Version May 2024
INTRODUCTION — Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. Although the diaphragmatic defect is surgically correctable, in utero herniation of viscera can result in pulmonary hypoplasia and pulmonary hypertension. A substantial percentage of CDH cases are associated with additional abnormalities, including major structural malformations in other organ systems, chromosomal abnormalities, and/or single gene disorders. Affected neonates usually present in the first few hours of life with respiratory distress that may be mild or so severe as to be incompatible with life. Survival has improved with advances in antenatal diagnosis and neonatal care, but affected infants remain at significant risk of morbidity and mortality.
This topic will discuss prenatal issues related to CDH. Postnatal issues are reviewed separately. (See "Congenital diaphragmatic hernia in the neonate".)
PATHOGENESIS — The period from just after the third week postfertilization (postconception) through the 16th week of gestation is a critical period of lung development. Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including [1-7]:
●Reduction in bronchiolar branching.
●Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.
●Loss of pulmonary mass, leading to postnatal pulmonary hypoplasia.
●Surfactant system dysfunction.
●Hypoplasia of ipsilateral cardiac structures.
The spectrum and severity of adverse effects in an affected fetus vary depending on the gestational age when the viscera herniate.
The reason for failure of normal diaphragmatic closure is unknown. Genetic and/or environmental triggers may disrupt differentiation of mesenchymal cells during formation of the diaphragm and other somatic structures [8-10]. Although familial cases involving autosomal recessive, autosomal dominant, and X-linked inheritance patterns have been reported [11-14], the vast majority of CDH occurs sporadically, with no identifiable familial link. Even among monozygotic twins, concordance for CDH is rare: in a large CDH registry, there were no concordant cases among the five monozygotic twin pairs [15]. Many different genetic defects (eg, aneuploidies, deletions, duplications, translocations) have been identified among sporadic cases [16-18]. These cases may represent de novo mutational events in genes for normal diaphragmatic development or reflect polygenic or multifactorial inheritance, or both.
The possibility of an environmental trigger is supported by cases of CDH associated with vitamin A deficiency [19-24] or exposure to thalidomide, anticonvulsants, or quinine [25].
PREVALENCE AND EPIDEMIOLOGY — The prevalence of CDH is approximately 1 to 4 cases per 10,000 live births [26-28]. In an analysis of data from 31 population-based European registries over a 29-year period and including over 12 million births, the overall prevalence of CDH was 2.3 per 10,000 live births and the prevalence of isolated CDH was 1.6 per 10,000 live births [27]. However, these figures do not account for terminations of pregnancy and stillbirths, which accounted for 30 percent of all cases of CDH in one study [28].
Most studies have not observed a sex association, although at least one study reported a slightly higher prevalence in males [29]. Prevalence does not appear to be associated with maternal age [27].
ANATOMIC FINDINGS — Classic CDH is an opening in the diaphragm due to failure of normal closure of the pleuroperitoneal folds. Absence of the hemidiaphragm (diaphragmatic agenesis) is the most extreme form of CDH and has poorer prognosis than classic CDH [30,31].
●Approximately 95 percent of the diaphragmatic defects are posterolateral (Bochdalek hernia) [26], with the remainder anterior-retrosternal or anterior-peristernal (Morgagni hernia), or rarely central (figure 1).
●Herniation is on the left in 80 to 85 percent of cases, on the right in 10 to 15 percent of cases [29,32], and bilateral in <2 percent of cases [26].
●Left-sided herniation most often involves displacement of the stomach and may involve the liver; right-sided herniation almost always involves upward displacement of the liver. Both right- and left-sided hernias may involve small or large bowel. The herniated abdominal contents may be covered by a pleuroperitoneal sac (called "sac type" CDH).
●Abnormal pulmonary vascular development and function can occur bilaterally. Pulmonary changes are most severe on the ipsilateral side but usually also occur on the contralateral side if the mediastinum shifts and compresses the contralateral lung. Poor pulmonary blood flow results from a reduction in the cross-sectional area of the pulmonary vascular bed in the hypoplastic lungs, thickening of the adventitia and media of the pulmonary arterial walls [33], and vasoconstriction with altered pulmonary vasoreactivity.
●Left-sided hernias with mediastinal shift may diminish left ventricular mass, which may lead to hypoplastic left heart syndrome [7,34].
●A substantial percent of cases of CDH are associated with major extracardiac malformations (68 percent in one study [34]).
PRENATAL DIAGNOSIS
Utility — Prenatal diagnosis of CDH gives parents the opportunity to obtain multidisciplinary counseling about their child's prognosis and their options, which include prenatal intervention (in utero tracheal occlusion) or expectant prenatal management, postnatal intervention or postnatal palliative care, as well as pregnancy termination [35].
Presentation — Over 60 percent of CDH cases are initially suspected on a routine 18 to 22 week sonographic fetal anatomic survey [26]. Others may be identified incidentally at a subsequent examination. Presentation at an older gestational age may be due to lack of early herniation of abdominal contents into the fetal thorax, which can happen with a small defect, or because of technical or interpretive issues on an earlier examination.
Mild cases may not be identified until later in postnatal life when the patient presents with mild gastrointestinal or respiratory symptoms or has a chest radiograph [36].
Ultrasound findings — Definitive prenatal sonographic diagnosis of CDH is based on visualization of abdominal organs in the fetal chest, rather than visualization of an abnormal diaphragm. These characteristic anatomic findings may be accompanied by polyhydramnios or (rarely) hydrops [37]. Reported sensitivity of ultrasound in detection of CDH varies widely. It is higher when associated abnormalities are present, when the defect is large, with advancing gestational age, and when experienced fetal ultrasonographers are performing the examination [38].
●Left-sided CDH – Left-sided CDH is characterized by the presence of a heterogeneous lesion (small bowel) in the left chest that often results in right mediastinal shift (image 1). Fluid and peristalsis in the heterogeneous mass help to distinguish CDH from other intrathoracic masses (see 'Differential diagnosis' below). The fluid-filled stomach may be absent from the abdomen. In these cases, it is displaced into the lower thorax and identified next to or just behind the left heart and separate from the heterogeneous lesion. A portion of the liver may be herniated, as well, appearing as a homogeneous hypoechoic mass in the chest at the level of the heart and continuous with the intraabdominal liver. Color Doppler ultrasound can be used to document the location of the liver by demonstrating the course of the intrahepatic vessels. The gallbladder and hepatic or umbilical veins may be abnormally located within the abdomen, which can be scaphoid. The abdominal circumference may be smaller than expected for gestational age.
●Right-sided CDH – Right-sided CDH is characterized by the presence of a homogeneous mass (liver) in the right chest that often results in left mediastinal shift (image 2). Pleural fluid is often present and bowel may herniate with the liver. The left shift of the heart is a key finding since, sonographically, the liver is similar in appearance to fetal lung and bowel does not reliably herniate. As with left-sided CDH, color Doppler ultrasound can be used to document the location of the liver. Sometimes the gallbladder can be seen in the chest, which when present is another key finding diagnostic of right-sided CDH.
Right CDH is more frequently missed or misdiagnosed than left CDH because the herniated viscera primarily consists of the right lobe of the liver, which may have similar echogenicity to the lung or may be confused with a solid mass in the chest [39]. (See 'Differential diagnosis' below.)
●Polyhydramnios – With either left- or right-sided CDH, esophageal compression secondary to mediastinal shift can result in polyhydramnios, which is common in the late second to third trimester.
●Hydrops – Obstruction of venous return due to mediastinal shift rarely occurs and can result in hydrops.
Associated fetal abnormalities — CDH can be an isolated anomaly, part of a syndrome, or nonsyndromic but associated with other abnormalities.
Isolated CDH — Approximately 30 to 70 percent of cases of CDH are isolated. Pulmonary hypoplasia, intestinal malrotation, and cardiac dextroposition in these cases are due to the hemodynamic or mechanical consequences of CDH, thus they are usually considered part of the CDH sequence and do not negate the designation "isolated CDH." A fetal cardiac echocardiogram is required before deciding that CDH is isolated due to cardiac dextroposition, the frequently small left ventricle, and the known association of CDH with congenital heart disease. (See 'Postdiagnostic fetal evaluation' below.)
Complex, nonisolated, or syndromic CDH — Approximately 30 to 50 percent of CDH cases are called "complex," "nonisolated," or "syndromic" (CDH+) because they are associated with additional abnormalities, including major structural malformations, chromosomal abnormalities, and/or single gene disorders [29]. Associated malformations occur in all major organ systems, with no specific pattern. In a systematic review, 15 percent of infants with CDH also had congenital heart disease, which was critical in 42 percent [40].
Associated anomalies are most common with bilateral CDH and in stillborn infants with CDH, where the prevalence is as high as 95 percent [41-43]. Anomalies in stillbirths with CDH primarily consist of neural tube defects and cardiac anomalies (ventriculoseptal defects, vascular rings, and coarctation of the aorta) [44]. Other midline developmental anomalies have also been reported and include esophageal atresia, omphalocele, and cleft palate.
Conventional karyotypic abnormalities are identified in 10 to 20 percent of prenatally identified cases and are more common when additional anomalies are present; the most common aneuploidies are trisomy 18, 13, and 21 [15,37,41]. Other karyotypic abnormalities, such as monosomy X, tetrasomy 12 p (isochromosome 12p), partial trisomy 5, partial trisomy 20, and polyploidies, have also been reported [38,45]. Microarray improves diagnostic yield by detection of submicroscopic copy number variants potentially associated with CDH [46-50]. Microarray analysis can detect partial deletion of the short arm of chromosome 4 at 4p16.3 (Wolf-Hirschhorn syndrome), supernumerary derivative (22)t(11;22) (Emanuel syndrome), and copy number variation on chromosomes 1, 15, and 8, which account for many of the chromosomal causes of CDH.
Approximately 4 percent of all CDH cases and 10 to 15 percent of CDH cases with associated anomalies are syndromic [51]. Fryns syndrome is the most common autosomal recessive syndrome associated with CDH and consists of CDH, pulmonary hypoplasia, craniofacial anomalies, distal limb hypoplasia, and characteristic internal malformations [52]. Prenatal/postnatal findings in Donnai-Barrow syndrome (LRP2 mutation) may include CDH, absent corpus callosum, coloboma, high myopia, sensorineural hearing loss, and characteristic facial features (wide set eyes, widow's peak hairline, short nose/flat nasal bridge) [53]. Prenatal/postnatal findings in Pallister Killian mosaic syndrome (isochromosome 12p) may include CDH, extra-axial polydactyly, cleft palate, and postnatal hypotonia, abnormal skin pigmentation, and intellectual disability (usually profound) [54]. CDH is also an occasional component of Apert, CHARGE, Coffin-Siris, Goltz, Perlman, Swyer, Brachmann-Cornelia De Lange, Goldenhar sequence, Beckwith Wiedemann, Simpson-Golabi-Behmel, Matthew-Wood, Jarcho-Levin, Fraser, Stickler, Pierre Robin, Wolf-Hirschhorn, Emanuel, and other syndromes [26,38,45].
Differential diagnosis
Other thoracic lesions — Thoracic lesions that should be considered in differential diagnosis include congenital pulmonary airway malformation, bronchopulmonary foregut malformation, bronchogenic cysts, bronchial atresia, enteric cysts, and teratomas [38]. (Please see the individual topic reviews on these abnormalities.)
Key findings suggesting CDH rather than one of these other intrathoracic lesions are visualization of the stomach and/or peristalsis of small bowel in the chest and/or visualization of the diaphragmatic defect in the sagittal or coronal plane. We have found that stomach-down CDH cases are often classified as having a suspected congenital lung lesion because the echogenicity of decompressed bowel loops in stomach-down CDH and microcystic congenital pulmonary airway malformations is similar [55]. Evaluation of the course of the superior mesenteric artery is helpful for confirming intrathoracic herniation of bowel loops. (See "Congenital pulmonary airway malformation: Prenatal diagnosis and management".)
Diaphragmatic eventration and hernia sac — Diaphragmatic eventration refers to elevation of a portion of the diaphragm that is intact but thinned because of incomplete muscularization [56]. The thin and redundant membranous diaphragm resulting from an eventration defect may contain abdominal contents and become displaced into the thorax.
CDH with a hernia sac refers to a CDH in which a membranous sheet of tissue covers the herniated abdominal organs in the thorax. Twenty percent of CDH cases occur with a hernia sac [57,58].
Although severe diaphragmatic eventration can be associated with pulmonary hypoplasia and respiratory distress postnatally, it or CDH with a hernia sac is generally associated with a better prognosis than classic CDH [59-62]. Like classic CDH, diaphragmatic eventration is a component of several syndromes, including trisomy 18.
Classic CDH without a sac is a straightforward diagnosis due to unencapsulated abdominal contents within the chest and mediastinal shift. However, distinguishing CDH with a sac from eventration can be difficult. Clues that point to CDH with a sac include the degree of mediastinal shift and the location of the smooth dome off-center, posteriorly, or anteriorly, whereas an eventration is usually a more global elevation of the diaphragm. It is likely that eventration and sac type CDH diagnoses are often used interchangeably, making it difficult to estimate the true frequencies and prognoses of these entities.
POSTDIAGNOSTIC FETAL EVALUATION
Referral and counseling — When CDH is suspected on prenatal ultrasound examination, the patient should be evaluated at a tertiary center for confirmation of the diagnosis or determination of an alternative diagnosis; fetal echocardiography; assessment of CDH severity; evaluation for associated abnormalities; genetic studies if desired; and multidisciplinary counseling about options, prognosis, and planning further management [63,64]. The multidisciplinary team typically includes imaging, maternal-fetal medicine, neonatology, pediatric surgery, and genetics specialists.
If the planned delivery site does not have the expertise for stabilizing cardiopulmonary function and performing corrective surgery postnatally, referral to a tertiary facility for delivery should be arranged prenatally. (See "Congenital diaphragmatic hernia in the neonate".)
Imaging and genetic evaluation — Our prenatal evaluation includes:
●Detailed fetal anatomic survey by ultrasound with color Doppler to confirm the diagnosis, assess for associated anomalies, and begin assessment of severity/prognostic factors. This should be performed by sonologists with expertise in specialized fetal ultrasound examination. (See 'Evaluation of prognostic factors' below.)
●Ultrafast fetal magnetic resonance imaging (MRI) to identify the position of the liver and other viscera that have herniated, estimate lung volumes, and look for associated abnormalities, as these findings have prognostic significance and can alter decisions regarding fetal/neonatal intervention [65-68].
●Fetal echocardiography to detect structural and functional cardiac abnormalities that may be a component of a syndrome and/or may result in postnatal hemodynamic deterioration.
●Genetic evaluation and counseling, given the increased risk of chromosomal abnormalities in anomalous fetuses and the possibility of syndromic CDH. (See 'Complex, nonisolated, or syndromic CDH' above.)
We offer microarray to all patients to better inform prognostic counseling and decisions about pregnancy management. Exome sequencing or targeted gene sequencing has been performed in selected cases in which no cause for CDH could be identified but does not have a clear role in prenatal diagnosis at this time [29]. In a 10-year review including 89 complex/syndromic and 322 isolated/nonsyndromic infants with CDH at a single institution, mortality was increased in the complex/syndromic group and in the group with genetic testing [69]. Microarray was diagnostic in 9 percent and exome sequencing was diagnostic in 38 percent. Genetic testing was diagnostic in 57 percent of complex/syndromic infants, but in only 2 percent of isolated/nonsyndromic infants. We offer testing for specific single gene disorders when the disorder is suspected by ultrasound examination and testing is available. There is no genetic panel for CDH.
The European reference network on rare inherited and congenital anomalies has published a similar practical and instructional guide for standardized prenatal evaluation of the fetus with CDH [70].
Evaluation of prognostic factors — The prognosis for survival of affected infants depends on a number of prenatally assessable factors. Postnatal survival appears to be less likely in the setting of [71,72]:
●Abnormal microarray or findings suggestive of a fetal syndrome
●Serious associated anomalies
●Large volume of liver herniation
●Lower fetal lung volume
Although a large defect is more likely to result in pulmonary hypoplasia and death than a small defect, the size of the defect is not typically measurable prenatally, so the presence and extent of liver herniation and low fetal lung volume serve as proxies for defect size.
Several clinical features initially thought to be related to low likelihood of survival have not been confirmed as consistently reliable prognostic indicators. These features include early gestational age at diagnosis, right-sided hernia, severe mediastinal shift, polyhydramnios, small lung-thorax transverse area ratio, low left ventricle/right ventricle index, left heart hypoplasia, and the stomach in the chest [55,73-79].
Liver herniation — Liver herniation is a poor prognostic factor, whereas the absence of liver herniation is the most reliable prenatal predictor of postnatal survival. However, a small portion of the left lobe of the liver in the chest in left-sided hernia likely does not affect prognosis. Survival rates with and without herniation were 45 and 74 percent, respectively, in a 2010 systematic review that included 710 affected fetuses [80]. These results are limited by wide variability in definitions and imaging procedures among the studies.
Ultrafast fetal MRI using rapid half-Fourier acquisition single-shot turbo spin-echo (HASTE) technique is the most powerful tool to accurately demonstrate liver herniation (image 3) [65,66,81-83].
Ultrasound can also demonstrate liver herniation (image 4), but MRI provides more quantitative information. When ultrasound is performed, color flow Doppler visualization of bowing of the ductus venosus to the left of the midline or coursing of the portal branches or hepatic veins to the lateral segment of the left lobe above the diaphragm is consistent with liver herniation.
Fetal lung volume — Low absolute or relative fetal lung volume appears to be useful for predicting survival, and is much more useful than the lung area to head circumference ratio in fetuses without liver herniation [84]. However, the optimum equation for estimating fetal lung volume has not been determined [85]. Several small studies have suggested that postnatal survival is poor when fetal lung volume measured by MRI is less than approximately 30 percent of expected lung volume for gestational age [76,86-90] and especially when less than 15 percent [91].
Lung volume can also be assessed using 3D sonography, but MRI may be more reliable. In comparative studies, 3D ultrasound either underestimated the volume measured with MRI [92,93] or provided good agreement [94]. The volume of the ipsilateral lung is difficult to measure with either technique, and there are no comparative studies correlating method of lung volume assessment with outcome.
Lung area to head circumference ratio — The lung area to head circumference ratio (LHR) is an estimate of contralateral lung size and mediastinal shift at the level of the atria on transverse scan of the fetal thorax. Although there is a significant correlation between LHR and survival [75,84,95-102], the lower limit of LHR compatible with survival has been falling over time, so the test is less predictive than in the past [103]. In our experience, LHR is now more indicative of morbidity than mortality.
The three methods for calculating lung area are (a) multiplication of the anteroposterior (AP) diameter of the lung at the midclavicular line by the transverse diameter at the midpoint of the AP diameter (AP method); (b) multiplication of the longest diameter of the lung by its longest perpendicular diameter (longest diameter method); and (c) manual tracing of the limits of the lungs (trace method) [104,105]. We use the AP and trace methods. In left CDH, LHR by the AP method is calculated from a transverse view of the cardiac atria using the two-dimensional perpendicular linear measurement of right lung area (in square millimeters) divided by the head circumference (in millimeters) to minimize lung size differences owing to gestational age (image 1) [95]. In right CDH, the LHR of the left lung area is calculated in the same way. In multicenter studies, a systematic review found that the trace method (method c) had the highest inter-rater agreement with the lowest bias [106].
Because lung growth is four times greater than head growth during pregnancy [104], some experts suggest the LHR should be expressed as a function of gestational age (observed [o]/expected [e] LHR). The o/e LHR can be calculated using a formula specifically developed for this measuring technique and has been validated in 354 fetuses with unilateral isolated CDH in terms of both mortality and morbidity [102,107]. A calculator is available online. In general, o/e LHR is classified as [26]:
●Extreme: <15 percent
●Severe: 15 to 25 percent
●Moderate: 26 to 35 percent
●Mild: 36 to 45 percent
In one study, the overall survival rates for isolated left-sided CDH with extreme, severe, moderate, or mild o/e LHR managed expectantly were approximately 0, 20, 30 to 60, and >75 percent [108]. The survival rate for each classification was higher when the liver was in the abdomen and lower when in the thorax.
PREGNANCY MANAGEMENT
Fetal endoscopic tracheal occlusion (FETO) — The goal of in utero therapy in severe CDH is to prevent or reverse pulmonary hypoplasia and restore adequate lung growth for neonatal survival [75,109]. Fetal tracheal occlusion (TO) appears to be effective (reduces mortality, rate of pulmonary hypertension, and use of extracorporeal membrane oxygenation [ECMO] in severe CDH) [110]. The rationale for this approach is that the dynamics of fetal lung fluid can dramatically affect lung growth [111-113]. Under normal circumstances, the lungs are net producers of amniotic fluid with lung liquid volume and intratracheal pressure maintained at constant values by fetal laryngeal mechanisms [114]. Prenatal TO obstructs the normal egress of lung fluid during pulmonary development, thereby increasing transpulmonic pressure and resulting in large fluid-filled lungs (figure 2).
A percutaneous procedure using a balloon for fetal endoscopic tracheal occlusion (FETO) under maternal local anesthesia, with fetal analgesia and immobilization, has been developed to decrease the risks of preterm labor, reduce the risk of uterine rupture later in pregnancy, and restore surfactant deficiency [115-123]. Videos are available online (eg, our institution: Children's Hospital of Philadelphia). The procedure has improved survival and decreased morbidity compared with previous approaches. (See 'Outcome of FETO' below.)
The optimal timing, duration, and release of the occlusion are not known. In left-sided CDH, one experienced group inserts the balloon at 27+0 to 29+6 weeks in severe cases (o/e LHR <25 percent) because earlier occlusion has a high complication rate [26]. In moderate cases (o/e LHR: 25 to 35 percent with liver in any position, 35 to 45 percent with liver herniation), they perform the procedure later in gestation, at 30+0 to 31+6 weeks, because although delaying FETO may be less beneficial than an earlier procedure, moderate cases have a better prognosis overall and preterm birth, if it occurs as a result of the procedure, is less morbid at this gestational age [124]. This group also performs FETO for severe right-sided CDH (o/e LHR <45 percent with liver herniation).
Ideally, the occlusion is reversed at 34 weeks, usually by fetoscopy or ultrasound-guided puncture, and the pregnancy is allowed to continue, but reversal can also be performed after partial fetal delivery with the fetus still on placental circulation [121].
Candidates — Fetal endoscopic tracheal occlusion (FETO) is an investigational therapy and should only be considered for fetuses with a poor CDH prognosis. Our criteria are isolated left CDH, observed/expected lung area to head circumference ratio (o/e LHR) <25 percent, normal microarray, singleton pregnancy, absence of short cervical length, and gestational age 27+0 to 29+6 weeks at the time of the procedure. A few centers are also offering FETO to moderate (o/e LHR <35 percent) prognosis CDH at 30+0 to 31+6 weeks gestation. We discuss the results of the TOTAL trial (described below) with our patients and point out that the standard of care control group had higher survival rates in North American sites, although information on long-term outcomes is not yet available. Parents need to consider the survival benefit of FETO in fetuses with severe pulmonary hypoplasia in the context of the variability in sonographic prediction of pulmonary hypoplasia, the increased risks of preterm birth and preterm prelabor rupture of membranes, and lack of information regarding longer-term outcomes in infants after FETO [125]. (See 'Outcome of FETO' below.).
Inclusion and exclusion criteria vary among centers. Some clinicians will perform the procedure in fetuses who do not meet criteria, following individual case discussion by a multidisciplinary team and taking into account the postnatal prognosis and the parent's wishes [118].
Outcome of FETO
●Left CDH – Promising results of improved survival reported in early observational studies of FETO [118] led to randomized trials that have provided clearer data.
•The TOTAL trial, which was conducted at centers with experience in FETO and other types of prenatal surgery, randomly assigned patients with singleton fetuses with isolated severe left CDH (observed-to-expected lung-to-head ratio <25 percent, irrespective of liver position) to FETO or to expectant care at 27 to 29 weeks of gestation, followed by standardized postnatal care [126]. The trial was stopped early for efficacy.
In an intention-to-treat analysis that included 80 pregnancies, FETO resulted in 40 percent higher survival to both discharge and to six months of age (40 versus 15 percent; relative risk [RR] 2.67, 95% CI 1.22-6.11). The incidence of pulmonary hypertension among infants who survived to discharge was similar in both groups (15 out of 16 versus 6 out of 6).
FETO also resulted in a higher rate of preterm prelabor rupture of membranes (PPROM: 47 versus 11 percent; RR 4.51, 95% CI 1.83-11.9) and preterm birth (PTB: 75 versus 29 percent; RR 2.59, 95% CI 1.59-4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal.
•The TOTAL trial also evaluated FETO versus expectant care in singleton fetuses with isolated moderate left CDH (observed-to-expected lung-to-head ratio 25 to 34.9 percent, irrespective of liver position, or 35 to 44.9 percent with intrathoracic liver herniation) at 30 to 32 weeks of gestation [127]. In an intention-to-treat analysis involving 196 pregnancies, FETO resulted in a 27 percent higher survival to discharge (63 versus 50 percent; RR 1.27, 95% CI 0.99-1.63) and a 23 percent higher survival to six months of age without oxygen supplementation (54 versus 44 percent; RR 1.23, 95% CI 0.93-1.65), but the possibility of smaller or no improvement in either outcome cannot be excluded, given these confidence intervals. The incidence of pulmonary hypertension among infants who survived to discharge was similar in both groups (42 out of 57 [74 percent] versus 33 out of 49 [67 percent]).
The incidences of PPROM and PTB were increased similar to those in the trial of patients with severe left CDH (PPROM: 44 versus 12 percent; RR 3.79, 95% CI 2.13-6.91; PTB: 64 versus 22 percent; RR 2.86, 95% CI 1.94-4.34). There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death associated with balloon removal.
●Right CDH – In the European experience of 86 cases of isolated right CDH managed expectantly from 2008 to 2018, the survival rate in those with o/e LHR 30 to 45 and >45 percent was 15 and 61 percent, respectively; there were no survivors with o/e LHR <30 [128]. For the 120 cases managed with FETO, survival was 41 percent for both those with o/e LHR <30 and those with o/e LHR 30 to 45 percent.
FETO generally has few adverse effects on the developing trachea [26]. We have not seen reports of increased tracheomalacia with CDH alone. Neonates have tracheomegaly, which does not seem to have a clinical impact other than a barking cough on effort, which diminishes over time.
At least 12 deaths have been attributed to difficulty with balloon removal before or at the time of emergency delivery [126,127,129,130]. Some experts believe balloon retrieval is ideally performed >24 hours before birth to avoid removal in an emergency setting and to allow repopulation of type-II cells for surfactant production. A single center that reported an average gestational age at delivery of 39+2 weeks of gestation employed a strategy ultrasound-guided needle puncture at 32+1 to 34+4 weeks, which avoided the potential complications of a second fetoscopy [131].
In a 2019 meta-analysis, the frequency of severe maternal complications (excluding obstetric complications such as preterm labor and PPROM) in 634 FETO procedures was 1.08 percent (95% CI 0.23-2.54) and consisted of four cases of placental abruption [132]. The frequency of minor complications was 2.39 percent (95% CI 0.71-5.02); chorioamnionitis accounted for 7 of the 13 events. No uterine ruptures occurred in the studies included in this review.
In a prospective study of 18 patients with severe CDH undergoing FETO at an experienced North American center, this cohort had less pulmonary hypertension, pulmonary morbidity, and gastroesophageal reflux compared with 17 similar patients who did not undergo FETO [133]. However, most of the FETO group remained on bronchodilators/inhaled corticosteroids (58 percent) and were feeding tube-dependent (67 percent) at median 5.8 years follow-up.
Future directions for FETO include the Smart-TO balloon which utilizes a magnetic valve that can be activated in the fringe magnetic field of an MRI machine for nonoperative reversal of tracheal occlusion [134,135].
Prenatal care
Fetal assessment
●Serial ultrasound examinations and biophysical profiles – There are no data from well-designed studies on which to base recommendations for antepartum obstetric management. The risk of fetal demise is 2 to 8 percent, and even higher depending on the other anomalies that are present [26,136,137]. The reason for the increased risk of fetal demise, even with isolated CDH, is not known. For this reason, we monitor fetuses closely with:
•Serial ultrasound examinations every four weeks to measure fetal growth and the amniotic fluid index. We increase the frequency to every two weeks if there is evidence of growth restriction or fluid abnormalities.
•Weekly biophysical profiles beginning at 32 to 34 weeks. We increase the frequency to twice weekly biophysical profiles or modified biophysical profiles in patients with fetal growth restriction, oligohydramnios, or severe polyhydramnios.
We monitor the fetus closely because growth restriction, oligohydramnios, or signs of secondary complications, such as particulate meconium in amniotic fluid or hydrops fetalis, may lead us to deliver the fetus preterm to reduce the risk of stillbirth. (See "Fetal growth restriction: Evaluation" and "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations".)
●Estimating fetal weight – CDH may affect sonographic estimation of fetal weight since it may affect the abdominal circumference. If only one biometric parameter for fetal growth calculation is abnormal and this measurement involves a body part related to the anomaly, then we discount that measurement and look at the other biometric parameters. For example, if the abdominal circumference is small or low normal in size, but the head circumference, biparietal diameter, and femur length are all at or above the normal range, then we would not make a diagnosis of fetal growth restriction. If we are unsure because the other biometric measurements are in the lower normal range, then we use Doppler to look for changes that can be seen in fetal growth restriction. (See "Fetal growth restriction: Pregnancy management and outcome", section on 'Fetal surveillance'.)
●Management of polyhydramnios – Polyhydramnios may develop at 28 to 32 weeks and suggests fetal swallowing is impaired. Amnioreduction may be necessary remote from term due to maternal discomfort. For patients at term with severe polyhydramnios in whom cord prolapse upon rupture of membranes is a concern, we deliver at 38 weeks. (See "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations".)
Antenatal glucocorticoids — Antenatal glucocorticoids are administered according to standard protocols to decrease morbidity and mortality when preterm birth is anticipated. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)
There are inadequate data in humans to support use of these drugs because of CDH alone (ie, without anticipated preterm birth) [138]. However, pilot studies in which prenatal glucocorticoids were given to fetal sheep that underwent prolonged TO therapy for severe diaphragmatic hernia reported this therapy improved gas exchange, ventilation efficiency, and lung morphology, and decreased medial hypertrophy of pulmonary arterioles [139-141].
Delivery
Site — Delivery should occur at a medical center with the expertise for stabilizing neonatal pulmonary and cardiovascular function and performing corrective surgery when appropriate. In our experience, up to 50 percent of newborns with CDH require extracorporeal membrane oxygenation (ECMO); therefore, we recommend delivery at a tertiary center with ECMO capability [142]. Even patients with favorable lung parameters may experience severe pulmonary hypertension and therefore benefit from advanced level care.
Timing and mode of delivery — The optimal mode and gestational age for delivery of the fetus with CDH is uncertain. We suggest a planned induction of labor at 39 weeks of gestation to minimize complications from early term delivery and to ensure that the fetus is monitored from the earliest stage of labor and pediatric surgery and neonatology services are prepared to care for the infant. A study of 135 consecutive CDH patients at a single institution reported those born before 39 weeks of gestation were more likely to score (corrected for gestational age) below average for at least one composite (cognitive, language, motor) score compared with full-term peers [143]. Cesarean birth is performed for standard obstetric indications; there is no evidence that routine cesarean birth is beneficial [144,145]. As discussed above, earlier delivery may be indicated because of growth restriction, abnormalities of amniotic fluid volume, nonreassuring fetal testing, meconium passage, or hydrops fetalis.
In contrast to this approach, some investigators have suggested that early term delivery in all infants with CDH may improve survival because the severity of pulmonary hypoplasia and pulmonary hypertension may increase with increasing gestational age. However, a 2023 meta-analysis did not support this hypothesis: The cumulative rate of survival to discharge was similar for CDH neonates delivered at an early term versus at full term (76.7 and 73.9 percent, respectively; RR 1.01, 95% CI 0.89-1.16) [146].
NEONATAL MANAGEMENT AND OUTCOME — The major issues at birth are respiratory insufficiency and persistent pulmonary hypertension. Initiating resuscitation before umbilical cord clamping may support the neonate during the fetal-neonatal transition [147]. Neonatal management and outcome are discussed separately. (See "Congenital diaphragmatic hernia in the neonate".)
RECURRENCE RISK — The recurrence risk may be known when a specific chromosomal abnormality or syndrome has been identified.
In the absence of a family history of CDH, the risk of isolated CDH in future siblings is 1 to 2 percent after one affected child [15,148,149]. Although low, this risk is far higher than the general population risk of approximately 1 to 4 per 10,000 live births. No data are available to guide counseling of recurrence risk in CDH with multiple additional malformations when no specific chromosomal abnormality or genetic syndrome can be identified. In general, the recurrence risk is estimated to be <5 percent when a previous child has multiple congenital anomalies of unknown etiology [45].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Congenital hernia of the diaphragm (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – Congenital diaphragmatic hernia (CDH) is a developmental defect in the diaphragm that allows abdominal viscera to herniate into the chest, thereby interfering with normal development of pulmonary airways, blood vessels, and parenchyma. Although the defect is surgically correctable, pulmonary hypoplasia and pulmonary arterial hypertension can result in life-threatening respiratory compromise. (See 'Pathogenesis' above.)
●Prenatal diagnosis – Prenatal diagnosis is based upon ultrasound examination. The principal findings include a chest mass (which may exhibit peristalsis) and mediastinal shift, often with malposition of the stomach and/or liver in the chest. (See 'Presentation' above and 'Ultrasound findings' above.)
•Associated abnormalities – Chromosomal abnormalities and structural malformations in other major organ systems (eg, congenital heart disease, neural tube defects) are often associated with CDH. (See 'Associated fetal abnormalities' above.)
●Prenatal care
•Patients should be referred for consultation with appropriate imaging, maternal-fetal medicine, neonatology, and pediatric surgery specialists. (See 'Referral and counseling' above.)
•The prenatal assessment of patients with suspected CDH should include a detailed fetal anatomic survey, fetal chromosomal microarray, ultrafast fetal magnetic resonance imaging to determine the degree of liver herniation and estimate lung volume, and echocardiography. (See 'Imaging and genetic evaluation' above.)
•Serial ultrasound examinations are performed in all patients to monitor fetal growth and amniotic fluid volume, and for development of hydrops. Antepartum fetal testing (biophysical profile) is performed because these fetuses are at increased risk of fetal demise. Antenatal glucocorticoids are administered to decrease morbidity and mortality when preterm birth is anticipated, according to standard protocols. (See 'Prenatal care' above.)
●Prognosis – Prognosis is worse in the setting of an abnormal chromosomal microarray, severe associated anomalies, liver herniation, and lower fetal lung volume (see 'Evaluation of prognostic factors' above). Absence of liver herniation is a strong predictor of postnatal survival. (See 'Liver herniation' above.)
●Fetal endoscopic tracheal occlusion – Fetal endoscopic tracheal occlusion (FETO) is an investigational therapy that obstructs the normal egress of lung fluid during pulmonary development, thereby increasing lung fluid and transpulmonic pressure and preventing the abnormal development of lung parenchyma and pulmonary vasculature seen in CDH. (See 'Fetal endoscopic tracheal occlusion (FETO)' above.)
FETO should only be considered for fetuses with a poor CDH prognosis. Our criteria are isolated left CDH, observed/expected lung area to head circumference ratio (o/e LHR) <25 percent, normal microarray, singleton pregnancy, absence of short cervical length, and gestational age 27+0 to 29+6 weeks at the time of the procedure. (See 'Fetal endoscopic tracheal occlusion (FETO)' above.)
●Delivery – In most patients, we plan induction of labor at 39 weeks of gestation. Delivery should occur at a medical center with the expertise for stabilizing neonatal pulmonary and cardiovascular function and performing corrective surgery when appropriate. (See 'Delivery' above.)
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