Acute Fetal Metabolomic Changes in Twins Undergoing Fetoscopic Surgery for Twin-Twin Transfusion Syndrome.

Fetuses undergo major surgical stress as well as fluid shifts secondary to both twin-twin transfusion (TTTS) as well as the fetoscopic surgery for treatment of TTTS. While the pathophysiology of TTTS is understood, the acute metabolic changes that fetuses experience from fetoscopic surgery are not. We sought to evaluate the changes in recipient metabolomic profile secondary to TTTS surgery. Amniotic fluid was collected at the beginning and end of four TTTS surgical cases performed from 12/2022-2/2023. Samples were immediately processed and evaluated via NMR-based Metabolomics Facility protocol. In univariate analysis, 12 metabolites (glucose, lactate, and 10 key amino acids) showed statistically significant changes between the beginning and end of the surgery. Among these, 11 metabolites decreased at the end, while only lactate increased. Supervised oPLS-DA modeling revealed pyruvate and lactate as the two metabolites most impact on the variance between cases, and that 40% of metabolomic changes could be attributed directly to the timing that the sample was taken (i.e., if pre- or postoperatively). These results indicate significant metabolic changes in the recipient twin during fetoscopic surgery for TTTS. These findings of decreased glucose, increased lactate, and decreased amnio acids would indicate increased catabolism during surgery. This study raises questions regarding optimal maternal and fetal nutrition during surgery and if nutritional status could be optimized to further improve twin survival during fetoscopic surgery.

Association of amnioinfusion volume at the time of surgery for twin-twin transfusion syndrome and latency to delivery.

OBJECTIVE: To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP). METHODS: Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (<1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency. RESULTS: Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion <1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) <34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery <32 weeks (aRR 2.6, 95% CI 1.5-4.5), 30 weeks (aRR 2.4, 95% CI 1.5-3.8), and 28 weeks (aRR 1.9, 95% CI 1.1-2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1-1.2). CONCLUSION: Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM <34 weeks.

Twin-twin transfusion syndrome recipient with arterial calcification and heterozygous variant in ABCC6: Evidence of a gene-environment interaction?

We report a case of a twin-twin transfusion syndrome (TTTS) recipient who, after successful fetoscopic surgery, developed a large pericardial effusion and calcifications of the aorta and main pulmonary artery. The donor fetus never had cardiac strain and never developed cardiac calcifications. A heterozygous likely pathogenic variant in ABCC6 (c.2018T > C, p.Leu673Pro) was identified in the recipient twin. While TTTS recipient twins are at risk of arterial calcifications and right heart failure secondary to the disease, calcifications of the great vessels are also observed in generalized arterial calcification of infancy, a Mendelian genetic disorder with associated biallelic pathogenic variations in ABCC6 or ENPP1, which can result in significant pediatric morbidity or mortality. The recipient twin in this case had some degree of cardiac strain prior to TTTS surgery; however, the progressive calcification of the aorta and pulmonary trunk occurred weeks after TTTS resolution. This case raises the possibility of a gene-environment interaction and emphasizes the need for genetic evaluation in the setting of TTTS and calcifications.

Creation of a novel synthetic amniotic fluid for use in fetal therapy with in vitro testing on human amniotic membranes.

BACKGROUND: Normal saline or lactated Ringer's solutions are usually infused at the time of fetal interventions; however, the effect of these fluids on the amniotic membranes has never been assessed. Given both the significant differences between the composition of normal saline solution, lactated Ringer's solution, and amniotic fluid and the significant risk of prematurity after fetal interventions, an investigation is warranted. OBJECTIVE: This study aimed to evaluate the effect of current amnioinfusion fluids on the human amnion compared with a novel synthetic amniotic fluid. STUDY DESIGN: Amniotic epithelial cells from term placentas were isolated and cultured per protocol. A synthetic amniotic fluid was created with similar electrolyte, pH, albumin, and glucose concentrations to human amniotic fluid, termed "Amnio-well." The cultured human amniotic epithelium was exposed to normal saline solution, lactated Ringer's solution, and Amnio-well. As a control, 1 group of cells remained in culture media. Cells were evaluated for apoptosis and necrosis. A second analysis to examine if cells could be "rescued" was performed, wherein the cells were allowed to remain in the culture media for an additional 48 hours after amnioinfusion. Subsequently, tissue testing with human amniotic membrane explants was evaluated similarly. Immunofluorescent intensity studies were undertaken to evaluate reactive oxygen species-mediated cell damage. Real-time quantitative polymerase chain reaction was used to evaluate gene expression in apoptotic pathways. RESULTS: With simulated amnioinfusion, 44%, 52%, and 89% of amniotic epithelial cells were alive after exposure to normal saline solution, lactated Ringer's solution, and Amnio-well, respectively, compared with 85% in control (P<.001). After amnioinfusion and attempted cell rescue, 21%, 44%, 94%, and 88% of cells were alive after exposure to normal saline solution, lactated Ringer's solution, Amnio-well, and control, respectively (P<.001). In simulated amnioinfusion with full-thickness tissue explants, 68%, 80%, 93%, and 96% of cells were viable in normal saline solution, lactated Ringer's solution, Amnio-well, and control, respectively (P<.001). In culture, reactive oxygen species production was higher in normal saline solution, lactated Ringer's solution, and Amnio-well than in control (4.9-, 6.6-, and 1.8-fold higher, respectively, P<.001); however, this could be mitigated in Amnio-well by adding ulin-A-statin and ascorbic acid. Gene expression data revealed abnormal signaling in the p21 and BCL2/BAX pathways with normal saline solution compared with control (P=.006 and P=.041); changes were not seen with Amnio-well. CONCLUSION: In vitro, normal saline and lactated Ringer's solutions caused increased amniotic membrane reactive oxygen species and cell death. The use of a novel fluid similar to human amniotic fluid led to the normalization of cellular signaling and less cell death.

Influence of the COVID-19 pandemic on social determinants of health among an inner-city obstetrical population.

BACKGROUND: Social determinants of health are a well-described influencer of pregnancy-related morbidity and mortality. It is unclear how societal changes secondary to the COVID-19 pandemic altered the social determinants of health among pregnant patients. OBJECTIVE: This study aimed to investigate differences in the social determinants of health among patients who experienced pregnancy before and during the COVID-19 pandemic. STUDY DESIGN: This was a secondary analysis of an ongoing prospective cohort study examining the social determinants of health in postpartum patients at a single inner-city academic medical center. The planned secondary analysis was to compare the social determinants of health between patients that experienced societal changes before the pandemic and patients that experienced societal changes during the pandemic. Patients were included in the pandemic group if they delivered on or after March 30, 2020; moreover, patients in the pandemic group were compared with those who delivered before March 30, 2020 (referent group). Medical records were used to collect sociodemographic, pregnancy, and infant outcome data. The study participants were interviewed to collect detailed information regarding their perceived social, emotional, and physical environment as indicators of social determinants of health. Generalized linear modeling estimated the influence of social determinants of health  on births during the COVID-19 pandemic. RESULTS: Overall, 577 patients were enrolled in the study, of which 452 (78%) delivered before the COVID-19 pandemic and 125 (22%) delivered during the pandemic. Patients who delivered during the pandemic were more likely to report limited social or emotional support (relative risk, 1.62; 95% confidence interval, 1.02-2.59) and higher race-based discrimination (relative risk, 1.59; 95% confidence interval, 1.00-2.53). Mothers in the prepandemic group were more likely to have used federally funded programs, such as Medicaid, food stamps, and the Special Supplemental Nutrition Program for Women, Infants, and Children, during their pregnancy. Furthermore, the referent group reported more limited access to transportation. In addition, mothers in the prepandemic group were more likely to initiate prenatal care at a later gestational age and have fewer total prenatal care visits. CONCLUSION: The COVID-19 pandemic created unprecedented changes in pregnancy care, and these were reflected in social determinants of health. It is imperative that we focus on the social determinants of health that were mitigated during this time and their effects on maternal and infant health.

Comparison of Pregnancy Outcomes of Previable and Periviable Rupture of Membranes After Laser Photocoagulation for Twin-Twin Transfusion Syndrome.

OBJECTIVE: To describe the pregnancy outcomes of patients who experienced previable and periviable prelabor rupture of membranes (PROM) after the treatment of twin-twin transfusion syndrome. METHODS: We conducted a retrospective cohort study of patients whose pregnancies were complicated by twin-twin transfusion syndrome who were treated with fetoscopic laser photocoagulation at a single fetal center and subsequently experienced PROM from April 2010 to June 2019. Outcomes were infant survival and latency from PROM to delivery. Patients were grouped by gestational age at PROM (before 26 weeks of gestation and 26 weeks or later). The group with PROM before 26 weeks of gestation was stratified by gestational age at PROM for further description of outcomes. RESULTS: Two-hundred fifty of 653 patients (38%) developed PROM, 81 before 26 weeks of gestation and 169 after 26 weeks of gestation. In the setting of PROM before 26 weeks of gestation, the rate of survival of both twins to neonatal intensive care unit (NICU) discharge was 46.3%, compared with 76.9% in the setting of PROM at 26 weeks of gestation or later ( P <.001); the survival rate of at least one twin was 61.2% and 98.5%, respectively ( P <.001). Fourteen, 22, and 45 patients experienced PROM at 16-19 6/7, 20-22 6/7, and 23-25 6/7 weeks of gestation, respectively. Survival of both twins and at least one twin to NICU discharge was 25.0%, 47.4%, 52.8% (for two) and 33.3%, 47.4%, and 77.8% (for at least one), respectively, among those groups. Fifty-seven of the 81 patients with PROM before 26 weeks of gestation experienced a latency longer than 48 hours. In the setting of PROM before 26 weeks of gestation, when latency lasted longer than 48 hours, overall survival was improved (69.6% vs 53.7%, respectively, P =.017). With latency longer than 48 hours and PROM at 16-19 6/7, 20-22 6/7, and 23-25 6/7 weeks of gestation, survival of both twins to NICU discharge was 60.0%, 61.5%, and 60.7%, respectively, and survival of at least one twin was 80.0%, 61.5%, and 85.7%, respectively. CONCLUSION: Earlier gestational age at PROM after laser photocoagulation is associated with longer latency but lower rates of survival. When PROM occurs before 26 weeks of gestation and latency exceeds 48 hours, rates of neonatal survival are significantly improved.

Association between mode of delivery and infant survival at 22 and 23 weeks of gestation.

BACKGROUND: Cesarean delivery is currently not recommended before 23 weeks' gestation unless for maternal indications, even in the setting of malpresentation. These recommendations are based on a lack of evidence of improved neonatal outcomes and survival following cesarean delivery and the maternal risks associated with cesarean delivery at this early gestational age. However, as neonatal resuscitative measures and obstetrical interventions improve, studies evaluating the potential neonatal benefit of periviable cesarean delivery have reported inconsistent findings. OBJECTIVE: This study aimed to compare the survival rates at 1 year of life among resuscitated infants delivered by cesarean delivery with those delivered vaginally at 22 and 23 weeks of gestation. STUDY DESIGN: We conducted a population-based cohort study of all resuscitated livebirths delivered between 22 0/7 and 23 6/7 weeks of gestational age in the United States between 2007 and 2013. The primary outcome was the rate of infant survival at 1 year of life for different routes of delivery (cesarean vs vaginal delivery) at both 22 and 23 weeks of gestation. The secondary outcome variables included infant survival rates for neonates who survived beyond 24 hours of life, neonatal survival, and the length of survival. A secondary analysis also included a comparison of the infant survival rates between the different routes of delivery cohorts stratified by fetal presentation, steroid exposure, and ventilation. Information about composite adverse maternal outcomes were limited to infants who were delivered between 2011 and 2013 (when these items were first reported) and were defined as a requirement for blood transfusion, an unplanned operating room procedure following delivery, unplanned hysterectomy, and intensive care unit admission; the composite adverse maternal outcomes were also compared between the different delivery route cohorts for deliveries occurring between 22 and 23 weeks of gestation. Multivariable logistic regression analysis was used to determine the association between cesarean delivery and infant survival and other neonatal and maternal outcomes. RESULTS: Resuscitated infants delivered by cesarean delivery had higher rates of survival at 22 weeks (44.9 vs 23.0%; P<.001) and at 23 weeks (53.3 vs 43.4%; P<.001) of gestation regardless of fetal presentation. Multivariable logistic regression analysis demonstrated that infants who were delivered by cesarean delivery at 22 weeks (adjusted relative risk, 2.3; 95% confidence interval, 1.9-2.8) and 23 weeks (adjusted relative risk, 1.4; 95% confidence interval, 1.2-1.5) of gestation were more likely to survive than those delivered vaginally. When the cohort was limited to neonates who survived beyond the first 24 hours of life, vertex neonates born by cesarean delivery were not more likely to survive at 22 weeks (adjusted relative risk, 1.2; 95% confidence interval, 0.9-1.7) or 23 weeks (adjusted relative risk, 1.1; 95% confidence interval, 0.9-1.3) of gestation. An increased risk for composite adverse maternal outcomes (adjusted relative risk, 1.7; 95% confidence interval, 1.1-2.7) was associated with cesarean delivery at 22 to 23 weeks of gestation. CONCLUSION: Cesarean delivery is associated with increased survival at 1 year of life among resuscitated, periviable infants born between 22 0/7 and 23 6/7 weeks of gestation, especially in the setting of nonvertex presentation. However, cesarean delivery is associated with increased maternal morbidity.

Unique Considerations: Preterm Prelabor Rupture of Membranes in the Setting of Fetal Surgery and Higher Order Pregnancies.

Two unique aspects of antenatal care occur in the setting of fetal surgery and multiple gestations. As fetal interventions increase, so do the number of cases of iatrogenic preterm prelabor rupture of membranes (PPROM). Because of the amniotic sac's inability to heal, the risk of PPROM after surgery is directly correlated with the number of interventions, the size of the defect, and the surgery performed. Higher order gestations also carry an increased risk of PPROM. This paper reviews the risks and management of PPROM in the setting of the various prenatal interventions as well as in the setting of multiple gestations.

Association of Prior Cesarean Delivery With Early Term Delivery and Neonatal Morbidity.

OBJECTIVE: To assess whether a history of prior cesarean delivery is associated with an increased risk of earlier delivery timing and resultant neonatal morbidity. METHODS: We performed a population-based retrospective cohort study using U.S. birth certificate data, 2012-2016. The study population included women with one or more prior cesarean deliveries compared with a referent group of parous women without prior cesarean delivery. To enrich for a population with minimized risk factors for early delivery, we excluded women with history of preterm birth, pregnancies complicated by multifetal gestation, pregnancy-induced hypertension, anomaly, small for gestational age, or malpresentation. Analyses were limited to births from 35 to 42 weeks of gestation. Women with a vaginal birth after cesarean delivery were excluded. The primary outcome was the risk of birth at each week of gestational age. Secondary outcomes included adverse neonatal and maternal outcomes. RESULTS: Patients were stratified by number of prior cesarean deliveries (one, two, three, or four or more) compared with parous patients without prior cesarean delivery. The adjusted relative risk (aRR) of delivery at 35 weeks of gestation was highest in women with four or more prior cesarean deliveries (aRR 2.79, 95% CI 2.74-2.82). Prior cesarean delivery also had a significant influence on neonatal morbidity. As the number of prior cesarean deliveries increased, the risk of composite neonatal morbidity increased, from 8.0% (aRR 1.5, 95% CI 1.48-1.51) with one prior cesarean delivery up to 21.0% (aRR 4.9, 95% CI 4.76-5.04) with four or more prior cesarean deliveries compared with a baseline risk of 5.5% in parous women without prior cesarean delivery. CONCLUSION: Prior cesarean delivery is correlated with earlier delivery and increased neonatal morbidity. Advocating trial of labor after cesarean delivery may provide maternal and neonatal benefit.

Restoring femoral offset is the most important technical factor in preventing total hip arthroplasty dislocation.

PURPOSE: Our aim was to determine if acetabular component position, femoral offset restoration, or leg-length equality is most important for total hip arthroplasty (THA) stability. METHODS: A matched case (n = 67)-control (n = 247) design and conditional logistic regression model were used to examine risk factors for dislocation in primary THA. RESULTS: When femoral offset was at least 3 mm greater than that of the contralateral hip, risk of dislocation was lower (p = 0.0192). Neither leg-length difference nor acetabular component abduction or version angle was associated with dislocation. CONCLUSIONS: Our data suggest restoring femoral offset is the most important technical factor in preventing THA dislocation.

A streamlined protocol for the use of the semi-sitting position in neurosurgery: a report on 48 consecutive procedures.

The semi-sitting position has lost favor among neurosurgeons partly due to unproven assumptions of increased complications. Many complications have been associated with this position; the most feared: venous air embolism and paradoxical air embolism. We report on this retrospective study of the outcome over 4 years of 48 neurosurgical patients operated on consecutively using a standardized protocol: 41 (85%) in the semi-sitting position, and seven (15%) in the prone position. Procedures included: tumor resection (34), posterior fossa decompression (12), cyst resection (1) and resection of arteriovenous malformation (1). Pre-operative workup was standardized. Vigilant intra-operative observation was done by an experienced neuroanesthetist. Pertinent data was extracted from surgical records. Of the 48 patients, 10 (20.8%) were found to have a patent foramen ovale (PFO) on trans-esophageal echocardiography. Of these, four (40%) patients underwent procedures in the semi-sitting position while six (60%) did not. A clinically significant venous air embolism (VAE) was detected during 2 of the 41 semi-sitting procedures (4.9%). Neither patient suffered any obvious sequelae. No other morbidity was encountered associated with surgical position. Our study suggests that a model similar to ours is effective in preventing major complications associated with the semi-sitting position. The semi-sitting position is a safe, practical position that should be considered in appropriate cases. The fear of dreadful complications seems unwarranted.

Atypical E2F repressors and activators coordinate placental development.

The evolutionarily ancient arm of the E2f family of transcription factors consisting of the two atypical members E2f7 and E2f8 is essential for murine embryonic development. However, the critical tissues, cellular processes, and molecular pathways regulated by these two factors remain unknown. Using a series of fetal and placental lineage-specific cre mice, we show that E2F7/E2F8 functions in extraembryonic trophoblast lineages are both necessary and sufficient to carry fetuses to term. Expression profiling and biochemical approaches exposed the canonical E2F3a activator as a key family member that antagonizes E2F7/E2F8 functions. Remarkably, the concomitant loss of E2f3a normalized placental gene expression programs, corrected placental defects, and fostered the survival of E2f7/E2f8-deficient embryos to birth. In summary, we identified a placental transcriptional network tightly coordinated by activation and repression through two distinct arms of the E2F family that is essential for extraembryonic cell proliferation, placental development, and fetal viability.