly reduced systolic blood pressure from 163.7 ± 5.2 mmHg to 123.5 ± 4.1 mmHg (p < 0.001), decreased urinary protein from 2.91 ± 0.27mg/mL to 1.12 ± 0.13mg/mL (p < 0.01), and increased fetal weights by 28.4% compared to the PIH group. Moreover, β-CD/SA@NR treatment downregulated JAK2 and STAT3 expression by 64.7% and 58.3%, respectively (p < 0.001), along with a significant reduction in IL-6 and TNF-α levels. These results indicate that β-CD/SA@NR nanocarriers effectively manage PIH by delivering NR to suppress JAK/STAT3 signaling, highlighting their translational potential as a safe maternal-fetal therapeutic strategy.

ObjectiveTo explore the predictive value of thyroid hormone (TH) related indices for postpartum hemorrhage (PPH) in pregnant women with hypothyroidism-complicated pregnancy (HCP).Methods273 pregnant women with HCP admitted to our hospital from January 2021 to December 2024 were retrospectively selected. The patients were divided into PPH group (n=50) and non-PPH group (n=223) based on whether PPH occurred. The influencing factors were analyzed with univariate and Binary logistic regression analysis. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of TH related indices for PPH in pregnant women with HCP.ResultsThere were statistically significant differences in manual placental removal, delivery conditions, fetal weight >4000g, TSH, and FT4 (P < 0.05). The results of Binary logistic regression analysis showed that delivery conditions, TSH, and FT4 were independent influencing factors for PPH in pregnant women with HCP (P < 0.05). The ROC analysis results showed that the area under the curve for TSH+FT4 was 0.823, with a standard error of 0.032 (95% CI: 0.761~0.886), Youden index=0.48, sensitivity of 66.00%, and specificity of 81.61%. Patients with high TSH and low FT4 levels had lower Apgar scores for newborns and higher rates of postpartum hemorrhage.ConclusionTSH and FT4 have certain value in predicting PPH in pregnant women with HCP, and it is recommended to include them in predictive indices/models.

Evaluation of the Accuracy of Fetal Weight Prediction Technology in Predicting Fetal Macrosomia

Placental complications resulting in fetal growth restriction have been associated with dysregulated placental gene expression tied to an increased risk of schizophrenia. In rat offspring, it has been demonstrated that ∆9-tetrahydrocannabinol exposure in pregnancy results in fetal growth restriction and schizophrenia-like phenotypes (e.g., decreased pre-pulse inhibition of the acoustic startle response). However, it remains elusive if prenatal ∆9-tetrahydrocannabinol exposure induces this schizophrenia signature of placental gene expression. Therefore, our objective was to determine if these established predictive markers of schizophrenia are altered in a preclinical model of gestational oral ∆9-tetrahydrocannabinol exposure in rodents. We observed significantly reduced fetal weights in male and female prenatal ∆9-tetrahydrocannabinol-exposed offspring in the absence of maternal pregnancy outcomes. Placentae from ∆9-tetrahydrocannabinol-exposed males and females revealed altered expression of genes previously identified in human transcriptomic datasets of schizophrenia (i.e., Furin, Rccd1, and Atp5mk), with some expression changes being sex-specific (i.e., Eif5, Rps10, Vps33b, and Iqgap1). A subset of these genes were found differentially expressed in human BeWo cells exposed to ∆9-tetrahydrocannabinol. Targets were next examined in the adult rodent (postnatal day70) brain, and a subgroup of these genes (i.e., Furin, Rps10, and Rccd1) were increased concomitant with schizophrenia-like behavior (e.g., decreased pre-pulse inhibition). We further detected ∆9-tetrahydrocannabinol-induced upregulation of FURIN in patient-derived cerebral organoids, an effect observed in both control and schizophrenia cell lines. Collectively, these findings demonstrate prenatal ∆9-tetrahydrocannabinol exposure can lead to altered gene expression in established prioritized markers of schizophrenia in the placenta in both animal and human models.

Prolonged exposure to nitrate in drinking water does not adversely impact prenatal or birth outcomes in a rat model.

Maternal hyperhomocysteinemia (HHcy) is closely linked to fetal growth restriction (FGR), yet the underlying mechanisms remain incompletely understood. In this study, we established a rat model of HHcy by administering a high-methionine diet during pregnancy and confirmed the presence of FGR through fetal weight analysis. Histological evaluation of the maternal-fetal interface revealed reduced vascular density in both the decidua and placenta, accompanied by dysregulated expression of key angiogenic factors in decidua. To elucidate the mechanistic basis of these changes, primary decidual stromal cells (DSCs) were isolated and RNA sequencing was performed. HHcy impaired the proangiogenic capacity of DSCs by suppressing vascular endothelial growth factor A (VEGFA) secretion. Transcriptomic profiling identified significant enrichment of lipid metabolism pathways in HHcy-exposed decidua. Further molecular analyses revealed that CD36 played a central role in mediating HHcy-induced lipid metabolic disturbances, which in turn activated the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Importantly, pharmacological inhibition of CD36 in DSCs alleviated lipid accumulation, suppressed PPAR pathway activation, and restored VEGFA expression and secretion, thereby rescuing DSCs-mediated angiogenesis. Collectively, our findings suggest that maternal HHcy upregulates CD36 expression in DSCs, leading to lipid metabolism dysregulation and impaired VEGFA-mediated angiogenesis possibly via the PPAR pathway, ultimately contributing to the pathogenesis of FGR. This is the first study to implicate lipid metabolism as a critical regulator of decidual angiogenesis, offering novel mechanistic insights and a potential therapeutic target for HHcy-associated pregnancy complications.

Angiogenic factors are elevated in fetal growth restriction (FGR), but their clinical value for assessing the severity of FGR and the potential influence of coexisting pre-eclampsia has scarcely been investigated. In this study, our aim was to investigate the profile of maternal angiogenic factors across severity stages of fetal smallness compared with controls, analyzed overall and stratified by the presence or absence of pre-eclampsia, and to investigate whether values of these angiogenic factors, such as placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and the sFlt-1/PlGF ratio, are helpful in determining the severity stage of fetal smallness. This was a prospective cohort study of women with a singleton pregnancy diagnosed with fetal smallness (defined as birth weight < 10th centile) (n = 604) between October 2010 and December 2017, compared with a control group of pregnant women with an appropriate-for-gestational-age (AGA) singleton fetus (defined as birth weight ≥ 10th centile) (n = 424). At diagnosis, ultrasound was performed to assess estimated fetal weight (EFW) and Doppler pulsatility indices (PI) of the uterine artery (UtA), umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV), and these parameters were monitored regularly until delivery. Cerebroplacental ratio (CPR) was calculated as MCA-PI/UA-PI. Small fetuses were classified as: small-for-gestational age (SGA) if EFW ≥ 3rd and < 10th centile, with normal Doppler parameters; FGR Stage I if either EFW < 3rd centile, persistent MCA-PI < 5th centile, UA-PI > 95th centile, CPR < 5th centile or UtA-PI > 95th centile; FGR Stage II if there was absent end-diastolic flow in the UA; FGR Stage III if there was reversed end-diastolic flow in the UA or DV-PI ≥ 95th centile; or FGR Stage IV if there was non-reassuring cardiotocography or absent/reversed DV atrial flow. Maternal peripheral venous blood concentrations of PlGF and sFlt-1 were determined using enzyme-linked immunosorbent assay, and the sFlt-1/PlGF ratio was calculated. Linear trendof proportions was tested using the Mantel-Haenszel chi-square test. Among AGA controls (n = 424), SGA (n = 192), FGR Stage I (n = 380), FGR Stage II (n = 16) and FGR Stages III-IV (n = 16) fetuses, the proportion of cases with a sFlt-1/PlGF ratio > 95th centile was 12.7%, 7.8%, 30.8%, 43.8% and 62.5%, respectively (P = 0.0001), and the median multiples of the median (MoM) values for the sFlt-1/PlGF ratio were 0.55 (interquartile range (IQR), 0.19-2.00), 1.00 (IQR, 0.31-2.67), 3.03 (IQR, 0.91-8.20), 3.94 (IQR, 0.85-9.13) and 7.32 (IQR, 1.44-16.29), respectively (P = 0.24). Pre-eclampsia was diagnosed at any time between inclusion and delivery in 1.9% of controls, 3.6% of SGA, 21.1% of FGR Stage I, 37.5% of FGR Stage II and 50.0% of FGR Stages III-IV fetuses. Among all small fetuses with vs without pre-eclampsia, the proportion of pregnancies with sFlt-1/PlGF ratio > 95th centile was 56.9% vs 15.4% (P < 0.001) and the median MoM of the sFlt-1/PlGF ratio was 8.11 (IQR, 3.83-27.09) vs 1.59 (IQR, 0.52-5.04) (P = 0.18). Serum levels of angiogenic factors became more abnormal as the severity stage of fetal smallness increased. This association with severity was stronger in the presence of pre-eclampsia. However, absolute values of serum levels showed substantial overlap in both the presence and the absence of pre-eclampsia, making their use in determining the severity stage of fetal smallness challenging. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.

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.