Abstract
Objective:
To determine if preterm infants with surgical necrotizing enterocolitis (sNEC) or spontaneous intestinal perforation (SIP) with short bowel syndrome (SBS) have worse neurodevelopmental and growth outcomes than those with sNEC/SIP without SBS, and those with no NEC, SIP, or SBS.
Study Design:
Retrospective analysis of prospectively collected data from infants born between 22–26 weeks’ gestational age (GA) in NICHD Neonatal Research Network centers 1/1/2008–12/31/2016. Survivors were assessed at 18–26 months corrected age (CA) by standardized neurologic exam and Bayley Scales of Infant and Toddler Development (Bayley-III). The primary outcome was moderate-severe neurodevelopmental impairment (NDI). Growth was assessed using WHO z-score standards. Adjusted relative risks (aRR) were estimated using modified Poisson regression models.
Results:
Mortality was 32%, 45%, and 21% in the three groups, respectively. 89% of survivors were seen at 18–26 months CA. Moderate-severe NDI was present in 77% of children with SBS compared to 62% with sNEC/SIP without SBS, (aRR 1.22 [95% CI: 1.02–1.45], p=0.03) and 44% with no NEC, SIP or SBS (aRR 1.60 [95% CI: 1.37–1.88], p<0.001). Children with SBS had lower cognitive, language, and motor scores than children with sNEC/SIP without SBS. At follow-up, length and head circumference z-scores remained more than one standard deviation below the mean for children with SBS.
Conclusions:
Preterm infants with sNEC/SIP and SBS had increased risk of adverse ND outcomes at 18–26 months CA and impaired growth compared to peers with sNEC/SIP without SBS or without any of these conditions.
Introduction:
Surgical necrotizing enterocolitis (sNEC) requiring extensive bowel resection is the leading cause of short bowel syndrome (SBS) in preterm children.(1) The incidence of SBS is 0.7% in very low birth weight infants <1500 grams and 1.1% among infants < 1000 grams with a mortality rate in affected neonates up to 50%.(1, 2) SBS is associated with limited intestinal absorption of nutrients needed to maintain growth and fluid and electrolyte balance. Affected children have impaired growth, prolonged use of parenteral nutrition, cholestasis and are at increased risk for sepsis, each of which is independently associated with adverse neurologic outcome.(1, 3–5) Previous studies have shown that extremely low birth weight infants with sNEC and those with intestinal failure are at increased risk for poor neurodevelopmental outcome compared to their unaffected peers.(2, 4, 6–12) Hintz, et al compared neurodevelopmental outcomes of preterm infants with sNEC to those with medical NEC and found lower cognitive and motor scores on the Bayley Scales of Infant Development-IIR and an increased risk of cerebral palsy (CP) among those with sNEC.(4) In a cohort of 33 children with intestinal failure and mean gestational age 34 weeks, So et al found that gross motor abnormalities were present in >50% at both 1 and 2 years adjusted age and the majority had early learning deficits by 2 years of age.(11, 12).
There are limited reports evaluating neurodevelopmental outcomes of extremely preterm infants with a history of both sNEC and SBS leaving clinicians to extrapolate predicted outcome based on data from similar cohorts with a diagnosis of sNEC or intestinal failure. We used data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) to examine in-hospital morbidities, growth at 36 weeks postmenstrual age (PMA), and ND outcomes and growth at 18–26 months corrected age (CA) in children born prematurely with a history of sNEC or spontaneous intestinal perforation (SIP) and SBS, sNEC/SIP without SBS, and neither NEC, SIP, nor SBS. Infants with a primary diagnosis of NEC or SIP were included in this analysis based on the overlap between these two surgical conditions.(13, 14) We hypothesized that preterm infants with sNEC/SIP and SBS would have worse neurocognitive performance and poorer somatic growth at 18–26 months CA than survivors with sNEC/SIP without SBS and those unaffected by these conditions.
Patients and Methods:
Study participants were included in a registry of high-risk infants maintained by the NRN. The study population consisted of infants born at 22–26 weeks gestational age (GA) at 21 NRN centers who survived >12 hours. Infants with a major birth defect or chromosomal anomaly were excluded. Surviving children who attended follow-up were assessed at 18–22 months CA (births before July 2012; 49% of the cohort) or 22–26 months CA (births in or after July 2012). The registry and follow-up studies were approved by the institutional review board at each center.
Maternal and neonatal data were collected from birth to discharge, transfer, 120 days, or death. Morbidities were defined in previous NRN publications.(15–18.) NEC was defined as Bell stage IIA or greater (19, 20) with stage IIIB considered sNEC and stages IIA-IIIA considered medical NEC. SBS was defined based on documentation in the medical record and/or operative report and included malabsorption, severe diarrhea, gastric hypersecretion, bacterial overgrowth and failure to thrive. Patients were categorized based on initial clinical impression but updated during the hospitalization if diagnosed with SBS.
The follow-up assessment included a neurologic examination and a developmental evaluation using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Both were administered by certified examiners who completed annual training to ensure inter-rater reliability.(21)
When the NRN initially transitioned to the Bayley-III in 2006, only the cognitive and language subscales were administered. The motor scale of the Bayley-III was added starting January 1, 2010. Over 99% of children in the cohort were assessed in 2010 or later. The Bayley-III cognitive and motor composite scores are each normalized to mean (standard deviation, SD) scores of 100 (15). The gross motor and fine motor subscale scores have a mean (SD) of 10 (3). Cerebral palsy (CP) was defined using the Gross Motor Function Classification System (GMFCS) as mild (level ≤1), moderate (level 2–3), or severe (level 4–5).(22)
Moderate/severe neurodevelopmental impairment was defined as one or more of: moderate to severe motor impairment defined by GMFCS ≥2, with or without CP; bilateral blindness with corrected vision < 20/200; bilateral hearing impairment defined as permanent hearing loss that did not permit the child to understand directions and communicate, with or without amplification; Bayley-III cognitive composite score <85; or Bayley-III motor composite score <85. Severe neurodevelopmental impairment was defined as one or more of: GMFCS ≥4, with or without CP; bilateral blindness, bilateral hearing impairment with or without amplification; Bayley-III cognitive composite score <70; or Bayley-III motor composite score <70.
Intestinal failure was defined as requiring parenteral nutrition > 60 days.(23) Enteral autonomy was defined as reaching 120 ml/kg/day of feedings. Feeding status at follow-up was determined by caretaker report. Weight, length and head circumference were assessed by z-scores using Olsen standards(24) at birth and 36 weeks PMA, and using WHO standards at follow-up based on CA.(25, 26)
Statistical Analysis
Neurodevelopmental and growth outcomes were considered missing if the follow-up visit occurred at <14 or >32 months CA (1.5% of those assessed). Pairwise comparisons were made between infants with sNEC/SIP with SBS versus infants with sNEC/SIP without SBS and unaffected infants. Statistical significance for unadjusted comparisons was determined by χ2 test (categorical variables) or Wilcoxon test (continuous variables); both are nonparametric tests which do not assume normality of the underlying distributions of the variables. Poisson regression models with robust variance estimators were used to assess risk of binary outcomes, including in-hospital morbidities, death, the composite outcome death or moderate/severe neurodevelopmental impairment, and moderate/severe neurodevelopmental impairment, for infants with SBS compared to infants in the other groups while adjusting for study center, maternal race/ethnicity, maternal age, antenatal steroid use, multiple birth, infant sex, GA, and BW.(27) Maternal education was included in models assessing neurodevelopmental and growth outcomes. Adjusted relative risks, 95% confidence intervals, and p-values by the Wald χ2 test from these models were reported. Normally distributed continuous outcomes, including Bayley-III composite and scaled scores and growth z-scores, were compared using linear regression models. BW was not included in the model assessing BW z-score. To address any concern of bias in our results due to inclusion of infants with SIP/SBS, a sensitivity analysis was performed assessing the composite outcome death or moderate/severe neurodevelopmental impairment and the outcome moderate/severe neurodevelopmental impairment in survivors excluding infants with SIP as a primary diagnosis from the sNEC groups. A p-value < 0.05 was considered significant. No adjustment was made for multiple comparisons; therefore, one result in 20 may be statistically significant by chance. Analyses were performed using SAS version 9.4.(28)
Results:
Between January 1, 2008 and December 31, 2016, 7,999 infants born at NRN centers with GA 22–26 weeks survived >12 hours, had no major birth defect, and were eligible for follow-up (Figure 1 online). Of these, 429 infants diagnosed with medical NEC, 11 with SBS without NEC or SIP, and 7 with inconsistent data were not studied. The remaining 7,552 infants were divided into three study groups: sNEC or SIP with SBS (N=116), sNEC or SIP without SBS (N=770), and no NEC, SIP or SBS (N=6,666). Overall, 76% survived to follow-up age (68% of infants with sNEC/SIP with SBS, 55% with sNEC/SIP without SBS, 79% without NEC/SIP/SBS), and 89% of survivors completed a follow-up visit between October 2009 and August 2019, with similar proportions in each group (Figure 1 online). Of the 71 infants with SBS, 56 had sNEC and 15 had SIP; of the 373 infants with sNEC/SIP without SBS, 138 had sNEC and 235 had SIP. The 15 children in the SIP with SBS group had a median of 4 additional surgeries during the hospital stay, including bowel resection and ostomy placement.
Figure 1 Online.
Study population flow diagram.
Attendance at follow-up was defined based on the presence of two key study forms: Infant Examination Form and Bayley III Scales Summary Score Sheet. Infants without these forms but with other limited data reported were considered to have incomplete follow-up. Due to missing information, moderate/severe neurodevelopmental impairment could not be determined for all infants who attended follow-up. Survivors to follow-up included: surgical NEC/SIP with SBS— 69 with non-missing moderate/severe neurodevelopmental impairment, 2 with key forms but missing moderate/severe neurodevelopmental impairment, 1 with incomplete follow-up, 7 lost to follow-up; surgical NEC/SIP without SBS—367 non-missing moderate/severe neurodevelopmental impairment, 6 with key forms but missing moderate/severe neurodevelopmental impairment, 9 with incomplete follow-up or late visit outside of the allowable time frame, 40 lost to follow-up; no NEC, SIP, or SBS—4521 with non-missing moderate/severe neurodevelopmental impairment, 163 with key forms but missing moderate/severe neurodevelopmental impairment, 110 incomplete follow-up or late visit, 470 lost to follow-up.
Maternal and neonatal characteristics of infants with SBS were similar to those of infants in the other groups (Table 1). Children with sNEC/SIP with SBS were less likely to achieve enteral autonomy, required more days of parenteral nutrition, and had longer length of stay compared to those without SBS and those who were unaffected.
Table 1.
Maternal and neonatal characteristics of children born at 22–26 weeks GA who attended follow-up at 18–26 Months corrected age
| n (column %) or as shown1/ | Surgical NEC/SIP + SBS N=71 | Surgical NEC/SIP without SBS N=373 | No NEC, SIP, or SBS N=4684 |
|---|---|---|---|
| Maternal and delivery characteristics | |||
| Maternal age, y | |||
| Mean (SD) | 27.3 (6.1) | 27.6 (6.2) | 28.1 (6.3) |
| Maternal education | 43 | 296 | 3,699 |
| Less than high school degree | 10 (23.3) | 57 (19.3) | 769 (20.8) |
| High school degree | 14 (32.6) | 101 (34.1) | 1,062 (28.7) |
| Partial college, trade or technical school | 12 (27.9) | 72 (24.3) | 940 (25.4) |
| College degree or more | 7 (16.3) | 66 (22.3) | 928 (25.1) |
| Maternal race/ethnicity | |||
| Black | 28 (39.4) | 133 (35.7) | 1,934 (41.5) |
| White | 27 (38.0) | 148 (39.7) | 1,788 (38.4) |
| Hispanic | 8 (11.3) | 75 (20.1) | 702 (15.1) |
| Other | 8 (11.3) | 17 (4.6) | 234 (5.0) |
| Antenatal steroids | 66 (93.0) | 339 (90.9) | 4,253 (90.9) |
| Cesarean delivery | 46 (64.8) | 241 (64.6) | 3,035 (64.8) |
| Multiple birth | 23 (32.4) | 101 (27.1) | 1,174 (25.1) |
| Infant characteristics | |||
| Gestational age, weeks | |||
| Mean (SD) | 24.8 (1.1) | 24.5 (1.1)* | 25.0 (1.0) |
| By gestational age week | |||
| 22 | 1 (1.4) | 7 (1.9)* | 43 (0.9) |
| 23 | 8 (11.3) | 64 (17.2) | 399 (8.5) |
| 24 | 19 (26.8) | 118 (31.6) | 1,019 (21.8) |
| 25 | 20 (28.2) | 108 (29.0) | 1,424 (30.4) |
| 26 | 23 (32.4) | 76 (20.4) | 1,799 (38.4) |
| Birth weight, grams | |||
| Mean (SD) | 735 (163) | 714 (139) | 763 (160) |
| SGA (23–26 weeks) | 10 (14.3) | 39 (10.7) | 514 (11.1) |
| Male | 39 (54.9) | 202 (54.2) | 2,279 (48.7) |
| Apgar <5 at 5 min | 20 (28.2) | 107 (28.7) | 950 (20.3) |
| Postnatal steroids for prevention/treatment of BPD | 12 (17.1) | 96 (26.4) | 1,031 (23.2) |
| Parenteral nutrition during initial hospitalization, days | |||
| Median (25th-75th percentile) | 110 (74, 119) | 70 (47, 96)*** | 23 (16, 34)*** |
| Intestinal Failure2/ | 60 (84.5) | 228 (61.3)*** | 178 (3.8)*** |
| Full enteral feeds achieved during hospital stay (120 ml/kg/day) | 52 (73.2) | 348 (93.3)*** | 4,654 (99.4)*** |
| Hospital stay, days | |||
| Median (25th-75th percentile) | 167 (137, 208) | 136 (113, 168)*** | 106 (89, 129)*** |
| PMA at discharge, weeks | |||
| Median (25th-75th percentile) | 49 (45, 56) | 44 (41, 48)*** | 41 (38, 44)*** |
SD, standard deviation; SGA, small for gestational age; BPD, bronchopulmonary dysplasia; PMA, postmenstrual age.
Information was missing for maternal education, 1090 infants; maternal race/ethnicity, 26 infants; antenatal steroids, 6 infants; cesarean delivery, 1 infant; birth weight, 1 infant; infant sex, 4 infants; Apgar at 5 minutes, 12 infants; postnatal steroids, 259 infants; parenteral nutrition days, 11 infants; intestinal failure, 12 infants; full enteral feeds achieved, 1 infant; days until full feeds achieved, 78 infants; hospital stay and PMA at discharge, 160 infants (most were transfers with date of discharge to home missing). Among the 5077 infants born at 23–26 weeks GA, SGA was missing for 5 infants in the group with no NEC, SIP, or SBS.
Defined as requiring >60 days of parenteral nutrition.
p ≤ 0.05,
p ≤ 0.01,
p ≤ 0.001 for pairwise comparisons between infants with sNEC/SIP + SBS versus infants in each of the other two groups by the Wilcoxon test (maternal age, GA, BW, days on parenteral nutrition, days until full enteral feeds achieved, hospital stay, PMA at discharge), the row mean score chi-square test (categorical GA), the general association chi-square or Fisher’s exact test.
Rates of complications during the birth hospitalization are shown in Table 2 (online). Rates of late onset sepsis were higher in infants with NEC/SIP with or without SBS vs. infants with no NEC/SIP/SBS (59%, 54%, and 25% respectively). In contrast, PVL occurred more frequently in infants with SBS compared to infants with sNEC/SIP without SBS (18% vs 10%, aRR 2.09 [95% CI: 1.16–3.76], p=0.01) and unaffected infants (18% vs. 5%, aRR 3.31 [95% CI: 1.97–5.55], p<0.001). ROP ≥stage 3 was higher in infants with SBS compared to those without NEC/SIP/SBS (43% vs. 19%). The proportion of infants with BPD was highest among infants with SBS.
Table 2 Online.
In-hospital morbidities for infants born at 22–26 weeks GA who attended follow-up
| Outcome, n (column %o)1/ | Surgical NEC/SIP + SBS N=71 | Surgical NEC/SIP without SBS N=373 | No NEC, SIP, or SBS N=4684 | Adjusted RR (95% CI) for outcome2/ | |
|---|---|---|---|---|---|
| SBS vs surgical NEC/SIP w/o SBS | SBS vs no NEC/SIP/SBS | ||||
| RDS | 67 (94.4) | 368 (98.7) | 4,578 (97.7) | 0.96 (0.91–1.02) | 0.96 (0.91–1.02) |
| PDA | 41 (57.7) | 231 (61.9) | 2,606 (55.6) | 0.85 (0.69–1.03) | 0.94 (0.78–1.13) |
| EOS | 2 (2.8) | 13 (3.5) | 96 (2.0) | 0.86 (0.20–3.68) | 1.31 (0.34–5.04) |
| LOS | 42 (59.2) | 200 (53.6) | 1,186 (25.3) | 1.19 (0.95–1.47) | 2.20 (1.80–2.68) |
| Number of infants with cranial sonogram within 28 d | 71 | 371 | 4,665 | ||
| Severe IVH | 12 (16.9) | 88 (23.7) | 661 (14.2) | 0.91 (0.54–1.55) | 1.27 (0.77–2.09) |
| Number of infants with cranial imaging within 28 d and/or closest to 36 weeks | 71 | 373 | 4,678 | ||
| PVL | 13 (18.3) | 36 (9.7) | 249 (5.3) | 2.09 (1.16–3.76) | 3.31 (1.97–5.55) |
| Number of infants evaluated for severe ICH or PVL3/ | 71 | 371 | 4,666 | ||
| Severe IVH or PVL | 22 (31.0) | 102 (27.5) | 750 (16.1) | 1.37 (0.93–2.01) | 1.98 (1.40–2.82) |
| Number of infants in hospital at 28 d examined for ROP | 70 | 373 | 4,645 | ||
| ROP | 62 (88.6) | 330 (88.5) | 3,270 (70.4) | 1.06 (0.97–1.17) | 1.23 (1.13–1.35) |
| ROP stage ≥ 3 | 30 (42.9) | 153 (41.0) | 888 (19.1) | 1.19 (0.86–1.66) | 2.04 (1.49–2.79) |
| Number of infants evaluated for bpd4/ | 71 | 373 | 4,666 | ||
| BPD (oxygen use at 36 weeks) | 51 (71.8) | 247 (66.2) | 2,741 (58.7) | 1.11 (0.95–1.29) | 1.16 (1.01–1.33) |
| Number of infants evaluated for physiologic BPD | 69 | 370 | 4,645 | ||
| BPD by physiologic definition | 49 (71.0) | 252 (68.1) | 2,639 (56.8) | 1.05 (0.90–1.23) | 1.16 (1.00–1.34) |
RDS, respiratory distress syndrome defined as clinical features within 24 hours of birth and/or surfactant use within 72 hours; PDA, patent ductus arteriosus; EOS, early onset sepsis; LOS, late onset sepsis; ICH, intracranial hemorrhage; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; BPD, bronchopulmonary dysplasia.
Information was missing for PDA, 1 infant.
RRs and CIs from Poisson regression models fit to each outcome that included the group indicator, study center, maternal age, maternal race/ethnicity (black, white, Hispanic, other), maternal antenatal steroid use, multiple birth, infant sex, GA (categorical), and BW (continuous), except as noted. The RRs comparing risk of RDS, EOS, and PVL were adjusted for GA and BW only due to small numbers in some groups.
Presence of ICH and/or PVL was determined for infants with non-missing ICH and PVL outcomes, except that a diagnosis of either condition was sufficient to set the outcome.
Of infants evaluated for BPD, 93% were still in the hospital at 36 weeks PMA, 4% had been discharged home, and 3% had been transferred to another hospital.
Death before follow-up occurred in 32% of children with sNEC/SIP with SBS vs. 45% of children with sNEC/SIP without SBS (aRR 0.78 [95% CI: 0.57–1.05], p=0.10) and 21% of children without NEC/SIP/SBS (aRR 1.42 [95% CI: 1.06–1.90], p=0.02) (Table 3). Table 4 (online) provides information on timing of death in each group and distribution of deaths before and after discharge. For sNEC/SIP groups with or without SBS, the primary cause of death was NEC with or without proven sepsis (data not shown). Risk for the composite outcome of death or moderate/severe neurodevelopmental impairment was similar for children who had sNEC/SIP with vs. without SBS (85% vs 81%, p=0.09); children with SBS were at increased risk for death or moderate/severe neurodevelopmental impairment compared to those without NEC/SIP/SBS (85% vs 57%, aRR 1.43 [95% CI: 1.30–1.58], p<0.001) (Table 3).
Table 3.
Death and NDI in infants born at 22–26 weeks GA who were eligible for follow-up
| Outcome, n (column %) | Surgical NEC/SIP + SBS | Surgical NEC/SIP without SBS | No NEC, SIP, or SBS | Adjusted RR (95% CI) for outcome1/ | |
|---|---|---|---|---|---|
| SBS vs surgical NEC/SIP w/o SBS | SBS vs no NEC/SIP/SBS | ||||
| Number of children eligible for follow-up | 116 | 770 | 6,666 | ||
| Died >12 h after birth and before follow-up | 37 (31.9) | 348 (45.2) | 1,402 (21.0) | 0.78 (0.57–1.05) | 1.42 (1.06–1.90) |
| Number of children who died before follow-up or survived and had non-missing moderate/severe NDI | 106 | 715 | 5,923 | ||
| Death or moderate/severe NDI | 90 (84.9) | 576 (80.6) | 3,402 (57.4) | 1.09 (0.99–1.21) | 1.43 (1.30–1.58) |
| Number of children who died before follow-up or survived and had non-missing severe NDI | 104 | 711 | 5,875 | ||
| Death or severe NDI | 71 (68.3) | 485 (68.2) | 2,163 (36.8) | 1.11 (0.95–1.31) | 1.81 (1.55–2.11) |
| Number of children seen at follow-up with non-missing moderate/severe NDI | 69 | 367 | 4,521 | ||
| Moderate/severe NDI | 53 (76.8) | 228 (62.1) | 2,000 (44.2) | 1.22 (1.02–1.45) | 1.60 (1.37–1.88) |
| Number of children seen at follow-up with non-missing severe NDI | 67 | 363 | 4,473 | ||
| Severe NDI | 34 (50.7) | 137 (37.7) | 761 (17.0) | 1.46 (1.09–1.95) | 2.68 (2.05–3.49) |
RRs and CIs from Poisson regression models fit to each outcome that included the group indicator, study center, maternal age, maternal race/ethnicity (black, white, Hispanic, other), maternal education at the time of delivery (less than high school degree, high school degree, partial college, college degree or more, missing), maternal antenatal steroid use, multiple birth, infant sex, GA (categorical), and BW (continuous).
Table 4 online.
Death before follow-up in infants eligible for follow-up
| Group | Proportion of infants who died, n/N (%) | Timing of death (day of life) | |||
|---|---|---|---|---|---|
| All deaths before FU | Deaths before discharge | Deaths after discharge | Mean (SD) | Median (p25, p75) | |
| 1: sNEC/SIP + SBS | 37/116 (31.9) | 32/116 (27.6) | 5/116 (4.3) | 141 (134.0) | 76 (30, 229) |
| 2: sNEC/SIP without SBS | 348/770 (45.2) | 334/770 (43.4) | 14/770 (1.8) | 53.4 (92.7) | 26 (13, 48) |
| 3: No NEC, SIP or SBS | 1402/6666 (21.0) | 1333/6666 (20.0) | 69/6666 (1.0) | 40.6 (85.9) | 9 (3, 23.5) |
| 1: sNEC + SBS1/ | 33/96 (34.4) | 29/96 (30.2) | 4/96 (4.2) | 123 (127) | 64 (29, 178) |
| 1: SIP + SBS2/ | 4/20 (20.0) | 3/20 (15.0) | 1/20 (5.0) | 288 (106) | 291 (203, 372.5) |
| 2: sNEC3/ | 206/365 (56.4) | 201/365 (55.1) | 5/365 (1.4) | 50.5 (77.4) | 28 (19, 48) |
| 2: SIP | 142/405 (35.3) | 133/405 (32.8) | 9/405 (2.2) | 57.5 (111) | 16 (10, 45) |
The difference in the proportion of infants who died before follow-up, 34% vs 20%, was not significant, p=0.29. However, median age at death differed between these subgroups, p=0.02.
These 4 infants died on day of life 165, 241, 341, 404.
The difference in the proportion of infants who died before follow-up, 56% vs 35%, was significant, p<0.001, and median age at death differed between these subgroups, p<0.001.
Among survivors evaluated at follow-up, 77% of children with SBS had moderate/severe neurodevelopmental impairment compared to 62% of those with sNEC/SIP without SBS (aRR 1.22 [95% CI: 1.02–1.45], p=0.03) and 44% of those without NEC/SIP/SBS (aRR 1.60 [95% CI: 1.37–1.88], p<0.001). About half of the children with SBS had severe neurodevelopmental impairment compared to 38% of children with sNEC/SIP without SBS and 17% of those with no NEC/SIP/SBS. CP was diagnosed in 31% of children with sNEC/SIP with SBS compared to 28% of those with sNEC/SIP without SBS (aRR 1.40 [95% CI: 0.96–2.06], p=0.08) and 13% of those unaffected (aRR 2.40 [95% CI: 1.69–3.41], p<0.001) (Table 5). Children with SBS had lower Bayley-III cognitive, language, and motor composite and subscale scores compared to children in the other two groups. When infants with a primary diagnosis of SIP were excluded, the relative risks for death or moderate/severe neurodevelopmental impairment, and moderate/severe neurodevelopmental impairment in survivors, were similar to those observed for the original groups. (Table 6 online)
Table 5.
Neurodevelopmental outcomes in children who attended follow-up at 18–26 months corrected age
| Outcome, n (column %) | Surgical NEC/SIP + SBS | Surgical NEC/SIP without SBS | No NEC, SIP, or SBS | Adjusted RR (95% CI) for outcome or adjusted p-value1/ | |
|---|---|---|---|---|---|
| SBS vs surgical NEC/SIP w/o SBS | SBS vs no NEC/SIP/SBS | ||||
| Number of children examined at followup2/ | 71 | 373 | 4,678 | ||
| Bilateral blindness | 4 (5.6) | 15 (4.0) | 58 (1.2) | 1.57 (0.54–4.61) | 4.18 (1.53–11.42) |
| Hearing impairment | 2 (2.8) | 18 (4.9) | 131 (2.8) | 0.62 (0.15–2.64) | 0.96 (0.24–3.84) |
| CP, any grade | 22 (31.0) | 103 (27.6) | 618 (13.2) | 1.40 (0.96–2.06) | 2.40 (1.69–3.41) |
| CP, mild | 4 (5.6) | 35 (9.4) | 331 (7.1) | 0.63 (0.23–1.72) | 0.75 (0.29–1.97) |
| CP, moderate | 11 (15.5) | 33 (8.8) | 173 (3.7) | 1.95 (1.04–3.63) | 3.78 (2.17–6.61) |
| CP, severe | 7 (9.9) | 35 (9.4) | 114 (2.4) | 1.20 (0.55–2.61) | 3.76 (1.79–7.91) |
| Number of children with a Bayley III cognitive test | 66 | 364 | 4,557 | ||
| Cognitive CS, mean (STD) | 75.2 (15.9) | 81.5 (16.6) | 88.0 (15.3) | <0.001 | <0.001 |
| Cognitive CS < 85 | 22 (33.3) | 82 (22.5) | 491 (10.8) | 1.61 (1.08–2.40) | 2.67 (1.86–3.85) |
| Cognitive CS < 70 | 22 (33.3) | 82 (22.5) | 491 (10.8) | 1.61 (1.08–2.40) | 2.67 (1.86–3.85) |
| Number of children with a Bayley III language test3/ | 65 | 362 | 4,547 | ||
| Language CS, mean (STD) | 71.9 (17.1) | 77.6 (18.2) | 83.4 (17.1) | 0.009 | <0.001 |
| Language CS < 85 | 45 (70.3) | 222 (62.0) | 2,246 (50.3) | 1.08 (0.89–1.31) | 1.24 (1.04–1.48) |
| Language CS < 70 | 31 (48.4) | 122 (34.1) | 891 (20.0) | 1.48 (1.07–2.04) | 2.14 (1.60–2.87) |
| Expressive communication scaled score, mean (STD) | 5.8 (3.7) | 6.5 (3.0) | 7.3 (3.0) | 0.09 | <0.001 |
| Receptive communication scaled score, mean (STD) | 5.5 (2.6) | 6.6 (3.0) | 7.2 (3.0) | 0.008 | <0.001 |
| Number of children with a Bayley III motor test4/ | 66 | 360 | 4,515 | ||
| Motor CS, mean (STD) | 70.6 (19.1) | 77.9 (18.8) | 87.1 (16.0) | <0.001 | <0.001 |
| Motor CS < 85 | 47 (73.4) | 192 (54.4) | 1,492 (33.7) | 1.34 (1.09–1.63) | 1.94 (1.62–2.33) |
| Motor CS < 70 | 29 (45.3) | 114 (32.3) | 543 (12.3) | 1.52 (1.09–2.11) | 3.27 (2.42–4.43) |
| Gross motor scaled score, mean (STD) | 5.0 (3.4) | 6.0 (3.0) | 7.4 (2.7) | 0.006 | <0.001 |
| Fine motor scaled score, mean (STD) | 5.6 (3.3) | 7.2 (3.3) | 8.5 (2.9) | <0.001 | <0.001 |
CP, cerebral palsy; CS, composite score.
RRs and CIs from Poisson regression models fit to each outcome that included the group indicator, study center, maternal age, maternal race/ethnicity (black, white, Hispanic, other), maternal education at the time of delivery (less than high school degree, high school degree, partial college/trade or technical school, college degree or more, missing), maternal antenatal steroid use, multiple birth, infant sex, GA (categorical), and BW (continuous), except as noted. RRs for blindness, hearing impairment, mild CP, moderate CP, and severe CP were adjusted for GA and BW only due to small numbers in some groups. Adjusted p-values by t-test from linear regression models that included the covariates listed above.
Among children seen at follow-up with a child examination form, information was missing for blindness, 10 children; hearing impairment, 38 children; CP, 10 children.
Among children with at least one of a Bayley-III language composite, expressive communication, or receptive communication score, information was missing for language composite score, 87 children; expressive communication score, 163 children; receptive communication score, 141 children.
Among children with at least one of a Bayley-III motor composite, gross motor, or fine motor score, information was missing for motor composite score, 92 infants; gross motor score, 165 infants; fine motor score, 122 infants.
Table 6 online.
Death and NDI in infants born at 22–26 weeks GA who were eligible for follow-up excluding infants with SIP without surgical NEC
| Outcome, n (column %) | Surgical NEC + SBS | Surgical NEC without SBS | No NEC, SIP, or SBS | Adjusted RR (95% CI) for outcome1/ | |
|---|---|---|---|---|---|
| SBS vs surgical NEC w/o SBS | SBS vs no NEC/SBS | ||||
| Number of children eligible for follow-up | 96 | 365 | 6,666 | ||
| Died ≥ 12 h after birth and before follow-up | 33 (34.4) | 206 (56.4) | 1,402 (21.0) | 0.66 (0.47–0.92) | 1.54 (1.12–2.12) |
| Number of children who died before follow-up or survived and had non-missing moderate/severe NDI | 87 | 342 | 5,923 | ||
| Death or moderate/severe NDI | 76 (87.4) | 290 (84.8) | 3,402 (57.4) | 1.08 (0.97–1.21) | 1.47 (1.33–1.63) |
| Number of children who died before follow-up or survived and had non-missing severe NDI | 85 | 339 | 5,875 | ||
| Death or severe NDI | 58 (68.2) | 260 (76.7) | 2,163 (36.8) | 0.99 (0.82–1.19) | 1.84 (1.54–2.19) |
| Number of children seen at follow-up with non-missing moderate/severe NDI | 54 | 136 | 4,521 | ||
| Moderate/severe NDI | 43 (79.6) | 84 (61.8) | 2,000 (44.2) | 1.27 (1.03–1.57) | 1.61 (1.36–1.90) |
| Number of children seen at follow-up with non-missing severe NDI | 52 | 133 | 4,473 | ||
| Severe NDI | 25 (48.1) | 54 (40.6) | 761 (17.0) | 1.24 (0.86–1.78) | 2.44 (1.79–3.32) |
RRs and CIs from Poisson regression models fit to each outcome that included the group indicator, study center, maternal age, maternal race/ethnicity (black, white, Hispanic, other), maternal education at the time of delivery (less than high school degree, high school degree, partial college/trade or technical school, college degree or more, missing), maternal antenatal steroid use, multiple birth, infant sex, GA (categorical), and BW (continuous).
At follow-up, 31 of the 71 children with SBS (44%) were independently feeding themselves compared to 65% of children with sNEC/SIP without SBS and 78% of those without NEC/SIP/SBS (p<0.001). Eight children (11%) with SBS continued to receive parenteral nutrition compared to one child (0.3%) with sNEC/SIP without SBS and 7 (0.2%) of those without NEC/SIP/SBS (p<0.001). Tube feedings were received by 23 children (32%) with SBS, 17% of those with sNEC/SIP without SBS and 9% of those without these diagnoses. Over half of the children with SBS were receiving high calorie supplements (63%) compared to 42% and 27% in the other two groups (p<0.001). Mean z-scores for weight, length, and head circumference were close to zero at birth in all groups, and decreased between one and two standard deviations at 36 weeks PMA (Figure 2). Decreases for infants with SBS did not differ significantly compared to infants with sNEC/SIP without SBS, but were lower on all measures compared to infants with no NEC/SIP/SBS (p<0.001 for each). At 18–26 months CA, z-scores had improved in all groups but continued to be lower than at birth.
Figure 2.
Mean z-scores for sex and age at birth, 36 weeks postmenstrual age (PMA), and 18-26 months corrected age in children who attended follow-up. Narrow bars show 95% CIs.
Discussion
Despite many advances in neonatal care, necrotizing enterocolitis continues to be a major complication of premature birth and children with NEC/SIP are at increased risk for adverse neurodevelopmental outcome compared to unaffected peers.(4, 8, 9, 12) However, limited data are available on the neurodevelopmental outcomes of those who develop SBS as a consequence of this disease process.
Using the NRN database, Wadhawan et al found surviving preterm infants with a history of surgical NEC or SIP had a two-fold increased risk of death and/or moderate/severe neurodevelopmental impairment at 18–22 months compared to those who were unaffected(29). We now report that tSBS further modifies these outcomes; the proportion of children with moderate/severe neurodevelopmental impairment was larger and mean cognitive, language, and motor scores lower for children with sNEC/SIP and SBS than for children with sNEC/SIP without SBS. Our data are consistent with previous analyses by So and Chesley who reported that motor and cognitive delays are common in children with a history of neonatal intestinal failure in early childhood.(10–11)
Necrotizing enterocolitis continues to be an important cause of neonatal mortality in preterm infants. In our cohort, the proportion of infants who died before follow-up was largest among those with sNEC/SIP without SBS (45%) with smaller proportions among infants with sNEC/SIP and SBS (32%) and in those unaffected (21%). These patterns are similar to a prior 2008 report from the NRN (1) and a recent meta-analysis of infants with NEC.(2) Infants with sNEC/SIP without SBS may include those who died before or shortly after surgical intervention that could have preceded a diagnosis of SBS. Therefore, surviving infants without SBS may have been those with less severe disease. This potential selection bias may have impacted our findings.
There is a complex relationship between prematurity, neonatal morbidity and brain injury. In our study, infants with SBS were more likely to have neonatal morbidities such as BPD, late onset sepsis, and PVL, all known to be independently associated with adverse neurodevelopmental outcome. The additive effect of premature birth, compromised nutrition and increased risk of exposure to pro-inflammatory states due to bowel injury, chronic inflammation or blood stream infection is unknown. Animal and clinical models demonstrate that the developing white matter in the preterm brain is vulnerable to cytotoxic injury.(30, 31) We speculate that morbidities associated with a pro-inflammatory state likely modify the risk for adverse neurodevelopmental outcome in this population.
There is a positive correlation between nutrition, brain volume and ND outcomes at 2 years in children born preterm.(32) We tracked longitudinal growth outcome data in this high-risk population of premature children with a history of sNEC/SIP, and found deficits in weight, length, and head circumference measurements for infants with and without SBS that were sustained at follow-up. Children with sNEC with or without SBS were also more likely to have abnormal feeding at follow-up, which highlights the importance of close post-discharge nutritional management in these children.
A strength of our study was the ability to include comprehensive, prospectively collected data for preterm infants from 21 centers. Even though surgical NEC is a common complication of prematurity, SBS is a rare subgroup that is difficult to study. However, a limitation of our data collection was that we lacked detailed surgical data, including remaining bowel length or presence of an ileocecal valve. The definition of SBS was based on abstraction from the medical record which could result in over or under representation of the disease population. We have limited data on the use of lipid minimization strategies and therefore are unable to interpret any potential impact on outcome.
In conclusion, surviving preterm infants with sNEC/SIP and SBS were at greater risk for neurodevelopmental impairment and cognitive, language, and motor deficits at 18–26 months CA than children with sNEC/SIP without SBS. The impact of suboptimal nutrition during critical periods of brain development in this population needs further study to understand whether it independently modifies long term outcome in this population.
Acknowledgements
NRN Steering Committee Chair: Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011-present). Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006-2011).
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (UG1 HD27904) - Abbot R. Laptook, MD; Martin Keszler, MD; Betty R. Vohr, MD; Angelita M. Hensman, MS RNC-NIC; Barbara Alksninis, RNC PNP; Carmena Bishop; Robert T. Burke, MD MPH; Melinda Caskey, MD; Laurie Hoffman, MD; Katharine Johnson, MD; Mary Lenore Keszler, MD; Teresa M. Leach, MEd CAES; Elisabeth C. McGowan, MD; Bonnie E. Stephens, MD; Kristin Basso, MaT RN; Elisa Vieira, BSN RN; ; Emily Little BSN RN; Lucille St. Pierre BS; Victoria E. Watson, MS CAS.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (UG1 HD21364) - Michele C. Walsh, MD MS; Anna Maria Hibbs, MD MSCE; Nancy S. Newman, RN; Deanne E. Wilson-Costello, MD; Bonnie S. Siner, RN; Monika Bhola, MD; Gulgun Yalcinkaya, MD. Children’s Mercy Hospital (UG1 HD68284) - William E. Truog, MD; Eugenia K. Pallotto, MD MSCE; Howard W. Kilbride MD; Cheri Gauldin, RN BS CCRC; Anne Holmes RN MSN MBAHCM CCRC; Kathy Johnson RN, CCRC; Allison Scott, RNC-NIC BSN CCRC; Prabhu S. Parimi, MD; Lisa Gaetano, RN MSN.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (UG1 HD27853, UL1 TR77) - Brenda B. Poindexter, MD MS; Kurt Schibler, MD; Suhas G. Kallapur, MD; Kimberly Yolton, PhD; Barbara Alexander, RN; Teresa L. Gratton, PA; Cathy Grisby, BSN CCRC; Kristin Kirker, CRC; Lenora D. Jackson, CRC; Jean J. Steichen, MD; Sandra Wuertz, RN BSN CLC.
Duke University School of Medicine, University Hospital, University of North Carolina, Duke Regional Hospital, and WakeMed Health and Hospitals (UG1 HD40492, UL1 TR1117) - C. Michael Cotten, MD MHS; Ronald N. Goldberg, MD; Ricki F. Goldstein, MD; William F. Appendix (e-appended) Malcolm, MD; Patricia L. Ashley, MD PhD; Joanne Finkle, RN JD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Sandra Grimes, RN BSN; Kathryn E. Gustafson, PhD; Melody B. Lohmeyer, RN MSN; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN; Janice Wereszczak, CPNP-AC/PC; Stephen D. Kicklighter, MD; Ginger Rhodes-Ryan, ARNP MSN, NNP-BC.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (UG1 HD27851, UL1 TR454) - David P. Carlton, MD; Ellen C. Hale, RN BS CCRC; Yvonne Loggins, RN; Diane Bottcher, RN; Sheena L. Carter, PhD; Salathiel Kendrick-Allwood, MD; Maureen Mulligan LaRossa, RN; Colleen Mackie, RRT; Irma Seabrook, RRT; Gloria Smikle, PNP MSN; Lynn Wineski, NNP.
Eunice Kennedy Shriver National Institute of Child Health and Human Development - Rosemary D. Higgins, MD; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (UG1 HD27856, UL1 TR6) - Gregory M. Sokol, MD; Brenda B. Poindexter, MD MS; Anna M. Dusick, MD FAAP (deceased); Faithe Hamer, BS; Dianne E. Herron, RN; Abbey C. Hines, PsyD; Carolyn Lytle, MD MPH; Lucy C. Miller, RN BSN CCRC; Heike M. Minnich, PsyD HSPP; Lu Ann Papile, MD; Leslie Richard, RN; Lucy Smiley, CCRC; Leslie Dawn Wilson, BSN CCRC.
McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, and Memorial Hermann Southwest Hospital (UG1 HD21373) - Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Barbara J. Stoll, MD; Julie Arldt-McAlister, RN BSN; Katrina Burson, RN BSN; Allison G. Dempsey, PhD; Elizabeth Eason, MD; Patricia W. Evans, MD; Carmen Garcia, RN CCRP; Charles Green, PhD; Donna Hall, RN; Beverly Harris, RN BSN; Margarita Jiminez, MD MPH; Janice John, CPNP; Patrick M. Jones, MD MA; M. Layne Lillie, RN BSN; Karen Martin, RN; Sara C. Martin, RN BSN; Georgia E. McDavid, RN; Shawna Rodgers, RN BSN; Saba Khan Siddiki, MD; Daniel Sperry, RN; Emily K. Stephens, RN BSN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT (ASCP). Nationwide Children’s Hospital and the Ohio State University Medical Center (UG1 HD68278) - Pablo J. Sánchez, MD; Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN;Christine A. Fortney, PhD RN; Gail E. Besner; Nehal A. Parikh, MD.
RTI International (UG1 HD36790) - Abhik Das, PhD; Dennis Wallace, PhD; Marie G. Gantz, PhD; Jeanette O’Donnell Auman, BS; Margaret Crawford, BS; Jenna Gabrio, MPH; Jamie E. Newman, PhD MPH; Carolyn M. Petrie Huitema, MS; W. Kenneth Poole, PhD (deceased); Kristin M. Zaterka-Baxter, RN BSN.
Tufts Medical Center (U10 HD53119) - Ivan D. Frantz III, MD; John M. Fiascone, MD; Elisabeth C. McGowan, MD; Brenda L. MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN BSN; Paige T. Church, MD.
Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (UG1 HD27880, UL1 TR93) - Krisa P. Van Meurs, MD; David K. Stevenson, MD; Marian M. Adams, MD; M. Bethany Ball, BS CCRC; Barbara Bentley, PhD; Elizabeth Bruno, PhD; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN PNP; Lynne C. Huffman, MD; Magdy Ismael, MD MPH; Jean G. Kohn, MD MPH; Casey Krueger, PhD; Andrew Palmquist, RN; Melinda S. Proud, RCP; Nicholas H. St. John, PhD; Hali Weiss, MD.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (UG1 HD34216) - Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Kathleen G. Nelson, MD; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Stephanie A. Chopko, PhD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Fred J. Biasini, PhD; Kristen C. Johnston, MSN CRNP; Mary Beth Moses, PT MS PCS; Kathleen G. Nelson, MD; Cryshelle S. Patterson, PhD; Vivien A. Phillips, RN BSN; Julie Preskitt, MSOT MPH; Richard V. Rector, PhD; Sally Whitley, MA OTR-L FAOTA.
University of California - Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (UG1 HD68270) - Uday Devaskar, MD; Meena Garg, MD; Isabell B. Purdy, PhD CPNP; Teresa Chanlaw, MPH; Rachel Geller, RN BSN.
University of Iowa and Mercy Medical Center (UG1 HD53109, UL1 TR442) - Edward F. Bell, MD; Tarah T. Colaizy, MD MPH; Michelle L. Baack, MD; John A. Widness, MD; Jane E. Brumbaugh, MD; Michael J. Acarregui, MD MBA; Dan L. Ellsbury, MD; Karen J. Johnson, RN BSN; Jacky R. Walker, RN; Claire A. Goeke, RN; Diane L. Eastman, RN CPNP MA; Donia B. Campbell, RNC-NIC; Tracy L. Tud, RN.
University of New Mexico Health Sciences Center (UG1 HD53089, UL1 TR41) - Kristi L. Watterberg, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Sandra Brown, BSN; Janell Fuller, MD; Carol Hartenberger, BSN MPH; Jean R. Lowe, PhD; Rebecca A. Thomson, RN BSN; Sandra Sundquist Beauman, MSN RNC-NIC; Mary Hanson, RN BSN; Elizabeth Kuan RN BSN.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (UG1 HD68244) - Barbara Schmidt, MD MSc; Haresh Kirpalani, MB MSc; Sara B. DeMauro, MD MSCE; Aasma S. Chaudhary, BS RRT; Soraya Abbasi, MD; Toni Mancini, RN BSN CCRC; Dara M. Cucinotta, RN; Judy C. Bernbaum, MD; Marsha Gerdes, PhD; Hallam Hurt, MD; Jonathan Snyder, BSN RN.
University of Rochester Medical Center, Golisano Children’s Hospital, and the University at Buffalo Women’s and Children’s Hospital of Buffalo (UG1 HD68263, UL1 TR42) - Carl T. D’Angio, MD; Dale L. Phelps, MD; Ronnie Guillet, MD PhD; Gary J. Myers, MD; Satyan Lakshminrusimha, MD; Anne Marie Reynolds, MD; Linda J. Reubens, RN CCRC; Erica Burnell, RN; Ann Marie Scorsone, MS CCRC; Kyle Binion, BS; Constance Orme; Holly I.M. Wadkins, MA; Michael G. Sacilowski, MAT CCRC; Rosemary L. Jensen; Joan Merzbach, LMSW; William Zorn, PhD; Osman Farooq, MD; Dee Maffett, RN; Ashley Williams, MSEd; Julianne Hunn, BS; Stephanie Guilford, BS; Kelley Yost, PhD; Mary Rowan, RN; Diane Prinzing; Karen Wynn, RN; Melissa Bowman, RN NP.
University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children’s Medical Center Dallas (UG1 HD40689) - Myra H. Wyckoff, MD; Luc P. Brion, MD; Pablo J. Sánchez, MD; Roy J. Heyne, MD; Diana M. Vasil, MSN BSN RNC-NIC; Sally S. Adams, MS RN CPNP; Lijun Chen, RN PhD; Maria M. De Leon, RN BSN; Francis Eubanks, RN BSN; Alicia Guzman; Elizabeth T. Heyne, MS MA PA-C PsyD; Lizette E. Lee, RN; Melissa H. Leps, RN; Linda A. Madden, BSN RN CPNP; Nancy A. Miller, RN; Janet S. Morgan, RN; Lara Pavageau, MD; Pollieanna Sepulveda, RN; Cathy Twell Boatman, MS CIMI.
University of Utah University Hospital, Intermountain Medical Center, McKay-Dee Hospital, Utah Valley Hospital, and Primary Children’s Medical Center (UG1 HD87226, U10 HD53124, UL1 RR25764) - Bradley A. Yoder, MD; Mariana Baserga, MD MSCI; Roger G. Faix, MD; Stephen D. Minton, MD; Mark J. Sheffield, MD; Carrie A. Rau, RN BSN CCRC; Sarah Winter, MD; Karen A. Osborne, RN BSN CCRC; Cynthia Spencer, RNC; Kimberlee Weaver-Lewis, RN MS; Shawna Baker, RN; Jill Burnett, RNC; Mike Steffen, PhD; Manndi C. Loertscher, BS CCRP; Kathryn D. Woodbury, RN BSN; Brixen A. Reich, RNC BSN CCRC; Susan T. Schaefer, RRT RN BSN; Laura Cole-Bledsoe, RN; Jennifer O. Elmont, RN ASN; D. Melody Parry, RN BSN; Trisha Marchant, RN; Susan Christensen, RNC BSN; Earl Maxson, BSN; Brandy Davis, RN.
Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (UG1 HD21385) - Seetha Shankaran, MD; Beena G. Sood, MD MS; Athina Pappas, MD; Girija Natarajan, MD; Sanjay Chawla, MD; Monika Bajaj, MD; Rebecca Bara, RN BSN; Kirsten Childs, RN BSN; Bogdan Panaitescu, MD; Mary E. Johnson, RN BSN; Laura A. Goldston, MA; Stephanie A. Wiggins, MS; Mary K. Christensen, BA RRT; Martha Carlson, MD; John Barks, MD.
Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 TR142) - Richard A. Ehrenkranz, MD; Harris Jacobs, MD; Christine G. Butler, MD; Patricia Cervone, RN; Sheila Greisman, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Janet Taft, RN BSN; Joanne Williams, RN BSN; Elaine Romano, MSN.
Funding:
The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (U10 HD27871, U10 HD53119, UG1 HD21364, UG1 HD21373, UG1 HD21385, UG1 HD27851, UG1 HD27853, UG1 HD27856, UG1 HD27880,UG1 HD27904, UG1 HD34216, UG1 HD36790, UG1 HD40492, UG1 HD40689, UG1 HD53089, UG1 HD53109, UG1 HD68244, UG1 HD68270, UG1 HD68278, UG1 HD68263, UG1 HD68284, UG1 HD87226, UG1 HD87229) and the National Center for Advancing Translational Sciences (NCATS) (UL1 TR6, UL1 TR41, UL1 TR42, UL1 TR77, UL1 TR93, UL1 TR442, UL1 TR454, UL1 TR1117) provided grant support through cooperative agreements for the Neonatal Research Network’s Generic Database and Follow-up Studies. NICHD staff provided input into the study design, conduct, analysis, and manuscript drafting; NCRR and NCATS cooperative agreements provided infrastructure support to the NRN. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations:
- BPD
Bronchopulmonary dysplasia
- CA
corrected age
- EOS
early onset sepsis
- GA
gestational age
- ICH
Intracranial hemorrhage
- LOS
late onset sepsis
- NDI
moderate/severe neurodevelopmental impairment
- NICHD
National Institute of Child Health and Human Development
- PDA
patent ductus arteriosus
- PMA
postmenstrual age
- PVL
periventricular leukomalacia
- RDS
Respiratory distress syndrome
- ROP
retinopathy of prematurity
- SIP
spontaneous intestinal perforation
- SBS
short bowel syndrome
- sNEC
surgical necrotizing enterocolitis
Footnotes
Disclosures:
Coauthors do not have any financial disclosures or conflicts of interest.
Data Sharing:
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
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