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Myelomeningocele: A risk factor for necrotizing enterocolitis in term infants
Volume 113 Number 6
Clinical and laboratory observations
H I V IgA or IgM was detected in the serum sample of the two women whose milk was positive for those markers. In loco m a m m a r y synthesis of these immunoglobulins is therefore very likely. Infiltration of the interstitium by mononuclear cells with large germinal centers adjacent to the lactiferous ducts has been identified in m a m m a r y glands of sheep infected by the visna (maedi) virus, an animal lentivirus very similar to HIV, indicating that local synthesis Of lentivirus antibodies may occur? Specific milk antibodies have been implicated in the protection of breast-fed neonates against viral infections. ~~ In particular, secretory IgA produced in milk can resist inactivation in the digestive tract of the breast-fed infant and has been shown to bind to viruses and prevent invasion of susceptibl e cells? ~ One of the two mothers in whose milk H I V antibodies of the three subclasses were detected had a 10-month-old breast-fed infant who was H I V seronegative and asymptomatic, indicating that the child had not been infected through his mother's milk. Nevertheless, whether the presence of H I V antibodies in the milk may reduce the risk of transmission of H I V or the risk of development of disease or both, in the breast-fed infant remains to be clarified. REFERENCES
2.
3.
4.
5.
6.
7.
8.
9.
10.
10 41
transmission of AIDS-associated retrovirus from mother to infant. Lancet 1985;1:896-7. Lepage P, Van de Perre P, Carael M, et al. Postnatal transmission of HIV from mother to child [Letter]. Lancet 1987; 2:400. Weinbreck P, Loustaud V, Denis F, Vidal F, Mounier M, De Lumey L. Postnatal transmission of HIV infection [Letter]. Lancet 1988;1:482. Dworsky M, Yow M, Stagno S, Pass RF, Alford C. Cytomegalovirus infection of breast milk and transmission iv. infancy. Pediatrics 1983;72:2950. De Bower GF, Terpstra C, Houwers D J, Hendriks J. Studies in epidemiology Of maedi/visna in sheep. Res Vet Sci 1979;26:202-8. Hino S, Yamagushi K, Katamine S, et al. Mother-to-child transmission of human T-cell leukemia virus type I. Jpn J Cancer Res 1985;76:474-80. Thiry L, Sprecher-Goldberg S, Jonckheer T, et al. Isolation of AiDS virus from cell-free breast milk of three healthy virus carriers. Lancet 1985;2:891-2. Baillou A, Barin F, Allain JP; et al. Human immunodeficiency virus antigenemia in patients with AIDS and AIDS-related disorders: a comparison between European and Central African populations. J Infect Dis t987;156:830-3; Narayan O, Cork LC. Lentiviral diseases of sheep and goats: chronic pneumonia leukoencephalomyelitis and arthritis. Rev Infect Dis 1985;7:89-98. Welsh JK, May JT. Anti-infective properties of breast milk. J PEDIATR 1979;94:1-9.
1. Ziegler JB, Cooper DA, Johnson RD, Gold J. Postnatal
Myelomeningocele' A risk factor for necrotizing enterocolitis in term infants S i m o n C o s t e l l o , MBBS, FRACP, J o n a t h a n Kei Lui, MBBS, FRACP
H e l l m a n n , MB, BCh, FRCP(C), a n d
From the Department of Paediatrics, Division of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada
Necrotizing enterocolitis is a disease that primarily affects premature newborn infants, with up to 90% of cases occurring in very low birth weight infants. 1 Although numerous risk factors have been recognized for infants weighing <1500 gm, those for full-term infants are less well established. 2 Myelomeningocele has been infrequently associated with N E C in previously published reports. 3'4 Our impression Was that this association was more fre-
quent, and this led us to review our experience with N E C and M M C . NEC MMC
N ecrotizing enterocolitis Myelomeningocele
See related article, p. 1044. METHODS
Submitted for publication June 8, 1988; accepted Aug. 1, 1988. Reprint requests: J. Hellmann, MB, BCh, FRCP(C), Departmerit of Paediatrics, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.
All cases of N E C that occurred in infants with M M C who had been admitted to The Hospital for Sick Children, Toronto, over a 10-year period, from 1977 to 1987, were
10 4 2
Clinical and laboratory observations
The Journal of Pediatrics December 1988
Table. Clinical features of infants with myelomeningocele and necrotizing enterocolitis Patient No.
Site
1
L-S
Distension(day 4), tenderness
-
2 3 4
L T-L L-S
+ + ++
5
T-L
Rectal bleeding (day 2) Rectal bleeding (day 4) Distension,vomiting, rectal bleeding (day 3) Vomiting,distension, rectal bleeding (day 2)
6
L-S
Rectal bleeding (day 9), distension
+++
7 8 9
T-L T T-L
Vomiting,rectal bleeding, (day 3) Distension, rectal bleeding (day 7) Distension,vomiting, rectal bleeding (day 3)
+ ++ +++
Clinical (age)
Radiology (pneumatosis)
++
Culture Positlve (blood) (Enterobacter cloacae," Klebsiella aerogenes) Positive (blood) (Pseudomonas maltophilia) Positive (blood) (Clostridium butyricum) Positive (peritoneal fluid) (Escherichia coli)
Outcome Death
Normal Normal Surgery Death
Death
Normal Normal Surgery
T, Thoracic; T-L. thoracolumbar;L, lumbar;L-S, lumbosacral.
reviewed. All infants with MMC were usually admitted to a neurosurgery ward. Only those with clinical signs of NEC were transferred to the neonatal intensive care unit for further management. A diagnosis of NEC was made when signs of abdominal distension or rectal bleeding were present, together with radiologic evidence of intramural air or gastrointestinal perforation. The putative risk factors for NEC, 4'5 including gestational age, growth retardation, perinatal asphyxia, umbilical vessel catheterization, respiratory distress, congenital heart disease, polycythemia, exchange transfusion, and enteral feeding, were sought in the study group of infants with MMC and NEC. The anatomic characteristics of MMC, with particular attention to the site and size of the spinal lesion, were also analyzed. RESULTS Three hundred fifty-eight infants with MMC were admitted during the 10-year study period; NEC was diagnosed in nine (2.5%) of these infants. Over this period, NEC was diagnosed in 119 infants weighing >2500 gm. All nine infants with NEC and MMC were at least 38 weeks gestation and weighed >2500 gm a t birth. The clinical details are summarized in the Table. There was a female/male ratio of 2:1. Mean birth weight was 3205 gm (range 2660 to 3800) and mean gestation 40,3 weeks (range 38 to 42). In three additional infants, NEC was diagnosed during this period; however, there was no definite pneumatosis despite strong clinical evidence, so they were excluded from the study. Seven infants were seen
between day 2 and day 4 of life, and the other two on day 7 and day 9, respectively. Vomiting and poor feeding were present i n four (44%) of the nine patients, and lethargy was reported in four (44%). Abdominal distension and rectal bleeding ,,were prominent clinical features, occurring in seven (77%) of the patients. Of note was the paucity of abdominal signs other than distension, with abdominal tenderness in only one infant. Intestinal perforation occurred in five infants. There were three deaths, all related to NEC. Radiologically, definite pneumatosis was present in eight infants. In the one infant without pneumatosis (patient 1), NEC was confirmed at autopsy. Extensive pneumatosis involving the entire colon was present in five infants. Pathologic confirmation of NEC was obtained in the three infants who died, and in two others in whom colonic resection was performed for perforation. The cases of NEC were evenly distributed throughout the 10-year period, with no clustering to suggest a common infectious cause. No infants had any of the previously associated risk factors for NEC. Fetal monitoring information was not available in all cases, but the only direct evidence of fetal distress was in patient 6, who was delivered by cesarean section and had subsequent Apgar scores of nine at both 1 and 5 minutes. All infants had a 5-minute Apgar score of 9 or 10. All infants had hematocrit values in the normal range. Eight of the nine infants had received some enteral formula feeding before the onset of symptoms; one infant had received only 5% dextrose solution orally.
Volume 113 Number 6
The sites of the spinal defect of the 9 infants included the following: thoracolumbar (4 cases), lumbosacral (3), thoracic (1), and lumbar (1). No association was observed between high or low lesions and the severity of N E C and its outcome. Two infants (patients 9 and 11) had an indwelling ventriculoperitoneal shunt inserted 8 and 4 days, respectively, before the onset of N E C . The cerebrospinal fluid culture after shunt insertion was negative in both cases. DISCUSSION Current theory in the pathogenesis of N E C suggests that a combination of factors results in a predisposition to intestinal ischemia and bacterial overgrowth. These factors are particularly pertinent to premature infants, but the picture is less clear in infants weighing >2500 gm. The incidence of N E C in term infants is extremely low; Wiswell's study group had an incidence of 0.19/1000 live births. 4 PrevioUs reports of N E C in term infants have alluded to few potential risk factors. Wilson et al? examined 23 infants weighing >2000 gm and demonstrated an association among respiratory distress, hypoglycemia, polycythemia, and N E C . Lloyd 6 showed a correlation between birth asphyxia and gastrointestinal perforation. Dickinson et al. 7 reported N E C in 14 of 111 term infants with congenital heart disease after cardiac catheterization. Polin et al? examined 13 term infants with N E C and described prolonged diarrhea in eight as a predisposing factor. Thilo et al. 3 reported one infant with M M C in her study of 13 infants with N E C diagnosed in the first 24 hours of life. Wiswell et al. 4 detected three infants with M M C , in a group of 43 term infants, but did not mention whether these infants had other risk factors. Necrotizing enterocolitis has been reported to occur postoperatively, but these cases were almost all associated with a gastrointestinal anomaly, particularly gastroschisis and duodenal atresia. 9, ~0 Mollitt and Golladay ~~described one infant who underwent ileostomy for aganglionic megacolon; subsequent development of severe N E C resulted in death. We reviewed the operating records of the two infants who underwent ventriculoperitoneal shunts and found no evidence of cardiorespiratory instability. Anesthesia in each case was standard general anesthesia with no complications. The nine infants in this report represent an unusually high incidence of 2.5% of M M C cases in the hospital population. There was no evidence of previously implicated risk factors. Although an added factor t h a t may be of significance is the presence of the shunt in the peritoneum, seven of the nine infants had N E C before the insertion of the shunt. A contributing factor to severity of disease may
Clinical and laboratory observations
10 4 3
be the tendency to nurse these infants in the prone position. Studies of peripheral circulatory responses to enteral feeding in low birth weight infants have shown a lack of compensatory decrease in cutaneous blood flow, suggesting immature circulatory reflexes as a predisposing factor for N E C in that group of infants. H A similar scenario may occur in term infants with M M C because of disruption of the vascular autonomic reflex during enteral feeding. Alternatively, a disturbance of intestinal motility, a recognized feature of M M C , may allow proliferation of pathogens. Enterocolitis is a recognized association with Hirschsprung disease. ~2Merkler et al. ~adescribed an infant with M M C and Hirschsprung disease and proposed that failure of the formation of lumbosacral neural crest cells could interrupt the autonomic nervous system development and innervation of colonic smooth muscle. ~3 It is conceivable, therefore, that N E C in mature infants such as these is not related to mucosal damage but, rather, is of neurogenic origin with disturbance of peristalsis. These data were collected in a retrospective manner, and total population figures for a tertiary referral institution such as ours are difficult to obtain. However, the absence of previously documented risk factors in our group strongly favors a primary role for M M C as an etiologic factor in N E C in these infants. We therefore recommend that a high index of suspicion be maintained for the possibility of N E C in infants with M M C ; perhaps a more cautious approach to the introduction of feeding should also be taken. REFERENCES
1. Kliegman RM, Fanaroff AA. Neonatal necrotizing enterocolitis: a nine-year experience. Am J Dis Child 1981;135: 603-7. 2. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging9 Pediatr Clin North Am 1986;33:179201. 3. Thilo EH, Lazarte RA, Fernandez JA. Necrotizing enterocolitis in the first 24 hours of life. Pediatrics 1984;73:476-80. 4. Wiswell TE, Robertson CF, Jones TA, Tuttle DJ. Necrotizing enterocolitis in full-term infants: a case control study. Am J Dis Child 1988;142:532-5. 5. Wilson R, del Portillo M, Schmidt E, et al. Risk factors for necrotizing enterocolitis in infants weighing more than 2000 g at birth. Pediatrics 1983;71 : 19-22. 6. Lloyd JR. Etiology of G-1 perforation in the newborn. J Pediatr Gastroenterol Nutr 1984;3:89-94. 7. Dickinson DF, Galloway RW, Wilkinson JL, Arnold R. Necrotizing enterocolitis after neonatal cardiac catheterization. Arch Dis Child 1982;57:431-3. 8. Polin RA, Pollack P, Barlow B, et al. Necrotizing enterocolitis in term infants. J PEDIATR 1976;89:460-2. 9. Amoury RA, Goodwin CD, McGill CW, et al. Necrotizing enterocolitis following operation in the neonatal period J Pediatr Surg 1980;15:1-8.
10 4 4
Clinical and laboratory observations
10. Mollitt DL, Golladay ES. Postoperative neonatal necrotizing enterocolitis. J Pediatr Surg 1982;17:757-63. 11. Raziuddin K, Kim MH, Yao AC. Peripheral circulatory response to feeding in newborn low birthweight infants. J Pediatr Gastroenterol Nutr 1984;3:89-94.
The Journal of Pediatrics December 1988
12. Cooperstock MS. C. difficile, enterocolitis, and Hirschsprung's disease [Letter]. Lancet 1982;1:800. 13. Merkler RG, Solish SB, Scherzer AL. Meningomyelocele and Hirschsprung's disease: theoretical and clinical significance. Pediatrics 1985;76:299-300.
Necrotizing enterocolitis in neonates with symptomatic congenital heart disease Maurice P. Leung, MBBS,MRCP, Kai-tung Chau, MBBS,MRCP, Ping-wai Hui, PhD, Alfred Y. C. Tam, MBBS,MRCP, F. L. Chan, MBBS,FRCR, Ching-lung Lai, MBBS,FRCP,FRCP(E),a n d C h a p - y u n g Yeung, MBBS,FRCP(C) From the Departments of Paediatrics and Radiology, Queen Mary Hospital and Grantham Hospital, University of Hong Kong
Necrotizing enterocolitis is a disease predominantly affecting premature babies in the neonatal intensive care unit. l, 2 The disease appears to be a single response of the immature intestine to injury initiated by multiple factors. Numerous agents and adverse events have been hypothesized as the responsible cause? -6 Of these, congenital heart disease is recognized as predisposing to NEC. 7,8 However, a detailed study on the interrelationship between the two diseases has not been carried out before. We undertook a study to examine the incidence and factors predisposing to NEC in neonates with major CHD. METHODS This study included all symptomatic neonates with proven CHD admitted into the Cardiology Division, Department of Paediatries, University of Hong Kong, between January 1985 and December 1986. The cardiac abnormalities in these neonates with and without NEC are shown in Table I. The diagnosis of NEC was based on histopathologic study of surgical or postmortem specimens or the presence of abdominal signs and symptoms with roentgenologic evidence of pneumatosis intestinalis. To identify possible risk factors predisposing to NEC, we examined 22 factors that might cause or aggravate the existing disturbed cardiovascular hemodynamics in these babies. Such factors, related to the morphologic findings and the medical and surgical treatment of the cardiac lesions, would directly or indirectly affect the intestinal perfusion. The following factors were included: presence of birth asphyxia, primary pulmonary parenchymal abnorSubmitted for publication Nov. 12, 1987; accepted May 25, 1988. Reprint requests: Maurice P. Leung, MBBS, MRCP, Department of Paediatrics, University of Hong Kong, The Grantham Hospital, 125 Wong Chuk Hang Rd., Hong Kong.
mality, infection, polycythemia, severe heart failure and hypoxemia, administration of digoxin or dopamine, prostaglandin E2 infusion, apnea and hypotension induced by PGE2 infusion, the requirement of intermittent positive CHD NEC PGE2
Congestive heart disease Necrotizing enterocolitis Prostaglandin E2
See related article, p. 1041. pressure ventilation secondary to apnea and severe heart failure, cardiac catherization, presence of a patent ductus arteriosus and a ductus-dependent pulmonary or systemic circulation, cyanotic cardiac lesion, the presence of left or right ventricular outflow obstruction, requirement of cardiac surgery, and aortic clamping. We then compared the incidence of these factors in babies with and without NEC within this study group. Statistical analyses were performed using the Fisher exact test. A p value >0.05 was considered as not significant. RESULTS Nine (7%) of 133 neonates with symptomatic CHD developed NEC during the study period. Among the 22 factors that might adversely affect the hemodynamics and intestinal perfusion, three possible risk factors were identified (Table II): PGE2 infusion (p = 0.02) and hypotensive episodes (p = 0.0008) and apnea (p -- 0.008) induced by PGE2 administration. There were no statistically significant differences in incidence for the remaining 18 factors in neonates with and without NEC. In particular, cardiac catheterization, the presence of a patent ductus arteriosus or left ventricular outflow obstruction, the need for cardiac surgery, and aortic
Clinical and laboratory observations
H I V IgA or IgM was detected in the serum sample of the two women whose milk was positive for those markers. In loco m a m m a r y synthesis of these immunoglobulins is therefore very likely. Infiltration of the interstitium by mononuclear cells with large germinal centers adjacent to the lactiferous ducts has been identified in m a m m a r y glands of sheep infected by the visna (maedi) virus, an animal lentivirus very similar to HIV, indicating that local synthesis Of lentivirus antibodies may occur? Specific milk antibodies have been implicated in the protection of breast-fed neonates against viral infections. ~~ In particular, secretory IgA produced in milk can resist inactivation in the digestive tract of the breast-fed infant and has been shown to bind to viruses and prevent invasion of susceptibl e cells? ~ One of the two mothers in whose milk H I V antibodies of the three subclasses were detected had a 10-month-old breast-fed infant who was H I V seronegative and asymptomatic, indicating that the child had not been infected through his mother's milk. Nevertheless, whether the presence of H I V antibodies in the milk may reduce the risk of transmission of H I V or the risk of development of disease or both, in the breast-fed infant remains to be clarified. REFERENCES
2.
3.
4.
5.
6.
7.
8.
9.
10.
10 41
transmission of AIDS-associated retrovirus from mother to infant. Lancet 1985;1:896-7. Lepage P, Van de Perre P, Carael M, et al. Postnatal transmission of HIV from mother to child [Letter]. Lancet 1987; 2:400. Weinbreck P, Loustaud V, Denis F, Vidal F, Mounier M, De Lumey L. Postnatal transmission of HIV infection [Letter]. Lancet 1988;1:482. Dworsky M, Yow M, Stagno S, Pass RF, Alford C. Cytomegalovirus infection of breast milk and transmission iv. infancy. Pediatrics 1983;72:2950. De Bower GF, Terpstra C, Houwers D J, Hendriks J. Studies in epidemiology Of maedi/visna in sheep. Res Vet Sci 1979;26:202-8. Hino S, Yamagushi K, Katamine S, et al. Mother-to-child transmission of human T-cell leukemia virus type I. Jpn J Cancer Res 1985;76:474-80. Thiry L, Sprecher-Goldberg S, Jonckheer T, et al. Isolation of AiDS virus from cell-free breast milk of three healthy virus carriers. Lancet 1985;2:891-2. Baillou A, Barin F, Allain JP; et al. Human immunodeficiency virus antigenemia in patients with AIDS and AIDS-related disorders: a comparison between European and Central African populations. J Infect Dis t987;156:830-3; Narayan O, Cork LC. Lentiviral diseases of sheep and goats: chronic pneumonia leukoencephalomyelitis and arthritis. Rev Infect Dis 1985;7:89-98. Welsh JK, May JT. Anti-infective properties of breast milk. J PEDIATR 1979;94:1-9.
1. Ziegler JB, Cooper DA, Johnson RD, Gold J. Postnatal
Myelomeningocele' A risk factor for necrotizing enterocolitis in term infants S i m o n C o s t e l l o , MBBS, FRACP, J o n a t h a n Kei Lui, MBBS, FRACP
H e l l m a n n , MB, BCh, FRCP(C), a n d
From the Department of Paediatrics, Division of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada
Necrotizing enterocolitis is a disease that primarily affects premature newborn infants, with up to 90% of cases occurring in very low birth weight infants. 1 Although numerous risk factors have been recognized for infants weighing <1500 gm, those for full-term infants are less well established. 2 Myelomeningocele has been infrequently associated with N E C in previously published reports. 3'4 Our impression Was that this association was more fre-
quent, and this led us to review our experience with N E C and M M C . NEC MMC
N ecrotizing enterocolitis Myelomeningocele
See related article, p. 1044. METHODS
Submitted for publication June 8, 1988; accepted Aug. 1, 1988. Reprint requests: J. Hellmann, MB, BCh, FRCP(C), Departmerit of Paediatrics, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.
All cases of N E C that occurred in infants with M M C who had been admitted to The Hospital for Sick Children, Toronto, over a 10-year period, from 1977 to 1987, were
10 4 2
Clinical and laboratory observations
The Journal of Pediatrics December 1988
Table. Clinical features of infants with myelomeningocele and necrotizing enterocolitis Patient No.
Site
1
L-S
Distension(day 4), tenderness
-
2 3 4
L T-L L-S
+ + ++
5
T-L
Rectal bleeding (day 2) Rectal bleeding (day 4) Distension,vomiting, rectal bleeding (day 3) Vomiting,distension, rectal bleeding (day 2)
6
L-S
Rectal bleeding (day 9), distension
+++
7 8 9
T-L T T-L
Vomiting,rectal bleeding, (day 3) Distension, rectal bleeding (day 7) Distension,vomiting, rectal bleeding (day 3)
+ ++ +++
Clinical (age)
Radiology (pneumatosis)
++
Culture Positlve (blood) (Enterobacter cloacae," Klebsiella aerogenes) Positive (blood) (Pseudomonas maltophilia) Positive (blood) (Clostridium butyricum) Positive (peritoneal fluid) (Escherichia coli)
Outcome Death
Normal Normal Surgery Death
Death
Normal Normal Surgery
T, Thoracic; T-L. thoracolumbar;L, lumbar;L-S, lumbosacral.
reviewed. All infants with MMC were usually admitted to a neurosurgery ward. Only those with clinical signs of NEC were transferred to the neonatal intensive care unit for further management. A diagnosis of NEC was made when signs of abdominal distension or rectal bleeding were present, together with radiologic evidence of intramural air or gastrointestinal perforation. The putative risk factors for NEC, 4'5 including gestational age, growth retardation, perinatal asphyxia, umbilical vessel catheterization, respiratory distress, congenital heart disease, polycythemia, exchange transfusion, and enteral feeding, were sought in the study group of infants with MMC and NEC. The anatomic characteristics of MMC, with particular attention to the site and size of the spinal lesion, were also analyzed. RESULTS Three hundred fifty-eight infants with MMC were admitted during the 10-year study period; NEC was diagnosed in nine (2.5%) of these infants. Over this period, NEC was diagnosed in 119 infants weighing >2500 gm. All nine infants with NEC and MMC were at least 38 weeks gestation and weighed >2500 gm a t birth. The clinical details are summarized in the Table. There was a female/male ratio of 2:1. Mean birth weight was 3205 gm (range 2660 to 3800) and mean gestation 40,3 weeks (range 38 to 42). In three additional infants, NEC was diagnosed during this period; however, there was no definite pneumatosis despite strong clinical evidence, so they were excluded from the study. Seven infants were seen
between day 2 and day 4 of life, and the other two on day 7 and day 9, respectively. Vomiting and poor feeding were present i n four (44%) of the nine patients, and lethargy was reported in four (44%). Abdominal distension and rectal bleeding ,,were prominent clinical features, occurring in seven (77%) of the patients. Of note was the paucity of abdominal signs other than distension, with abdominal tenderness in only one infant. Intestinal perforation occurred in five infants. There were three deaths, all related to NEC. Radiologically, definite pneumatosis was present in eight infants. In the one infant without pneumatosis (patient 1), NEC was confirmed at autopsy. Extensive pneumatosis involving the entire colon was present in five infants. Pathologic confirmation of NEC was obtained in the three infants who died, and in two others in whom colonic resection was performed for perforation. The cases of NEC were evenly distributed throughout the 10-year period, with no clustering to suggest a common infectious cause. No infants had any of the previously associated risk factors for NEC. Fetal monitoring information was not available in all cases, but the only direct evidence of fetal distress was in patient 6, who was delivered by cesarean section and had subsequent Apgar scores of nine at both 1 and 5 minutes. All infants had a 5-minute Apgar score of 9 or 10. All infants had hematocrit values in the normal range. Eight of the nine infants had received some enteral formula feeding before the onset of symptoms; one infant had received only 5% dextrose solution orally.
Volume 113 Number 6
The sites of the spinal defect of the 9 infants included the following: thoracolumbar (4 cases), lumbosacral (3), thoracic (1), and lumbar (1). No association was observed between high or low lesions and the severity of N E C and its outcome. Two infants (patients 9 and 11) had an indwelling ventriculoperitoneal shunt inserted 8 and 4 days, respectively, before the onset of N E C . The cerebrospinal fluid culture after shunt insertion was negative in both cases. DISCUSSION Current theory in the pathogenesis of N E C suggests that a combination of factors results in a predisposition to intestinal ischemia and bacterial overgrowth. These factors are particularly pertinent to premature infants, but the picture is less clear in infants weighing >2500 gm. The incidence of N E C in term infants is extremely low; Wiswell's study group had an incidence of 0.19/1000 live births. 4 PrevioUs reports of N E C in term infants have alluded to few potential risk factors. Wilson et al? examined 23 infants weighing >2000 gm and demonstrated an association among respiratory distress, hypoglycemia, polycythemia, and N E C . Lloyd 6 showed a correlation between birth asphyxia and gastrointestinal perforation. Dickinson et al. 7 reported N E C in 14 of 111 term infants with congenital heart disease after cardiac catheterization. Polin et al? examined 13 term infants with N E C and described prolonged diarrhea in eight as a predisposing factor. Thilo et al. 3 reported one infant with M M C in her study of 13 infants with N E C diagnosed in the first 24 hours of life. Wiswell et al. 4 detected three infants with M M C , in a group of 43 term infants, but did not mention whether these infants had other risk factors. Necrotizing enterocolitis has been reported to occur postoperatively, but these cases were almost all associated with a gastrointestinal anomaly, particularly gastroschisis and duodenal atresia. 9, ~0 Mollitt and Golladay ~~described one infant who underwent ileostomy for aganglionic megacolon; subsequent development of severe N E C resulted in death. We reviewed the operating records of the two infants who underwent ventriculoperitoneal shunts and found no evidence of cardiorespiratory instability. Anesthesia in each case was standard general anesthesia with no complications. The nine infants in this report represent an unusually high incidence of 2.5% of M M C cases in the hospital population. There was no evidence of previously implicated risk factors. Although an added factor t h a t may be of significance is the presence of the shunt in the peritoneum, seven of the nine infants had N E C before the insertion of the shunt. A contributing factor to severity of disease may
Clinical and laboratory observations
10 4 3
be the tendency to nurse these infants in the prone position. Studies of peripheral circulatory responses to enteral feeding in low birth weight infants have shown a lack of compensatory decrease in cutaneous blood flow, suggesting immature circulatory reflexes as a predisposing factor for N E C in that group of infants. H A similar scenario may occur in term infants with M M C because of disruption of the vascular autonomic reflex during enteral feeding. Alternatively, a disturbance of intestinal motility, a recognized feature of M M C , may allow proliferation of pathogens. Enterocolitis is a recognized association with Hirschsprung disease. ~2Merkler et al. ~adescribed an infant with M M C and Hirschsprung disease and proposed that failure of the formation of lumbosacral neural crest cells could interrupt the autonomic nervous system development and innervation of colonic smooth muscle. ~3 It is conceivable, therefore, that N E C in mature infants such as these is not related to mucosal damage but, rather, is of neurogenic origin with disturbance of peristalsis. These data were collected in a retrospective manner, and total population figures for a tertiary referral institution such as ours are difficult to obtain. However, the absence of previously documented risk factors in our group strongly favors a primary role for M M C as an etiologic factor in N E C in these infants. We therefore recommend that a high index of suspicion be maintained for the possibility of N E C in infants with M M C ; perhaps a more cautious approach to the introduction of feeding should also be taken. REFERENCES
1. Kliegman RM, Fanaroff AA. Neonatal necrotizing enterocolitis: a nine-year experience. Am J Dis Child 1981;135: 603-7. 2. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging9 Pediatr Clin North Am 1986;33:179201. 3. Thilo EH, Lazarte RA, Fernandez JA. Necrotizing enterocolitis in the first 24 hours of life. Pediatrics 1984;73:476-80. 4. Wiswell TE, Robertson CF, Jones TA, Tuttle DJ. Necrotizing enterocolitis in full-term infants: a case control study. Am J Dis Child 1988;142:532-5. 5. Wilson R, del Portillo M, Schmidt E, et al. Risk factors for necrotizing enterocolitis in infants weighing more than 2000 g at birth. Pediatrics 1983;71 : 19-22. 6. Lloyd JR. Etiology of G-1 perforation in the newborn. J Pediatr Gastroenterol Nutr 1984;3:89-94. 7. Dickinson DF, Galloway RW, Wilkinson JL, Arnold R. Necrotizing enterocolitis after neonatal cardiac catheterization. Arch Dis Child 1982;57:431-3. 8. Polin RA, Pollack P, Barlow B, et al. Necrotizing enterocolitis in term infants. J PEDIATR 1976;89:460-2. 9. Amoury RA, Goodwin CD, McGill CW, et al. Necrotizing enterocolitis following operation in the neonatal period J Pediatr Surg 1980;15:1-8.
10 4 4
Clinical and laboratory observations
10. Mollitt DL, Golladay ES. Postoperative neonatal necrotizing enterocolitis. J Pediatr Surg 1982;17:757-63. 11. Raziuddin K, Kim MH, Yao AC. Peripheral circulatory response to feeding in newborn low birthweight infants. J Pediatr Gastroenterol Nutr 1984;3:89-94.
The Journal of Pediatrics December 1988
12. Cooperstock MS. C. difficile, enterocolitis, and Hirschsprung's disease [Letter]. Lancet 1982;1:800. 13. Merkler RG, Solish SB, Scherzer AL. Meningomyelocele and Hirschsprung's disease: theoretical and clinical significance. Pediatrics 1985;76:299-300.
Necrotizing enterocolitis in neonates with symptomatic congenital heart disease Maurice P. Leung, MBBS,MRCP, Kai-tung Chau, MBBS,MRCP, Ping-wai Hui, PhD, Alfred Y. C. Tam, MBBS,MRCP, F. L. Chan, MBBS,FRCR, Ching-lung Lai, MBBS,FRCP,FRCP(E),a n d C h a p - y u n g Yeung, MBBS,FRCP(C) From the Departments of Paediatrics and Radiology, Queen Mary Hospital and Grantham Hospital, University of Hong Kong
Necrotizing enterocolitis is a disease predominantly affecting premature babies in the neonatal intensive care unit. l, 2 The disease appears to be a single response of the immature intestine to injury initiated by multiple factors. Numerous agents and adverse events have been hypothesized as the responsible cause? -6 Of these, congenital heart disease is recognized as predisposing to NEC. 7,8 However, a detailed study on the interrelationship between the two diseases has not been carried out before. We undertook a study to examine the incidence and factors predisposing to NEC in neonates with major CHD. METHODS This study included all symptomatic neonates with proven CHD admitted into the Cardiology Division, Department of Paediatries, University of Hong Kong, between January 1985 and December 1986. The cardiac abnormalities in these neonates with and without NEC are shown in Table I. The diagnosis of NEC was based on histopathologic study of surgical or postmortem specimens or the presence of abdominal signs and symptoms with roentgenologic evidence of pneumatosis intestinalis. To identify possible risk factors predisposing to NEC, we examined 22 factors that might cause or aggravate the existing disturbed cardiovascular hemodynamics in these babies. Such factors, related to the morphologic findings and the medical and surgical treatment of the cardiac lesions, would directly or indirectly affect the intestinal perfusion. The following factors were included: presence of birth asphyxia, primary pulmonary parenchymal abnorSubmitted for publication Nov. 12, 1987; accepted May 25, 1988. Reprint requests: Maurice P. Leung, MBBS, MRCP, Department of Paediatrics, University of Hong Kong, The Grantham Hospital, 125 Wong Chuk Hang Rd., Hong Kong.
mality, infection, polycythemia, severe heart failure and hypoxemia, administration of digoxin or dopamine, prostaglandin E2 infusion, apnea and hypotension induced by PGE2 infusion, the requirement of intermittent positive CHD NEC PGE2
Congestive heart disease Necrotizing enterocolitis Prostaglandin E2
See related article, p. 1041. pressure ventilation secondary to apnea and severe heart failure, cardiac catherization, presence of a patent ductus arteriosus and a ductus-dependent pulmonary or systemic circulation, cyanotic cardiac lesion, the presence of left or right ventricular outflow obstruction, requirement of cardiac surgery, and aortic clamping. We then compared the incidence of these factors in babies with and without NEC within this study group. Statistical analyses were performed using the Fisher exact test. A p value >0.05 was considered as not significant. RESULTS Nine (7%) of 133 neonates with symptomatic CHD developed NEC during the study period. Among the 22 factors that might adversely affect the hemodynamics and intestinal perfusion, three possible risk factors were identified (Table II): PGE2 infusion (p = 0.02) and hypotensive episodes (p = 0.0008) and apnea (p -- 0.008) induced by PGE2 administration. There were no statistically significant differences in incidence for the remaining 18 factors in neonates with and without NEC. In particular, cardiac catheterization, the presence of a patent ductus arteriosus or left ventricular outflow obstruction, the need for cardiac surgery, and aortic