**4.1. Congenital diaphragmatic hernia**

#### *4.1.1. Pregnancy management*

Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH [42]. After CDH is identified, further management involves referral to a tertiary center for confirmation of the diagnosis, assessment of severity and associated anatomic and genetic abnormalities, multidisciplinary counseling about options and prognosis, and planning further management. Management may be expectant with prenatal referral to a center with expertise in caring for these infants, termination of pregnancy, or fetal intervention [43]. The mean gestational age at diagnosis is about 24 weeks. Polyhydramnios may be present due to esophageal compression. Hydrops fetalis can occur from mediastinal shift and compression of the great vessels.

• Assessment for associated anomalies. Ultrafast fetal MRI to look for associated abnormalities and liver herniation and to estimate lung volumes and fetal echocardiography should be performed.

mild ventriculomegaly may resolve by the third trimester; progression occurs in 16% of cases and has been associated with a worse outcome [36, 39]. Follow-up ultrasounds have detected fetal abnormalities not detected on the initial scan in 13% of cases [36]. Therefore, at least one additional detailed ultrasound examination should be performed between 28 and 34 weeks of gestation to look for CNS and non-CNS abnormalities and regression or progression of dilatation. Antepartum fetal testing has no proven benefit in pregnancies with isolated fetal ventriculomegaly in the absence of other findings, such as intrauterine

• Fetal intervention. Intrauterine treatment with ventriculoamniotic shunting was performed in the 1980s. The expert consensus at that time was that these results did not represent an improvement in outcome over expectant management, which led to a de facto moratorium on such procedures [40]. At present, however, such procedures are investigational [36].

Ventriculomegaly may or may not be accompanied by macrocephaly. Most infants with ventriculomegaly have a normal head circumference (HC), there is no increased risk of cephalopelvic disproportion, and cesarean delivery is not required except for standard obstetric complications. When the HC exceeds 40 cm, abdominal delivery should be considered.

Cephalocentesis, which almost always results in fetal death, is rarely used to decompress the head, allow vaginal delivery, and avoid maternal morbidity from cesarean delivery, in cases in which the neurological prognosis is so dismal (trisomy 13 or 18 or lethal co-existent

Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH [42]. After CDH is identified, further management involves referral to a tertiary center for confirmation of the diagnosis, assessment of severity and associated anatomic and genetic abnormalities, multidisciplinary counseling about options and prognosis, and planning further management. Management may be expectant with prenatal referral to a center with expertise in caring for these infants, termination of pregnancy, or fetal intervention [43]. The mean gestational age at diagnosis is about 24 weeks. Polyhydramnios may be present due to esophageal compression. Hydrops fetalis

can occur from mediastinal shift and compression of the great vessels.

growth restriction or oligohydramnios.

480 Congenital Anomalies - From the Embryo to the Neonate

*3.9.2. Delivery management*

anomalies) [41].

**4. Fetal thoracic anomalies**

*4.1.1. Pregnancy management*

**4.1. Congenital diaphragmatic hernia**

CDH can be an isolated anomaly, part of a syndrome, or nonsyndromic but associated with other abnormalities. Approximately 50–70% of cases of CDH are isolated. Pulmonary hypoplasia, intestinal malrotation, and cardiac dextroposition 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.' The other 30–50% of cases are called 'complex', 'nonisolated', or 'syndromic' CDH (CDH+) because they are associated with additional abnormalities, including major structural malformations, chromosomal abnormalities, and/ or single gene disorders. Malformations occur in all major organ systems, with no specific pattern [43]. An underlying syndrome is present in approximately 10% of CDH cases occurring with associated anomalies [43]. CDH is a prominent finding in the Fryns phenotype; facial dysmorphology, distal digital hypoplasia, and cardiac/renal/brain anomalies can also occur. CDH and diaphragmatic eventration are also an occasional component of many other syndromes, including Apert, Killian/Teschler-Nicola (Pallister-Killian), CHARGE, Coffin-Siris, Goltz, Perlman, Swyer, Brachmann-Cornelia De Lange, Goldenhar sequence, Beckwith Wiedemann, Simpson-Golabi-Behmel, Donnai-Barrow, Mathew-Wood, Jarcho-Levin, Fraser, Stickler, Pierre Robin, and others [43, 44].

Associated anomalies are most common with bilateral CDH and in stillborn infants with CDH, where the prevalence is as high as 95% [43]. Anomalies in stillborn infants with CDH primarily consist of neural tube defects (anencephaly, myelomeningocele, hydrocephalus, and encephaloceles) and cardiac defects (ventriculoseptal defects, vascular rings, and coarctation of the aorta) [45].


Liver herniation is the most reliable prenatal predictor of postnatal survival. A systematic review of studies that used ultrasound or MRI to evaluate outcome of fetuses with liver herniation included 710 fetuses and reported significantly higher survival rate in fetuses without herniation (74% versus 45% with herniation) [49]. Ultrafast fetal MRI using rapid HASTE technique is the most powerful tool to accurately demonstrate liver herniation [50]. Ultrasound can be useful; in particular, color flow Doppler can visualize 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; however, ultrasound has not always accurately demonstrated liver herniation in the fetus with left-sided CDH [43, 50].

procedure under local anesthesia, with fetal pain relief and immobilization, is possible [57]. Fetal TO in severe CDH is associated with a high incidence of PPROM and preterm delivery but a substantial improvement in survival. Smaller and fewer trocars were utilized in another study, resulting in a lower rate of preterm rupture of membranes and

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Important factors in offering prenatal therapy continue to be, first and foremost, determining which fetuses have a poor prognosis. The optimal timing, duration, and release of occlusion in humans are not known. The Eurofetus group has had early success with fetal TO [59]. The insertion of the balloon at 26–28 weeks for severe cases and 30–32 weeks for moderate cases is recommended. Ideally, the occlusion is reversed before delivery at 34 weeks, usually by

The FETO Consortium subsequently reported the outcome of 210 consecutive procedures [57]. Compared with the outcome of expectantly managed cases enrolled in their registry, FETO increased survival in severe cases with left CDH from 24–49% and right CDH from 0–35% (p < 0.001) [57]. However, at least 10 deaths attributed to difficulty with balloon removal before or at the time of emergent delivery have been reported [60]. The Eurofetus consortium also noted that preterm delivery, usually due to premature rupture of membranes, is a common complication and occurred in 17% of cases within 3 weeks of the procedure [43]. FETO has resulted in few clinical side effects on the developing trachea, except in very early occlusions and complications arising at the time of removal [43]. Neonates have tracheomegaly, which does not seem to have a clinical impact other than a barking cough on effort. The Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial is ongoing in Europe and feasibility studies for FETO are ongoing at several North American fetal

• Follow-up assessment. There are no data from well-designed studies on which to base recommendations for antepartum obstetrical management. The intrauterine risk of fetal demise is 2–8%, but higher when other anomalies are present [43]. Twice-weekly nonstress testing or biophysical profile testing at 33–34 weeks should be offered [43]. Ultrasound examinations at 28, 30, 32, and 34–35 weeks of gestation to assess fetal growth and amniotic fluid volume. Polyhydramnios may develop at 28–32 weeks if fetal swallowing is impaired, and oligohydramnios may develop if the fetus is compromised later in gestation. Signs of secondary complications, such as particulate meconium in fluid, dilated stomach in chest, effusions, or ascites, may lead us to deliver the fetus preterm. Fetal growth restriction or oligohydramnios may also lead us to deliver the fetus early. Antenatal glucocorticoids are given, if appropriate, to decrease morbidity from preterm delivery as for

The optimal mode and gestational age for delivery of an infant diagnosed prenatally with CDH is uncertain [43]. A planned induction of labor between 38 and 39 weeks of gestation is suggested so that the fetus is monitored from the earliest stage of labor and so pediatric

preterm delivery [58].

centers [43].

standard indication [43].

*4.1.2. Delivery management*

fetoscopy or ultrasound-guided puncture.

Absolute or relative fetal lung volume appears to be useful for predicting survival, but the optimum equation has not been determined [43, 51]. Several small studies have suggested that postnatal survival is poor when fetal lung volume measured by MRI is less than about 30% of expected lung volume for gestational age and especially when <15% [43]. Lung volume can also be assessed using 3D sonography, but MRI may be more reliable.

Right- versus left-sided lesion. Right-sided CDH have a poorer outcome than that reported for fetuses with left-sided CDH with similar lung size before birth [52].

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, the lower limit of LHR compatible with survival is dropping, so the test is less predictive than in the past [43, 53]. LHR is now more indicative of morbidity than mortality [43]. In left CDH, the LHR is calculated using a 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 [43]. Measurement of fetal lung volume is much more useful than LHR in fetuses without liver herniation [54]. Because lung growth is four times greater than head growth during pregnancy [55], some experts suggest that 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 fetuses with unilateral isolated CDH in terms of both mortality and morbidity [53]. An online calculator is available (www.totaltrial.eu). O/E LHR is considered extreme if <15%, severe at 15–25%, moderate at 26–35%, and mild if 36–45% [44].

• Fetal interventions. Fetal endoscopic tracheal occlusion (FETO) is an investigational procedure for treatment of isolated severe congenital diaphragmatic hernia to prevent or reverse pulmonary hypoplasia and restore adequate lung growth for neonatal survival. The rationale for this approach is that the dynamics of fetal lung fluid can dramatically affect lung growth [43]. 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 [43]. Prenatal tracheal occlusion (TO) obstructs the normal egress of lung fluid during pulmonary development, increasing transpulmonic pressure and resulting in large fluid-filled lungs. Lack of lung expansion 2 and 7 days after TO is a poor prognostic sign and may indicate that the occlusion is inadequate [56]. Techniques to achieve minimally invasive fetoscopic reversible fetal TO have been developed to decrease the risks of preterm labor and restore surfactant deficiency [43]. A percutaneous procedure under local anesthesia, with fetal pain relief and immobilization, is possible [57]. Fetal TO in severe CDH is associated with a high incidence of PPROM and preterm delivery but a substantial improvement in survival. Smaller and fewer trocars were utilized in another study, resulting in a lower rate of preterm rupture of membranes and preterm delivery [58].

Important factors in offering prenatal therapy continue to be, first and foremost, determining which fetuses have a poor prognosis. The optimal timing, duration, and release of occlusion in humans are not known. The Eurofetus group has had early success with fetal TO [59]. The insertion of the balloon at 26–28 weeks for severe cases and 30–32 weeks for moderate cases is recommended. Ideally, the occlusion is reversed before delivery at 34 weeks, usually by fetoscopy or ultrasound-guided puncture.

The FETO Consortium subsequently reported the outcome of 210 consecutive procedures [57]. Compared with the outcome of expectantly managed cases enrolled in their registry, FETO increased survival in severe cases with left CDH from 24–49% and right CDH from 0–35% (p < 0.001) [57]. However, at least 10 deaths attributed to difficulty with balloon removal before or at the time of emergent delivery have been reported [60]. The Eurofetus consortium also noted that preterm delivery, usually due to premature rupture of membranes, is a common complication and occurred in 17% of cases within 3 weeks of the procedure [43]. FETO has resulted in few clinical side effects on the developing trachea, except in very early occlusions and complications arising at the time of removal [43]. Neonates have tracheomegaly, which does not seem to have a clinical impact other than a barking cough on effort. The Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial is ongoing in Europe and feasibility studies for FETO are ongoing at several North American fetal centers [43].

• Follow-up assessment. There are no data from well-designed studies on which to base recommendations for antepartum obstetrical management. The intrauterine risk of fetal demise is 2–8%, but higher when other anomalies are present [43]. Twice-weekly nonstress testing or biophysical profile testing at 33–34 weeks should be offered [43]. Ultrasound examinations at 28, 30, 32, and 34–35 weeks of gestation to assess fetal growth and amniotic fluid volume. Polyhydramnios may develop at 28–32 weeks if fetal swallowing is impaired, and oligohydramnios may develop if the fetus is compromised later in gestation. Signs of secondary complications, such as particulate meconium in fluid, dilated stomach in chest, effusions, or ascites, may lead us to deliver the fetus preterm. Fetal growth restriction or oligohydramnios may also lead us to deliver the fetus early. Antenatal glucocorticoids are given, if appropriate, to decrease morbidity from preterm delivery as for standard indication [43].

#### *4.1.2. Delivery management*

herniation (74% versus 45% with herniation) [49]. Ultrafast fetal MRI using rapid HASTE technique is the most powerful tool to accurately demonstrate liver herniation [50]. Ultrasound can be useful; in particular, color flow Doppler can visualize 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; however, ultrasound has not always accurately

Absolute or relative fetal lung volume appears to be useful for predicting survival, but the optimum equation has not been determined [43, 51]. Several small studies have suggested that postnatal survival is poor when fetal lung volume measured by MRI is less than about 30% of expected lung volume for gestational age and especially when <15% [43]. Lung vol-

Right- versus left-sided lesion. Right-sided CDH have a poorer outcome than that reported

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, the lower limit of LHR compatible with survival is dropping, so the test is less predictive than in the past [43, 53]. LHR is now more indicative of morbidity than mortality [43]. In left CDH, the LHR is calculated using a 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 [43]. Measurement of fetal lung volume is much more useful than LHR in fetuses without liver herniation [54]. Because lung growth is four times greater than head growth during pregnancy [55], some experts suggest that 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 fetuses with unilateral isolated CDH in terms of both mortality and morbidity [53]. An online calculator is available (www.totaltrial.eu). O/E LHR is considered extreme if <15%, severe at 15–25%, moderate at 26–35%, and mild

• Fetal interventions. Fetal endoscopic tracheal occlusion (FETO) is an investigational procedure for treatment of isolated severe congenital diaphragmatic hernia to prevent or reverse pulmonary hypoplasia and restore adequate lung growth for neonatal survival. The rationale for this approach is that the dynamics of fetal lung fluid can dramatically affect lung growth [43]. 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 [43]. Prenatal tracheal occlusion (TO) obstructs the normal egress of lung fluid during pulmonary development, increasing transpulmonic pressure and resulting in large fluid-filled lungs. Lack of lung expansion 2 and 7 days after TO is a poor prognostic sign and may indicate that the occlusion is inadequate [56]. Techniques to achieve minimally invasive fetoscopic reversible fetal TO have been developed to decrease the risks of preterm labor and restore surfactant deficiency [43]. A percutaneous

demonstrated liver herniation in the fetus with left-sided CDH [43, 50].

482 Congenital Anomalies - From the Embryo to the Neonate

for fetuses with left-sided CDH with similar lung size before birth [52].

if 36–45% [44].

ume can also be assessed using 3D sonography, but MRI may be more reliable.

The optimal mode and gestational age for delivery of an infant diagnosed prenatally with CDH is uncertain [43]. A planned induction of labor between 38 and 39 weeks of gestation is suggested so that the fetus is monitored from the earliest stage of labor and so pediatric surgery and neonatology services are prepared to care for the infant. The fetal lung maturity prior to delivery should not be assessed [43]. Up to 50% of cases require extracorporeal membrane oxygenation (ECMO); therefore, the delivery at a tertiary center with ECMO capability is recommended [43]. Cesarean delivery is performed for standard obstetrical indications [43].

renal agenesis or dysgenesis, intestinal atresia, other pulmonary malformations, and diaphragmatic, cardiac, central nervous system, and bony anomalies [61]. Fetal echocardiography is recommended in all patients at time of diagnosis to rule out congenital cardiac

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• Follow-up assessment. All patients should have serial prenatal follow-up examinations every 1 to 4 weeks to assess change in size of the lung mass, change in CVR, and development of polyhydramnios and hydrops [61]. The frequency depends on the gestational age and CVR. Closer follow-up should be performed in those patients at high risk of developing hydrops (CVR ≥1.6, age < 26 weeks), whereas the interval between examinations can be lengthened if the CPAM is very small, CVR is <0.91 [63]. The presence of hydrops is a sign for impending fetal demise and thus it is an indication for fetal intervention [61]. The recommendation of proceeding with fetal intervention is based on results from small case

For fetuses greater than 32–34 weeks of age, early delivery with immediate postnatal resection is a reasonable option [61]. Ex utero intrapartum therapy (EXIT) has been used to stabilize

For gestations between 20 and 32 weeks, several interventions with the goal of improving fetal hemodynamics and preventing lung hypoplasia have been described and appear to improve survival [61]. Drainage procedures are used for CPAMS with dominant cysts, while solid masses are treated by resection or ablation. Karyotype analysis is recommended prior to initiating fetal therapy [61]. All of the following interventions should be considered

Antenatal corticosteroids are the only medical treatment of CPAM. They are used primarily for treatment of microcystic CPAM, since these masses cannot be managed by minimally invasive procedures, but have been used for macrocystic disease, as well [61]. In uncontrolled studies, maternal steroid administration appeared to reverse hydrops and improve outcome [61]. Multiple courses of antenatal betamethasone for high-risk fetal CPAMs often result in favorable short-term outcomes without the need for open fetal resection. The fetuses who did not respond to a first course of steroids stabilized or improved (e.g., reduction in lesion size, resolving hydrops) after receiving two to four courses of therapy [65]. The median interval between the first and second courses of steroids was about 2 weeks (range

• Fetal intervention. Successful fetal surgery depends on surgical experience, optimal maternal anesthesia, uterine relaxation, hysterotomy, fetal exposure, and intraoperative fetal

• Thoracentesis—For fetuses with large pleural effusions, thoracentesis to prevent pulmonary hypoplasia is possible, but rapid reaccumulation of fluid limits its usefulness [61]. The

fluid should be sent for cell count to exclude an infectious etiology [61].

series showing good survival (>90%) if hydrops resolves [61].

fetuses with large lesions expected to have difficulty breathing at delivery [64].

anomalies.

investigational.

1–6 weeks) [61].

monitoring.

*4.2.2. Drainage procedures*
