Is there a role for fetal interventions in gastroschisis management? - An updated comprehensive review.

We conducted a comprehensive evidence-based review on the epidemiology and current standard of care of gastroschisis management as well as the pathophysiology, rationale and feasibility of fetal therapy as a viable alternative. Gastroschisis is a periumbilical abdominal wall defect characterized by abdominal viscera herniation in utero. It affects 4 in 10 000 live births, but the prevalence has steadily increased in recent years. Gastroschisis is typically diagnosed on routine second-trimester ultrasound. The overall prognosis is favorable, but complex gastroschisis, which accounts for about 10% to 15% of cases, is associated with a higher mortality, significant disease burden and higher healthcare costs due to long- and short-term complications. The current standard of care has yet to be established but generally involves continued fetal surveillance and multidisciplinary perinatal care. Postnatal surgical repair is achieved with primary closure, staged silo closure or sutureless repair. Experimental animal studies have demonstrated the feasibility of in utero closure, antiinflammatory therapy and prenatal regenerative therapy. However, reports of early preterm delivery and amnioinfusion trials have failed to show any benefit in humans. Further experimental studies and human trials are necessary to demonstrate the potential benefit of fetal therapy in gastroschisis.

Reproducibility of Lung and Liver Volume Measurements on Fetal Magnetic Resonance Imaging in Left-Sided Congenital Diaphragmatic Hernia.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) affects 1 in 3,000 live births and is associated with significant morbidity and mortality. METHODS: A review of fetal magnetic resonance imaging (MRI) examinations was performed for fetuses with left CDH and normal lung controls. Image review and manual tracings were performed by 4 pediatric radiologists; right and left lung volumes in the coronal and axial planes as well as liver volume above and below the diaphragm in the coronal plane were measured. Intra- and interreviewer reproducibility was assessed using intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Excellent intra- and interreviewer reproducibility of the right and left lung volume measurements was observed in both axial planes (interreviewer ICC: right lung: 0.97, 95% CI: 0.95-0.99; left lung: 0.97, 95% CI: 0.95-0.98) and coronal planes (interreviewer ICC: right lung: 0.97, 95% CI: 0.95-0.98; left lung: 0.96, 95% CI: 0.93-0.98). Moderate-to-good interreviewer reproducibility was observed for liver volume above the diaphragm (ICC 0.7, 95% CI: 0.59-0.81). Liver volume below the diaphragm had a good-to-excellent interreviewer reproducibility (ICC 0.88, 95% CI: 9.82-0.93). CONCLUSIONS: The present study demonstrated an excellent intra- and interreviewer reproducibility of MRI lung volume measurements and good-to-moderate inter- and intrareviewer reproducibility of liver volume measurements after standardization of the methods at our fetal center.

Sequential Minimally Invasive Fetal Interventions for Two Life-Threatening Conditions: A Novel Approach.

INTRODUCTION: In utero interventions are performed in fetuses with "isolated" major congenital anomalies to improve neonatal outcomes and quality of life. Sequential in utero interventions to treat 2 anomalies in 1 fetus have not yet been described. CASE PRESENTATION: Here, we report a fetus with a large left-sided intralobar bronchopulmonary sequestration (BPS) causing mediastinal shift, a small extralobar BPS, and concomitant severe left-sided congenital diaphragmatic hernia (CDH). At 26-week gestation, the BPS was noted to be increasing in size with a significant reduction in right lung volume and progression to fetal hydrops. The fetus underwent ultrasound-guided ablation of the BPS feeding vessel leading to complete tumor regression. However, lung development remained poor (O/E-LHR: 0.22) due to the left-sided CDH, prompting fetal endoscopic tracheal occlusion therapy at 28-week gestation to allow increased lung growth. After vaginal delivery, the newborn underwent diaphragmatic repair with resection of the extralobar sequestration. He was discharged home with tracheostomy on room air at 9 months. DISCUSSION/CONCLUSION: Sequential in utero interventions to treat 2 severe major anomalies in the same fetus have not been previously described. This approach may be a useful alternative in select cases with otherwise high morbidity/mortality. Further studies are required to confirm our hypothesis.

Vasa previa: a multicenter retrospective cohort study.

OBJECTIVE: The objective of the study was to describe the characteristics and outcomes of patients with antenatal diagnosis of vasa previa and evaluate the predictive factors of resolution in a contemporary large, multicenter data set. STUDY DESIGN: This was a retrospective multicenter cohort study of all antenatally diagnosed cases of vasa previa, identified via ultrasound and electronic medical record, between January 2011 and July 2018 in 5 US centers. Records were abstracted to obtain variables at diagnosis, throughout pregnancy, and outcomes, including maternal and neonatal variables. Data were reported as median [range] or n (percentage). Descriptive statistics, receiver-operating characteristics, and logistic regression analysis were used as appropriate. RESULTS: One hundred thirty-six cases of vasa previa were identified in 5 centers during the study period, 19 (14%) of which resolved spontaneously at median estimated gestational age of 27 weeks [19-34]. All subjects with unresolved vasa previa underwent cesarean delivery at a median estimated gestational age of 34 weeks [27-39] with the median estimated blood loss of 800 mL [250-2000]. Rates for vaginal bleeding, preterm labor, premature rupture of membrane, and need for blood product transfusion were not different between the resolved and unresolved group (P = NS). The odds ratio for resolution in those with the estimated gestational age of less than 24 weeks at the time of diagnosis was 7.9 (95% confidence interval, 2.1-29.4) after adjustment for confounding variables. CONCLUSION: Our data suggest that outcomes in antenatally diagnosed cases of vasa previa are excellent. Furthermore, our data report a higher chance of resolution when the condition is diagnosed before 24 weeks of gestation.

Progressive hydrocephalus despite early complete reversal of hindbrain herniation after prenatal open myelomeningocele repair.

OBJECTIVE: Open prenatal myelomeningocele (MMC) repair is typically associated with reversal of in utero hindbrain herniation (HBH) and has been posited to be associated with a reduction in both postoperative prenatal and immediate postnatal hydrocephalus (HCP) risks. However, the long-term postnatal risk of HCP following HBH reversal in these cases has not been well defined. The authors describe the results of a long-term HCP surveillance in a cohort of patients who underwent prenatal MMC repair at their institution. METHODS: A retrospective review of all prenatal MMC repair operations performed at the Mayo Clinic between 2012 and 2017 was conducted. Pertinent data regarding the clinical courses of these patients before and after MMC repair were summarized. Outcomes of interest were occurrences of HBH and HCP and the need for intervention. RESULTS: A total of 9 prenatal MMC repair cases were identified. There were 7 cases in which MRI clearly demonstrated prenatal HBH, and of these 86% (6/7) had evidence of HBH reversal after repair and prior to delivery. After a mean postnatal follow-up of 20 months, there were 3 cases of postnatal HCP requiring intervention. One case that failed to show complete HBH reversal after MMC repair required early ventriculoperitoneal shunting. The other 2 cases were of progressive, gradual-onset HCP despite complete prenatal HBH reversal, requiring endoscopic third ventriculostomy with choroid plexus cauterization at ages 5 and 7 months. CONCLUSIONS: Although prenatal MMC repair can achieve HBH reversal in a majority of well-selected cases, the prevention of postnatal HCP requiring intervention appears not to be predicated on this outcome alone. In fact, it appears that in a subset of cases in which HBH reversal is achieved, patients can experience a progressive, gradual-onset HCP within the 1st year of life. These findings support continued rigorous postnatal surveillance of all prenatal MMC repair patients, irrespective of postoperative HBH outcome.

Standardization and reproducibility of sonographic stomach position grades in fetuses with congenital diaphragmatic hernia.

OBJECTIVES: The purpose of this study was to evaluate the reproducibility of stomach position grading in congenital diaphragmatic hernia (CDH) as proposed by Cordier et al and Basta et al after standardization of the methods at our center. METHODS: We collected sonographic images from 23 fetuses with left-sided CDH at our center from 2010 to 2018. Nine operators (one maternal fetal medicine expert and eight sonographers) reviewed the selected images and graded the stomach position according to the methods of Cordier et al and Basta et al. We assessed the interoperator agreement with Fleiss's kappa statistics. RESULTS: Overall agreement amongst all operators was moderate for both methods proposed by Cordier et al (k = 0.60, SE 0.07, 95% CI 0.47-0.73, P < .0001) and Basta et al (k = 0.60, SE 0.06, 95% CI 0.47-0.73, P < .0001). Interoperator agreement was moderate for grade 3 with the method by Cordier et al (k = 0.45, SE 0.09, 95% CI 0.27-0.64, P < .0001) and fair for grade 4 with the method by Basta et al (k = 0.33, SE 0.08, 95% CI 0.18-0.49 P < .0001). CONCLUSIONS: Our study demonstrates a fair to moderate interoperator agreement of the stomach position grading methods proposed in the literature after standardization of the methods at our center. Further multicenter studies are needed to confirm our results.

Obstetric outcomes after fetal intervention - a single-center descriptive review.

BACKGROUND: Advancements in fetal interventions have enabled in utero management of several fetal congenital anomalies and conditions; these are accomplished via ultrasound-guided, fetoscopic or open techniques. Understanding the risk of preterm labor associated with each technique is critical for patient counseling and choice of intervention; however, data on obstetrical outcomes associated with each type of intervention remains limited. OBJECTIVE: To provide descriptive information on the risk of preterm birth following fetal intervention, based on underlying disease and procedure performed. STUDY DESIGN: This is a retrospective cohort study of patients who underwent fetal intervention at our institution between 1 October 2016 and 31 December 2019. Interventions were stratified into three groups- ultrasound-guided, fetoscopic and open procedures. Procedures included fetoscopic laser ablation (FLA) for twin-to-twin transfusion syndrome (TTTS), fetoscopic endotracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH), vesicoamniotic shunt (VAS) for lower urinary tract obstruction (LUTO), fetal cystoscopy for LUTO, and open and fetoscopic myelomeningocele repair. The primary outcomes were gestational age at delivery and frequency of premature rupture of the membranes. RESULTS: Sixty-eight patients were included; 20 (29.4%) underwent ultrasound- guided procedures, 37 (54.4%) underwent fetoscopy, and 11 (16.2%) open in utero intervention. The diagnoses and type of intervention within each group were different. The mean gestational age (GA) ± standard deviation (SD) at intervention for ultrasound- guided, fetoscopic, open procedures were 24.1 ± 4.4 weeks, 22.8 ± 3.7 weeks, and 25.0 ± 0.9 weeks, respectively. The mean GA ± SD at delivery were 31.9 ± 4.9 weeks, 31.6 ± 4.6 weeks, and 32.6 ± 5.5 weeks, respectively. The mean interval from time of intervention to delivery were 54 ± 39, 62 ± 37 and 55 ± 36 days, respectively (p = 0.82); and the risk of PPROM was 26.3%, 21.6% and 27.3%, respectively. The mean GA at delivery and the frequency of PPROM were different for each specific disease that was treated. CONCLUSION: The risk of preterm birth and PPROM following fetal intervention with different procedures, categorized under ultrasound- guided, fetoscopic and open fetal interventions at our institution were similar amongst the three groups, but they were different depending on the diagnosis of the treated anomaly.

What do we know about the diagnosis and management of mirror syndrome?

INTRODUCTION: Mirror syndrome is a rare disease associated with high fetal mortality of up to 67.2%. It is thought to be underdiagnosed and is often associated with preeclampsia. Mirror syndrome is characterized by "triple edema": generalized maternal, placental, and fetal edema. OBJECTIVE: This comprehensive review aims to thoroughly summarize the existing data and provide a broad update on the topic to help accurate diagnosis and encourage further research. METHODS: A comprehensive search of several databases (Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus) was conducted. RESULTS: The last systematic review of mirror syndrome cases was conducted in 2016 and included 113 patients. Much is still unknown about the pathophysiology of the disease and it remains underdiagnosed. CONCLUSIONS AND RELEVANCE: Mirror syndrome is likely more prevalent than current data suggests for it is often misdiagnosed as pre-eclampsia. The differential of Mirror syndrome should be considered in anomalous presentations of pre-eclampsia as intervention may save the fetus and improve maternal symptoms. It is important to further the study on the pathophysiology of the disease to better understand, diagnose and potentially treat it, to avoid its high morbidity and mortality.

Interventional resealing of preterm premature rupture of the membranes: a systematic review and meta-analysis.

OBJECTIVE: To compare the effectiveness and outcomes of interventional resealing of membranes, "amniopatch" for spontaneous vs. iatrogenic preterm premature rupture of the membranes (sPPROM and iPPROM). METHODS: We performed a systematic review of literature involving an electronic search of the following databases: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Scopus. An indirect meta-analysis was then performed to compare the obstetric, maternal, fetal, and neonatal outcomes of amniopatch between the sPPROM and iPPROM groups. RESULTS: The mean gestational age (GA) at the time rupture was 17.8 ± 1.8 and 25.2 ± 3.8 weeks for iPPROM and sPPROM, respectively, p = .005. Mean GA at the time of amniopatch procedure was 19.2 ± 2.07 weeks for iPPROM and 23 ± 3.1 weeks of gestation for sPPROM, p = .023. The rates of fluid re-accumulation (sPPROM 26% and iPPROM 53%, p = .09) were comparable between the sPPROM and iPPROM groups. Neonatal outcomes except for the rate of IUFD were also comparable between the groups. The incidence of IUFD was significantly higher in the iPPROM group (ES: 24%; 95% CI: 8.00-44.0%; p < .001), compared to sPPROM (ES: 0%; 95% CI: 0.00-4.00%). Obstetric and maternal outcomes were comparable between the two groups. CONCLUSIONS: Amniopatch appears to be a feasible and safe procedure for PPROM treatment. Further research is warranted to investigate the effectiveness of this procedure and establish a standardized criterion for the appropriate selection of patients that could benefit from this intervention.

Impact of congenital diaphragmatic hernia on diaphragm muscle function in neonatal rats.

Congenital diaphragmatic hernia (CDH) is characterized by incomplete partitioning of the thoracic and abdominal cavities by the diaphragm muscle (DIAm). The resulting in utero invasion of the abdominal viscera into the thoracic cavity leads to impaired fetal breathing movements, severe pulmonary hypoplasia, and pulmonary hypertension. We hypothesized that in a well-established rodent model of Nitrofen-induced CDH, DIAm isometric force generation, and DIAm fiber cross-sectional areas would be reduced compared with nonlesioned littermate and Control pups. In CDH and nonlesioned pups at embryonic day 21 or birth, DIAm isometric force responses to supramaximal field stimulation (200 mA, 0.5 ms duration pulses in 1-s duration trains at rates ranging from 10 to 100 Hz) was measured ex vivo. Further, DIAm fatigue was determined in response to 120 s of repetitive stimulation at 40 Hz in 330-ms duration trains repeated each second. The DIAm was then stretched to Lo, frozen, and fiber cross-sectional areas were measured in 10 µm transverse sections. In CDH pups, there was a marked reduction in DIAm-specific force and force following 120 s of fatiguing contraction. The cross-sectional area of DIAm fibers was also reduced in CDH pups compared with nonlesioned littermates and Control pups. These results show that CDH is associated with a dramatic weakening of the DIAm, which may contribute to poor survival despite various surgical efforts to repair the hernia and improve lung development.NEW & NOTEWORTHY There are notable respiratory deficits related to congenital diaphragmatic hernia (CDH), yet the contribution, if any, of frank diaphragm muscle weakness to CDH is unexplored. Here, we use the well-established Nitrofen teratogen model to induce CDH in rat pups, followed by diaphragm muscle contractility and morphological assessments. Our results show diaphragm muscle weakness in conjunction with reduced muscle fiber density and size, contributing to CDH morbidity.

Perinatal outcomes of fetal intra-abdominal umbilical vein varix: a multicenter cohort study.

OBJECTIVES: To investigate the perinatal outcomes of fetuses with antenatal diagnoses of intra-abdominal umbilical vein varix (UVV). METHODS: A multicenter retrospective study was conducted in four countries on fetuses diagnosed with intra-abdominal UVV between 2012 and 2019. Collected data included gestational age (GA), UVV maximum diameter at diagnosis and delivery, associated anatomical and chromosomal anomalies, birth weight, and neonatal outcomes. RESULTS: Twenty fetuses were identified, of which 20% had associated chromosomal and/or anatomical abnormalities, most resulting in poor outcomes (either intrauterine fetal death or pregnancy termination). Mean maternal age was 34.1 ± 7.0 years, UVV was diagnosed at 26.5 ± 4.5 weeks of GA on average with a maximum diameter of 12.0 ± 4.0 mm. Mean GA at delivery was 35.4 ± 5.6 weeks. Survival rate was 85%. CONCLUSION: Our study shows a satisfactory outcome when intra-abdominal UVV is an isolated finding, with minimal obstetrical and perinatal consequences. The prognosis is worse when UVV is associated with other anomalies.

Adnexal Torsion After Isolated Salpingeal Torsion, an Undesired Complication of Conservative Management: A Case Report.

Objective: Isolated salpingeal torsion (IST) is a rare cause of acute abdomen in women of the reproductive age group. The lack of pathognomonic clinical, laboratory or radiographic findings makes early diagnosis a challenge. We describe a case of IST in a 13-year-old who suffered from a repeat torsion following initial conservative management. Case Report: A 13-year-old girl presented with acute right lower quadrant abdominal pain of insidious onset. Her past medical history was non-contributory and her initial workup was unremarkable. Exploratory laparoscopy subsequently revealed isolated torsion of the right fallopian tube which was detorted. She presented 10 months later with similar complaints and further workup demonstrated right adnexal torsion which was confirmed by laparoscopy; salpingo-oophorectomy was necessary due to gangrenous necrosis. Conclusion: Conservative management of fallopian tube torsion confers the advantage of fertility preservation but the risk of repeat torsion remains clinically significant.

SARS-CoV-2 Infection and COVID-19 During Pregnancy: A Multidisciplinary Review.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has been associated with worse outcomes in several patient populations, including the elderly and those with chronic comorbidities. Data from previous pandemics and seasonal influenza suggest that pregnant women may be at increased risk for infection-associated morbidity and mortality. Physiologic changes in normal pregnancy and metabolic and vascular changes in high-risk pregnancies may affect the pathogenesis or exacerbate the clinical presentation of COVID-19. Specifically, SARS-CoV-2 enters the cell via the angiotensin-converting enzyme 2 (ACE2) receptor, which is upregulated in normal pregnancy. Upregulation of ACE2 mediates conversion of angiotensin II (vasoconstrictor) to angiotensin-(1-7) (vasodilator) and contributes to relatively low blood pressures, despite upregulation of other components of the renin-angiotensin-aldosterone system. As a result of higher ACE2 expression, pregnant women may be at elevated risk for complications from SARS-CoV-2 infection. Upon binding to ACE2, SARS-CoV-2 causes its downregulation, thus lowering angiotensin-(1-7) levels, which can mimic/worsen the vasoconstriction, inflammation, and pro-coagulopathic effects that occur in preeclampsia. Indeed, early reports suggest that, among other adverse outcomes, preeclampsia may be more common in pregnant women with COVID-19. Medical therapy, during pregnancy and breastfeeding, relies on medications with proven safety, but safety data are often missing for medications in the early stages of clinical trials. We summarize guidelines for medical/obstetric care and outline future directions for optimization of treatment and preventive strategies for pregnant patients with COVID-19 with the understanding that relevant data are limited and rapidly changing.

Complications and outcomes of SARS-CoV-2 in pregnancy: where and what is the evidence?

OBJECTIVES: To add to the growing evidence on SARS-CoV-2 infection during pregnancy, so as to better inform clinical decision making and optimize patient outcomes. METHODS: A systematic search of relevant databases was perfomed on 25 March 2020 and a repeat search, on 10 April 2020. Reports of pregnant patients with SARS-CoV-2 infection at any time during their pregnancy were reviewed and summarized . RESULTS: We summarized the outcomes of a total of 155 pregnant women and 118 neonates. The evidence suggests a similar rate of severe COVID-19 cases in pregnant women and the general population. The frequency of cesarean deliveries is high, against guidelines recommendations. CONCLUSION: Limited data on COVID-19 during preganacy, associated with a wide variation in the methodology make accurate data interpretation difficult.

SARS-CoV-2 in Pregnancy: A Comprehensive Summary of Current Guidelines.

Since the declaration of the global pandemic of COVID-19 by the World Health Organization on 11 March 2020, we have continued to see a steady rise in the number of patients infected by SARS-CoV-2. However, there is still very limited data on the course and outcomes of this serious infection in a vulnerable population of pregnant patients and their fetuses. International perinatal societies and institutions including SMFM, ACOG, RCOG, ISUOG, CDC, CNGOF, ISS/SIEOG, and CatSalut have released guidelines for the care of these patients. We aim to summarize these current guidelines in a comprehensive review for patients, healthcare workers, and healthcare institutions. We included 15 papers from 10 societies through a literature search of direct review of society's websites and their journal publications up till 20 April 2020. Recommendations specific to antepartum, intrapartum, and postpartum were abstracted from the publications and summarized into Tables. The summary of guidelines for the management of COVID-19 in pregnancy across different perinatal societies is fairly consistent, with some variation in the strength of recommendations. It is important to recognize that these guidelines are frequently updated, as we continue to learn more about the course and impact of COVID-19 in pregnancy.

In Utero Restoration of Hindbrain Herniation in Fetal Myelomeningocele as Part of Prenatal Regenerative Therapy Program at Mayo Clinic.

OBJECTIVE: To assess our initial experience with prenatal restoration of hindbrain herniation following in utero repair of myelomeningocele (MMC). PATIENTS AND METHODS: Three consecutive patients with prenatally diagnosed MMC (between January 1, 2018 and September 30, 2018) were managed with open in utero surgery. As per institutional review board approval and following a protocol designed at the Mayo Clinic Maternal & Fetal Center, fetal intervention was offered between 19 0/7 and 25 6/7 weeks of gestation. Prenatal improvement of hindbrain herniation was the declared restorative end point. Obstetrical and perinatal outcomes were also assessed. RESULTS: Diagnosis of MMC was confirmed upon referral between 20 and 21 weeks' gestation by using fetal ultrasound and magnetic resonance imaging. In all cases reported here, the spinal defect was lumbosacral with evidence of hindbrain herniation. Open in utero MMC repair was performed between 24 and 25 weeks' gestation with no notable perioperative complications. Postprocedure fetal magnetic resonance imaging performed 6 weeks after in utero repair documented improvement of hindbrain herniation. Deliveries were at 37 weeks by cesarean section without complications. Most recent postnatal follow-ups were unremarkable at both 11 months (baby 1) and 3 months of age (baby 2), with mild ventriculomegaly. Antenatal and postnatal follow-up of baby 3 at 1 month of age was also unremarkable. CONCLUSION: Our study highlights the prenatal restoration of hindbrain herniation following in utero MMC repair in all cases presented here as an example of a prenatal regenerative therapy program in our institution.