Fetal Therapy

Guiding Principles

Fetal surgery is a field with complicated pathophysiology, technical approaches, and bioethics. As such, all interventions require careful consideration of every aspect of care as it pertains to the fetus as well as the mother. In 1982, Harrison and colleagues established a series of guiding principles for fetal operations ( Table 10.1 ). Among them was the recognition that fetal surgery is complicated, not only by the risk to the unborn patient, but by the risk to the mother as well. Fetal intervention does not impart a direct health benefit to the mother, yet places her at a significant risk for morbidity and potential mortality. In this light, when balancing the risk/benefits of fetal intervention, all the benefits reside with the fetus but the risks lies with both mother and fetus. The primary morbidity following fetal surgery has been, and remains, preterm labor resulting in premature delivery, usually between 25 and 35 gestational weeks. Preventing preterm labor after fetal intervention remains the Holy Grail for fetal surgeons. Known complications can also arise from endotracheal intubation, general anesthesia, epidural and spinal anesthesia, blood transfusion, premature rupture of membranes (PROM), chorioamniotic separation (CMS), chorioamnionitis, and placental abruption. Long-term morbidity from the open hysterotomy procedures includes infertility, uterine rupture with the current and future pregnancies, and mandatory cesarean section with future pregnancies, although subsequent fertility following fetal intervention does not appear to be affected. Based on these risks, fetal surgery should be considered only when there is a clear advantage to the future child for fetal intervention compared with postnatal intervention.

Although Harrison’s original principles were developed more than 35 years ago and directed at guiding new fetal therapies, the key messages hold true today for any fetal surgery. The complexities of two patients requires an intimate collaboration among multidisciplinary teams that can provide not only the technical abilities to perform the operation on the mother and fetus, but also the experience and understanding of the physiology of pregnancy as well as pathophysiology of an ill fetus. Harrison’s insistence on a multidisciplinary approach cannot be overstated. This requires institutions to provide the highest level of obstetric and neonatal care in preparation for all potential complications.

Multidisciplinary meetings not only cover the medical and surgical aspects of the patient’s care, but also include the ethical and social considerations specific to each case. In most institutions, a Fetal Therapy Oversight Committee or Data Safety and Monitoring Board that includes subspecialists and bioethicists, while excluding any of the clinicians involved in direct patient care, provides a 360-degree evaluation of difficult cases. These often include fetal conditions that do not have explicit data-driven evidence for fetal therapy but where the clinical team may have the technical expertise and experience to offer prenatal intervention, which may alter the natural history and improve outcomes.

However, the distinction between innovation and research remains a constant challenge for all clinicians involved in fetal interventions. The advent of fetal surgery was based on a sound scientific approach with a hypothesis-driven process. Surgical techniques were tested and perfected through animal models. Harrison and his group utilized fetal lambs and primates to develop surgical procedures and understand the impact of surgical intervention and the effects of maternal and fetal anesthesia.

Recently, the widespread adoption of fetal surgery for myelomeningocele (MMC) (spina bifida) represents the first application of maternal-fetal surgery for a nonlethal prenatally diagnosed congenital anomaly. The implications of children born with MMC have been well known to include motor and sensory deficits, hindbrain herniation with hydrocephalus, fecal and urinary incontinence, and cognitive disabilities. Animal models were also created to test the hypothesis for fetal intervention including timing and technique of fetal correction of MMC. Eventually, preclinical research moved to human intervention through a small case series and prospective randomized trials comparing fetal surgery to conventional treatment were performed. As a result, clinicians have been provided with the highest possible level of evidence for the benefits of in utero MMC repair, objective estimates of treatment effect, and a comprehensive understanding of the fetal and maternal risks.

Fetal Access, Anesthesia, and Operative Setup

Proper preoperative planning is essential to optimize fetal access and anesthesia. Technical challenges can occur with open and minimally invasive approaches if not adequately considered. There are three techniques for accessing the fetus: percutaneous procedures, fetoscopy, and open hysterotomy. In all three approaches, preoperative and intraoperative US are crucial for defining the anomaly or anomalies, delineating the placental anatomy, determining the position of the fetus, detecting the location of the maternal blood vessels, and monitoring the fetal heart rate during the procedure. With percutaneous and fetoscopic procedures, US is particularly important due to the lack of visualization of the fetus, placenta, and uterus during the procedure. However, in all procedures, avoidance of the placenta is critical.

The mother is typically positioned supine. Depending on the surgical technique, the patient may sometimes be placed in lithotomy position. A roll is placed under her right hip to facilitate her left side down in order to minimize compression of the inferior vena cava by the gravid uterus, which could diminish venous return. Depending on the operation, maternal anesthesia can be local spinal, epidural, general, or combination. For percutaneous or fetoscopic operations, maternal anesthesia is often achieved through intravenous conscious sedation with local anesthesia. Occasionally, a fetoscopic-assisted approach is needed, which requires general anesthesia for the mother. General anesthesia is achieved through use of volatile anesthetics, which induce the dose-dependent uterine relaxation necessary for optimal access and adequate placental function. Desflurane and sevoflurane induce uterine relaxation more effectively than isofurane, but all three are commonly utilized. If general anesthesia is used in minimal access procedures, less volatile anesthetics should be administered, as uterine relaxation can inhibit proper fetal positioning. One recent animal study suggests that supplementary propofol and remifentanil intravenous anesthesia (SIVA) produces less maternal hypotension and fetal acidosis than is observed with high-dose inhalational anesthesia.

In addition, fetal anesthesia is often needed when performing a fetal procedure. Although the fetus will become anesthetized through the placental transfer of general anesthesia, conscious sedation cases may require direct fetal administration to prevent movement. An intramuscular injection, either in the buttocks or thigh, of an opiate and a non-depolarizing neuromuscular blocking agent is often used. An estimated fetal weight is achieved based on US. A fetal cocktail is created in one syringe that includes fentanyl (10 μg/kg), atropine (20 μg/kg), and vecuronium (0.1 mg/kg). In addition, rescue drugs for resuscitation are available on the surgical field with each individual medication drawn up separately including epinephrine (10 μg/kg).

US-guided percutaneous procedures are performed through small skin incisions on the mother’s abdominal wall. During these operations, real-time US is needed to visualize the fetal and maternal anatomy. Catheters and shunts can be inserted into the fetus to drain cystic masses, ascites, or pleural fluid into the amniotic space. In addition, radio frequency ablation (RFA) probes can be deployed into the amniotic space to treat various twin gestational anomalies. The needles used to place these catheters, as well as the RFA probes, are approximately 1.5–2 mm in diameter, potentially minimizing morbidity to the mother and irritation of the uterus.

Fetoscopic procedures are generally performed using a 3-mm fetoscope and instruments. Occasionally, standard 5-mm laparoscopic telescopes and instruments are used. For many fetoscopic procedures, a 3-mm fetoscope with a 1-mm working channel is sufficient. It is important to identify a “window” in the uterus that is devoid of the placenta to reduce the risk of maternal bleeding, placental abruption, and fetal morbidity. Occasionally, the amniotic fluid is not clear enough for good visualization with the small endoscopes. In such cases, we perform amnio-exchange, using warmed crystalloid solutions to provide a clear operative view.

Open fetal procedures require general anesthesia with a combination of preoperative indomethacin and high mean alveolar concentration of inhalational agents to maintain uterine relaxation. An epidural is also inserted for postoperative analgesia.

A low, transverse maternal incision is usually used with a vertical or transverse fascial incision, depending on the exposure needed. Preoperative and intraoperative US are crucial to map out the placenta and avoid iatrogenic injury. Uterine staplers with absorbable staples have been developed specifically for fetal surgery and allow a hemostatic hysterotomy with minimal blood loss. Absorbable staples prevent infertility as nonabsorbable materials can act as an intrauterine device and prevent future pregnancies. The uterus is stabilized within the maternal abdomen. Care is taken to minimize tension on the uterine blood vessels, as excess tension can decrease placental flow. Also, exposure of the fetus is limited to the specific body part in question. Most of the fetus is left inside the uterus, and great care is taken not to handle or stretch the umbilical cord, as this can cause fetal ischemia from injury or vasospasm. Amniotic fluid volume is maintained using warmed, isotonic crystalloid solution. After the fetal procedure is completed, the fetus is returned to the uterus, the amniotic fluid is completely restored, and the uterus is closed in multiple layers using absorbable sutures. Postoperatively, the mother and fetus are monitored continuously for uterine contractions and heart rate, respectively. Often, the uterus is irritable and contractions require control with tocolytic agents.

Open fetal surgery requires cesarean section for future pregnancies due to the potential for uterine rupture with subsequent births. While vaginal delivery after cesarean section (VBAC) can be considered following routine, lower uterine segment hysterotomy, VBAC is not an option after hysterotomy for fetal surgery.

As previously mentioned, complications can occur after any fetal intervention. Bleeding can originate from the fetus, the placenta, the uterine wall, or the maternal abdominal wall despite identifying the uterine vessels with US and specifically avoiding them to prevent injury and minimize bleeding. Premature rupture of membranes and preterm labor remain a common problem complicating fetal surgery. These problems are often the result of inadequate membrane closure, chorioamnionitis, CMS, and uterine contractions. At least one maternal death has occurred in the United States following a percutaneous procedure for twin–twin transfusion syndrome.

Anomalies Amenable to Fetal Surgery

Congenital Diaphragmatic Hernia

Despite significant advances in neonatal respiratory support, survival for children born with congenital diaphragmatic hernia (CDH) remains only 60–70% throughout the United States and other countries. Additionally, survival for prenatally diagnosed CDH may be as low as 25% due to intrauterine fetal demise (IUFD) and stillborns that are not included in conventional postnatal survival data. This high mortality rate has made CDH a primary area of interest for the development of effective prenatal intervention. In fact, improving outcomes specifically for CDH was a significant driving force in the genesis of fetal surgery.

Prognostic Criteria

One of the key elements in developing fetal intervention for CDH has been identifying what factors will identify those fetuses at the greatest risk for a poor outcome. The factors most consistently associated with a poor outcome on prenatal US are (1) the presence of liver herniation into the chest and (2) a low lung-to-head ratio (LHR). In general, survival has been near 100% in fetuses with CDH that do not have liver herniation on prenatal US and 56% in fetuses with CDH and liver herniation into the chest. The LHR is calculated as the area of the contralateral lung at the level of the cardiac atria divided by the head circumference. This LHR value has been shown to statistically correlate with survival: 100% survival with an LHR >1.35, 60% survival with an LHR between 0.6 and 1.35, and 0% survival with an LHR <0.6.

While the LHR has been a reliable predictor of outcomes in our experience, five other institutions have suggested the LHR does not account for discrepant growth rates between the head and lung during gestation and therefore may not be reliable at certain gestational ages. To account for this, the observed to expected LHR (OE LHR) has been developed. The OE LHR is represented as a percentage of what the expected LHR would be in a normal fetus of the same gestational age. For left-sided defects, an OE LHR <25% is associated with a 20% survival, whereas an OE LHR >45% correlates with 90% survival. Alternatively, some researchers have suggested that the quantitative lung index (QL1) is the best way in which to normalize LHR against gestational changes and most accurately predict both survival and the need for prenatal intervention.

Magnetic resonance imaging (MRI) for volumetric measurement of the lungs is a promising modality for prognosis with CDH. MRI can be used to calculate the percent predicted lung volume (PPLV). Results for PPLV have varied. In one study, a PPLV >20% was associated with 100% survival, whereas survival was only 40% when PPLV was <15%. In another study, a PPLV <25% was associated with a 13% survival and a PPLV >35% correlated with 83% survival. MRI can also be used to determine the percentage of liver herniation, although the prognostic value of this finding is still being investigated.

Fetal Interventions

CDH and its effect on fetal lung development has been studied in animal models. In the fetal lamb model, compression of the lungs, either with an intrathoracic balloon or by creation of a diaphragmatic hernia, results in uniformly fatal pulmonary hypoplasia. In fact, pulmonary hypoplasia is the biggest predictor of mortality and morbidity in CDH-affected fetuses, closely followed by persistent pulmonary hypertension. However, in utero correction of the compressing lesion leads to sufficient lung growth and development, which improves postnatal survival.

This concept of early, in utero correction of CDH has been studied and applied in humans. Fetal surgery for CDH initially involved open repair of the diaphragmatic defect. The first successful case was reported in 1990, which demonstrated the feasibility of open fetal repair using a two-step approach involving creation of an abdominal silo to accommodate the reduced viscera and prevent compression of the umbilical vessels. This initial success was followed by a prospective trial at UCSF comparing open fetal surgery to postnatal repair in severe cases of prenatally diagnosed CDH. However, in this study, there was no difference in survival or in the need for extracorporeal membranous oxygenation (ECMO) between fetal repair and postnatal repair. Concordant with this effort, investigators at UCSF observed that fetuses with congenital high airway obstruction syndrome (CHAOS) had pulmonary hyperplasia. Also, fetal tracheal occlusion had been shown to cause pulmonary hyperplasia. In this condition, the lung parenchyma creates fluid that is “exhaled” by the fetus. Occluding the trachea causes a build-up of this fluid and subsequent pulmonary hyperplasia. The inability to improve outcomes with open fetal repair for severe cases of CDH led to an interest in this physiologic process.

The first eight patients were treated with open hysterotomy and tracheal occlusion using a metallic clip. This approach proved to be problematic for several reasons. First, the open hysterotomy led to significant prematurity due to premature labor. Second, the use of clips was associated with tracheal stenosis and also required a stringent delivery plan—which was later described as the ex utero intrapartum treatment (EXIT) procedure—whereby the fetus was exposed through a hysterotomy and maintained on utero-placental circulation while the clip was removed and a patent airway established prior to delivering the baby. However, outcomes with this approach were poor, with only a 15% survival rate.

Ongoing advancements in fetal surgery led to fetoscopic balloon placement for tracheal occlusion ( Fig. 10.1 ). This technique has the advantages of being less invasive, carries a lower risk of tracheal stenosis, and the balloon is much easier to remove, although still necessitating an EXIT procedure. Results in the first eight cases were favorable, with a 75% survival rate compared with a 38% survival rate in historical, case-matched controls managed with postnatal repair. A recent study reported a 47% survival rate for fetuses with severe isolated unilateral CDH who underwent balloon insertion at a median gestational age of 28.1 weeks.

These early results led to an National Institutes of Health (NIH) funded, prospective randomized trial comparing in utero fetoscopic tracheal occlusion to standard postnatal care for fetuses diagnosed with severe left-sided CDH (liver up and LHR <1.4) and no other detectable anomalies. However, results of the trial showed no difference in survival between the tracheal occlusion group and the standard postnatal care group (73% vs 77%, respectively). Unexpectedly, the survival in the postnatal repair group was considerably greater when compared with historical controls. Although this study did not demonstrate a difference in survival between the prenatal intervention group and the postnatal group, the results of this trial demonstrated the tremendous importance of proper randomized controlled trials for novel fetal surgical procedures.

Further data regarding fetal tracheal occlusion have suggested that temporary, short-term reversible tracheal occlusion may be preferable to a longer duration of occlusion. Animal models of fetal tracheal occlusion have shown that long-term tracheal occlusion can be deleterious to type II pneumocytes (the cells that secrete surfactant) and that this adverse effect is not seen with a shorter duration of tracheal occlusion. To test the hypothesis that temporary fetal tracheal occlusion is better, Deprest et al. studied patients undergoing fetal tracheal balloon occlusion who also had the balloon removed prenatally to limit the duration of occlusion. In this group of patients, improved lung growth was evident on fetal MRI and was also associated with improved postnatal survival. Although reversal of the tracheal occlusion requires a second maternal and fetal intervention for balloon removal, it obviates the need for an EXIT procedure at birth. Early results have been promising.

These favorable findings with temporary tracheal occlusion have led to its current application in Europe. The European FETO consortium has reported a 48% survival rate among 210 cases of severe CDH treated with temporary fetal tracheal occlusion, and the Euro-fetus group is currently sponsoring a prospective fetal tracheal occlusion trial that seeks to determine the ideal time and duration for tracheal occlusion. Several groups are currently offering reversible fetal tracheal balloon occlusion for fetuses with liver herniation in the chest and an LHR of <1.0, as these babies continue to have a very high mortality. The U.S. study has Food and Drug Administration oversight and involves percutaneous placement of a fetoscopic tracheal balloon between 26 and 28 weeks of gestation, with removal of the balloon via a second percutaneous fetoscopic procedure between 32 and 34 weeks.

More recent studies have yielded even more promising findings. Of particular importance was the international randomized Tracheal Occlusion to Accelerate Lung growth (TOTAL) trial, which focused on the efficacy of fetal intervention in CDH-related pulmonary hypoplasia. One fetal rabbit model of CDH found that fetal perfluorooctylbromide treatment may be an effective treatment for CDH-induced pulmonary hypoplasia.