Comparison of outcomes of infants with giant omphaloceles over two decades

Abstract

BACKGROUND:

The purpose of this study was to compare the outcomes of infants with giant omphalocele (GO) born in two different epochs over two decades at a single institution. Specifically, it examined whether the utilization of selective pulmonary vasodilators and extracorporeal membrane oxygenator (ECMO) in the management of pulmonary hypertension in the second epoch were associated with improved outcomes.

METHODS:

The medical records of all patients diagnosed with GO at a large children’s hospital from January 1, 1996 to December 31, 2016 were reviewed and divided into two epochs. Patients were classified as having an isolated GO or GO with minor or major associated anomalies. GO was defined as a defect more than or equal to 5 cm in size and/or liver in the sac.

RESULTS:

During the study period, 59 infants with GO were identified. The duration of invasive mechanical ventilation was significantly shorter among the survivors from the second epoch (p = 0.03), with none greater than seven days. There were no significant differences in the outcomes of survival to NICU discharge and length of stay (LOS) between infants in the two epochs.

CONCLUSIONS:

Infants with GO who required invasive mechanical ventilation for more than seven days did not survive in the second epoch. Survival did not improve with use of selective pulmonary vasodilators and ECMO. This information could be shared with families during prenatal and postnatal counselling to facilitate informed decision making regarding goals of care.

Keywords

Giant omphalocele outcomes mechanical ventilation pulmonary vasodilators extracorporeal membrane oxygenator (ECMO)

1 Background

Omphalocele is a midline ventral abdominal wall defect in which herniated abdominal viscera are extruded into a sac that is continuous with the umbilical cord. It is one of the most common congenital abdominal wall defects, with a prevalence of approximately 1 in 4000–7000 live birth [1]. This defect is often associated with other minor or major anomalies and/or genetic abnormalities [2]. It can be divided into three categories: giant, small and ruptured, based on the contents and integrity of the sac. While multiple definitions exist for these categories, in this study, giant omphalocele (GO) was defined as a defect more than or equal to 5 cm in size and/or liver in the sac.

The goal in the management of GO is initial medical stabilization of the infant with supportive care, followed ultimately by reduction of abdominal contents and closure of the midline ventral abdominal wall defect. The physiology of infants with this defect uniquely complicates this management, because they are prone to respiratory insufficiency, the etiology of which is likely multifactorial. Respiratory failure in these infants has previously been ascribed to increased intra-abdominal pressure caused by reduction of abdominal viscera [3]. However, even with improved surgical techniques to minimize this effect, there is a subset of patients that continues to have severe and/or prolonged respiratory insufficiency, even pre-operatively. Thus, pulmonary maldevelopment, including chest wall deformities, pulmonary hypoplasia and associated abnormal pulmonary vasculature likely is a major cause of morbidity and mortality in these infants [4, 5]. Partridge et al. found that pulmonary hypertension was observed in 37% of infants with GO and represented a significant complication of GO [6].

Within the last several decades, selective pulmonary vasodilators and extracorporeal membrane oxygenation (ECMO) have been employed in the medical management of pulmonary hypertension in infants with GO, with the ultimate goal of improving outcomes. However, at this time, the association between these treatments and improved outcomes has not been subjected to rigorous scientific evaluation. The purpose of this study was to compare the outcomes of infants with giant omphalocele (GO) born in two different epochs over two decades at our institution. Selective pulmonary vasodilators, specifically nitric oxide, and ECMO were not offered in the management of pulmonary hypertension in the first epoch, whereas they were in the second epoch, offering the opportunity for comparison of associated outcomes.

2 Methods

2.1 Study design

This is a retrospective cohort study, approved by the Human Research Protection Office at the Washington University School of Medicine.

2.2 Patient population

The medical records of all infants admitted to the neonatal intensive care unit (NICU) at St. Louis Children’s Hospital with a diagnosis of GO between January 1, 1996 and December 31, 2016 were reviewed. This group of 59 infants was divided into two epochs, with the first ending on December 31, 2005 and the second starting on January 1, 2006. As stated above, GO was defined as a defect more than or equal to five cms in size and/or liver in the sac.

2.3 Postnatal outcomes

Data collected included: demographic data including gestational age, birth weight, prenatal diagnosis, site of birth, associated minor/major anomalies and genetic abnormalities; treatment for pulmonary hypertension with selective pulmonary vasodilators and ECMO; outcomes including duration of mechanical invasive ventilation, survival to discharge from NICU, length of stay (LOS). We also collected developmental outcomes and autopsy findings, when available.

Major anomalies were defined as cardiac, genitourinary, or ano- rectal defects requiring immediate medical or surgical management, Bochdalek-type congenital diaphragmatic hernia, alveolar-capillary dysplasia, or chromosomal aneuploidy or duplication. All other anomalies were classified as minor. Classification based on Akinkuotu et al. [7].

2.4 Statistical analysis

Statistical analysis was performed using Student t-test and Mann-Whitney U tests for parametric and nonparametric continuous variables, respectively. Chi-square analysis was used for categorical variables. A P value of <0.05 was considered statistically significant.

3 Results

During the study period, 59 infants with GO were identified. There were no significant differences between demographics of infants in the two epochs (Table 1). Treatments for pulmonary hypertension, specifically nitric oxide (iNO) and ECMO, were only used in the second epoch. Within this group, 21 infants were diagnosed with pulmonary hypertension. No survivors received these treatments, while eight non-survivors received iNO, of which one was also placed on ECMO. In terms of the diagnosis of pulmonary hypertension, there was significant heterogeneity in the echocardiogram quality and information contained in read. Of the seven of eight non-survivors who were diagnosed based on echocardiogram, the only consistent finding was a flattened intraventricular septum. Each additionally had one or more of the following right sided changes: elevated right ventricular pressure, right ventricular dilation, right atrial dilation, decreased right ventricular function. None had right ventricular hypertrophy.

Table 1
Demographics and outcomes

Survivors Non-Survivors

Epoch 1 Epoch 2 p value Epoch 1 Epoch 2 p value

Total number 18/27 17/32 0.42 9/27 15/32 0.4

Inborn 14 15 0.6 7 11 0.6

Prenatal diagnoses 16 16 1.0 7 14 1.00

Birth weight (grams) 2830 (806) 2896 (566) 0.785 2206 (940) 2437 (701) 0.49

Gestational age (weeks) 36.3 (2.59) 36.8 (1.5) 0.45 34.2 (5.4) 34.8 (3.3) 0.72

Duration of invasive mechanical ventilation days 28 (35) 1.6 (2.6) 0.003 106 (106) 46 (82.4) 0.1

LOS (days) 27.5 (7.2) 39.9 (24.7) 0.32 81.8 (94.8) 57.5 (95.4) 0.70

	Survivors		Non-Survivors
Total number	18/27	17/32	0.42	9/27	15/32	0.4
Inborn	14	15	0.6	7	11	0.6
Prenatal diagnoses	16	16	1.0	7	14	1.00
Birth weight (grams)	2830 (806)	2896 (566)	0.785	2206 (940)	2437 (701)	0.49
Gestational age (weeks)	36.3 (2.59)	36.8 (1.5)	0.45	34.2 (5.4)	34.8 (3.3)	0.72
Duration of invasive mechanical ventilation days	28 (35)	1.6 (2.6)	0.003	106 (106)	46 (82.4)	0.1
LOS (days)	27.5 (7.2)	39.9 (24.7)	0.32	81.8 (94.8)	57.5 (95.4)	0.70

Values in Mean (SD).

The duration of invasive mechanical ventilation was significantly shorter among the survivors from the second epoch (p = 0.03), with none greater than seven days. There were no significant differences between the two epochs in the outcomes of survival to NICU discharge and LOS (Table 1). There were no significant differences in prevalence of associated major anomalies between the two epochs, nor between survivors and non-survivors (Table 2).

Table 2

Overview and details of associated major anomalies

	Survivors			Non-Survivors
	Epoch 1	Epoch 2	p value	Epoch 1	Epoch 2	p value
Associated anomalies with complex heart defects	3	2	1.0	0	2	1.0
	1) TGV,VSD, pulmonary atresia	1) DORV, meningo-myelocele		1) HLHS, Dandy Walker, CHARGE syndrome
	2) HRHS, Robinow syndrome	2) TOF, duodenal web		2) TOF, extrophy, myelo-cystocele
	3) Hypoplastic aortic arch, VSD
Associated anomalies without complex heart defects	2	2	1.0	1	1	1.0
	1) CDH	1) Meningo-myelocele		1) TEF	1) CDH
	2) CCAM, dextrocardia	2) Apert’s syndrome, long QT
Beckwith Wiedemann syndrome	1	1		0	3	1.0
Trisomy 13	1	1		0	0	1.0
Total	7	6		1	6

TGV = Transposition of great vessels; VSD = Ventricular Septal Defect; HRHS = Hypoplastic Right Heart Syndrome; HLHS = Hypoplastic Left Heart Syndrome; DORV = Double Outlet Right Ventricle; TOF = Tetralogy of Fallot; TEF = Tracheo-Esophageal Fistula; CDH = Congenital Diaphragmatic Hernia; CCAM = Congenital Cystic Adenomatous Malformation; CHARGE = Coloboma, Heart Defect, Atresia of choanae, Retardation of growth, Genitourinary anomalies and Ear abnormalities.

Autopsies were performed on 5 out of 9 (56%) non-survivors in epoch one and four out of 15 (27%) in epoch 2. Of these, all had pulmonary pathology including: pulmonary hypertension, pulmonary hypoplasia, pulmonary hemorrhage, pneumonia, and bronchopulmonary dysplasia (BPD).

Developmental testing was performed on more infants from the second epoch, but the overall numbers were low to compare them statistically. Of the survivors in epoch one, none were evaluated using Denver II and 1/18 (5%) were evaluated using BSID. In epoch two, 4/17 (23%) were evaluated using Denver II and 5/17 (29%) were evaluated using BSID.

4 Discussion

In this study, we compared the outcomes of infants diagnosed with GO between two epochs over two decades at our institution, in which selective pulmonary vasodilators and ECMO were only used in the second epoch. The strengths of our study are the large sample size and the unique comparison of outcomes between two epochs over two decades with different utilization rates of therapies for pulmonary hypertension. Most importantly, the findings of this study add to the current body of literature regarding the management of infants with GO because it examined whether treatment for pulmonary hypertension was associated with improved outcomes. The results suggest that it is not. There was no difference in the survival between the two epochs despite use of nitric oxide and ECMO in the second epoch. In fact, all infants who received treatment for pulmonary hypertension were ultimately non-survivors.

All survivors in the second epoch were invasively mechanically ventilated for less than a week. These findings suggest that survival of an infant with GO depends on the underlying pulmonary maldevelopment, and hence, the resultant pulmonary compliance and the associated pulmonary hypertension. The shorter duration of invasive mechanical ventilation in the survivors from the second epoch suggests that they had minimal to no pulmonary dysfunction. Although small in number, the data available from autopsies of non-survivors with GO confirmed the lung pathology found in prior studies [5].

There was no increase in the diagnosis of genetic abnormalities in the second epoch despite the routine evaluation of all infants with a congenital anomaly with a chromosomal microarray analysis (CMA). The overall survival in our entire cohort was 60%, and of those, 33% had major anomalies. Akinkuotu et al. [7] describes outcomes of infants with omphaloceles over an eleven year period, which includes a smaller cohort with GO (40 compared to our 59). The overall survival in their cohort was 80%, and of those, 50% had major anomalies.

All infants in our cohort had their abdominal wall closed more than 3 hours after birth. By definition this qualifies as delayed closure [8], and hence, we could not compare outcomes based on the timing of the closure of the abdominal wall. Moreover, 20 babies in our study did not undergo any abdominal wall closure prior to death.

The limitations of the study are its retrospective nature, lack of prenatal data, and limited long-term follow up data. Prior studies have found neurological impairments in more than half of GO survivors and increased likelihood of gross motor defects [9, 10]. However, there remains a dearth of longitudinal information regarding neurodevelopmental outcomes in survivors with GO. Additionally, there is a lack of agreement on the on the definition of GO. For the purposes of this study, we defined GO as a defect of >5 cm, whereas others define it as a defect of >6 cm. Akinkuotu et al. defined GO as >50% of the liver in the sac [7]. However, most resources define it by the presence of liver within the sac. Thus, this makes comparisons of outcomes across cohorts from different institutions difficult.

In conclusion, our study reveals that infants with GO who were invasively mechanically ventilated for over a week did not survive. Survival did not improve despite use of treatments targeting pulmonary hypertension, specifically selective pulmonary vasodilators and ECMO. This information could be shared with families during prenatal counselling and during hospitalization to guide goals of care decisions when an infant with GO cannot be extubated after a certain period of time.

Financial disclosure statement

The authors have no potential or actual financial interests to disclose.

Human research statement

The authors affirm that research was approved by Human Research Protection Office the Institutional Review Board at the Washington University School of Medicine.

References

Tassin

, Descriaud

, Elie

, Houfflin Debarge

, Dumez

, Perrotin

, et al. Omphalocele in the first trimester: prediction of perinatal outcome. Prenat Diagn. 2013;33(5):497–501.

Calvert

, Damiani

, Sunario

, Bower

, Dickinson

. The outcomes of pregnancies following a prenatal diagnosis of fetal exomphalos in Western Australia. Aust N Z J Obstet Gynaecol. 2009;49(4):371–5.

Schwaitzberg

, Pokorny

, McGill

, Harberg

. Gastroschisis and omphalocele. Am J Surg. 1982;144(6):650–4.

Hershenson

, Brouillette

, Klemka

, Raffensperger

, Poznanski

, Hunt

. Respiratory insufficiency in newborns with abdominal wall defects. J Pediatr Surg. 1985;20(4):348–53.

Argyle

. Pulmonary hypoplasia in infants with giant abdominal wall defects. Pediatr Pathol. 1989;9(1):43–55.

Partridge

, Hanna

, Panitch

, Rintoul

, Peranteau

, Flake

, et al. Pulmonary hypertension in giant omphalocele infants. J Pediatr Surg. 2014;49(12):1767–70.

Akinkuotu

, Sheikh

, Olutoye

, Lee

, Fernandes

, Welty

, et al. Giant omphaloceles: surgical management and perinatal outcomes. J Surg Res. 2015;198(2):388–92.

, Liu

, Cui

, Zhang

, Yin

, Li

. Immediate repair compared with delayed repair of congenital omphalocele: short-term neonatal outcomes in China. J Int Med Res. 2011;39(6):2344–51.

Hijkoop

, Peters

NCJ

, Lechner

, van Bever

, van Gils-Frijters

, Tibboel

, et al. Omphalocele: from diagnosis to growth and development at 2 years of age. Arch Dis Child Fetal Neonatal Ed. 2019;104(1):F18–F23.

10.

Danzer

, Gerdes

, D’Agostino

, Bernbaum

, Hoffman

, Rintoul

, et al. Patient characteristics are important determinants of neurodevelopmental outcome during infancy in giant omphalocele. Early Hum Dev. 2015;91(3):187–93.