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 [email protected]; [email protected] 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.
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
2 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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)
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 3
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
4 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 5
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
6 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 7
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
8 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 9
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
10 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 11
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
12 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
3 Terzic A, Nelson TJ. Regenerative medicine primer. Mayo Clin Proc 2013;88:766-75. doi:10.1016/j.mayocp.2013.04.017
4 Liley AW. Intrauterine transfusion of foetus in haemolytic disease. Br Med J 1963;2:1107-9. doi:10.1136/bmj.2.5365.1107
5 Ruano R, Enninga EAL, Brana Rivera PE, Terzic A. Regenerative prophylaxis in utero. Clin Pharmacol Ther 2019;105:39-41. doi:10.1002/cpt.1262
6 Adzick NS. Prospects for fetal surgery. Early Hum Dev 2013;89:881-6. doi:10.1016/j.earlhumdev.2013.09.010
7 Harrison MR, Golbus MS, Filly RA, Nakayama DK, deLorimier AA. Fetal surgical treatment. Pediatr Ann 1982;11:896-9, 901-3.
8 Harrison MR, Filly RA, Golbus MS, et al. Fetal treatment 1982. N Engl J Med 1982;307:1651-2. doi:10.1056/NEJM198212233072623
9 Luks FI. Requirements for fetal surgery: the diaphragmatic hernia model. Eur J Obstet Gynecol Reprod Biol 2000;92:115-8. doi:10.1016/S0301-2115(00)00434-6
10 Roberts DJ, Zygun DA, Ball CG, et al. Challenges and potential solutions to the evaluation, monitoring, and regulation of surgical innovations. BMC Surg 2019;19:119. doi:10.1186/s12893-019-0586-5
11 Chervenak FA, McCullough LB. The ethics of maternal-fetal surgery. Semin Fetal Neonatal Med 2018;23:64-7. doi:10.1016/j.siny.2017.09.008
12 Antiel RM, Flake AW. Responsible surgical innovation and research in maternal-fetal surgery. Semin Fetal Neonatal Med 2017;22:423-7. doi:10.1016/j.siny.2017.05.002
13 Joyeux L, Engels AC, Russo FM, et al. Fetoscopic versus open repair for spina bifida aperta: a systematic review of outcomes. Fetal Diagn Ther 2016;39:161-71. doi:10.1159/000443498
14 McGivern MR, Best KE, Rankin J, et al. Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 2015;100:F137-44. doi:10.1136/archdischild-2014-306174
15 Torfs CP, Curry CJ, Bateson TF, Honoré LH. A population-based study of congenital diaphragmatic hernia. Teratology 1992;46:555-65. doi:10.1002/tera.1420460605
16 Dott MM, Wong LY, Rasmussen SA. Population-based study of congenital diaphragmatic hernia: risk factors and survival in Metropolitan Atlanta, 1968-1999. Birth Defects Res A Clin Mol Teratol 2003;67:261-7. doi:10.1002/bdra.10039
17 Skari H, Bjornland K, Haugen G, Egeland T, Emblem R. Congenital diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr Surg 2000;35:1187-97. doi:10.1053/jpsu.2000.8725
18 Wenstrom KD, Weiner CP, Hanson JW. A five-year statewide experience with congenital diaphragmatic hernia. Am J Obstet Gynecol 1991;165:838-42. doi:10.1016/0002-9378(91)90425-Q
19 Ruano R, Bunduki V, Silva MM, et al. Prenatal diagnosis and perinatal outcome of 38 cases with congenital diaphragmatic hernia: 8-year experience of a tertiary Brazilian center. Clinics (Sao Paulo) 2006;61:197-202. doi:10.1590/S1807-59322006000300003
20 Stoll C, Alembik Y, Dott B, Roth MP. Associated non diaphragmatic anomalies among cases with congenital diaphragmatic hernia. Genet Couns 2015;26:281-98.
21 Langham MRJr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia. Epidemiology and outcome. Clin Perinatol 1996;23:671-88. doi:10.1016/S0095-5108(18)30201-X
22 Mayer S, Metzger R, Kluth D. The embryology of the diaphragm. Semin Pediatr Surg 2011;20:161-9. doi:10.1053/j.sempedsurg.2011.03.006
23 Sefton EM, Gallardo M, Kardon G. Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle. Dev Biol 2018;440:64-73. doi:10.1016/j.ydbio.2018.04.010
24 Adzick NS, Outwater KM, Harrison MR, et al. Correction of congenital diaphragmatic hernia in utero. IV. An early gestational fetal lamb model for pulmonary vascular morphometric analysis. J Pediatr Surg 1985;20:673-80. doi:10.1016/S0022-3468(85)80022-1
25 Harrison MR, Bressack MA, Churg AM, de Lorimier AA. Correction of congenital diaphragmatic hernia in utero. II. Simulated correction permits fetal lung growth with survival at birth. Surgery 1980;88:260-8.
26 Warburton D, El-Hashash A, Carraro G, et al. Lung organogenesis. Curr Top Dev Biol 2010;90:73-158. doi:10.1016/S0070-2153(10)90003-3
27 Mous DS, Kool HM, Wijnen R, Tibboel D, Rottier RJ. Pulmonary vascular development in congenital diaphragmatic hernia. Eur Respir Rev 2018;27:170104. doi:10.1183/16000617.0104-2017
28 Parera MC, van Dooren M, van Kempen M, et al. Distal angiogenesis: a new concept for lung vascular morphogenesis. Am J Physiol Lung Cell Mol Physiol 2005;288:L141-9. doi:10.1152/ajplung.00148.2004
29 Stenmark KR, Gebb SA. Lung vascular development: breathing new life into an old problem. Am J Respir Cell Mol Biol 2003;28:133-7. doi:10.1165/rcmb.F259
30 deMello DE, Reid LM. Embryonic and early fetal development of human lung vasculature and its functional implications. Pediatr Dev Pathol 2000;3:439-49. doi:10.1007/s100240010090
31 George DK, Cooney TP, Chiu BK, Thurlbeck WM. Hypoplasia and immaturity of the terminal lung unit (acinus) in congenital diaphragmatic hernia. Am Rev Respir Dis 1987;136:947-50. doi:10.1164/ajrccm/136.4.947
32 DiFiore JW, Fauza DO, Slavin R, Wilson JM. Experimental fetal tracheal ligation and congenital diaphragmatic hernia: a pulmonary vascular morphometric analysis. J Pediatr Surg 1995;30:917-23, discussion 923-4. doi:10.1016/0022-3468(95)90313-5
33 Chandrasekharan PK, Rawat M, Madappa R, Rothstein DH, Lakshminrusimha S. Congenital Diaphragmatic hernia - a review. Matern Health Neonatol Perinatol 2017;3:6. doi:10.1186/s40748-017-0045-1
34 Barghorn A, Koslowski M, Kromminga R, Hufnagl P, Tennstedt C, Vogel M. Alpha-smooth muscle actin distribution in the pulmonary vasculature comparing hypoplastic and normal fetal lungs. Pediatr Pathol Lab Med 1998;18:5-22. doi:10.1080/107710498174173
35 Levin DL, Fixler DE, Morriss FC, Tyson J. Morphologic analysis of the pulmonary vascular bed in infants exposed in utero to prostaglandin synthetase inhibitors. J Pediatr 1978;92:478-83. doi:10.1016/S0022-3476(78)80453-3
36 Miniati D. Pulmonary vascular remodeling. Semin Pediatr Surg 2007;16:80-7. doi:10.1053/j.sempedsurg.2007.01.002
37 Sluiter I, van der Horst I, van der Voorn P, et al. Premature differentiation of vascular smooth muscle cells in human congenital diaphragmatic hernia. Exp Mol Pathol 2013;94:195-202. doi:10.1016/j.yexmp.2012.09.010
38 Garne E, Haeusler M, Barisic I, Gjergja R, Stoll C, Clementi M, Euroscan Study Group. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002;19:329-33. doi:10.1046/j.1469-0705.2002.00635.x
39 Gallot D, Coste K, Francannet C, et al. Antenatal detection and impact on outcome of congenital diaphragmatic hernia: a 12-year experience in Auvergne, France. Eur J Obstet Gynecol Reprod Biol 2006;125:202-5. doi:10.1016/j.ejogrb.2005.06.030
40 Mesas Burgos C, Hammarqvist-Vejde J, Frenckner B, Conner P. Differences in outcomes in prenatally diagnosed congenital diaphragmatic hernia compared to postnatal detection: a single-center experience. Fetal Diagn Ther 2016;39:241-7. doi:10.1159/000439303
41 Russo FM, Cordier AG, De Catte L, Saada J, Benachi A, Deprest J, Workstream Prenatal Management, ERNICA European reference network. Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA). Prenat Diagn 2018;38:629-37. doi:10.1002/pd.5297
42 Basurto D, Russo FM, Van der Veeken L, et al. Prenatal diagnosis and management of congenital diaphragmatic hernia. Best Pract Res Clin Obstet Gynaecol 2019;58:93-106. doi:10.1016/j.bpobgyn.2018.12.010
43 Ruano R, Takashi E, da Silva MM, Campos JA, Tannuri U, Zugaib M. Prediction and probability of neonatal outcome in isolated congenital diaphragmatic hernia using multiple ultrasound parameters. Ultrasound Obstet Gynecol 2012;39:42-9. doi:10.1002/uog.10095
44 Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996;31:148-51, discussion 151-2. doi:10.1016/S0022-3468(96)90338-3
45 Peralta CF, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2005;26:718-24. doi:10.1002/uog.2651
46 Jani J, Nicolaides KH, Keller RL, et al, Antenatal-CDH-Registry Group. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol 2007;30:67-71. doi:10.1002/uog.4052
47 Gucciardo L, Deprest J, Done’ E, et al. Prediction of outcome in isolated congenital diaphragmatic hernia and its consequences for fetal therapy. Best Pract Res Clin Obstet Gynaecol 2008;22:123-38. doi:10.1016/j.bpobgyn.2007.08.006
48 Jani J, Nicolaides KH, Benachi A, et al. Timing of lung size assessment in the prediction of survival in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2008;31:37-40. doi:10.1002/uog.5198
49 Alfaraj MA, Shah PS, Bohn D, et al. Congenital diaphragmatic hernia: lung-to-head ratio and lung volume for prediction of outcome. Am J Obstet Gynecol 2011;205:43.
50 Kehl S, Siemer J, Brunnemer S, et al. Prediction of postnatal outcomes in fetuses with isolated congenital diaphragmatic hernias using different lung-to-head ratio measurements. J Ultrasound Med 2014;33:759-67. doi:10.7863/ultra.33.5.759
51 Jani J, Keller RL, Benachi A, et al, Antenatal-CDH-Registry Group. Prenatal prediction of survival in isolated left-sided diaphragmatic
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 13
hernia. Ultrasound Obstet Gynecol 2006;27:18-22. doi:10.1002/uog.2688
52 Sananes N, Britto I, Akinkuotu AC, et al. Improving the prediction of neonatal outcomes in isolated left-sided congenital diaphragmatic hernia by direct and indirect sonographic assessment of liver herniation. J Ultrasound Med 2016;35:1437-43. doi:10.7863/ultra.15.07020
53 Jani JC, Benachi A, Nicolaides KH, et al, Antenatal-CDH-Registry group. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet Gynecol 2009;33:64-9. doi:10.1002/uog.6141
54 Albanese CT, Lopoo J, Goldstein RB, et al. Fetal liver position and perinatal outcome for congenital diaphragmatic hernia. Prenat Diagn 1998;18:1138-42. doi:10.1002/(SICI)1097-0223(199811)18:11<1138::AID-PD416>3.0.CO;2-A
55 Hedrick HL, Danzer E, Merchant AM, et al. Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia. Am J Obstet Gynecol 2007;197:422.
56 Lusk LA, Wai KC, Moon-Grady AJ, Basta AM, Filly R, Keller RL. Fetal ultrasound markers of severity predict resolution of pulmonary hypertension in congenital diaphragmatic hernia.Am J Obstet Gynecol 2015;213:216.
57 Lazar DA, Ruano R, Cass DL, et al. Defining “liver-up”: does the volume of liver herniation predict outcome for fetuses with isolated left-sided congenital diaphragmatic hernia?J Pediatr Surg 2012;47:1058-62. doi:10.1016/j.jpedsurg.2012.03.003
58 Ruano R, Lazar DA, Cass DL, et al. Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2014;43:662-9. doi:10.1002/uog.13223
59 Cordier AG, Jani JC, Cannie MM, et al. Stomach position in prediction of survival in left-sided congenital diaphragmatic hernia with or without fetoscopic endoluminal tracheal occlusion. Ultrasound Obstet Gynecol 2015;46:155-61. doi:10.1002/uog.14759
60 Kitano Y, Okuyama H, Saito M, et al. Re-evaluation of stomach position as a simple prognostic factor in fetal left congenital diaphragmatic hernia: a multicenter survey in Japan. Ultrasound Obstet Gynecol 2011;37:277-82. doi:10.1002/uog.8892
61 Basta AM, Lusk LA, Keller RL, Filly RA. Fetal stomach position predicts neonatal outcomes in isolated left-sided congenital diaphragmatic hernia. Fetal Diagn Ther 2016;39:248-55. doi:10.1159/000440649
62 Cordier AG, Cannie MM, Guilbaud L, et al. Stomach position versus liver-to-thoracic volume ratio in left-sided congenital diaphragmatic hernia. J Matern Fetal Neonatal Med 2015;28:190-5. doi:10.3109/14767058.2014.906576
63 Mahieu-Caputo D, Sonigo P, Dommergues M, et al. Fetal lung volume measurement by magnetic resonance imaging in congenital diaphragmatic hernia. BJOG 2001;108:863-8. doi:10.1111/j.1471-0528.2001.00184.x
64 Oluyomi-Obi T, Kuret V, Puligandla P, et al. Antenatal predictors of outcome in prenatally diagnosed congenital diaphragmatic hernia (CDH). J Pediatr Surg 2017;52:881-8. doi:10.1016/j.jpedsurg.2016.12.008
65 Victoria T, Bebbington MW, Danzer E, et al. Use of magnetic resonance imaging in prenatal prognosis of the fetus with isolated left congenital diaphragmatic hernia. Prenat Diagn 2012;32:715-23. doi:10.1002/pd.3890
66 Jani J, Cannie M, Sonigo P, et al. Value of prenatal magnetic resonance imaging in the prediction of postnatal outcome in fetuses with diaphragmatic hernia. Ultrasound Obstet Gynecol 2008;32:793-9. doi:10.1002/uog.6234
67 Ruano R, Joubin L, Sonigo P, et al. Fetal lung volume estimated by 3-dimensional ultrasonography and magnetic resonance imaging in cases with isolated congenital diaphragmatic hernia. J Ultrasound Med 2004;23:353-8. doi:10.7863/jum.2004.23.3.353
68 Ruano R, Benachi A, Joubin L, et al. Three-dimensional ultrasonographic assessment of fetal lung volume as prognostic factor in isolated congenital diaphragmatic hernia. BJOG 2004;111:423-9. doi:10.1111/j.1471-0528.2004.00100.x
69 Ruano R, Aubry MC, Barthe B, Mitanchez D, Dumez Y, Benachi A. Quantitative analysis of fetal pulmonary vasculature by 3-dimensional power Doppler ultrasonography in isolated congenital diaphragmatic hernia. Am J Obstet Gynecol 2006;195:1720-8. doi:10.1016/j.ajog.2006.05.010
70 Costlow RD, Manson JM. The heart and diaphragm: target organs in the neonatal death induced by nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether). Toxicology 1981;20:209-27. doi:10.1016/0300-483X(81)90052-4
71 Manson JM. Mechanism of nitrofen teratogenesis. Environ Health Perspect 1986;70:137-47. doi:10.1289/ehp.8670137
72 Chiu PP. New insights into congenital diaphragmatic hernia—a surgeon’s introduction to CDH animal models. Front Pediatr 2014;2:36. doi:10.3389/fped.2014.00036
73 Fauza DO, Tannuri U, Ayoub AA, Capelozzi VL, Saldiva PH, Maksoud JG. Surgically produced congenital diaphragmatic hernia in fetal rabbits. J Pediatr Surg 1994;29:882-6. doi:10.1016/0022-3468(94)90008-6
74 Wigglesworth JS, Desai R, Hislop AA. Fetal lung growth in congenital laryngeal atresia. Pediatr Pathol 1987;7:515-25. doi:10.3109/15513818709161415
75 Richards DS, Yancey MK, Duff P, Stieg FH. The perinatal management of severe laryngeal stenosis. Obstet Gynecol 1992;80:537-40.
76 Hashim E, Laberge JM, Chen MF, Quillen EWJr. Reversible tracheal obstruction in the fetal sheep: effects on tracheal fluid pressure and lung growth. J Pediatr Surg 1995;30:1172-7. doi:10.1016/0022-3468(95)90015-2
77 Alcorn D, Adamson TM, Lambert TF, Maloney JE, Ritchie BC, Robinson PM. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat 1977;123:649-60.
78 Nardo L, Hooper SB, Harding R. Lung hypoplasia can be reversed by short-term obstruction of the trachea in fetal sheep. Pediatr Res 1995;38:690-6. doi:10.1203/00006450-199511000-00010
79 VanderWall KJ, Skarsgard ED, Filly RA, Eckert J, Harrison MR. Fetendo-clip: a fetal endoscopic tracheal clip procedure in a human fetus. J Pediatr Surg 1997;32:970-2. doi:10.1016/S0022-3468(97)90379-1
80 Harrison MR, Mychaliska GB, Albanese CT, et al. Correction of congenital diaphragmatic hernia in utero IX: fetuses with poor prognosis (liver herniation and low lung-to-head ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998;33:1017-22, discussion 1022-3. doi:10.1016/S0022-3468(98)90524-3
81 Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000;183:1059-66. doi:10.1067/mob.2000.108871
82 Harrison MR, Sydorak RM, Farrell JA, Kitterman JA, Filly RA, Albanese CT. Fetoscopic temporary tracheal occlusion for congenital diaphragmatic hernia: prelude to a randomized, controlled trial. J Pediatr Surg 2003;38:1012-20. doi:10.1016/S0022-3468(03)00182-9
83 Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg 1993;28:1433-9, discussion 1439-40. doi:10.1016/0022-3468(93)90426-L
84 Hedrick MH, Estes JM, Sullivan KM, et al. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg 1994;29:612-7. doi:10.1016/0022-3468(94)90724-2
85 Luks FI, Wild YK, Piasecki GJ, De Paepe ME. Short-term tracheal occlusion corrects pulmonary vascular anomalies in the fetal lamb with diaphragmatic hernia. Surgery 2000;128:266-72. doi:10.1067/msy.2000.107373
86 Flageole H, Evrard VA, Piedboeuf B, Laberge JM, Lerut TE, Deprest JA. The plug-unplug sequence: an important step to achieve type II pneumocyte maturation in the fetal lamb model. J Pediatr Surg 1998;33:299-303. doi:10.1016/S0022-3468(98)90451-1
87 Bratu I, Flageole H, Laberge JM, Chen MF, Piedboeuf B. Pulmonary structural maturation and pulmonary artery remodeling after reversible fetal ovine tracheal occlusion in diaphragmatic hernia. J Pediatr Surg 2001;36:739-44. doi:10.1053/jpsu.2001.22950
88 Harrison MR, Adzick NS, Bullard KM, et al. Correction of congenital diaphragmatic hernia in utero VII: a prospective trial. J Pediatr Surg 1997;32:1637-42. doi:10.1016/S0022-3468(97)90472-3
89 Harrison MR, Adzick NS, Flake AW, et al. Correction of congenital diaphragmatic hernia in utero VIII: Response of the hypoplastic lung to tracheal occlusion. J Pediatr Surg 1996;31:1339-48. doi:10.1016/S0022-3468(96)90824-6
90 Harrison MR, Adzick NS, Flake AW, et al. Correction of congenital diaphragmatic hernia in utero: VI. Hard-earned lessons. J Pediatr Surg 1993;28:1411-7, discussion 1417-8. doi:10.1016/S0022-3468(05)80338-0
91 Harrison MR, Langer JC, Adzick NS, et al. Correction of congenital diaphragmatic hernia in utero, V. Initial clinical experience. J Pediatr Surg 1990;25:47-55, discussion 56-7. doi:10.1016/S0022-3468(05)80163-0
92 Harrison MR, Ross NA, de Lorimier AA. Correction of congenital diaphragmatic hernia in utero. III. Development of a successful surgical technique using abdominoplasty to avoid compromise of umbilical blood flow. J Pediatr Surg 1981;16:934-42. doi:10.1016/S0022-3468(81)80849-4
93 Harrison MR, Jester JA, Ross NA. Correction of congenital diaphragmatic hernia in utero. I. The model: intrathoracic balloon produces fatal pulmonary hypoplasia. Surgery 1980;88:174-82.
94 Harrison MR, Adzick NS, Longaker MT, et al. Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
14 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
from the left thorax. N Engl J Med 1990;322:1582-4. doi:10.1056/NEJM199005313222207
95 Harrison MR, Albanese CT, Hawgood SB, et al. Fetoscopic temporary tracheal occlusion by means of detachable balloon for congenital diaphragmatic hernia. Am J Obstet Gynecol 2001;185:730-3. doi:10.1067/mob.2001.117344
96 Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916-24. doi:10.1056/NEJMoa035005
97 Deprest J, Gratacos E, Nicolaides KH, Group FT, FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol 2004;24:121-6. doi:10.1002/uog.1711
98 Jani JC, Nicolaides KH, Gratacós E, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2009;34:304-10. doi:10.1002/uog.6450
99 Mychaliska GB, Bealer JF, Graf JL, Rosen MA, Adzick NS, Harrison MR. Operating on placental support: the ex utero intrapartum treatment procedure. J Pediatr Surg 1997;32:227-30, discussion 230-1. doi:10.1016/S0022-3468(97)90184-6
100 Ruano R, da Silva MM, Campos JA, et al. Fetal pulmonary response after fetoscopic tracheal occlusion for severe isolated congenital diaphragmatic hernia. Obstet Gynecol 2012;119:93-101. doi:10.1097/AOG.0b013e31823d3aea
101 Ruano R, Peiro JL, da Silva MM, et al. Early fetoscopic tracheal occlusion for extremely severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: preliminary results. Ultrasound Obstet Gynecol 2013;42:70-6. doi:10.1002/uog.12414
102 Belfort MA, Olutoye OO, Cass DL, et al. Feasibility and outcomes of fetoscopic tracheal occlusion for severe left diaphragmatic hernia. Obstet Gynecol 2017;129:20-9. doi:10.1097/AOG.0000000000001749
103 Ruano R, Klinkner DB, Balakrishnan K, et al. Fetoscopic therapy for severe pulmonary hypoplasia in congenital diaphragmatic hernia: a first in prenatal regenerative medicine at Mayo Clinic. Mayo Clin Proc 2018;93:693-700. doi:10.1016/j.mayocp.2018.02.026
104 Ruano R, Yoshisaki CT, da Silva MM, et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2012;39:20-7. doi:10.1002/uog. 10142
105 Style CC, Olutoye OO, Belfort MA, et al. Fetal endoscopic tracheal occlusion reduces pulmonary hypertension in severe congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2019;54:752-8. doi:10.1002/uog.20216
106 Fauza DO. Tissue engineering in congenital diaphragmatic hernia. Semin Pediatr Surg 2014;23:135-40. doi:10.1053/j.sempedsurg.2014.04.004
107 Quan Y, Wang D. Clinical potentials of human pluripotent stem cells in lung diseases. Clin Transl Med 2014;3:15. doi:10.1186/2001-1326-3-15
108 Ghaedi M, Niklason LE, Williams J. Development of lung epithelium from induced pluripotent stem cells. Curr Transplant Rep 2015;2:81-9. doi:10.1007/s40472-014-0039-0
109 Schilders KA, Eenjes E, van Riet S, et al. Regeneration of the lung: Lung stem cells and the development of lung mimicking devices. Respir Res 2016;17:44. doi:10.1186/s12931-016-0358-z
110 Malin G, Tonks AM, Morris RK, Gardosi J, Kilby MD. Congenital lower urinary tract obstruction: a population-based epidemiological study. BJOG 2012;119:1455-64. doi:10.1111/j.1471-0528.2012.03476.x
111 Anumba DO, Scott JE, Plant ND, Robson SC. Diagnosis and outcome of fetal lower urinary tract obstruction in the northern region of England. Prenat Diagn 2005;25:7-13. doi:10.1002/pd.1074
112 Ruano R, Sananes N, Sangi-Haghpeykar H, et al. Fetal intervention for severe lower urinary tract obstruction: a multicenter case-control study comparing fetal cystoscopy with vesicoamniotic shunting. Ultrasound Obstet Gynecol 2015;45:452-8. doi:10.1002/uog.14652
113 Ruano R, Yoshisaki CT, Salustiano EM, Giron AM, Srougi M, Zugaib M. Early fetal cystoscopy for first-trimester severe megacystis. Ultrasound Obstet Gynecol 2011;37:696-701. doi:10.1002/uog.8963
114 Ruano R. Fetal surgery for severe lower urinary tract obstruction. Prenat Diagn 2011;31:667-74. doi:10.1002/pd.2736
115 Lewis MA. Demography of renal disease in childhood. Semin Fetal Neonatal Med 2008;13:118-24. doi:10.1016/j.siny.2007.09.011
116 Ethun CG, Zamora IJ, Roth DR, et al. Outcomes of fetuses with lower urinary tract obstruction treated with vesicoamniotic shunt: a single-institution experience. J Pediatr Surg 2013;48:956-62. doi:10.1016/j.jpedsurg.2013.02.011
117 Keswani SG, Wilson RD, Johnson MP. Ten Percutaneous intrauterine fetal shunting. Operat Obstetr 4E 2017.
118 Morris RK, Kilby MD. Long-term renal and neurodevelopmental outcome in infants with LUTO, with and without fetal intervention. Early Hum Dev 2011;87:607-10. doi:10.1016/j.earlhumdev.2011.07.004
119 Harrison MR, Ross N, Noall R, de Lorimier AA. Correction of congenital hydronephrosis in utero. I. The model: fetal urethral obstruction produces hydronephrosis and pulmonary hypoplasia in fetal lambs. J Pediatr Surg 1983;18:247-56. doi:10.1016/S0022-3468(83)80094-3
120 Glick PL, Harrison MR, Noall RA, Villa RL. Correction of congenital hydronephrosis in utero III. Early mid-trimester ureteral obstruction produces renal dysplasia. J Pediatr Surg 1983;18:681-7. doi:10.1016/S0022-3468(83)80003-7
121 Matsell DG, Bennett T, Bocking AD. Characterization of fetal ovine renal dysplasia after mid-gestation ureteral obstruction. Clin Invest Med 1996;19:444-52.
122 Kitagawa H, Pringle KC, Koike J, Zuccollo J, Nakada K. Different phenotypes of dysplastic kidney in obstructive uropathy in fetal lambs. J Pediatr Surg 2001;36:1698-703. doi:10.1053/jpsu.2001.27964
123 Pringle KC, Zuccollo J, Kitagawa H, Koike J, Delahunt B. Renal dysplasia produced by obstructive uropathy in the fetal lamb. Pathology 2003;35:518-21. doi:10.1080/00313020310001 619145
124 Robyr R, Benachi A, Daikha-Dahmane F, Martinovich J, Dumez Y, Ville Y. Correlation between ultrasound and anatomical findings in fetuses with lower urinary tract obstruction in the first half of pregnancy. Ultrasound Obstet Gynecol 2005;25:478-82. doi:10.1002/uog.1878
125 Moise KJJr, ed. Toward consistent terminology: assessment and reporting of amniotic fluid volume. Sem Perinatol, 2013.
126 Bernardes LS, Aksnes G, Saada J, et al. Keyhole sign: how specific is it for the diagnosis of posterior urethral valves?Ultrasound Obstet Gynecol 2009;34:419-23. doi:10.1002/uog.6413
127 Morris RK, Malin GL, Khan KS, Kilby MD. Antenatal ultrasound to predict postnatal renal function in congenital lower urinary tract obstruction: systematic review of test accuracy. BJOG 2009;116:1290-9. doi:10.1111/j.1471-0528.2009.02194.x
128 Nicolini U, Fisk NM, Rodeck CH, Beacham J. Fetal urine biochemistry: an index of renal maturation and dysfunction. Br J Obstet Gynaecol 1992;99:46-50. doi:10.1111/j.1471-0528.1992.tb14391.x
129 Nicolini U, Spelzini F. Invasive assessment of fetal renal abnormalities: urinalysis, fetal blood sampling and biopsy. Prenat Diagn 2001;21:964-9. doi:10.1002/pd.212
130 Muller F, Dommergues M, Mandelbrot L, Aubry M-C, Nihoul-Fekete C, Dumez Y. Fetal urinary biochemistry predicts postnatal renal function in children with bilateral obstructive uropathies. Obstet Gynecol 1993;82:813-20.
131 Morris RK, Quinlan-Jones E, Kilby MD, Khan KS. Systematic review of accuracy of fetal urine analysis to predict poor postnatal renal function in cases of congenital urinary tract obstruction. Prenat Diagn 2007;27:900-11. doi:10.1002/pd.1810
132 Abdennadher W, Chalouhi G, Dreux S, et al. Fetal urine biochemistry at 13-23 weeks of gestation in lower urinary tract obstruction: criteria for in-utero treatment. Ultrasound Obstet Gynecol 2015;46:306-11. doi:10.1002/uog.14734
133 Ruano R, Dunn T, Braun MC, Angelo JR, Safdar A. Lower urinary tract obstruction: fetal intervention based on prenatal staging. Pediatr Nephrol 2017;32:1871-8. doi:10.1007/s00467-017-3593-8
134 Enninga EA, Ruano R. Fetal surgery for lower urinary tract obstruction: the importance of staging prior to intervention. Minerva Pediatr 2018;70:263-9.
135 Farrugia MK, Braun MC, Peters CA, Ruano R, Herndon CD. Report on The Society for Fetal Urology panel discussion on the selection criteria and intervention for fetal bladder outlet obstruction. J Pediatr Urol 2017;13:345-51. doi:10.1016/j.jpurol.2017.02.021
136 Ruano R, Safdar A, Au J, et al. Defining and predicting ‘intrauterine fetal renal failure’ in congenital lower urinary tract obstruction. Pediatr Nephrol 2016;31:605-12. doi:10.1007/s00467-015- 3246-8
137 Sananes N, Cruz-Martinez R, Favre R, et al. Two-year outcomes after diagnostic and therapeutic fetal cystoscopy for lower urinary tract obstruction. Prenat Diagn 2016;36:297-303. doi:10.1002/pd.4771
138 Ruano R, Sananes N, Wilson C, et al. Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity. Ultrasound Obstet Gynecol 2016;48:476-82. doi:10.1002/uog.15844
139 Fontanella F, van Scheltema PNA, Duin L, et al. Antenatal staging of congenital lower urinary tract obstruction. Ultrasound Obstet Gynecol 2019;53:520-4. doi:10.1002/uog.19172
140 Fontanella F, Duin L, Adama van Scheltema PN, et al. Antenatal workup of early megacystis and selection of candidates for fetal therapy. Fetal Diagn Ther 2019;45:155-61. doi:10.1159/000488282
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 15
141 Fontanella F, Duin L, Adama van Scheltema PN, et al. Fetal megacystis: prediction of spontaneous resolution and outcome. Ultrasound Obstet Gynecol 2017;50:458-63. doi:10.1002/uog.17422
142 Fontanella F, Duin LK, Adama van Scheltema PN, et al. Prenatal diagnosis of LUTO: improving diagnostic accuracy. Ultrasound Obstet Gynecol 2018;52:739-43. doi:10.1002/uog.18990
143 Morris RK, Malin GL, Quinlan-Jones E. Percutaneous vesicoamniotic shunting versus conservative management for fetal lower urinary tract obstruction (PLUTO): a randomized trial. Lancet 2013;382:1496-506. doi:10.1016/S0140-6736(13)60992-7
144 Nassr AA, Shazly SAM, Abdelmagied AM, et al. Effectiveness of vesicoamniotic shunt in fetuses with congenital lower urinary tract obstruction: an updated systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017;49:696-703. doi:10.1002/uog.15988
145 Morris RK, Ruano R, Kilby MD. Effectiveness of fetal cystoscopy as a diagnostic and therapeutic intervention for lower urinary tract obstruction: a systematic review. Ultrasound Obstet Gynecol 2011;37:629-37. doi:10.1002/uog.8981
146 Quintero RA, Hume R, Smith C, et al. Percutaneous fetal cystoscopy and endoscopic fulguration of posterior urethral valves. Am J Obstet Gynecol 1995;172:206-9. doi:10.1016/0002-9378(95)90115-9
147 Sananes N, Favre R, Koh CJ, et al. Urological fistulas after fetal cystoscopic laser ablation of posterior urethral valves: surgical technical aspects. Ultrasound Obstet Gynecol 2015;45:183-9. doi:10.1002/uog.13405
148 Welsh A, Agarwal S, Kumar S, Smith RP, Fisk NM. Fetal cystoscopy in the management of fetal obstructive uropathy: experience in a single European centre. Prenat Diagn 2003;23:1033-41. doi:10.1002/pd.717
149 Vinit N, Gueneuc A, Bessières B, et al. Fetal cystoscopy and vesicoamniotic shunting in lower urinary tract obstruction: long term outcome and current technical limitations. Fetal Diagn Ther 2020;47:74-83. doi:10.1159/000500569
150 Bienstock JL, Birsner ML, Coleman F, Hueppchen NA. Successful in utero intervention for bilateral renal agenesis. Obstet Gynecol 2014;124(Suppl 1):413-5. doi:10.1097/AOG.0000000000000339
151 O’Hare EM, Jelin AC, Miller JL, et al. Amnioinfusions to treat early onset anhydramnios caused by renal anomalies: background and rationale for the Renal Anhydramnios Fetal Therapy Trial. Fetal Diagn Ther 2019;45:365-72. doi:10.1159/000497472
152 Thomas AN, McCullough LB, Chervenak FA, Placencia FX. Evidence-based, ethically justified counseling for fetal bilateral renal agenesis. J Perinat Med 2017;45:585-94. doi:10.1515/jpm-2016-0367
153 Nassr AA, Shamshirsaz AA, Erfani H, et al. Outcome of fetuses with lower urinary tract obstruction and normal amniotic fluid volume in second trimester of pregnancy. Ultrasound Obstet Gynecol 2019;54:500-5. doi:10.1002/uog.20288
154 Johnson MP, Danzer E, Koh J, et al, North American Fetal Therapy Network (NAFTNet). Natural history of fetal lower urinary tract obstruction with normal amniotic fluid volume at initial diagnosis. Fetal Diagn Ther 2018;44:10-7. doi:10.1159/000478011
155 Williams H. A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida. Cerebrospinal Fluid Res 2008;5:7. doi:10.1186/1743-8454-5-7
156 Centers for Disease Control and Prevention. Data and statistics on spina bifida. 2019. https://www.cdc.gov/ncbddd/spinabifida/data.html
157 Centers for Disease Control and Prevention. Racial/ethnic differences in the birth prevalence of spina bifida—United States, 1995-2005. MMWR Morbid Mortal Week Rep 2009;57:1409-13.
158 Au KS, Ashley-Koch A, Northrup H. Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Dev Disabil Res Rev 2010;16:6-15. doi:10.1002/ddrr.93
159 Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5. doi:10.1056/NEJM199212243272602
160 Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, Sutton LN, Whitehead AS. Spina bifida. Lancet 2004;364:1885-95. doi:10.1016/S0140-6736(04)17445-X
161 Carreras E, Maroto A, Illescas T, et al. Prenatal ultrasound evaluation of segmental level of neurological lesion in fetuses with myelomeningocele: development of a new technique. Ultrasound Obstet Gynecol 2016;47:162-7. doi:10.1002/uog.15732
162 Joyeux L, Danzer E, Flake AW, Deprest J. Fetal surgery for spina bifida aperta. Arch Dis Child Fetal Neonatal Ed 2018;103:F589-95. doi:10.1136/archdischild-2018-315143
163 Adzick NS, Thom EA, Spong CY, et al, MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364:993-1004. doi:10.1056/NEJMoa1014379
164 Sawin KJ, Liu T, Ward E, et al, NSBPR Coordinating Committee. The National Spina Bifida Patient Registry: profile of a large cohort of
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
16 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 17
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) ***************************
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
18 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
the bmj | BMJ 2020;370:m1624 | doi: 10.1136/bmj.m1624 19
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
STATE OF THE ART REVIEW
20 doi: 10.1136/bmj.m1624 | BMJ 2020;370:m1624 | the bmj
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from
No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe
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
on 27 Septem
ber 2020 by guest. Protected by copyright.
http://ww
w.bm
j.com/
BM
J: first published as 10.1136/bmj.m
1624 on 1 July 2020. Dow
nloaded from