Articles

Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia: Unraveling the Impact of Prematurity and Suboptimal Fetal Lung Growth.[1] Holden KI et al., Fetal Diagn Ther. 2025;52(6):644-649. PMID: 40532679.

Congenital diaphragmatic hernia (CDH) remains a high-risk neonatal condition, with outcomes largely driven by the degree of pulmonary hypoplasia and associated cardiopulmonary dysfunction. Prenatal risk stratification most commonly relies on the observed-to-expected lung-to-head ratio (o/e-LHR), with values < 25% defining severe disease and carrying high mortality rates. Fetoscopic endoluminal tracheal occlusion (FETO) was developed to stimulate fetal lung growth in severe CDH and has been shown in the TOTAL randomized trial to improve survival in selected patients with isolated severe left-sided CDH. Although FETO can accelerate fetal lung development, the response to FETO is variable and fetal intervention is associated with a high rate of preterm delivery. The independent and combined effects of prematurity and suboptimal fetal lung growth (SFLG) following FETO have not been well elucidated.

This large multicenter cohort from the Congenital Diaphragmatic Hernia Study Group examines the relationship between prematurity, fetal lung growth response and survival in infants with CDH undergoing FETO. It evaluated 106 patients treated between 2015 and 2023, with 43 having complete paired pre- and post-FETO o/e-LHR measurements. The authors demonstrate that prematurity and suboptimal fetal lung growth (SFLG) are critical, quantifiable factors associated with worse outcomes and decreased survival. Among patients with available pre- and post-FETO o/e-LHR data, nearly 70% were born preterm and 23% demonstrated suboptimal fetal lung growth (SFLG). Overall survival in the analyzed cohort was 72.1%, but outcomes diverged dramatically based on lung-growth response and gestational age at birth: term infants with adequate lung response had a 90.0% survival rate, whereas preterm infants with SFLG had survival of 57.1%. In multivariable analysis, the magnitude of change in o/e-LHR after FETO was the only factor independently associated with survival, while prematurity alone was not, underscoring the central importance of effective lung growth response. Additionally, 91.7% of deaths occurred in infants who were preterm and/or had SFLG, highlighting the combined impact of inadequate lung growth and prematurity on outcomes following FETO. These findings reinforce the need to minimize prematurity, optimize balloon management, and improve identification of fetuses most likely to demonstrate meaningful lung-growth response.

Evolving Practices in Prenatal Open Spinal Dysraphism: A Global Survey of Selection Criteria, Surgical Techniques, and Diagnostic Trends.[2] Keil C et al., Prenat Diagn. 2026 Jan;46(1):75-83. PMID: 41298113.

Prenatal repair of open spinal dysraphism (OSD) was established as beneficial by the Management of Myelomeningocele Study (MOMS) trial, which demonstrated improved neurological outcomes compared to postnatal repair. Because the benefits of fetal surgery were yet to be proven, the MOMS trial had strict eligibility criteria including gestational age limits (up to 25.6 weeks), BMI restrictions (£ 35), and exclusion of women with prior uterine surgery. Open fetal surgery was the primary technique studied. Since the 2011 publication of the trial, the field has evolved significantly , with emerging fetoscopic approaches and patient-specific modifications to selection criteria.

This global survey of 38 fetal surgery centers across 16 countries reveals significant evolution in prenatal OSD repair practices beyond the original MOMS criteria. Nearly half of centers (47.4%) now offer multiple surgical techniques, with open fetal surgery being most common (51.4%) but fetoscopic methods are increasingly utilized. Maternal eligibility criteria have broadened: 42.4% of centers operate beyond 25.6 weeks of gestation, 52.4% accept a maternal BMI 35-40%, with 28.6% of centers accepting BMI of 41%-45%, and 42.4% offering fetal surgery for women with prior uterine surgery; all deviations from MOMS exclusion criteria. Diagnostic approaches show considerable heterogeneity. While most centers (87.9%) combine ultrasound and MRI for anatomical assessment, genetic evaluation varies widely: 66.7% require karyotyping, 63.6% require chromosomal microarray, 18.2% use non-invasive prenatal testing, and 6.1% require no genetic testing prior to intervention. Notably, prognostic indicators such as ventriculomegaly severity and fetal motor function are increasingly incorporated into selection decisions, suggesting a shift toward individualized risk stratification rather than rigid protocol adherence. These findings demonstrate the international practice has moved toward more inclusive, personalized approaches.

Fetal Endoscopic Tracheal Occlusion (FETO) for Left and Right Congenital Diaphragmatic Hernia in Canada.[3] Kunpalin Y et al., Prenat Diagn. 2025 Jun;45(6):778-786. PMID: 40302114.

The TOTAL trial reported improved survival with fetal endoscopic tracheal occlusion (FETO) for severe left-sided congenital diaphragmatic hernias (CDH), despite increased rates of preterm premature rupture of membranes (PPROM) and preterm delivery. In contrast, subsequent non-randomized studies have yielded mixed results, with some showing no clear survival advantage with FETO, raising questions about generalizability across centers, patient selection, and contemporary postnatal management.

This retrospective Canadian single-center experience reports outcomes of FETO for both severe left- or right-sided CDH in a North American referral setting. Survival among fetuses with severe left-sided CDH (S-LCDH) was comparable to that reported in the TOTAL trial (38% vs 40%), despite a higher incidence of PPROM (67% vs 44-48%), while overall prematurity rates were similar. These findings support the reproducibility of randomized trial outcomes outside the primarily European trial network. Importantly, the study includes right-sided CDH (R-CDH), a cohort excluded from the TOTAL trial and underrepresented in the literature. Survival to discharge for R-CDH was 58%, exceeding that observed for S-LCDH within the same series (38%). In addition to survival outcomes, the authors detail the technical and logistic challenges associated with balloon removal. Half of removals were unplanned: 44% required an EXIT procedure and 30% required ultrasound-guided puncture, with 30% described as technically difficult. These findings underscore that successful FETO programs require specialized multidisciplinary teams with immediate airway expertise and advanced neonatal support.

Observed/Expected Lung‐To‐Head Ratio and Total Lung Volumes That Identify Fetuses With Severe Congenital Diaphragmatic Hernia in a North American Fetal Center. [4] Gebb J et al., Prenat Diagn. 2025 May;45(5):676-685. Epub 2025 Apr 1. PMID: 40169913.

Fetal endoluminal tracheal occlusion (FETO) improves survival and morbidity (pulmonary and neurodevelopmental) in certain fetuses with severe congenital diaphragmatic hernia (CDH). Although many centers offer FETO for both left and right CDH, there is a debate on the cut‐off to use for fetuses with the most severe CDH. There are also differences in survival in high-volume centers in North America, compared to those described in the TOTAL trial.

The authors sought to determine the O/E LHR and TLV cut‐offs that best differentiated survival and ECMO utilization among fetuses with prenatally diagnosed L and R CDH. This was a retrospective review of patients with CDH at CHOP between 2013-2023. They included 283 L CDH and 57 R CDH. For survival, O/E LHR of 28.1% and O/E TLV of 34.0% were the best cut-offs for L CDH; O/E LHR of 46.8% and O/E TLV of 17.6% were the best cut‐offs for R CDH. For ECMO utilization, O/E LHR of 32.8% and O/E TLV of 35.3% were the best cut-offs for L CDH. O/E LHR of 47.0% and O/E TLV of 22.0% were the best cut‐offs for R CDH. These measurements are higher than the < 25% cutoff currently used to define the most severe L CDH group. Taken together, their data support using an O/E LHR cut‐off of < 28.1–32.8% for L CDH and < 46.8–47.0% for R CDH to define the most severe groups. Using MRI, they also support O/E TLV cut‐off of < 32.8–34.0% for L CDH and < 17.6–22.0% for R CDH. Notably, neither O/E LHR nor O/E TLV were highly sensitive or specific, suggesting that defining the highest risk group for both death and ECMO utilization may require a combination of factors. In larger cohorts, adding factors such as stomach position/volume, liver herniation, and/or novel MRI lung measurements may improve the ability to predict morbidities and mortality. These results are useful in determining the group of patients that may benefit the most from fetal intervention in North America.

Association between distance traveled and abortion consideration and completion among people with fetal myelomeningocele. [5] Papastefan Stet al., Am J Obstet Gynecol MFM. 2025 Apr;7(4):101631. Epub 2025 Feb 4. PMID: 39914514.

Access to specialized fetal care centers (FCC) that offer prenatal repair of fetal myelomeningocele (fMMC) is limited, often requiring patients to travel long distances for consultation. This travel can be financial and psychologically burdensome, and may influence pregnancy decision-making including whether to undergo prenatal repair, continue the pregnancy expectantly with planned postnatal repair, or to consider abortion. This study aimed to explore whether greater travel distance to an FCC correlates with higher likelihood of abortion consideration and completion in fMMC.

In this study of 157 patients diagnosed with fetal myelomeningocele fMMC and referred to a tertiary FCC, those living farther distances were significantly less likely to consider abortion before consultation. Specifically, living beyond the median travel distance of 39 miles was associated with a 35% reduction (22.5 vs. 58.1%, p < 0.001) in the likelihood of considering abortion after adjusting for gestational age at presentation. Further, for every additional mile traveled the likelihood of considering abortion decreased by 1%. While abortion consideration varied with distance, the actual completion of abortion after consultation did not show an association with travel distance once gestational age was accounted for. These findings suggest that geographic barriers, represented by travel distance, influence initial pregnancy decision-making considerations among patients facing a severe congenital anomaly such as fMMC. While distance alone does not determine whether abortion is ultimately pursued, other factors including prognosis, personal beliefs, family support and anticipated caregiver burden play critical roles in their final decision. Understanding this dynamic can help tailor counseling and support services to address disparities in access and decision-making options for patients traveling long distances for specialized fetal care.

Gestational age at birth varies by surgical technique in prenatal open spina bifida repair: a systematic review and meta-analysis. [6] Zargarzadeh N et al., Am J Obstet Gynecol. 2025 Feb 19:S0002-9378(25)00094-8. PMID: 39983885.

The Management of Myelomeningocele Study (MOMS) demonstrated that open prenatal repair of myelomeninceles (MMC) was associated with postnatal reduction of hydrocephalus necessitating VP shunt and improvement in motor outcomes. Multiple surgical approaches have emerged since then in an attempt to decrease maternal and fetal complications of prenatal MMC repair. The optimal treatment strategy has yet to be identified.

Zargarzadeh et. al. conducted a systematic review and meta-analysis of 37 studies from 14 countries between 2010 and 2024 including 2,333 prenatal MMC repairs. The four repair types included were open (66%), mini-hysterotomy (14%), laparotomy-assisted fetoscopic (5%), and percutaneous fetoscopic (15%). The primary outcome investigated was gestational age (GA) at delivery, with PPROM, vaginal birth, and perinatal mortality as secondary outcomes. There was no significant difference in GA at delivery among the different surgical approaches (34 weeks). On pooled analysis, there was a significant difference between approaches with regard to preterm delivery, PPROM, vaginal birth, and time from surgery to delivery. The laparotomy-assisted fetoscopic repair had the smallest rate of preterm delivery (51%), highest rate of vaginal birth (49%), and longest time from surgery to delivery (10.53 weeks). There was significant heterogeneity in GA at birth, which was significantly affected by year of study publication and surgical technique on univariate meta-regression. On multivariate meta-regression, duration of surgery was the only influential variable on GA at birth. Bayesian analysis demonstrated significant differences between GA at birth for each surgical approach, with laparoscopic-assisted fetoscopic repair having the highest at 35.62 weeks. Finally, pairwise comparisons showed that laparotomy-assisted fetoscopic repair had significantly higher GA at birth compared to open repair and percutaneous fetoscopic repair (mean difference 1.55 (90%CI 0.83,2.27) and 3.26 weeks (90%CI 1.88, 4.65), respectively). The authors do not conclude that laparoscopic-assisted fetoscopic repair is the superior approach. They do, however, advise that the information gleaned from the study be used in a shared decision making model when advising parents and that additional studies comparing the techniques need to be performed.

The Process of Developing a Comprehensive Maternal-Fetal Surgery Center [7] Chon AH et al., Am J Obstet Gynecol MFM. 2024 Nov 22;7(1):101557. PMID: 39580116

Over the past few decades, the scope of maternal fetal therapy has expanded significantly, resulting in the development of many new maternal-fetal surgery centers nationally and abroad. Currently, over 50 centers exist in the US that provide varying levels of maternal fetal care; however the clinical and administrative process for establishing new centers of excellence has yet to be elucidated.

This article, which is published by a geographically and experientially diverse group of authors, describes a reproducible, staged approach to building a comprehensive maternal-fetal surgery center. The process is detailed in three phases: (1) business and strategic planning, (2) fetal surgeon recruitment, and (3) surgical implementation. Several programmatic themes are detailed which include understanding existing institutional resources, mapping out the entire patient process from maternal fetal referral through neonatal hospital discharge, enacting a clear governance structure, creating reliable and structured team communication across disciplines, and being transparent about planning and cultural vision. The authors emphasize the importance of executive leadership engagement, multidisciplinary collaboration, and commitment to research and innovation as key factors for success in developing a comprehensive maternal fetal surgery center.

Neonatal Outcomes of Multiple Congenital Thoracic Lesions [8] di Natale A et al., Fetal Diagn Ther. 2024 Sep 7:1-13. PMID: 39245038.

Congenital thoracic lesions (CTLs) most commonly present as solitary lesions. Since multiple lesions are very rarely encountered in surgical practice, the management of patients with bilobar or contralateral CTLs remains unclear.

This retrospective review describes the incidence, characteristics, and outcomes of patients born with multiple CTLs and managed at a large tertiary care center between 2013-2023. Multiple CTLs were defined as both a radiological and surgical diagnosis of two or more CTLs present in more than one lobe. Of a total of 701 patients with CTLs, 74 (10.5%) had multiple CTLs. The prenatal diagnosis of multiple CTLs was correctly made 12.9% of the time. Multiple CTLs were most often found confined to the right lung (n = 33, 44%). The incidence of bilateral lesions was 12.1%. The most common type of multiple CTLs was congenital pulmonary airway malformation (CPAM). A genetic syndrome was identified in 4% of the multiple CTL cohort, and 12.9% had another congenital anomaly. Treatment of multiple CTLs was almost evenly split between bilobectomy (51%) and lung-sparing surgery (49%). There were no differences in hospital length of stay between treatment groups, and overall mortality was 5.4%. This article represents the largest known cohort of patients with multiple CTLs, and their overall prognosis is favorable. Additional insights include the challenge of prenatal diagnosis, consideration to evaluate for other congenital anomalies and/or genetic syndromes, and resection with lung sparing surgery vs. bilobectomy.

The promise and pitfalls of care standardization in congenital diaphragmatic hernia [9] Dimmer A et al., Semin Pediatr Surg. 2024 Aug;33(4):151445. Epub 2024 Jul 2. PMID: 38972215.

There is a large degree of variability between providers and institutions for the treatment of congenital diaphragmatic hernia (CDH), not only in the US, but throughout the world. There is a greater push for standardization in medical care in the last few decades. Along similar lines, guidelines for standardization of care in CDH patients have been published by several international organizations. A debate exists as to whether standardization is, in fact, the best practice for this rare, complex disease.

The article discusses the advantages of standardization of medical care in general, including improving patient outcomes, reducing unwanted variation in care, and reduced cost of care. Disadvantages to standardization are also outlined, including deterring individualized treatment, implementation barriers, and low-quality evidence. The authors apply the aforementioned “promises” and “pitfalls” of standardization to demonstrate why standardization in CDH care should be pursued. They discuss guidelines that have been developed by various international societies to standardize CDH care over the last two decades. Challenges to CDH care standardization are elaborated upon, namely the lack of high-quality evidence available, lack of patient-reported outcome measures, and failure to address treatment and outcome disparities along racial and ethnic lines. The authors recommend not only publishing guidelines but actively raising awareness and endorsement of the guidelines by engaging professional societies, respected field leaders, and direct engagement of patient families, including the use of technology. They recommend “evergreening” guidelines and ensuring implementation using the electronic medical record and plan-do-study-act cycles. Perhaps most importantly, the authors advocate for international collaboration and multi-center data registries including long-term follow-up data and patient-reported outcomes to develop high-quality best practice evidence. Finally, artificial intelligence is mentioned as an avenue to assist with standardization in the future, for example, by stratifying patient severity. In summary, the article provides rationale for care standardization in CDH and identifies key steps to be taken to achieve this goal.

Characterization of suboptimal responses to fetoscopic endoluminal tracheal occlusion in congenital diaphragmatic hernia[10]. Espinoza J, et al. Fetal Diagn Ther. 2023;50(2):128-135. Epub 2023 Apr 11. PMID: 37040717.

After decades of experimental and clinical experience, the TOTAL trial demonstrated the safety and efficacy of FETO for patients with severe CDH.  However, the applicability of the TOTAL trial to the US experience has been questioned due to concerns about selection criteria and the higher conventional survival rate of severe CDH patients in US centers.  Over a decade ago, reports from the European experience suggested a threshold of lung responsiveness was required for survival after FETO.  This introduced the concept of FETO responders and non-responders which may impact survival.

This is a retrospective cohort study at one experienced US CDH institution with a high-volume of FETO patients from 2012 – 2021.  The authors demonstrated that a < 10% increase in observed-to-expected total lung volume (O/E TLV) after the FETO procedure is associated with lower infant survival to 12 months of age and higher ECMO requirement among infants with CDH.   This threshold change in lung responsiveness is helpful in predicting need for ECMO postnatally and risk stratifying mortality risk.  Risk stratification and application of FETO was similar between groups which raises many unanswered questions about the biology of lung responsiveness following FETO which will require further study.

Fetoscopic endoluminal tracheal occlusion for severe, left-sided congenital diaphragmatic hernia[11]. Bergh E, et al. Obstet Gynecol. 2024 Mar 1;143(3):440-448. Epub 2023 Dec 21. PMID: 38128107

Fetoscopic endoluminal tracheal occlusion (FETO) remains an intriguing approach to management of fetuses with moderate and severe congenital diaphragmatic hernia (CDH). While results of the TOTAL trial published in June, 2022 showed improved survival for a cohort of fetuses classified as “severe” CDH treated with FETO compared to conventional treatment, this trial has been challenged due to a number of factors including validity of “severe” classification, variability in CDH care in the many European centers involved in the study, overall low use of ECMO, low rate of surgical repair, and seemingly poor outcome in those with expectant management. In North America, FETO continues to be considered investigational with access limited to a small number of centers.

This well written manuscript reviews outcomes from most of the FETO cases performed in North America as compiled by the NAFTNet (North American Fetal Therapy Network) FETO Consortium. The paper summarizes results of 89 attempted FETO cases of which 87 were completed successfully. In addition, it compares results of 63 cases of severe, isolated left sided CDH (defined as ultrasound measured o/e LHR < 25%) to a cohort of similar fetuses followed expectantly. Though 6-month survival was 70% in the FETO group and 58% in the expectant group, the benefit was not statistically significant (p=0.3). ECMO use and days on ECMO were lower in the FETO group (37% vs 52%, p=.16; 12 vs 16 days, p=.06). As expected, FETO was associated with a higher rate of preterm premature ruptured membranes and earlier gestational age of birth (35.0 vs 38.3 weeks). The authors conclude that FETO may reduce morbidity in fetuses with CDH with persistently low lung volumes as measured by ultrasound. It is interesting to compare these results to those of the TOTAL trial that had only 40 fetuses randomized to FETO for severe CDH. Compared to the TOTAL trial, the cohort reported in this series had 75% higher survival rate after FETO and 280% higher survival with expectant management. These findings suggest differences in the management and outcomes of fetuses with CDH treated in North America and Europe that may limit the generalizability of the TOTAL trial results to North American centers.

In Utero therapy for congenital diaphragmatic hernia [12] Schwab ME et al. Clin Perinatol. 2022 Dec;49(4):863-872. doi: 10.1016/j.clp.2022.07.008. Epub 2022 Oct 13.

Despite many advances in the treatment of congenital diaphragmatic hernia (CDH), the overall survival remains 70%. Although several high-volume centers report higher survival, the mortality and morbidity of severe CDH remain high. Promising approaches include fetal treatment and enhanced protocolized postnatal strategies including gentle ventilation and optimal application of ECMO.

This study provides a succinct yet comprehensive history of the evolution of fetal treatment for CDH by Drs. Schwab, Lee and Tsao. The current state of prenatal risk stratification using ultrasound and fetal MRI is presented along with remaining limitations and the need for standardization across centers. In addition to presenting the seminal studies in the field, the authors deftly point out the strengths and limitations of randomized clinical trials in the field of fetal therapy. They unpack the results of the TOTAL trial which demonstrated benefits for patients with severe CDH. Despite promising trial results, the authors point out potential issues with inclusion criteria and higher survival rates for conventional treatment in US centers which limit the generalizability of this study. They point to the need for specialist center involvement to answer many remaining questions including the physiology of tracheal occlusion, inclusion criteria, and long-term morbidity of survivors. Lastly, promising prenatal medical and stem cell-based approaches to ameliorate pulmonary hypertension are presented.

In Utero enzyme-replacement therapy for infantile-onset Pompe’s disease [13] Cohen JL, Chakraborty P, et al. NEJM 387; 23, 2150-2158. DOI: 10.1056/NEJM0a2200587

Several early-onset lysosomal storage diseases have multiorgan involvement that begins prenatally. Initiating enzyme-replacement therapy (ERT) with recombinant enzymes postnatally after positive newborn screen helps to treat these conditions but organ damage is usually in place. Animal evidence suggests that initiation of this therapy in utero may limit disease progression and for this reason there are approvals for clinical trials of fetal ERT.

Tippi MacKenzie, a pediatric surgeon working at the University of California San Francisco, is a leader in the field of in utero gene therapy. This manuscript is a landmark report of successful use of in utero ERT for infantile onset Pompe’s disease from a multidisciplinary, multicenter scientific team of which Tippi helps lead. Published as a “brief report”, this manuscript details case details of a family with known Pompe’s Disease (three prior demises, one termination and two postnatally). When Pompe’s Disease was diagnosed in the first trimester of a 4th pregnancy, treatment began at 24 weeks’ gestation using ultrasound-guided administration of alglucosidase alfa. Fetal treatment continued every two weeks for ten weeks, in a protocol similar to in utero blood transfusions. At each medication administration, a small volume of blood was drawn to measure plasma trough levels of GAA enzyme activity and serum anti-drug antibody titers. At birth, the infant was treated with immune-tolerance induction, and continued with enzyme administration every two weeks. At 13 months of age, the child had no signs of cardiomyopathy, as found in 2 prior siblings, and normal developmental markers and milestones. This landmark proof-of-concept experiment was years in the making due to meticulous animal research, protocol development, and scientific teamwork.

The Rearing of Maternal-Fetal Surgery: The Maturation of a Field from Conception to Adulthood [14]Chen C, et al. Clin Perinatol. 2022 Dec;49(4):799-810. doi: 10.1016/j.clp.2022.06.003. Epub 2022 Oct 9.

The field of fetal diagnosis and treatment has evolved exponentially since the 1970’s. Technological advances in fetal ultrasound and fetal MRI has enhanced accuracy of fetal diagnosis. Development of fetoscopy scopes and instruments has permitted development of laser therapy for twin-twin transfusion syndrome, fetoscopic endotracheal occlusion for treatment of severe CDH, and more recently fetal repair of open neural tube defects. Maturation of this field has resulted from innovation, scientific experimentation, and multicenter collaboration.

This relatively short, well-written manuscript provides a summary of developments in the field of maternal-fetal surgery over a 60-year period, particularly discussing ethical, societal and moral issues involved. It is written from the perspective of Michael Harrison, a pediatric surgeon practicing at the University of California San Francisco, who most consider the “Father of Fetal Surgery.” The manuscript begins discussing the earliest fetal therapy, in utero transfusion for erythroblastalis fetalis. Naissance of this therapy prompts discussion of ethical dilemmas in fetal therapy, balancing universality and selectivity. The paper discusses many of the problems tackled by the group at UCSF, and then describes the growth of fetal therapy consortiums, like Eurofetus. the International Fetal Medicine and Surgery Society, and the North American Fetal Therapy Network (NAFTNet). The authors conclude with surveys of several successful fetal therapies: fetal tracheal occlusion, the MOMS trial for myelomeningocele, and in utero gene therapy. Overall, the brief article gives a whirlwind overview of the history of fetal therapy, and is an excellent jumping off point for residents, fellows, and others learning about the field.

Fetal Risk Stratification and Outcomes in Children with Prenatally Diagnosed Lung Malformations: Results from a Multi-Institutional Research Collaborative[15] . Kunisaki SM, et al. Ann Surg. 2022 Nov 1;276(5):e622-e630.

Fetal congenital lung malformations (CLMs) are a common set of diseases referred to pediatric surgeons for prenatal consultation. Based on single center studies, congenital pulmonary airway malformation volume ratio (CVR) has been an important biomarker used for prognosis in counseling parents and decision-making around birthing location and fetal therapy, with a CVR of >1.6 being a risk factor of fetal or neonatal intervention.

This multi-institutional study re-evaluated CVR as a risk factor for fetal and neonatal outcomes. It found that an initial CVR of < 1.4 was the optimal threshold for very low risk of fetal hydrops and maximum CVR of < 0.9 indicated a low risk of requiring neonatal respiratory support. The study provides an updated algorithm for perinatal management of CLMs. The low rate of CVR measurements in this cohort (< 50%) demonstrates an opportunity for improved standardization and quality of care in the prenatal evaluation of CLMs.

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting) [16]. Herzeg A, et al. J Clin Pharmacol. 2022 Sep;62 Suppl 1(Suppl 1): S36-S52.

Although there have been significant advances in fetal diagnosis and treatment of anatomic conditions, prenatal therapy for genetic conditions remains limited. Monogenic diseases are those that occur as a result of differences in a single gene and result in a variety of clinical manifestations. These diseases are often inherited. This review provides pertinent background information, rationale, and considerations for the use of prenatal somatic gene cell therapy (PSCGT) for the treatment of severe genetic diseases. PSCGT refers to in-utero gene replacement or editing of somatic cells. Preclinical data that highlight the promise of PSCGT have been shown in spinal muscular atrophy (SMA), Lysosomal storage diseases, Hemophilia A &B, hemoglobinopathies and cystic fibrosis. Gene therapies considered in this review article include: the use of antisense oligonucleotides (ASOs), gene replacement using a viral vector, gene editing, and gene activation or inhibition.

The authors describe criteria that should be met in order to consider a condition appropriate for PSCGT. These include a known natural history, effective means of diagnosis using routine screening, accurate means of prenatal molecular diagnosis, a clear indication that the benefits of PSCGT outweigh the risks of alternatives, and available expertise to perform the fetal interventions. The most relevant modes of delivery for PSCGT include intra-vascular, intra-amniotic, and intracerebroventricular injections.

PSCGT offers advantages over current strategies for gene therapy.  Given that PSCGT can be offered prenatally, it can be offered significantly earlier in the disease course, thus minimizing disease progression. It can also be used before the blood-brain barrier is formed, allowing the delivery of medications that would not otherwise cross this barrier. In addition, given that the fetal immune system is immature, PSCGT could result in minimal immune response, thus allowing for postnatal gene therapies. Lastly, PSCGT is likely less costly than current gene therapies.  This review also discusses potential risks of PSCGT such as the integration of viral vector genome with human genome, gene editing/replacement outside of the target gene, transduction of viral cells into germline, and maternal exposure to viral vectors. Procedural risks to consider include injury to umbilical vessels, bleeding, fetal bradycardia, and fetal demise.

The authors discuss important safety considerations including adverse event reporting, with fetal and maternal adverse events reported separately.  They also propose the need for a standard set of measures for PSCGT to evaluate its safety and efficacy. Lastly, the authors raise critical ethical considerations including issues of consent when the pregnant parent and non-pregnant parent are not in agreement, off-target effects of gene therapy on future offspring, costs and access to PSCGT.

Neonatal and Fetal Therapy of Congenital Diaphragmatic Hernia-related pulmonary hypertension [17]. De Bie FR, et al. Arch Dis Child Fetal Neonatal Ed. 2022 Sep;107(5):458-466. Epub 2021 Dec 24.

Congenital diaphragmatic hernia (CDH) is associated with significant neonatal mortality and morbidity, determined by the severity of pulmonary hypoplasia and pulmonary hypertension (PH). Although PH resolves in the majority of CDH patients in the neonatal period, those patients with refractory PH have worse outcomes. This comprehensive review explores the pathophysiology and interplay of pulmonary hypoplasia, pulmonary hypertension, and cardiac ventricular dysfunction. This review outlines evidence based multimodal treatment strategies in the treatment of CDH with particular emphasis on strategies to ameliorate PH.

Delivery room management includes early intubation and ventilation prior to cord clamping, if possible, to improve lung aeration, pulmonary blood flow and avoid hypoxia and acidosis. The principles of gentle ventilation are clearly delineated. A pressure-limited, volume-controlled ventilation strategy with permissive hypercapnia avoids barotrauma to the hypoplastic lung and avoids compromising pulmonary circulation.  In addition, evidence supports a lower FiO2 to achieve a preductal saturation >85% and post ductal saturation of >70% which reduces free radical release which can aggravate pulmonary vasoconstriction.

Optimizing cardiac output consists of adequate fluid resuscitation and use of dopamine and/or low dose epinephrine to support right ventricular function, and milrinone in the setting of left ventricular hypoplasia and dysfunction. Maintaining ductal patency may help reduce RV afterload. Pulmonary vasodilators may improve RV function, pulmonary circulation, and systemic oxygenation. Although inhaled nitric oxide is used in 62% of all neonates with CDH, current evidence suggests it is most beneficial in patients with preserved left ventricular function. Phosphodiesterase inhibitors, prostanoids, endothelial receptor antagonists, and calcium sensitizers are all treatment options and can improve function in certain patients. These therapies and the evidence for their use, as well as ongoing trials to prove efficacy, are discussed in this paper. 

Experimental strategies to improve pulmonary vasodilation, reverse remodeling, promote regeneration, and improve oxygenation are also reviewed. These include use of endothelial progenitor cells, tyrosine kinase inhibition, liquid ventilation, and others. Fetal therapies, including FETO and maternal sildenafil, as well as other more experimental synergistic agents are also discussed

Being small for gestational age is not an independent risk factor for mortality in neonates with Congenital Diaphragmatic Hernia: a multicenter study [18]. Zenilman A, et al. J Perinatol. 2022 Apr 21.

Neonates who are small for gestational age have overall increased morbidity and mortality. Various factors including prematurity, size of defect, low birth weight, and lung to head ratio have been demonstrated to correlate with outcomes for neonates with congenital diaphragmatic hernia. The impact of being small for gestational age on outcomes for neonates with congenital diaphragmatic hernias has not been fully evaluated.

The authors conducted a retrospective analysis of 589 neonates with CDH enrolled in the multicenter Diaphragmatic Hernia Research and Exploration, Advancing Molecular Science study. They compared the outcomes of neonates who were small for gestational age (n=90) to those appropriate for gestational age (n=499). Being small for gestational age was associated with worse outcomes on univariate analysis, but was not an independent risk factor on multivariate analysis.

Single Fetal Demise following Fetoscopic Ablation for Twin-to-Twin Transfusion Syndrome-cohort study, systematic review, and meta-analysis [19]. Mustafa HJ, et al. Am J Obstet Gynecol. 2022 Mar 4:S0002-9378(22)00164-8.

Fetoscopic laser photocoagulation improves survival in twin-twin transfusion syndrome. A number of studies have evaluated preoperative and operative risk factors associated with fetal demise, yet these results have varied between centers and a systematic review and meta-analysis have not yet been conducted.

The authors performed a retrospective cohort study of twin-twin transfusion cases that underwent fetoscopic laser photocoagulation at two fetal centers and evaluated risk factors for single fetal demise. They also performed a systematic review and meta-analysis of previously published papers. A total of 23 studies were included. The incidence of donor demise ranged from 10.9% to 35.8% and the incidence of recipient demise ranged from 7.3% to 24.5%. Abnormal umbilical artery flow, advanced stage, arterioarterial anastomoses, and low fetal weight were significant preoperative risk factors for single fetal demise. Sequential selective coagulation of vascular anastomoses was the only operative factor found to be protective against donor demise.

Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018 [20].Bell EF, et al. JAMA. 2022 Jan 18;327(3):248-263.

Survival after preterm birth has improved in the past few decades. Data on the outcomes of children born extremally premature, before 25 to 26 weeks, is limited.

The authors used prospectively collected registry data for extremally premature infants (between 22 weeks and 27 weeks) born at 19 academic medical centers in the US between 2013 and 2018. Morbidity and mortality for these infants were compared to a similar cohort of infants born between 2008 and 2013. Premature infants born in 2013-2018 had a significantly higher survival to discharge of 78.3% compared to 76.0%. This increase was particularly notable for the most premature infants, with an increase in survival to discharge for infants born at 23 weeks from 32% in 2008-2013 to 49% in 2013-2018. In the 2013-2018 cohort a total of 48% of the surviving infants had no or mild NDI, for infants born at 23 weeks 31% had no or mild NDI.

Perinatal Outcome in Fetuses with Dislodged Thoraco-Amniotic Shunts [21]. Abbasi N, et al. Fetal Diagn Ther. 2021;48(6):430-439.

Insertion of fetal thoraco-amniotic shunts can improve survival in large fetal pleural effusions and macrocystic CPAMs. However, shunt migration or blockage can occur in up to 15% of cases, often necessitating a repeat procedure. There is limited data on the long-term management of dislodged shunts.   

A retrospective review of 211 fetuses undergoing thoraco-amniotic shunt placement was performed. Shunts were dislodged in 18 fetuses (8.5%). Of the 18 dislodged shunts, there were 7 cases of extrathoracic migration and 11 cases of intrathoracic migration. Of the 11 shunts with intrathoracic migration, 9 were left in situ without complication. This suggests retained intrathoracic shunts are well tolerated and may not require surgical removal.

TOTAL Trial for Severe Hypoplasia Investigators. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia [22]. Deprest JA, et al. N Engl J Med. 2021 Jul 8;385(2):107-118. Epub 2021 Jun 8.

Fetal lung growth is stimulated by fetal occlusion. Fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH) in the fetus is demonstrated to have an acceptable safety profile for the mother. When compared to historical controls, neonatal survival among fetuses with CDH who underwent FETO is improved, but the risk of premature birth was higher.    

A randomized, prospective, multicenter study was performed to compare FETO to expectant prenatal care for fetuses with CDH and severe pulmonary hypoplasia. Enrollment was stopped after 80 patients for efficacy. Forty percent of infants in the FETO group survived to discharge from the NICU compared to 15% in the expectant care group. This increased survival persisted as 6 months of age. For fetuses with CDH with severe pulmonary hypoplasia FETO improves survival. 

Outcome of Twin-Twin Transfusion Syndrome according to Quintero stage of disease: Systematic Review and Meta-Analysis [23], Di Mascio et al. Ultrasound Obstet Gynecol. 2020 Dec;56(6):811-820.

The overall suspected survival rate after fetoscopic laser treatment for twin-twin transfusion syndrome (TTTS) is 50-70%. Laser therapy is considered the standard of care for Quintero stage II-IV TTTS.

This systematic review included 26 studies detailing 2699 twin pregnancies. Fetal survival in pregnancies complicated by TTTS was highest in Stage I and II. In Stage III and IV, survival of at least one twin remained high. In pregnancies complicated by Quintero stage I TTTS the rate of fetal survival of at least one twin was similar between different management strategies (expectant management, laser therapy, or amnioreduction). Amnioreduction was associated with a slightly higher rate of survival of both twins. Randomized control trials and long-term follow-up are necessary to provide further insight into the optimal management of stage I TTTS.

Prenatal assessment of Congenital Diaphragmatic Hernia at North American Fetal Therapy Network centers: A continued plea for standardization [24], Perrone et al. Prenat Diagn. 2021 Jan;41(2):200-206.

Prenatal assessment of congenital diaphragmatic hernia (CDH) includes ultrasound evaluation of the observed-to-expected lung-to-head ratio (o/e LHR). This is useful for prognostication, as o/e LHR inversely correlates with neonatal morbidity and an o/e LHR less than 25% may be used to select fetuses who could benefit from fetal endoluminal tracheal occlusion (FETO). Fetal MRI measurement of total fetal lung volume is also used to guide prenatal counseling. Currently, multiple methods to measure fetal lungs, both on ultrasound and on MRI, are used.

The authors conducted a survey of centers in the North American Fetal Therapy Network (NAFTNet) to evaluate fetal US and MRI practices. There was significant variation between centers in both US and MRI evaluation of fetal lungs. On US evaluation, only 58% of centers overall used the trace method, which is recommended by NAFTNet, to obtain LHR. Seventy-eight percent of centers overall used MRI for evaluation. There was variation between centers in the timing of MRI, ranging from < 24 weeks to 32-36 weeks, and in MRI lung volume calculation reference. There was increased consistency between the eleven centers that offered FETO, with 91% using the trace method in the US and 82% using fetal MRI. In response to the lack of uniformity in evaluation across fetal treatment centers, NAFTNet has developed a dedicated working group to standardize the prenatal prognostication and management of CDH.

Fetal Diagnosis and Therapy during the COVID-19 Pandemic: Guidance on Behalf of the International Fetal Medicine and Surgery Society [25], Deprest et al. Fetal Diagn Ther 2020; 47(9):689-698.

The COVID-19 pandemic has stressed patients and healthcare givers alike and challenged our practice of antenatal care including fetal diagnosis and therapy.

Reviews relevant recent information to allow optimize prenatal care delivery. Potential modifications to obstetric management and fetal procedures in SARS-CoV2-negative and SARS-CoV2-positive patients with fetal anomalies or disorders are discussed as most fetal therapies are time-sensitive and cannot be delayed.

Summary of recommendations

• Routine antenatal care should be adjusted by spacing out appointments and using telemedicine and home-based care. Ultrasound and noninvasive prenatal screening may also need re-arrangement.
• If resources allow, there may be a place for generalized testing of pregnant women for SARS-CoV-2 infection. We do recommend testing prior to any operative procedure.
• Pregnant women with SARS-CoV-2 infection may have a variable disease severity. It is uncertain whether they are at increased risk for COVID-19 disease. They should be managed based on the severity and nature of their complications. Cesarean delivery should be performed based on standard obstetric indications and considered in cases of septic shock or acute organ failure. Delivery may also facilitate maternal ventilation.
• There is minimal and unconfirmed evidence for spontaneous vertical transmission. This risk theoretically may be increased by fetal procedures by disruption of either the feto-maternal barrier or the fetal skin. One should avoid transplacental instrument passage.
• Fetal therapy is time-sensitive and hence should not be considered as elective care. In SARS-CoV-2 positive patients one may consider delaying an intervention to avoid surgical morbidity, provided the procedure can wait. This applies, in particular, to complex procedures under general anesthesia and in symptomatic patients. Conversely, life-saving minimally invasive procedures should continue.
• Procedures of unproven fetal benefit should not be offered.
• When caring for a neonate born to a mother with suspected or confirmed COVID-19, strict infection control measuresshould apply, including quarantine. Based on current data, the spectrum of COVID-19 infection in neonates is usually mild and their short-term outcomes are favorable.
• Health care workers incur a significant risk of SARS-CoV-2 infection which is an argument for testing patients. When caring for suspected or SARS-CoV-2-positive patients, appropriate personal protective equipment should always be used.
• The COVID-19 pandemic does not strike equally around the world. Centers must periodically review and adjust their approach to fetal therapy as demands and available resources change.
• When consenting women with SARS-CoV-2 infection for fetal procedures of proven benefit, there is no autonomy-based ethical obligation to provide information about theoretical risks. Informed consent provides information about reasonable options and their benefits and risks and supports patient understanding and evaluation based on their own values and beliefs.
• Termination of pregnancy is time sensitive and should not be considered as “elective.”
• Registration of maternal and fetal outcomes is recommended because large cohort data will rapidly boost our knowledge.

Ethical Challenges in Invasive Maternal-fetal Intervention [26], Austin et al. Semin Pediatr Surg. 2019;28(4):150819.

The field of maternal-fetal intervention is rapidly progressing and with it comes new and often complex ethical considerations that must be addressed.

Reviews the ethical issues that arise in maternal-fetal intervention and provides a list of recommended resources that any institution offering maternal-fetal intervention should have in place to meet the ethical obligations of such work.

Anhydramnios in the Setting of Renal Malformations: The National Institutes of Health Workshop Summary [27], Moxey-Mims et al. Obstet Gynecol 2018 Jun;131(6):1069-1079.

Anhydramnios is a lack of amniotic fluid surrounding the developing fetus defined as the deepest pocket of amniotic fluid measuring two cm or less in the second trimester. Anhydramnios due to fetal renal or urinary tract anomalies can result in severe pulmonary hypoplasia upon delivery. Amnioinfusion to restore amniotic fluid volume in pregnant women who carry a fetus with such anomalies may be a way to prevent pulmonary hypoplasia. This paper is a summary of a meeting of a panel of experts to further discuss this topic and to suggest an appropriate path to obtain meaningful research on the subject.

Ethical Considerations Concerning Amnioinfusions for Treating Fetal Bilateral Renal Agenesis [28], Sugarman et al. Obstet Gynecol 2018;131(1):130-134.

Legal and Ethical Issues in Fetal Surgery [29], Dickens et al. Int J Gynaecol Obstet 2011 Oct;115(1):80-3.

Weighing the Social and Ethical Considerations of Maternal-Fetal Surgery [30], Antiel et al. Pediatrics 2017 Dec;140(6).

Ethical Challenges in the New World of Maternal-Fetal Surgery [31], Antiel Semin Perinatol 2016 Jun;40(4):227-33.

Prevalence, Correlates, and Outcomes of Omphalocele in the United States, 1995-2005 [32], Marshall et al. Obstet Gynecol 2015 Aug;126(2):284-93.

Fetal MRI-Calculated Total Lung Volumes in the Prediction of Short-Term Outcome in Giant Omphalocele: Preliminary Findings [33], Danzer et al. Fetal Diagn Ther. 2012;31(4):248-53.

Management of Giant Omphaloceles: A Systematic Review of Methods of Staged Surgical vs. Nonoperative Delayed Closure [34], Bauman et al. J Pediatr Surg 2016 Oct;51(10):1725-30.

Giant Omphaloceles: Surgical Management and Perinatal Outcome [35], Akinkuotu et al. J Surg Res 2015 Oct;198(2):388-92.

Prenatal Steroids for Microcystic Congenital Cystic Adenomatoid Malformations [36], Curran et al. J Pediatr Surg 2010 Jan;45(1):145-50.

Cystic Adenomatoid Malformation Volume Ratio Predicts Outcome in Prenatally Diagnosed Cystic Adenomatoid Malformation of the Lung [37], Crombleholme et al. J Pediatr Surg 2002 Mar;37(3):338-8.

Congenital Lung Malformations: Informing Best Practice [38], Baird Ret al. Semin Pediatr Surg 2014 Oct; 23(5):270-7.

Gastroschisis outcomes in North America: a comparison of Canada and the United States [39], Youssef et al. J Pediatr Surg 2016 Jun;51(6):891-5.

Delivery planning for pregnancies with gastroschisis: findings from a prospective national registry [40], Al-Kaff et al. Am J Obstet Gynecol 2015 Oct;213(4):557.e1-8.

Effect of gestational age at birth on neonatal outcomes in gastroschisis [41], Carnaghan et al. J Pediatr Surg 2016 May;51(5):734-8.

Prenatal management of the fetus with isolated congenital diaphragmatic hernia in the era of the TOTAL trial [42], Deprest et al. Semin Fetal Neonatal Med 2014 Dec; 19(6):338-48.

Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia [43], Jani et al. Ultrasound Obstet Gynecol. 2007 Jul;30(1):67-71.

Use of magnetic resonance imaging in prenatal prognosis of the fetus with isolated left congenital diaphragmatic hernia [44], Victoria et al. Prenat Diagn 2012 Aug;32(8):715-23.

Unique Considerations: Preterm Prelabor Rupture of Membranes in the Setting of Fetal Surgery and Higher Order Pregnancies [45], Forde et al. Obstet Gynecol Clin North Am 2020 Dec;47(4):653-669.

Fetal Surgery and Delayed Cord Clamping: Neonatal Implications [46], Frank et al. Crit Care Nurs Clin North Am 2018 Dec;30(4):499-507.

Postoperative imaging following fetal open myelomeningocele repair: The clinical utility of magnetic resonance imaging and sonographic amniotic fluid volumes in detecting suspected hysterotomy scar dehiscence [47], Seaman et al. Prenat Diagn 2020 Jan;40(1):66-70.

References