Michael A. Belfort

Objective: To evaluate the feasibility, uptake and diagnostic yield of opportunistic prenatal genetic testing performed during FSLP for TTTS. Methods: We conducted a retrospective cohort study of monochorionic pregnancies undergoing FSLP for TTTS at a single tertiary fetal therapy center between 2012 and 2023. Patients undergoing clinically indicated amnioreduction during FSLP were offered opportunistic diagnostic genetic testing. Genetic testing results, including culture failure, abnormal findings, and clinically relevant abnormalities, were assessed. Results: During the study period, 417 patients underwent FSLP for TTTS. Of these, 325 (77.9%) underwent diagnostic genetic testing. Karyotype alone was performed in 292 cases (89.8%) and karyotype with chromosomal microarray (CMA) was performed in 33 cases (10.2%). Most genetic tests were normal (96%). Eight (2.5%) showed no cellular growth for genetic analysis. Six additional findings were likely benign chromosomal and copy number variants (1.8%). Over the study period, rates of completed genetic tests increased, while exclusions due to incomplete documentation decreased substantially. Conclusions: Opportunistic genetic testing during FSLP is feasible and associated with a high rate of successful analysis. However, the yield of clinically relevant abnormalities is low. These findings support individualized counseling regarding the potential benefits, limitations, and associated costs of genetic testing during fetal surgery.

Objective: Mirror syndrome is a rare, life‐threatening condition in which maternal fluid overload mirrors fetal hydrops. Data on genetic findings in affected pregnancies are limited. We compared genetic diagnoses in hydrops cases with and without mirror syndrome. Methods: We conducted a retrospective cohort study (2012–2023) of pregnancies with non‐immune hydrops at a single fetal center. Clinical data along with prenatal and postnatal genetic testing results were analyzed. Mirror syndrome was defined as fetal hydrops with new or worsening hypertension and significant maternal edema. Genetic testing rates and diagnostic yields were compared between the groups. Results: Of the 192 cases, 140 (73%) underwent genetic testing. Testing rates were similar between mirror (24/31, 77%) and non‐mirror cases (116/161, 72%; p = 0.54). Abnormal findings explaining the phenotype were identified in 29% of mirror and 32% of non‐mirror cases ( p = 0.79). Rates of single‐gene disorders, aneuploidy, and copy‐number variants did not differ ( p > 0.05). Most single‐gene diagnoses involve cardiovascular or lymphatic pathways. Conclusion: The rates and types of genetic diagnoses were similar in hydrops cases with and without mirror syndrome. Despite limited power to detect subtle differences, these findings support a similar approach to genetic counseling and evaluation for hydrops cases with and without mirror syndrome.

This article includes Author Insights, a video abstract available at: https://drive.google.com/file/d/1prySeL98K50RflO_VP9Sih7r2K5PKwFO/view?usp=sharing .

Objective: To characterize intestinal transcriptional profiles in gastroschisis, their temporal evolution, and response to fetal intervention. Summary Background Data: Gastroschisis causes significant intestinal dysfunction, with intra-abdominal bowel dilation clinically shown to correlate with worse outcomes. Although inflammation and neurovascular impairment have been implicated, genome-wide transcriptional characterization of disease severity remains lacking. Methods: Using a fetal-ovine model of complex gastroschisis, in which all gastroschisis animals demonstrated significant intra-abdominal bowel dilation at term, bulk RNA sequencing was performed on proximal small intestinal tissue from mid-gestation and term fetuses across 3 groups: normal, gastroschisis, and prenatally repaired gastroschisis. Differential gene expression (FDR≤0.05, |log ₂ fold change| ≥ 1.5) and pathway enrichment analyses were performed, with targeted interrogation of extracellular matrix (ECM), enteric nervous system (ENS), angiogenic, and inflammatory pathways. Results: At mid-gestation, gastroschisis intestine showed minimal transcriptional differences (150 differentially expressed genes [DEGs]) and some bowel dilation. By term, dysregulation was substantial (2423 DEGs) alongside significant dilation. Normal ontogenetic intestinal maturation patterns were altered, with fewer expected developmental gene changes and discordant pathway regulation. ECM pathway aberrations emerged early and persisted, whereas ENS, angiogenic, and inflammatory pathways were only dysregulated at term. Fetal repair was associated with normalization of gene expression at term (29 DEGs vs. controls). Conclusions: Intestinal transcriptional changes in experimental gastroschisis parallel progressive bowel dilation, consistent with a mechanical stress contribution to intestinal injury. Prenatal repair normalizes both dilation and gene expression, indicating a dynamic and potentially modifiable transcriptional program that supports the rationale for early fetal intervention.

Background/Objectives: This study assessed whether endometriosis is associated with an increased risk of placenta accreta spectrum (PAS) disorders and investigated if assisted reproductive technology (ART) further increases the risk in patients with endometriosis. Methods: This retrospective study used multi-institutional data from the TriNetX database to identify patients who experienced delivery on or before 31 December 2024, with a prior diagnosis of endometriosis and ART therapy, as coded by CPT and ICD-10 codes. The primary outcomes included up to 7-day perinatal results, such as PAS (accreta, increta, percreta), and maternal complications, including peripartum hysterectomy, transfusion, postpartum hemorrhage (PPH), ICU admission, and sepsis. Risk ratios, 95% confidence intervals, and p-values were calculated for endometriosis versus no endometriosis and endometriosis patients with ART versus without ART. Results: Out of 3,487,612 patients identified, 24,341 had a prior diagnosis of endometriosis prior to propensity score matching. Propensity score matching was used to control for age, demographic variables, previous procedures, and comorbidities. Compared to controls, endometriosis was linked to a higher risk of PAS disorders (RR 1.74), including accreta (RR 2.22), increta (RR 2.50), and percreta (RR 1.59). Additional complications included peripartum hysterectomy (RR 1.72), transfusion (RR 1.26), PPH (RR 1.35), ICU admission (RR 1.43), and sepsis (RR 1.56). Patients conceived via ART faced greater risks of PAS disorders (RR 2.00), accreta (RR 2.14), hysterectomy (RR 1.63), transfusion (RR 2.10), and PPH (RR 1.66). Conclusions: This study shows a positive link between endometriosis and the risk of PAS disorders and maternal complications, and the use of ART in patients with endometriosis further increases this risk, emphasizing the importance of comprehensive counseling and a multidisciplinary approach to delivery planning for this high-risk group.

Objectives: To determine whether a fetal lamb model reproducibly induces complex gastroschisis at term with its associated structural and functional bowel changes, and to compare its occurrence and associated bowel findings at different post-induction intervals. Methods: Gastroschisis was surgically induced in fetal lambs at gestational day 75 by creating a standardized abdominal wall defect stabilized with a silicone ring. Fetuses were assessed at term or at mid-gestation (13–21 days after induction), using non-operated littermates as controls. The primary outcome was occurrence of complex gastroschisis (bowel stenosis, atresia, volvulus, perforation, or necrosis) in survivors. At mid-gestation, this was compared between early (13–16 days) and late (17–21 days) groups, using Fisher’s exact test. Sample size for the primary outcome at term was determined a priori (α=0.05, 80% power). Mid-gestation sample size was determined using the same statistical assumptions, informed by an initial exploratory cohort. Secondary outcomes included prenatal and in vivo imaging, ex vivo bowel contractility, amniotic fluid composition, and histology. Results: Gastroschisis was induced in 32 fetuses. In the term cohort (n=14), 50% survived (7/14); all survivors had complex gastroschisis, with impaired bowel motility, altered enteric neural contractile responses, and smooth muscle remodeling compared with controls. Among fetuses assessed at mid-gestation (n=18), two died in utero; complex gastroschisis occurred more frequently in the late (5/7, 71%) than in the early (1/9, 11%; p =.04) group. Mid-gestation fetuses with gastroschisis had greater intra-abdominal bowel dilation on ultrasound and higher amniotic fluid digestive enzyme levels than controls, with the greatest dilation in fetuses with complex gastroschisis. Conclusions: This fetal lamb model reproducibly induced complex gastroschisis with structural and functional bowel changes in surviving lambs at term. Complex gastroschisis occurred more frequently at 17–21 than at 13–16 days after induction. At mid-gestation, fetuses with gastroschisis showed greater bowel dilation and differences in amniotic fluid composition than controls, whereas structural and functional bowel changes were not detected.

Background Little is known about the impact of spinal cord microstructural alterations after prenatal myelomeningocele (MMC) repair and their associations with neurological clinical assessments. Objective To assess spinal cord diffusivity using diffusion-weighted imaging (DWI) obtained between 10 months and 30 months of age in children who underwent prenatal MMC repair, and to explore associations with neurological clinical assessments. Materials and methods This retrospective cohort study included children who underwent prenatal MMC repair from November 2011 to May 2023. All children met the Management Of Myelomeningocele Study (MOMS) inclusion criteria. DWI (b=0 s/mm² and 800 s/mm²) was performed between 10 months and 30 months of age, and apparent diffusion coefficient (ADC) values were obtained at the level of the spinal lesion. Neurological clinical assessments included intact S1 motor and sensory level, need for anticholinergic therapy or clean intermittent catheterization at the evaluation closest to 12 months, and ambulatory status at the evaluation closest to 30 months. Associations between ADC values (expressed as median [interquartile range]) and neurological clinical assessments were evaluated using the Mann-Whitney U test. A P-value -3 mm²/s, P=0.01), intact S1 sensory level (1.36 [1.12-1.74] vs 1.21 [1.04-1.38]×10^-3 mm²/s, P=0.02), no anticholinergic therapy (1.31 [1.13-1.70] vs 1.22 [1.04-1.40]×10^-3 mm²/s, P=0.04), no catheterization (1.33 [1.04-1.74] vs 1.21 [1.12-1.32]×10^-3 mm²/s, P=0.04), and independent ambulation (1.36 [1.04-1.89] vs 1.19 [1.00-1.46]×10^-3 mm²/s, P=0.02). Conclusion Lower ADC values at the lesion level were associated with worse neurological and urological clinical assessments in children after prenatal MMC repair, suggesting that DWI may provide imaging biomarkers of spinal cord integrity. Graphical Abstract

Objective: This study aims to enhance antenatal detection of placenta accreta spectrum (PAS) and predict severe hemorrhage at delivery using machine learning by evaluating the association between antenatal hematologic index trends across trimesters, imaging markers, and patient history. Methods: We retrospectively analyzed 2017–2023 data from a PAS referral center, including demographics, laboratory results, ultrasounds, and outcomes. Patients with confirmed PAS (cases) were compared to those with antenatal risk but no histopathologic evidence of PAS (controls). Statistical analyses and machine learning models were developed to predict PAS. We also used machine learning to predict severe hemorrhage (>1500 mL) in the cases. Results: A total of 186 PAS cases and 217 controls were identified, showing significant differences in body mass index, gravidity, parity, prior cesarean deliveries, gestational age at delivery, and PAS ultrasound findings. Logistic regression highlighted prior cesarean deliveries (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.3–2.4) and second (OR 28.1; 95% CI 12.7–60.8) or third trimester ultrasound markers (OR 27.6; 95% CI 13.2–61.1) as strong predictors of PAS. Third trimester mean platelet volume was inversely associated with PAS (OR 0.55; 95% CI 0.39–0.78). Machine learning models achieved high accuracy. Model 1 predicted PAS with 90% accuracy. Model 2 predicted PAS with 88.8% accuracy using early gestational hematologic markers. Model 3 predicted severe hemorrhage (>1500 mL) with 74.3% accuracy. Conclusion: Machine learning models combining patient history, imaging, and hematologic markers detect PAS and predict hemorrhage with up to 90% accuracy. These tools improve antenatal diagnosis of PAS, which enhances maternal outcomes by enabling early identification and better resource allocation.

Objective: Myelomeningocele (MMC) is associated with significant alterations of the brain microstructure, which can impair long‐term neurodevelopmental outcomes. By measuring the random displacement of water molecules within the brain, magnetic resonance imaging (MRI)‐based diffusion‐weighted imaging (DWI) can provide objective metrics, such as apparent diffusion coefficient (ADC) values, which allow the fetal brain microstructure to be characterized. The aim of this study was to compare prenatal brain ADC values, obtained using MRI‐DWI, between infants with prenatally repaired MMC who had normal vs impaired neurodevelopmental outcomes, assessed ≥ 18 months of age. Methods: This retrospective study included children who underwent prenatal MMC repair using either a fetoscopic or open‐hysterotomy surgical approach between July 2012 and June 2022, at a single tertiary hospital. A 1.5‐Tesla MRI‐DWI scan of the fetal brain was performed using standard departmental protocols 6 weeks after surgery. ADC values were measured in the right and left hemispheric white matter of the frontal, parietal, temporal and occipital lobes, as well as within the basal ganglia, pons, cerebellar hemispheres and vermis. Neurodevelopment was evaluated by a developmental pediatrician at or after 18 months of age, using the Capute Scales (Clinical Adaptive Test (CAT) for problem‐solving skills and fine motor skills and Clinical Linguistic and Auditory Milestone Scale (CLAMS) test for language) and the gross motor domain of the Revised Gesell Developmental Schedules. The Developmental Profile‐3 (DP‐3) test was also conducted during parental interview at or after 18 months of age, which evaluates five qualities of development: physical, adaptive behavior, social–emotional, cognitive and communication skills. Developmental quotients were calculated as: (age equivalent on Capute Scales, gross motor or DP‐3 test/age at assessment) × 100. A normal developmental quotient score was defined as ≥ 85 and a score of < 85 indicated neurodevelopmental impairment (NDI), compared with reference values. ADC values measured in each brain region were compared between children who later had a normal developmental quotient score vs those with a score < 85, using the Mann–Whitney U ‐test and logistic regression analysis, adjusting for the child's age at the time of neurodevelopmental testing, gestational age at the time of MRI‐DWI and gestational age at delivery. Results: A total of 50 children were included (39 that underwent prenatal fetoscopic repair and 11 that underwent prenatal open‐hysterotomy repair). A prenatal MRI‐DWI scan was performed after surgery at a median of 30.9 (interquartile range (IQR), 30.5–31.4) weeks' gestation. The Capute Scales and gross motor scores were available in 31/50 (62.0%) and 29/50 (58.0%) cases, respectively, and were obtained at a median age of 23.0 (IQR, 18.0–25.5) months and 23.0 (IQR, 21.0–26.2) months, respectively. Among these cases, 22/31 (71.0%), 19/31 (61.3%) and 3/29 (10.3%) scored ≥ 85 on the CLAMS test, CAT and gross motor test, respectively. The DP‐3 test score was available in 42/50 (84.0%) children and was conducted at a median age of 24.5 (IQR, 19.0–26.7) months. Among these children, 18/42 (42.9%), 28/42 (66.7%), 38/42 (90.5%), 35/42 (83.3%) and 33/42 (78.6%) had a score ≥ 85 for the physical, adaptive behavior, social–emotional, cognitive and communication domains, respectively. After adjustment, fetal ADC values obtained 6 weeks after surgery were significantly higher in all fetal brain regions studied ( P < 0.05 for all), except for the vermis ( P = 0.12) and pons ( P = 0.05), in infants who later had a CLAMS test score indicating NDI compared to those with a score ≥ 85. Additionally, fetal ADC values were significantly higher in all fetal brain regions, except for the left temporal lobe ( P = 0.05), left occipital lobe ( P = 0.06), pons ( P = 0.30), right and left cerebellum ( P = 0.55 and 0.24, respectively) and vermis ( P = 0.76), in infants who later had a CAT score indicating NDI compared to those with a normal score. Fetal ADC values were also significantly higher in the parietal and temporal lobes as well as in the pons ( P < 0.05 for all) in infants who later had a DP‐3 cognitive and communication score indicating NDI compared to those with a normal score. There was no difference in fetal ADC values in any of the brain regions studied between children with scores indicating normal vs impaired neurodevelopment on the gross motor test, the DP‐3 physical, adaptive behavior and social–emotional domains or the DP‐3 general development score. Conclusion: Infants with NDI in problem‐solving, cognitive and communication skills exhibited significant differences in their brain microstructure, as demonstrated by higher ADC values measured in utero 6 weeks after prenatal MMC repair, compared to those with normal neurodevelopmental outcomes as assessed at or after 18 months of age. These findings have significant clinical implications, especially for the early identification and management of children at risk for NDI after prenatal MMC repair. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.