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Coexisting gastrointestinal and hepatobiliary tract anomalies in omphalocele and gastroschisis: A twenty-year experience in a single tertiary medical center
Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei, TaiwanDepartment of Pediatrics, National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan
Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei, TaiwanMacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei, TaiwanMacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei, TaiwanDepartment of Medicine, Mackay Medical College, New Taipei City, Taiwan
Corresponding author. Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei 10449, Taiwan.
Corresponding author. Department of Computer Science and Information Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan.
The Metabolomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, TaiwanGraduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, TaiwanDepartment of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan
Omphalocele and gastroschisis are the two most common congenital abdominal wall defects; however, no previous study has focused on gastrointestinal and hepatobiliary tract malformations in these two conditions. This study aimed to investigate the demographic characteristics, coexisting congenital gastrointestinal and hepatobiliary tract anomalies, hospital course, and outcomes of patients with gastroschisis and omphalocele.
Methods
This is retrospective chart review of all patients admitted to one tertiary medical center in Taiwan between January 1, 2000 and June 30, 2020 with a diagnosis of gastroschisis or omphalocele. The medical records were reviewed to obtain demographic data regarding coexisting gastrointestinal and hepatobiliary tract anomalies and outcomes.
Results
Of the 51 patients included, 21 had gastroschisis and 30 had omphalocele. Gastroschisis was associated with a significantly younger maternal age and a higher incidence of small for gestational age. Of the 30 patients with omphalocele, twelve had associated gastrointestinal and hepatobiliary anomalies. Seven of the 21 patients with gastroschisis had gastrointestinal anomalies, and none had hepatobiliary anomalies. Among the omphalocele patients, three (10%) had documented malrotation, and one developed midgut volvulus. Among gastroschisis patients, four patients (19%) had malrotation, and two developed midgut volvulus. There were no statistically significant differences in postoperative complications or mortality rates between those with and without gastrointestinal/hepatobiliary tract anomalies.
Conclusion
The diversity of coexisting gastrointestinal and hepatobiliary tract anomalies is higher in the omphalocele than in gastroschisis. In addition, we demonstrate that patients with gastroschisis or omphalocele have a higher rate of intestinal malrotation and midgut volvulus.
Omphalocele and gastroschisis are the two most common congenital abdominal wall defects. These two conditions differ widely in their embryopathogenesis, clinical characteristics, and associations with chromosomal abnormalities and other structural anomalies. Omphalocele is a herniation of the abdominal viscera that occurs through a midline abdominal wall defect, with the viscera covered by a membranous sac. Conversely, gastroschisis is a herniation of the bowel without a membranous covering.
The long-term outcomes are related to these anomalies rather than to the abdominal wall defect itself. In addition, mortality among infants with omphalocele is nearly 20% and may be related to the presence or absence of other anomalies.
Previous studies assessed the frequency and types of malformations associated with gastroschisis and omphalocele. However, no previous study has focused on gastrointestinal and hepatobiliary tract malformations in omphalocele and gastroschisis. This study aims to investigate the demographic characteristics, coexisting congenital gastrointestinal and hepatobiliary tract anomalies, hospital course, and outcomes of patients with gastroschisis and omphalocele.
2. Materials and methods
After Institutional Review Board approval (21MMHIS003e) was granted, the charts of all patients with an ICD-9 diagnosis code for congenital anomalies of the abdominal wall (756.7) and an ICD-10 diagnosis code for omphalocele (Q792) and gastroschisis (Q793) were retrospectively reviewed. Patients born between January 1, 2000 and June 30, 2020 at our hospital, a tertiary medical center in Taiwan, were included, and patients without a diagnosis of omphalocele or gastroschisis were excluded. The medical records were reviewed to obtain data on demographic characteristics and coexisting gastrointestinal and hepatobiliary tract anomalies. Outcome measures included length of hospital stay, prolonged parenteral nutrition (PN), complications, and mortality.
3. Statistical analysis
Statistical analyses were performed using the SPSS software package (version 25). Patient factors and outcomes were compared between the omphalocele and gastroschisis groups. An independent sample t-test was used to compare continuous variables. Chi-squared and Fisher's exact tests were applied for the analysis of categorical variables in the univariate analysis. Two-tailed P-values of less than 0.05 were considered to indicate statistically significant differences.
Partial least-squares discriminant analysis (PLS-DA) is a supervised machine learning tool that has recently become widely used in omics research. PLS-DA is a multivariate dimensionality-reduction approach used to transform the data from a high-dimensional space into lower-dimensional space with as few errors as possible. PLS-DA searches for a transformed lower-dimensional space that maximizes the between-class separation and generates the classification model. The generated PLS-DA model can predict the class membership of the samples for classification (e.g., disease classification). In addition, PLS-DA can provide the variable of importance in projection (VIP) to understand the causes of discrimination. The significance in the PLS-DA model means the influence on the model explaining the classification. A higher VIP value of a specific feature means more impact in the model.
Partial least-squares discrimination analysis (PLS-DA) was performed using the mixOmics package (version 6.8.5) with the R language (version 3.6.0). Clinical variables were used to build a prediction model with five components for discriminating patients with omphalocele and gastroschisis. Variable importance in the projection (VIP) coefficients was computed using mixOmics. The VIP coefficients displayed the relative importance of each clinical variable in the prediction model.
4. Results
Of the 55 patients identified using the diagnosis code, three patients had a diagnosis of ventral hernia and were excluded. Of the 52 patients with abdominal wall defects who met the inclusion criteria, 21 (40%) had gastroschisis, and 31 (60%) had omphalocele. One patient with omphalocele was excluded because of an excess of missing data. Table 1 shows the demographic data for the patients with gastroschisis and omphalocele. The diagnosis was made prenatally in 76.2% and 60% of patients with gastroschisis and omphalocele, respectively. Gastroschisis was associated with a significantly younger maternal age and a higher incidence of small for gestational age.
Table 1Demographic data of patients with gastroschisis and omphalocele.
Two missing data points for maternal age in the gastroschisis group and one in the omphalocele group were replaced with the mean. ∗P < 0.05. SGA: small for gestational age.
22 (±2.8)
33 (±6.2)
<0.001∗
Gestational age (weeks)
355
35
0.373
Prematurity
11 (52.4%)
10 (33.3%)
0.249
Birth weight (g) (mean, SD)
2204 (±520)
2649 (±696)
0.017∗
SGA
12 (57.1%)
7 (23.3%)
0.020∗
Male
6 (28.6%)
15 (50%)
0.156
a Two missing data points for maternal age in the gastroschisis group and one in the omphalocele group were replaced with the mean. ∗P < 0.05. SGA: small for gestational age.
Table 2 lists the distribution of gastrointestinal and hepatobiliary tract anomalies associated with omphalocele and gastroschisis. Of the 30 patients with omphalocele, 12 had an associated gastrointestinal or hepatobiliary anomaly. Moreover, seven of the 21 patients with gastroschisis had gastrointestinal anomalies. The coexisting gastrointestinal anomalies varied more widely in the omphalocele group than in the gastroschisis group. Two patients in the omphalocele group presented with coexisting hepatobiliary tract anomalies: multiple liver cysts and biliary atresia.
Table 2Gastrointestinal and hepatobiliary tract anomalies associated with gastroschisis and omphalocele.
In our study, a total of 7 (13.7%) patients had malrotation documented during the primary repair, and three patients developed midgut volvulus. Of the omphalocele patients, three (10%) had documented malrotation, and one developed midgut volvulus; in comparison, four patients (19%) with gastroschisis had documented malrotation, and two developed midgut volvulus. There was no statistically significant difference in the rate of documented malrotation and midgut volvulus between those with gastroschisis and those with omphalocele. Intestinal atresia occurred in two (9.5%) patients in the gastroschisis group and one (3.3%) in the omphalocele group. Meckel's diverticulum occurred in four (13.3%) patients with omphalocele and one (4.8%) with gastroschisis.
Postoperative complications occurred in 43.3% of the patients with omphalocele and 66.7% of those with gastroschisis (Table 3A). In the PLS-DA model, gastroschisis was more often complicated by sepsis, cholestasis, short bowel syndrome, and small bowel perforation (Fig. 1). There was no statistically significant difference in the rate of adhesive bowel obstruction requiring enterolysis between the gastroschisis and omphalocele patients (19.0% vs. 16.7%; P = 1.00). A total of 19 patients (37.3%) had coexisting gastrointestinal or hepatobiliary tract anomalies. There was no statistically significant difference in the rate of postoperative complications between those with and without gastrointestinal/hepatobiliary tract anomalies (44.4% vs. 55.6%; P = 0.260). The outcomes, including hospital stays, prolonged parenteral nutrition duration, and complications, showed no statistically significant differences between the omphalocele and gastroschisis patients (Table 3B). The prolonged parenteral nutrition duration, hospital stay, and postoperative complication showed no statistically significant differences between those with and without gastrointestinal/hepatobiliary tract anomalies (Table 3C). In the omphalocele patients, the mortality rate was 16.7% (n = 5); in the gastroschisis patients, it was 4.8% (n = 1). There was no statistically significant difference in the mortality between those with and without gastrointestinal/hepatobiliary tract anomalies (P = 0.267). Of the six infants who died, four died within 24 h after birth due to extremely low birth weight, severe respiratory distress syndrome, or low Apgar score. One patient died secondary to sepsis at 39 days old, and one patient died secondary to trisomy 13 with multiple anomalies at 27 days old. Only one had associated gastrointestinal/hepatobiliary tract malformations.
Table 3(A) Complications during the postoperative period. (B) Outcomes of omphalocele and gastroschisis. (C) Outcomes of those patients with and without coexisting gastrointestinal/hepatobiliary anomalies.
(A)
Gastroschisis N = 14 (%)
Omphalocele N = 13 (%)
P
Cholestasis
8 (38.1)
5 (16.7)
0.109
Sepsis
9 (42.9)
4 (13.3)
0.024∗
Wound infection
1 (4.8)
1 (3.3)
1.000
Omphalitis
0
1 (3.3)
1.000
Short bowel syndrome
3 (14.3)
0
0.064
Small bowel perforation
3 (14.3)
0
0.064
Gastrointestinal bleeding
3 (14.3)
7 (23.3)
0.495
GERD need fundoplication
0
3 (10.0)
0.259
Adhesion ileus requiring enterolysis
4 (19.0)
5 (16.7)
1.000
Ventral hernia requiring repair
3 (14.3)
4 (13.3)
1.000
Umbilical hernia requiring repair
0
1 (3.3)
1.000
(B)
Gastroschisis (N = 21)
Omphalocele (N = 30)
P
PN duration (days) (mean, SD)
47.4 (±50.2)
36.1 (±60.6)
0.487
Prolonged PN (>4 weeks)
8 (26.7%)
11 (37.3%)
0.082
Hospital stay (days) (mean, SD)
66.7 (±59.3)
51.0 (±67.3)
0.395
Complications
14 (66.7%)
13 (43.3%)
0.100
Mortality
1 (4.8%)
5 (16.7%)
0.381
(C)
With coexistence (N = 19)
Without coexistence (N = 32)
P
PN duration (days) (mean, SD)
56.2 (±64.3)
31.6 (±49.8)
0.163
Prolonged PN (>4 weeks)
8 (42.1)
11 (34.4%)
0.581
Hospital stay (days) (mean, SD)
81.4 (±74.1)
43.2 (±53.5)
0.06
Complications
12 (63.2%)
15 (46.9%)
0.260
Mortality
1 (5.3%)
5 (15.6%)
0.267
aP <0.05, GERD: gastroesophageal reflux disease, PN: parenteral nutrition.
Figure 1Comparison of clinical variables in the omphalocele and gastroschisis patients using A) the PLS-DA score plot (PLS-1 explained variances: 10%; PLS-2 explained variances: 10%) and B) important variables identified on PLS-1. X-axis: VIP scores corresponding to each variable on the Y-axis. Variables with higher VIP scores are the contributory variables for omphalocele and gastroschisis discrimination in the PLS-DA model (AUC = 0.95).
Omphalocele and gastroschisis are rare diseases with an incidence of approximately 1 per 4000 to 1 per 6000 live births and nearly 2 to 5 per 10,000 live births, respectively.
Previous reports have noted that omphalocele and gastroschisis are frequently associated with other congenital malformations. The frequency of associated malformations for omphalocele ranges from 27% to 63%; for gastroschisis, it ranges from 5% to 27%.
Coexisting anomalies affect the musculoskeletal, cardiac, urogenital, central nervous system, digestive, and pulmonary systems. In our study, the frequency of alimentary tract abnormalities associated with omphalocele was 40.0%, slightly higher than those in previous reports, which ranged from 9% to 33%.
Omphalocele and gastroschisis: prenatal diagnosis and peripartal management. A case analysis of the years 1989-1997 at the Department of Obstetrics and Gynecology, University of Homburg/Saar.
The frequency of gastrointestinal tract malformations associated with gastroschisis was 33.3%, which was also slightly higher than those reported in previous population-based studies, which the varied between 8% and 28%.
Hepatobiliary tract anomalies were observed in only the omphalocele group in our study. We presume that hepatobiliary tract anomalies were observed in only the omphalocele group because of the difference in embryopathogenesis between omphalocele and gastroschisis. Normal ventral body wall closure is completed by the 5th week of development. After ventral body wall closure, the primary intestinal loop rapidly becomes elongated. The midgut normally prolapses into the umbilical cord by approximately the 5th week of development. It returns to the abdominal cavity between the 10th week of development and the end of the first trimester.
Many theories about the embryopathogenesis of gastroschisis have been proposed, but none are consistent with clinical observations. One hypothesis is the failure of the mesoderm to form in the body wall. It is assumed that gastroschisis results from abnormal closure of the body, of early-onset, due to failure of the right lateral fold to move far enough ventrally to meet its counterpart in the middle.
During physiological umbilical herniation, the midgut grows into the open space and elongates outside of the abdominal cavity in a patient with gastroschisis.
In contrast, the embryopathogenesis of omphalocele occurs when the intestines fail to return to the abdominal cavity after normal physiological herniation into the umbilical cord during weeks 6–10 of development.
The liver primordium appears in the middle of the third week as an outgrowth of the endodermal epithelium at the distal end of the foregut. During the next few weeks, the liver bud grows within the ventral mesentery and retains a connection with the foregut that will become the bile duct. A cranial part of the liver bud will form the liver, and a caudal bud will form the gallbladder and cystic duct.
By approximately the 12th week, the gallbladder and cystic duct have developed. The cystic duct joins the hepatic duct to form the bile duct. We noted that because of the difference in embryopathogenesis, there was greater diversity in the coexisting gastrointestinal and hepatobiliary tract anomalies in the omphalocele group than in the gastroschisis group in our study.
In our study, documented malrotation rates during primary repair and midgut volvulus were markedly increased in both omphalocele and gastroschisis patients; thus, Ladd's procedure should be considered if malrotation is noted during surgery for congenital abdominal wall defects. Patients with abdominal wall defects have undergone a disruption in embryologic rotation events, which results in malrotation of the intestine with potential for midgut volvulus. Intestinal rotation abnormalities are present in both omphalocele and gastroschisis. Abnormal bowel rotation and fixation may lead to midgut volvulus, a catastrophic event associated with mortality and severe morbidities, including bowel necrosis and short bowel syndrome. However, in the published literature, malrotation and midgut volvulus with omphalocele or gastroschisis have rarely been described. The incidences of malrotation and midgut volvulus in patients with gastroschisis and omphalocele are unclear. Our study observed that the rates of documented malrotation and midgut volvulus were higher than those in the general population.
The percentage of malrotation in the general population is 0.2–1%.
A previous multi-institutional study revealed that 1% and 4.4% of patients with gastroschisis and omphalocele, respectively, developed midgut volvulus.
In our study, documented malrotation was noted in 19% of patients with gastroschisis, and 5.9% of patients developed midgut volvulus. Among the omphalocele patients, the frequency of documented malrotation was 10%, and 3.3% developed midgut volvulus. Thus, the rate of midgut volvulus is approximately 55–98 times higher than the highest estimate for the general population. In addition, we found that midgut volvulus occurred more frequently in patients with gastroschisis. The width of the mesenteric base is one of the risk factors for midgut volvulus.
The impaired mesenteric flow in gastroschisis was first emphasized by Rickam in 1963, and Shaw also mentioned bowel lesions with some degree of constriction of the loops at the ring.
We thought there was a higher incidence of midgut volvulus in the gastroschisis group because of the narrow mesenteric root. A Ladd procedure should be considered for patients with narrow mesenteric roots.
Meckel's diverticulum results from incomplete regression of the omphalomesenteric duct. In the general population, the prevalence of Meckel's diverticulum has been estimated to be approximately 1–4%.
Our study showed that Meckel's diverticulum occurred in 4.8% of those with gastroschisis and was nearly three times more frequent in those with omphalocele, with a rate of 13.3%. This rate is approximately 3–4 times higher than that of the general public. Our findings were similar to a previous report to the effect that Meckel's diverticulum was present in 8 out of 49 (16%) cases of omphalocele.
In this study, we found no statistically significant difference in the outcome, including hospital stay, prolonged parenteral nutrition duration, postoperative complications, and mortality between those with and without gastrointestinal/hepatobiliary tract anomalies. Mortality is associated with extremely low birth weight, severe respiratory distress syndrome, and a low Apgar score. Only one death case had associated gastrointestinal/hepatobiliary tract malformations. We presumed that patient outcomes and mortality rates might not be affected by coexisting gastrointestinal/hepatobiliary anomalies. However, patients with gastroschisis or omphalocele had a higher rate of intestinal malrotation, midgut volvulus, and Meckel's diverticulum than the general population. We need to pay more attention to the risk of midgut volvulus and Meckel's diverticulum in those patients with a medical history of gastroschisis or omphalocele.
The greatest strength of our work is that it provides a new perspective on gastroschisis and omphalocele in the gastrointestinal and hepatobiliary areas. However, there were limitations. The first limitation is its retrospective design. Second, the sample size was small because these two diseases are rare congenital disabilities. However, most patients are referred to our center, as one of the largest tertiary centers in our area, for further management. A multicenter registry study could increase the sample size and reflect the real-world situation.
In conclusion, the diversity of coexisting gastrointestinal and hepatobiliary tract anomalies was higher in the omphalocele group than in the gastroschisis group. In addition, we demonstrated that patients with gastroschisis or omphalocele had a higher rate of intestinal malrotation, midgut volvulus, and Meckel's diverticulum than the general population. Therefore, the risk of volvulus should be evaluated and treated with caution when a patient has abdominal wall defects.
Conflicts of interest statement and funding statement
This study was funded by the Ministry of Science and Technology, Taiwan, grant numbers MOST (109-2823-8-002-010-CV) and MOST (109-2320-B-002-040-); National Taiwan University, Taiwan, grant numbers NTU-CC-110L890803 and NTU-110L8809; Taiwan Food and Drug Administration, Taiwan, MOHW (110-FDA-D-114-000611). This study was performed using computing resources at the Laboratory of Computational Molecular Design and Metabolomics (CMDM), the Department of Computer Science and Information Engineering (CSIE), and the Graduate Institute of Biomedical Electronics and Bioinformatics (BEBI) from the National Taiwan University. The authors declare no conflicts of interest. The data used to support the findings of this study are included in the article.
Acknowledgment
This research was supported by MacKay Children's Hospital and the Department of Pediatric Gastroenterology, Hepatology, and Nutrition. We thank our colleagues from the Department of Pediatric Gastroenterology, Hepatology, and Nutrition, MacKay Children's Hospital, who provided expertise that greatly assisted the research.
Omphalocele and gastroschisis: prenatal diagnosis and peripartal management. A case analysis of the years 1989-1997 at the Department of Obstetrics and Gynecology, University of Homburg/Saar.
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