By Thomas N. Trevett, M.D., Larry Matsumoto, M.D. and Michael Belfort, MBBCH, M.D., Ph.D.
Advances in technology now allow the early diagnosis of fetal abnormalities and conditions that were previously only apparent in late gestation or after birth. High-resolution ultrasonography (US) and magnetic resonance imaging (MRI) are two specific technologies that enable the evaluation and monitoring of developing organs and the detection of functional abnormalities.
Using these modalities, we can now not only diagnose anomalies, but we can also determine the ongoing effects of those anomalies and malformations on other organ systems in the growing fetus. While the malformation itself (“the first hit”) may be extremely problematic, many times the impact of the malformation on the ongoing development of other structures (“the second hit”) is even more devastating.
This understanding has led to an increasing acceptance of fetal therapy as a way to not only save the life of an affected fetus, but also to improve the post-natal functionality and outcomes in those babies that survive to birth. Examples of this include twin-to-twin transfusion syndrome (TTTS) and spina bifida.
Laser Therapy for Twin-to-Twin Transfusion
One of the first disease states shown to be amenable to prenatal surgery is TTTS, which occurs in identical twins sharing a placenta, the monochorionic (MC) placenta. TTTS presents in MC/DA twins with more easily observed signs that include excessive fluid in the sac of the recipient (polyhydramnios) and deficient fluid (oligohydramnios) in the sac of the donor, and this finding is an essential criterion for the diagnosis.
Frequently, the hemodynamic effects of TTTS are rapidly progressive, leading to heart failure in the recipient baby. Because of the open anastomoses between the two babies, if one twin dies, blood from the other baby drains into the placenta and the remaining fetus dies or suffers devastating cerebral injury. Untreated, TTTS can have a mortality rate for both babies as high as 90 percent.
Although all monochorionic twins have connections between each other on the surface of the placenta, for some (currently unknown) reason, in about 15 percent of MC twins, a net volume or pressure imbalance occurs. Through postnatal study of placentas from twins with TTTS, investigators characterized these unbalanced vascular connections and suggested that by ablating the connections in-utero, the TTTS process could be halted and even reversed.
Advances in fetoscopy instrumentation has now allowed for these anastomoses to be identified during the pregnancy as early as 16 weeks’ gestation, and by coagulating the blood within them using laser energy, flow can be stopped. Loss of one or both twins, preterm delivery, and/or severe neurologic morbidity was the norm prior to the institution of any form of therapy. Recent literature evaluating the success of laser photocoagulation of the anastomotic vessels demonstrates an 80 percent to 90 percent rate of at least one surviving twin, and a 60 percent to 70 percent rate of two surviving twins. While the procedure is invasive and carries the risk of premature rupture of the membranes (~30 percent) and preterm delivery, laser therapy is an important intervention that can significantly reduce mortality and neurologic morbidity in TTTS.
Fetal Neural Tube Defect (NTD) closure
Fetal myelomeningocele (MMC), a relatively common NTD, occurs in approximately 1 per 3,000 pregnancies and can be associated with devastating neurologic (both sensory and motor) and other functional deficiencies in survivors. Typically, function of the limbs and organs below the spinal level of the lesion is diminished.
One of the major problems with MMC is herniation of the fetal hindbrain (including the cerebellum) into the spinal canal at the base of the brain. The herniation, called an Arnold-Chiari malformation (usually type II), obstructs drainage of the CSF produced in the choroid plexi in the ventricles of the brain, resulting in progressive dilatation of the ventricles (ventriculomegaly) in utero.
Postnatally, this blocked drainage pathway results in progressive enlargement of ventricles, which impacts the size of the baby’s head (hydrocephalus), and the pressure can have permanent and serious neurologic effects including cognitive loss and neurodevelopmental delay. Shunting of the CSF from the ventricles into the abdominal (peritoneal) cavity is frequently required to decompress the growing brain.
The shunting procedure can have significant complications, and these shunts frequently require revision. Most MMCs are detected through a combination of maternal serum screening and prenatal ultrasound occurring prior to 20 weeks of pregnancy. Prenatal closure of the MMC was hypothesized as being helpful in the reduction of fetal and postnatal morbidity and mortality.
The Management of Myelomeningocele Study (MOMS) trial, published in 2011, showed clearly that prenatal closure of the defect can significantly reduce the need for shunting and at the same time improves composite neurological and motor function. The fetal surgery involved creating a 7-10 cm opening in the mother’s uterus (hysterotomy) and then carrying out and open repair of the spinal defect. This was associated with high rates of maternal and fetal complications.
Investigators have suggested that switching to a fetoscopic technique could achieve similar neonatal outcomes with decreased trauma to the uterine wall and membranes, decreasing preterm delivery rates. Very few centers have significant experience in fetoscopic spina bifida repair (one each in Germany, Spain, Brazil and the U.S.). Long-term data comparing postnatal neurologic development between the open and fetoscopic techniques is still pending, however the preliminary outcomes are very promising.
While the challenges faced by the pioneers of in-utero fetal therapy were tremendous, their vision and efforts, in concert with those of current groups, are beginning to demonstrate the potential benefits of this innovative and recently developed discipline. The available techniques are still being modified and refined to achieve improved fetal and neonatal long-term outcomes. However, despite the experimental and innovative nature of many of these techniques, outcomes for thousands of children worldwide have been dramatically improved as a result of select procedures.
- Twin-to-twin transfusion syndrome: prenatal diagnosis and treatment. Benoit RM, Baschat AA. Am J Perinatol. 2014 Aug;31(7):583-94.
- A randomized trial of prenatal versus postnatal repair of myelomeningocele. Adzick NS, Thom EA, Spong CY, et al. MOMS Investigators. N Engl J Med. 2011 Mar 17;364(11):993-1004.