Open Fetal Surgery

Bladder outlet obstruction (BOO) or lower urinary tract obstruction (LUTO) is a congenital obstruction of the GU tract estimated to occur between 0.4 : 10,000 and 2.0 : 10,000 live births (9). It is usually a sporadic finding without a known genetic cause and constitutes 10% of prenatal uropathies. The magnitude of the problem is highlighted by the associated 33% incidence of end-stage kidney disease in children <4 years of age (11).

Fetal surgery for lower urinary tract obstruction (LUTO) has had limited success. Despite 40 years of intervention, the outcomes of fetal therapy for LUTO are still suboptimal, in part because we are still treating a GU problem based on its effect on pulmonary development without necessarily addressing the primary GU problem (14). The primary goal of fetal surgery in LUTO is to restore amniotic fluid dynamics to allow pulmonary development and postnatal survival. However, our interventions have not addressed the primary underlying cause, prevented ongoing renal damage, and prevented the progression to fetal renal failure.

Objective prediction of expected postnatal renal outcomes remains challenging, as not all fetuses with LUTO are good candidates for intervention (15). Some fetuses will clearly not benefit from intervention. Some are too healthy, so the risk of intervention outweighs any possible benefits (normal amniotic fluid index, non-obstructive dilatation, or unilateral renal involvement) or they are too sick, so intervention has minimal possibility of benefit and might harm the mother (cases of cystic renal dysplasia, abnormal urinary parameters, abnormal karyotype, or multiple associated anomalies). Patients who may benefit most from fetal intervention include those with high-grade LUTO with preserved renal function and the potential for compensatory lung growth and development once amniotic fluid is restored to normal (16).

The first technically successful open surgical in utero decompression for bladder outlet obstruction was achieved in 1982 when bilateral nephrostomies were performed in a 22-week gestation fetus: however, the neonate died from pulmonary hypoplasia (8). A series of eight fetal vesicostomies were performed and had 50% survival (14). Ultrasound-guided vesicoamniotic shunting quickly supplanted open fetal surgery for LUTO with significantly less maternal risk (17). While the shunts do restore amniotic fluid volume allowing lung development, the high intravesical pressures are transmitted to the kidneys with ongoing renal injury and progressive bladder hypertrophy and fibrosis.

More recently, in recognition of the poor renal outcome with vesicoamniotic shunting, we performed 4 open fetal surgeries for vesicostomy (18). The rationale for these cases was that vesicoamniotic shunting did not reduce the intravesical pressure due to the small size of the shunt lumen while vesicostomy would be able to prevent high intravesical pressures, and in theory, prevent ongoing injury to the kidneys. Of the four fetuses operated upon, one developed preterm labor and delivered at a previable gestational age. The remaining three survived but two developed progressively echogenic kidneys and decreasing amniotic fluid progressing fetal renal failure despite decompression of the urinary tract. The fourth baby was delivered at 36 weeks and had normal renal function at 2 years of follow-up and normal voiding cystourethrogram after reversal of the vesicostomy. All four fetuses were indistinguishable in terms of pre-operative imaging and fetal urine electrolyte parameters. While the one baby with a successful outcome suggests the potential for open fetal surgery for vesicostomy to preserve renal function and foster lung growth, until we can develop selection criteria to identify this subset the maternal risks of open fetal surgery are prohibitive (17).

Congenital diaphragmatic hernia was the next condition for which open fetal surgery was attempted to correct the defect in order to allow compensatory lung growth to correct the pulmonary hypoplasia (19). Again, this was preceded by years of work defining the prenatal natural history (20), developing selection criteria to limit the intervention to the most severely affected cases (21), and establishing proof of concept in experimental animal models that repair of CDH in utero like we do postnatally, would allow compensatory lung growth to occur and change the prenatal natural history of CDH (22). What was not anticipated was that the reduction of the herniated viscera, including the left lobe of the liver, would result in kinking of the ductus venosus obstructing all venous blood return from the placenta to the fetal heart causing fetal bradycardia (23). It became clear that complete repair of the diaphragmatic defect, as was done postnatally, would not be possible if there was liver herniation.

The most severely affected cases of left CDH all have herniation of the liver and those cases that did not were not sufficiently severe to warrant the risks of open fetal surgery. Another strategy was needed, which came from the physiologic observations in fetal rabbit models that occlusion of the fetal trachea. Tracheal occlusion causes retention of fetal lung fluid, which in turn, raises intratracheal pressure which drives lung development (24). This was replicated in lamb models of CDH establishing proof of concept that tracheal occlusion could accelerate lung growth (25).

Fetal tracheal occlusion was first performed by open fetal surgery to access the fetal neck, and dissect out the tracheal preserving the recurrent laryngeal nerves to place vascular surgical clips across the trachea (26,27). This approach had mixed results and obvious maternal risks, but established proof of concept that tracheal occlusion in severe left CDH could accelerate lung growth. Open fetal surgery was supplanted first by FETENDO, a fetoscopic approach using up to 5 ports to dissect the trachea and apply clips to occlude the trachea (28). Subsequently, a technique first described by DePrest et al., requiring only a single port using a detachable endoluminal balloon for tracheal occlusion (FETO) (29).

This was incorporated into the first NIH-sponsored trial of tracheal occlusion which did not show a benefit in the subset of CDH which were treated (30). Unfortunately, the selection criteria did not limit subjects to the most severely affected cases of CDH. Recently, the TOTAL trial which limited FETO to the most severely affected cases of left CDH, has now been shown in a prospective randomized clinical trial to significantly improve survival in severe cases of left CDH (31).

Congenital pulmonary artery malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a benign congenital cystic lung lesion of pulmonary tissue with proliferation of bronchial structures. Fetuses found to have a fetal chest mass on a screening US should undergo a comprehensive evaluation including ultrasonography, ultrafast magnetic resonance imaging (MRI), and fetal echocardiography. The differential diagnosis of a fetal chest mass includes CCAM, bronchopulmonary sequestration (BPS), bronchogenic cyst, and congenital diaphragmatic hernia.

CPAMs occur at the fifth or sixth week of gestation during the embryonic stage of lung development but do not tend to grow rapidly until 20 weeks gestation. The natural history of prenatally diagnosed lung lesions is variable and depends on their size resulting in physiologic derangements (32). Almost 20% of fetal CPAMs demonstrate a decrease in size, and two-thirds of BPS lesions shrink dramatically before birth (33). Because of this unpredictable growth, we recommend weekly or biweekly US evaluations until the growth plateau is achieved. To better understand the natural history and prognosticate CPAM lesions, we developed the CPAM- Volume-Ratio (CVR) (34). A CPAM volume is determined using the formula for a prolate ellipse (length × height × width × 0.52). The CVR is obtained by dividing the CPAM volume by head circumference to correct for differences in fetal size. A CVR >1.6 at the initial presentation is predictive of an 80% risk of developing hydrops.

The first attempts at open fetal surgery to resect a CPAM were in cases of solid or type III CPAMs with associated hydrops (35). In these cases the natural history had been demonstrated, with rare exception, to progress to intrauterine fetal demise (32). The fetal thoracotomy was performed through the hysterotomy but delivering the very large intrathoracic mass to perform the resection often precipitated terminal fetal bradycardia from which the fetus could not recover even with aggressive resuscitation with CPR and code drugs. This complication was avoided by performing a thoracoabdominal incision which allowed greater exposure of the hilum without the need to displace the CPAM from the intrathoracic position. Despite technical advances facilitating fetal surgical resection of massively enlarged microcystic CPAM with associated hydrops, of the 25 patients at 21 to 29 weeks gestation (35,36) only 16 fetuses survived (64%). In the survivors, CPAM resection led to hydrops resolution in 1 to 2 weeks, return of the mediastinum to the midline within 3 weeks, and impressive in-utero lung growth.

In a serendipitous observation, Tsao et al noted a response to maternal steroid administration in hydropic CPAMs, not candidates for open fetal surgery (37). Despite only anecdotal evidence in support of steroids in high-risk CPAMs this was quickly adopted. In a systematic review of the efficacy of antenatal steroids in the management of high-risk CPAMs, Patwardhan et al, identified 13 observational studies involving 163 pregnancies complicated by CPAM that were treated by a, single or multiple courses, of antenatal steroids (38). They found a significant mean decrease in the CVR of 1.16 and resolution of hydrops in 86%. Not all patients respond to a single course of steroids and Morris et al., have reported that two-thirds of patients that do not respond to an initial course of steroids will respond to a second course (39).

Open fetal surgery should be considered in predominantly solid large lung lesions associated with fetal hydrops and mediastinal shift, presenting before 32 weeks gestation that have not responded to at least two courses of maternal betamethasone. Open fetal surgery for hydropic CPAMs has become exceedingly rare since the introduction of steroids.

Sacrococcygeal teratoma (SCT), a congenital germ cell tumor, is a mass located at the base of the coccyx and occurs in an average of 1 : 40,000 births (40). Most newborns diagnosed with SCT have a very favorable outcome, with a very small risk of associated malignancy. In contrast, prenatally diagnosed SCT has a poor prognosis and is fatal 30% to 50% of the time (40,41). These tumors have a variable consistency, can undergo an unpredictable rate of growth, and demonstrate significant hemodynamic changes (42). While the US is the primary modality to diagnose SCT, MRI is crucial to delineate the intrapelvic extent of the SCT (33).

The high mortality associated with prenatally diagnosed SCTs may be caused by premature birth secondary to polyhydramnios, dystocia secondary to large tumors resulting in traumatic tumor rupture and hemorrhage, and high output cardiac failure as a result of a large blood vessel supplying the tumor, and hemorrhage into the tumor(43). A large tumor may result in vascular steal from the placenta that can be documented by Doppler US. Some of the associated manifestations include reversal of diastolic flow in the umbilical arteries, abnormalities of placental thickness, diameter of the suprahepatic inferior vena cava, combined ventricular output, and descending aortic flow velocity (42,43). The end result of this is fetal hydrops, placentomegaly, and ultimately maternal “mirror syndrome,” which can be life-threatening for both mother and fetus. Very similar to cases of CPAM with hydrops, fetal intervention in these cases is indicated at the earliest signs of hydrops or development of high-output cardiac failure but before the development of maternal mirror syndrome, at which point the only option is delivery.

The goal of open fetal surgery is to interrupt the high output flow through the SCT while preserving the anorectal sphincter complex. This is accomplished by stapling off the exophytic component of the SCT which interrupts the vessels feeding the SCT causing the high output state. The residual pelvic component can then be resected postnatally. The first successful open fetal surgery for SCT was performed at 26 weeks with a fetus with increased combined ventricular output and only early signs of evolving hydrops (44). The baby delivered at 29 weeks and at 2 months of age underwent resection of the residual SCT. This case had been preceded by multiple attempts in fetuses with more advanced hydrops which were thwarted by the development of maternal mirror syndrome (45). The next fetus to undergo resection of an SCT was at 23 6/7 weeks that developed closure of the ductus arteriosus in response to Indocin used as a tocolytic. The ductus remained closed and this fetus was delivered at 29.9 weeks and died of heart failure shortly thereafter. Two additional fetuses underwent resection of the exophytic portion of the SCT at 21 and 25 weeks, respectively. Both delivered prematurely at 31.7 and 27.6 weeks, respectively (46).

It became clear that while open fetal surgery was feasible, keeping the mother pregnant after the procedure was very challenging. For this reason focus has shifted more recently to other approaches for the treatment of high-risk SCT including the use of the EXIT-to-Resection strategy when the mother goes into labor and the use of intravascular laser photocoagulation of feeding vessels to the SCT to temporize the high output state and extend the gestation (47).

Fetal arrhythmias are most often ventricular extrasystoles or tachyarrhythmias. But bradyarrhythmias account for 9% of cases reported to the Fetal Arrhythmia Registry, half of which occur in structurally normal hearts due to transplacental passage of antibodies in mothers with collagen vascular disease (48). The other half occurs in structurally abnormal hearts, and bradyarrhythmia is almost uniformly fatal in that setting (48,49). In structurally normal hearts in which complete heart block (CHB) develops in mothers with collagen vascular disease, hydrops will develop in 25% and is usually refractory to medical therapy (50-52).

Based on the combined retrospective experience from the groups at Toronto Sick Kids and UCSF, fetuses with CHB may benefit from the combination of maternal steroids and β-mimetics . There is no expectation that steroids will improve the fetal heart rate but may reduce maternal antibody titer and transplacental passage and limit the ongoing injury to the fetal cardiac conduction system and the myocardium.

If low-output fetal heart failure cannot be reversed by increasing heart rate with β-agonists then fetal cardiac pacing is the only alternative. Carpenter et al. (1986) reported the first fetus treated by implantation of a percutaneous transthoracic pacemaker (51). Unfortunately, the fetus was severely hydropic and despite successful ventricular capture and pacing the fetus died within hours. The obvious problems with the percutaneous transthoracic pacemaker are the risks of dislodgment, the potential for infection (chorioamnionitis), and the temporary nature of the device in a fetus that will require pacing for the rest of gestation. These limitations prompted a group led by Michael Harrison at UCSF to attempt pacemaker placement by open fetal surgery. Previous work by Crombleholme et al. (53,54) had developed the techniques for acute and chronic fetal cardiac pacing and studied the effects of CHB in fetal lambs.

Based on this experimental work, Harrison placed a unipolar epicardial pacemaker in a fetus at 22 weeks of gestation with CHB and hydrops. Similar to Carpenter et al.’s (1986) experience, although able to achieve ventricular capture and pacing, the heart was irreversibly damaged by 6 weeks of in-utero cardiac failure and the procedure resulted in fetal death in the operating room. More recently, Crombleholme and colleagues performed open fetal surgery for the placement of epicardial pacing lead with an implantable programmable pulse generator in VVI mode (55,56). The pacemaker was set at 65 beats per minute doubling the combined ventricular output measured by echocardiography. The fetus expired on postoperative day 5 and autopsy was found to have extensive renal and hepatic ischemic injury that likely preceded the fetal surgery (56).

It is clear from these reports that a fetus with long-standing CHB with severe hydrops may already have significant end-organ injury that may be unsalvageable despite successful pacemaker placement. The survival of fetuses with CHB and ventricular escape rates of less than 50 beats per minute is poor (57). Placement of a pacemaker in the fetus with a ventricular response rate of less than 50 beats per minute before the development of hydrops may allow us to save these fetuses with an otherwise dismal prognosis. The ex-utero intrapartum treatment strategy has also been used to place a permanent pacemaker just prior to delivery (58). Pacing the fetal heart just prior to delivery allows the cardiac output to be increased by increasing the heart rate just prior to delivery when systemic vascular resistance will be increased.

Myelomeningocele is now the single most common indication for open fetal surgery (59). Neural tube defects (NTDs) are the leading cause of central nervous system malformation in humans and a devastating birth defects resulting in ongoing chemical and mechanical injury to the exposed developing spinal cord. The sequelae of NTDs include anatomic effects secondary to the primary defect, as well as functional, emotional, and psychologic morbidities including bladder and bowel incontinence, paralysis, musculoskeletal deformity, shunt malfunctions, and infections (60,61).

The associated morbidity is thought to be a result of prolonged mechanical trauma to exposed neural elements, stretching of the placode by the MMC, as well as chemical irritation and inflammation associated with exposure to toxic molecules in the amniotic fluid (62). Ultimately, the compound nature of this malformation results in an immense financial burden on the afflicted families and our healthcare system amounting to $1,400,000 per child affected by MMC, over a 20-year lifespan (59). The incidence has plateaued at around 1 in 1000 births following an initial decrease from widespread prenatal folic acid supplementation (63,64). With a global population of 7 billion and a yearly birth rate of 20 per 1,000 individuals, there are about 140,000 NTD cases per year worldwide (59).

In animal models, prenatal coverage of NTDs preserves neurologic function and improves hindbrain herniation (61). In addition, naturally occurring skin-covered NTDs are usually neurologically intact without the complications of open NTDs. Ultrasound (US) and autopsy studies have demonstrated that injury to the exposed neural tissues is progressive during gestation (62). Prenatal repair of open spina bifida at 23–24 weeks is associated with reversal of hindbrain herniation, a 50% reduction in the need for postnatal ventriculoperitoneal (VP) shunting as well as a higher likelihood of ambulation (63,64). The Management of Myelomeningocele Study (MOMS) trial randomized subjects to prenatal open fetal surgical repair versus postnatal repair with the rationale that achieving skin closure of the defect would prevent further neural damage and cerebrospinal fluid leak (65).

More recent follow-up results from the MOMS trial show that the size of the fetal lateral ventricles at the time of prenatal MMC repair determines the likelihood that VP shunting can be avoided. In addition, even though repair with dilated lateral ventricles (≥15 mm) may not prevent the need for VP shunting, prenatal repair may improve the neurologic function of lower extremities and decrease the need for chronic intermittent bladder catheterization (66,67).

The maternal abdomen is entered through a low transverse abdominal incision. Flaps are raised on the fascia from the umbilicus to the pubic symphysis and a midline fascial incision gains access to the peritoneal cavity. In cases of an anterior placenta, the uterus is tilted forward outside the abdominal cavity, providing access for a fundal or posterior hysterotomy depending upon placental location. An extra-large Alexis-O retractor (Applied Medical, CA, USA) is then placed deep to the fascia for improved exposure. It is important at this point to evaluate the degree of pressure on the uterine vessels which may require releasing the peritoneum and/or making a relaxing incision in the fascia if needed.

Depending on the uterine position needed, warm saline-soaked laparotomy pads are placed in the abdomen to retract the bowel and support the uterus out of the pelvis. At this point, intraoperative US is used to map the fetal position and placental location. Occasionally, some fetal repositioning is required to allow for a direct access to the required fetal part. This is performed by an external version, sometimes aided by the removal of the abdominal packs. The edge of the placenta is then identified and marked on the surface of the uterus using electrocautery.

The position and orientation of the hysterotomy are planned to stay parallel to, and 3–4 cm from, the closest edge of the placenta. Before initiation of the hysterotomy, communication with the anesthesia team is crucial to achieve optimal uterine relaxation. In some centers, inhalational agents are used during the induction of anesthesia.

In other centers, a supplemental intravenous anesthesia (SIVA) protocol is followed. In SIVA induction of anesthesia is performed by rapid sequence induction and maintained with intravenous propofol and remifentanil with inhalational agents reserved until the uterus is exteriorized and controlled uterine hyotonia is required (68). In rare cases (1% in author’s experience) uterine tone may be refractory to high-dose inhalational agents, magnesium sulfate infusion, and IV nitroglycerine and it may be necessary to back out of the operation.

Once optimal uterine relaxation is achieved a “box stitch” is then created using polydioxanone sutures (PDS) placed transmurally under US guidance to anchor the membranes to the uterine wall and allow for retraction of the uterine wall away from the fetal parts. A 1-cm cruciate uterine incision is then made through the myometrium and amnion using electrocautery. Once the amnion is exposed and entered, we confirm clarity of the amniotic fluid, then compress the myometrium with Bainbridge clamps (Aesculap, Tuttlingen, Germany). The failure rate of the uterine stapler was found to be as high as 25%, but this can be markedly reduced by compressing the myometrium with Bainbridge clamps prior to applying the stapler increases the efficacy of the uterine stapler.

The uterine incision is then created along the compressed tissues using a specially developed absorbable uterine stapler (Medtronic, Minneapolis, USA) that is fast, hemostatic, and seals the membranes to the myometrium (2,3). Once the hysterotomy is performed, a catheter attached to a Level I (Smith Medical, City USA) rapid-volume infusion device is placed into the uterine cavity followed by a steady stream infusion of lactated Ringer’s solution warmed to 38oC. This infusion is important to avoid cord compression, maintain uterine volume, and prevent fetal hypothermia. The appropriate fetal part is then brought into the field, leaving the rest of the fetus entirely within the womb.

Intraoperative fetal hemodynamic monitoring is a critical component of open fetal surgery, as fetal cardiovascular compromise has been reported in up to 60% of MMC repairs (69,70). Before the start of the surgery, a fetal echocardiogram is performed to establish baseline fetal cardiovascular status.

Continuous intraoperative fetal cardiac imaging begins after maternal abdominal incision and uterine exposure and extends through repositioning of the uterus within the maternal abdomen. Using an ultrasound probe in a sterile sheath, a pediatric cardiologist performs continuous fetal echocardiography on the exposed uterine wall to monitor fetal heart rate, ventricular filling, myocardial contractility, ductus arteriosus flow, and atrioventricular valve competence.

Complete hemodynamic data is collected approximately every 15 minutes throughout the surgery, increasing to every 2 minutes during the period of open hysterotomy. Acute fetal cardiovascular compromise, including fetal bradycardia, myocardial depression, valvular dysfunction, and constriction of the ductus arteriosus has been commonly reported (71,72). Fetal bradycardia is most frequently a result of mechanical compression or kinking of the umbilical cord that can be seen at the time of fetal positioning for the repair.

While the precise mechanism of fetal ventricular and valvular dysfunction remains unclear, the myocardial depressant effects of inhalational anesthesia may play a central role. The correlation between the duration and dosage of inhalational agents and fetal myocardial depression has been previously demonstrated (73), leading to modifications in anesthetic management. Finally, progressive constriction of the ductus arteriosus during open fetal MMC repair can occur and is speculated to result from the combined effects of preoperative indomethacin, supplemental oxygen, and concurrent inhalational anesthesia (74).

With careful echocardiographic monitoring during open fetal surgery, early recognition of fetal hemodynamic instability is possible. The real-time information provided from the fetal echocardiographic data can optimize intraoperative decision- making and guide therapy.

Open fetal surgical procedures are performed under deep general anesthesia. Preoperatively, a lumbar epidural catheter is inserted for postoperative pain control. The patient is placed supine on the operating table with a wedge to maintain at least 15 degrees of left uterine displacement. After adequate preoxygenation, a rapid sequence induction is performed to facilitate endotracheal intubation. In addition to standard American Society of Anesthesiologists monitors, a radial arterial catheter is inserted for beat-to-beat hemodynamic monitoring, and a second intravenous access is obtained. General anesthesia is maintained with either inhalational agents or intravenous anesthetic agents such as propofol and remifentanil infusions. Maintaining adequate uteroplacental blood flow is vital during open fetal surgery, and maternal hypotension is treated with vasopressors such as phenylephrine and ephedrine.

Achieving controlled uterine hypotonia is one of the central tenets of open fetal surgery and traditionally high doses (2–3 times minimum alveolar concentration [MAC]) of inhalational agents have been used to ensure adequate uterine relaxation. Unfortunately, significant fetal cardiac dysfunction has been reported with prolonged fetal exposure to high doses of inhalational agents (60). Alternatively, using intravenous anesthetic agents (propofol and remifentanil infusions) for maintenance of maternal general anesthesia and starting inhalational agents just before hysterotomy, has enabled lowering the dose and duration of inhalational agents (1.5 MAC) for adequate uterine relaxation and minimized fetal cardiac dysfunction (75). In addition, a 6-gram load of intravenous magnesium sulfate followed by 2 2-gram per hour infusion is started before hysterotomy. To minimize the risk of maternal pulmonary edema, intraoperative intravenous fluids are commonly limited to <1 L for the entire case.

Upon fetal exposure, a fetal intramuscular cocktail of fentanyl, muscle relaxant (pancuronium, vecuronium, or rocuronium), and atropine is administered to augment transplacental inhalational agents and ensure fetal anesthesia and immobilization. Estimated fetal weight–based resuscitation doses of epinephrine and atropine are available on the surgical field. Close communication between the surgical, cardiology, and anesthesia teams is critical throughout the open fetal surgical procedure.

Upon the successful completion of the procedure, the fetal part is returned to the uterine cavity followed by uterine closure. The absorbable uterine staples, made of polyglycolic acid, are left in place to avoid bleeding from the edge of the hysterotomy. Full-thickness 0 polydioxanone stay sutures are placed along the length of the hysterotomy. A running 0 PDS is used to complete the first layer. Before tying the running PDS, a deep vertical pocket (DVP) of amniotic fluid is measured followed by an infusion of 250–350 mL of warm lactated Ringer’s solution to reach a DVP of 3–5 cm. Ringer’s infusion is then followed by the instillation of 2 g of Nafcillin.

The second layer follows by tying the stay sutures, and then a third layer of serosa-to-serosa sutures is placed to imbricate the hysterotomy. An omental flap is then placed over the hysterotomy and tacked in place using 4-0 Vicryl. In the MOMS trial, the rate of partial uterine dehiscence was 9%, complete dehiscence 1%, and thinning of the hysterotomy was 25%. The hysterotomy closure was modified to include a third serosa-to-serosa layer which eliminated partial and complete dehiscence and reduced thinning to 4% (76). After hysterotomy closure, the maternal laparotomy incision is closed in layers with tacking of the subcutaneous tissue to the fascia to limit postoperative seroma. A subcuticular maternal skin closure is then performed, reinforced by Dermabond (Ethicon, Somerville, NJ) to allow postoperative US surveillance.

After the closure of the laparotomy, a transvaginal US is performed to document cervical length. The patient is extubated at the end of the surgical procedure after bolusing the epidural catheter and reversing muscle paralysis. Adequate analgesia is an integral part of postoperative management, as pain increases uterine irritability. We use continuous epidural fentanyl and local anesthetic (bupivacaine or ropivacaine), with patient-controlled rescue doses, and additional analgesics such as acetaminophen and ketorolac.

One of the most formidable consequences of open fetal surgery is preterm labor and premature rupture of membranes, secondary to the uterine incision needed to safely perform these procedures. To minimize that risk, we use an aggressive tocolytic management strategy, including a combination of indomethacin and magnesium sulfate, for the first 48 hours with transition to an oral calcium channel blocker thereafter (56). Despite such an aggressive approach, preterm labor is still a major risk in open fetal surgery, with the MOMS trial reporting a 38% risk of spontaneous labor and 50% of incidents of preterm premature rupture of membranes prior to 34 weeks.12

1. Harrison MR. Fetal surgery. West J Med. 1993;159:341-349.

2. Adzick NS, Harrison MR, Glick PL, et al. Automatic uterine stapling devices in fetal operation: Experience in a primate model. Surg Forum. 1985;36:479-480.

3. Bond SJ, Harrison MR, Slotnick RN, et al. Cesarean delivery and hysterotomy using an absorbable stapling device. Obstet Gynecol. 1989;74:25-28.

4. Deprest JA, Flake AW, Gratacos E, et al. The making of fetal surgery. Prenat Diagn. 2010;30:653-667.

5. Adamsons Jr K, Freda VJ, James LS, Towell ME. Prenatal treatment of erythroblastosis fetalis following hysterotomy. Pediatrics 1965; 35: 848-855

6. Diamond LE, Blackfan K, Baty JM. Erythroblastosis fetalis and its association with universal edema of the fetus, icterus gravis neonatorium and anemia of the newborn. J Pediatr 1932; 1 (3) 269-309

7. Liley AW. Intrauterine transfusion of foetus in haemolytic disease. BMJ 1963; 2 (5365) 1107-1109

8. Harrison MR, Golbus MS, Filly RA, Callen PW, Katz M, deLormier AA, Rosen M, Jonsen AR: Fetal surgery for congenital hydronephrosis. N Engl J Med 1982; 306: 591-593

9. Nakayama DK, Harrrison MR, deLormier AA: Prognosis of posterior urethral valves presenting at birth. J Pediatr Surg 1986, 21: 43-45

10. Mahoney BS, Callen PW, Filly RA: Fetal urethral obstruction: Ultrasound evaluation. Radiology 157; 221. 1985

11. Smith GHH, Canning DA, Schulman SL, Snyder HM, Ducket JW: The long-term outcomes of posterior urethral valves treated with primary valves ablation and observation. J Urol 1996, 155; 1730-1734

12. Harrison MR, Ross N, Noall R, et al. Correction of congenital hydronephrosis in utero. I. The model: fetal urethral obstruction produces hydronephrosis and pulmonary hypoplasia in fetal lambs. J Pediatr Surg. 1983;118: 247-256.

13. Harrison MR, Naakayama DK, Noall RA, et al. Correction of congenital hydronephrosis in utero. II. Decompression reverses effects of obstruction on the fetal lung and urinary tract. J Pediatr Surg. 1982;17:965-974.

14. Crombleholme TM, Harrison MR, Langer JC, et al. Congenital hydrone- phrosis: early experience with open fetal surgery. J Pediatr Surg. 1998;23:1114-1121.

15. Crombleholme TM, et al. Fetal intervention in obstructive uropathy: prognostic indicators and efficacy of intervention. Am J Obstet Gynecol. 1990;162(5):1239-1244.

16. Peters CA, Reid LM, Docimo S, et al. The role of kidney in lung growth and maturation in the setting of obstructive uropathy and oligohydramnios. J Urol. 1991;146:597-600.

17. Harrison MR, Golbus MS, Filly RA, et al: Management of the fetus with congenital hydronephrosis. J Pediaitr Surg 17; 728, 1982

18. Crombleholme personal communication

19. Harrison MR, Langer JC, Adzick NS et al: Correction of congenital diaphragmatic hernia in utero V: Initial clinical experience. J Pediatr Surg 25: 47, 1990

20. Harrison MR, Anderson J, Rosen MA et al: Fetal surgery in the primate I: Anesthetic, surgical and tocolytic management to maximize fetal-neonatal survival. J Pediatr Surg 17: 115, 1982

21. Adzick NS, Harrison MR, Glick PL et al: Diaphragmatic hernia in the fetus: Prenatal diagnosis and outcome in 94 cases. J Pediatr Surg 20: 357, 1985

22. Harrison MR, Ross NA, deLorimier AA: Correction of congenital diaphragmatic hernia in utero III: Development of successful surgical technique using abdominoplasty to avoid compromise of umbilical blood flow. J Pediatr Surg 16: 934, 1981

23. Harrison, MR: The fetus with diaphragmatic hernia in The Unborn Patient: The Art and Science of Fetal Therapy, Harrison MR, Evan MI, Adzick NS, Holzgreve eds 2001, WB Saunders Co pp 297-314

24. Carmel J, Friedman F, Adams F: Fetal tracheal ligation and fetal tracheal development. Am J Dis Child 109:452-456, 1965

25. DiFiore JW, Fauza DO, Slavin R et al: Experimental fetal tracheal ligation reverses the structural and physiologic effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 29: 248257, 1994

26. Harrison MR, Adzick NS, Flake AW et al: Correction of congenital diaphragmatic hernia in utero VIII: Response of the hypoplastic lung to tracheal occlusion. J Pediatr Surg 31: 1339-1348, 1996

27. Flake AW, Crombleholme TM, Johnson MP et al: Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: Experience with 15 cases. Am J Obstet Gynecol 183 (5): 1059-1066, 2000

28 Harrison MR, Mychaliska GB, Bealer JF et al: Correction of congenital diaphragmatic hernia IX: Fetuses with poor prognosis (liver herniation and low head-to-lung ratio) can be saved by fetoscopic temporary tracheal occlusions. J Pediatr Surg 33: 1017-1023, 1998

29. Deprest JA, Evrard VA, Van Ballaer PP, Verbeken E, Vandenberghe K, Lerut TE, Flageole H. Tracheoscopic endoluminal plugging using an inflatable device in the fetal lamb model. European Journal of Obstetrics & Gynecology and Reproductive Biology. 1998 Dec 1;81(2):165-9.

30. Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H, Filly RA, Farrell JA, Albanese CT. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. New England Journal of Medicine. 2003 Nov 13;349(20):1916-24.

31. Deprest JA, Nicolaides KH, Benachi A, Gratacos E, Ryan G, Persico N, Sago H, Johnson A, Wielgos M, Berg C, Van Calster B, Russo FM, for the TOTAL Trial for hypoplasia invetigators: Randomized trial of fetal surgery for severe left diaphragmatic hernia. N Engl J Med 2021; 385:119-129

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