Published online November 12, 2007
PEDIATRICS Vol. 120 No. 6 December 2007, pp. e1458-e1464 (doi:10.1542/peds.2006-2804)
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ARTICLE

Maternal Factors in Extremely Low Birth Weight Infants Who Develop Spontaneous Intestinal Perforation

Corinne J. Ragouilliaux, MDa, Susan E. Keeney, MDa, Hal K. Hawkins, MDb and Judith L. Rowen, MDc

a Neonatology Division
c Infectious Diseases and Immunology Division, Department of Pediatrics
b Department of Pathology, University of Texas Medical Branch, Galveston, Texas


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Spontaneous intestinal perforation of the extremely low birth weight infant (≤1000 g) is associated with a high incidence of Candida and coagulase-negative Staphylococcus sepsis. Little is known about prenatal risk factors, and histopathologic examination of placentas in infants with spontaneous intestinal perforation has not been reported.

OBJECTIVES. Our objective was to investigate maternal factors and specific placental findings in a sample of infants with spontaneous intestinal perforation. We compared the maternal factors and clinical outcomes to a matched control group.

PATIENTS AND METHODS. This single-center, retrospective cohort study was conducted between January 2001 and December 2005. The records of extremely low birth weight infants with spontaneous intestinal perforation were reviewed (n = 16). Study infants were matched to 2 infants in the control group; any twin of a study patient was also included as a control subject (n = 35). Histopathologic examination of placentas included standard hematoxylin and eosin and methenamine silver stains.

RESULTS. Infants with spontaneous intestinal perforation were more likely than control subjects to have severe placental chorioamnionitis with fetal vascular response (40% vs 12%); 2 placentas also tested positive for yeast versus none in the control subjects. Mothers of infants with spontaneous intestinal perforation were more likely than control subjects to have received antibiotics before or at delivery (93% vs 57%). Fifty percent of the infants had Candida, and 31% in the spontaneous intestinal perforation group had coagulase-negative Staphylococcus sepsis versus 6% in the control subjects. Finally, infants with spontaneous intestinal perforation had delayed enteral feeding (64 ± 30 vs 31 ± 10 days) and prolonged hospitalization (155 ± 48 vs 108 ± 36 days).

CONCLUSIONS. Spontaneous intestinal perforation in the extremely low birth weight infant is a neonatal disease related to placental inflammation. We alert practitioners to the importance of placental findings, because they may be positive for yeast.

Key Words: chorioamnionitis • funisitis • candidiasis • coagulase-negative Staphylococcus • neonate

Abbreviations: SIP—spontaneous intestinal perforation • ELBW—extremely low birth weight • NEC—necrotizing enterocolitis • CONS—coagulase-negative Staphylococcus

Spontaneous intestinal perforation (SIP) of the premature infant has now been well described as a specific clinical entity.1–4 The overall incidence of SIP in the extremely low birth weight (ELBW; ≤1000 g) infant population is estimated at 5% to 6%.5 Infants are extremely small (~700 g) and premature (~25 weeks).2,3,6 The clinical presentation is different from necrotizing enterocolitis (NEC): affected infants present earlier (7–10 days of life) and often have a bluish abdomen.2,4,6–8 Abdominal radiographs are remarkable for the absence of pneumatosis, and a gasless abdomen may accompany the clinical presentation.2,4,6–8 Hyperleukocytosis6–8 is reported in infants suffering from SIP, as well as a frequent association with Candida and coagulase-negative Staphylococcus (CONS) infection.2–4,6,9 Regional intestinal ischemia has been proposed as a mechanism.10 Reported risk factors include early neonatal hypotension,6 umbilical artery catheters,2 dehydration,11 and the use of indomethacin and steroid treatment.6,12,13 A recent article reported discharge outcomes of ELBW infants suffering from SIP and found an increased incidence of periventricular leukomalacia (PVL) and death, suggesting a possible role for inflammation related to peritonitis in these outcomes.14 A report on the largest series of ELBW infants suffering from SIP to date was published recently15 and confirmed the association with indomethacin exposure and the use of vasopressors, citing an overall mortality of 25% in the population of affected infants.

Although several neonatal risk factors have been associated with SIP, little is known about prenatal risk factors. Subclinical chorioamnionitis has been associated with a higher incidence of neonatal morbidities and specifically NEC, especially when fetal vascular response is present,16 suggesting that inflammation may have a role in prenatal intestinal injury. We speculated that the placentas of infants suffering from SIP would show histopathologic characteristics of inflammation. Moreover, given the high incidence of candidal sepsis reported in association with SIP, we hypothesized that transplacental transmission of Candida might be present in these subjects. To our knowledge, placental examination of infants suffering from SIP has not been reported to date.

This single-center retrospective cohort study was designed to provide additional insight into the prenatal risk factors for SIP. We describe the clinical characteristics, the maternal risk factors, and the histopathologic findings in the placentas in a sample of infants suffering from SIP. We also compare the placental findings, other prenatal risk factors, and clinical outcomes to a matched control group.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The study protocol was approved by the institutional review board for human subjects at the University of Texas Medical Branch. The medical charts of premature infants with a diagnosis of SIP during the 5-year period from January 2001 to December 2005 were reviewed. Patients were identified by searching the database of infants admitted to the NICU at the University of Texas Medical Branch. Only preterm infants of <28 weeks’ gestation, weighing <1000 g at birth and without multiple and/or congenital gastrointestinal anomalies were included.

Medical charts were reviewed for demographic data; prenatal risk factors; feeding history; radiographic, surgical, and pathologic findings; infectious disease data; and clinical outcomes. Patients were considered confirmed subjects with SIP if the clinical diagnosis was supported by surgical reports and/or histopathology. Specifically, the clinical criteria included perforation occurring at ≤3 weeks of age and absence of pneumatosis on abdominal radiographs. Surgical and histopathologic criteria were a necrotic area of ≤3 cm and evidence of focal inflammation, respectively. Patients with surgical findings or histopathology consistent with NEC or meconium plug were excluded. Systemic candidiasis was defined as the isolation of Candida from central cultures (blood, cerebrospinal fluid, catheterized urine, or peritoneal fluid). CONS infection was defined as ≥2 positive central cultures in the context of systemic signs and symptoms. A retrospective histopathologic analysis of the placenta was performed by a pediatric pathologist who was masked to the infants’ clinical history. In addition to standard hematoxylin and eosin staining, a methenamine silver stain was performed on slides from each placenta. The diagnostic schema was derived from templates published by the Society for Pediatric Pathology-Perinatal Section for identification and grading of lesions related to amniotic fluid infection.17

For the comparison of prenatal complications, placental findings, and clinical outcomes, a control group of infants was matched to the study group. To have a SIP-negative control group, study patients were matched to infants who had survived ≥14 days, which was the latest day for SIP in our series. The infants born immediately before and after the study infant, weighing ±100 g and being ±1 week of gestational age of the study infant were included (n = 32). Any twin of a study patient was also included in the control group (n = 3). Infants were excluded from the control group if they had multiple and/or gastrointestinal anomalies.

When appropriate, data are presented as means ± SD. Group comparisons were performed by using the 2-tailed Student's t test for continuous measures and Mantel-Haenszel or Fisher's exact tests for dichotomous variables. When data were not normally distributed, Mann-Whitney analysis was performed. For the outcomes other than death, analysis was restricted to those who had survived. Analysis of risk factors was univariate. Statistical significance was evaluated at the P = .05 level.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the 5-year period, there were 2991 admissions to the University of Texas Medical Branch Infant Special Care Unit. In total, 392 infants had a birth weight <1000 g; 287 viable infants weighed <1000 g and were <28 weeks’ gestation. Through our database, we identified a total of 22 patients with a probable diagnosis of SIP during the 5-year period. On review of hospital charts, 6 infants were eliminated from the study, 1 with NEC, 2 with meconium plug syndrome, 1 with mucormycosis, 1 with no perforation at laparotomy, and 1 with a clinical diagnosis of SIP. In the latter patient, surgery was declined, and the patient died without autopsy. Three pairs of twins were identified with only 1 infant suffering from SIP and 2 pairs of twins with both infants suffering from SIP. With a total of 16 patients identified, this yielded an incidence of SIP of 4.6% of all of the ELBW infants. The matched control group consisted of 35 infants, including the control subjects and twins of study patients. Fifteen placentas in the study group and 33 placentas in the control group were available for review. All of the infants were inborn.

Descriptive information and maternal risk factors for the 16 infants who suffered from SIP compared with the control subjects are presented in Table 1. Study infants had a mean weight of 669 ± 52 g and a mean gestational age of 24.4 ± 0.8 weeks. Study and control infants were well matched for birth weight and gestational age. There were trends toward a higher incidence of male and black infants in the study group compared with the control subjects. There were no differences in method of delivery or Apgar scores between the 2 groups. Mothers of infants suffering from SIP were younger and tended to have a lower number of previous gestations. There were no differences in the documented clinical diagnosis of chorioamnionitis, but mothers of infants suffering from SIP showed a trend toward increased prolonged rupture of membranes (53% vs 31%) and were significantly more likely to have received antibiotics at the time of delivery (93% vs 57% in the control group; P = .018). Most maternal antibiotic use was ampicillin or penicillin for group B streptococcal prophylaxis or erythromycin for treatment of Chlamydia; 25% of case patients and 17% of control subjects were born to mothers who received antibiotics other than ampicillin/penicillin ± erythromycin (P = .7). We did not find significant associations between SIP and small for gestational age, pregnancy-induced hypertension, maternal diabetes mellitus, or maternal group B Streptococcus colonization. Maternal treatment with steroids was common and did not differ in frequency between groups (73% [infants with SIP] vs 85% [control subjects]). No neonate had a prenatal exposure to indomethacin.


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  		TABLE 1 Demographic and Maternal Data Concerning the Patient Population

 
Table 2 shows the placental findings in the case and control subject groups. The overall incidence of chorioamnionitis was high in both groups. More infants in the study group had placentas showing features of severe chorioamnionitis (53% vs 27% in the control group), although the difference was not significant (P = .08). The placentas of infants suffering from SIP had a higher incidence of umbilical cord lesions, reflecting chorioamnionitis with fetal vascular response: 40% vs 12% in the control group (P = .04). In addition, 2 placentas in the study group tested positive for yeasts compared with none in the control group.


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  		TABLE 2 Placental Findings

 
The infants suffering from SIP were diagnosed at a mean age of 9.5 ± 3.5 days, and the age at diagnosis ranged from 4 to 14 days of life. All of the infants but 2 were on antibacterial agents at the time of perforation. All of the case and control subject infants received ampicillin and gentamicin beginning on day-of-life 1; 44% of case subject infants versus 20% of control subjects received vancomycin or a third-generation cephalosporin before the date of perforation (P = .099). Four infants had additionally been started on antifungal therapy 1 to 3 days before the diagnosis of SIP. Enteral feedings had been started in 69% of the case patients and 94% of matched control subjects (P = .025). Abdominal distension was the most common presenting symptom (81%), followed by abdominal bluish discoloration (69%) and the presence of a gastric residual (seen in 37%; defined as >30% of 3 hours of intake). Systemic hypotension was present in 62% of the infants at the time of perforation. The white blood cell count at the time of diagnosis was 31.0 ± 21.0 x 103/µL, and the platelet count was 171000 ± 108000/µL with 56% of infants having a platelet count of <150000/µL. Metabolic acidosis was noted in 43% of the patients at the time of diagnosis. Abdominal radiographs were abnormal in all of the case subjects; the majority of infants had free air on plain abdominal radiographs (62%). In the remainder of infants, the bowel gas pattern showed either a gasless abdomen (25%) or a paucity of gas (13%).

We analyzed different risk factors potentially involved in modifying the gastrointestinal blood flow. The day of first enteral feeding and first stool were similar in both groups. Infants in the 2 groups had similar electrolyte values during the first 7 days of life, suggesting no difference in the state of hydration. There was a trend toward a higher number of infants requiring early treatment with dopamine for hemodynamic instability in the SIP group (50% vs 26% in the control group; P = .09). There were no differences between the SIP and control groups in the number of infants with umbilical arterial catheters, the number receiving indomethacin treatment for PDA (13% vs 14%), or the number receiving steroids in the first 2 weeks of life (19% vs 9%).

All of the case patients underwent an exploratory laparotomy with ileostomy. Three (19%) had a Penrose drain placement performed acutely and then had surgery within 24 hours. The most common location for perforation was the distal ileum (56%) followed by the mid ileum (25%), the jejunum (12%), and the cecum (6%). The amount of intestine resected averaged 3.7 ± 2.9 cm. Pathology reports were available for 13 infants and showed focal areas of necrosis with minimal inflammatory reaction. Two of the pathology reports were also remarkable for the presence of yeasts within the intestinal tissue. Peritoneal fluid cultures were available for 11 infants and positive in 63% of these: 2 were positive for Candida and CONS; 2 for Candida only; 1 for CONS and Citrobacter; 1 for CONS, Klebsiella, and Citrobacter; and 1 for Klebsiella and Enterococcus. Blood cultures were performed at the time of surgery in 8 infants and were positive in 7. Of these, 5 blood cultures matched the peritoneal fluid cultures: 1 for Candida and CONS, 2 for Candida, and 2 for CONS. Two infants had an isolated blood culture that was positive for CONS and sterile peritoneal fluid, and these isolates were considered contaminants. Of note, 5 infants had a sepsis workup performed before perforation: 1 had CONS isolated from sputum and urine, 1 had Citrobacter bacteremia, 1 had candidal fungemia, and 2 had both cutaneous and urinary candidal infections.

It can be seen from Table 3 that the overall incidence of Candida and CONS infection was significantly higher in the group of infants suffering from SIP than in the control group: 50% vs 6% (P = .0006) and 31% vs 6% (P = .02), respectively. When the analysis was restricted to the time before or at perforation, the difference remained significant: 31.0% vs 2.8% (P = .009) and 25.0% vs 2.8% (P = .03), respectively.


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  		TABLE 3 Infectious Disease Data

 
Clinical outcomes and morbidities are presented in Table 4. Postoperative complications occurred in 62% of our case patients and included high ostomy output (n = 3), intestinal obstruction (n = 3), hemoperitoneum (n = 3), ileocutaneous fistula and wound dehiscence (n = 1), wound abscess (n = 1), and fulminant sepsis with death (n = 1). The time to reach full enteral feeding was delayed in infants suffering from SIP, at 64 ± 30 vs 31 ± 10 days in the control group (P = .003). Infants suffering from SIP required a longer hospital stay than infants in the control group, at 155 ± 48 vs 108 ± 36 days (P = .007). Brain lesions known to increase the risk for abnormal neurodevelopmental outcome (grades III to IV intraventricular hemorrhage and periventricular leukomalacia) were more likely in the SIP group, at 25.0% vs 2.8% in the control subjects (P = .03). Finally, there was a trend toward an increased incidence of retinopathy of prematurity requiring laser therapy in the SIP group (50% vs 26% in the control subjects; P = .13).


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  		TABLE 4 Clinical Outcomes and Morbidities of the Patient Population Compared With the Control Group

 

   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In this study, we report that there are differences in the histopathologic findings in the placentas of infants who later develop SIP compared with those of a group of infants who do not. To our knowledge, there have been no previous publications regarding the placentas of infants with SIP. The finding of a very high percentage of histologic chorioamnionitis in both case and control patients is consistent with reports that it is inversely related to gestational age and is as high as 66% at 20 to 24 weeks of gestation.18 Our results showed a trend toward more severe chorioamnionitis in the SIP group (53% vs 27%). However, the most striking finding was a higher percentage of placentas showing fetal inflammatory response in the SIP group. Long-term fetal exposure to elevated levels of inflammatory cytokines can result in tissue injury to the lungs and brain.16,19,20 There is evidence that prenatal inflammation also targets the fetal intestine, because there is an increased incidence of NEC in infants whose placentas display a fetal inflammatory response16 and in preterm infants with elevated umbilical proinflammatory mediator levels.21 In addition, placental production of interleukin 1-β is increased in chorioamnionitis19 and has been linked to intestinal mucosal injury.22 We postulate that similar tissue injury is involved in the pathogenesis of SIP.

A unique finding in our study is the association of positive placental testing for yeasts in 2 of the case patients versus none in the control group. This is the first report published in the literature describing candidal chorioamnionitis in relation to neonatal SIP. Candidal chorioamnionitis has been linked to neonatal cutaneous candidiasis, pneumonia,23–25 and stillbirth. In stillborn infants, hyphae and spores are frequently found in the lungs of the fetus and in the gastrointestinal tract, mainly in the lumina or on surfaces.25,26 Of note, both of our infants with candidal chorioamnionitis also had severe chorioamnionitis associated with funisitis. Although 1 infant had characteristic gross umbilical cord findings with fungal colonies on the surface,25 in the other patient, the presence of yeast was identified only when the methenamine silver stain was performed. Finally, these 2 infants were not started on antifungal therapy until the day of perforation for 1 (for positive candidal peritoneal and blood cultures) and 14 days after perforation for the second for Candida isolated from sputum and urine (no cultures were performed at the time of perforation).

In addition to the placental findings, we report a very high overall incidence of either Candida or CONS infection in the SIP infants, particularly in the first 2 weeks of life. Our finding of a 50% overall incidence of candidal infection is higher than those of previous studies, which have reported incidences of 17% to 33% for positive candidal cultures.2,3,6,7 In our infants, Candida and CONS were found predominantly in peritoneal fluid cultures. Coates et al9 reported an incidence of 44% for Candida and 50% for CONS in positive peritoneal cultures in infants with SIP, which underscores the importance of obtaining these cultures during surgery. We hypothesize that our higher incidence may be related to the deletion of infants with meconium plug syndrome as the etiology of the perforation. Mucosal sites are an important source of CONS colonization in the neonate, and the bacteria has been implicated in the pathogenesis of NEC.27 In an animal model, bacterial translocation of CONS occurs after intestinal ischemia/reperfusion injury.28 The role of Candida in the pathogenesis of SIP remains unclear. Two of the histopathologic surgical reports showed evidence of yeast within the intestinal tissue. Candida has specific abilities to bind to mucosal surfaces,29 as well as enteroinvasive properties.30 Moreover, Nucci and Anaissie31 found evidence in their meta-analysis that the gut was an important source of candidemia. In fragile infants exposed to intestinal tissue damage from inflammation and/or ischemia, the mechanisms described above may have facilitated candidal and staphylococcal translocation into the systemic circulation. Moreover, the intestinal dysmotility of extreme preterm infants and/or the functional ileus secondary to inflammation probably act as additional pathogenic factors by adding pressure on a previously damaged mucosa. We did not detect an association between SIP and early vasopressor use, indomethacin treatment, or steroid exposure. These associations have been reported previously, and our lack of findings may have been related to our small sample size.

The most striking prenatal difference noted in our study was the very high incidence of antibiotic use before or at delivery in mothers of infants suffering from SIP. This may represent a higher index of clinical suspicion for maternal infection in the case mothers or it may be that administration of antibiotics resulted in the selection of yeasts, with subsequent transplacental and/or transvaginal transmission to the neonate. In support of the latter theory, Whyte et al23 reported 18 cases of candidal chorioamnionitis, with a higher proportion of mothers being treated with antibiotics than in the control group. In our study group, there was a preponderance of male infants of black background, which is comparable to other published data.9 Of note, the black infants in our study were also more likely to develop a candidal infection (5 of 7 infants versus 3 of 9 in the remaining patients; P = .11), which is consistent with previous studies.32,33 Moreover, previous studies have identified that black women are more likely to be colonized with Candida during pregnancy.34

The clinical findings at presentation were similar in our group to those reported previously.2–4,6,8,14 The recent prospective cohort study by the National Institute of Child Health and Human Development Neonatal Research Network on postoperative outcomes of ELBW with NEC or isolated intestinal perforation35 has reported that the variables that most accurately predict the diagnosis of SIP are the absence of pneumatosis, the presence of a gasless abdomen, and the age at surgery. There is ongoing debate as to surgical options for infants suffering from SIP.35,36 Peritoneal drainage in our institution is used only as a temporary treatment before a laparotomy can be performed. The infants suffering from SIP in our study had a high incidence of postoperative complications, especially strictures (19.0%), as compared with the 10.3% reported previously.35 This may explain in part the delayed enteral feeding and prolonged hospital stay in our case subjects. In addition, the case patients showed a trend toward increased incidence of associated morbidities, which is consistent with data published previously.14 Of note, in our study, the higher incidence of brain lesions and the trend for a higher mortality in the SIP group may have been biased by the characteristics of our control group, composed of infants who survived ≥14 days.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This study provides new information about risk factors for SIP. SIP is most likely a multifactorial disease of the very fragile ELBW infant born at the limit of viability. The high incidence of occult presentation without an obvious pneumoperitoneum may make the disease process difficult to identify, and the physician has to maintain a high index of suspicion, particularly in the case of an acute gasless abdomen in a very small infant. There is considerable physical and financial burden on these infants, because they have a higher incidence of neonatal morbidities and a prolonged hospital stay. Prospective evaluation of placentas may provide additional insights into the pathophysiology of this important complication in the ELBW infant.


   FOOTNOTES
 
Accepted May 14, 2007.

Address correspondence to Judith L. Rowen, MD, Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0375. E-mail: jrowen{at}utmb.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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