Factors Associated with Hospital Readmission One Year Post-Discharge in Infants with Gastroschisis.

INTRODUCTION: Gastroschisis is the most common congenital abdominal wall defect with a rising prevalence. Infants with gastroschisis are at risk for multiple complications, leading to a potential increased risk for hospital readmission after discharge. We aimed to find the frequency and factors associated with an increased risk of readmission. METHODS: A retrospective analysis of infants born with gastroschisis between 2013 and 2019 who received initial surgical intervention and follow-up care in the Children's Wisconsin health system was performed. The primary outcome was the frequency of hospital readmission within 1 year of discharge. We also compared maternal and infant clinical and demographic variables between those readmitted for reasons related to gastroschisis, and those readmitted for other reasons or not readmitted. RESULTS: Forty of 90 (44%) infants born with gastroschisis were readmitted within 1-year of the initial discharge date, with 33 (37%) of the 90 infants being readmitted due to reasons directly related to gastroschisis. The presence of a feeding tube (p < 0.0001), a central line at discharge (p = 0.007), complex gastroschisis (p = 0.045), conjugated hyperbilirubinemia (p = 0.035), and the number of operations during the initial hospitalization (p = 0.044) were associated with readmission. Maternal race/ethnicity was the only maternal variable associated with readmission, with Black race being less likely to be readmitted (p = 0.003). Those who were readmitted were also more likely to be seen in outpatient clinics and utilize emergency healthcare resources. There was no statistically significant difference in readmission based on socioeconomic factors (all p > 0.084). CONCLUSION: Infants with gastroschisis have a high hospital readmission rate, which is associated with a variety of risk factors including complex gastroschisis, multiple operations, and the presence of a feeding tube or central line at discharge. Improved awareness of these risk factors may help stratify patients in need of increased parental counseling and additional follow-up.

Abdominal Wall Defects: A Review of Current Practice Guidelines.

The 2 most common congenital abdominal wall defects are gastroschisis and omphalocele. Gastroschisis is a defect in the abdominal wall with exposed abdominal contents. Mortality rates are low but lengths of stay are often prolonged by bowel dysmotility and other intestinal abnormalities in complicated cases. Omphalocele is a defect through the umbilical cord with herniated abdominal contents covered by a sac. It is associated with other genetic abnormalities and other anomalies that can lead to significant morbidity and mortality. Prenatal diagnosis in both conditions allows for improved prenatal consultation and coordinated perinatal care to improve clinical outcomes.

Controversies in Fetal Surgery: Prenatal Repair of Myelomeningocele in the Modern Era.

Fetal surgery is a constantly evolving field that showed noticeable progress with the treatment of myelomeningocele (MMC) using prenatal repair. Despite this success, there are ongoing questions regarding the optimal approach for fetal myelomeningocele repair, as well as which patients are eligible. Expansion of the inclusion and exclusion criteria is an important ongoing area of study for myelomeningocele including the recent Management of Myelomeningocele Plus trial. The significant personal and financial burden required of families seeking treatment has likely limited its accessibility to the general population.

Placental Location in Maternal-Fetal Surgery for Myelomeningocele.

INTRODUCTION: Uterine incision based on the placental location in open maternal-fetal surgery (OMFS) has never been evaluated in regard to maternal or fetal outcomes. OBJECTIVE: The aim of this study was to investigate whether an anterior placenta was associated with increased rates of intraoperative, perioperative, antepartum, obstetric, or neonatal complications in mothers and babies who underwent OMFS for fetal myelomeningocele (fMMC) closure. METHODS: Data from the international multicenter prospective registry of patients who underwent OMFS for fMMC closure (fMMC Consortium Registry, December 15, 2010-June 31, 2019) was used to compare fetal and maternal outcomes between anterior and posterior placental locations. RESULTS: The placental location for 623 patients was evenly distributed between anterior (51%) and posterior (49%) locations. Intraoperative fetal bradycardia (8.3% vs. 3.0%, p = 0.005) and performance of fetal resuscitation (3.6% vs. 1.0%, p = 0.034) occurred more frequently in cases with an anterior placenta when compared to those with a posterior placenta. Obstetric outcomes including membrane separation, placental abruption, and spontaneous rupture of membranes were not different among the 2 groups. However, thinning of the hysterotomy site (27.7% vs. 17.7%, p = 0.008) occurred more frequently in cases of an anterior placenta. Gestational age (GA) at delivery (p = 0.583) and length of stay in the neonatal intensive care unit (p = 0.655) were similar between the 2 groups. Fetal incision dehiscence and wound revision were not significantly different between groups. Critical clinical outcomes including fetal demise, perinatal death, and neonatal death were all infrequent occurrences and not associated with the placental location. CONCLUSIONS: An anterior placental location is associated with increased risk of intraoperative fetal resuscitation and increased thinning at the hysterotomy closure site. Individual institutional experiences may have varied, but the aggregate data from the fMMC Consortium did not show a significant impact on the GA at delivery or maternal or fetal clinical outcomes.

Insights from barium variability in a Siderastrea siderea coral in the northwestern Gulf of Mexico.

Coral Ba/Ca is a proxy for seawater barium concentration that varies with upwelling, terrigenous input, and marine productivity whereas coral Sr/Ca varies with temperature. We examine monthly coral Ba/Ca and Sr/Ca before and during offshore oil exploration in a Siderastrea siderea coral from West Flower Garden Bank located on the continental shelf edge in the Gulf of Mexico. Coral Ba/Ca variations lack pulses driven by upwelling or river outflow and are not in sync with coral Sr/Ca that exhibit a different seasonal pattern. Seasonal variations in chlorophyll-a concentration negatively correlate with coral Ba/Ca explaining 25% of that variability. A significant increase in mean coral Ba/Ca of 1.76 µmol/mol between 1931-1944 and 1976-2004 corresponds to the increase in the United States barite production and consumption primarily used in offshore oil drilling, which escalated in the 1970s, suggesting oil drilling operations are increasing seawater Ba concentration in the Gulf of Mexico.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Abdominal wall defects.

Abdominal wall defects are common congenital anomalies with the most frequent being gastroschisis and omphalocele. Though both are the result of errors during embryologic development of the fetal abdominal wall, gastroschisis and omphalocele represent unique disorders that have different clinical sequelae. Gastroschisis is generally a solitary anomaly with postnatal outcomes related to the underlying integrity of the prolapsed bowel. In contrast, omphalocele is frequently associated with other structural anomalies or genetic syndromes that contribute more to postnatal outcomes than the omphalocele defect itself. Despite their embryological differences, both gastroschisis and omphalocele represent anomalies of fetal development that benefit from multidisciplinary and translational approaches to care, both pre- and postnatally. While definitive management of abdominal wall defects currently remains in the postnatal realm, advancements in prenatal diagnostics and therapies may one day change that. This review focuses on recent advancements, novel techniques, and current controversies related to the prenatal diagnosis and management of gastroschisis and omphalocele.

Risk factors for perioperative hypothermia and infectious outcomes in gastroschisis patients.

INTRODUCTION: Prior data suggest that infants with gastroschisis are at high risk for hypothermia and infectious complications (ICs). This study evaluated the associations between perioperative hypothermia (PH) and ICs in gastroschisis using a multi-institutional cohort. METHODS: Retrospective review of infants with gastroschisis who underwent abdominal closure from 2013-2017 was performed at 7 children's hospitals. Any-IC and surgical site infection (SSI) were stratified against the presence or absence of PH, and perioperative characteristics associated with PH and SSI were determined using multivariable logistic regression. RESULTS: Of 256 gastroschisis neonates, 42% developed PH, with 18% classified as mild hypothermia (35.5-35.9 °C), 10.5% as moderate (35.0-35.4 °C), and 13% severe (<35 °C). There were 82 (32%) ICs with 50 (19.5%) being SSIs. No associations between PH and any-IC (p = 0.7) or SSI (p = 0.98) were found. Pulmonary comorbidities (odds ratio (OR)=3.76, 95%CI:1.42-10, p = 0.008) and primary closure (OR=0.21, 95%CI:0.12-0.39, p<0.001) were associated with PH, while silo placement (OR=2.62, 95%CI:1.1-6.3, p = 0.03) and prosthetic patch (OR=3.42, 95%CI:1.4-8.3, p = 0.007) were associated with SSI on multivariable logistic regression. CONCLUSIONS: Primary abdominal closure and pulmonary comorbidities are associated with PH in gastroschisis, however PH was not associated with increased risk of ICs. Independent risk factors for SSI include silo placement and prosthetic patch closure.

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10-6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10-3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Comparative outcomes of right versus left congenital diaphragmatic hernia: A multicenter analysis.

BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs in 1 out of 2500-3000 live births. Right-sided CDHs (R-CDHs) comprise 25% of all CDH cases, and data are conflicting on outcomes of these patients. The aim of our study was to compare outcomes in patients with right versus left CDH (L-CDH). METHODS: We analyzed a multicenter prospectively enrolled database to compare baseline characteristics and outcomes of neonates enrolled from January 2005 to January 2019 with R-CDH vs. L-CDH. RESULTS: A total of 588, 495 L-CDH, and 93 R-CDH patients with CDH were analyzed. L-CDHs were more frequently diagnosed prenatally (p=0.011). Lung-to-head ratio was similar in both cohorts. R-CDHs had a lower frequency of primary repair (p=0.022) and a higher frequency of need for oxygen at discharge (p=0.013). However, in a multivariate analysis, need for oxygen at discharge was no longer significantly different. There were no differences in long-term neurodevelopmental outcomes assessed at two year follow up. There was no difference in mortality, need for ECMO, pulmonary hypertension, or hernia recurrence. CONCLUSION: In this large series comparing R to L-CDH patients, we found no significant difference in mortality, use of ECMO, or pulmonary complications. Our study supports prior studies that R-CDHs are relatively larger and more often require a patch or muscle flap for repair. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level II.

Ex utero intrapartum treatment (EXIT) procedures.

Ex Utero Intrapartum Treatment (EXIT) is a technique developed to safely and efficiently establish cardiopulmonary support at delivery while maintaining placental bypass. Indications for the EXIT approach are expanding and currently include EXIT-to-airway, EXIT-to-resection, EXIT-to-extracorporeal membrane oxygenation (ECMO), and EXIT-to-separation of conjoined twins. The EXIT technique involves planned partial delivery of the fetus via hysterotomy while maintaining uterine relaxation and placental support, allowing for the establishment of neonatal cardiopulmonary stability in a controlled manner. Fetal interventions performed during EXIT can include endotracheal intubation, tracheostomy, mass excision, removal of a temporary tracheal occlusive device, ECMO cannulation, and others. The most important aspect of an EXIT procedure is the formation of a multi-disciplinary team with broad expertise in fetal intervention to collaborate throughout the pre, intra, and post-partum periods. This chapter reviews the prenatal workup, decision making, surgical indications, and operative considerations associated with EXIT procedures.

Subsequent pregnancy outcomes after open maternal-fetal surgery for myelomeningocele.

BACKGROUND: Open maternal-fetal surgery for fetal myelomeningocele results in reduction in neonatal morbidity related to spina bifida but may be associated with fetal, neonatal, and maternal complications in subsequent pregnancies. OBJECTIVE: The objective of this study was to ascertain obstetric risk in subsequent pregnancies after open maternal-fetal surgery for fetal myelomeningocele closure. STUDY DESIGN: An international multicenter prospective observational registry created to track and report maternal, obstetric, fetal/neonatal, and subsequent pregnancy outcomes following open maternal-fetal surgery for fetal myelomeningocele was evaluated for subsequent pregnancy outcome variables. Institutional Review Board approval was obtained for the registry. RESULTS: From 693 cases of open maternal-fetal surgery for fetal myelomeningocele closure entered into the registry, 77 subsequent pregnancies in 60 women were identified. The overall live birth rate was 96.2%, with 52 pregnancies delivering beyond 20 weeks gestational age and median gestational age at delivery of 37 (36.3-37.1) weeks. The uterine rupture rate was 9.6% (n = 5), resulting in 2 fetal deaths. Maternal transfusion was required in 4 patients (7.7%). CONCLUSION: The risk of uterine rupture or dehiscence in subsequent pregnancies with associated fetal morbidity after open maternal-fetal surgery is significant, but is similar to that reported for subsequent pregnancies after classical cesarean deliveries. Future pregnancy considerations should be included in initial counseling for women contemplating open maternal-fetal surgery.

National Practice Patterns for Prenatal Monitoring in Gastroschisis: Gastroschisis Outcomes of Delivery (GOOD) Provider Survey.

BACKGROUND: Gastroschisis is an abdominal wall defect with increasing incidence. Given the lack of surveillance guidelines among maternal-fetal medicine (MFM) specialists, this study describes current practices in gastroschisis management. MATERIALS AND METHODS: An online survey was administered to MFM specialists from institutions affiliated with the North American Fetal Therapy Network (NAFTNet). Questions focused on surveillance timing, testing, findings that changed clinical management, and delivery plan. RESULTS: Responses were obtained from 29/29 (100%) NAFTNet centers, comprising 143/371 (39%) providers. The majority had a regimen for antenatal surveillance in patients with stable gastroschisis (94%; 134/141). Antenatal testing began at 32 weeks for 68% (89/131) of MFM specialists. The nonstress test (55%; 72/129), biophysical profile (50%; 63/126), and amniotic fluid index (64%; 84/131) were used weekly. Estimated fetal weight (EFW) was performed monthly by 79% (103/131) of providers. At 28 weeks, abnormal EFW (77%; 97/126) and Doppler ultrasound (78%; 99/127) most frequently altered management. In stable gastroschisis, 43% (60/140) of providers delivered at 37 weeks, and 29% (40/ 140) at 39 weeks. DISCUSSION: Gastroschisis management differs among NAFTNet centers, although the majority initiate surveillance at 32 weeks. Timing of delivery still requires consensus. Prospective studies are necessary to further optimize practice guidelines and patient care.

De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

Meconium-stained amniotic fluid as a predictor of poor outcomes in gastroschisis.

OBJECTIVE: The aim of this study was to determine if meconium-stained amniotic fluid (MSAF) was associated with neonatal outcomes in gastroschisis. STUDY DESIGN: A retrospective chart review of gastroschisis patients from 2000 to 2014 at a single, tertiary institution was performed. Statistical analysis was performed with Fisher exact test, Welch's t-test, logistic regression and/or linear regression with significance at p < 0.05. RESULTS: Sixty-four of 135 (47.4%) gastroschisis patients had MSAF. On univariate analysis, patients with MSAF were more likely to require staged closure (30 (46.9%) vs. 18(25.4%), p = 0.012), had more ventilator days (8.9 ±â€¯11.1 vs. 5.3 ±â€¯6.3, p = 0.021) and longer times to commence enteral feeds (24.9 ±â€¯21.7 vs. 18.5 ±â€¯14.5, p = 0.045). However, multi-variate regression analysis controlling for the type of closure, showed that delayed closure, but not MSAF, was associated with worse outcomes. CONCLUSIONS: In gastroschisis patients, MSAF is associated with delayed closure but is not associated with outcomes independent of closure type. This association may be because of the matting of the bowel or increased intestinal damage. The MSAF status will aid in setting expectations for parents during their initial NICU stay and further investigation is warranted. TYPE OF STUDY: Clinical Research Paper Level of evidence: III.

Is isomerism a risk factor for intestinal volvulus?

INTRODUCTION: Isomerism, or heterotaxy syndrome, affects many organ systems anatomically and functionally. Intestinal malrotation is common in patients with isomerism. Despite a low reported risk of volvulus, some physicians perform routine screening and prophylactic Ladd procedures on asymptomatic patients with isomerism who are found to have intestinal malrotation. The primary aim of this study was to determine if isomerism is an independent risk factor for volvulus. METHODS: Kid's Inpatient Database data from 1997 to 2012 was utilized for this study. Characteristics of admissions with and without isomerism were compared with a particular focus on intestinal malrotation, volvulus, and Ladd procedure. A logistic regression was conducted to determine independent risk factors for volvulus with respect to isomerism. RESULTS: 15,962,403 inpatient admissions were included in the analysis, of which 7970 (0.05%) patients had isomerism, and 6 patients (0.1%) developed volvulus. Isomerism was associated with a 52-fold increase in the odds of intestinal malrotation by univariate analysis. Of 251 with isomerism and intestinal malrotation, only 2.4% experienced volvulus. Logistic regression demonstrated that isomerism was not an independent risk factor for volvulus. CONCLUSION: Isomerism is associated with an increased risk of intestinal malrotation but is not an independent risk factor for volvulus. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level III.

Outcomes of gastroschisis early delivery: A systematic review and meta-analysis.

BACKGROUND/PURPOSE: Elective preterm delivery (EPD) of a fetus with gastroschisis may prevent demise and ameliorate intestinal injury. While the literature on optimal timing of delivery varies, we hypothesize that a potential benefit may be found with EPD. METHODS: A meta-analysis of publications describing timing of delivery in gastroschisis from 1/1990 to 8/2016 was performed, including studies where either elective preterm delivery (group 1, G1) or preterm gestational age (GA) (group 2, G2) were evaluated against respective comparators. The following outcomes were analyzed: total parenteral nutrition (TPN), first enteral feeding (FF), length of stay, ventilator days, fetal demise, complex gastroschisis, sepsis, and death. RESULTS: Eighteen studies describing 1430 gastroschisis patients were identified. G1 studies found less sepsis (p<0.01), fewer days to FF (p=0.03), and 11days less of TPN (p=0.07) in the preterm cohort. Comparatively, G2 studies showed less days to FF in term GA (p=0.02).Whereas G1 BWs were similar, G2 preterm had a significantly lower BW compared to controls (p=0.001). CONCLUSIONS: Elective preterm delivery appears favorable with respect to feeding and sepsis. However, benefits are lost when age is used as a surrogate of EPD. A randomized, prospective, multi-institutional trial is necessary to delineate whether EPD is advantageous to neonates with gastroschisis. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level III.

The significance of organ prolapse in gastroschisis.

PURPOSE: The aim of this study was to evaluate the incidence and importance of organ prolapse (stomach, bladder, reproductive organs) in gastroschisis. METHODS: This is a retrospective review of gastroschisis patients from 2000 to 2014 at a single tertiary institution. Statistical analysis was performed using a chi-square test, Student's t test, log-rank test, or Cox regression analysis models. All tests were conducted as two-tailed tests, and p-values <0.05 were considered statistically significant. RESULTS: One hundred seventy-one gastroschisis patients were identified. Sixty-nine (40.6%) had at least one prolapsed organ besides bowel. The most commonly prolapsed organs were stomach (n=45, 26.3%), reproductive organs (n=34, 19.9%), and bladder (n=15, 8.8%). Patients with prolapsed organs were more likely to have simple gastroschisis with significant decreases in the rate of atresia and necrosis/perforation. They progressed to earlier enteral feeds, discontinuation of parenteral nutrition, and discharge. Likewise, these patients were less likely to have complications such as central line infections, sepsis, and short gut syndrome. CONCLUSIONS: Gastroschisis is typically described as isolated bowel herniation, but a large portion have prolapse of other organs. Prolapsed organs are associated with simple gastroschisis, and improved outcomes most likely due to a larger fascial defect. This may be useful for prenatal and postnatal counseling of families. TYPE OF STUDY: Case Control/Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.