Randomized Clinical Trial of Early Delivery in Fetal Gastroschisis vs. Routine Care

Gastroschisis is a congenital malformation in which abdominal organs protrude through an
abdominal wall defect, leading to considerable morbidity and mortality during infancy. In
contrast to the second class of congenital abdominal wall defects, omphalocele, there is no
association of gastroschisis with aneuploidy and there are no familial cohorts or
heritability indices to suggest genetic etiology to gastroschisis. Although multiple
population and cohort based-studies have implicated various environmental and maternal
factors in the pathogenesis of gastroschisis (e.g. young age, smoking), the causes and
mechanisms of this condition remain relatively unclear.

The herniated bowel often accumulates a fibrinous covering possibly due to inflammation
induced by the amniotic fluid. There is usually a 25% or greater risk of intrauterine growth
restriction with gastroschisis. Although long term intact survival is excellent (exceeding
95%), the associated morbidity is significant including gastrointestinal complications such
as stricture, adhesions, and volvulus. Furthermore, there is a known association between
fetal gastroschisis and late gestational intra-uterine fetal demise (IUFD). Late gestation
IUFD is believed to result from acute volvulus of the small bowel and resultant bowel
necrosis and death.

Until recently, there were no indications for early delivery, however; now there is mounting
evidence supporting delivery at an earlier gestational age. This is supported with the
prevailing hypothesis that early delivery prevents further insult from the amniotic fluid to
the small bowel. However, these hypotheses have yet to be examined in a well designed,
adequately powered, randomized clinical trial. Consequently, it is our primary objective to
test the hypothesis that elective early delivery will protect the fetal bowel from the
deleterious intrauterine factors late in the pregnancy. Our secondary objective is to
introduce a standardized protocol for diagnostic, antepartum, and post-natal surgical
management of infants with gastroschisis.

To date, four studies have attempted to evaluate the effect of delivery timing on neonatal
outcomes. In a retrospective review of 57 cases, Huang was unable to demonstrate an
association between earlier delivery and shorter time to surgical repair or oral feeds.
Logge and colleagues performed a randomized controlled trial of delivery at 36 weeks (early)
versus awaiting spontaneous labor (later). Although the study did demonstrate a trend toward
improved outcomes in the earlier group, it was underpowered especially considering that the
mean gestational age for delivery in the early versus later groups differed by only a week
and were 35.8 and 36.7 weeks, respectively. In a recent report by Serra, 13 patients were
delivered electively at 34 weeks and compared to historical controls. The early delivery
group demonstrated shorter time to oral feeds and closure, along with decreased acute and
late complications. This corroborated similar findings by Peiro where 6 patients were
delivered at 34 weeks. In the latter, the morphology of the bowel demonstrated no evidence
of inflammation or thickening, which was uniformly seen in those delivered at term.

As mentioned earlier the hypothesis of improved benefit from early delivery has yet to be
examined in a well designed, adequately powered, randomized clinical trial. The preliminary
data underscore the need for 1) an adequately powered randomized controlled trial, 2)
clearly defined objective outcome measures, and 3) a standardized evidence-based management
protocol to attempt and control varying practices by obstetricians and pediatric surgeons,
which may undoubtedly impact the results.

Fetal gastroschisis is generally diagnosed after 14 weeks gestation via ultrasound. The
subjects will be identified after referral has been made to the Texas Children's Pavilion
for Women Ultrasound unit, Texas Children's Fetal Center, or the Ben Taub Hospital's
Ultrasound unit. The subject population will consist of patients from the investigator or
co-investigators practice.

The patient will be approached by the principal or co-investigators. Informed consent will
be obtained before any study related procedures are done. Risks, benefits, and alternatives
to study participation will be discussed in their entirety and all questions answered.

Standard care presently includes delivery at 38-39 weeks with cesarean delivery reserved for
obstetrical indications. The care under this research protocol will include standard care
(as mentioned above) for the "late" group, versus delivery at 34 weeks (research care) for
the "early" group. Otherwise, the remainder of the care will not differ regardless of the
allocation arm.

The procedure will be as follows:

1. All patients with a suspected diagnosis of fetal gastroschisis will undergo a
comprehensive ultrasound examination to confirm the diagnosis. If confirmed, as part of
routine clinical care, the patient will undergo a Maternal-Fetal Medicine consultation.
After the visit, the patient will be approached regarding participation in this trial.

2. If the patient agrees to participate and meets all inclusion criteria, the patient will
be enrolled into the study and assigned into the "early" or "late" delivery arm. After
informed consent, the patient will be assigned to a study arm using a concealed
envelope, which will be created prior to the start of the study using a randomization
scheme- prepared prior to start of study by non-participating statistician.

3. Antepartum care will be similar for both groups except for timing of delivery. This
will include ultrasound fetal growth evaluations every 3 weeks and a weekly fetal
biophysical profile (antenatal fetal well-being testing) starting at 32 weeks.

4. The early group will undergo induction of labor at 34 weeks with cesarean delivery
reserved for obstetrical indications with two injections of celestone (12mg/kg) prior
to induction.

5. The late group will undergo induction of labor at 38-39 weeks with cesarean delivery
reserved for obstetrical indications.

6. The trial will be conducted in an intent-to-treat fashion. With regards to the
postnatal management of the neonate, the neonate will be evaluated by a neonatologist
and pediatric surgeon immediately after birth. All neonates, regardless of allocation
arm, will undergo routine care including intubation and initiation of total parenteral
nutrition immediately after birth.

With respect to nutritional care, all neonates will be managed per the Texas Children's
Hospital's neonatal intensive care (NICU) feeding protocol, which consists of exclusive
human milk. This is also applicable at Ben Taub General Hospital. Total Parenteral
Nutrition (TPN) will be continued until total oral intake exceeds 100 ml/kg/day.

7. Two teaspoons (10mL) of maternal blood will be collected and will be stored
appropriately.

With respect to surgical care, the neonates will be grouped as simple gastroschisis or
complicated gastroschisis. The latter will consist of cases complicated by perforation or
intestinal atresia.

1. In all cases of simple gastroschisis, where immediate closure is not possible, they
will be placed in a silo with closure within 4 days (day of life 5).

2. In complicated cases with intestinal atresia, a silo closure will be undertaken within
4 days (day of life 5), and the neonates will be returned to the operating room at 6
weeks of life for resection.

3. In complicated cases with perforation, the neonates will be taken immediately to the
operating room for ostomy and/or bowel ligation with closure.

The study will include the following neonatal and pediatric components: 1. In all cases,
neonatal data will be collected during the initial post-delivery stay. This will include the
following variables: a. INITIAL STAY AFTER DELIVERY - length at birth and discharge - weight
at birth and discharge - head circumference at birth and discharge, - enteral feeding data
and parenteral nutrition throughout admission - nutrition related labs - APGAR scores -
medications- lasix, chlorothiazide, dopamine, hydrocortisone and dexamethasone - morbidities
such as necrotizing enterocolitis, patent ductus arteriosus, spontaneous intestinal
perforation, intraventricular hemorrhage, sepsis, and chronic lung disease b. 1 MONTH POST
DELIVERY - length - weight - head circumference - demographic, socioeconomic, and
nutritional information c. 6 MONTHS POST DELIVERY - length - weight - head circumference d.
12 MONTHS POST DELIVERY - length - weight - head circumference e. 18 MONTHS POST DELIVERY -
length - weight - head circumference - the Bayley Scales of Infant Development II by a
certified practitioner Subject participation will be approximately 1 1/2 years.

Inclusion Criteria:

1. Pregnant

2. 16-50 years of age

3. Prenatal diagnosis of fetal gastroschisis

4. Less than 34 weeks and 0 days gestation

Exclusion Criteria:

1. Greater than 34 weeks gestation

2. 2. Fetus with massive gastroschisis defect that is not treatable after delivery