Most disorders diagnosed before birth are best managed by treatment after birth. However, a few diseases with predictable devastating developmental consequences may benefit from fetal treatment. Surgical intervention on the human fetus has been performed for more than two decades in the United States, primarily at two centres. Recently, fetal surgery has become an international endeavour, with nearly a dozen centres worldwide. Also until recently, only fetuses with life threatening defects were considered candidates for prenatal correction. Now fetal surgical procedures are being performed for non-lethal conditions. Despite the expansion of fetal surgery, several ethical considerations still linger.
Ethical considerations
The fundamental conflict in fetal surgery is balancing the risks to both mother and fetus against the potential benefit to only the fetus.1 As the mother is an innocent bystander in the endeavour her involvement entails only risk. A major intervention to save the life of a fetus seems warranted if maternal risks can be minimised and good fetal outcome assured.2,3 If one can minimise maternal risk by avoiding hysterotomy and its attendant lifelong risk of uterine rupture then a more minor improvement in fetal outcome might be tolerated. Fetal oversight committees have been created at most centres performing fetal surgery to act as multidisciplinary advisory and quality assurance committees. These committees review every single fetal surgical procedure performed in their institution. This nascent field is largely self regulated through the commitment of those involved in the International Fetal Medicine and Surgical Society.
Principles developed in the 1980s that underlie clinical application of fetal surgery remain largely unchanged: documentation of the natural history of the untreated disease in utero before clinical application, sound pathophysiological rationale for treatment before birth, demonstration of safety and efficacy of the fetal procedure in an appropriate animal model, and development of inclusion and exclusion selection criteria for treatment. Rigorous groundwork has been accomplished for several anomalies that are amenable to fetal surgical intervention.
Congenital diaphragmatic hernia
Congenital diaphragmatic hernia results from a defect in the development of the fetal diaphragm, in which the herniated abdominal viscera compress the growing fetal lung and prevent normal growth. To promote growth of the lungs and reverse the effects of potentially lethal pulmonary hypoplasia, strategies for treatment in utero have developed over the past 20 years. The trends in the treatment for congenital diaphragmatic hernia mirror the trends in all of fetal surgery, namely the trend from open hysterotomy to minimally invasive “fetoscopic” repair, the move away from recapitulation of the postnatal repair to a direct assault on the fetal pathophysiological defect, and the trend from reports of anecdotal case series to randomised trials to test the new modalities.
A decade has passed since the first successful open fetal surgery for severe congenital diaphragmatic hernia was performed at the University of California, San Francisco. The procedure entailed complete anatomic repair of the diaphragmatic defect after a maternal hysterotomy and partial removal of the fetus. While complete repair before birth was feasible, it did not improve outcome over postnatally repaired controls in a prospective randomised trial. This approach has since been abandoned.
An alternative strategy was then developed to occlude the trachea temporarily, distending the hypoplastic lungs. This “fetoscopic” approach uses small scopes and video equipment, for detachable balloon placement by fetal bronchoscopy. An obvious major advantage of using video fetoscopic technology (FETENDO) surgery was the lack of maternal hysterotomy and its associated morbidity. In a pilot study, survival for severely affected fetuses was 75% compared with 40-50% for historic controls who were patients treated after birth during the same period at the same institution.4 The safety and efficacy of fetoscopic temporary tracheal occlusion to treat severe congenital diaphragmatic hernia is being tested in a trial sponsored by the National Institutes of Health that is currently under way. Only fetuses most severely affected with liver herniated into the chest, diagnosis before 24 weeks, and a ratio of lung to head of less than 1.4 are eligible for treatment. Less severely affected fetuses are best managed after birth.
Obstructive uropathy
Anomalies of the fetal urinary tract, most commonly posterior urethral valves, may lead to oligohydramnios, pulmonary hypoplasia, and even death. Fetuses with posterior urethral valves have been salvaged by drainage of the obstructed urinary system and restoration of amniotic fluid to normal levels. This was initially accomplished by open fetal surgery with vesicoamniotic shunting and is now done worldwide by inserting percutaneously placed vesicoamniotic shunts in a clinical office based setting. Careful selection of patients and timing are necessary to avoid salvaging fetuses whose lungs are functional but who go on to develop renal failure.5 The true efficacy of this procedure is unknown as a clinical trial was never performed and the international registry is no longer active.
Congenital cystic adenomatoid malformation
Most fetuses diagnosed with a lung mass are found to have a congenital cystic adenomatoid malformation (a cystic pulmonary lesion), which either undergoes spontaneous resolution or is best managed with close surveillance and treatment after birth. A small subset of fetuses with large lung lesions will become hydropic, deteriorate rapidly, and die in utero. For this subset, open fetal surgical resection of the lung mass, involving maternal hysterotomy, fetal thoracotomy, and ligation and resection of the mass has proved successful. Over 16 fetuses have undergone fetal intervention, with a survival rate of over 60%.6
Sacrococcygeal teratoma
As with congenital cystic adenomatoid malformation, some fetuses with sacrococcygeal teratoma are susceptible to demise in utero if the vasculature of the tumour grows to a tremendous size and results in hydrops from high output cardiac failure.7 Maternal hysterotomy and resection of the tumour can save these rare fetuses. Recently, effectively stopping the blood flow to the tumour via percutaneous radiofrequency ablation has shown promise in saving the lives of two fetuses, although injury to the adjacent soft tissues occurred in both cases.8
Twin-twin transfusion syndrome
Twin-twin transfusion syndrome is a devastating complication of monochorionic twin pregnancies, in which placental vascular connections result in one twin “stealing” the blood supply to the other twin, ultimately resulting in the death of both twins. Mortality of twin-twin transfusion syndrome diagnosed in the mid-trimester is greater than 80%. Randomised controlled trials are under way in both Europe and the United States, comparing fetoscopic laser ablation of abnormal placental vessels with amnioreduction to treat this disorder.9
Myelomeningocele
Although spina bifida is not a fatal lesion, it is undeniably devastating. Prenatal treatment of myelomeningocele has brought this once relatively small field of fetal surgery to worldwide attention. To date, over 100 women and their fetuses have undergone in utero surgery to repair the spinal defect. No fetus has been cured of the disease. Published reports and informal surveys indicate that most fetuses show no appreciable improvement in their level of paralysis compared with that seen after optimum postnatal care.10–12 However, as many as a third of the fetuses may have improvement in the Chiari malformation, thus decreasing the need for ventriculoperitoneal shunting.
However, fetal surgery for this disorder has been associated with serious maternal and fetal complications, including uterine rupture, maternal bleeding, fetal death, and prematurity. In addition, the long term outcome for these patients is largely unknown as follow up for most of these fetuses has been poor. Many women elect termination of pregnancy, and others choose natural birth and postnatal care for their afflicted fetuses. For women who wish to consider treatment before birth, a multicentre randomised controlled trial of fetal surgery for myelomeningocele sponsored by the National Institutes of Health is under way. The results of this trial are critical to establish both the safety and the efficacy of this procedure before it becomes widely disseminated.
Footnotes
Competing interests: None declared.
References
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