Betty R. Vohr

Growth in the Neonatal Intensive Care Unit Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants

OBJECTIVES. The objectives of this study were to assess whether (1) in-hospital growth velocity is predictive of neurodevelopmental and growth outcomes at 18 to 22 months’ corrected age among extremely low birth weight (ELBW) infants and (2) in-hospital growth velocity contributes to these outcomes after controlling for confounding demographic and clinical variables. METHODS. Infants 501 to 1000 g birth weight from a multicenter cohort study were divided into quartiles of in-hospital growth velocity rates. Variables considered for the logistic-regression models included gender, race, gestational age, small for gestational age, mother’s education, severe intraventricular hemorrhage, periventricular leukomalacia, age at regaining birth weight, necrotizing enterocolitis, late-onset infection, bronchopulmonary dysplasia, postnatal steroid therapy for pulmonary disease, and center. RESULTS. Of the 600 discharged infants, 495 (83%) were evaluated at 18 to 22 months’ corrected age. As the rate of weight gain increased between quartile 1 and quartile 4, from 12.0 to 21.2 g/kg per day, the incidence of cerebral palsy, Bayley II Mental Developmental Index (MDI) <70 and Psychomotor Developmental Index (PDI) <70, abnormal neurologic examination, neurodevelopmental impairment, and need for rehospitalization fell significantly. Similar findings were observed as the rate of head circumference growth increased. The in-hospital rate of growth was associated with the likelihood of anthropometric measurements at 18 months’ corrected age below the 10th percentile values of the Centers for Disease Control and Prevention 2000 growth curve. Logistic-regression analyses, controlling for potential demographic or clinical cofounders, and adjusted for center, identified a significant relationship between growth velocity and the likelihood of cerebral palsy, MDI and PDI scores of <70, and neurodevelopmental impairment. CONCLUSIONS. These analyses suggest that growth velocity during an ELBW infant’s NICU hospitalization exerts a significant, and possibly independent, effect on neurodevelopmental and growth outcomes at 18 to 22 months’ corrected age.

Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.

Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks’ gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for ≥28 days but not at 36 weeks’ postmenstrual age (PMA) or discharge, moderate BPD as O2 for ≥28 days plus treatment with <30% O2 at 36 weeks’ PMA, and severe BPD as O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36 weeks’ PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. Methods. Data from 4866 infants (birth weight ≤1000 g, GA <32 weeks, alive at 36 weeks’ PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months’ corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks’ PMA (36 weeks’ definition), and with the consensus definition of BPD. Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months’ corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

Beneficial Effects of Breast Milk in the Neonatal Intensive Care Unit on the Developmental Outcome of Extremely Low Birth Weight Infants at 18 Months of Age

OBJECTIVE. Beneficial effects of breast milk on cognitive skills and behavior ratings have been demonstrated previously in term and very low birth weight infants. Extremely low birth weight infants are known to be at increased risk for developmental and behavior morbidities. The benefits of breast milk that is ingested in the NICU by extremely low birth weight infants on development and behavior have not been evaluated previously. METHODS. Nutrition data including enteral and parenteral feeds were collected prospectively, and follow-up assessments of 1035 extremely low birth weight infants at 18 months’ corrected age were completed at 15 sites that were participants in the National Institute of Child Health and Human Development Neonatal Research Network Glutamine Trial between October 14, 1999, and June 25, 2001. Total volume of breast milk feeds (mL/kg per day) during hospitalization was calculated. Neonatal characteristics and morbidities, interim history, and neurodevelopmental and growth outcomes at 18 to 22 months’ corrected age were assessed. RESULTS. There were 775 (74.9%) infants in the breast milk and 260 (25.1%) infants in the no breast milk group. Infants in the breast milk group were similar to those in the no breast milk group in every neonatal characteristic and morbidity, including number of days of hospitalization. Mean age of first day of breast milk for the breast milk infants was 9.3 ± 9 days. Infants in the breast milk group began to ingest non–breast milk formula later (22.8 vs 7.3 days) compared with the non–breast milk group. Age at achieving full enteral feeds was similar between the breast milk and non–breast milk groups (29.0 ± 18 vs 27.4 ± 15). Energy intakes of 107.5 kg/day and 105.9 kg/day during the hospitalization did not differ between the breast milk and non–breast milk groups, respectively. At discharge, 30.6% of infants in the breast milk group still were receiving breast milk. Mothers in the breast milk group were significantly more likely to be white (42% vs 27%), be married (50% vs 30%), have a college degree (22% vs 6%), and have private health insurance (34% vs 18%) compared with the no breast milk group. Mothers who were black, had a low household income (≤

Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks' gestation between 1993 and 1998.

20000), or had higher parity were less likely to provide breast milk feeds. The analysis of outcomes between the any human milk and no human milk groups were adjusted for maternal age, maternal education, marital status, race/ethnicity, and the other standard covariates. Children in the breast milk group were more likely to have a Bayley Mental Development Index ≥85, higher mean Bayley Psychomotor Development Index, and higher Bayley Behavior Rating Scale percentile scores for orientation/engagement, motor regulation, and total score. There were no differences in the rates of moderate to severe cerebral palsy or blindness or hearing impairment between the 2 study groups. There were no differences in the mean weight (10.4 kg vs 10.4 kg), length (80.5 cm vs 80.5 cm), or head circumference (46.8 cm vs 46.6 cm) for the breast milk and no breast milk groups, respectively, at 18 months. Multivariate analyses, adjusting for confounders, confirmed a significant independent association of breast milk on all 4 primary outcomes: the mean Bayley (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and incidence of rehospitalization). For every 10-mL/kg per day increase in breast milk ingestion, the Mental Development Index increased by 0.53 points, the Psychomotor Development Index increased by 0.63 points, the Behavior Rating Scale percentile score increased by 0.82 points, and the likelihood of rehospitalization decreased by 6%. In an effort to identify a threshold effect of breast milk on Bayley Mental Development Index and Psychomotor Development Index scores and Behavior Rating Scale percentile scores, the mean volume of breast milk per kilogram per day during the hospitalization was calculated, and infants in the breast milk group were divided into quintiles of breast milk ingestion adjusted for confounders. Overall, the differences across the feeding quintiles of Mental Development Index and Psychomotor Development Index were significant. There was a 14.0% difference in Behavior Rating Scale scores between the lowest and highest quintiles. For the outcomes (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and Rehospitalization <1 year), only the values for the >80th percentile quintile of breast milk feeding were significantly different from the no breast milk values. In our adjusted regression analyses, every 10 mL/kg per day breast milk contributed 0.53 points to the Bayley Mental Development Index; therefore, the impact of breast milk ingestion during the hospitalization for infants in the highest quintile (110 mL/kg per day) on the Bayley Mental Development Index would be 10 × 0.53, or 5.3 points. CONCLUSIONS. An increase of 5 points potentially would optimize outcomes and decrease costs by decreasing the number of very low birth weight children who require special education services. The societal implications of a 5-point potential difference (one third of an SD) in IQ are substantial. The potential long-term benefit of receiving breast milk in the NICU for extremely low birth weight infants may be to optimize cognitive potential and reduce the need for early intervention and special education services.

The Rhode Island Hearing Assessment Program: experience with statewide hearing screening (1993-1996)

Objective. This study evaluated the impact of changes in perinatal management on neurodevelopmental impairment (NDI) at 18 to 22 months’ corrected age of low gestation (22–26 weeks) and higher gestation (27–32 weeks) extremely low birth weight infants (401–1000 g birth weight) who were cared for in the National Institute of Child Health and Human Development Neonatal Research Network during 3 epochs (1993–1994, 1995–1996, and 1997–1998). It was hypothesized that outcomes would improve over the 3 epochs. Methods. A multicenter cohort study was conducted of the outcomes of 3785 infants with assessments at 18 to 22 months’ corrected age. Regression analyses were completed to evaluate for epoch effects, gestational age effects, and time plus gestational age interaction. Regression analyses were also performed to identify the independent associations of epoch and 4 study perinatal interventions: antenatal steroids (yes, no), high-frequency ventilation (yes, no), number of days to regain birth weight as a marker of nutritional intake, and postnatal steroids for treatment of bronchopulmonary dysplasia (yes, no) with outcomes. Results. Survival improved for both the low (55%–61%) and higher (82%–86%) gestational age groups during the 3 epochs. Regression analyses indicated that the decreased risk for adverse outcome was significantly lower in epoch 2 compared with epoch 1 with decreased rates of low Bayley Mental Development Index (MDI) and neurodevelopmental impairment (NDI). Antenatal steroids were associated with decreased risk for moderate to severe cerebral palsy (CP) and low Bayley Psychomotor Development Index. High-frequency ventilation was associated with a low Bayley MDI and NDI, and postnatal steroids were associated with moderate to severe CP, any CP, low Bayley MDI, low Bayley Psychomotor Development Index, and increased NDI. Conclusion. Survival of extremely low birth weight infants improved between 1993 and 1998. Although some outcomes remained unchanged, the rates of low Bayley MDI scores and NDI improved. Antenatal steroid administration was the only study intervention associated with improved outcomes.

Persistent Beneficial Effects of Breast Milk Ingested in the Neonatal Intensive Care Unit on Outcomes of Extremely Low Birth Weight Infants at 30 Months of Age

OBJECTIVE The objective of this study was to evaluate key outcomes of a universal hearing screen/rescreen program for all births with transient evoked otoacoustic emissions in all 8 maternity hospitals in the state of Rhode Island over a 4-year period. STUDY DESIGN This was a retrospective analysis of the hearing screen/rescreen refer data collected prospectively for 53,121 survivors born in Rhode Island between January 1, 1993, and December 31, 1996. Primary outcomes included the first-stage refer rates, rescreen compliance, diagnostic referral rates, identification rates, and the age of amplification. RESULTS During this 4-year time period 11 infants were identified with permanent hearing loss, resulting in an impairment rate of 2 per 1000. The mean age of hearing loss confirmation decreased from 8.7 months to 3.5 months, and the age at amplification declined from 13.3 months to 5.7 months. CONCLUSION We conclude that time and experience are important factors in the development and refinement of a universal hearing screen program. Hearing screen outcome data collected over a 4-year period in Rhode Island reveal a steady improvement in the percent of infants completing the 2-stage screen process, the stage 1 and stage 2 refer rates, compliance with rescreen and diagnostic testing, and significant improvement in the age of identification and age of amplification.

Delayed cord clamping in very preterm infants reduces the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial.

BACKGROUND. We previously reported beneficial effects of breast milk ingestion by infants with extremely low birth weight in the NICU on developmental outcomes at 18 months’ corrected age. The objective of this study was to determine whether these effects of breast milk in infants with extremely low birth weight persisted at 30 months’ corrected age. METHODS. Nutrition data, including enteral and parenteral feeds, were prospectively collected, and 30 months’ corrected age follow-up assessments were completed on 773 infants with extremely low birth weight who participated in the National Institute of Child Health and Human Development Neonatal Research Network Glutamine Trial. A total of 593 ingested some breast milk during the neonatal hospitalization, and 180 ingested none. Neonatal feeding characteristics and morbidities and 30-month interim history, neurodevelopmental outcomes, and growth parameters were analyzed. Children were divided into quintiles of breast milk volume to evaluate the effects of volume of human milk ingested during the NICU hospitalization. RESULTS. At 30 months, increased ingestion of breast milk was associated with higher Bayley Mental Developmental Index scores, higher Bayley behavior score percentiles for emotional regulation, and fewer rehospitalizations between discharge and 30 months. There were no differences in growth parameters or cerebral palsy. For every 10 mL/kg per day increase in breast milk, the Mental Developmental Index increased by 0.59 points, the Psychomotor Developmental Index by 0.56 points, and the total behavior percentile score by 0.99 points, and the risk of rehospitalization between discharge and 30 months decreased by 5%. CONCLUSIONS. Beneficial effects of ingestion of breast milk in the NICU persist at 30 months’ corrected age in this vulnerable extremely low birth weight population. Continued efforts must be made to offer breast milk to all extremely low birth weight infants both in the NICU and after discharge.

Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants

OBJECTIVE. This study compared the effects of immediate (ICC) and delayed (DCC) cord clamping on very low birth weight (VLBW) infants on 2 primary variables: bronchopulmonary dysplasia (BPD) and suspected necrotizing enterocolitis (SNEC). Other outcome variables were late-onset sepsis (LOS) and intraventricular hemorrhage (IVH). STUDY DESIGN. This was a randomized, controlled unmasked trial in which women in labor with singleton fetuses <32 weeks’ gestation were randomly assigned to ICC (cord clamped at 5–10 seconds) or DCC (30–45 seconds) groups. Women were excluded for the following reasons: their obstetrician refused to participate, major congenital anomalies, multiple gestations, intent to withhold care, severe maternal illnesses, placenta abruption or previa, or rapid delivery after admission. RESULTS. Seventy-two mother/infant pairs were randomized. Infants in the ICC and DCC groups weighed 1151 and 1175 g, and mean gestational ages were 28.2 and 28.3 weeks, respectively. Analyses revealed no difference in maternal and infant demographic, clinical, and safety variables. There were no differences in the incidence of our primary outcomes (BPD and suspected NEC). However, significant differences were found between the ICC and DCC groups in the rates of IVH and LOS. Two of the 23 male infants in the DCC group had IVH versus 8 of the 19 in the ICC group. No cases of sepsis occurred in the 23 boys in the DCC group, whereas 6 of the 19 boys in the ICC group had confirmed sepsis. There was a trend toward higher initial hematocrit in the infants in the DCC group. CONCLUSIONS. Delayed cord clamping seems to protect VLBW infants from IVH and LOS, especially for male infants.

Prematurely Born Children Demonstrate White Matter Microstructural Differences at 12 Years of Age, Relative to Term Control Subjects : An Investigation of Group and Gender Effects

BACKGROUND Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth. METHODS We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%). RESULTS Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation. CONCLUSIONS Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.).

Identification of neonatal hearing impairment : Evaluation of transient evoked otoacoustic emission, distortion product otoacoustic emission, and auditory brain stem response test performance

OBJECTIVE. The goal was to use diffusion tensor imaging to test the hypothesis that prematurely born children demonstrate long-term, white matter, microstructural differences, relative to term control subjects. METHODS. Twenty-nine preterm subjects (birth weight: 600–1250 g) without neonatal brain injury and 22 matched, term, control subjects were evaluated at 12 years of age with MRI studies, including diffusion tensor imaging and volumetric imaging; voxel-based morphometric strategies were used to corroborate regional diffusion tensor imaging results. Subjects also underwent neurodevelopmental assessments. RESULTS. Neurodevelopmental assessments showed significant differences in full-scale, verbal, and performance IQ and Developmental Test of Visual Motor Integration scores between the preterm and term control subjects. Diffusion tensor imaging studies demonstrated widespread decreases in fractional anisotropy (a measure of fiber tract organization) in the preterm children, compared with the control subjects. Regions included both intrahemispheric association fibers subserving language skills, namely, the right inferior frontooccipital fasciculus and anterior portions of the uncinate fasciculi bilaterally, and the deep white matter regions to which they project, as well as the splenium of the corpus callosum. These changes in fractional anisotropy occurred in subjects with significant differences in frontal, temporal, parietal, and deep white matter volumes. Fractional anisotropy values in the left anterior uncinate correlated with verbal IQ, full-scale IQ, and Peabody Picture Vocabulary Test-Revised scores for preterm male subjects. In addition, preterm male subjects were found to have the lowest values for fractional anisotropy in the right anterior uncinate fasciculus, and fractional anisotropy values in that region correlated with both verbal IQ and Peabody Picture Vocabulary Test-Revised scores for the preterm groups; these findings were supported by changes identified with voxel-based morphometric analyses. CONCLUSIONS. Compared with term control subjects, prematurely born children with no neonatal ultrasound evidence of white matter injury manifest changes in neural connectivity at 12 years of age.