the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 1

STATE OF THE ART REVIEW

Prenatal regenerative fetoscopic interventions for congenital anomaliesRodrigo Ruano

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology and Center for Regenerative Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USACorrespondence to: R Rodrigo ruano.rodrigo@mayo.edu; rodrigoruano@hotmail.comCite this as: BMJ 2020;370:m1624 http://dx.doi.org/10.1136/bmj.m1624

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors.

IntroductionAdvances in early diagnostics have enabled therapeutic approaches before birth.1 An exciting output is the overarching goal of achieving regenerative correction prenatally, thereby averting florid disease before it becomes a chronic debilitating condition reliant on delayed postnatal clinical management. Indeed, congenital anomalies left untreated are associated with high mortality and morbidity. They are collectively responsible for a considerable number of perinatal deaths, and also carry serious emotional impact on families and economically on health systems. Infants with congenital anomalies need multidisciplinary care, including long duration management in tertiary centers and neonatal intensive care units. Of those who survive, most need complex postnatal surgeries and multidisciplinary medical care, especially when vital organs such as the heart, brain, lungs, and/or kidneys are affected.2 3

In utero interventions aim to avoid perinatal demise.1 The first described fetal therapy was intrauterine fetal blood transfusion for erythrobla­stosis fetalis, when antibodies from rhesus negative mothers cross the placenta and attack fetal rhesus positive red cells.4 These fetuses develop severe anemia, cardiac failure, and hydrops fetalis (ana­sarca) and then progress to in utero demise. Under ultrasound guidance, blood can be transfused to the umbilical cord to prevent cardiac failure and ensure fetal vitality.4

The potential to affect a congenital anomaly while the fetus is still linked to the placenta is now a reality. Clinical deployment of in utero interventions to

address life threatening congenital diaphragmatic hernia (CDH), lower urinary tract obstruction (LUTO), and spina bifida are prime examples of how the field has evolved. Collectively, “prenatal regenerative therapies” have been proposed with the objective of reversing or preventing organ damage through restoration and/or regrowth of affected organs.5

This review summarizes evidence spanning more than 20 years that underpins the roll out of re­generative prenatal interventions for CDH, LUTO, and spina bifida. The growing experience with fetal therapy aims to restore fetal organ structure and function and improve postnatal outcomes, and provides the basis to expand the scope of regenerative medicine to a clinically applicable portfolio of prenatal interventions.

Sources and selection criteriaWe identified the references in this review through a comprehensive search of the following databases: Ovid MEDLINE(R) and Epub ahead of print, In­Process and other non­indexed citations, and Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Scopus. An experienced librarian designed and conducted the search strategy with the input of the primary author. Controlled vocabulary was used to search for diagnostic methods, prognostic indicators, and fetal therapy for congenital diaphragmatic hernia, spina bifida, and congenital lower urinary tract obstruction. We included only English language articles, and we considered all study types—including case reports, case series, randomized controlled trials, reviews, and experimental animal studies—for this review. Articles outside of the topic of interest or

ABSTRACT

Fetal intervention has progressed in the past two decades from experimental proof-of-concept to practice-adopted, life saving interventions in human fetuses with congenital anomalies. This progress is informed by advances in innovative research, prenatal diagnosis, and fetal surgical techniques. Invasive open hysterotomy, associated with notable maternal-fetal risks, is steadily replaced by less invasive fetoscopic alternatives. A better understanding of the natural history and pathophysiology of congenital diseases has advanced the prenatal regenerative paradigm. By altering the natural course of disease through regrowth or redevelopment of malformed fetal organs, prenatal regenerative medicine has transformed maternal-fetal care. This review discusses the uses of regenerative medicine in the prenatal diagnosis and management of three congenital diseases: congenital diaphragmatic hernia, lower urinary tract obstruction, and spina bifida.

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beyond the scope of this review were excluded. The search strategies are available as appendix files.

Guiding principles of fetal interventionsFetal interventions were introduced to improve perinatal survival, but their role has expanded to improve morbidity, quality of life, and regenerate or restore malformed fetal organs.6 Proper selection of candidates is important to avoid unnecessary procedures in fetuses with highly fatal conditions or those with good prognosis without in utero intervention.7 8 The International Fetal Medicine and Surgery Society has proposed guiding principles including

• Precise prenatal diagnosis• Well known pathophysiology of the congenital

anomaly• Absence of genetic/chromosomal disease• Absence of associated major anomalies• Natural course of the congenital anomaly sho­

wing a life threatening situation or even severe debilitation despite postnatal management

• Morbidity of the intervention should be accep­table for the mother and fetus

• Multidisciplinary evaluation and consensus• A family informed consent after extensive coun­

selling about potential risks and benefits of the proposed procedure

• Absence of adequate postnatal treatment for the condition

• Feasible in utero intervention, and• Implementation of adequate ethical principles.9

To accomplish these principles requires rigorous experimental and clinical research studies.10 Experi­mental research and observational studies are important to understand the history and patho physiology of congenital anomalies.11 Thereafter, investigations of possible in utero interventions are undertaken to establish feasibility, safety, and efficacy in clinical settings.12 Fetal surgeries have progressed from open hysterotomies to less invasive fetoscopic techniques with the objective of improving maternal and fetal outcomes.13

Fetal endoscopic surgeriesFetal endoscopic surgeries, or fetoscopic procedures, are considered to be less invasive compared with open fetal surgery with hysterotomy. The aim is to improve

survival and reduce morbidity by regenerating (restoring) malformed fetal organs relying on innate corrective healing or re­differentiating processes. This concept is illustrated in fetal endoscopic tracheal occlusion (FETO) for CDH, fetal intervention for lower urinary tract obstruction (LUTO); and fetoscopic spina bifida repair.

Fetal endoscopic tracheal occlusion for congenital diaphragmatic herniaDefinition and epidemiology of congenital diaphragmatic herniaCDH is a failure of the diaphragm to fully close during early development, resulting in the herniation of abdominal contents into the chest cavity. CDH is associated with high mortality because of pulmonary hypoplasia and pulmonary hypertension (fig 1). The prevalence of CDH is approximately 2.5/10 000 pregnancies and isolated CDH has a predilection for male fetuses (1.5:1 male to female).14 15 Defects are more common on the left side (80­90%) and occur in the posterolateral portion (90%).15­17

CDH is often associated with major structural abnormalities and chromosomal aneuploidy (complex CDH). Major structural abnormalities are seen in 28­34% of fetuses, with cardiac, nervous system, and musculoskeletal being the most common14 16­18; however the reported incidence of complex CDH can be high as 55­61%.19 20 Additionally, 8­18% of fetuses with CDH have aneuploidy, with trisomy 18 being most common, or other genetic syndromes such as Fryn’s or Apert syndrome.14 20 21

Pathophysiology of congenital diaphragmatic herniaFormation of the diaphragm occurs between the fourth and 10th week of gestation.22 The course of CDH occurs in the setting of aberrant formation of the pleuroperitoneal folds or the post­hepatic mesenchymal plate.22 23 The predominant com­plications associated with CDH are pulmonary hypoplasia and pulmonary arterial hypertension.24 25 Initially it was suspected that these complications occur as a result of compression from the abdominal contents protruding into the chest; however other data suggest a complex pathogenic process.

Lung development occurs in four stages starting at 4 weeks’ gestation and continuing into the postnatal period.26 27 Lung budding is seen from 16 to 24 weeks’ gestation, and alveolar formation and maturation from 24 weeks’ gestation to 3 years of postnatal life.26 Concurrent with this process is pulmonary vascular development which occurs through neovascularization and branching of pre­existing conduits between weeks 10 and 11.27­30 Initially the pulmonary vessels are thick and muscular with high vascular resistance that decreases with gestation and after birth to promote gas exchange.27 In fetuses with CDH, on histologic exam the lungs appear less developed for gestational age, with the ipsilateral more severely affected than the contralateral lung.31 Decreased branching of

GLOSSARY• CDH Congenital diaphragmatic hernia• LUTO Lower urinary tract obstruction• FETO Fetal endoscopic tracheal occlusion• ELMO Extracorporeal membrane oxygenation therapy• LHR Lung to head ratio• MRI Magnetic resonance imaging• TFLV Total fetal lung volume• VAS Vesicoamniotic shunting• NTD Neural tube defect• MMC Meningomyelocele (open spins bifida)

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bronchioles with subsequent acinar hypoplasia is apparent.31­33 Fetal lungs affected by CDH from 17 to 24 weeks also show a decreased number of vessels and total vascular bed volume.34 35 Additionally, pulmonary vessels are hyper­muscularized, with variable vascular reactivity contributing to postnatal pulmonary hypertension.36 37

Advances in postnatal care of infants with CDH have reduced postnatal mortality. However, affected infants require complex postnatal treatment, in­cluding extracorporeal membrane oxygenation therapy (ECMO) and prolonged neonatal intensive care unit admission. Despite advances in postnatal management, postnatal mortality is 20­40%. There­fore, prenatal interventions for CDH were proposed to promote lung growth and development while the fetus is still oxygenated by the placenta.

Prenatal diagnosis and prognostication of fetuses with congenital diaphragmatic herniaOutcomes in children with CDH are dependent upon the degree of pulmonary hypoplasia and pulmonary arterial hypertension. Previously, prenatal ultra­sound was used to identify these lesions, which allowed for planning for delivery and immediate resuscitation efforts.38 39 Prenatally diagnosed CDH tends to be more severe or complex (associated with other malformations) with lower long term survival than in infants diagnosed postnatally (73% versus 93%).40

While ongoing efforts to improve detection rates are needed, additional goals of prenatal evaluation have focused on prognostication markers for counseling prospective parents and identifying high risk fetuses that could benefit from early in utero intervention.41 42 Different prognostic indicators have been proposed, but the most commonly used include

the observed­to­expected lung­to­head ratio (o/e LHR) and observed­to­expected total lung volume (o/e TLV) as well as liver herniation (table 1).

Pulmonary hypoplasia and pulmonary arterial hypertensionPulmonary hypoplasia and pulmonary arterial hypertension are the predominant complications associated with CDH morbidity and mortality. Many studies have evaluated how to best measure and predict lung volume. One study44 described the lung­to­head circumference ratio (LHR) which is obtained by tracing the contralateral lung area in a trans­axial view at the level of the four chamber heart and dividing it by the head circumference.44 It was subsequently noted that the lung grew more rapidly than the head circumference, leading to increasing LHR throughout gestation, however, the LHR in CDH fetuses compared with normal gestational age equivalents remains stable through­out pregnancy.45  46 This o/e LHR has become the most utilized ultrasound tool to predict postnatal morbidity and mortality in clinical practice. Survival of neonates with isolated CDH based on o/e LHR of less than 25%, 25­45%, and greater than 45% was 18%, 66%, and 89%, respectively.46 47 Other studies have confirmed a notable improvement in survival with increasing o/e LHR.43 48­50 Assessment of the liver position (being up or down), or liver­to­thorax ratio, in combination with o/e LHR improves predictability of postnatal outcomes.51­53

Liver positionLiver position (intra­abdominal or intrathoracic) also correlates with postnatal outcomes. Initial classification of liver­up or ­down determined by color­flow Doppler ultrasonography was used to predict postnatal morbidity and survival.51 54­56 Additionally, studies have shown an association between the need for ECMO (25% versus 80%)55 and persistent pulmonary hypertension (12% versus 40%) in liver­down compared with liver­up, respectively.56 Magnetic resonance imaging (MRI) of the fetus allows for quantification of liver herniation, with higher herniated volume associated with mortality and ECMO requirement.57 58

Stomach locationPostnatal identification of the stomach in the chest was a known predictor of increased mortality, which led to it being used as a prenatal marker. Subsequent studies have further refined prognostication by stomach location with a four­grade system, assessed in a trans­axial image at the level of the four chamber heart. This grading system in order of severity is described as: intra­abdominal, anterior left chest, mid­to­posterior chest, and retro­cardiac.59 60 Post­natal morbidity and mortality correlate with stomach position grade.56 59 61 The association with stomach position and mortality also appears to correlate with the degree of liver herniation.62

Fig 1 | A fetus with left sided congenital diaphragmatic hernia at 28 weeks’ gestation. L=lungs; H=heart; D=diaphragm; Li=liver; S=stomach; B=bowel

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Total fetal lung volumeMRI of the fetus has enabled evaluation of total fetal lung volume (TFLV).63 Similar to LHR, TFLV is usually compared with the expected for gestational age (o/e TFLV). A meta­analysis showed correlation between o/e TFLV and postnatal mortality.64 Survival with o/e TFLV less than 35% ranges from 0% to 25% compared with 75­89% survival with o/e TFLV greater than 35%.49 58 65 66 In addition, one study58 showed improved prognostication when percentage liver herniation is incorporated with o/e TFLV.58 If MRI is not available, 3D ultrasound can also be used to calculate TFLV.67 68

The above studies have evaluated markers that appear to correlate with the degree of pulmonary hypoplasia. One study69 used 3D power Doppler ultrasound to evaluate pulmonary vascular indices and showed a correlation between these indices and the severity of postnatal pulmonary arterial hypertension.69 This can serve as an additional tool to evaluate fetuses that may benefit from in utero intervention.

Fetal interventions for congenital diaphragmatic herniaIn the 1980s, it was identified that exposure of pregnant rodents to nitrofen (2, 4­dichloro­1(4­nitrophenoxy)benzene) resulted in varying degrees of CDH.70 71 This enabled research into the course of CDH to better understand the embryology and pathophysiology of the disease. Lamb and rabbit models were introduced, in which an open in utero surgical procedure was performed to create a defect, which was subsequently closed and the pregnancy monitored for the remainder of gestation.72 73 Current in utero treatment for CDH would not exist without these models.

The hypothesis that transitory tracheal fetal occlusion could prevent severe pulmonary hypo­plasia was based on the clinical observation of congenital laryngeal/tracheal atresia. Fetuses with these conditions develop hyperplastic lungs, a finding that could address lung hypoplasia in fetuses with CDH.74­78 Imposing fetal tracheal occlusion has been tested in the experimental lamb model including open neck dissection, external metal

clips, or occlusion with silicone balloon followed by measuring fetal lung response.76 79­85 These models proved that temporary occlusion trapped pulmonary secretions in the airways, which led to stretching of the pulmonary tissue and reversal of vascular changes.32 86 87 With success in animal models, procedures were refined and translated into clinical practice.

Details of open in utero repair in animals and subsequently in humans have been documen­ted.24 25 88­94 These included testing the feasibility of closing the defect via an open approach. In those with liver­up, however, trying to replace the liver intra­abdominally led to obstruction of the ductus venosus blood flow and in utero demise.94 A prospective non­randomized trial88 that evaluated postnatal outcomes of open in utero repair of CDH found no benefit when compared with traditional postnatal repair; thus, the idea of open in utero repair was abandoned.88 With advancement of ultrasonography and fetoscopic instruments came the development of the FETO procedure. Compared with the open approach, this procedure could be done with a small port, which limited the risk of uterine rupture.80 89 95 Initial surgeries95 96 were performed with a low transverse skin incision and hysterotomy. The procedure was then refined97  98 and a FETO technique developed that could be performed entirely percutaneously. The fetoscope is advanced into the uterus, at which point the surgeon directs the scope into the fetal mouth, larynx, and then trachea. When in the appropriate position, a detachable balloon is inflated and deployed (fig 2A). The balloon is left in place for several weeks of pregnancy. Removal was initially performed using the ex utero intrapartum treatment procedure (EXIT).96 99 The current standard for balloon retrieval includes fetoscopic balloon removal at around 34 weeks, percutaneous ultrasound guided punc­ture, or postnatal tracheoscopy immediately after birth.95 97 98 100­103 Prenatal or immediate postnatal deflation of the tracheal balloon is essential to avoid neonatal demise.

The initial FETO randomized control trial was performed in fetuses with moderate to severe disease (defined as an LHR less than 1.4 measured between

Table 1 | Prenatal classification of severity of fetal CDH and fetal intervention options according to the severity of the disease41-43

Ultrasound findings Prognosis

Indication of fetal intervention

Fetal intervention options

  Lung area to head circumference ratio (mm)

Observed-to-expectant lung area to head circumference ratio

Observed-to-expectant total lung volume (mm3)

Stomach position (for left sided CDH)

Survival rate to discharge

   

Extremely severe

<0.70 <0.15 <0.29 posterior 5% to 10% Yes Early fetal endoscopic tracheal occlusion (22 to 26 weeks)

Severe 0.70 to 1.00 0.15 to 0.24 0.29 to 0.31 Mid to posterior 10% to 40% Yes Standard fetal endoscopic tracheal occlusion (26-29 weeks)

Moderate 1.01 to 1.90 0.25 to 0.35 0.32 to 0.39 anterior 40% to 80% Under investigation

Possibly late fetal endoscopic tracheal occlusion (29 to 32 weeks)

Mild >1.90 >0.35 >0.39 intra-abdominal >80% No Not indicated

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22 and 28 weeks with liver herniation) through laparotomy and hysterotomy.96 This trial found a higher frequency of prematurity (73% in the fetal tracheal occlusion group versus 31% in the standard postnatal treatment group, P=0.10) and no significant benefit in the FETO group (P=1.00), possibly related to hysterotomy; however the standard of care group had a higher than expected survival rate96 (survival rate of 73% in the fetal tracheal occlusion group versus 77% in the standard postnatal treatment group, P=1.00). Subsequently, the technique was refined97 to a percutaneous method, and showed statistically significant improvement in perinatal morbidity and mortality with FETO. A prospective non­randomized study98 of 210 fetuses who under­went FETO confirmed the feasibility of the procedure with successful balloon placement on first attempt in 97% of cases, and median procedure duration of 10 minutes. The study found improved survival compared with what was expected based on disease severity. The survival increased significantly in concordance with higher o/e LHR (survival rate (%)=(258×(o/e LHR (%))−28.68)/100; r=0.974, P<0.0001.98

A randomized trial104 included 41 fetuses with severe CDH defined as LHR <1.0 with liver herniation. It found that survival at 6 months was significantly increased from 5% to 50% in the standard FETO group for severe CDH (with balloon placement between 26 and 29 weeks’ gestation) (relative risk10.5 (95% confidence interval 1.5 to 74.7) P<0.01).104 Another trial101 also showed the feasibility of early FETO and improved outcomes in fetuses with extremely severe CDH (defined as LHR <0.7 or o/e LHR <0.17) with balloon placement as early as 22­24 weeks, compared with the standard balloon placement at 26­30 weeks. Survival of infants with extremely severe CDH with early placement was

63%, compared with 11% for the standard timing, and 0% for fetuses without FETO (P<0.01).101

Some studies have even suggested that FETO may improve fetal pulmonary vasculature and therefore it prevents severe pulmonary arterial hypertension.100  105 A large European multicenter randomized controlled trial (Tracheal Occlusion To Accelerate Lung Growth, TOTAL), is recruiting patients to confirm the benefits of FETO for fetuses with severe left sided CDH (ClinicalTrials.gov Identifier: NCT01240057) as well as moderate CDH (ClinicalTrials.gov Identifier: NCT02875860).

The most common complications associated with FETO are premature pre­labor rupture of membranes and preterm delivery, ranging from 36% to 47% and 31% to 42%, respectively.97 98 101 104 Ongoing trials will continue to provide information to optimize timing and safety of the FETO procedure.

Prenatal regenerative therapy for congenital diaphragmatic herniaWe have proposed that FETO serve as a prenatal regenerative therapy for CDH by promoting fetal lung regrowth and organ redevelopment.5 Our studies have shown that FETO performed at 28 weeks for severe CDH (o/e LHR between 20% and 25%) promotes fetal lung growth until a plateau of maximal growth six weeks after the procedure (at 34 weeks)100 (fig 2B). Our studies have also suggested that FETO improves pulmonary vasculature status associated with decreased risk of pulmonary arterial hypertension.100 103 Adequate fetal lung growth and pulmonary response were associated with increased survival rate. However, minimal fetal lung response was observed in fetuses with extremely severe CDH who underwent FETO at 28 weeks.100

A multicenter clinical trial compared early FETO (at 22­24 weeks) with classic FETO (at 26­30 weeks) in 27 fetuses with extremely severe CDH (o/e LHR <17%),101 showing that early FETO was associated with a higher survival rate as a consequence of a better fetal pulmonary response (survival rate of 62.5% in the early FETO group, 11.1% in the classic FETO group, and 0% in the postnatal standard treatment group, P<0.01).101 The response was not only more pronounced, but also persisted longer, with a plateau of maximal fetal pulmonary response achieved at 8­10 weeks after the procedure (around 32 weeks).101 This finding in early FETO can be explained by the physiology and embryological development of the lung in utero.101 Early FETO is performed during the end of the canalicular period of lung development, during which the terminal bronchioles, respiratory bronchioles, alveolar ducts, and capillary network are formed. Based on our experience, we propose early FETO for extremely severe CDH (now at o/e LHR <20%), and classical FETO for severe CDH (o/e LHR between 20% and 25%). Currently, our group does not offer FETO for mild CDH (table 1).

Based on the fetal pulmonary response, FETO may promote fetal lung regeneration.103 Animal and clinical studies have confirmed that FETO promotes

Fig 2A | Illustration of a fetal endoscopic tracheal occlusion in a fetus with left sided congenital diaphragmatic hernia at 28 weeks’ gestation

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fetal lung hyperplasia and growth; however, the exact mechanisms involved in fetal lung regeneration after FETO remains unknown. Future studies are necessary to investigate fetal lung development after FETO.106­109

Fetal cystoscopy for lower urinary tract obstructionDefinition and epidemiology of lower urinary tract obstructionFetal LUTO is defined as bladder outlet obstruction resulting from congenital renal outflow tract anomalies, and affects two to three infants per 10 0000 live births. The prevalence of antenatal LUTO is likely much higher, however, when considering elective termination and intrauterine fetal death.

LUTO represents a heterogeneous group of urinary outflow tract anomalies, each with distinct prevalence and/or gender predilection. It can occur as an isolated defect (isolated LUTO) or may be accompanied by other congenital abnormalities (complex LUTO) including chromosomal, cardiac, rectal, brain/spine, or skeletal anomalies.110 111 Posterior urethral valve is the most common cause of LUTO (63%). Less common causes include urethral atresia, urethral stenosis, prune belly syndrome, and “unspecified” LUTO (9.9%, 7%, 2.5%, and 17.6%, respectively).110 112 Previous studies have also shown an association between gestational age at diagnosis and a high prevalence of less common LUTO causes. such as urethral atresia.113 Etiological classification of LUTO not only provides specific prevalence and outcome data, but is also of prognostic significance correlating with survival. In addition, the wide range of manifestations seen in LUTO likely re­present a variation in severity of outflow tract obstruction (complete versus partial bladder outlet obstruction).114

The high perinatal morbidity and mortality of LUTO are primarily owing to complications of renal

impairment, oligohydramnios, and pulmonary hypoplasia.111 114 LUTO accounts for 15% to 20% of pediatric end stage renal failure115 as well as 10% to 60% of pediatric renal transplantations.111 Mortality rates vary but can be as high as 80% to 90%.114 116

Pathophysiology of lower urinary tract obstructionLUTO results in fetal bladder dilation (megacystis) with subsequent bladder muscle hypertrophy/hyperplasia and increased intravesical pressure and hydro­ureter and hydronephrosis.117 Urinary stasis in the renal pelvis and calyces leads to renal dysplasia.117 The downstream effects of fetal anuria and in utero renal dysfunction include oligohydramnios (or anhydramnios) and pulmonary hypoplasia.117 118 Animal models of LUTO have documented the natural course of LUTO in fetal rabbit, fetal rat, pigs, and guinea pigs. The fetal lamb model has been the most reliable.119 These studies119 120 have confirmed the downstream effects of bladder outflow obstruction. According to one study,121 histologic analysis of the obstructed kidneys in LUTO shows cystic dysplasia in the sub­capsular renal cortex, dilated primitive ductules with fibrous tissue cuffs, primitive glomeruli, and disorganized interstitia. The pattern of renal dysplasia documented in these animal studies is similar to that of human neonates,120 122 123 which suggests a possible causal link between LUTO and renal dysplasia.

The rationale for fetal intervention in LUTO is based on the understanding of the natural course and detrimental outcomes of LUTO. Fetal therapy has the potential to ameliorate pulmonary hypoplasia and possibly prevent end stage renal disease.

Prenatal diagnosis and prognostication of fetuses with lower urinary tract obstructionPrenatal detection and prognostication of LUTO facilitates proper counselling of potential parents as well as appropriate selection of candidates for fetal therapy. Fetal anatomic ultrasound screening has improved prenatal detection of LUTO. According to a large population study, prenatal detection of LUTO increased from 33% to 62% over the 14 year study period.111 Comprehensive fetal anatomic survey is also warranted to rule out complex LUTO, which makes up approximately 20% of all cases.110 111 Hence, fetal echocardiography, genetic counselling, chorionic villus sampling, or amniocentesis are all essential components of investigating LUTO depending on initial presentation or clinical suspicion.

The sensitivity of ultrasound diagnosis of LUTO is between 50% and 59%, according to two large LUTO population series110 111 but sensitivity as high as 95% has been reported for certain ultrasound parameters, such as renal hyper­echogenicity.124 Ultrasound findings in LUTO include oligohydramnios (or anhydramnios), which is defined as an amniotic fluid index <5 cm or maximum vertical pocket <2 cm,125 dilated bladder with thickened wall, “key hole” sign, ureteral dilation, hydronephrosis, renal hyper­echogenicity, subcortical renal cysts, or renal dysplasia124 (fig 3A).

Fig 2B | Illustration of fetal lung growth after fetal endoscopic tracheal occlusion

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Dilated bladder (sensitivity, 96.8% P<0.001) and thickened bladder wall (sensitivity, 93.5%, P<0.001) were the best sonographic indicators of LUTO, according to a retrospective cohort study.126 Fetal ultrasound can also be used to prognosticate the outcomes of fetuses with LUTO. A systematic review of the accuracy of prenatal ultrasound in fetuses with LUTO showed a high sensitivity and specificity of the following sonographic parameters in pre­dicting outcome: oligohydramnios, renal cortical appearance, and early diagnosis of LUTO (before 24 weeks’ gestation). Renal cortical appearance was the most predictive of postnatal renal function (sensitivity 0.57 (95% confidence interval 0.37 to 0.76); specificity 0.84 (95% confidence interval 0.71 to 0.94); area under curve 0.78).127 Prenatal ultrasound also helps to rule out other fetal anomalies. However, definitive diagnosis or prognosis of LUTO cannot be provided by ultrasound alone.114 124

Fetal urine biochemistry is another component of LUTO investigation that can be used to estimate fetal renal function. It involves fetal urine sampling, urine analysis, and interpretation of urinary electrolyte levels. According to a prospective cohort study of 24 LUTO patients (and 26 controls), urinary electrolytes decreased and urinary creatinine increased with gestational age in normal fetus controls (likely because of normal fetal renal system maturation).128 Conversely, LUTO patients with or without renal dysplasia had statistically significantly higher levels of electrolytes when compared with controls. Furthermore, LUTO fetuses with renal dysplasia had higher levels of urinary electrolytes and β2­microglobulin.128 A reference range for urine biochemistry was suggested as “favorable” and hence amenable to fetal surgery when urine osmolarity is <200 mOsm/L, sodium <100 mEq/L, chloride <90 mEq/L, and β2­microglobulin <6 mg/L.114 129 130 Reports in the literature are conflicting, however. One meta­analysis showed low sensitivity and specificity of fetal urinary biochemistry in predicting postnatal renal function.131 Conversely, a retrospective study of 72 fetuses with megacystis showed a statistically

significant correlation between fetal urinary electro­lytes and postnatal renal outcomes.132 The use of fetal urinary biochemistry to evaluate fetal renal function should, therefore, take into account three main considerations: (1) the available evidence is mostly based on studies that evaluated fetal urinary biochemistry during the second trimester; (2) fetal urinary biochemistry is only a “snapshot picture” of fetal renal function, which means that many other factors could influence renal function prenatally and postnatally; and (3) fetal urinary biochemistry is only a part of comprehensive fetal evaluation and should be interpreted along with fetal renal imaging for appropriate staging of disease severity.112 133­137

Accurate prenatal detection and prognostication of LUTO is vital to the appropriate selection of fetal intervention candidates to optimize perinatal outcomes. To this end, standardized prenatal LUTO diagnosis using prenatal ultrasound, fetal urine biochemistry, and clinical parameters has been proposed to improve LUTO prognostication.138­141 A retrospective study133 134 138 described a prenatal LUTO staging system that correlates with postnatal survival and also proposed fetal intervention according to disease severity (table 2).

Similar findings were confirmed by a large retrospective study of 261 LUTO patients who were managed conservatively.139 A clinical scoring system that combines specific sonographic findings, clinical parameters, and fetal urinary biochemistry is under investigation.142

Fetal interventions for lower urinary tract obstructionThe main aims of fetal intervention are to prevent severe pulmonary hypoplasia and end stage renal disease (for stage II LUTO). Fetal urine can be collected by fetal vesicocentesis under ultrasound guidance. Sequential urine sampling (up to three samples) over a 24­48 hour interval (to avoid repeat sampling of stagnant urine) is preferred to better reflect renal function.114 131 138 Following proper risk stratification and disease prognostication, fetal intervention may be considered depending on LUTO severity (table 2).

Vesicoamniotic shuntingVesicoamniotic shunting (VAS) aims for sustained bladder decompression with the help of a bladder catheter which allows continuous bladder drainage for the remainder of gestation. The Percutaneous Vesicoamniotic Shunting versus Conservative Management for Fetal Lower Urinary Tract Obstruc­tion (PLUTO) randomized controlled trial assessed the effectiveness of VAS for treating LUTO.143 This trial compared 16 patients who underwent VAS with 15 patients managed conservatively and showed significantly higher neonatal survival to 28 days of life with VAS (relative risk 3.2, 95% CI 1.06 to 9.62; P=0.03). However, the study failed to show a long term reduction in pediatric morbidity at 1 to 2 years of age, and the trial was halted early because of poor recruitment. Robust standardization of LUTO

Fig 3A | Illustration of a fetus with LUTO at 22 weeks’ gestation, with smaller lungs (pulmonary hypoplasia) and bilateral hydroureter and hydronephrosis

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investigation could potentially address the problem of poor recruitment and help stratify management in order to accurately assess the outcomes of fetal intervention in future prospective LUTO trials.138 139

A meta­analysis including 112 LUTO patients treated with VAS (and 134 controls), found that VAS was associated with higher perinatal survival (57.1% with VAS versus 38.8% with conservative management, P<0.01). However, there were no significant differences in 6­12 month survival, two year­survival, or postnatal renal function in treatment compared with control groups.144 Our protocol is investigating the benefits of fetal VAS for Stages II (to prevent severe pulmonary hypoplasia and end stage renal disease) and III LUTO (to prevent severe pulmonary hypoplasia as a bridge to renal dialysis/transplantation).

Fetal cystoscopyFetal cystoscopy involves direct visualization of the urinary outflow tract (with a fetoscope) for etiological diagnosis and specific treatment of LUTO113 133­137 144­148 (fig 3B). The fetoscope is placed into the bladder outlet (under ultrasound guidance) and pediatric posterior urethral valve (PUV), the commonest etiology of LUTO, can be treated with laser fulguration of occluding membranes.114

Fetal cystoscopy is still under investigation, but initial results are optimistic. According to a systematic review of non­randomized trials that evaluated fetal cystoscopy as a diagnostic and therapeutic modality for LUTO, the sensitivity was 100% to correctly diagnose the cause of LUTO. Compared with conservative management, fetal cystoscopy was associated with higher perinatal survival (odds ratio 20.51 (95% CI, 3.87 to 108.69)).145 A multicenter study comparing VAS, cystoscopy, and conservative management revealed that although VAS and fetal cystoscopy improved six month survival rate, only fetal cystoscopy significantly improved postnatal renal function (absolute risk reduction 2.66 (95% CI, 1.25 to 5.70)),112 probably related to better patient selection. However, fetal cystoscopy is a challenging procedure associated with some technical limitations that can lead to complications such as urological

fistulas (in approximately 10% of the cases) and prematurity with a mean gestational age at delivery of 34.6 ± 2.5 weeks (range 28–37 weeks).137 147 Urological fistulas are usually caused by inadequate curvature of the instrument, fetal mobilization, and limited surgeon experience.147 The long term benefits of fetal cystoscopy over VAS remain undeter­mined and improvements of the instruments and techniques are warranted.149 Our group is currently investigating the benefits, safety, and risks related to fetal cystoscopy for stage II LUTO (ClinicalTrials.gov Identifier: NCT03281798).

Serial amnioinfusionSerial amnioinfusion, which involves repeated infusion of sterile warm saline or lactated Ringer’s solution to restore amniotic fluid, is indicated for stage IV LUTO (intrauterine fetal renal failure) that occurs spontaneously or after fetal VAS (in stage III LUTO), according to our protocol (ClinicalTrials.gov Identifiers: NCT03723564, NCT03101891133 134 138). It aims to prevent severe pulmonary hypoplasia and perinatal demise, working as a bridge to postnatal dialysis and renal transplantation.150 151 However, ethical and clinical questions persist on its benefits and safety particularly because renal transplantation cannot usually be offered to children under 2.152 For this reason, serial amnioinfusion is still under investigation,151 and clinical trials are under way (ClinicalTrials.gov Identifiers: NCT03723564, NCT03101891).

Some investigators have suggested treating stage I LUTO (with normal amount of amniotic fluid).153 154 However, this suggestion is controversial because these newborns usually don’t have severe pulmonary hypoplasia or progress to end stage renal disease. No evidence suggests that fetal interventions can prevent renal damage in these infants; fetal interventions are associated with obstetrical complications.

Prenatal regenerative therapy for lower urinary tract obstructionWe have proposed a new concept of prenatal regenerative therapy for LUTO.5 “Regenerative pro­phylaxis” in LUTO involves possible restoration of fetal renal function preserving organ development.

Table 2 | Prenatal LUTO staging and fetal intervention options according to the severity of the disease133 134 138

Ultrasound findingsUrinary biochemistry Prognosis Indication of fetal intervention

Fetal intervention options

  Fetal kidneys Bladder refilling

Amount of amniotic fluid

Lungs Kidneys

Stage I Normal or mild/moderate bilateral hydronephrosis

Complete refill

Normal Favorable Good Good Not indicated Not indicated

Stage II Renal hyper-echogenicity (+/- bilateral hydronephrosis)

Complete refill

Oligohydramnios / anhydramnios

Favorable / Borderline

Variable Variable Indicated to prevent severe pulmonary hypoplasia and end stage renal disease

Ultrasound-guided fetal vesicoamniotic shunt placement or fetal cystoscopy

Stage III Renal hyper-echogenicity (+/- cysts or dysplasia )

Partial refill

Oligohydramnios / anhydramnios

Unfavorable Poor Poor Indicated to prevent severe pulmonary hypoplasia and maybe end stage renal disease

Ultrasound-guided fetal vesicoamniotic shunt placement with possible serial amnioinfusions later

Stage IV Renal hyper-echogenicity with cysts and dysplasia

Minimal refill

Severe oligohydramnios / anhydramnios

Unfavorable Very poor

Very poor

May be considered to prevent severe pulmonary hypoplasia as a bridge to renal transplant

Serial amnioinfusions

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The ability of VAS and fetal cystoscopy to decompress the fetal urinary tract in LUTO, restore amniotic fluid volume, and therefore possibly promote better fetal lung and renal development may be considered as a form of regenerative medicine.5 Along with serial amnioinfusions, these therapies provide pulmonary palliation and may promote adequate lung development through unknown mechanisms.

Fetal endoscopic repair of spina bifidaDefinition and epidemiology of spina bifidaNeural tube defect (NTD) describes congenital malformations of the central nervous system (CNS) that occur secondary to lack of the neural tube closure during early development. Spina bifida is the most common non­lethal congenital defect of the central nervous system.155

The incidence of neural tube defects ranges from 1.0 to 10.0 per 1000 births. The estimated birth prevalence of spina bifida in the US is 3.5 per 10 000 live births. The Centers for Disease Control and Prevention (CDC) report that Hispanic people have the highest rate (3.80 per 10 000 live births), when compared with non­Hispanic white people (3.09 per 10 000 live births) and non­Hispanic black people (2.73 per 10 000 live births).156 157

Epidemiological studies discovered that maternal folate status is critical for proper neural tube closure during embryogenesis.158 This prompted the US Public Health Service to recommend 400 µg of folic daily acid in women considering pregnancy to prevent NTDs. This has resulted in a statistically significant reduction in the prevalence of NTDs.159 Despite this recommendation and advancements in diagnosis and postnatal management, however, spina bifida remains a major source of morbidity and mortality.160

Pathophysiology of spina bifidaOpen spina bifida or meningomyelocele (MMC) is characterized by failure of the neural tube closure

with herniation of the meninges and spinal cord through a vertebral arch defect. This results in lifelong motor, sensory, and neurodevelopmental disabilities. The severity and extent of the disease is defined by the upper level of the anatomic defect161 and can range from bladder, bowel, and sexual dysfunction, to involvement of the lower and even upper extremities with secondary orthopedic disabilities.160

The pathophysiology is characterized by a “two hit” process, which is initiated by the failure of the posterior neuropore closure, followed by inflammatory and traumatic spinal cord damage resulting from amniotic fluid toxicity in utero. Children affected by this condition also invariably have an associated Arnold Chiari II malformation (or hindbrain herniation) possibly as a result of cerebrospinal fluid leakage, leading to progressive downward displacement of the hindbrain. This malformation is also associated with hydrocephalus and developmental brain abnormalities162 163 (fig 4A). The rationale for fetal intervention is to prevent the “second hit” and therefore limit inflammation and downstream effects of MMC.

According to data from the US Spina Bifida Registry, approximately 80% of MMC patients underwent ventriculo­peritoneal shunt placement to treat hydrocephalus, 96% had impaired bladder function, 92% had bowel dysfunction, and close to 40% were not able to walk.164 Data from the Danish database showed that 7% of MMC patients died in the first year of life secondary to pneumonia, meningitis, peritonitis, pyelonephritis, or sepsis.165 These data highlight the significant morbidity and mortality associated with MMC.

Prenatal diagnosis and prognostication of fetuses with spina bifidaMMC is diagnosed on routine second trimester ultrasound. It is often identified in the sagittal plain as a cystic lesion on the posterior spine with varying degrees of lumbosacral vertebral distortion.166 Associated cranial features, including ventriculomegaly, microcephaly, frontal bone scalloping (“lemon” sign), an abnormal posterior curvature of the cerebellum (“banana” sign), or “absent” cerebellum, may also be seen on ultrasound.166 167 Given the correlation between MMC level and disease severity, functional sonographic evaluation of lesion level has been proposed161 as a predictor of postnatal ambulation prognosis. In a prospective study, the authors evaluated the segmental lesion level based on the most distal active muscle movement on antenatal ultrasound (table 3) and postnatal evaluation. The agreement between the designated prenatal and postnatal segmental levels was 91.7% and 88.9% for the right and left limbs, respectively.161

Fetal MRI is another important component of a comprehensive investigation of spina bifida. It provides a detailed assessment of the fetal spine and brain and also helps to rule out other associated anomalies. The presence or absence of an MMC

Fig 3B | Illustration of ultrasound guided fetal cystoscopy

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sac, the size of the sac (when present), and size of the vertebral arch defect are all relevant spine MRI parameters; the presence or absence of hindbrain herniation, degree of hindbrain herniation (when present), and ventricular size are important brain MRI parameters.168 These findings are all of prognostic significance as they guide the approach to management. Indeed, the inclusion or exclusion criteria for prenatal treatment of MMC, adopted by the Management of Myelomeningocele Study (MOMS) trial and other fetal centers worldwide, are based on prenatal diagnostic parameters.

Fetal interventions for spina bifidaHistorically, MMC was repaired postnatally with surgical closure of the lesion and ventricular shunt placement for hydrocephalus treatment. Recently, studies have shown benefits of in utero intervention for MMC.163 169 Prenatal MMC repair was first performed in humans in 1997.

Early data suggested a dramatic improvement in hindbrain herniation of the fetuses, but with an inherent risk of preterm birth, uterine dehiscence, fetal or neonatal death. Further investigation with the MOMS trial,163 which compared in utero MMC closure with routine postnatal repair, showed that prenatal repair significantly decreased need for shunting, reversed hindbrain herniation, and improved

neurologic function when compared with postnatal repair.169 The trial highlighted several benefits of prenatal repair, including a 50% reduction in the need for postnatal shunt placement (P<0.001); at 12 months of age, 36% of infants in the prenatal repair group had no hindbrain herniation compared with only 4% in the postnatal repair group. Children in the prenatal surgery group were also more likely to walk without orthotics (42% versus 21%) and had better motor function. Importantly, those in the prenatal repair group had a higher Bayley Psychomotor Development Index score.170 171

However, the MOMS trial also reported several important complications associated with in­utero open repair of MMC. There was a significantly increased risk of preterm delivery, premature rupture of membranes. and uterine dehiscence (only 64% had an intact well healed hysterotomy site at the time of planned caesarean section). Maternal risks included approximately 6% risk of pulmonary edema (attributed to use of tocolytics), 9% risk of blood transfusion at delivery, and need for a caesarean section for all future pregnancies, irrespective of other obstetric indications.163 Other studies have also found evidence of myometrium scarring and substantial thinning or dehiscence of the hysterotomy after open MMC repair.172 Tocolytics have been used preoperatively and postoperatively to minimize the risk of preterm birth after open MMC repairs.173

Recognizing the conflicting outcomes of neonatal benefit versus maternal morbidity has led to the exploration of fetoscopy as a less invasive approach to in utero MMC repair. Several attempts have been made to improve techniques and clinical outcomes for fetoscopic repair, and some groups perform this procedure completely percutaneously while others opt for maternal laparotomy with fetoscopy. Fetoscopic repair of MMC is still under investigation to evaluate benefits, safety, and technical aspects.174 175

The first described literature on in utero fetoscopic repair of MMC in humans dates back to 1997.176 Here, the authors described two cases where a maternal split­thickness skin graft was placed over the exposed neural placode. One fetus died from complications of prematurity and the other survived following a planned caesarean delivery at 35 weeks’ gestation. The same authors performed a non­randomized trial study in 2000 comparing outcomes of fetoscopic versus open repair of MMC with four fetuses in each group. They found that the open repair group delivered at a later gestational age had a shorter operative time and better wound healing when compared with the fetoscopic repair group.177

Others175 have suggested draining some amniotic fluid and partially filling the uterus with carbon dioxide gas for better visualization before the surgical repair, using a completely percutaneous approach (fig 4B). This led to a concern for fetal acidemia and placental dysfunction from carbon dioxide exposure, as seen in sheep studies.178­180 A cohort study of patients who underwent fetoscopic repair of MMC181

Fig 4A | Illustration of fetal myelomeningocele, with hindbrain herniation and ventriculomegaly

Table 3 | Ultrasonographic functional evaluation of the neurological level according to muscular movements of fetuses with MMC161

Ultrasound functional evaluation Key muscles Segmental levelHip flexion Psoas L1Hip adduction Hip adductor L2Knee extension Quadriceps L3Knee flexion Hamstrings/gluteus L4Dorsal flexion of ankle Anterior tibialis L5Plantar flexion of ankle Gastrocnemius/soleus/gluteus S1

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evaluated venous cord blood gas in three fetuses before and after laparoscopic­fetoscopic repair with carbon dioxide insufflation and found that the partial pressure of oxygen and carbon dioxide remained in the normal range, suggesting that carbon dioxide insufflation during fetoscopic MMC repair does not cause acidemia in human fetuses. Another retrospective cohort study 182 looked at fetal growth outcomes following laparoscopic­fetoscopic MMC repair carbon dioxide insufflation versus open MMC repair. It found that infants exposed to fetoscopic or open MMC repair in utero did not show statistically significant differences in fetal or postnatal growth parameters.

Appropriate anesthesia protocol is paramount to the success of open and fetoscopic repair of MMC in utero. Data from a retrospective cohort study comparing anesthesia protocol in open with fetoscopic MMC repair found that open surgery was associated with higher doses of halogenated anesthetic agents, sevoflurane, increased need for intra­operative tocolytic drugs with nitroglycerine, and postoperative tocolysis with magnesium sulfate, and a higher volume of colloids.183 From a hemodynamic standpoint, median mean arterial pressure was lower in open versus fetoscopic surgery; systolic blood pressure, diastolic blood pressure, and mean blood pressure decreased during uterine exposure, and this descent was more acute in open surgery.183 These results suggest a possible advantage of fetoscopic over open MMC repair.

As techniques for fetoscopic repair have gradually improved over the years, so have the outcomes. While open in utero spina bifida has remained the standard approach, fetoscopic repair holds promising results for optimizing maternal obstetric outcomes, with the hope of maintaining similar fetal and neonatal outcomes.170 184 185 Future randomized controlled trials are necessary to confirm recent reports.

Prenatal regenerative therapy for spina bifidaRegenerative prophylaxis with respect to spina bifida involves the restoration of hindbrain anatomy in utero. Hindbrain herniation in MMC is a result of “cranio­spinal dissociation” as the normal interaction between cerebrospinal fluid (CSF) spaces of the cranium and spine is disrupted by CSF flow abnormalities.5 155 Early MMC closure restores hindbrain herniation, which has been associated with a lower risk of hydrocephalus when compared with postnatal MMC closure.163 Small series have shown that in utero MMC closure improves hind­brain herniation prenatally, as early as 4­6 weeks postoperatively.168 186

ConclusionsIn the past 20 years, progress in fetal surgeries has been extraordinary, with refined techniques, indications, implementations, and applications. In utero procedures have increasingly become a part of perinatal options in tertiary centers specialized in the treatment of congenital anomalies. Our group has introduced the concept of fetal regenerative therapy, where fetal surgeries are implemented to promote restoration, growth, and regeneration of abnormally developed fetal organs, aimed at improving perinatal survival and reducing morbidity. The future of this field is promising, pending the results of ongoing clinical trials. Understanding the mechanisms in­volved in restoration or regeneration of fetal organs will also open an opportunity for even less invasive novel fetal regenerative therapies. A collaborative effort among medical specialties is necessary to foster the success of this evolving practice.

Financial support and competing interests: I acknowledge the financial support from the State of Minnesota (RMM 102516008). Dr R. Ruano is a recipient of the Regenerative Medicine Minnesota Clinical Trial grant: “Fetoscopic Regenerative Therapy for Severe Pulmonary Hypoplasia – a feasibility pre-randomized control trial study.”Acknowledgments: I thank Dr Eniola R. Ibirogba, Dr Kavita Narang, Dr Michelle Wyatt, and Dr Andre Terzic for their contributions to the content and review of this manuscript. I also thank Ms. Jan H. Case for her work in preparing illustrations and the Mayo Clinic Library staff for their support with the literature search.Provenance and peer review: commissioned; externally peer reviewed.

1  Ruano R, Vega B. Fetal surgery: how recent technological advancements are extending its applications. Expert Rev Med Devices 2019;16:643-5. doi:10.1080/17434440.2019.1641404 

2  Nelson TJ, Behfar A, Terzic A. Strategies for therapeutic repair: The “R(3)” regenerative medicine paradigm. Clin Transl Sci 2008;1:168-71. doi:10.1111/j.1752-8062.2008.00039.x 

RESEARCH QUESTIONS• Can fetal surgeries restore fetal organ structures and

functions as well as improve postnatal outcomes using less invasive techniques?

Fig 4B | Illustration of fetoscopic repair of myelomeningocele

HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS ARTICLE• No patients were involved

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participants from the first 10 clinics. J Pediatr 2015;166:444-50.e1. doi:10.1016/j.jpeds.2014.09.039 

165  Borgstedt-Bakke JH, Fenger-Grøn M, Rasmussen MM. Correlation of mortality with lesion level in patients with myelomeningocele: a population-based study. J Neurosurg Pediatr 2017;19:227-31. doi:10.3171/2016.8.PEDS1654 

166  Copp AJ, Adzick NS, Chitty LS, Fletcher JM, Holmbeck GN, Shaw GM. Spina bifida. Nat Rev Dis Primers 2015;1:15007. doi:10.1038/nrdp.2015.7 

167  Van den Hof MC, Nicolaides KH, Campbell J, Campbell S. Evaluation of the lemon and banana signs in one hundred thirty fetuses with open spina bifida. Am J Obstet Gynecol 1990;162:322-7. doi:10.1016/0002-9378(90)90378-K 

168  Nagaraj UD, Bierbrauer KS, Stevenson CB, et al. Prenatal and postnatal MRI findings in open spinal dysraphism following intrauterine repair via open versus fetoscopic surgical techniques. Prenat Diagn 2019. doi:10.1002/pd.5540

169  Moldenhauer JS, Flake AW. Open fetal surgery for neural tube defects. Best Pract Res Clin Obstet Gynaecol 2019;58:121-32. doi:10.1016/j.bpobgyn.2019.03.004 

170  Kabagambe SK, Jensen GW, Chen YJ, Vanover MA, Farmer DL. Fetal surgery for myelomeningocele: a systematic review and meta-analysis of outcomes in fetoscopic versus open repair. Fetal Diagn Ther 2018;43:161-74. doi:10.1159/000479505 

171  Moron AF, Barbosa MM, Milani H, et al. Perinatal outcomes after open fetal surgery for myelomeningocele repair: a retrospective cohort study. BJOG 2018;125:1280-6. doi:10.1111/1471-0528.15312 

172  Ochsenbein-Kölble N, Brandt S, Bode P, et al. Clinical and histologic evaluation of the hysterotomy site and fetal membranes after open fetal surgery for fetal spina bifida repair. Fetal Diagn Ther 2019;45:248-55. doi:10.1159/000488941 

173  Novoa Y Novoa V, Shazly S, Araujo Júnior E, Tonni G, Ruano R. Tocolysis for open prenatal repair of myelomeningocele: systematic review. J Matern Fetal Neonatal Med 2020;33:1786-91. doi:10.1080/14767058.2018.1528222 

174  Farmer DL, von Koch CS, Peacock WJ, et al. In utero repair of myelomeningocele: experimental pathophysiology, initial clinical experience, and outcomes. Arch Surg 2003;138:872-8. doi:10.1001/archsurg.138.8.872 

175  Kohl T, Hering R, Heep A, et al. Percutaneous fetoscopic patch coverage of spina bifida aperta in the human--early clinical experience and potential. Fetal Diagn Ther 2006;21:185-93. doi:10.1159/000089301 

176  Bruner JP, Tulipan NE, Richards WO. Endoscopic coverage of fetal open myelomeningocele in utero. Am J Obstet Gynecol 1997;176:256-7. doi:10.1016/S0002-9378(97)80050-6 

177  Bruner JP, Tulipan NB, Richards WO, Walsh WF, Boehm FH, Vrabcak EK. In utero repair of myelomeningocele: a comparison of endoscopy and hysterotomy. Fetal Diagn Ther 2000;15:83-8. doi:10.1159/000020981 

178  Moise KJJr, Flake A. Fetoscopic open neural tube defect repair: development and refinement of a two-port, carbon dioxide insufflation technique. Obstet Gynecol 2017;130:648. doi:10.1097/AOG.0000000000002221 

179  Luks FI, Deprest J, Marcus M, et al. Carbon dioxide pneumoamnios causes acidosis in fetal lamb. Fetal Diagn Ther 1994;9:105-9. doi:10.1159/000263916 

180  Gratacós E, Wu J, Devlieger R, Van de Velde M, Deprest JA. Effects of amniodistention with carbon dioxide on fetal acid-base status during fetoscopic surgery in a sheep model. Surg Endosc 2001;15:368-72. doi:10.1007/s004640090024 

181  Baschat AA, Ahn ES, Murphy J, Miller JL. Fetal blood-gas values during fetoscopic myelomeningocele repair performed under carbon dioxide insufflation. Ultrasound Obstet Gynecol 2018;52:400-2. doi:10.1002/uog.19083 

182  Sanz Cortes M, Davila I, Torres P, et al. Does fetoscopic or open repair for spina bifida affect fetal and postnatal growth?Ultrasound Obstet Gynecol 2019;53:314-23. doi:10.1002/uog.20220 

183  Manrique S, Maiz N, García I, et al. Maternal anaesthesia in open and fetoscopic surgery of foetal open spinal neural tube defects: A retrospective cohort study. Eur J Anaesthesiol 2019;36:175-84. doi:10.1097/EJA.0000000000000930 

184  Inversetti A, Van der Veeken L, Thompson D, et al. Neurodevelopmental outcome of children with spina bifida aperta repaired prenatally vs postnatally: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2019;53:293-301. doi:10.1002/uog.20188 

185  Miller JL, Groves ML, Baschat AA. Fetoscopic spina bifida repair. Minerva Ginecol 2019;71:163-70. doi:10.23736/S0026-4784.18.04355-1 

186  Ruano R, Daniels DJ, Ahn ES, et al. In utero restoration of hindbrain herniation in fetal myelomeningocele as part of prenatal regenerative therapy program at Mayo Clinic. Mayo Clin Proc 2020;95:738-46. doi:10.1016/j.mayocp.2019.10.039 

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Search Strategy

a. Congenital Diaphragmatic Hernia Database: EBM Reviews - Cochrane Central Register of Controlled Trials <August 2019>, EBM Reviews - Cochrane Database of Systematic Reviews <2005 to October 3, 2019>, Embase <1974 to 2019 October 03>, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to October 03, 2019> Search Strategy: -------------------------------------------------------------------------------- 1 exp Fetal Diseases/di, su, th (39104) 2 exp Fetus/ (343236) 3 (fetus* or fetal or foetal or foetus*).ti,ab,hw,kw. (912921) 4 1 or 2 or 3 (944727) 5 exp Hernias, Diaphragmatic, Congenital/di, su, th (3094) 6 ("agenesis of hemidiaphragm" or "bochdalek hernia*" or CDH or "congenital diaphragmatic abnormalit*" or "congenital diaphragmatic defect*" or "congenital diaphragmatic hernia*" or "diaphragm unilateral ageneses" or "diaphragm unilateral agenesis" or "hemidiaphragm ageneses" or "hemidiaphragm agenesis" or "morgagni hernia*" or "morgagnis hernia*" or "unilateral agenesis of diaphragm").ti,ab,hw,kw. (15481) 7 5 or 6 (16074) 8 4 and 7 (4223) 9 (balloon or clip* or endotracheal or FETENDO or FETO or fetoscop* or graft* or intervention* or ligation* or manag* or occlusion or operat* or patch* or plug* or procedure* or reconstruction* or repair* or resect* or surg* or therap* or treat*).ti,ab,hw,kw. (27107341) 10 8 and 9 (3039) 11 limit 10 to english language [Limit not valid in CDSR; records were retained] (2772) 12 ((meta adj analys*) or metaanalys* or (systematic* adj3 review*) or ((retrospective or "ex post facto") adj3 (study or survey or analysis or design)) or retrospectiv* or "prospective study" or "prospective survey" or "prospective analysis" or prospectiv*).mp,pt. (4995670) 13 11 and 12 (653) 14 (alpaca or alpacas or amphibian or amphibians or animal or animals or antelope or armadillo or armadillos or avian or baboon or baboons or beagle or beagles or bee or bees or bird or birds or bison or bovine or buffalo or buffaloes or buffalos or "c elegans" or "Caenorhabditis elegans" or camel or camels or canine or canines or carp or cats

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or cattle or chick or chicken or chickens or chicks or chimp or chimpanze or chimpanzees or chimps or cow or cows or "D melanogaster" or "dairy calf" or "dairy calves" or deer or dog or dogs or donkey or donkeys or drosophila or "Drosophila melanogaster" or duck or duckling or ducklings or ducks or equid or equids or equine or equines or feline or felines or ferret or ferrets or finch or finches or fish or flatworm or flatworms or fox or foxes or frog or frogs or "fruit flies" or "fruit fly" or "G mellonella" or "Galleria mellonella" or geese or gerbil or gerbils or goat or goats or goose or gorilla or gorillas or hamster or hamsters or hare or hares or heifer or heifers or horse or horses or insect or insects or jellyfish or kangaroo or kangaroos or kitten or kittens or lagomorph or lagomorphs or lamb or lambs or llama or llamas or macaque or macaques or macaw or macaws or marmoset or marmosets or mice or minipig or minipigs or mink or minks or monkey or monkeys or mouse or mule or mules or nematode or nematodes or octopus or octopuses or orangutan or "orang-utan" or orangutans or "orang-utans" or oxen or parrot or parrots or pig or pigeon or pigeons or piglet or piglets or pigs or porcine or primate or primates or quail or rabbit or rabbits or rat or rats or reptile or reptiles or rodent or rodents or ruminant or ruminants or salmon or sheep or shrimp or slug or slugs or swine or tamarin or tamarins or toad or toads or trout or urchin or urchins or vole or voles or waxworm or waxworms or worm or worms or xenopus or "zebra fish" or zebrafish).ti,ab,hw,kw. (14289651) 15 13 not 14 (623) 16 limit 15 to (letter or conference abstract or editorial or erratum or note or addresses or autobiography or bibliography or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in CCTR,CDSR,Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] (90) 17 from 16 keep 1 (1) 18 (15 not 16) or 17 (534) 19 remove duplicates from 18 (334) ***************************

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b. Lower Urinary Tract Obstruction

Ovid

Database(s): EBM Reviews - Cochrane Central Register of Controlled Trials August 2019, EBM Reviews - Cochrane Database of Systematic Reviews 2005 to September 18, 2019, Embase 1974 to 2019 October 01, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to October 01, 2019 Search Strategy: # Searches Results

1 exp Fetal Diseases/di, dg, dh, dt, su, th, mo [Diagnosis, Diagnostic Imaging, Diet Therapy, Drug Therapy, Surgery, Therapy, Mortality] 29224

2 exp Fetus/ 343168 3 (fetus* or fetal or foetal or foetus*).ti,ab,hw,kw. 912979 4 1 or 2 or 3 943028 5 exp Ureteral Obstruction/ and (lower or LUTO).ti,ab,hw,kw. 2204 6 ("lower urinary tract obstruction*" or "lower ureteral obstruction*").ti,ab,hw,kw. 1000 7 5 or 6 3156 8 4 and 7 427 9 Prognosis/ 1055018 10 (predict* or prognos* or "reference value*" or sensitivity or specificity).ti,ab,hw,kw. 8235906 11 9 or 10 8235906 12 8 and 11 181 13 exp Cystoscopy/ 28381 14 cystoscopy*.ti,ab,hw,kw. 36559 15 13 or 14 36559 16 8 and 15 79 17 12 or 16 228 18 limit 17 to english language [Limit not valid in CDSR; records were retained] 219

19

limit 18 to (letter or conference abstract or editorial or erratum or note or addresses or autobiography or bibliography or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in CCTR,CDSR,Embase,Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained]

28

20 18 not 19 191

21

(alpaca or alpacas or amphibian or amphibians or animal or animals or antelope or armadillo or armadillos or avian or baboon or baboons or beagle or beagles or bee or bees or bird or birds or bison or bovine or buffalo or buffaloes or buffalos or "c elegans" or "Caenorhabditis elegans" or camel or camels or canine or canines or carp or cats or cattle or chick or chicken or chickens or chicks or chimp or chimpanze or chimpanzees or chimps or cow or cows or "D melanogaster" or "dairy calf" or "dairy calves" or deer or dog or dogs or donkey or donkeys or drosophila or "Drosophila melanogaster" or duck or

14289392

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duckling or ducklings or ducks or equid or equids or equine or equines or feline or felines or ferret or ferrets or finch or finches or fish or flatworm or flatworms or fox or foxes or frog or frogs or "fruit flies" or "fruit fly" or "G mellonella" or "Galleria mellonella" or geese or gerbil or gerbils or goat or goats or goose or gorilla or gorillas or hamster or hamsters or hare or hares or heifer or heifers or horse or horses or insect or insects or jellyfish or kangaroo or kangaroos or kitten or kittens or lagomorph or lagomorphs or lamb or lambs or llama or llamas or macaque or macaques or macaw or macaws or marmoset or marmosets or mice or minipig or minipigs or mink or minks or monkey or monkeys or mouse or mule or mules or nematode or nematodes or octopus or octopuses or orangutan or "orang-utan" or orangutans or "orang-utans" or oxen or parrot or parrots or pig or pigeon or pigeons or piglet or piglets or pigs or porcine or primate or primates or quail or rabbit or rabbits or rat or rats or reptile or reptiles or rodent or rodents or ruminant or ruminants or salmon or sheep or shrimp or slug or slugs or swine or tamarin or tamarins or toad or toads or trout or urchin or urchins or vole or voles or waxworm or waxworms or worm or worms or xenopus or "zebra fish" or zebrafish).ti,ab,hw,kw.

22 20 not 21 186

23

((meta adj analys*) or metaanalys* or (systematic* adj3 review*) or (control* adj3 study) or (control* adj3 trial) or (randomized adj3 study) or (randomized adj3 trial) or (randomised adj3 study) or (randomised adj3 trial) or "pragmatic clinical trial" or (random* adj1 allocat*) or (doubl* adj blind*) or (doubl* adj mask*) or (singl* adj blind*) or (singl* adj mask*) or (tripl* adj blind*) or (tripl* adj mask*) or (trebl* adj blind*) or (trebl* adj mask*) or "latin square" or placebo* or nocebo* or multivariate or "comparative study" or "comparative survey" or "comparative analysis" or (intervention* adj2 study) or (intervention* adj2 trial) or "cross-sectional study" or "cross-sectional analysis" or "cross-sectional survey" or "cross-sectional design" or "prevalence study" or "prevalence analysis" or "prevalence survey" or "disease frequency study" or "disease frequency analysis" or "disease frequency survey" or cohort* or "longitudinal study" or "longitudinal survey" or "longitudinal analysis" or "longitudinal evaluation" or longitudinal* or ((retrospective or "ex post facto") adj3 (study or survey or analysis or design)) or retrospectiv* or "prospective study" or "prospective survey" or "prospective analysis" or prospectiv* or "concurrent study" or "concurrent survey" or "concurrent analysis" or "case study" or "case series" or "clinical series" or "case studies" or "clinical study" or "clinical trial" or (("phase 0" or "phase 1" or "phase I" or "phase 2" or "phase II" or "phase 3" or "phase III" or "phase 4" or "phase IV") adj5 (trial or study)) or ((correlation* adj2 study) or (correlation* adj2 analys*)) or "case control study" or "case base study" or "case referrent study" or "case referent study" or "case referent study" or "case compeer study" or "case comparison study" or "matched case control" or "multicenter study" or "multi-center study" or "odds ratio" or "confidence interval" or "change analysis" or ((study or trial or random* or control*) and compar*) or (case adj3 report)).mp,pt.

25110849

24 22 and 23 136 25 from 24 keep 2, 4, 11-12, 16, 19, 26... 30 26 24 not 25 106 27 remove duplicates from 26 67

c. Spina Bifida Ovid

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Database Field Guide EBM Reviews - Cochrane Central Register of Controlled Trials November 2019, Database Field Guide EBM Reviews - Cochrane Database of Systematic Reviews 2005 to December 11, 2019, Database Field Guide Embase 1974 to 2019 Week 49, Database Field Guide Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to December 10, 2019

1 exp Fetal Diseases/di, dg, dh, dt, su, th, mo 29346

2 exp Fetus/ 343679

3 (fetus* or fetal or foetal or foetus*).ti,ab,hw,kw. 915846

4 1 or 2 or 3 946062

5 exp Spinal Dysraphism/ 19892

6 spina bifida.ti,ab,hw,kw. 19723

7 5 or 6 29998

8 4 and 7 5345

9 (fetal surgery or fetal surgeries or foetal surgery or foetal surgeries).ti,ab,hw,kw. 2815

10 8 and 9 694

11 (alpaca or alpacas or amphibian or amphibians or animal or animals or antelope or armadillo or armadillos or avian or baboon or baboons or beagle or beagles or bee or bees or bird or birds or bison or bovine or buffalo or buffaloes or buffalos or "c elegans" or "Caenorhabditis elegans" or camel or camels or canine or canines or carp or cats or cattle or chick or chicken or chickens or chicks or chimp or chimpanze or chimpanzees or chimps or cow or cows or "D melanogaster" or "dairy calf" or "dairy calves" or deer or dog or dogs or donkey or donkeys or drosophila or "Drosophila melanogaster" or duck or duckling or ducklings or ducks or equid or equids or equine or equines or feline or felines or ferret or ferrets or finch or finches or fish or flatworm or flatworms or fox or foxes or frog or frogs or "fruit flies" or "fruit fly" or "G mellonella" or "Galleria mellonella" or geese or gerbil or gerbils or goat or goats or goose or gorilla or gorillas or hamster or hamsters or hare or hares or heifer or heifers or horse or horses or insect or insects or jellyfish or kangaroo or kangaroos or kitten or kittens or lagomorph or lagomorphs or lamb or lambs or llama or llamas or macaque or macaques or macaw or macaws or marmoset or marmosets or mice or minipig or minipigs or mink or minks or monkey or monkeys or mouse or mule or mules or nematode or nematodes or octopus or octopuses or orangutan or "orang-utan" or orangutans or "orang-utans" or oxen or parrot or parrots or pig or pigeon or pigeons or piglet or piglets or pigs or porcine or primate or primates or quail or rabbit or rabbits or rat or rats or reptile or reptiles or rodent or rodents or ruminant or ruminants or salmon or sheep or shrimp or slug or slugs or swine or tamarin or tamarins or toad or toads or trout or urchin or urchins or vole or voles or waxworm or waxworms or worm or worms or xenopus or "zebra fish" or zebrafish).ti,ab,hw,kw. 14362338

12 10 not 11 545

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STATE OF THE ART REVIEW

13 ((meta adj analys*) or metaanalys* or (systematic* adj3 review*) or (control* adj3 study) or (control* adj3 trial) or (randomized adj3 study) or (randomized adj3 trial) or (randomised adj3 study) or (randomised adj3 trial) or "pragmatic clinical trial" or (random* adj1 allocat*) or (doubl* adj blind*) or (doubl* adj mask*) or (singl* adj blind*) or (singl* adj mask*) or (tripl* adj blind*) or (tripl* adj mask*) or (trebl* adj blind*) or (trebl* adj mask*) or "latin square" or placebo* or nocebo* or multivariate or "comparative study" or "comparative survey" or "comparative analysis" or (intervention* adj2 study) or (intervention* adj2 trial) or "cross-sectional study" or "cross-sectional analysis" or "cross-sectional survey" or "cross-sectional design" or "prevalence study" or "prevalence analysis" or "prevalence survey" or "disease frequency study" or "disease frequency analysis" or "disease frequency survey" or cohort* or "longitudinal study" or "longitudinal survey" or "longitudinal analysis" or "longitudinal evaluation" or longitudinal* or ((retrospective or "ex post facto") adj3 (study or survey or analysis or design)) or retrospectiv* or "prospective study" or "prospective survey" or "prospective analysis" or prospectiv* or "concurrent study" or "concurrent survey" or "concurrent analysis" or "case study" or "case series" or "clinical series" or "case studies" or "clinical study" or "clinical trial" or (("phase 0" or "phase 1" or "phase I" or "phase 2" or "phase II" or "phase 3" or "phase III" or "phase 4" or "phase IV") adj5 (trial or study)) or ((correlation* adj2 study) or (correlation* adj2 analys*)) or "case control study" or "case base study" or "case referrent study" or "case referent study" or "case referent study" or "case compeer study" or "case comparison study" or "matched case control" or "multicenter study" or "multi-center study" or "odds ratio" or "confidence interval" or "change analysis" or ((study or trial or random* or control*) and compar*) or (case adj3 report)).mp,pt. 25335411

14 12 and 13 337

15 limit 14 to english language [Limit not valid in CDSR; records were retained] 326

16 remove duplicates from 15 261

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