The intrinsic connectivity distribution: a novel contrast measure reflecting voxel level functional connectivity.

Resting-state fMRI (rs-fMRI) holds promise as a clinical tool to characterize and monitor the phenotype of different neurological and psychiatric disorders. The most common analysis approach requires the definition of one or more regions-of-interest (ROIs). However this need for a priori ROI information makes rs-fMRI inadequate to survey functional connectivity differences associated with a range of neurological disorders where the ROI information may not be available. A second problem encountered in fMRI measures of connectivity is the need for an arbitrary correlation threshold to determine whether or not two areas are connected. This is problematic because in many cases the differences in tissue connectivity between disease groups and/or control subjects are threshold dependent. In this work we propose a novel voxel-based contrast mechanism for rs-fMRI, the intrinsic connectivity distribution (ICD), that neither requires a priori information to define a ROI, nor an arbitrary threshold to define a connection. We show the sensitivity of previous methods to the choice of connection thresholds and evaluate ICD using a survey study comparing young adults born prematurely to healthy term control subjects. Functional connectivity differences were found in hypothesized language processing areas in the left temporal-parietal areas. In addition, significant clinically-relevant differences were found between preterm and term control subjects, highlighting the importance of whole brain surveys independent of a priori information.

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVES: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants. METHOD: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. RESULTS: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONS: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

Fluid regimens in the first week of life may increase risk of patent ductus arteriosus in extremely low birth weight infants.

BACKGROUND: High fluid volumes may increase neonatal morbidity. However, evidence supporting fluid restriction is inconclusive and restricting fluids may restrict caloric intake. OBJECTIVE: To determine if higher fluid intake was associated with increased risk of patent ductus arteriosus (PDA) or bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. STUDY DESIGN: A total of 204 ELBW (170 ml kg(-1) day(-1)) in the first days of life is associated with increased risk of PDA.

Effects of a transition home program on preterm infant emergency room visits within 90 days of discharge.

OBJECTIVE: To evaluate effects of a transition home program (THP) and risk factors on emergency room (ER) use within 90 days of discharge for preterm (PT) infants <37 weeks gestation. STUDY DESIGN: This is a prospective 3-year cohort study of 804 mothers and 954 PT infants. Mothers received enhanced neonatal intensive care unit transition support services until 90 days postdischarge. Regression models were run to identify the effects of THP implementation year and risk factors on ER visits. RESULTS: Of the 954 infants, 181 (19%) had ER visits and 83/181 (46%) had an admission. In regression analysis, THP year 3 vs year 1 and human milk at discharge were associated with decreased risk of ER visits, whereas increased odds was associated with non-English speaking, maternal mental health disorders and bronchopulmonary dysplasia. CONCLUSION: Enhanced THP services were associated with a 33% decreased risk of all ER visits by year 3. Social and environmental risk factors contribute to preventable ER visits.

Postpartum contraception needs of women with preterm infants in the neonatal intensive care unit.

OBJECTIVES: To evaluate postpartum contraception experiences of mothers with premature infants in the neonatal intensive care unit (NICU), their knowledge of risk factors for preterm delivery and their interest in a family planning clinic located near the NICU. STUDY DESIGN: This is a cross-sectional survey of English or Spanish-speaking women 18 or older whose premature neonate had been in the NICU for 5 days or more in a current stable condition. RESULTS: A total of 95 women were interviewed at a median of 2.7 weeks postpartum (range 0.6-12.9). Approximately 75% of women were currently using or planning to use contraception, with 33% using less effective methods. Half of women reported they would obtain contraception at a family planning clinic near the NICU. Only 32% identified a short interpregnancy interval as a risk factor for preterm delivery. CONCLUSION: Lack of knowledge of short interpregnancy interval as a risk factor for a future preterm delivery highlights the need to address postpartum contraception education and provision in this high-risk population.

Growth patterns of large-for-gestational-age and appropriate-for-gestational-age infants of gestational diabetic mothers and control mothers at age 1 year.

OBJECTIVE: The purpose of this study was to explore the development of adiposity in macrosomic and normosomic infants of mothers with gestational diabetes mellitus (GDM) and control subjects between birth and age 1 year, and assess its relation to maternal prenatal factors and neonatal factors. RESEARCH DESIGN AND METHODS: This was a prospective observational study of 192 infants, including 47 large-for-gestational-age (LGA) infants of GDM mothers, 47 appropriate-for-gestational-age (AGA) infants of GDM mothers, 55 LGA control infants, and 44 AGA control infants who were evaluated at birth and age 1 year. Maternal prenatal and pregnancy anthropometric measurements were recorded. Multiple infant anthropometric measurements, including skinfold thicknesses, were obtained at birth and age 1 year. Regression models were run to detect the independent effects of various maternal and infant factors on 1-year child adiposity, adjusting for their effects at birth. RESULTS: LGA infants of GDM mothers had a higher BMI, waist circumference, and abdominal skinfold at age 1 year compared with all other study groups. Among infants of GDM mothers, the mean 2-h postprandial glucose value for the second and third trimester correlated with waist circumference (r = 0.28, P < 0.04) and subscapular skinfold (r = 0.37, P < 0.007), and correlated marginally with 1-year sum of four skinfolds. Among infants of GDM mothers, a regression of 1-year sum of four skinfolds was significantly related to maternal prepregnancy weight after controlling for sum of skinfolds at birth. For control infants, the maternal glucose screen value was significantly associated with 1-year sum of skinfolds adjusted for the birth sum of skinfolds. CONCLUSIONS: We concluded that macrosomic infants of GDM mothers have unique patterns of adiposity that are present at birth and persist at age 1 year. Further, we concluded that maternal factors, including adiposity and intrauterine fuel environment, influence the presence and distribution of adiposity for both infants of GDM mothers and control infants.

Lipid levels in former gestational diabetic mothers.

OBJECTIVE: To investigate lipid levels in former gestational diabetic mothers, 5-6 years postpartum, and to evaluate the relationship of these values to glucose, insulin, BMI, and blood pressure. RESEARCH DESIGN AND METHODS: The subjects studied were 56 former gestational diabetic mothers and 48 control mothers 5-6 years postpartum. Two hours after a 50-g carbohydrate meal, total cholesterol (TC), triglycerides (TG), HDL and LDL cholesterol, glucose, and insulin were measured and compared between the two groups (analysis of variance). BMI and blood pressure were also evaluated. The risk of finding an abnormal metabolic, anthropometric, or hemodynamic parameter in either group was assessed (chi 2 analysis and Fisher's exact test). Correlation coefficients were assessed between the lipids versus insulin, glucose, BMI, and blood pressure. RESULTS: Mean TC, TG, LDL cholesterol, glucose, and systolic blood pressure were significantly higher in the gestational diabetic mothers than in the control mothers. In addition, there was greater likelihood of finding an abnormal TC > or = 5.17 mmol/l, LDL cholesterol > or = 4.14 mmol/l, and systolic blood pressure > 140 mmHg in gestational diabetic mothers. Triglycerides correlated with BMI, insulin, systolic and diastolic blood pressure, and HDL cholesterol correlated inversely with insulin in gestational diabetic mothers. CONCLUSIONS: We conclude that at 5-6 years postpartum, former gestational diabetic mothers demonstrate changes in lipid levels that differ from control mothers and that specific lipids correlate with cardiovascular risk factors. Further study is needed to evaluate gestational diabetic mothers for the development of cardiovascular risk factors including insulin resistance.

Effects of maternal gestational diabetes on offspring adiposity at 4-7 years of age.

OBJECTIVE: The purpose of this study was to assess the long-term effects of maternal prenatal factors, including gestational diabetes mellitus (GDM), adiposity, and weight gain during pregnancy, on adiposity of offspring from 4 to 7 years of age. A second purpose was to investigate the relationships among childhood adiposity, blood pressure, and 2-h postprandial glucose level. RESEARCH DESIGN AND METHODS: Prospective observational study of four groups of children including large-for-gestational-age (LGA) offspring of mothers with gestational diabetes (OGDM); appropriate-for-gestational-age (AGA) OGDM; LGA control subjects; and AGA control subjects. Anthropometrics including skin-fold measurements, blood pressure measurements, and a 2-h postprandial glucose measurement were obtained at each visit. Repeated measures analysis of variance models were used to detect different patterns of longitudinal change among the groups. RESULTS: LGA OGDM were more likely to be heavier, have larger circumferences and skin-fold measurements, and have a higher BMI than AGA OGDM and control subjects, and these findings increased with increasing age. Blood pressures and postprandial glucose values were similar for OGDM and control subjects at 4-7 years. Multivariable analyses showed that infant BMI and maternal prepregnant BMI predicted 7-year BMI for OGDM, whereas for control subjects, maternal prepregnancy BMI and weight gain during pregnancy were positive predictors with a small negative contribution from birth BMI. CONCLUSIONS: We conclude that LGA OGDM have evidence of increasing body size and adiposity with increasing age and that maternal GDM and maternal prepregnant adiposity are significant predictors of their unique growth patterns.

Effects of maternal gestational diabetes and adiposity on neonatal adiposity and blood pressure.

OBJECTIVE: To determine the effects of maternal factors, including prepregnancy maternal adiposity, weight gain during pregnancy, degree of abnormality of the glucose tolerance test, glycemia during pregnancy, and treatment with insulin versus diet therapy, on neonatal body weight, adiposity, and blood pressure in infants of mothers with gestational diabetes (IGDM) and control patients. RESEARCH DESIGN AND METHODS: A total of 119 term IGDM, including 57 large-for-gestational-age (LGA) and 62 appropriate-for-gestational-age (AGA) infants, and 143 term control infants, including 74 LGA and 69 AGA infants, were prospectively enrolled. Maternal measurements of prepregnancy weight, height, and weight gain were abstracted from medical records. A diagnosis of gestational diabetes was made on the basis of an initial 1-h 50-g glucose screen value > or = 130 mg/dl followed by two abnormal values in a 100-g oral glucose tolerance test. Infant anthropometric measurements were obtained, and blood pressure was measured on day 2 of life. Correlation analyses and multiple regression analyses were performed to assess the relationships among maternal factors and neonatal adiposity and blood pressure. RESULTS: Multiple regression analyses to determine the effects of significant maternal factors on infant body mass index (BMI) revealed that prepregnancy weight and weight gain were significant predictors for both IGDM and control infants. An increased glucose screen predicted BMI for control subjects, whereas the mean 2nd and 3rd trimester glucose values were the significant predictors for IGDM. Also, increased newborn triceps skinfold thickness measurements correlated with increased systolic blood pressure for IGDM (r = 0.29, P < 0.03). CONCLUSIONS: Increased maternal prepregnancy weight, weight gain in pregnancy, and glycemia in pregnancy all place IGDM at increased risk of macrosomia and adiposity. Increased adiposity in the IGDM appears to be related to increased infant blood pressure. Longitudinal evaluation is needed to determine whether neonatal adiposity in IGDM is predictive of increased adiposity and blood pressure during childhood.

Do currently recommended Bayley-III cutoffs overestimate motor impairment in infants born <27 weeks gestation?

OBJECTIVE: To determine whether a Bayley-III motor composite score of 85 may overestimate moderate-severe motor impairment by analyzing Bayley-III motor components and developing cut-point scores for each. STUDY DESIGN: Retrospective study of 1183 children born <27 weeks gestation at NICHD Neonatal Research Network centers and evaluated at 18-22 months corrected age. Gross Motor Function Classification System determined gross motor impairment. Statistical analyses included linear and logistic regression and sensitivity/specificity. RESULTS: Bayley-III motor composite scores were strong indicators of gross/fine motor impairment. A motor composite cut-point of 73 markedly improved the specificity for identifying gross and/or fine motor impairment (94% compared with a specificity of 76% for the proposed new cut-point of 85). A Fine Motor Scaled Score <3 differentiated mild from moderate-severe fine motor impairment. CONCLUSIONS: This study indicates that a Bayley-III motor composite score of 85 may overestimate impairment. Further studies are needed employing term controls and longer follow-up.

Age of diphtheria, tetanus, and pertussis immunization of special care nursery graduates.

Diphtheria, tetanus, and pertussis (DTP) immunization data were collected on 103 special care nursery graduates in our neonatal follow-up clinic to determine whether DTP immunization schedules were significantly delayed relative to recommendations of the American Academy of Pediatrics (2, 4, and 6 months for DTP 1, 2, and 3, respectively). An inverse correlation was found between birth weight and immunization for first, second, and third DTP (r = 0.319, P less than .01; r = .205, P less than .05; and r = .236, P less than .05, respectively). We subsequently conducted a mail survey to determine the DTP immunization policy present in effect in 25 neonatal intensive care units in the United States and Canada. The survey indicates that procedural approaches remain markedly heterogeneous, and 10 of 25 (40%) units have no existing policy for implementation of DTP immunization. These data suggest that special care nursery populations are at potential risk for pertussis, which requires a conscious implementation of DTP immunization by the special care nursery, the follow-up clinic personnel, and the primary care physician.

Neurodevelopmental and school performance of very low-birth-weight infants: a seven-year longitudinal study.

The changing patterns of neurologic and developmental functioning between 1 and 7 years of age were studied in very low-birth-weight infants (birth weight less than or equal to 1,500 g). Subjects included 42 infants born in 1975 who were followed for 7 years. Based on the 1-year neurologic assessment, 22 infants were classified as normal, 12 as suspect, and eight as abnormal. The three groups did not differ in birth weight, gestational age, sex, or Hollingshead socioeconomic status (SES) score. The neurologic findings at 7 years of age were significantly related to the neurologic examination findings at 1 year of age. Seventy-seven percent of the normal group, 58% of the suspect group, and 100% of the abnormal group remained in the same neurologic category at 7 years of age. Children in the abnormal group had the greatest improvement in cognitive functioning between 1 and 7 years of age but did not achieve the IQ level of children in the normal group. Forty-five percent of the normal group, 75% of the suspect group, and 100% of the abnormal group had poor visual-motor integration. Fifty-eight percent of the suspect group and 87% of the abnormal group were reading below age level. Of the total sample, 54% required special education or resource help at 7 years of age, and the three groups differed significantly in their need for a special educational plan (P less than .05). These data indicate that a neurologic classification at 1 year of age provides a guide for monitoring very low-birth-weight infants and can be helpful in alerting school personnel to potential needs.

Economic analysis of regionalized neonatal care for very low-birth-weight infants in the state of Rhode Island.

Cost-benefit analysis was utilized to evaluate the economic outcome of regionalized neonatal care in the state of Rhode Island, with specific reference to newborns weighing less than 1,500 g at birth. Two time periods consisting of two calendar years each, were analyzed: 1974 to 1975 (initiation of perinatal regionalization) and 1979 to 1980 (regionalization established). The neonatal mortality for infants weighing between 501 and 1,500 g decreased significantly between the two time periods. Neurodevelopmental morbidity was unchanged. The costs per survivor (hospital charges plus estimated costs of long-term care of handicapped survivors) were consistent over the time periods studied. The estimated benefits per survivor increased between the time periods, although this increase was not statistically significant. Benefits outweighed costs in both study periods. When one compares the economic data of 1974 to 1975 with that of 1979 to 1980, the increase in the absolute number of normal survivors since the establishment of regionalized neonatal care has resulted in benefits surpassing costs by $2 million (a greater than twofold increase). Regionalized neonatal care in the state of Rhode Island has had a positive economic outcome.

Cost-benefit analysis of neonatal intensive care for infants weighing less than 1,000 grams at birth.

Cost-benefit analysis was performed on the care of 247 infants weighing between 500 and 999 g at birth, admitted to Women and Infants Hospital of Rhode Island between January 1977 and December 1981. The neonatal mortality was 68%. Eighty-seven percent of the survivors were evaluated neurodevelopmentally for 1 to 5 years: 74% were normal or minimally impaired, 10% were moderately impaired, and 16% were severely handicapped. Using these data in conjunction with cost information obtained from the hospital and therapeutic care facilities for handicapped children, total lifetime costs for the care of these infants were estimated. In 1982 dollars, present values of costs ranged from $362,992 per survivor for those weighing between 600 and 699 g to $40,647 per survivor for those weighing between 900 and 999 g, resulting in an inverse correlation between cost per survivor and birth weight (P less than .001). We estimated present values of expected lifetime earnings per survivor, with a range of zero earnings for infants between 500 and 699 g, to $77,084 for those with birth weight of 900 to 999 g. It is concluded that from the standpoint of cost-benefit analysis as was used for this study population, neonatal intensive care may not be justifiable for infants weighing less than 900 g at birth.

Behavioral responsiveness in preterm infants with intraventricular hemorrhage.

Preterm infants with varying degrees of intraventricular hemorrhage (none, n = 21; grade I to II, n = 22; grade II to IV, n = 24) and a group of full-term infants (n = 21) were compared with regard to behavioral responsiveness and parental reports of the infant's temperament. Behavioral responsiveness was assessed during the presentation of 15 visual, auditory, and tactile stimuli at 3 months of age (corrected age for preterm infants). Summary scores for positive and negative responsiveness, as well as sociability, soothability, and overall activity levels, were derived from behavioral observations by coders who were unaware of the infant's characteristics. The Bates Infant Characteristic Questionnaire was completed by the main care giver and scored on four summary variables: fussy-difficult, unadaptable, dull, and unpredictable. Preterm infants, regardless of the presence or severity of intraventricular hemorrhage, showed less positive responses and less overall activity in response to stimulation. Infants with grade I to II intraventricular hemorrhage were less sociable and more difficult to soothe than full-term control infants. Individual differences in positive, negative, sociability, and soothability were related to the questionnaire scores of fussy-difficult and unadaptability. Both prematurity and degree of intraventricular hemorrhage affect behavioral responsiveness and these individual differences are related to parental reports of the infant's temperament.

Developmental outcome as a function of the goodness of fit between the infant's cry characteristics and the mother's perception of her infant's cry.

OBJECTIVE: To determine whether the "goodness of fit" between infant cry characteristics and the mother's perception of the cry is related to developmental outcome at 18 months of age. DESIGN: This was a prospective, longitudinal study from birth to 18 months performed in a blinded manner. SETTING: The study was conducted in a maternity hospital, including normal and special care nurseries and a laboratory for developmental follow-up. PATIENTS: The 121 term and preterm infants and their mothers were selected to meet medical criteria. MEASUREMENT: Acoustic analysis of 1-month infant cry and the mother's perception of the same cry was used to divide subjects into four groups representing matches and mismatches between infant cry characteristics and maternal cry perception. Primary outcome measures of cognitive, language, motor, and neurologic outcome were administered at 18 months. Caretaking environment measures were also recorded. RESULTS: Statistically significant (P < .05) findings showed that matched groups scored higher on measures of language and cognitive performance than infants in the mismatch groups, with a particular advantage for infants in the matched group in which mothers accurately perceived the higher-pitched cries of their infants. There were no differences between the groups in biologic or sociodemographic factors. Group differences were observed in social support and maternal self-esteem. CONCLUSIONS: Matches and mismatches between infant cry characteristics at 1 month and the mother's perception of the cry are related to cognitive and language outcome at 18 months in term and preterm infants. This relation is probably due to transactional processes in which developmental outcome is affected by the clarity of the infants' signals and by the ability of the mother to accurately perceive her infant's signals. The mother's ability to read her infant's cues may be affected by factors such as social support and self-esteem.

Outcome of children in the indomethacin intraventricular hemorrhage prevention trial.

BACKGROUND: For preterm infants, intraventricular hemorrhage (IVH) may be associated with adverse neurodevelopmental outcome. We have demonstrated that early low-dose indomethacin treatment is associated with a decrease in both the incidence and severity of IVH in very low birth weight preterm infants. In addition, we hypothesized that the early administration of low-dose indomethacin would not be associated with an increase in the incidence of neurodevelopmental handicap at 4.5 years of age in our study children. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for the 384 very low birth weight survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial. Three hundred thirty-seven children (88%) were evaluated at 54 months' corrected age, and underwent neurodevelopmental examinations, including the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Peabody Picture Vocabulary Test-Revised (PPVT-R), and standard neurologic examinations. RESULTS: Of the 337 study children, 170 had been randomized to early low-dose indomethacin therapy and 167 children had received placebo. Twelve (7%) of the 165 indomethacin children and 11 (7%) of the 158 placebo children who underwent neurologic examinations were found to have cerebral palsy. For the 233 English-monolingual children for whom cognitive outcome data follow, the mean gestational age was significantly younger for the children who received indomethacin than for those who received placebo. In addition, although there were no differences in the WPPSI-R or the PPVT-R scores between the 2 groups, analysis of the WPPSI-R full-scale IQ by function range demonstrated significantly less mental retardation among those children randomized to early low-dose indomethacin (for the indomethacin study children, 9% had an IQ <70, 12% had an IQ of 70-80, and 79% had an IQ >80, compared with the placebo group, for whom 17% had an IQ <70, 18% had an IQ of 70-80, and 65% had an IQ >80). Indomethacin children also experienced significantly less difficulty with vocabulary skills as assessed by the PPVT-R when compared with placebo children. CONCLUSIONS: These data suggest that, for preterm neonates, the early administration of low-dose indomethacin therapy is not associated with adverse neurodevelopmental function at 54 months' corrected age.

The etiology and outcome of cerebral ventriculomegaly at term in very low birth weight preterm infants.

BACKGROUND: Despite improvements in survival data, the incidence of neurodevelopmental handicaps in preterm infants remains high. To prevent these handicaps, one must understand the pathophysiology behind them. For preterm infants, cerebral ventriculomegaly (VM) may be associated with adverse neurodevelopmental outcome. We hypothesized that although the causes of VM are multiple, the incidence of handicap at 4.5 years of age in preterm infants with this ultrasonographic finding at term would be high. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for all 440 very low birth weight survivors of the Multicenter Randomized Indomethacin Intraventricular Hemorrhage (IVH) Prevention Trial. A total of 384 children (87%) were evaluated at 54 months' corrected age (CA), and 257 subjects were living in English-speaking, monolingual households and are included in the following data analysis. RESULTS: Moderate to severe low pressure VM at term was documented in 11 (4%) of the English-speaking, monolingual survivors. High grade IVH and bronchopulmonary dysplasia (BPD) were both risk factors for the development of VM. Of 11 (45%) children with VM, 5 suffered grades 3 to 4 IVH, compared with 2/246 (1%) children without VM who experienced grades 3 to 4 IVH. Similarly, 9/11 (82%) children with VM had BPD, compared with 120/246 (49%) children without VM who had BPD. Logistic regression analysis was performed using birth weight, gestational age, gender, Apgar score at 5 minutes, BPD, sepsis, moderate to severe VM, periventricular leukomalacia, grade of IVH, and maternal education to predict IQ <70. Although maternal education was an important and independent predictor of adverse cognitive outcome, in this series of very low birth weight prematurely born children, VM was the most important predictor of IQ <70 (OR: 19.0; 95% CI: 4.5, 80.6). Of children with VM, 6/11 (55%) had an IQ <70, compared with 31/246 (13%) of children without VM. Children with VM had significantly lower verbal and performance scores compared with children without VM. CONCLUSIONS: These data suggest that, for preterm neonates, VM at term is a consequence of the vulnerability of the developing brain. Furthermore, its presence is an important and independent predictor of adverse cognitive and motor development at 4.5 years' CA.

Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial.

OBJECTIVES: Low-dose indomethacin has been shown to prevent intraventricular hemorrhage (IVH) in very low birth weight neonates, and long-term neurodevelopmental follow-up data are needed to validate this intervention. We hypothesized that the early administration of low-dose indomethacin would not be associated with adverse cognitive outcome at 36 months' corrected age (CA). METHODS: We enrolled 431 neonates of 600 to 1250 g birth weight with no IVH at 6 to 12 hours in a randomized, prospective trial to determine whether low-dose indomethacin would prevent IVH. A priori, neurodevelopmental follow-up examinations, including the Stanford-Binet Intelligence Scale and Peabody Picture Vocabulary Test-Revised, and standard neurologic examinations were planned at 36 months' CA. RESULTS: Three hundred eighty-four of the 431 infants survived (192 [92%] of 209 infants receiving indomethacin versus 192 [86%] of 222 infants receiving saline), and 343 (89%) children were examined at 36 months' CA. Thirteen (8%) of the 166 infants who received indomethacin and 14 (8%) of 167 infants receiving the placebo were found to have cerebral palsy. There were no differences in the incidence of deafness or blindness between the two groups. For the 248 English-monolingual children for whom IQ data follow, the mean gestational age was significantly younger for the infants who received indomethacin than for those who received the placebo. None of the 115 infants who received indomethacin was found to have ventriculomegaly on cranial ultrasound at term, compared with 5 of 110 infants who received the placebo. The mean +/- SD Stanford-Binet IQ score for the 126 English-monolingual children who had received indomethacin was 89.6 +/- 18.92, compared with 85.0 +/- 20.79 for the 122 English-monolingual children who had received the placebo. Although maternal education was strongly correlated with Stanford-Binet IQ at 36 months' CA, there was no difference in educational levels between mothers of the infants receiving indomethacin and the placebo. CONCLUSIONS: Indomethacin administered at 6 to 12 hours as prophylaxis against IVH in very low birth weight infants does not result in adverse cognitive or motor outcomes at 36 months' CA.

Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial.

OBJECTIVES: Parenchymal involvement of intraventricular hemorrhage (IVH) is a major risk factor for neurodevelopmental handicap in very low birth weight neonates. Previous trials have suggested that indomethacin would lower the incidence and severity of IVH in very low birth weight neonates. METHODS: We enrolled 431 neonates of 600- to 1250-g birth weight with no evidence for IVH at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that low-dose indomethacin (0.1 mg/kg intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would lower the incidence and severity of IVH. Serial cranial ultrasound examinations and echocardiographs were performed. RESULTS: There were no differences in the birth weight, gestational age, sex, Apgar scores, and percent of neonates treated with surfactant between the indomethacin and placebo groups. Within the first 5 days, 25 (12%) indomethacin-treated and 40 (18%) placebo-treated neonates developed IVH (P = .03, trend test). Only one indomethacin-treated patient experienced grade 4 IVH compared with 10 placebo-treated neonates (P = .01). Sixteen indomethacin-treated neonates and 29 control neonates died (P = .08); there was a difference favoring indomethacin with respect to survival time (P = .06). Eighty-six percent of all neonates had a patent ductus arteriosus on the first postnatal day; indomethacin was associated with significant ductal closure by the fifth day of life (P < .001). There were no differences in adverse events attributed to indomethacin between the two treatment groups. CONCLUSIONS: Low-dose prophylactic indomethacin significantly lowers the incidence and severity of IVH, particularly the severe form (grade 4 IVH). In addition, indomethacin closes the patent ductus arteriosus and is not associated with significant adverse drug events in very low birth weight neonates.