oi») VIAMEDICA REVIEW / OBSTETRICS Ghetoloal Psa ov, yel 88 na 24-30 copyight = 2017 a Medes isswoot?-0ot1 Da 10560376 70005 Congenital diaphragmatic hernia: pathogenesis, prenatal diagnosis and management — literature review Przemystaw Kosiriski, Mirostaw Wielgos Department of Obstetrics and Gynecology, Medical University of Warsaw, Poland ABSTRACT Congenital diaphragmatic hernia (CDH) is 2 developmental discontinuity ofthe diaphragm It allows abdominal viscera {to hermiat into the chest nd leads to ung hypoplasia, Congenital diaphragmatic hernias one of the most severe birth defects, wth extremely high neonatal mortality. This paper presentsa review ofthe available literature on prenatal diagnosis, ‘management and treatment options for CH. In selected cases a prenatal procedure to improve neonatal survivals possible, ‘Theauthors ofthis manuscript believe thei work might contribute to a better understanding ofcongenital ciaphragmatic hernia and patient selection forthe FETO (fetal endoscopic tracheal occlusion) surgery or expectant management. Key words: congenital diaphragmatic hernia, FETO procedure tracheal balloon occlusion, lung hypoplasia INTRODUCTION ‘Congenital diaphragmatichemnia (CDH) isadevelopmen- talclosure defect resulting in discontinuity ofthe diaphragm. Thisallows abdominal viscera to herniate into the chest. CDH ‘occurs in approximately 7 in 3000 lve births andl results in high neonatal morbidity and mortality (1). Iis also associated with severe pulmonary hypoplasia and pulmonary hyperten- sion. The posterolateral left side ofthe diaphragmis the most common localization (75-90% f cases), butthe defect can be also right-sided (10-15% of cases), or even bilateral (1-2% of cases) [2], Some authors reported a slightly higher incidence, ‘of CDH in male fetuses. CDH prevalence does not appear to be associated with matemal age. Although diaphragmatic herniation is surgically cor- rectable, in utero herniation of the viscera may result in complications, which are often fatal. Since the FETO (fetal endoscopic tracheal occlusion) surgery has become avail- able, adequate patient selection and eligiblity forthe proce- dure are of vital importance. The aim of FETOisto minimize pulmonary hypoplasia and reduce mortality. As any other surgical procedure, FETO has some contraindications and may carry the isk of possible adverse side effects, ‘This paper presents review ofthe literature on prenatal diagnosis, embryology, possible pathogenesis and manage- Conespaning autor: Prams ests Departnent of sti and Greg, Mada Une of Wasan Staten St 13, 02-45 ara Pa 1) 22585030 fin 8) 2583030, ‘mal planstowonedugt Py Ginekologia Polska 2017; 88, 12:24-30 ment options for this rare and severe anatomical defect. It may help clinicians to be more confident at diagnosis ‘and particularly when counseling a case with congenital diaphragmatic hernia. It also reviews the indications risks, and clinical implications of FETO for severe congenital dia- phragmatic hernia, EMBRYOLOGY AND PATHOGENESIS ‘Thediaphragmis derived from the septum transversum, the pleuroperitoneal folds, derivatives from the body wall, the dorsal mesentery, and a pair of pre-muscle masses ying ‘opposite the forth cervical segment of the 9 mm embryo. The septum transversum originates around day 22 at a cer- vical level, but caudal to the developing heart. In normal conditions, the pleuroperitoneal folds fuse with the septum transversum, the esophageal mesentery and the muscular ingrowth from the body wall invade the folds, forming the muscular part of the diaphragm. Incomplete fusion of any of these components may produce a hernia of Morgagni, a pleuroperitoneal defect, a hiatal hernia, or eventration of the diaphragm. There re several types of diaphragmatic her- ria. The mast common defectislocatedin the posterolateral Ventanas ™ ee ars » den et » Aoi ct * i es He den * cen i spiny Pitosewsesn TH Tatonepgaeh Neve ees » Calne dec » cute * pea a aT = cette » ‘matic eventration is less severe than CDH and sometimes. remains symptomless until early childhood. Diaphragmatic agenesis,on theother hand, s considered the mostextreme, form of CDH, Other thoracic lesions which should be con- sidered in differential diagnosis include congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestration, bronchopulmonary foregut malformation, bronchogenic cysts, bronchial atresia, enteric cysts, and Vianney int {animal models) [13] copter Tesoeics Apt tae re Dato Gronsione Te o ms sngeome SRM a mace SS aE am es fre ae Congenital cystic aenomatidmafrmation (CAM) Bronchopulmonary sequestration Diaphragmatic evetatton Tertoma a ae Bronchial atresia Entencgsts Bronchopulmonary foregut malformation teratomas (9). Multiple cystic lesions in the chest are more likely to be CCAM than CDH, and a presence of a systemic feeding vessel to a cystic or solid mass is consistent with a bronchopulmonary sequestration. The differential diag- nosis may be difficult, however, CDH can be excluded by the presence of normal intraabdominal organs and on the ‘other hand - the diagnosis is certain if intestinal peristalsis is seen within the fetal thorax [9]. The most common lung lesions which need to be excluded in differential diagnosis cof CDH are summarized in Table 4 PROGNOSTIC FACTORS ‘The prognosis forthe survival depends on several fac- tors. If CDH is associated with a chromosomal defect, the long-term prognosis depends on the type of genetic ab- normality and coexisting abnormalities (in particular central nervous system and heart defects). Several studies have shown thatinfants with right-sided CDH havealower survival rate than those with left-sided lesions (50 vs, 758) (17). For the isolated cases of congenital diaphragmatic hemia, the most commonly accepted prognostic parameter is the as- sessment of the amount of the lung tissuein the etal chest. It Ispresented asa lung area to head circumference ratio (LHR ww journaaviamedicaplginckologia_ polska 7ioekoegla olka 2077, vel 8 9. However, lung volume growth ina developing fetus s diffe tent as compared to head grovith. To correct for gestational age, LHR may be expressed as a percentage of normal (ob- served [OV/expected {E!) LHR [18]. Currently, o/e LHR is the ‘most accepted and validated parameter for the estimation of fetal lung size measured by ultrasound. The area of the con- tralateral lung to the defectis measured, divided by the head circumference and the ofe LHR ratiols calculated (19). While innotmal fetuses LHR increases with gestational age,o/eLHR ‘seems to be constant over the course of pregnancy 20].One ofthe predictive prenatal markers of postnatal survivalis the absence or presence ofliver hemiation. Also, the amount of the liver herniated into the chest may be measured by MRI and calculated as herniated-liver-o-thoracic-volume-rato. Low o/e LHR values combined with liver herniation corre- spond to increased mortality and early neonatal morbidity [211.In a group of 329 fetuses with isolated left-sided CDH, Janjetal, observed the rate of postnatal survival to increase from 18% at ofe LHR < 25% t0.66 % at o/e LHR 26-45% and {89% at o/e LHA > 45% [22]. The prognosis is more severe in cases ofa right-sided defect, liver herniation, low lung area tohead circumference ratio (LHR) and low O/E ratio. large defect is more likely to result in pulmonary hypoplasia and early neonatal death as compared toa small defect. Several predictors for lung hypoplasia and pulmonary hypertension have been described. Some ofthe predictors assess fetal ung vasculature. The McGoon index MGI on ultrasound and the ‘modified McGoon index on MRI are calculated as the sum of the diameters of the right and left pulmonary arteries ‘measured at the bifurcation and divided by the diameter of the aorta. According to some authors, these indices may be useful for predicting neonatal survival and severity of postnatal pulmonary hypertension [23]. Other ultrasound ‘markers are also emerging —suchas the position of the etal stomach inthe chest, for example [24] The intra-abdominal fetal stomach position is associated with a more favorable prognosis, whereas the presence of the stomach within the thorax during the fetal or neonatal period has been shown in multiple studies to correlate with an adverse outcome. Recently, Cordier et al. have confirmed that fetal stomach position was predictive of postnatal survival and the need for patch repair 25], According to some papers, there might be a strong association between neonatal death, ECMO (extracorporeal membrane oxygenation) requirement and short-term respiratory morbidity, depending on the post tion of the fetal stomach [24]. According to Russo eta, the need for ECMO may be predicted based on lung size and liver herniation [26). PRENATAL TREATMENT Severe and extremely severe diaphragmatic hernias have poor outcomes and the affected patients may be of- {feted fetal endoscopic tracheal occlusion FETO).The prima- 'y goal of FETO isto minimize pulmonary hypoplasia and re- ‘duce mortality. Harrison etal, 27], wete the fistto introduce the concept in animal model by deflation of a previously inflated intra-thoracic balloon. Sinceits clinica introduction, FETO has been performed for severe cases at 26-28 weeks and for moderate cases at 30-32 weeks of gestation. Tra- ccheal occlusion leads to the accumulation of the lung fluid, hich causes increased lung tissue stretch and accelerated ‘growth (28. On the other hand, it reduces the number of type Il pneumocytes and surfactant expression. This is the major rationale for balloon retrieval at 33-34 weeks of ‘gestation [29], Prenatal balloon removal is also associated with lower morbidity and better survival ate [30}.Janietal,, ‘demonstrated that, in severe CDH, the FETO procedure in- creased the survival rate from 24.19% to-49.1% [22]. recently published meta-analysis gathered data from five different studies [31]. Lung-to-head ratio (LHR) of s 1.0 was uniformly Used to define severe congenital diaphragmatichernia and used as an inclusion criterion for FETO. These five studies includeda total numberof 211 patients — 101 inthe control and 110 inthe FETO groups. Mean gestation at FETO and at livery was 28 and 35.6 weeks, respectively. The reported Incidence of premature rupture of membranes was 35.3% In the FETO group vs. 27.8% in the control group. Severe pulmonary hypoplasia and pulmonary hypertension were the leading cause of neonatal death in both groups. The meta-analysis revealed that the survival rate was better in the FETO group, with 7-fold greater odds of survival after, FETO. The risk of death was 899% in the control group as ‘compared to 50% in the FETO group (31). Deprest et al, described that premature rupture of membranes, the most ‘common complication of FETO, occurs within three weeks after the procedure in approximately 179 of the cases [18] Tracheal occlusion may also have some side effects for the fetus and the most common is tracheomegaly, with litle ‘or no clinical impact [32]. Following delivery the surviving neonates still require a diaphragm surgery, often including ‘a prosthetic patch repair. In most CDH cases, administration of antenatal gluco- corticoids may be considered, unless contraindicated. This may decrease morbidity resulting from preterm delivery. Animal studies confirmed improved gas exchange, lung morphology and decreased medial hypertrophy of pulmo- nary arterioles after administration of antenatal steroids [33] POSTNATAL TREATMENT Some newborns with severe CDH may require extra conporeal membrane oxygenation. It consists of the can- ulation of both carotid arteries and jugular vein and their ‘connection to the circuit with a membrane gas exchange ‘chamber. It allows oxygen and carbon dioxide exchange 28 wn journasviamedicaplginckoloia_ polskaProemysaw Koss, Most Wega Congenital aphnagmatic etna: pathogenesis prenatal dagnesis and management without involving the lungs. ECMO use is typically restricted toinfants > 2kg and gestational age > 34 weeks in the ab- sence of significantintracranial hemorrhage, chromosomal anomalies or other congenital anomalies (34), Theres anot survivable subset of CDH fetuses due to extremely severe pulmonary hypoplasia for whom ECMO may befutile. Some authors reported reduced number of patients treated with this method due to weakevidence ofitsreal benefits in such neonates [35]. Postnatal therapy is complex and includes immediate intubation, small volume, high-frequency oscil- latory ventilation, and intensive pharmacological treatment, Including nitric oxide use. A more detailed description of ‘neonatal care is beyond the scope of this paper. CONCLUSIONS ‘Congenital diaphragmatic herniaisa complex abnormal- ity. The prognosis remains vety poor if the defect is severe. and prognostic factors are compound. Mortality and morbid ityrates remain high despite modem and intensivecare. Also, the genetics of CDHiscomplexasit might be associated with chromosomal abnormalities or rare genetic syndromes, but the specific inheritance pattern is difficult to establish. Lung hypoplasia and pulmonary hypertension arethe mostsevere ‘neonatal complications. Differing degrees of bilateral pulmo- nary hypoplasia may explain variation in severity among neo- nates presenting with respiratory distress and CDH. Prenatal Intervention aims at stimulating lung development and this ‘might be achieved by fetal endoscopic tracheal acclusion. In aselected group of newborns with severe CDH extracorpor- eal membrane oxygenation may be beneficial. Randomized trials and clear guidelines are necessary to establish the true role of an invasive prenatal treatment. The "Tracheal Occlu- sion To Accelerate Lung growth’ tral (warw.totaltrialeu) Is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia Inthe future, also other alternatives to surgical fetal therapy should be explored and studied. The results ofthis research ‘may offer answersto many questions concerning congenital diaphragmatic hernia, REFERENCES. 1. Wynn JY Chung WK. Genetic causes of congenital daphragmaic hemi. 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