Fetal surgery: how recent technological advancements are extending its applications

KEYWORDS:

• Fetal surgery
• prenatal diagnosis
• congenital anomaly
• ultrasound
• congenital diaphragmatic hernia
• spina bifida
• myelomeningocele
• lower urinary tract obstruction
• twin-to-twin transfusion syndrome

1. Introduction

Since its inception in 1965, fetal surgery has evolved remarkably, providing families with better outcomes for life-threatening congenital anomalies. Types of interventions range from open hysterotomy, which involves a surgical incision through the uterus, to minimally invasive fetoscopic surgery, whereby the surgeon uses a fiber-optic endoscope and ultrasound to view the fetus, and lastly percutaneous fetal therapy, which uses ultrasound-guided catheters to drain excess fluid [1]. Innovations in imaging and instrumentation have propelled this advancement in fetal surgical techniques.

2. Expert commentary

A remarkable technological advancement in prenatal therapies is the progression from open fetal operations with hysterotomies to fetoscopies. The present article is focused on advancements in fetal endoscopic treatments.

The first example is the use of fetoscopy to map and guide the fulguration of placental anastomoses in twin-to-twin transfusion syndrome (TTTS) [2]. TTTS occurs in 10–20% of monochorionic pregnancies with the natural history showing a mortality rate of near 90%. In TTTS, abnormal vascular communications lead to an unbalanced blood flow from one twin (the donor) to the other twin (the recipient) [2]. This can cause anuria, oligohydramnios and poor fetal growth in the donor twin due to hypovolemia, as well as polyuria, polyhydramnios, heart failure, and hydrops in the recipient twin due to hypervolemia. Fetoscopic selective laser coagulation (FSLC) of the placental anastomoses has become the standard-of-care treatment in severe TTTS [2]. Essentially, a 1-3 mm endoscope is introduced into the polyhydramniotic sac of the recipient twin and a laser fiber is used to cauterize the placental anastomoses. Originally, the photocoagulation of the anastomoses was done in a non-selective laser ablation of placental anastomoses, meaning that all vessels crossing the intertwin membranes were targeted by the laser [3]. However, research indicated that non-selective photocoagulation of placental anastomoses was associated with higher frequency of donor twin demise [3]. Therefore, a selective laser ablation was developed that endoscopically identifies all anastomoses and occludes only such connections avoiding ablating important vessels to the twins that are not causing TTTS. Residual anastomosis leading to twin anemia polycythemia sequence (TAPS) and recurrent TTTS were found to be an issue with this technique in up to 33% of cases. In order to minimize the risk of residual anastomoses that are invisible to the naked eye, the Solomon technique was introduced. After selectively ablating the anastomoses, we ablate the area between the anastomoses making a line on the placental vascular equator, with the objective of occluding small anastomoses that are usually not seen through fetoscope. The Solomon technique is different than the non-selective technique initially described since we follow the placental vascular equator where the anastomoses are really located, preserving important vessels to both twins. Solomonization not only coagulates all identified anastomotic vessels, but it also creates a continuous line of coagulation on the chorionic plate [3]. Recent studies demonstrated that this approach significantly reduces the incidence of TAPS and recurrent TTTS in comparison to the selective laser method and may improve survival and neonatal outcome [3]. Fortunately, because of the technological advancements, outcomes for fetoscopic laser surgery have significantly improved over the past 25 years, with up to 70% overall double survival and >80% single survival rates [1]. Flexible mini-telescopes have recently been applied to allow for better visualization of the vascular equator in anterior placentas, especially in cases where anastomoses are close to the insertion site of the fetoscope [3].

Fetoscopic treatment of congenital diaphragmatic hernia (CDH) has also undergone considerable development. CDH accounts for 8% of all major congenital anomalies [4]. It is a developmental discontinuity of the diaphragm that allows abdominal viscera to herniate into the fetus’ chest and compress vital organs such as the lungs, leading to severe pulmonary hypoplasia and pulmonary arterial hypertension. The severity of isolated CDH is mainly determined by the lung size measured by ultrasound (lung area-to-head circumference ratio or LHR) and magnetic resonance imaging (total lung volumes). Severe CDHs are characterized by a LHR < 1 or observed-to-expected LHR < 25% with a high postnatal mortality rate and need for Extracorporeal Membrane Oxygenation (ECMO). Fetal Endoscopic Tracheal Occlusion (FETO) has been offered to patients with severe forms of CDH (LHR <1.0 and observed-to-expected LHR<25%) between 24 and 30 weeks of gestation [5,6]. FETO aims to promote lung growth and reduce perinatal mortality and morbidity [6–8]. Recent studies have demonstrated that FETO promotes fetal lung re-growth and may decrease the severity of pulmonary arterial hypertension as a clinical example of Regenerative Medicine [6–8]. Hence, it seems to improve postnatal survival and reduce the need for ECMO [7]. FETO technique has evolved significantly over time from open hysterotomy with fetal neck dissection and tracheal clip [5] to percutaneous fetoscopic insertion of a tracheal balloon [4,6]. In contrast to open fetal surgery, FETO is associated with reduced prematurity and better outcomes for the fetuses. Nowadays, this procedure lasts an average of 15 minutes and is performed with local maternal anesthesia and fetal intramuscular anesthesia [7,8]. During the surgery, a detachable balloon is inserted into the fetal mouth through a fetoscope that is inserted into the amniotic cavity [4,6]. A multicenter randomized controlled trial (TOTAL trial) is active now to confirm the efficacy of FETO. Future steps in FETO include the development of a smart balloon that may be deflated by magnetic field, avoiding the second unplugging procedure [9].

Fetal cystoscopy for lower urinary tract obstruction (LUTO) is another example of technological advancements. LUTO is a rare congenital defect that occurs in approximately 2.2 out of 10,000 pregnancies, mostly seen in males [10]. These malformations result in a blockage of the fetal urinary tract, restricting or preventing the flow of urine out of the body and into the amniotic sac. In severe cases, LUTO can result in marked perinatal morbidity and mortality due to severe pulmonary hypoplasia and renal impairment. Depending on the fetus’ renal function, specific perinatal management can be offered [10]. Fetal vesico-amniotic shunt or fetal cystoscopy is offered to fetuses with severe LUTO but with preserved renal function. If intrauterine renal failure is diagnosed, experimental serial amnioinfusions may be an option. Fetal cystoscopy for LUTO is an alternative to the vesicoamniotic shunt with the advantage of being diagnostic and therapeutic at the same time. However, it is technically challenging and should only be offered in very highly experienced centers, where adequate training and surgical instrumentations are available. During this ultrasound-guided procedure, a 2.2 mm trochar and a 1 mm fetoscope are introduced and advanced toward the bladder neck. If posterior urethral valves are identified, these are fulgurated using laser. Fetal cystoscopy plays an important role in the diagnosis of the etiology of LUTO, which facilitates the selection of candidates for fetal therapy [10–12]. There is only one study reported in the literature that evaluate long-term outcome in children who have undergone fetal cystoscopy. This multicenter study showed a modest long-term survival (54%) but with adequate preserved normal renal function (73.3%) in 2 years [12]. However, fetal cystoscopy is still under investigation and further clinical trials are necessary to demonstrate its safety and efficiency related to long-term outcomes.

Recently, fetoscopy has also been applied to the in utero repair of spina bifida (SB). Spina bifida, usually myelomeningocele (MMC), is a congenital defect, in which the spine fails to fully close around the spinal cord [13]. As a result, the spinal cord protrudes through the opening of the spinal column and may be enclosed in a fluid-filled sac. MMC is associated with significant life-long disabilities from complications such as hydrocephalus, motor and cognitive defects, bowel and bladder dysfunction, and social and emotional challenges. Open MMC repair involves a combination of general and epidural anesthesia as well as fetal anesthesia. In 2011, a prospective multicenter randomized controlled trial known as the Management of Myelomeningocele Study (MOMS) demonstrated a decreased need for ventriculoperitoneal shunting, reversal of hindbrain herniation, and improved neurologic function in the prenatal repair group compared to the postnatal repair group [14]. Due to its efficacy, fetal MMC closure has become a standard of care option for prenatally diagnosed spina bifida. However, the procedure comes with several tradeoffs including higher rates of obstetrical complications such as oligohydramnios, chorioamniotic membrane separation, placental abruption, premature rupture of membranes, preterm delivery, and uterine scar dehiscence. In order to reduce the rate of these complications associated with open fetal MMC repair, a fetoscopic approach has been developed. Initial studies have demonstrated that fetoscopic MMC repair is associated with similar results compared to the open in utero repair (MOMS trial) with less complications to the mothers (possibility of vaginal deliveries and reduced prematurity) [13]. Because of this technique’s development, some groups are now attempting the two-layer closure with the fetoscopic approach [13]. However, further studies are still necessary to compare long-term outcomes after fetoscopic MMC repair with open MMC repair.

Key issues

Based on these technological advancements in fetal surgery, the next five years are promising. Better and thinner scopes and instruments will be developed with improved quality and design. The success of fetal cystoscopy warrants better instrumentations with adequate curvature to properly visualize the urethral obstruction in the fetus as well as a system that combines cystoscopy and vesico-amniotic shunt placement for urethral atresia [10]. There is also potential in the use of gas in utero for the repair of spina bifida and other congenital anomalies. Recently, amniotic bands were released using small scissors through fetoscopy under a half gas/half amniotic fluid environment [15]. These innovative under gas fetoscopies can promote the development of new in utero therapies for gastroschisis and fetal hydrocephalus.

However, the innovation of new instruments for fetal and pediatric surgeries, especially for congenital anomalies, faces some challenges such as high cost, lack of funding opportunities and narrow niche. Animal studies are still mandatory to provide proof of concept and to better understand the pathophysiology, allowing for improved selection of fetal surgery candidates. Additionally, performing strong randomized trials can be difficult since those diseases are considered rare.

In conclusion, technological advancements in fetal surgeries have remarkably evolved in the past two decades and will continue to progress. The future is promising but still with some challenges!

Declaration of interest

R Ruano is a recipient of the Regenerative Medicine Minnesota Clinical Trial grant (RMM 102,516,008): ‘Fetoscopic Regenerative Therapy for Severe Pulmonary Hypoplasia - a feasibility pre-randomized control trial study’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.