Live Births Research Articles

Accounting for Twins and Other Multiple Births in Perinatal Studies of Live Births Conducted Using Healthcare Administration Data

The analysis of perinatal studies is complicated by twins and other multiple births even when multiples are not the exposure, outcome, or a confounder of interest. In analyses of infant outcomes restricted to live births, common approaches to handling multiples include restriction to singletons, counting outcomes at the pregnancy-level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and accounting for clustering of outcomes, such as by using generalized estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example.

Uplift of genetic diagnosis of rare respiratory disease using airway epithelium transcriptome analysis.

Rare genetic respiratory disease has an incidence rate of more than 1:2500 live births in Northern Europe and carries significant disease burden. Early diagnosis improves outcomes, but many individuals remain without a confident genetic diagnosis. Improved and expanded molecular testing methods are required to improve genetic diagnosis rates and thereby improve clinical outcomes. Using primary ciliary dyskinesia (PCD) as an exemplar rare genetic respiratory disease, we developed a standardized method to identify pathogenic variants using whole transcriptome RNA-sequencing (RNA-seq) of nasal epithelial cells cultured at air-liquid interface (ALI). The method was optimized using cells from healthy volunteers, and people with rhino-pulmonary disease but no diagnostic indication of PCD. We validated the method using nasal epithelial cells from PCD patients with known genetic cause. We then assessed the ability of RNA-seq to identify pathogenic variants and the disease mechanism in PCD likely patients but in whom DNA genetic testing was inconclusive. The majority of 49 targeted PCD genes were optimally identified in RNA-seq data from nasal epithelial cells grown for 21days at ALI culture. Four PCD-likely patients without a previous genetic diagnosis received a confirmed genetic diagnosis from the findings of the RNA-seq data. We demonstrate the clinical potential of RNA-seq of nasal epithelial cells to identify variants in individuals with genetically unsolved PCD. This uplifted genetic diagnosis should improve genetic counselling, enables family cascade screening, opens the door to potential personalised treatment and care approaches. This methodology could be implemented in other rare lung diseases such as cystic fibrosis.

Uterus Transplantation from Deceased Donors: First Italian Experience

Background: Uterus transplantation (UTx) is currently the only available treatment for absolute uterine factor infertility. Deceased donors have recently emerged as a valid alternative to living donors for uterus transplantation, with similar results. Methods: We report the first experience in Italy of uterus transplantation from deceased donors. Three uterus transplantations from deceased donors were performed at the Organ Transplant Unit of the University Hospital of Catania, Italy, between August 2020 and January 2022. Results: Two patients underwent UTx due to Mayer–Rokitansky–Küster–Hauser syndrome, while one patient had a previous hysterectomy due to benign disease. The donors’ ages were between 25 and 43 years and the mean cold ischemia time was 18.3 h. The mean age of the recipients was 31.6 years, and the mean recipient surgery duration was 5.3 h, with a mean blood loss of 766.66 mL. Two recipients developed a post-transplant hematoma, which was treated conservatively. No uterus recipient needed a re-operation during the first 30 days after transplantation. No histological signs of acute rejection were detected at the cervical biopsies performed at 1, 3, and 6 months after transplantation. First menstruation occurred in all recipients after 39 ± 12 days after transplantation. One live birth was reported 15 months after UTx. One graft was lost three months after UTx due to graft thrombosis. Conclusions: Uterus transplantation from deceased donors is emerging as a valid alternative to living donors in order to increase the donor pool.

Natural evolution of a cesarean scar pregnancy up to 34 weeks complicated by an early subserosal uterine rupture and placenta accreta spectrum disorders

Cesarean scar pregnancy (CSP) is an extremely rare form of ectopic pregnancy. A 39-year-old woman with a history of multiple uterine surgeries was diagnosed with a CSP at seven weeks by transvaginal ultrasound. The CSP was misdiagnosed at 13 weeks and 5 days during a second medical opinion. At 22 weeks of gestation, a 3.8 cm subserosal uterine rupture was visualized. Expectant management was decided. A live birth was achieved through an elective cesarean section at 34 weeks of gestation. The complications were early subserosal uterine rupture and placenta accreta spectrum that led to a hysterectomy. Due to risk of uterine rupture, management should consist of early termination of the pregnancy.

Nutritional status and factors associated with gestational weight gain in the city of São Paulo, 2012 to 2020: a retrospective cohort study.

Gestational weight gain (GWG) is a critical issue related to postpartum health in newborns and mothers. In Brazil, pregnant women's public health recommends monitoring GWG. Therefore, the objective of this study is to evaluate gestational weight gain and associated health factors of pregnant women monitored at Unified Health System (SUS) in the city of São Paulo between 2012 and 2020. This is a retrospective cohort study of pregnant women seen from 2012 to 2020 in São Paulo, Brazil. The database used was from the Integrated Health Care Management System related to the Live Birth Information System. Data distribution was assessed using the Kolmogorov-Smirnov test. Comparisons between groups according to weight gain (LWG vs. AWG vs. EWG) were performed using analysis of variance (ANOVA) with Tukey post hoc. Inclusion criteria considered that pregnant women had a recorded initial weight before 13 weeks and up to 15 days before delivery and a single pregnancy. The final database includes 276.220 pregnant women. The frequency of women according to initial body mass index (BMI) was 12.004 (4.4%) underweight, 132.049 (48.3%) normal weight, 78.856 (28.8%) overweight, and 50.660 (18.5%) living with obesity. The population consisted of 59.881 (21.9%), 37.217 (13.6%) and 176.471 (64.5%) women with LWG, AWG and EWG, respectively. Weight gain was associated with initial BMI, type of birth, color/ethnicity, marital status, women's age and antenatal care visits. The proportion of pregnant women with inadequate weight gain is high, relating initial BMI, type of birth, color/ethnicity, marital status, women's age and antenatal care visits. Interventions such as nutritional education should be suggested to help achieve adequate GWG.

Fine Particulate Matter, Its Constituents, and Spontaneous Preterm Birth.

The associations of exposure to fine particulate matter (PM2.5) and its constituents with spontaneous preterm birth (sPTB) remain understudied. Identifying subpopulations at increased risk characterized by socioeconomic status and other environmental factors is critical for targeted interventions. To examine associations of PM2.5 and its constituents with sPTB. This population-based retrospective cohort study was conducted from 2008 to 2018 within a large integrated health care system, Kaiser Permanente Southern California. Singleton live births with recorded residential information of pregnant individuals during pregnancy were included. Data were analyzed from December 2023 to March 2024. Daily total PM2.5 concentrations and monthly data on 5 PM2.5 constituents (sulfate, nitrate, ammonium, organic matter, and black carbon) in California were assessed, and mean exposures to these pollutants during pregnancy and by trimester were calculated. Exposures to total green space, trees, low-lying vegetation, and grass were estimated using street view images. Wildfire-related exposure was measured by the mean concentration of wildfire-specific PM2.5 during pregnancy. Additionally, the mean exposure to daily maximum temperature during pregnancy was calculated. The primary outcome was sPTB identified through a natural language processing algorithm. Discrete-time survival models were used to estimate associations of total PM2.5 concentration and its 5 constituents with sPTB. Interaction terms were used to examine the effect modification by race and ethnicity, educational attainment, household income, and exposures to green space, wildfire smoke, and temperature. Among 409 037 births (mean [SD] age of mothers at delivery, 30.3 [5.8] years), there were positive associations of PM2.5, black carbon, nitrate, and sulfate with sPTB. Adjusted odds ratios (aORs) per IQR increase were 1.15 (95% CI, 1.12-1.18; P < .001) for PM2.5 (IQR, 2.76 μg/m3), 1.15 (95% CI, 1.11-1.20; P < .001) for black carbon (IQR, 1.05 μg/m3), 1.09 (95% CI, 1.06-1.13; P < .001) for nitrate (IQR, 0.93 μg/m3), and 1.06 (95% CI, 1.03-1.09; P < .001) for sulfate (IQR, 0.40 μg/m3) over the entire pregnancy. The second trimester was the most susceptible window; for example, aORs for total PM2.5 concentration were 1.07 (95% CI, 1.05-1.09; P < .001) in the first, 1.10 (95% CI, 1.08-1.12; P < .001) in the second, and 1.09 (95% CI, 1.07-1.11; P < .001) in the third trimester. Significantly higher aORs were observed among individuals with lower educational attainment (eg, less than college: aOR, 1.16; 95% CI, 1.12-1.21 vs college [≥4 years]: aOR, 1.10; 95% CI, 1.06-1.14; P = .03) or income (<50th percentile: aOR, 1.17; 95% CI, 1.14-1.21 vs ≥50th percentile: aOR, 1.12; 95% CI, 1.09-1.16; P = .02) or who were exposed to limited green space (<50th percentile: aOR, 1.19; 95% CI, 1.15-1.23 vs ≥50th percentile: aOR, 1.12; 95% CI, 1.09-1.15; P = .003), more wildfire smoke (≥50th percentile: aOR, 1.19; 95% CI, 1.16-1.23 vs <50th percentile: aOR, 1.13; 95% CI, 1.09-1.16; P = .009), or extreme heat (aOR, 1.51; 95% CI, 1.42-1.59 vs mild temperature: aOR, 1.11; 95% CI, 1.09-1.14; P < .001). In this study, exposures to PM2.5 and specific PM2.5 constituents during pregnancy were associated with increased odds of sPTB. Socioeconomic status and other environmental exposures modified this association.

Subsequent Pregnancy Outcomes Following Prepregnancy Cerclage in Patients with Absent Ecto-Cervix

Background: We aimed to determine whether the prepregnancy cerclage for women with cervical incompetence with absent ecto‑cervix affects the time from surgery to conception and subsequent pregnancy outcome. Methods: This retrospective study was carried out on patients with at least one previous history of second-trimester abortion and extremely short cervix found by gynecological examination. A total of 40 cases of McDonald's cerclage before pregnancy were performed. The time from surgery to conception and pregnancy outcome were followed up for 4 years. The main outcomes were the time from surgery to conception, and the gestational week of delivery, miscarriage rate, preterm delivery rate. Results: Between September 2018 and December 2022, 37 women became pregnant following prepregnancy cerclage. In total, 36 babies were born to 37 mothers. The recurrence rate of second-trimester miscarriage was 8.11% (3/37) and the preterm birth rate was 29.73% (11/37). Mean time from surgery to conception was 38w (range 2w-160w).Mean gestational age at delivery was 36 weeks +4 (256 days).The live birth rate was 100%. There were no maternal complications, no intestinal and bladder injuries. Conclusion: Cervical incompetence patients with absent ecto‑cervix may benefit from prepregnancy cerclage without affecting the interpregnancy interval.

Noonan Syndrome: Relation of Genotype to Cardiovascular Phenotype—A Multi-Center Retrospective Study

Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of specific genetic mutations and their impact on cardiovascular and other outcomes in NS. Methods: We conducted a retrospective clinical study of 25 pediatric patients diagnosed with NS at two institutions: The Mother and Child Health Care Institute of Serbia and the Clinic for Children Diseases, University Clinical Center of the Republic of Srpska. Patients underwent whole-exome sequencing (WES) to identify genetic mutations. Clinical data, including cardiovascular manifestations, psychomotor development, and stature, were analyzed in relation to mutation types. Results: The cohort comprised 60% male and 40% female patients, with a median age at diagnosis of 7.2 years. Cardiovascular abnormalities were present in 88% of patients. Mutations in PTPN11 were most commonly associated with pulmonary valve stenosis (PVS), while RAF1 mutations were prevalent in patients with hypertrophic cardiomyopathy (HCM). No significant association was found between cardiac disease and delayed psychomotor development (p = 0.755), even though the likelihood ratio showed significance in that regard (p = 0.018). Short stature was observed in 48% of patients but was not significantly correlated with genetic type of disease, presence of cardiac disease, or developmental delay. Conclusions: The study confirms the high prevalence of cardiovascular manifestations in NS and highlights genotype–phenotype correlations. While cardiac abnormalities are common, their impact on psychomotor development and stature is less clear. Further research is needed to explore genetic interactions influencing these outcomes and refine clinical management strategies.

Abstract 4122486: Multicenter Study of Primary Fetal Cardiomyopathy: Clinical Outcomes And Genetic Etiologies, A Fetal Heart Society Research Collaborative Study

Background: Fetal cardiomyopathy (FCM) affects 8 per 100,000 live births, often with unknown etiology. Progress in fetal cardiac screening, genetic testing and management may have impacted historically poor outcomes. Aims: We sought to investigate genetic associations and clinical outcomes of FCM in the current era. Methods: This was a retrospective Fetal Heart Society Research Collaborative cohort study of FCM cases diagnosed from January 2017-December 2021 in 39 centers. Cases of fetal myocardial disease attributable to maternal diabetes, structural heart disease, arrhythmia or extra-cardiac conditions were excluded. Data including outcomes to 1 year after birth were collected. Significance of genetic testing results and FCM subtype were classified by each center. Results: There were 138 FCM cases diagnosed at a median gestational age of 27 +4 weeks (range 13-39 weeks). Suspected fetal heart disease (41%, 56/138) was the most common referral indication. There was a known family history of CM in 19% (26/138). FCM phenotypes included 38% (52/138) dilated, 24% (33/138) hypertrophic, 17% (24/138) non-compacted, 10% (14/138) mixed, 5% (7/138) restrictive, 3% (4/138) ventricular aneurysm, 3% (4/138) unspecified. Hydrops was present at diagnosis in 15% (20/138) and by delivery or at fetal demise in 26% (36/138). Of 128 continued pregnancies, 7% (9/128) had a fetal demise, 92% (118/128) a live birth and one was lost to follow-up. Among live births, 10% (12/118) received only palliative care. Of 106 actively treated, 75% (80/106) survived to 1 year; 7% (7/106) required ECMO, and 22% (23/106) were listed for transplant with 18 of these successfully transplanted. Of the cohort, a total of 80% (110/138) had genetic testing (including 30 with invasive prenatal testing), with 38% (52/138) having a confirmed genetic etiology and 28% (38/138) with a variant of uncertain significance (VUS) (Figure 1). Transplant-free survival to 1 year was similar for those with and without a genetic diagnosis (40%,21/52 vs 47%,40/86, p=0.48). Conclusion: Outcomes remain poor in FCM, with &lt;50% 1-year survival overall. Confirmed genetic etiologies are now identified in nearly 40%, highlighting the importance of genetic testing.

Abstract 4123308: Trends in Gestational Diabetes Mellitus By US State, 2019 -2023

Introduction/ Background: Gestational diabetes mellitus (GDM) is one of the most frequent adverse pregnancy outcomes and increases the risk of lifetime cardiometabolic disease. Given known geographic disparities in maternal morbidity and mortality in the US, we examined state-level prevalence and trends in GDM from 2019-2023. Methods: We conducted a serial, cross-sectional analysis of maternal health data recorded on birth certificates from all livebirths in the US using the National Center for Health Statistics Natality Files. We included pregnant individuals aged 15-44 years who gave birth from 2019-2023, had a singleton, live birth, and did not have pre-pregnancy diabetes. We calculated the age-standardized prevalence and average-annual percent change (AAPC) in GDM from 2019-2023, overall, by U.S. census region (Northeast, Midwest, South, and West), and in each US state and the District of Columbia (DC). Results: Of the 17,432,486 individuals with live births between 2019 and 2023, overall prevalence of GDM per 100 live births (95% confidence interval) was 6.9 (6.9, 6.9) in 2019 and 8.0 (8.0, 8.1) in 2023 (AAPC 3.2 [-1.7, 8.5]). There was significant geographic variation in overall prevalence of GDM by US region and state ( Figure 1 ). In 2023, prevalence was higher in the Midwest (8.8 [8.7, 8.9]) and Western states (8.6, [8.5,8.6]) compared with the Southern (7.3, [7.3, 7.4]) and Northeastern states (8.1, [8.0,8.2]), ranging from 5.5 (4.9,6.0) in DC to 13.0 (12.2,13.8) in Alaska. Prevalence was higher in 2023 compared with 2019 in all US regions and states and DC, except Alaska, Connecticut, Idaho, Maine, New Jersey, and Wyoming. Prevalence increased most rapidly in the Western US states (AAPC 4.2%/year [0.1, 8.4]) with the greatest change observed in Montana from 5.1 (4.7, 5.6) in 2019 to 8.0 (7.5, 8.5) in 2023 (AAPC 10.3%/year [5.6, 15.3]). Conclusions: GDM prevalence increased significantly from 2019-2023 with substantial heterogeneity by US region and state. More localized state-level analysis with context-specific polices that address factors associated with geographic differences in GDM are needed to promote maternal cardiometabolic health equity in the US.

Abstract 4112716: The Trend In Racial Differences In Mortality Attributed To Congenital Heart Diseases In Infants In The United States From 2005 To 2019

Background: Deaths from congenital heart disease (CHD) in children have been decreasing in the United States. We examined the differences in mortality trends between Non-Hispanic Black (NHB) and Non-Hispanic White (NHW) infants. Methods: We retrospectively analyzed publicly available data from the Centers for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research (CDC WONDER). The data was obtained from the linked birth/infant deaths from 2005 to 2019. We evaluated all infant deaths up to 1 year of age with the cause of death listed as CHD (International classification of diseases, 10 th revision (ICD-10) codes Q20-Q26 (except atrial septal defect, Q21.1 and patent ductus arteriosus, Q25. CHD infant mortality rate (IMR) was calculated per 100,000 live births. Race was ascertained based on death certificate reporting. Joinpoint regression was used to examine CHD-IMR by year, including stratification by NHB vs NHW, and neonatal vs postneonatal. The difference between NHB and NHW CHD-IMR was ascertained via the Mann-Whitney U test. P&lt;0.05 was considered statistically significant. Results: Out of 60,243,988 live births, there were 19,004 CHD-related infant deaths. The characteristics of the study population are displayed in Table 1. The overall CHD-IMR declined from 36.1 to 27.0 per 100,000 live births (25.2%) with an average annual percentage change (AAPC) of -2.1 [95% CI -2.6, -1.572] (Figure 1). The CHD-IMR was significantly higher in NHB than in NHW (40 vs 29.3; P&lt;0.0001) and this difference remained when the mortality rate was stratified by neonatal and post-neonatal periods. The CHD-IMR decreased significantly in NHW [AAPC: -2%; 95% CI: -2.5, -1.5%], but not in NHB [AAPC of -1.4%, 95% CI, -3.0, 0.3%]. The NHB-to-NHW CHD-IMR ratio, a measure of CHD-IMR disparity averaged 1.4 over the study period [AAPC: 0.8%; 95% CI: -0.2, 1.8%] (Figure 2). Conclusions: The CHD-IMR declined significantly for NHW, but not in NHB in the US from 2005 to 2019. The CHD-IMR was higher in NHB than in NHW. There was no significant change in the NHB-to-NHW CHD-IMR ratio, signifying no change in the disparity that exists between NHB and NHW IMR. These findings may have implications for patient care and public health policymaking. They lay the groundwork for additional studies to determine and understand the drivers behind these findings such as in prenatal diagnosis.

Abstract 4138718: Teen Pregnancy and Risk of Premature Major Adverse Cardiovascular Events

Introduction: Teen pregnancy (TP), defined as pregnancy between 10 and 19 years, is associated with adverse pregnancy outcomes and perpetuates socioeconomic disadvantage, but the impact in later life is not well studied. We investigated the association of TP with premature major adverse cardiovascular events (PMACE) Methods: We used data from the National Health and Nutrition Examination Survey 1999–2018. Surveys were linked with the National Death Index to ascertain mortality records. Only adult females aged 20 years and older were included in the analysis. Participants were divided into 3 groups based on age at their first life birth: 19 or younger (TP), 20 and above (non-TP), and nulliparous women (NP). TP was ascertained by age at first life birth ≤ 19 years, and PMACE was defined as any self-reported diagnosis of coronary artery disease, stroke, heart failure, or all-cause mortality occurring before age 65. We assessed the association between these groups and PMACE using univariate and multivariate logistic regression models. Result: Among 19,737 (weighted frequency of 83,450,668) adult females, 24.2% had a history of TP, 54.3% had a history of non-TP and 21.5% were NP. Compared with NP females, females with TP had a higher odd of PMACE with an unadjusted odd ratio of 3.75 (95%CI, 2.80 - 5.01) versus 2.07 (1.55 – 2.75) among non-TP. Adjusting for age, race, alcohol use, smoking, and social determinants of health factors such as income, educational status, insurance status, and food insecurity, TP remained independently associated with higher odds of PMACE with an adjusted odd ratio of 1.66 (95%CI, 1.19 – 2.30); p=0.003, but this association was not statistically significant among non-TP females with aOR 1.32 (0.95 – 1.84); p=0.10. Conclusion: Teen pregnancy was associated with higher likelihood of PMACE. This association may be indicative of the enduring impact of social determinants of health factors associated with teen pregnancy into adulthood.

Abstract 4145822: The Enigma of Chest Pain: Rare Presentation of ALCAPA Syndrome in a Young Adult

Introduction: Anomalous Left Coronary Artery Arising from the Pulmonary Artery (ALCAPA), also known as Bland-White-Garland syndrome, is a rare congenital anomaly(incidence:1 in 300,000 live births) typically presenting during infancy. Adult presentations are even rarer due to a high mortality rate of nearly 90% in the first year of life without surgical intervention. This report examines an adult patient with exercise-induced chest pain who received a delayed diagnosis of ALCAPA via multimodal imaging. Case Summary: A 21-year-old male presented to the emergency department(ED) with severe retrosternal chest pain radiating to both shoulders and arms, which began during exercise 30 minutes prior. He had a history of similar, milder episodes during exercise, previously treated as musculoskeletal pain and gastroesophageal reflux disease in the ED. His medical, social, and family histories were unremarkable. Physical examination revealed a soft, continuous murmur along the left sternal border. During this visit, An EKG done showed sinus tachycardia at 110 bpm and deep T-wave inversions in the anterolateral leads, a dynamic ST-T changes from his baseline.Serial Cardiac biomarkers and a lipid profile were within normal ranges. Initially managed for acute coronary syndrome-unstable angina with antithrombotic therapy, beta-blockers, and nitrates, he underwent urgent coronary angiography. This revealed a dilated right coronary artery (RCA) with retrograde flow to the left coronary artery (LCA) into the main pulmonary artery (PA) via collaterals, with no evidence of atherosclerosis (Figure 1).Echocardiography (Figure 2) and coronary CT angiography (Figure 3) confirmed the diagnosis of ALCAPA. The patient underwent successful surgical repair with aortic reimplantation of the LCA and was discharged in good health. Discussion: In adult ALCAPA patients, good collateral circulation may develop; however, myocardial ischemia can occur due to the "coronary steal phenomenon" and poor collateral flow regulation, leading to angina, arrhythmias, and sudden cardiac death. ALCAPA should be considered a differential diagnosis in adults presenting with exercise intolerance, as most sudden cardiac death cases occur by the fourth decade. A high index of clinical suspicion and a multimodality imaging approach is essential for the early diagnosis of this rare coronary anomaly, underscoring the critical role of early surgical intervention in preventing catastrophic, life-threatening events.

Abstract 4134619: A Novel Missense Mutation in TNNT2 Gene in a Lebanese Pedigree With Ebstein Anomaly And Wolf-Parkinson-White Syndrome: A Case Report

Background: Ebstein anomaly (EA) is a rare congenital heart defect occurring in 1.2 to 5 in 100,000 live births, characterized by a downward displacement of the tricuspid valve, thin-walled right ventricle, and tricuspid valve regurgitation. It can present variably from asymptomatic cases to severe symptoms like arrhythmias and right-sided heart failure. EA is often associated with other anomalies such as interatrial communication and mitral valve prolapse. The condition can lead to accessory atrioventricular pathways, frequently resulting in Wolff-Parkinson-White syndrome (WPW), which involves abnormal heart electrical activity and increases the risk of sudden cardiac death. While the genetic basis of EA is not fully understood, it appears to involve multiple genes like FLNA and NKX2-5, MYH6, MYH7 suggesting a complex polygenic inheritance pattern. TNNT2 is known to be associated with Cardiomyopathy but has not been previously associated with EA and WPW. Case: In this report, we present findings from a lebanese family with EA, comprising 2 affected individuals. Whole exome sequencing in the affected individuals identified a pathogenic variant in the TNNT2 gene at coding strain position 260 (a missense mutation: C to T), resulting in the substitution of Proline with Leucine at position 87 in affected individuals (Figure 1). No variants were detected in any other candidate gene examined. Individuals I:1 and II:2 were found to be normal, with no EA findings on echocardiography. Methods: Whole exome sequencing in the patients involved collecting blood samples after obtaining consent. These samples were sent to Centogene lab, where genomic DNA is enzymatically fragmented. The regions of interest are then enriched using DNA capture probes, facilitating detailed genetic analysis. Results: The whole exome sequencing identified a heterozygous missense mutation in both the father and his daughter. This nonsynonymous variant is located on chromosome 1 (GRCh37) in the TNNT2 gene region. The specific variant, NM_001276345.1:c.260C&gt;T p.(Pro87Leu), was found in both individuals. Conclusion: In conclusion, the genetic basis of EA is rather complex and remains poorly understood. It is established that mutations in the TNNT2 gene are linked to several cardiomyopathies, none of them overlap with the described phenotype of our patients. In this report, we therefore confirm the potential role of TNNT2 gene mutation in the genetic basis of familial EA with WPW.

Abstract 4130622: Neonatal Outcomes of Hypertensive Women Across US Races: 2016-2022

Background: Maternal hypertension, a major pregnancy complication, can adversely affect newborn health. We aim to evaluate the racial and ethnic disparities in neonatal outcomes among hypertensive pregnant women in the United States. Methods: Using data from the CDC WONDER Natality database, we conducted a retrospective cohort study focusing on live births to hypertensive mothers from 2016 to 2022. Neonatal outcomes, including NICU admissions, low birth weight, infant mortality, and assisted ventilation, were analyzed by calculating rates [95% CIs] per 1000 live births across maternal racial/ethnic groups and the US Census Bureau's regional classification: Northeast, Midwest, South, and West. Results: We analyzed 2,336,679 live births to hypertensive women (23% pre-pregnancy; 77% gestational). This cohort comprised: 0.2% infants born to Native Hawaiian/other Pacific Islander women (NH/PI), 0.9% to American Indian/Alaska Native women (AI/AN), 3.8% to Asian American women (AA), 19.6% to Hispanic/Latino women (H/L), 20.0% to Black/African American women (BA), and 55.4% to White American women (WA). Infant mortality rates were highest in BA (3.6 [3.5, 3.8]), followed by AA (2.1 [1.8, 2.4]), AI/AN (2.1 [1.6, 2.7]), H/L (1.9 [1.8, 2.0]), NH/PI (1.9 [1.0, 3.3]), and lowest in WA (1.5 [1.4, 1.6]). Similarly, NICU admission rates were highest in BA (217.2 [216.1, 218.4]) and lowest in WA (156 [155.4, 156.6]). Assisted ventilation rates were highest in NH/PI (131.8 [123.4, 140.7]) and lowest in AA (87.8 [86.0, 89.7]). Low birth weight rates were highest in BA (235.1 [233.9, 236.3]) and lowest in WA (121.8 [121.2, 122.4]). The Midwest had the highest rates for NICU admissions in NH/PI (254.2 [217.2, 295.2]), assisted ventilation in AI/AN (143.8 [133.2, 155.1]), and mortality in BA (4.1 [3.7, 4.5]). The South had the highest rate of low birth weight for BA (244.4 [242.9, 246.0]). Conclusion: Significant racial and regional disparities exist in neonatal outcomes among hypertensive women in the US. BA mothers consistently experienced the poorest outcomes, while WA mothers had the best. Further research is crucial to understand the reasons behind these disparities and develop targeted interventions for high-risk populations.

Infant Mortality among the Tea Garden Workers in Upper Assam: Insights from a Field Survey

Infant mortality rate is an important indicator that reflects not only the health status of the infant but also the well-being of society as a whole. The north-eastern state of Assam is one of the states having the highest number of maternal and infant deaths within the country. For the first time, infant mortality in Assam registered a decline to 31.9 compared to the national average of 35.2 per 1,000 live births (NFHS-5). Though the overall rank of the state in terms of infant mortality has improved (from the 34th position to the 25th position), it is not enough and is not evenly distributed across the communities within the state. Human rights violations are particularly prominent among the tea garden workers of Assam and are mostly seen against the Adivasi children and woman, which is reflected by high maternal and infant deaths. The study aims to determine the factors responsible for infant mortality among tea garden workers by using primary data collected from 300 women workers across tea gardens in the Sonitpur and Tinsukia districts of Upper Assam. The binary logistic regression method is used for the analysis. It was observed that among the six probable factors, namely educational qualifications of the mother, marriage age of the mother, daily working hours, daily wage as tea garden labour, total number of births and the source of drinking water, the following three factors—namely the total number of births, age at marriage and the source of drinking water—are found to be the significant determinants of infant mortality among the tea garden labourers of Assam. JEL Codes: I12, I15

Abstract 4140108: A CRISPR-Activation CROP-seq Screen Identifies HMGN1 as a Dosage-Sensitive Regulator of Heart Defects in Down Syndrome

Introduction/Background: Congenital heart defects (CHD) are the most common form of developmental abnormalities, occurring in ~1% of live births, and can arise due to altered dosage of genes essential for cardiogenesis. Aneuploidy accounts for nearly 15% of CHD and the most frequent form involves trisomy of chromosome 21 (Ch21), resulting in Down Syndrome (DS). CHD is present in ~50% of DS cases, with a 1000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction of the atria and ventricles. Hypothesis: We hypothesize that the presence of a third copy of one or more genes on Ch21 underlies AVC and other cardiac defects; however, the dosage-sensitive CHD gene(s) on Ch21 causing this are not fully defined. Methods: We used human pluripotent stem cells derived from an individual mosaic for DS, allowing us to compare Ch21 trisomy cells with isogenic control cells disomic for Ch21. We performed single cell RNA-sequencing (scRNA-seq) to define the transcriptional dysregulation associated with DS in atrioventricular canal myocardial cells (AVCM). We then introduced a CRISPR-activation transgene to disomic cells and delivered small guide RNAs (sgRNAs) against 66 candidate Ch21 CHD genes. We developed a new machine learning algorithm to assign a trisomic score to CRISPR perturbed (CROP-seq) cells. Finally, we reduced the copy number of our top candidate gene in a mouse model of Down Syndrome and used microCT to assess incidence of cardiac septal defects. Results: Using human pluripotent stem cell and mouse models of DS, we identify HMGN1, a nucleosome-binding epigenetic factor on Ch21, as a dosage-sensitive regulator of cardiac defects in DS. Single cell transcriptomics revealed that human AVC cardiomyocytes shifted to a more ventricular myocardial state in trisomy 21 hiPS-derived cells. CRISPR-activation in isogenic disomic cells of 66 candidate Ch21 genes expressed in heart development, followed by single cell RNA-sequencing (CROP-seq) combined with machine learning predictions indicated that increased expression levels of HMGN1 altered the transcriptional state of atrioventricular cardiomyocytes similar to trisomy 21. Finally, reduction of Hmgn1 from three to two alleles in a mouse model of DS attenuated the incidence of cardiac septal defects. Conclusion: Our results identify HMGN1 as a dosage sensitive regulator of heart defects in DS and represent a generalizable approach for identifying candidate genes within areas of aneuploidy.

Progress in High Intensity Focused Ultrasound Ablation for Fertility Preservation Therapy of Uterine Fibroids and Adenomyosis.

High intensity focused ultrasound (HIFU) is an effective and safe non-invasive treatment method, widely used in the treatment of uterine fibroids and adenomyosis in the field of gynecology. The side effects in HIFU is low in incidence and mild. HIFU can significantly alleviate the symptoms of patients, reduce lesion volumes, improve quality of life, and has good cost-effectiveness. HIFU can accurately ablate the uterine fibroids and adenomyosis lesions, without destroying normal myometrium and endometrium, and thus HIFU is a promising alternative to myomectomy in uterine fibroids patients with fertility desire. Several studies have shown that in terms of ovarian endocrine function protection, HIFU treatment is superior to uterine artery embolization, and similar to myomectomy. Existing limited researches show that patients with uterine fibroids have a favorable pregnancy rate and live birth rate, as well as a lower natural abortion rate after HIFU treatment. Pregnancy rate after HIFU treatment for uterine fibroids is not lower than myomectomy, and higher than uterine artery embolization. HIFU may have significant advantages in shortening pregnancy interval compared with myomectomy. However, the proportion of cesarean section delivery after HIFU treatment is relatively high, and gestational uterine rupture after HIFU treatment exist in literature. Higher quality clinical data is needed to confirm the pregnancy outcomes and safety after HIFU treatment in future.

Raloxifene Protects Oxygen-Glucose-Deprived Astrocyte Cells Used to Mimic Hypoxic-Ischemic Brain Injury

Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5–10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen–glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O2 for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival—65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen–glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen–glucose-deprived astrocyte cells, used to mimic hypoxic–ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion.

Incidence and risk factors of congenital heart disease in Qingdao

Objective: To analyze the incidence and risk factors of congenital heart disease (CHD) in Qingdao. Methods: A prospective study was adapted, and study participants were pregnant women who underwent prenatal screening in Qingdao from August 2018 to June 2020 and their offspring (the whole population coverage). CHD in neonates was screened by using the pulse oximetry saturation and heart auscultation, and the final diagnosis was determined by the result of echocardiography. Multivariable logistic regression was performed to analyze the risk factors of CHD. Results: The study included 115 238 live births, among which 709 were diagnosed with CHD, with an incidence of 6.15/1 000. Ventricular septal defect, atrial septal defect, as well as ventricular septal defect and atrial septal defect were the main CHD subtypes, with incidences of 2.97/1 000 (342/115 238), 1.01/1 000 (116/115 238), and 0.39/1 000 (45/115 238), respectively, comprising 48.2% (342/709), 16.4% (116/709), and 6.3% (45/709) of the CHD cases. The results of multivariable logistic regression showed that the offspring of women with a graduate degree (compared to junior high school or below) (OR=1.66, 95%CI: 1.15-2.40), pregnancy history of CHD (OR=9.50, 95%CI: 5.37-16.81), pregestational diabetes mellitus (OR=3.40, 95%CI: 1.58-7.32) had a higher risk of having CHD, whereas the offspring of multiparous women was associated with a lower risk of CHD (OR=0.84, 95%CI: 0.71-0.99). In addition, compared with male newborns, female newborns have a higher risk of having CHD (OR=1.18, 95%CI: 1.01-1.39). Conclusions: The incidence of CHD in Qingdao is 6.15/1 000, with ventricular septal defect, atrial septal defect, as well as ventricular septal defect and atrial septal defect being the main subtypes. Maternal education, parity, pregnancy history of CHD, pregestational diabetes mellitus, and offspring gender are associated with CHD occurrence.