Chapter 40. Fetal Disorders

The combination of extraordinary advances in molecular genetics, prenatal genetic diagnosis,1 and the continuous technologic innovations in prenatal imaging2,3 now make it possible to diagnose prenatally virtually any condition with high levels of confidence. This capability has afforded the opportunity to consider prenatal treatment for an ever-expanding list of conditions that in years past depended on postdelivery assessments. In many instances, irreparable organ injury or even death occurred as a result of this delay. Fetal therapy holds significant promise to change the natural history and improve not only perinatal survival but long-term outcomes as well.4 Fetal therapy has expanded the conditions that may be considered for medical treatment, including congenital pulmonary airway malformations (CPAM),5,6 fetal arrhythmias,7 congenital adrenal hyperplasia,8 and even congenital diaphragmatic hernia.9-11 Possible indications for open fetal surgery have broadened to conditions such as myelomeningocele,12 sacrococcygeal teratoma,13,14 bladder outlet obstruction,15,16 and CPAM.6 But perhaps the most striking area of growth in fetal intervention is for conditions that may be treated by fetoscopic techniques,17 such as twin-twin transfusion syndrome,17-20 twin reversed arterial perfusion sequence,21,22 and congenital diaphragmatic hernia.9-11

Fetal intervention is only possible with precise prenatal imaging, a complete understanding of the maternal history, selection criteria for the intervention, and techniques that are safe for both mother and baby. Recent advances in ultrasound imaging, especially 3-dimensional and 4-dimensional scanning capabilities, have dramatically improved the quality of ultrasound affording diagnostic precision and image-guided capabilities not previously available.3 Ultrasound imaging is complemented by the greater imaging capacity afforded by fetal magnetic resonance imaging, particularly for the central nervous system and chest. Similarly, fetal cardiac assessment has benefited by technical advances not only in fetal echocardiographic imaging but also in the development of fetal magnetocardiography for the accurate diagnosis of tachyarrhythmias.23,24

In the past, fetal intervention was limited to conditions in singletons in which the life of the fetus was threatened. In recent years, the indications for fetal intervention have been extended to non–life-threatening conditions, such as myelomeningocele,12 and to multiple gestations for twin-twin transfusion syndrome,18-20 which in fact is currently the most common indication for fetal surgery. The sophistication of the average expectant mother also has increased. Expecting parents increasingly seek out expertise in fetal imaging, prenatal diagnosis, and fetal intervention and are willing to travel if expertise is not locally available. The evolution of fetal intervention holds tremendous promise for altering prenatal natural history of a disorder in ways not possible after delivery. It also is fraught with potential risk for mothers considering interventions who derive no direct benefit from these procedures. Critical appraisal of the potential maternal and fetal risks of fetal intervention must be carefully weighed by all parents considering these options.

Medical treatment options still remain limited if one excludes the use of corticosteroids to enhance lung maturity. Examples of other treatment options range from transplacental treatment of fetal tachyarrhythmias with maternal antiarrhythmic medications to maternal steroid administration for the treatment of congenital pulmonary airway malformations, rapidly involuting congenital hemangiomas, and complete heart block in the setting of maternal systemic lupus erythematosus. Rapidly involuting congenital hemangiomas in newborns are quite responsive to steroids. These lesions prenatally can cause high output failure and hydrops but can be induced to regress with transplacental steroid treatment.25,26 The most common fetal arrhythmia is supraventricular tachycardia (see Chapter 482).

Fetal complete heart block in the setting of a structurally normal heart is usually due to transplacental passage of anti-Ro/SS-A and anti-La/SS-B maternal antibodies, which cross-react with antigens expressed in the conduction system of the fetal heart (see Chapter 482). Maternal steroids in fetal complete heart block with or without the addition of β-mimetic agents can improve survival.27,28

Congenital pulmonary airway malformations grow extremely rapidly between 20 and about 26 weeks’ gestational age. Occasionally, this rapid growth results in nonimmune hydrops due to severe shift in the mediastinum, obstructed venous return, and compression of the heart. In the past, when these malformations were associated with hydrops, fetal surgery was the only treatment alternative because they were uniformly fatal in this setting. A course of maternal steroids can arrest the growth of the solid component of the malformation and allow the fetus to grow, although the response can be variable and steroids do not always eliminate the need for fetal surgery.5,29

In the most common form of congenital adrenal hyperplasia, 21-hydroxylase deficiency, 17-hydroprogesterone accumulates and can be detected in the amniotic fluid. In families known to be at risk for congenital adrenal hyperplasia, maternal steroid administration prior to 9 weeks’ gestation may prevent virilization in genotypic female fetuses.30-32 Treatment before 5 weeks’ gestation may be necessary to prevent the virilizing effects on the fetal brain (see Chapter 538).

Fetoscopic Surgery

Fetoscopic surgery is now the most commonly employed fetal surgical technique used in a range of indications.17 The most common is twin-twin transfusion syndrome, which occurs exclusively in monochorionic gestations affecting 10% to 15% of monochorionic twin pregnancies and accounting for 17% of all prenatal mortality in twins. While the cause of twin-twin transfusion syndrome is not known, chorioangiopagus, the vascular connections between the twins, that normally occurs in monochorionic pregnancies is a necessary prerequisite for this disease of polyhydramnios in the “recipient” twin and severe oligohydramnios in the “donor” twin. In addition, the recipient twin (the twin receiving blood) develops a hypertrophic cardiomyopathy. Selective fetoscopic laser photocoagulation of vascular connections can arrest the progression of twin-twin transfusion syndrome.18-20 Untreated, it is almost uniformly fatal, but with selective fetoscopic laser photocoagulation, survival rates of 70% to 77% have been reported with up to 64% of pregnancies having both twins survive and 92% of pregnancies having 1 or both fetuses survive. Other treatments, such as amnioreduction, may be effective in 20% to 30% of patients. Ultrasound-guided radiofrequency intrafetal umbilical cord ablation may be indicated as salvage therapy to protect 1 twin from the death of the cotwin.

Twin reversed arterial perfusion sequence is another highly lethal anomaly in which vascular connections between a “pump” twin and an acardiac acephalic twin result in polyhydramnios, preterm labor, heart failure, and death in the pump twin. Intrafetal radiofrequency ablation of the umbilical cord to the acardius results in 95% survival of the “pump” twin in cases in which adverse pregnancy outcome is anticipated.22

Tracheal occlusion can accelerate fetal lung growth. During lung development, there is a net egress of tracheal fluid that can be blocked by tracheal occlusion, resulting in increased intratracheal pressure and accelerated lung growth. In a prospective randomized trial of fetoscopic balloon tracheal occlusion, there was no difference in survival in left congenital diaphragmatic hernia compared to postnatal therapy in cases with lung-to-head-circumference ratio (LHR) less than 1.4.9 The result was not surprising given the favorable outcome of fetuses with LHR greater than 1.0, and the majority of patients had LHR greater than 0.9. This fetoscopic technique was tried for fetuses with congenital diaphragmatic hernia with LHR less than 1.0 and liver herniation. Balloon tracheal occlusion was reversed before delivery with 83% survival compared to 11% survival with conventional postnatal care in European neonatal centers.10,11 This therapy is currently not available in the United States due to lack of an FDA-approved detachable balloon device.

Fetoscopic surgery has been successfully used to treat amniotic band syndrome. Amniotic bands may form as a result of amniocentesis or spontaneously encircle a limb and result in a tourniquet like effect with subsequent limb amputation or death if the band involves the umbilical cord. Fetoscopic laser release of amniotic bands has prevented not only limb amputation but death from cord accidents. The limbs affected by amniotic bands may have abnormalities from amniotic bands, even if released, that include a secondary form of lymphedema or failure of the distal limb to grow.33

Congenital high airway obstruction syndrome results from complete airway obstruction due to tracheal or laryngeal atresia. Up to one third of fetuses with congenital high airway obstruction syndrome will spontaneously perforate through the atresia into the larynx or esophagus with resolution of hydrops.34 Several patients have now undergone fetoscopic laser perforation of laryngeal or tracheal atresia to allow hydrops to resolve.35 An EXIT (ex utero intrapartum treatment) procedure (discussed later in this chapter) is necessary for delivery of these infants, but the resolution of hydrops can result in much healthier newborns.

Bladder outlet obstruction due to posterior urethral valves results in megacystic kidneys, oligohydramnios, and, if untreated, severe renal dysplasia and death from pulmonary hypoplasia. This condition has been treated by vesicoamniotic shunting or open vesicostomy (see next section). Cases that present prior to 20 weeks’ gestation may be candidates for fetoscopic/cystoscopic laser ablation of the posterior urethral valves with restoration of amniotic fluid volume. It is unknown if a better renal outcome will also be achieved by this approach.16,36,37

Open Fetal Surgery

The indications for open fetal surgery remain relatively few, and rarely do these conditions require this form of fetal intervention. As mentioned earlier, steroids can to be effective in reversing nonimmune hydrops in congenital pulmonary airway malformations (CPAM). Steroid refractory CPAM with progression of hydrops, however, remains an indication for open fetal surgery.5,6,29 The maternal risks with open fetal surgery are higher than with fetoscopic intervention because of the large laparotomy incision, the hysterotomy, and the aggressive tocolytic regimen required for management. With the notable exception of myelomeningocele, open fetal surgery may be indicated for cases in which the life of the fetus is jeopardized. In open fetal surgery for CPAM, a thoracoabdominal incision is used for exposure, and care is taken to preserve even the tiniest of compressed remaining hypoplastic lobe, as CPAM is usually lobar. The fetal survival rate following an open fetal surgery for hydropic CPAM is 60%. However, many losses occur when patients are referred late in the course of the disease with end-stage nonimmune hydrops. Those fetuses that are followed closely and show progression to hydrops despite steroid administration are better risk candidates if the surgery is performed earlier in the course of the disease.

Sacrococcygeal teratoma is a rare condition that occurs in only 1 of 25,000 live births. It can grow rapidly, causing high-output cardiac failure, polyhydramnios, preterm labor and/or delivery, or death in utero from nonimmune hydrops. Almost uniformly fatal in the setting of hydrops, recent successful resections in utero have been reported.13,14,38 The key to successful cases has been intervention early in the development of hydrops. The goal of fetal surgery in sacrococcygeal teratoma is to interrupt the large vascular connections responsible for nonimmune hydrops. Care is taken to preserve the anorectal sphincter complex, and a complete resection of the sacrococcygeal teratoma is not attempted. The resection of the pelvic component of the fetal sacrococcygeal teratoma must be performed postnatally. These infants must be followed for at least 3 years with serial α-fetoprotein levels, serial MRIs, and physical examinations as surveillance for recurrent sacrococcygeal teratoma or malignant transformation.39,40

Open fetal surgery has also been employed to treat other life-threatening conditions for which no other therapy exists or conventional approaches have failed. Examples are resection of pericardial teratomas and fetal pacemaker placement for fetuses with complete heart block that develop hydrops despite steroid and β-mimetic therapy. Perhaps the most significant change in the field of fetal surgery has been the application of this technique in non–life-threatening conditions such as myelomeningocele.12 Although folic acid supplementation has reduced the incidence of myelomeningocele, it still occurs in up to 1 in 2000 births. While myelomeningocele is a devastating anomaly, it is not usually fatal in utero. Early reports suggest that fetal surgery to repair myelomeningocele can reverse the hindbrain herniation of the associated Chiari II malformation, slow the rate of enlargement of the ventriculomegaly, and perhaps decrease the need for postnatal ventriculoperitoneal shunting. The Management of Myelomeningocele study (MOMS Trial) is a National Institutes of Health–sponsored prospective randomized clinical trial to answer the question of whether fetal myelomeningocele repair reduces the need for postnatal shunting and improves neurodevelopmental outcome.41 The trial had recruited 130 of the projected 200 patients over 5 years, but the National Institutes of Health has committed to complete the trial.

Bladder outlet obstruction due to posterior urethral valves was the first structural anomaly treated by open fetal surgery. It was quickly supplanted by vesicoamniotic shunting because of the markedly less invasive nature of these shunts. While vesicoamniotic shunts can restore amniotic fluid and allow lung growth, they do not protect the kidney or bladder from progressive injury. In fact, over 50% of successfully treated cases go on to renal failure requiring dialysis and/or renal transplantation. Often, these children are poor transplant candidates because of a fibrotic, hypertrophied, poorly compliant bladder.16,36,37 Recently, open fetal surgery for vesicostomy creation in bladder outlet obstruction has again been employed as the most definitive means to decompress the genitourinary tract and to protect both the bladder and the kidneys.

Ex Utero Intrapartum Treatment

Ex utero intrapartum treatment (EXIT) has been one of the most useful techniques that developed from open fetal surgery for tracheal clip application. Originally developed as a means of operating with placental support to remove surgical clips from the trachea of a baby with congenital diaphragmatic hernia at the time of delivery, it was applied to management of neck masses such as cervical teratoma and lymphangioma causing airway obstruction, intrinsic airway obstruction due to congenital high airway obstruction syndrome, intrathoracic airway obstruction due to teratoma or congenital pulmonary airway malformations, as well as a means of safely transitioning to extracorporeal membrane oxygenation support in severe congenital diaphragmatic hernia or hypoplastic left heart syndrome.42-45