Correction of congenital diaphragmatic hernia in utero, V. Initial clinical experience

Correction of Congenital Diaphragmatic Hernia in Utero, V. Initial Clinical Experience By Michael R. Harrison, Jacob C. Langer, N. Scott Adzick, Mitchell S. Golbus, Roy A. Filly, Robert L. Anderson, Mark A. Rosen, Peter W. Callen, Ruth B. Goldstein, and Alfred A. deLorimier San Francisco, California 9 Review of our experience w i t h 45 cases of prenatally diagnosed congenital diaphragmatic hernia (CDH) confirms t h a t most fetuses (77%) will not survive despite optimal pre- and postnatal care. Polyhydramnios, associated anomalies, early diagnosis, and a large v o l u m e of herniated viscera (including liver) are associated w i t h a particularly dismal prognosis. After extensive e x p e r i m e n t a l w o r k demonstrated the efficacy, feasibility, and safety of repair in utero, w e a t t e m p t e d t o salvage six highly selected fetuses w i t h severe CDH by open fetal surgery. Five had liver incarcerated in the chest: t h r e e died at operation because a t t e m p t s to reduce the liver compromised umbilical venous return. In one, a Goretex diaphragm was constructed around the liver, but the baby died after birth. The last t w o fetuses, one w i t h incarcerated liver, w e r e successfully repaired. Both demonstrated rapid g r o w t h of t h e lung in utero, had surprisingly good lung function a f t e r birth despite prematurity, had t h e abdominal patch removed at 2 weeks, and subsequently died of n o n p u l m o n a r y problems (an unrelated nursery accident in one and intestinal complications in the other). The only maternal complication was amniotic fluid leak and preterm labor. All six women are well and four have had subsequent normal children. From this phase I experience, w e conclude t h a t fetal surgery appears safe for the m o t h e r and her reproductive potential, t h a t fetal CDH repair is feasible in selected cases, and t h a t the fetal lung responds quickly after decompression. However, fetal repair remains a formidable technical challenge. 9 1990 by W.B. Saunders Company.

INDEX WORDS: Congenital diaphragmatic hernia; fetal surgery.

ESPITE RECENT advances in postnatal manD agement including improved methods of ventilation? '2 pharmacologic manipulation of persistent fetal circulation?'4 delayed surgical repair, 5'6 and extracorporeal membrane oxygenation (ECMO) support, 7'8 most neonates with congenital diaphragmatic hernia (CDH) die. The mortality reported from pediatric centers treating babies by all these techniquesH~ should be viewed with skepticism because they consider only those neonates who survive birth and transport to a pediatric center, and neglect the "hidden mortality" resulting from stillbirth and unexplained neonatal demise, l1-15The true mortality for babies with CDH diagnosed before birth (ie, unselected by survival at birth) is much worse, exceeding 75% in recent reviews. J5-20 Most babies with CDH die because their lungs are inadequate to support life at birth. "Pulmonary hypoJournal of Pediatric Surgery, Vol 25, No 1 (January), 1990: pp 47-57

plasia" in CDH means underdevelopment of both the parenchyma and the pulmonary vascular bed, leading to persistent fetal circulation. Because pulmonary hypoplasia results from compression of the growing lung by herniated viscera during fetal life, repair in utero may be the only way to reverse this potentially fatal pulmonary maldevelopment and permit survival in s e v e r e eases. 2]24 Because hysterotomy for open fetal surgical repair puts the mother at risk, we set three conditions for clinical application: (1) The pathophysiological rationale had to be proven correct in an animal model. We have demonstrated in the fetal lamb that fatal pulmonary hypoplasia is caused by pulmonary compression21 and can be reversed by prenatal repair, 22that repair is feasible using an abdominal patch to enlarge the abdomen,23 and that the pulmonary vascular changes that correlate with persistent fetal circulation also can be reversed. 24 Experimental work by others is consistent. 25"29(2) The natural history of CDH in the human fetus had to be established by careful sonographic study of untreated fetuses and some criteria for selecting high risk fetuses identified. We and others have shown that prenatal diagnosis is associated with a high mortality (>75%), that polyhydramnios is not only a marker for the disease but is associated with higher mortality, and that fetuses with associated severe anomalies can be detected and excluded by prenatal diagnostic techniques. ~5"2~Fetuses at particularly high risk are those who present earlier in gestation with polyhydramnios, with a dilated stomach in the chest, and with a low lung/thorax ratio. Conversely, fetuses who present late in gestation with normal amniotic fluid volume, etc, are at lower risk and are not candidates for repair before birth. (3) Techniques for maternal anesthesia, hysterotomy, fetal monitoring, and From the Fetal Treatment Program, the Departments of Surgery, Radiology, Anesthesia, Pediatrics, and Obstetrics. Gynecology, and Reproductive Sciences, University of California, San Francisco, CA. Presented at the 20th Annual Meeting of the American Pediatric Surgical Association, Baltimore, Maryland, May 28-31, 1989. Address reprint requests to Michael R. Harrison, MD, University of California, San Francisco, Room 585-HSE, San Francisco, CA 94143-0510. 9 1990 by W.B. Saunders Company. 0022-3468/90/2501-0009503.00/0

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anomalies, and sonographic evidenceof liver in the chest. All fetuses in this series had the stomach noted in the chest sonographically. There were two fetuses with hydrops; both died. Mortality as a function of gestational age at diagnosis is shown in Fig 2. There were 3 survivors among 13 fetuses diagnosed before 25 weeks. Maternal factors such as age, serum alpha-fetoprotein, and previous history did not correlate with fetal outcome. Because of our wide referral base, many babies were not delivered at our institution and postnatal

tocolytic control of p r e t e r m labor had to developed a n d open fetal surgery proven safe for mother and fetus in a rigorous n o n h u m a n p r i m a t e model. W e satisfied this most difficult criterion over the last decade by developing the necessary surgical, anesthetic, and tocolytic techniques and d e m o n s t r a t i n g safety for the mother and her future reproductive potential in monkeys. 3~ In the present report, we s u m m a r i z e our clinical experience with 45 cases of p r e n a t a l l y diagnosed C D H and describe our initial experience a t t e m p t i n g to salvage a few highly selected, very severely affected fetuses by open fetal surgery.

management could not be standardized. However, 26 of the 31 were transported to and delivered at a tertiary perinatal center. All five who were outborn died.

Phase I Trial of Fetal Surgical Repair We satisfied the criteria for a trial of open fetal surgery and obtained the approval of the Committee on Human Research in 1983. Because our selection criteria were so stringent, we have attempted repair in only six cases in 6 years. We decided that the only candidates for this experimental procedure would be fetuses with an unequivocal isolated diaphragmatic hernia containing stomach and small bowel with marked mediastinal shift and polyhydramnios present before 28 weeks' gestation. In addition, there could he no evidence of another anomaly by thorough sonographic evaluation at our center, by amniocentesis or percutaneous umbilical cord sampling for chromosome analysis, and by eehocardiography. Finally, it was imperative that families understand the risks and be willing to travel to San Francisco. Finances were a major stumbling block for many families as insurance companies refused to cover any expenses associated with this procedure. Although there were no professional fees, the cost for the procedures and hospitalization was still considerable and was borne by the investigating institution. Although we have been contacted by telephone about a large number

MATERIALS AND METHODS

Clinical Material Since 1980, 45 cases of prenatally diagnosed CDH have been referred to the Fetal Treatment Program at the University of California, San Francisco. Mean gestational age at diagnosis was 27.2 _+ 5.4 weeks. Nine fetuses were aborted either spontaneously (two) or electively (seven). Of the remaining 36, 5 were repaired in utero, and 31 proceeded to delivery. These 31 have been analyzed separately to determine natural history and prognostic features.

Natural History The outcome for fetuses with CDH and the factors that affect mortality are summarized in Fig 1. Factors that were found to have a significant bearing on outcome were polyhydramnios, associated

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N u m b e r of Fetuses

Number of Fetuses 10

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No Polyhydramnios

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N u m b e r of Fetuses

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0 Associated Anomalies Fig 1.

No Associated Anomalies

~ Liver in Chest

Mortality factors in 31 untreated cases of fetal diaphragmatic hernia.

No Liver in Chest

DIAPHRAGMATIC HERNIA CORRECTION IN UTERO

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10 Im [] []

Number of Fetuses 5

Aborted Dead Alive

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16-20

21-24

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Gestational Age at Diagnosis (wks) Fig 2.

Outcome related to gestationa# age at diagnosis.

of fetuses with CDH, only a fraction (< 1 in 10) were even candidates to come to San Francisco for further evaluation. Of the potential candidates, at least half were excluded because of social and financial considerations. The initial experience with six highly selected, very severe cases was discouraging, but each of these cases contributed invaluable knowledge and experience, and will be presented chronologically with the lessons summarized. Features common to all six procedures included an anesthetic and tocolytic regimen (previously developed in nonhuman primate studies) that included: preoperative indomethacin, deep halothane anesthesia, a low transverse abdominal incision to expose the uterus, aspiration and preservation of excess amniotic fluid, intraoperative sterile sonography for placental localization and fetal monitoring, intraoperative fetal heart rate and oxygen saturation monitoring, a hysterotomy incision placed to avoid the placenta, prophylactic antibiotics, and postoperative tocolysis with magnesium sulfate, indomethacin, and betamimetics. CASE REPORTS

Case 1 A 30-year-old G1 P0 was referred from Florida carrying a 27-week fetus with a large left CDH containing stomach and liver. Polyhydramnios was present and the placenta was posterior. Through an anterior transverse hysterotomy, the left arm of the fetus was delivered and electrocardiographic (ECG) leads were placed on the chest. Through a left subcostal incision, the bowel and stomach were easily pulled out of the chest, but the liver was found to be densely adherent to the mediastinum. The incision was extended into the chest, and the very friable liver mobilized with difficulty, leading to bleeding and episodes of bradycardia. The diaphragm was repaired with a patch, the chest filled with warm Ringer's lactate and closed, and the abdominal part of the incision closed with a silastic patch abdominoplasty. Unfortunately, ECG monitoring during repair proved unreliable, and after the repair was complete, sonography revealed no fetal heart activity. The uterus was evacuated and closed. The mother had an uneventful recovery and was discharged after 5 days. Four years later she discontinued birth control, conceived, and has recently delivered a normal girl.

Comment. We had not recognized preoperatively that the liver had herniated into the chest and did not anticipate how difficult it was to mobilize the herniated fetal liver without significant bleeding. Electronic monitoring proved unreliable, probably due to amniotic fluid conduction of the maternal signal. Fetal monitoring proved absolutely essential for fetal manipulation of this magnitude. Case 2 A 17-year-old G1 P0 was referred from Washington carrying a 27-week fetus with a large left CDH and polyhydramnios. A careful examination for liver in the chest was inconclusive. The placenta was posterior. When a fundal hysterotomy was made, the uterus was noted to be very contracted and thickened. ECG monitoring was satisfactory using two atrial pacing leads sutured to the fetal chest and a third to the uterus, but a transcutaneous oximeter attached by suction did not work well. When a left subcostal incision was made, the intestines squirted out under pressure, indicating that the fetus and the uterus were not adequately relaxed; the halothane anesthesia was deepened. After the intestines, spleen and stomach were removed from the chest, the liver was found stuck to the mediastinum. The incision was then extended into the chest, and the liver carefully dissected from the mediastinum. Repeated attempts to tilt the liver back down into the abdomen resulted in fetal bradycardia and hemodynamic deterioration. Repair of the diaphragm was begun using Teflon mesh, but during repair, the fetal heart slowed, and resuscitation with cardiac massage, intracardiac transfusion of O negative irradiated blood, and medications was unsuccessful. The uterus was evacuated and closed. The mother recovered uneventfully and has not tried to conceive again. Postmortem examination revealed that the mechanism by which return of the liver to the abdomen caused fetal deterioration and demise was by kinking of the umbilical vein. Comment. Despite its newly discovered clinical importance, herniation of the liver proved very difficult to detect sonographically. The herniated intrathoracic liver presented a problem that goes beyond the technical problem of bleeding; tipping the liver down into the abdomen kinks the umbilical vein and compromises umbilical blood flow (Fig 3). Inadequate uterine relaxation made fetal surgery

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exceedingly difficult and reconfirmed the importance of deep halothane anesthesia to insure complete relaxation of the uterus and the fetus. In our first attempt at fetal resuscitation, we found that intracardiac administration of drugs and blood was possible, but awkward, and led us to consider direct umbilical venous access.

Case 3

Fig 3. Five of six attempted repairs had herniated liver. In the first cases, attempts to reduce the liver caused fetal deterioration and demise; autopsy revealed that kinking of the umbilical vein compromised venous return.

A 26-year-old G2 P1 was referred from Detroit carrying a 24-week fetus with a large left diaphragmatic hernia, polyhydramnios, and liver in the chest. Because the placenta was directly anterior and we were reluctant to tilt the uterus up to open posteriorly, we used a low anterior oblique uterine incision that paralleled the edge of the placenta. Initial dissection was outside the amniotic membranes and the uterine muscle was opened using an absorbable stapling device. The left arm was delivered, ECG leads placed on the fetal chest, and a pulse oximeter placed around the wrist. Anticipating intrathoracic liver, a thoracoabdominal incision was made and the bowel and stomach were easily pulled out of the chest. However, the entire left lobe of the liver was adherent to the mediastinum and could not be reduced without inducing fetal bradycardia. In desperation, we attempted to fashion a Goretex diaphragm around the herniated liver (Fig 4). Although this allowed us to complete the procedure without compromising the fetus, we were not satisfied that the new patch diaphragm would keep the bowel out of the chest, so the abdominal portion of the incision was left open with the intestine out to provide complete thoracic decompression. The fetus was returned, amniotic fluid volume restored, and the uterus closed with difficulty because the hysterotomy was too close to the placenta, and the stapler opening made it difficult to include the membranes in the closure. Postoperatively, uterine irritability was controlled by intravenous ritodrine and indomethacin suppositories for 4 days, and then by oral terbutaline. Most worrisome was a small amniotic fluid leak and persistent oligohydramnios. The mother recovered uneventfully, was discharged after 10 days, and returned to Detroit to be followed by

Fig 4. In case 3, the liver could not be reduced without fetal collapse, and construction of a prosthetic diaphragm without reducing the incarcerated liver proved inadequate.

DIAPHRAGMATIC HERNIA CORRECTION IN UTERO

the referring obstetrician. Intermittent amniotic fluid leak and oligohydramnios persisted, and 10 weeks later, chorioamnionitis led to preterm labor and cesarean delivery of a 34-week, 2,000 g baby with Apgars of 3 and 4. An attempt was made to repair the diaphragmatic hernia soon after birth; the surgeon described dense inflammatory adhesions and reherniation of the bowel into the chest between the liver and the Gortex patch diaphragm. The infant died postoperatively and autopsy confirmed persistent pulmonary hypoplasia. The mother has subsequently had a normal baby girl. Comment. Our hysterotomy incision was both too close to the placenta, which made it difficult to incorporate the membranes in the closure, and too close to the cervix, which contributed to the amniotic fluid leak. We have subsequently learned that a posterior hysterotomy, which would have been safer and easier, can be accomplished by tipping the uterus forward. The use of the stapler without including the membranes led to dissection under the membranes; the amniotic fluid leak produced oligohydramnios (which may have contributed to lung hypoplasia), and eventually to chorioamnionitis. The use of simultaneous pulse oximetry, ECG, and intraoperative sonography allowed continuous monitoring of the fetus' condition even when one modality failed temporarily. The idea of leaving the intrathoracic liver alone, and placing a thoracoabdominal patch to act as a diaphragm to keep the bowel out of the chest was physiologically sound, but proved technically impossible. The diaphragmatic patch could not be attached to the liver, and this allowed reherniation of the bowel, so the lung was not adequately decompressed. In retrospect, an inadequate repair is far worse than intraoperative fetal demise because the continued gestation of an inadequately repaired fetus poses a significant medical and psychological risk to the mother. Leaving the bowel exteriorized proved less desirable than covering it with an abdominal patch since there were dense inflammatory adhesions, possibly related to chorioamnionitis. Allowing the family to return home and attempting to manage these complicated pregnancies long distance has proven unsatisfactory. Unfortunately, financial and social considerations make it exceedingly difficult to keep the families near the Fetal Treatment Center.

Case 4 A 38-year-old G3 P2 was referred from Arizona carrying a 21-week fetus with a large diaphragmatic hernia, polyhydramnios, no liver seen in the chest, and an anterior placenta. At operation, 1 L of amniotic fluid was aspirated and saved. Intraoperative sonography allowed us to mark the edge of the placenta and make a hysterotomy high in the posterior aspect of the fundus, tipping the uterus forward on towels. Because the fetus was head down, the legs had to be brought out first, and there were intermittent problems with herniation and compression of the umbilical cord throughout the procedure. A pulse oximeter was placed on the foot, and ECG leads were secured on the chest. A thoracoabdominal incision was made, and the bowel, stomach, and spleen were easily removed from the chest. Although the left lobe of the liver was in the chest, it could be reduced into the abdomen. Because there was no diaphragm posteromedially and anteriorly, attaching the Goretex patch diaphragm was very difficult. The abdomen was easily closed without a patch. The fetus did well until the uterus was closed, when sonography revealed bradycardia with poor cardiac contractility. The uterus was reopened, and resuscitation attempted including administration of fluid, epinephrine, and atropine by direct umbilical puncture, but the fetus succumbed and was removed. The mother recovered uneventfully and has subsequently delivered a normal boy. Comment. It was not clear why the fetus deteriorated after being returned to the uterus following a difficult but successful repair. One possibility is that the long and difficult procedure led to unrecognized third space fluid loss and heat loss in this tiny 21-week

51

fetus. Fetal hypovolemia is difficult to detect until too late, underscoring the need to develop methods to monitor perfusion and techniques to replace blood and crystalloid intraoperatively. Another possibility is that intermittent umbilical cord compression caused by herniation of the cord contributed to fetal deterioration. Manipulation of the cord is difficult to avoid when the feet are exteriorized, so every effort should be made to deliver only the left arm and part of the chest. 3. Closure of the abdomen without abdominoplasty may have increased intraabdominal pressure enough to compromise umbilical vein flow as we have demonstrated experimentally, especially if the fetus was marginally hypovolemic.

Case 5 A 30-year-old G2 P1 was referred from Detroit carrying a 26-week fetus with a large diaphragmatic hernia, polyhydramnios, and no evidence of liver in the chest. The placenta was anterior. Before opening the uterus, intraoperative sonography was used to aspirate fetal cord blood for a baseline hematocrit and solute determination, and to mark the edge of the placenta. A transverse posterior hysterotomy was made 4 cm from the edge of the placenta (Fig 5A). The left arm was delivered, and the pulse oximeter and ECG leads were placed (Fig 5B). A subcostal incision was made, and the bowel and stomach were easily brought out of the chest (Fig 5C). The defect was dosed primarily and the abdominal incision was closed with Gortex (Fig 5D). The operation went smoothly, and the fetal heart rate remained at 130 to 140 throughout the procedure. The uterus was dosed and the amniotic space restored with warm preserved amniotic fluid. Postoperatively, uterine irritability was controlled with intravenous ritodrine and rectal indomethacin, and subsequently by oral terbutaline. The mother was discharged after 12 days and returned home to be followed by the referring obstetrician. The fetus appeared completely normal on repeat sonogram. Mother and fetus did well until 31 weeks' gestation when increasing contractions did not respond to tocolytics and cesarean section was performed at their local hospital. The infant weighed 1,520 g, and had Apgar scores of 7 and 9. The neonate was transferred to a pediatric surgical center. At 17 days of age, the Goretex patch was removed and the abdomen closed uneventfully. The baby was being slowly weaned from the ventilator, when the endotracheal tube became accidentally dislodged in the middle of the night and the infant died. The family has since had a normal baby girl. Comment. In this case, we were able to implement many of the lessons learned in the previous cases. Prenatal sonography was accurate in predicting the absence of liver in the chest. Intraoperarive monitoring of the fetus was successful using pulse oximetry, ECG leads, and intraoperative sonographic assessment of the fetal heart. The use of preoperative and intraoperative fetal blood sampling allows periodic assessment of fetal hematocrit, which is helpful in following fetal blood loss and volume status. Problems with the hysterotomy were avoided by using intraoperative sonography to precisely localize the edge of the placenta closest to the proposed uterine incision, by using the cautery with manual compression (rather than the absorbable stapler) to make a full thickness hysterotomy, and by opening the posterior wall of the uterus (rather than low anterior) to avoid the anterior placenta. Tragically, a successful outcome was spoiled by an unrelated mishap.

Case 6 A 19-year-old G3 P1 was referred from Cincinnati carrying a 27-week fetus with a large left CDH, no liver seen in the chest, and an anterior fundal placenta. She had had some bleeding and contractions throughout the pregnancy. Through a transverse low anterior hysterotomy and a fetal subcostal incision, the spleen,

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HARRISON ETAL

D

o

Pulse ,rnot.

Gortexpatch

~ ,,~~r

r

Diaphragm

i;i;

Fig 5. Illustration of successful fetal repair in case 5, (A) Percutaneous umbilical cord sampling for preoperative fetal blood studies. Because the placenta was anterior, the hysterotomy had to be posterior. (BI The left arm and chest are exposed and the fetus continuously monitored by ECG, pulse oximetry, and sterile ultrasound. (C) The intestines and stomach are reduced through a subcosta! incision. (D) The diaphragm is reconstructed, the chest filled with warm saline, and the abdomen enlarged with a patch.

intestines and stomach were removed from the chest. The liver was herniated into the chest, and the only diaphragmatic remnant was a small rim anteriorly. Retraction of the liver downward caused severe bradycardia requiring frequent repositioning. With careful monitoring, the liver was intermittently reduced to allow placement of interrupted sutures medially. Finally, a Goretex patch could be secured medially and used to gradually reduce the liver. It was then relatively easy to secure the remainder of the diaphragmatic patch to the ribs and costal margin with running suture. Bradycardic episodes stabilized after the repair was complete. The large amount of viscera removed from the chest was accommodated with a Goretex patch abdominoplasty. Despite the difficult 1 hour procedure, the fetus remained stable without further bradycardia while the uterus was closed with two layers of running suture and amniotic fluid volume restored with warm Ringer's lactate. During placement of an epidural catheter, the mother bucked violently on the endotracheal tube and clear amniotic fluid leaked from the vagina. Postoperatively, the fetus did well with the mediastinum shifted back to the midline and good lung visible in the left chest, but the amniotic fluid leak persisted and uterine contractions were difficult to control. Contractions were temporarily controlled with indomethacin, but

recurred when the patient was weaned to oral terbutaline on the fifth postoperative day. Eight days postoperatively, preterm labor recurred and the patient was taken to the delivery room and prepared for exploration, but the baby delivered quite easily vaginalty. Although the hysterotomy remained intact, it was elected under the same anesthesia to reopen and freshen the hysterotomy to minimize the potential for difficulty with subsequent pregnancies. After initial resuscitation, the infant's respiratory situation stabilized, and ventilation and oxygen requirements diminished dramatically by 24 hours. Mild persistent fetal circulation was easily managed with paralysis, ventilation, and pharmacologic manipulation. The infant improved rapidly and by 2 weeks of age was stable on minimal respiratory support, with a normal appearing lung on x-ray and no evidence of pulmonary hypoplasia. However, when the Goretex patch was removed from the abdominal wall, there was dense fibrotic scarring and extensive bowel damage requiring resection and reconstruction. The Goretex diaphragm was fine. Recurrent obstruction, perforation, and sepsis led to death at 3 weeks of age. Comment. This ease proved that repair of even the most severe CDH is technically feasible, including reduction of herniated liver, creation of a prosthetic diaphragm, and prosthetic abdominoplasty.

DIAPHRAGMATIC HERNIA CORRECTION IN UTERO

It further showed that the fetus can tolerate very extensive and prolonged surgical manipulation as long as heart rate is accurately and continuously monitored. Amniotic fluid leak and premature delivery foiled an otherwise successful fetal repair. Two problems that may have contributed are the low anterior uterine incision (a short distance for fluid to dissect to the cervix) and the violent straining during emergence from anesthesia (the hydraulic force necessary to initiate the leak). Surveillance for preterm labor after surgery was also inadequate in this case: several episodes were misinterpretted delaying tocolytic therapy. The virulence of the inflammatory reaction and intestinal damage that proved fatal was surprising and suggests that handling of the fetal bowel and/or reaction to the Goretex patch material contributed to the dense scarring. Although material that induces fibrous ingrowth is appropriate for the diaphragm, the temporary abdominal patch should be a nonreactive silastic material. The pulmonary function of the premature neonate was surprisingly good; and certainly not the cause of death. This suggests that even the relatively short period in which the developing fetal lung was decompressed (before it is needed for gas exchange at birth) allowed considerable rapid growth and development.

DISCUSSION

Prenatal diagnosis provides new insight into the natural history and developmental pathophysiology of CDH. The high mortality (77%) in our experience is similar to that previously reported from this center, 16 from our survey of centers in North America, 17 and from other institutions, Is'2~ confirming the suspicion that many severe cases are never seen at pediatric centers and constitute a significant "hidden mortality. ''~'15 The fact that associated anomalies are more common in prenatally diagnosed CDH 17,Is and in autopsy series 13"~5 further supports this hypothesis. Fortunately, associated anomalies can be accurately detected by careful prenatal evaluation. ~6"2~ Our experience with fetal CDH suggests that the wide spectrum in severity of pulmonary hypoplasia (and thus mortality) seen after birth can be explained by variations in the timing and volume of visceral herniation and lung compression. The diaphragmatic defect is present from early in gestation (< 10 weeks) in all cases, but visceral herniation may occur early causing severe pulmonary hypoplasia or late causing minimal disturbance in lung development. The association of polyhydram,lios with poor prognosis may be explained by obstruction of the esophagus or duodenum. Herniation of the stomach into the chest can kink the duodenum and produce gastric outlet obstruction, which we have documented at autopsy. Gastric outlet obstruction produces both polyhydraminos and gastric dilation with significant intrathoracic volume displacement and compression of the lungs. Thus, the severity of pulmonary hypoplasia may be directly linked to polyhydramnios by partial duodenal obstruction. In this report, we note for the first time that the presence of herniated liver carries a dismal prognosis

53

not only because it displaces lung but also because it greatly complicates any attempt at fetal repair. The fetal liver is prone to bleed from manipulation, and attempts to return the liver to the abdomen can torque the umbilical vein and compromise venous return. Our initial experience with attempted repair underscores how difficult it is for the fetal sonographer to assess preoperatively whether the liver is herniated. Because of its prognostic significance as well as the technical implications with respect to in utero repair, this is a subtle but important distinction. Two sonographic techniques have proven useful: the portal vein can be followed to see if distal branches appear above the level of the diaphragm, and the presence of a solid mass between the left border of the heart (recognized by motion) and the herniated stomach bubble (recognized by peristalsis) suggests herniated liver. Color flow doppler imaging can help identify portal vein in hepatic tissue. What are the clinically important lessons from our initial experience with fetal CDH repair? First, the learning curve for open fetal surgery is very steep. In the comments following each case, we have presented hard-earned lessons about maternal anesthesia and uterine relaxation; choice of uterine incision in relation to the placenta; handling of amniotic fluid; techniques of fetal exposure; methods to reduce herniated liver and replace the diaphragm; the limits of fetal manipulation in terms of third space fluid loss and blood loss; the need for continuous fetal monitoring using ECG, pulse oximetry, and sonography; the need for improved methods of fetal resuscitation including vascular access; the importance of sealing the amniotic membranes during uterine closure; the alternatives for opening and closing the uterus including the use of absorbable staples; the crucial role of perioperative tocolytic management; and the need for surveillance and aggressive treatment of preterm labor after fetal surgery. Beyond these technical points, we have learned that, as a general principle, fetal surgery should be "all or none," ie, the fetal repair should be complete and adequate to insure a good chance for survival, or else the otherwise doomed fetus should be removed. A partial or inadequate repair presents an ongoing threat to the mother for little potential benefit. The most important issue in this phase I experience is maternal safety. Fortunately, the initial experience with these six patients and nine others is encouraging,a3 The only complication has been amniotic fluid leak, and the only morbidity is related to the postoperative management of premature uterine contractions. All four women who tried have had no difficulty conceiving, carrying, and delivering subsequent normal pregnancies. All six mothers when recently contacted

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maintain a positive attitude about their experience and express no regret about their heroic sacrifice in accepting some risk and considerable discomfort in attempting to help their unborn baby. Their contribution to the advancement of this field and to the care of children yet unborn should not go unrecognized. Management of the fetus with a prenatally diagnosed CDH remains challenging, but some generalizations may prove helpful in counseling families about their options. Because no course of action is demonstrably superior, the family's choice should always be respected. Figure 6 shows our proposed algorithm for management. Once a diaphragmatic hernia is suspected by sonographic visualization of viscera in the chest, demonstration of a shifted mediastinum, and absence of a stomach bubble in the abdomen, the patient should be referred for chromosomal analysis by amniocentesis (results in about 2 weeks) or percutaneous umbilical blood sampling (results in about 2 days), screening for other anatomic abnormalities by an experienced obstetrical sonographer, and evaluation for cardiac abnormalities by fetal echocardiography. When associated serious anomalies are discovered, the family may choose to terminate the pregnancy. Fetuses with isolated defects should be aggressively managed before and after birth, as it is not yet possible to reliably predict which will survive to be normal children. There is a wide spectrum of severity. Some mildly affected fetuses will survive with conventional treatment after birth. In general, these fetuses will be detected later in gestation, develop polyhydramnios later or not at all, and have a smaller volume of viscera in the chest (stomach not herniated and/or dilated, less mediastinal shift, and more lung visible on a transverse

Fig 6.

Algorithm for management of the fetus with CDH.

scan at the level of a four chamber view of the heart). These fetuses should be followed by sonogram and delivered at an appropriate tertiary perinatal center after the lungs are mature. It is not known whether induced preterm delivery after lung maturity is documented is beneficial; the rationale is that the baby is growing rapidly while the compressed lung is static so that the lung/body ratio decreases with continuing gestation. Without compelling data, it seems reasonable to plan delivery near term, but to insist on maternal transport to a perinatal center experienced in all the postnatal techniques that may enhance survival of "marginal" cases: delayed surgery, ECMO, high frequency ventilation, and in the future neonatal lung transplantation?4 Unfortunately, the majority of fetuses will be on the severe end of the spectrum and will not survive even with optimal conventional preand postnatal management. In general, these fetuses will be detected earlier, develop polyhydramnios earlier, and have a larger volume of viscera in the chest (dilated stomach, impressive mediastinal shift, little lung visible in either thorax). Every effort should be made to determine if the liver is herniated into the chest as this affects prognosis and the feasibility of repair before birth. It is not possible to determine precisely the severity of pulmonary hypoplasia in any individual fetus because assessment of lung volume is imprecise and measurement of lung function is impossible before the lung begins to function at birth. Gestational age at time of diagnosis and referral play a major role in counseling these families (Fig 6). Before 24 weeks, the family has three choices: terminate the pregnancy even though there is a chance the baby could survive, continue the pregnancy and arrange for the best possible care after birth, or consider surgical repair before birth. Between 24 and 32 weeks, the family can choose between conventional management or fetal repair depending on assessment of severity and their personal attitude. After 32 weeks, the only option is conventional management aimed at maximizing postnatal care. Although fetal repair is theoretically possible until 32 weeks, it is probably best performed before 30 weeks for two reasons. First, the longer the decompressed lung has to grow before it is required to support life at birth the better (and preterm labor associated with hysterotomy may shorten the remaining gestation). Second, it is our impression that the risk of inducing preterm labor is greater when the procedure is performed later in gestation. Although it would seem technically advantageous to operate on a larger fetus with more mature tissues, surgical procedures have proven feasible in fetuses as young as 19 weeks. At present, we will consider fetuses between 22 and 30 weeks' gestation for in utero repair. There are an astounding number of unresolved

DIAPHRAGMATIC HERNIA CORRECTION IN UTERO

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questions and potential problems that arise in the conduct of in utero repair of d i a p h r a g m a t i c hernia and in the m a n a g e m e n t of the p r e g n a n c y before, d u r i n g and after fetal surgery. At the b e g i n n i n g of our experience, the limiting factor was the fetal repair itself, particularly when the liver could not be reduced without compromising umbilical venous return. This difficult problem has proven s u r m o u n t a b l e . T h e other factors that limit success after fetal intervention are

the sequelae of hysterotomy, ie, a m n i o t i c fluid leak from disruption or dissection of the m e m b r a n e s a n d the constant threat of preterm labor. This last b a r r i e r to fetal surgery is g r a d u a l l y yielding to improved tocolytic techniques and increasing surgical experience. Nevertheless, fetal C D H repair r e m a i n s a f o r m i d a b l e technical challenge involving frightening risks a n d should not be considered without extensive preparation by a c o m m i t t e d multidisciplinary team.

REFERENCES

1. Bohn DJ, Tamura M, Perrin D, et al: Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia confirmed by morphometry. J Pediatr 111:423-431, 1987 2. Tamura M, Tsuchida Y, Kawano T, et al: Piston-pump-type high frequency oscillatory ventilation for neonates with congenital diaphragmatic hernia: A new protocol. J Pediatr Surg 23:478-482, 1988 3. Geggel RL, Murphy JD, Langelben D, et al: Congenital diaphragmatic hernia: Arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 107:457464, 1985 4. Vacanti JP, O'Rourke PP, Lillehei CW, et al: The cardiopulmonary consequencesof high-risk congenital diaphragmatic hernia. Pediatr Surg lnt 3:1-5, 1988 5. Langer JC, Filler RM, Bohn DJ, et al: Timing of surgery for congenital diaphragmatic hernia: Is emergency operation necessary? J Pediatr Surg 23:731-734, 1988 6. Hazebroek FWJ, Pattenier JW, Tibboel D, et al: Congenital diaphragmatic hernia: The impact of preoperative stabilization. J Pediatr Surg (in press) 7. Bartlett RH, Gazzaniga AB, Toomasian J, et al: Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure, 100 cases. Ann Surg 204:236-242, 1986 8. Stolar C, Dillon P, Reyes C: Selective use of extracorporeal membrane oxygenation in the management of congenital diaphragmatic hernia. J Pediatr Surg 23:207-211, 1988 9. SimsonJNL, Eckstein HB: Congenital diaphragmatic hernia: A 20-year experience. Br J Surg 72:733-736, 1985 I0. Anderson KD: Congenital diaphragmatic hernia. Pediatr Surg 52:589-591, 1986 11. Harrison MR, Bjordal RI, Landmark F, et al: Congenital diaphragmatic hernia: The hidden mortality. J Pediatr Surg 13:227230, 1979 12. Harrison MR, deLorimier AA: Congenital diaphragmatic hernia. Surg Clin North Am 61:1023-1035, 1981 13. Butler NR, Claireaux AE: Congenital diaphragmatic hernia as a cause of perinatal mortality. Lancet 1:659-663, 1962 14. Puri P, Gorman F: Lethal nonpulmonary anomalies associated with congenital diaphragmatic hernia: Implications for early intra-uterine surgery. J Pediatr Surg 19:29-32, 1984 15. Patterson GA, Cooper JD: Status of lung transplantation. Surg Clin North Am 68:545-559, 1988 16. Nakayama DK, Harrison MR, Chinn DH, et al: Prenatal diagnosis and management of the fetus with a congenital diaphragmatic hernia: Initial clinical experience. J Pediatr Surg 20:118-124, 1985 17. Adzick NS, Harrison MR, Glick PL, et al: Diaphragmatic hernia in the fetus: Prenatal diagnosis and outcome in 94 cases. J Pediatr Surg 20:357-361, 1985 18. Adzick NS, Vacanti JP, Lillehei CW, et al: Fetal diaphragmatic hernia: Ultrasound diagnosisand clinical outcome in 38 cases. J Pediatr Surg 24:654-658, 1989

19. Harrison MR, Adzick NS, Nakayama DK, et al: Diaphragmatic hernia in the fetus: Fatal but fixable. Semin Perinatol 9:103, 1985 20. Benacerraf BR, Adzick NS: Fetal diaphragmatic hernia: Ultrasound diagnosis and clinical outcome in 19 cases. Am J Obstet 156:573-576, 1987 21. Harrison MR, Jester JA, Ross NA: Correction of congenital diaphragmatic hernia in utero. I. The model: Intrathoracic balloon produces fatal pulmonary hypoplasia. Surgery 88:174-182, 1980 22. Harrison MR, Bressack MA, Churg AM, et al: Correction of congenital diaphragmatic hernia in utero. II. Simulated correction permits fetal lung growth with survivalat birth. Surgery 88:260-268, 1980 23. Harrison MR, Ross NA, deLorimier AA: Correction of congenital diaphragmatic hernia in utero. III. Development of a successful surgical technique using abdominoplastyto avoid compromise of umbilical blood flow. J Pediatr Surg 16:934-942, 1981 24. Adzick NS, Davies P, Harrison MR, et al: Correction of congenital diaphragmatic hernia in utero. IV. Pulmonary vascular morphometric analysis. J Pediatr Surg 20:673-680, 1985 25. deLorimier AA, Tierney DF, Parker HR: Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery 62:12-17, 1967 26. Hardy KJ, Auddist AW, Shilkes A: Congenital diaphragmatic hernia: Intrauterine repair in sheep. Med J Aust 6:233-235, 1982

27. Hailer JA, Signer RD, Golladay ES, et al: Pulmonary hemodynamicsin studies of simulated diaphragmatic hernia of fetal and newborn lambs. J Pediatr Surg 11:675-677, 1976 28. Kent GM, Olley PM, Creighton RE, et al: Hemodynamics and pulmonary changes following surgical creation of diaphragmatic hernia in lambs. Surgery 72:427-433, 1972 29. Soper RT, Pringle KC, Scofield JC: Creation and repair of diaphragmatic hernia in the fetal lamb: Techniques and survival. J Pediatr Surg 19:33-40, 1984 30. 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 17:115-122, 1982 31. Nakayama DK, Harrison MR, Seron-Ferre M, et al: Fetal surgery in the primate. II. Uterine electromyographic response to operative procedure and pharmacologic agents. J Pediatr Surg 19:333-344, 1984 32. Adzick NS, Harrison MR, Glick PL, et al: Fetal surgery in the primate. III. Maternal outcome after fetal surgery. J Pediatr Surg 21:477-480, 1986 33. Longaker MT, Harrison MR, Adzick NS, et al: Maternal safety in open fetal surgery. N Engl J Med (submitted) 34. Crombleholme TM, Adzick NS, Hardy K, et al: Pulmonary lobar transplantation in neonatal swine: A model for treatment of congenital diaphragmatic hernia. J Pediatr Surg 25:11-18, 1990

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HARRISON ET AL

Discussion David Wesson (Toronto, Ontario): What evidence do you have that the lung growth actually accelerated in the baby that survived the first month between the time of the repair and birth? M. Harrison, (reply): Of course we will never be able to answer that definitively since there is no way to measure lung function before and then after repair to show definitively that repair made a difference. All the work, experimental and clinical, says that decompressing the lung allows it to grow and develop rather quickly back toward normal. J. Alex Haller, Jr (Baltimore, MD): I have to agree that this is a remarkable but also a disturbing report. Do I understand that each of these mothers-to-be required two cesarean sections, one for the correction of the anomaly and one for delivery? One of the scientific concerns that I have is that although you and your group have established a good animal model in the lamb and shown that this diaphragmatic defect can be corrected in utero, the hypoplasia of the lung appears to be reversed. However, in none of those animal studies has there been the associated retention of severe pulmonary artery hypertension of a degree that is comparable with that which we see in babies born with diaphragmatic hernia who subsequently die. Death is apparently associated more with the pulmonary artery hypertension and the vascular abnormality than the hypoplasia of the lung. It, therefore, requires a considerable leap in faith to assume that correcting the human anomaly (in utero after 24 weeks), which will almost certainly have pulmonary artery hypertension associated with it, will correct the vascular anomaly. I don't believe we yet know enough about the pathophysiology of this condition in utero to accept these remarkable operative photos which are of experimental animals that are human beings! I would, therefore, ask how you got approval from your committee on human experimentation? What do you tell them, and then what do you tell the mothers in a situation in which none of these babies has survived? While I realize that this is experimental phase I, I am equally concerned about experimental phase II. M. Harrison (reply): Thank you very much, Dr Haller. The first big question is about the relation between persistent fetal circulation and pulmonary hypoplasia. When I talk about pulmonary hypoplasia what I mean is hypoplasia of the whole shooting match, including underdevelopment of the pulmonary vascular bed, not just the airways and alveoli. Is the pulmonary vascular bed problem (and its anatomic correlate, extension and hypertrophy of muscle out to the resistance vessels) reversible with correction of diaphrag-

matic hernia? The answer to that is yes, as Scott Adzick has so nicely demonstrated in lambs. I am not too worried about the general problem of hypoplasia and persistent fetal circulation: I think they are exactly the same thing and I think they are reversible. The second question is how do we deal with families and with our human experimentation committee about a procedure that, as you all fully appreciate, is experimental. The answer is you have to be honest. You have to tell them what you know and what you don't know. You have to tell them what the track record is. You have to tell them what the risks are. You have to tell them that it may involve two operations including cesarean delivery. You have to tell them all the alternatives, and explain that other alternatives may be more appropriate for this particular family. You have to tell them all those things, and you have to have people who are uninvolved in the procedure (who do not have a stake in it) talk to them. You have to say to the family and write in your protocol that you will never ask for a decision in a short amount of time. You have to say, we refuse to accept any decision until you go home, talk to everyone you possibly can, get all the advice you possibly can, talk to your doctor, your priest, your Rabbi, your family and anyone else, because this is an important decision that involves real risk to the mother. Fortunately, so far in our experience now with about 15 open cases, we have not had a significant problem with the mothers or with future reproduction. We now have seven normal children who have been born after open fetal surgery. Robert Filler (Toronto, Ontario): I have two questions for Dr Harrison. One deals with the selection of the children. What are the current criteria for selection of infants for in utero repair? Perhaps you can be a little bit more specific. The second question is about the timing of the surgery. When is the best time? I know that in your report most of the children were operated on at 27 weeks gestation. I wondered what would happen if surgery were delayed a little bit longer. M. Harrison (closing): Selection is an extremely important issue. We used fetal age, polydramnios and the time in gestation when it appears, and the volume of viscera in the chest, including a lung-to-thorax ratio, which can be standardized in a four-chamber view of the heart. All of that is well and good, but we still don't have what we want: a way to assess fetal lung function. Nor are we going to get it. Unlike the urinary tract, where we looked for and found a way to assess fetal renal function, we will probably never have a good function test for the fetal lung, because the fetal lung

DIAPHRAGMATIC HERNIA CORRECTION IN UTERO

does not perform its crucial gas exchange function until birth. Timing of intervention is also interesting. The earlier you operate the better it is for lung growth, but the more difficult it might be technically. Our initial prejudice was that it would be very difficult to operate on fetuses early in gestation, b u t w e have not had difficulty with the urinary tracts down to 18 weeks

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and one of the diaphragmatic hernias at 23 weeks. I think the best time to operate is around 24 weeks, but it can be done up to 30 weeks. The limiting factor on the up-end is that the later in gestation you fool around with the uterus the more likely you are to have difficulty with preterm labor.