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* Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California
Research Triangle Institute, Research Triangle Park, North Carolina
Department of Pediatrics, Emory University, Atlanta, Georgia
|| Department of Pediatrics, Women and Infants Hospital, Providence, RI
¶ Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio
# Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
** Department of Pediatric Surgery, University of Texas, Houston, TX
National Institute of Child Health and Human Development, Washington, DC
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Methods. Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight <1000 g in the National Institute of Child Health and Human Development Neonatal Research Network Registry. Neurodevelopment and growth were assessed at 18 to 22 months' postmenstrual age. 
2, t test, and logistic regression analyses were used.
Results. A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference <10 percentile at 18 to 22 months were significantly more likely among SurgNEC but not MedNEC compared with NoNEC infants. After correction for anthropometric measures at birth and adjusted age at follow-up, all growth parameters at 18 to 22 months for SurgNEC but not MedNEC infants were significantly less than for NoNEC infants. SurgNEC but not MedNEC was a significant independent risk factor for Mental Developmental Index <70 (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.05–2.50), Psychomotor Developmental Index <70 (OR: 1.95; 95% CI: 1.25–3.04), and neurodevelopmental impairment (OR: 1.78; 95% CI: 1.17–2.73) compared with NoNEC.
Conclusions. Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease.
Key Words: necrotizing enterocolitis • extremely low birth weight • neurodevelopmental outcome • cerebral palsy • Bayley Scales of Infant Development • growth
Abbreviations: NEC, necrotizing enterocolitis • ELBW, extremely low birth weight • VLBW, very low birth weight • SurgNEC, surgically managed necrotizing enterocolitis • MedNEC, medically managed necrotizing enterocolitis • NICHD, National Institute of Child Health and Human Development • NoNEC, no history of necrotizing enterocolitis • IRB, Institutional Review Board • cPVL, cystic periventricular leukomalacia • BPD, bronchopulmonary dysplasia • CP, cerebral palsy • BSID II, Bayley Scales of Infant Development II • NDI, neurodevelopmental impairment • MDI, Mental Developmental Index • PDI, Psychomotor Developmental Index • HC, head circumference • ROM, rupture of membranes • PNS, postnatal steroid • OR, odds ratio • CI, confidence interval
Necrotizing enterocolitis (NEC) continues to be a potentially devastating complication for the extremely low birth weight (ELBW) premature infant.1,2 Although survival rates of >80% have been reported in some premature populations,3,4 ELBW patients fare much worse with survival ranging from 41% to 55%.4,5 Short-term medical and surgical complications associated with NEC have been found to be more prevalent and life-threatening among extremely premature and lower birth weight infants.6–8
Neurodevelopmental outcomes in ELBW patients with NEC have not been widely reported.9 Previous single-center and multi-institutional studies have variably found the diagnosis of NEC to be associated with a nonsignificant trend toward10 or an independent risk factor for11,12 adverse neurodevelopmental outcomes. To date, outcomes studies of ELBW or very low birth weight (VLBW) survivors of NEC have included only single-center reviews with small numbers of patients. Sonntag et al13 found significant neurodevelopmental delay in 20 VLBW survivors of NEC at 12 and 20 months compared with gestational age–matched control subjects. Infants who require surgery for NEC are likely to be more severely ill with the disease and may be at even higher risk for neurodevelopmental and neuromotor delay. Single-center analyses have suggested that motor delay at 15 months' corrected age may be more prevalent in VLBW NEC survivors who require abdominal incisions than in those who were medically managed14 and that VLBW and ELBW survivors of surgically managed NEC (SurgNEC) have significantly worse neurodevelopmental outcome and growth than control subjects or infants with medically managed NEC (MedNEC).15,16
The extent to which NEC has an impact on long-term somatic growth has been debated. Early small studies reported normal anthropometric measurements at 1 year in the absence of short-bowel syndrome.17 Sonntag et al13 found no somatic growth differences between VLBW NEC survivors and control subjects at 12 or 20 months. However, others have found that infants who require surgery for NEC have a higher incidence of growth delay than control subjects.18,19 Walsh et al20 also found that a higher stage of NEC was associated with both severe growth restriction and neurodevelopmental delay at 20 months' adjusted age compared with lower stage of NEC or control subjects.
In this analysis of ELBW infants who were in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network VLBW Registry and born form 1995 to 1998, we sought to compare neurodevelopmental and growth outcomes of ELBW infants with SurgNEC and MedNEC with infants without a history of NEC (NoNEC) at 18 to 22 months' corrected age and, through regression analysis, to assess whether SurgNEC or MedNEC was an independent risk factor for adverse neuromotor, neurosensory, and cognitive outcomes.
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METHODS |
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3-week range of when several estimates existed, the median estimate of gestational age was used. Small for gestational age was defined as weight <10th percentile for gestational age using the fetal growth curves of Alexander et al.23 Data were also collected on diagnoses (including patent ductus arteriosus), treatments, and in-hospital morbidities until death, discharge, or 120 days; after 120 days or if the patient was transferred, then data were collected regarding death or discharge to home. Surfactant treatment was defined as 1 or more doses of any surfactant during hospitalization. Indomethacin was defined as treatment with the drug for closure of a patent ductus arteriosus. Intraventricular hemorrhage was reported according to the classification of Papile et al.24 Cystic periventricular leukomalacia (cPVL) was defined specifically as diagnosis by head ultrasound performed after 2 weeks of age; if a head ultrasound was not obtained after 2 weeks of age, then no report was made as to the presence or absence of cPVL. Cranial ultrasounds were not interpreted by a central reader but rather by radiologists at individual network centers. Early sepsis was defined as a positive blood culture at 
72 hours of age, and late sepsis was defined as a positive blood culture at >72 hours of age. Data regarding NEC were collected for infants who survived >12 hours and was defined as Modified Bell's classification stage IIA or greater.25 Surgery for NEC was at the discretion of each individual network center and included any surgical intervention (drain, laparotomy, or both). Bronchopulmonary dysplasia (BPD) was defined as receiving supplemental oxygen at 36 weeks' postmenstrual age as determined by best obstetric estimate. Comprehensive follow-up at 18 to 22 months' postmenstrual age was considered standard of care for ELBW infants at network sites. The IRBs at each center approved participation in the follow-up study. Waivers of consent were granted, or informed consent was sought per the specifications of each center's IRB. Contact to schedule the follow-up visit was made by telephone call, postcard, or letter. The elements of the follow-up visit have been previously described in detail.11 All neurologic assessments were performed by certified, masked developmentalists who had been trained in the examination procedure in an annual 2-day workshop. The neurologic examination was based on the Amiel-Tison26 assessments, and the gross motor skills examination was developed from the work of Russell et al27 and Palisano et al.28 Cerebral palsy (CP) was defined as a nonprogressive central nervous system disorder characterized by abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture. The Bayley Scales of Infant Development-II (BSID-II)29 was administered by experienced testers at each site who had been certified by 1 of 4 gold standard examiners. BSID-II scores of 100 ± 15 represent the mean ± 1 SD. Scores of <70 are 2 SDs below the mean. Scores of 49 were assigned to infants whose extremely severe neurologic or neurodevelopmental impairment prevented their examination. Examiners noted the reasons for unsuccessful BSID-II testing. Deafness was defined as using hearing aids in both ears. Blindness was defined as no useful vision in either eye. Neurodevelopmental impairment (NDI) was defined as 1 or more of the following: Mental Developmental Index (MDI) <70, Psychomotor Developmental Index (PDI) <70, CP, deafness, or blindness. Weight, length, and head circumference (HC) measurements were also made at the time of the 18- to 22-month follow-up visit. Determinations of weight, length, and HC percentiles for age were based on age corrected for prematurity, using growth charts developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (published May 30, 2000). Socioeconomic status information, including highest level of education attained by the primary caregiver, was also obtained at the time of the follow-up visit.
Statistical analyses were performed using continuity-adjusted 2 or Fisher exact test for categorical data, and t test, analysis of variance, or analysis of covariance was used for continuous data. Logistic regression models were developed to evaluate NEC management-related risk for CP, BSID-II MDI <70, BSID-II PDI <70, and the combined outcome of NDI (defined as deafness, blindness, CP, MDI <70, or PDI <70) while adjusting for differences in perinatal and neonatal variables. Demographic, maternal, and neonatal risk factors that are known to be associated with neurodevelopmental outcomes were entered into the regression models. These factors included network center, use of antenatal glucocorticoids, rupture of membranes (ROM) >24 hours, outborn status, estimated gestational age, gender, race, birth weight, small for gestational age, surfactant therapy, intraventricular hemorrhage grade 3 or 4 or cPVL, sepsis, postnatal steroid (PNS) treatment, BPD, and highest level of education attained by the primary caregiver.
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RESULTS |
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The association of SurgNEC with growth failure among ELBW infants in this analysis is concerning. This finding may seem to be inconsistent with the results of previous smaller studies. Abbasi et al17 reported comparable growth measures at 12 months between NEC and control patients; however, that cohort was not limited to ELBW infants, and included only 4 surgically managed patients among the 22 cases of NEC. Sonntag et al13 also reported no significant differences in weight, length, or HC between 20 VLBW NEC patients, among whom only 7 had undergone surgery, and 40 VLBW control subjects at 20 months. Although the authors indicated that there were no significant differences in growth parameters between NEC treatment groups, there was a lower median weight at 20 months in the surgically managed group (9.85 kg) as compared with control (10.7 kg). In contrast, Walsh et al20 reported a significant correlation between severity of NEC and growth delay at 20 months among a VLBW cohort, which is similar to our findings. The Walsh et al study, which examined growth outcomes as a function of NEC staging rather than management, demonstrated substantially greater proportions of stage III NEC compared with control infants with weight (39% vs 24%) and HC (30% vs 13%) >2 SD below the mean. The great majority of infants with stage III NEC had undergone surgery (17 of 23), supporting the notion that the most severely ill NEC patients are more likely to be managed with surgery. Significant growth impairment has also been reported in studies of survivors of surgically treated NEC,30–32 without contemporaneous control subjects.
The SurgNEC group in the current analysis was also at significantly greater risk for poor neurosensory and neurodevelopmental outcomes than the MedNEC group when compared with NoNEC. This finding is consistent with many previous, smaller reports.14–16 Major neurodevelopmental impairment was found in 43% of severe NEC survivors compared with 15% of mild to moderate NEC survivors at 20 months by Walsh et al.20 In follow-up studies of only surgical NEC survivors, significant motor and cognitive delay has been reported in one third to one half.3,30,31 The current study differs from others in that it focuses specifically on the ELBW population, arguably the highest risk group, and has a much larger sample size. This advantage allows for analysis of NEC management-related adjusted risk for important neurodevelopmental outcomes that, to our knowledge, has not been reported previously for this patient population. Despite the nearly 3000 ELBW infants studied, however, very few in either NEC treatment strategy group had a diagnosis of blindness or deafness. Nonetheless, the outcomes of CP and BSID-II scores <70 were relatively common.
The profound neurodevelopmental impairment observed in the SurgNEC group may be linked closely to significant growth impairment, particularly in HC. Previous studies of VLBW and ELBW infants have demonstrated that subnormal head growth at 8 months33 and 12 months34 is associated with poor cognitive ability and academic difficulties at school age. Failure to achieve catch-up head growth to above the fifth percentile by 6 months of age has also been reported to be associated with abnormal motor performance at 12 months among VLBW premature infants.35 Weight <10th percentile at 2 years' corrected age is also correlated with poor neurodevelopmental and neuromotor outcomes among high-risk ELBW patients, including those with a history of NEC.36 Although differences in somatic growth in the MedNEC compared with the NoNEC group did not reach statistical significance in the present analysis, growth for this entire ELBW population at 18 to 22 months' adjusted age is disturbing, with >50% of the overall cohort with weights <10th percentile. This is not a novel finding. Connors et al36 reported that 49% of an ELBW cohort had weights <10th percentile at 2 years' corrected age. Similarly, previous studies have found that as many as half of ELBW and VLBW infants at follow-up had HCs that fell below the 10th percentile at 6 to 8 months.34,35 In the present study, it may be speculated that prenatal factors or events that predispose certain patients for development of NEC also could have led to the lower mean weight, HC, and length at birth in NEC compared with NoNEC groups. Subsequent morbidities may have differentially affected the NEC treatment groups, resulting in more severe growth delay in SurgNEC at 18 to 22 months. The more pronounced growth impairment observed in the SurgNEC group may also have occurred through a mechanism of persistent nutritional deficits, which might involve the effects of short bowel including malabsorption. Severe short-bowel syndrome has also been linked with subtle visual-spatial impairment at school age.37 During the study period, no detailed interval nutritional history was gathered at the time of follow-up. This important issue is a crucial area for additional, prospective study, currently ongoing in the NICHD Neonatal Research Network38; the current 18- to 22-month follow-up assessment includes questions that address gastrointestinal dysfunction.
Although this study is among the largest to examine the potential association between NEC treatment and neurodevelopmental outcomes using prospectively collected perinatal and neonatal data in ELBW patients, it still does not clarify the specific causes of the increased risk for poorer outcomes in the SurgNEC group. We speculate that this process is likely to be multifactorial. It has been suggested that perinatal events play a potentially important role in the pathogenesis of NEC, with fetal hypoperfusion leading to mucosal vulnerability and gut ischemia.39,40 The subsequent profound inflammatory response may be associated with release of chemical mediators such as tumor necrosis factor-
, interleukin-6, platelet activating factor, and nitric oxide, purported to contribute to a mechanism that leads to hemodynamic instability, tissue necrosis, and white matter injury.40–43 The fetus may also be exposed to such proinflammatory cytokines as a consequence of intrauterine infection. Of note, both ROM >24 hours and diagnosis of cPVL were more likely in the SurgNEC group on univariate comparisons. It therefore is possible that the cascade of events that lead to adverse neurodevelopmental outcomes is programmed in utero. More detailed early neuroimaging studies that focus on subtle white matter changes might help to clarify whether there exists a common fetal determinant for PVL and NEC. Alternatively, the fetal environment may predispose the infant to but not absolutely determine neurodevelopmental consequences unless a specific postnatal milieu is also in place. For example, the severity of the clinical condition contemporaneous with the NEC episode may be an additive or independent determinant of outcome. NEC staging information was not available during the entire study period; thus, outcomes cannot be evaluated on that basis, but it is likely that greater severity of disease does correlate with perceived need for surgery.16,20 Other in-hospital factors such as late sepsis, BPD, and PNS, which have been linked to adverse neurodevelopmental outcomes, were also significantly more frequent in SurgNEC but not MedNEC compared with NoNEC infants. Whether these morbidities and treatments occurred as a directed consequence of a potentially greater severity of illness in the SurgNEC group is not known. Despite attempts to adjust for differences in these factors through regression modeling, SurgNEC was an independent risk factor for MDI <70, PDI <70, and NDI.
Common postsurgical complications including sepsis, wound infection, strictures, and short-gut syndrome4 may be a reflection of the severity of the disease process rather than the surgical therapy. Therefore, the "need for surgery" might be considered simply a surrogate for advanced NEC. In the current study, the decision to proceed with surgical intervention for NEC was at the discretion of the surgical teams at each individual network site; no data regarding the specific type of surgical intervention (drain, laparotomy, or both) or the basis for the management approach were collected. Previous reports have suggested that smaller, sicker infants may be more likely to receive drainage in the setting of perforated NEC.44 Thus, the possibility of a delay to "definitive" treatment in this subgroup cannot be ruled out. A prospective study of surgical treatment for NEC among ELBW infants has recently been completed in the Neonatal Research Network, which will provide detailed assessments of surgical practices, reasons for and types of interventions undertaken, pathologic findings, and complications. These data will be useful in determining the significance of the risk that these factors impart independently on short- and long-term outcomes.
In summary, at 18 to 22 months, ELBW infants who received surgical intervention for management of NEC had significantly reduced weight, length, and HC compared with NoNEC infants, but growth parameters of MedNEC and NoNEC groups were not statistically different. SurgNEC but not MedNEC was also found to be an independent risk factor for BSID MDI <70, PDI <70, and NDI. Numerous factors, including prenatal factors, severity of illness, nutritional deficits, and the surgical intervention and subsequent complications, may have contributed to the poorer outcomes observed in the SurgNEC group. The results of this multicenter, retrospective analysis pose additional crucial questions as to the pathogenesis and natural history of adverse neurodevelopmental consequences of severe NEC among ELBW infants.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Reprint requests to (S.R.H.) Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, 750 Welch Rd, Suite 315, Palo Alto, CA 94304. E-mail: srhintz{at}stanford.edu
No conflict of interest declared.
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REFERENCES |
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