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Jejunoileal atresia and associated malformations: Correlation with the timing of in utero insult
Jejunoileal Atresia and Associated Malformations: Correlation With the Timing of In Utero Insult By Brian Sweeney, Rajendra Surana, and Prem Puri Dublin, Ireland
Purpose: Duodenal atresia is associated with a higher incidence of associated congenital malformations than jejunoileal atresia, supporting the hypothesis that the duodenal obstruction occurs early in fetal life. In this study, the authors analyzed the incidence of major associated malformations in jejunal atresia (JA) and ileal atresia (IA) to determine if there is a positive correlation between the proximity of the intestinal atresia and the association of other major anomalies. Methods: Records of all patients with jejunoileal atresias treated at the authors’ institution between 1980 and 1997 were examined. Results: There were 83 patients with jejunoileal atresias, 38 with JA, and 45 with IA. Sixteen (42%) of the JA patients had an associated major congenital malformation, whereas only 1 (2%) of the IA patients had an associated malformation. A
T
HE MIDGUT is the portion of the intestine supplied by the mesenteric artery and extends from the duodenum to the midtransverse colon.1 An ischemic insult to the developing midgut at some stage during fetal development is widely accepted to result in jejunoileal atresia (JA).2 Other organ anomalies associated with jejunoileal atresia are reported to be rare.1 Jejunoileal atresias have been reported in association with gastroschisis, but these are thought to result from mechanical injury caused by exposure of the bowel to amniotic fluid or pressure on the intestine from the edge of the abdominal wall defect.3 In contrast, duodenal atresia, which is considered to be a primary malformation, is believed to result from failure of recanalization during the first trimester.1,4,5 The frequent coexistence of associated anomalies in other organ systems in patients with duodenal atresia supports the hypothesis of an early intrauterine From the Children’s Research Centre, Our Lady’s Hospital for Sick Children, Dublin, Ireland. Presented at the 32nd Annual Meeting of the Canadian Association of Paediatric Surgeons, Chaˆteau Montebello, Quebec, Canada, September 15-18, 2000. Address reprint requests to Prem Puri, MS, FRCS, FRCS (Ed), FACS, Director of Research, Children’s Research Centre, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3605-0024$35.00/0 doi:10.1053/jpsu.2001.22958
774
single atresia was found in 18 (47%) of JA patients and 41 (91%) of IA patients. Twenty (53%) of the JA patients had either multiple or apple-peel atresia. Thirteen patients (16%) died, 11 with JA, and 2 with IA. Of the 11 patients with JA who died, 6 had multiple atresias, 4 had cystic fibrosis, and 1 had small bowel volvulus.
Conclusion: The higher incidence of associated major congenital extraintestinal malformations in JA compared with IA patients suggests that some cases of JA may arise from a malformative process. J Pediatr Surg 36:774-776. Copyright © 2001 by W.B. Saunders Company. INDEX WORDS: Jejunoileal atresia, duodenal atresia, associated malformations, in utero insult.
insult accounting for this condition.6 We reviewed our experience of jejunoileal atresia to determine if the proximity of the jejunoileal atresia correlated with the likelihood of having another associated congenital anomaly and, thus, gain additional insight into the timing of the intrauterine insult or insults that may produce this form of atresia. MATERIALS AND METHODS The medical records of all patients with jejunoileal atresia treated at our hospital between January 1980 and December 1997 were reviewed. Information was recorded regarding the anatomic location and the number of atresias in each patient. Any associated intestinal or extraintestinal malformations were recorded. Those cases of hereditary multiple atresias were excluded from the study. The form of surgical treatment, morbidity, and mortality also were documented.
RESULTS
There were 83 patients with jejunoileal atresia treated during the period of study. Thirty-eight (46%) had jejunal atresia, and 45 (54%) had ileal atresia (IA). Sixteen (42%) of the JA patients weighed were premature (gestational age, less than 36 weeks) and 10 (22%) of the IA patients were premature. Eighteen (47%) of the JA patients weighed less than 2.5 kg at birth, whereas only 9 (20%) of the IA patients weighed less than 2.5 kg at birth. Associated congenital anomalies were found in 27 patients; 26 had jejunal atresia, and 1 had ileal atresia (Table 1). Various associated anomalies or genetic de-
Journal of Pediatric Surgery, Vol 36, No 5 (May), 2001: pp 774-776
JEJUNOILEAL ATRESIA
775
Table 1. Jejunoileal Atresias and Associated Anomalies
Jejunal atresia (n ⫽ 38)
Ileal atresia (n ⫽ 45)
Anomaly
No. of Patients
Cystic fibrosis Malrotation Congenital heart disease Down’s syndrome (trisomy 21) Congenital dislocation of hips Anorectal and vertebral anomalies Neural tube defect Microcephaly
10 7 4 1 1 1 1 1
Vesicoureteric reflux
1
NOTE. This table indicates the type and number of intestinal and extraintestinal anomalies associated with jejunoileal atresia in our series of patients.
fects in JA patients included cystic fibrosis, malrotation, congenital heart disease, and Down’s syndrome. A single atresia was found in 18 (47%) JA patients and 41 (91%) IA patients. The remaining 24 patients had multiple or apple peel atresia. A resection and primary anastomosis was performed in 26 (68%) JA and 40 (89%) IA patients. Postoperative complications occurred in 22 (58%) of JA and 10 (22%) IA patients and included necrotising enterocolitis in 4, lactose intolerance in 2, septicaemia in 10, pneumonia in 3, adhesive obstruction in 9, anastomotic leak in 1, anastomotic stricture in 1, and stomal prolapse in 1. The morbidity rate was higher in patients with JA 22 of 38 as compared with IA 9 of 45 (P ⬍ .05). Deaths occurred in 13 (11 JA and 2 IA). Seven of them had multiple atresia, and 4 had cystic fibrosis. DISCUSSION
There is compelling evidence in the literature that a late intrauterine mesenteric vascular accident results in jejunoileal atresia.7,8 Pathogenetic mechanisms that can cause this vascular disruption of the blood supply include abnormalities in either the formation or normal resorption of fetal blood vessels during development, compression or twisting of the mesenteric vessels as a result of a volvulus, or the release of emboli through placental vascular connections from a deceased monozygotic twin.5 The vascular insult also can be secondary to other lesions
affecting the alimentary tract such as cystic fibrosis, intussusception, and gastroschisis.2,3 In the current study, there was a significantly higher incidence of associated anomalies in JA patients compared with IA patients. The presence of cystic fibrosis (meconeum ileus) in 10 patients and malrotation in 7 of the JA group would suggest that intestinal ischemia was the cause of the jejunal atresia in these patients. However, a definite subgroup of 9 patients emerged in our analysis of JA patients who had extra intestinal malformations in association with their atresia. These 9 patients had a range of neural, skeletal, cardiac, and syndromic abnormalities (Table 1). It would appear that these patients were subjected to an early in utero insult that interfered with embryogenesis resulting in malformations of multiple organ systems including the jejunum. Interestingly, Diez-Pardo et al9 have described an Adriamycin rat model of congenital intestinal atresia. Adriamycin was administered on day 6 through 9 of gestation, and the subsequent fetuses were delivered at term minus 1 day. At a dose of 2 mg/kg, 53% of the fetuses had small bowel atresia, and 47% had duodenal atresia compared with no atresias in controls. The mechanism whereby Adriamycin produced these results is unclear, but it has been shown to produce cytogenetic abnormalities in cultured human lymphocytes.10 This work has been extended in our laboratory.11 The Adriamycin rat model was used to produce multiple gastrointestinal atresias, and these were examined histopathologically. Ninety percent of the atresias were in the form of multiple blind-ending atresias or sausagelike multiple atresias that resembled human nonhereditary atresias. There was no evidence of atresia caused by vascular insult, and it appears likely that in this model the atresias were the result of a malformative process. The high incidence of associated extra intestinal anomalies in our series of JA patients compared with the IA group suggests that JA may occur earlier than IA in utero. Although the majority of cases JA arise from a vascular insult, there appears to be an important subgroup of JA patients, based on our study and emerging animal models, whereby a malformative process accounts for the development of this form of bowel obstruction.
REFERENCES 1. Skandalakis JE, Gray SW, Ricketts R, et al: The small intestines, in Skandalakis JE, Gray SW (eds): Embryology for Surgeons. Baltimore, MD, Williams & Wilkins, 1994, pp 184-241 2. Nixon HH, Tawes R: Etiology and treatment of small intestinal atresia: Analysis of a series of 127 jejunoileal atresias and comparison with 62 duodenal atresias. Surgery 69:41-51, 1970 3. Gornall P: Management of intestinal atresia complicating gastroschisis. J Pediatr Surg 24:522-524, 1989 4. Weber DM, Freeman NV: Duodenojejunal atresia with apple peel configuration of the ileum and absent superior mesenteric ar-
tery: Observations on pathogenesis. J Pediatr Surg 34:1427-1429, 1999 5. Cragan JD, Martin ML, Moore CA, et al: Descriptive epidemiology of small intestinal atresia, Atlanta, Georgia. Teratology 48:441450, 1993 6. Rescorla FJ, Grosfeld JL: Intestinal atresia and stenosis: Analysis of survival in 120 cases. Surgery 98:668-676, 1985 7. Grosfeld JL, Ballantine TVN, Shoemaker R: Operative management of intestinal atresia and stenosis based on pathological findings. J Pediatr Surg 14:368-375, 1979
776
8. Dalla Vecchia LK, Grosfeld JL, West K, et al: Intestinal atresia and stenosis. A 25-year experience with 277 cases. Arch Surg 133: 490-497, 1998 9. Diez-Pardo JA, Baoquan Q, Navarro C: A new rodent experimental model of esophageal atresia and tracheoesophageal fistula: Preliminary report. J Pediatr Surg 31:498-502, 1996
SWEENEY, SURANA, AND PURI
10. Vig BK: Chromosome aberrations induced in human leucocytes by the antileukemic antibiotic adriamycin. Cancer Res 31:32-38, 1971 11. Fourcade L, Miyazaki E, Shima H, et al: Multiple gastrointestinal atresias result from disturbed morphogenesis. Presented at the 30th Annual Meeting of the American Pediatric Surgical Association, Rancho Mirage, California May 16-19, 1999
Purpose: Duodenal atresia is associated with a higher incidence of associated congenital malformations than jejunoileal atresia, supporting the hypothesis that the duodenal obstruction occurs early in fetal life. In this study, the authors analyzed the incidence of major associated malformations in jejunal atresia (JA) and ileal atresia (IA) to determine if there is a positive correlation between the proximity of the intestinal atresia and the association of other major anomalies. Methods: Records of all patients with jejunoileal atresias treated at the authors’ institution between 1980 and 1997 were examined. Results: There were 83 patients with jejunoileal atresias, 38 with JA, and 45 with IA. Sixteen (42%) of the JA patients had an associated major congenital malformation, whereas only 1 (2%) of the IA patients had an associated malformation. A
T
HE MIDGUT is the portion of the intestine supplied by the mesenteric artery and extends from the duodenum to the midtransverse colon.1 An ischemic insult to the developing midgut at some stage during fetal development is widely accepted to result in jejunoileal atresia (JA).2 Other organ anomalies associated with jejunoileal atresia are reported to be rare.1 Jejunoileal atresias have been reported in association with gastroschisis, but these are thought to result from mechanical injury caused by exposure of the bowel to amniotic fluid or pressure on the intestine from the edge of the abdominal wall defect.3 In contrast, duodenal atresia, which is considered to be a primary malformation, is believed to result from failure of recanalization during the first trimester.1,4,5 The frequent coexistence of associated anomalies in other organ systems in patients with duodenal atresia supports the hypothesis of an early intrauterine From the Children’s Research Centre, Our Lady’s Hospital for Sick Children, Dublin, Ireland. Presented at the 32nd Annual Meeting of the Canadian Association of Paediatric Surgeons, Chaˆteau Montebello, Quebec, Canada, September 15-18, 2000. Address reprint requests to Prem Puri, MS, FRCS, FRCS (Ed), FACS, Director of Research, Children’s Research Centre, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3605-0024$35.00/0 doi:10.1053/jpsu.2001.22958
774
single atresia was found in 18 (47%) of JA patients and 41 (91%) of IA patients. Twenty (53%) of the JA patients had either multiple or apple-peel atresia. Thirteen patients (16%) died, 11 with JA, and 2 with IA. Of the 11 patients with JA who died, 6 had multiple atresias, 4 had cystic fibrosis, and 1 had small bowel volvulus.
Conclusion: The higher incidence of associated major congenital extraintestinal malformations in JA compared with IA patients suggests that some cases of JA may arise from a malformative process. J Pediatr Surg 36:774-776. Copyright © 2001 by W.B. Saunders Company. INDEX WORDS: Jejunoileal atresia, duodenal atresia, associated malformations, in utero insult.
insult accounting for this condition.6 We reviewed our experience of jejunoileal atresia to determine if the proximity of the jejunoileal atresia correlated with the likelihood of having another associated congenital anomaly and, thus, gain additional insight into the timing of the intrauterine insult or insults that may produce this form of atresia. MATERIALS AND METHODS The medical records of all patients with jejunoileal atresia treated at our hospital between January 1980 and December 1997 were reviewed. Information was recorded regarding the anatomic location and the number of atresias in each patient. Any associated intestinal or extraintestinal malformations were recorded. Those cases of hereditary multiple atresias were excluded from the study. The form of surgical treatment, morbidity, and mortality also were documented.
RESULTS
There were 83 patients with jejunoileal atresia treated during the period of study. Thirty-eight (46%) had jejunal atresia, and 45 (54%) had ileal atresia (IA). Sixteen (42%) of the JA patients weighed were premature (gestational age, less than 36 weeks) and 10 (22%) of the IA patients were premature. Eighteen (47%) of the JA patients weighed less than 2.5 kg at birth, whereas only 9 (20%) of the IA patients weighed less than 2.5 kg at birth. Associated congenital anomalies were found in 27 patients; 26 had jejunal atresia, and 1 had ileal atresia (Table 1). Various associated anomalies or genetic de-
Journal of Pediatric Surgery, Vol 36, No 5 (May), 2001: pp 774-776
JEJUNOILEAL ATRESIA
775
Table 1. Jejunoileal Atresias and Associated Anomalies
Jejunal atresia (n ⫽ 38)
Ileal atresia (n ⫽ 45)
Anomaly
No. of Patients
Cystic fibrosis Malrotation Congenital heart disease Down’s syndrome (trisomy 21) Congenital dislocation of hips Anorectal and vertebral anomalies Neural tube defect Microcephaly
10 7 4 1 1 1 1 1
Vesicoureteric reflux
1
NOTE. This table indicates the type and number of intestinal and extraintestinal anomalies associated with jejunoileal atresia in our series of patients.
fects in JA patients included cystic fibrosis, malrotation, congenital heart disease, and Down’s syndrome. A single atresia was found in 18 (47%) JA patients and 41 (91%) IA patients. The remaining 24 patients had multiple or apple peel atresia. A resection and primary anastomosis was performed in 26 (68%) JA and 40 (89%) IA patients. Postoperative complications occurred in 22 (58%) of JA and 10 (22%) IA patients and included necrotising enterocolitis in 4, lactose intolerance in 2, septicaemia in 10, pneumonia in 3, adhesive obstruction in 9, anastomotic leak in 1, anastomotic stricture in 1, and stomal prolapse in 1. The morbidity rate was higher in patients with JA 22 of 38 as compared with IA 9 of 45 (P ⬍ .05). Deaths occurred in 13 (11 JA and 2 IA). Seven of them had multiple atresia, and 4 had cystic fibrosis. DISCUSSION
There is compelling evidence in the literature that a late intrauterine mesenteric vascular accident results in jejunoileal atresia.7,8 Pathogenetic mechanisms that can cause this vascular disruption of the blood supply include abnormalities in either the formation or normal resorption of fetal blood vessels during development, compression or twisting of the mesenteric vessels as a result of a volvulus, or the release of emboli through placental vascular connections from a deceased monozygotic twin.5 The vascular insult also can be secondary to other lesions
affecting the alimentary tract such as cystic fibrosis, intussusception, and gastroschisis.2,3 In the current study, there was a significantly higher incidence of associated anomalies in JA patients compared with IA patients. The presence of cystic fibrosis (meconeum ileus) in 10 patients and malrotation in 7 of the JA group would suggest that intestinal ischemia was the cause of the jejunal atresia in these patients. However, a definite subgroup of 9 patients emerged in our analysis of JA patients who had extra intestinal malformations in association with their atresia. These 9 patients had a range of neural, skeletal, cardiac, and syndromic abnormalities (Table 1). It would appear that these patients were subjected to an early in utero insult that interfered with embryogenesis resulting in malformations of multiple organ systems including the jejunum. Interestingly, Diez-Pardo et al9 have described an Adriamycin rat model of congenital intestinal atresia. Adriamycin was administered on day 6 through 9 of gestation, and the subsequent fetuses were delivered at term minus 1 day. At a dose of 2 mg/kg, 53% of the fetuses had small bowel atresia, and 47% had duodenal atresia compared with no atresias in controls. The mechanism whereby Adriamycin produced these results is unclear, but it has been shown to produce cytogenetic abnormalities in cultured human lymphocytes.10 This work has been extended in our laboratory.11 The Adriamycin rat model was used to produce multiple gastrointestinal atresias, and these were examined histopathologically. Ninety percent of the atresias were in the form of multiple blind-ending atresias or sausagelike multiple atresias that resembled human nonhereditary atresias. There was no evidence of atresia caused by vascular insult, and it appears likely that in this model the atresias were the result of a malformative process. The high incidence of associated extra intestinal anomalies in our series of JA patients compared with the IA group suggests that JA may occur earlier than IA in utero. Although the majority of cases JA arise from a vascular insult, there appears to be an important subgroup of JA patients, based on our study and emerging animal models, whereby a malformative process accounts for the development of this form of bowel obstruction.
REFERENCES 1. Skandalakis JE, Gray SW, Ricketts R, et al: The small intestines, in Skandalakis JE, Gray SW (eds): Embryology for Surgeons. Baltimore, MD, Williams & Wilkins, 1994, pp 184-241 2. Nixon HH, Tawes R: Etiology and treatment of small intestinal atresia: Analysis of a series of 127 jejunoileal atresias and comparison with 62 duodenal atresias. Surgery 69:41-51, 1970 3. Gornall P: Management of intestinal atresia complicating gastroschisis. J Pediatr Surg 24:522-524, 1989 4. Weber DM, Freeman NV: Duodenojejunal atresia with apple peel configuration of the ileum and absent superior mesenteric ar-
tery: Observations on pathogenesis. J Pediatr Surg 34:1427-1429, 1999 5. Cragan JD, Martin ML, Moore CA, et al: Descriptive epidemiology of small intestinal atresia, Atlanta, Georgia. Teratology 48:441450, 1993 6. Rescorla FJ, Grosfeld JL: Intestinal atresia and stenosis: Analysis of survival in 120 cases. Surgery 98:668-676, 1985 7. Grosfeld JL, Ballantine TVN, Shoemaker R: Operative management of intestinal atresia and stenosis based on pathological findings. J Pediatr Surg 14:368-375, 1979
776
8. Dalla Vecchia LK, Grosfeld JL, West K, et al: Intestinal atresia and stenosis. A 25-year experience with 277 cases. Arch Surg 133: 490-497, 1998 9. Diez-Pardo JA, Baoquan Q, Navarro C: A new rodent experimental model of esophageal atresia and tracheoesophageal fistula: Preliminary report. J Pediatr Surg 31:498-502, 1996
SWEENEY, SURANA, AND PURI
10. Vig BK: Chromosome aberrations induced in human leucocytes by the antileukemic antibiotic adriamycin. Cancer Res 31:32-38, 1971 11. Fourcade L, Miyazaki E, Shima H, et al: Multiple gastrointestinal atresias result from disturbed morphogenesis. Presented at the 30th Annual Meeting of the American Pediatric Surgical Association, Rancho Mirage, California May 16-19, 1999