Michael Vincer

Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants.

BACKGROUND The prophylactic administration of indomethacin reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage in very-low-birth-weight infants (those with birth weights below 1500 g). Whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in renal, intestinal, and cerebral blood flow is not known. METHODS Soon after they were born, we randomly assigned 1202 infants with birth weights of 500 to 999 g (extremely low birth weight) to receive either indomethacin (0.1 mg per kilogram of body weight) or placebo intravenously once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months. Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly within the same time frame. Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, ultrasonographic evidence of intracranial abnormalities, necrotizing enterocolitis, and retinopathy. RESULTS Of the 574 infants with data on the primary outcome who were assigned to prophylaxis with indomethacin, 271 (47 percent) died or survived with impairments, as compared with 261 of the 569 infants (46 percent) assigned to placebo (odds ratio, 1.1; 95 percent confidence interval, 0.8 to 1.4; P=0.61). Indomethacin reduced the incidence of patent ductus arteriosus (24 percent vs. 50 percent in the placebo group; odds ratio, 0.3; P<0.001) and of severe periventricular and intraventricular hemorrhage (9 percent vs. 13 percent in the placebo group; odds ratio, 0.6; P=0.02). No other outcomes were altered by the prophylactic administration of indomethacin. CONCLUSIONS In extremely-low-birth-weight infants, prophylaxis with indomethacin does not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of patent ductus arteriosus and severe periventricular and intraventricular hemorrhage.

Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy An Updated Systematic Review and Meta-analysis

OBJECTIVE To establish the evidence of therapeutic hypothermia for newborns with hypoxic ischemic encephalopathy(HIE). DATA SOURCES Cochrane Central Register of Controlled Trials, Oxford Database of Perinatal Trials, MEDLINE, EMBASE, and previous reviews. STUDY SELECTION Randomized controlled trials that compared therapeutic hypothermia to normothermia for newborns with HIE. INTERVENTION Therapeutic hypothermia. MAIN OUTCOME MEASURES Death or major neurodevelopmental disability at 18 months. RESULTS Seven trials including 1214 newborns were identified. Therapeutic hypothermia resulted in a reduction in the risk of death or major neurodevelopmental disability(risk ratio [RR], 0.76; 95% CI, 0.69-0.84) and increase in the rate of survival with normal neurological function (1.63; 1.36-1.95) at age 18 months. Hypothermia reduced the risk of death or major neurodevelopmental disability at age 18 months in newborns with moderate HIE (RR, 0.67; 95% CI, 0.56-0.81) and in newborns with severe HIE (0.83; 0.74-0.92). Both total body cooling and selective head cooling resulted in reduction in the risk of death or major neurodevelopmental disability(RR, 0.75; 95% CI, 0.66-0.85 and 0.77; 0.65-0.93,respectively). CONCLUSION Hypothermia improves survival and neurodevelopment in newborns with moderate to severe HIE.Total body cooling and selective head cooling are effective methods in treating newborns with HIE. Clinicians should consider offering therapeutic hypothermia as part of routine clinical care to these newborns.

Increasing Prevalence of Cerebral Palsy Among Very Preterm Infants: A Population-Based Study

OBJECTIVES. It is unclear whether declines in neonatal and infant mortality have led to changes in the occurrence of cerebral palsy. We conducted a study to examine and investigate recent temporal changes in the prevalence of cerebral palsy in a population-based cohort of very preterm infants who were 24 to 30 weeks of gestational age. METHODS. A population-based cohort of very preterm infants who were born between January 1, 1993, and December 31, 2002, was evaluated by the Perinatal Follow-up Program of Nova Scotia. Follow-up extended to age 2 years to ascertain the presence or absence of cerebral palsy and for overall survival. Infant survival and cerebral palsy rates were compared by year and also in two 5-year periods, 1993–1997 and 1998–2002. Logistic regression analyses were used to identify factors that potentially were responsible for temporal changes in cerebral palsy rates. RESULTS. A total of 672 liveborn very preterm infants were born to mothers who resided in Nova Scotia between 1993 and 2002. Infant mortality among very preterm infants decreased from 256 per 1000 live births in 1993 to 114 per 1000 live births in 2002, whereas the cerebral palsy rates increased from 44.4 per 1000 live births in 1993 to 100.0 per 1000 live births in 2002. Low gestational age, postnatal dexamethasone use, patent ductus arteriosus, severe hyaline membrane disease, resuscitation in the delivery room, and intraventricular hemorrhage were associated with higher rates of cerebral palsy, whereas antenatal corticosteroid use was associated with a lower rate. CONCLUSION. Cerebral palsy has increased substantially among very preterm infants in association with and possibly as a consequence of large declines in infant mortality.

Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion

BACKGROUND AND OBJECTIVE. Extremely low birth weight infants frequently receive red cell transfusions. We sought to determine whether a restrictive versus liberal hemoglobin transfusion threshold results in differences in death or adverse neurodevelopmental outcomes of extremely low birth weight infants. PATIENTS AND METHODS. Extremely low birth weight infants previously enrolled in the Preterm Infants in Need of Transfusion Trial, a randomized, controlled trial of low versus high hemoglobin transfusion thresholds, were followed up at 18 to 21 months’ corrected age. Erythrocyte transfusion was determined by an algorithm of low (restrictive) or high (liberal) hemoglobin transfusion thresholds, differing by 10 to 20 g/L and maintained until first hospital discharge. The primary composite outcome was death or the presence of cerebral palsy, cognitive delay, or severe visual or hearing impairment. RESULTS. Of 451 enrolled infants, the primary outcome was available in 430. There was no statistically significant difference in the primary outcome, found in 94 (45%) of 208 in the restrictive group and 82 (38%) of 213 in the liberal group. There were no statistically significant differences in preplanned secondary outcomes. However, the difference in cognitive delay (Mental Development Index score < 70) approached statistical significance. A posthoc analysis with cognitive delay redefined (Mental Development Index score < 85) showed a significant difference favoring the liberal threshold group. CONCLUSIONS. Maintaining the hemoglobin of extremely low birth weight infants at these restrictive rather than liberal transfusion thresholds did not result in a statistically significant difference in combined death or severe adverse neurodevelopmental outcome.

Effect of timing of cerebral ultrasonography on the prediction of later neurodevelopmental outcome in high-risk preterm infants

To determine the predictive value of cranial ultrasonographic examination in high-risk preterm infants at different postnatal ages, we scanned 110 infants less than or equal to 32 weeks gestational age at 1, 2, 3, and 6 weeks postnatal ages and at 40 weeks postconceptional age (PCA). Cranial abnormalities detected by ultrasonography at each postnatal age of examination were classified as minor (periventricular superolateral echogenicity with or without intraventricular hemorrhage, grades 1 to 3) or major (cystic periventricular leukomalacia with or without intraventricular hemorrhage, grade 4) and correlated with neurodevelopmental outcome determined by 1 year of age. Major abnormalities detected by ultrasonography were present in four infants at 1 week, four at 2 weeks, eight at 3 weeks, and 11 infants at 6 weeks and 40 weeks PCA, respectively. Nineteen infants (17%) had moderate to severe functional handicaps defined as cerebral palsy, cognitive or visual deficit, or deafness. The positive and negative predictive values of ultrasound examinations, with regard to later neurodevelopmental outcome, improved with increasing postnatal age at examination and was best at 40 weeks PCA. Negative results of ultrasound study at 40 weeks PCA most correctly predicted satisfactory outcome. Although only 58% of moderately to severely handicapped infants were correctly identified by ultrasound examination at 40 weeks PCA, all infants with major ultrasonographic abnormalities at 40 weeks PCA had moderate or severe handicap. Our data demonstrate that the timing of cerebral ultrasonography is important in the prediction of later neurodevelopmental outcome in high-risk preterm infants.

Determinants of developmental outcomes in a very preterm Canadian cohort

Objectives Identify determinants of neurodevelopmental outcome in preterm children. Methods Prospective national cohort study of children born between 2009 and 2011 at <29 weeks gestational age, admitted to one of 28 Canadian neonatal intensive care units and assessed at a Canadian Neonatal Follow-up Network site at 21 months corrected age for cerebral palsy (CP), visual, hearing and developmental status using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Stepwise regression analyses evaluated the effect of (1) prenatal and neonatal characteristics, (2) admission severity of illness, (3) major neonatal morbidities, (4) neonatal neuroimaging abnormalities, and (5) site on neurodevelopmental impairment (NDI) (Bayley-III score < 85, any CP, visual or hearing impairment), significant neurodevelopmental impairment (sNDI) (Bayley-III < 70, severe CP, blind or hearing aided and sNDI or death. Results Of the 3700 admissions without severe congenital anomalies, 84% survived to discharge and of the 2340 admissions, 46% (IQR site variation 38%–51%) had a NDI, 17% (11%–23%) had a sNDI, 6.4% (3.1%–8.6%) had CP, 2.6% (2.5%–13.3%) had hearing aids or cochlear implants and 1.6% (0%–3.1%) had a bilateral visual impairment. Bayley-III composite scores of <70 for cognitive, language and motor domains were 3.3%, 10.9% and 6.7%, respectively. Gestational age, sex, outborn, illness severity, bronchopulmonary dysplasia, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity, abnormal neuroimaging and site were significantly associated with NDI or sNDI. Site variation ORs for NDI, sNDI and sNDI/death ranged from 0.3–4.3, 0.04–3.5 and 0.12–1.96, respectively. Conclusion Most preterm survivors are free of sNDI. The risk factors, including site, associated with neurodevelopmental status suggest opportunities for improving outcomes.

Language development in low birth weight infants: the first two years of life.

ABSTRACT. The four main aims of this cohort study were to (1) determine the number of consecutively referred low birth weight (LBW) infants presenting with delayed language at 12 and 24 months of age, (2) examine language profiles by measuring both functional and spontaneous language ability in 24-month-olds, (3) examine the relationship between perinatal medical history and language status at 12 and 24 months, and (4) examine the clinical validity of the Early Language Milestone (ELM) scale, a brief language screening instrument. Only infants without serious sensory impairment or mental handicap were included in the final sample. Seventy-one LBW infants (36 12-month-olds, 35 24-month-olds) were seen for developmental and language assessments. The findings suggest that within the first 2 years of life, low to moderate rates of language delay are evident in LBW infants who have already been screened for serious sensory or mental handicap. At 12 months of age, 8.3% of the infants had delayed expressive language; none had delayed receptive language. At 24 months of age, 28% of the infants had delayed expressive language; 5.7% had delayed receptive language. Furthermore, only 32% of those with normal expressive language and sufficient language sample had a mean length of response within the normal range. Language status was not related to a specific perinatal medical variable. Additional study into the clinical validity of the ELM as a screening measure for the LBW population is warranted. The ELM specificity for both receptive and expressive language domains was good at both ages (80 to 100%), but sensitivity was low to moderate (0 to 68%). J Dev Behav Pediatr 14:21–27, 1993. Index terms: language development, low birth weight.

Severe retinopathy of prematurity associated with FZD4 mutations

Purpose: To determine whether mutations in the FZD4 gene are a risk factor for developing severe ROP. Methods: Three Canadian tertiary care centers recruited premature infants prospectively and retrospectively, and assigned affectation status based on the maximum degree of severity of ROP recorded in both eyes. Mutation screening of the FZD4 gene was performed using direct sequencing. All sequence changes were evaluated for functional significance. Results: Two novel FZD4 mutations (Ala370Gly or Lys203Asn) were identified in two infants from the severe ROP group (n=71). No mutation was detected in the mild to no ROP group (n=33), and the two novel mutations were absent in 173 random Caucasian samples. Mutation Ala370Gly was also found in one sibling and one parent of the affected infant, but no signs of familial exudative vitreoretinopathy (FEVR), a condition with phenotypic overlap with ROP known to be caused by FZD4 mutations, were present in either family member. Conclusions: Mutations in the FZD4 gene in this group of premature infants supports a role for the FZD4 pathway in the development of severe ROP and accounts for approximately 3% of severe ROP in Caucasian premature infants.

Twin-twin transfusion syndrome: a population-based study.

OBJECTIVE: To study the incidence and mortality and morbidity rates of twin–twin transfusion syndrome in a complete population-based cohort in Nova Scotia. METHODS: A population-based cohort study of all monochorionic diamniotic twin pregnancies of 20 weeks of gestation or longer born to Nova Scotia (Canada) residents between 1988 and 2000 was examined. The effect of gestational age adjustment and birth weight discordancy of more than 20% on mortality and 1-year survival was studied. Other outcomes studied included birth depression, respiratory distress syndrome, chronic lung disease, interventricular hemorrhage, periventricular leukomalacia, acute renal failure, and congestive heart failure. RESULTS: Of 404 monochorionic-diamniotic twin pregnancies examined, 48 were identified with twin–twin transfusion syndrome. Total mortality rates per pregnancy were significantly greater in the twin–twin transfusion syndrome group than in the remainder of our monochorionic diamniotic population (P < .01). However, when adjusted for gestational age, mortality failed to achieve statistical significance. Similarly, no differences were noted for 1-year survival and other outcomes of liveborn infants after gestational age adjustment. Discordance in birth weight predicted a higher incidence of morbid outcomes per pregnancy, but this effect was lost after gestational age adjustment. CONCLUSION: Increased morbidity and mortality of twins with twin–twin transfusion syndrome is likely to be due to a higher incidence of preterm birth. Birth weight discordancy was not found to be an independent predictor of mortality after controlling for gestational age and twin-twin transfusion syndrome. LEVEL OF EVIDENCE: II-2

One-year follow-up of 89 infants with birth weights of 500 to 749 grams and respiratory distress syndrome randomized to two rescue doses of synthetic surfactant or air placebo☆☆☆★

Abstract Double-blind neurodevelopmental and physical evaluations were conducted at 1-year adjusted age in 89 infants with birth weights of 500 to 749 gm who had respiratory distress syndrome in the neonatal period and were randomized to receive two rescue doses of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome Co., Research Triangle Park, N.C.) or air placebo. The trial used a common protocol and was conducted at 13 hospitals; patients were entered in the trial between February 1988 and September 1990. Ninety-five percent of surviving infants were assessed. Growth and development in the two groups were equivalent. Mean Bayley Scales of Infant Development scores were comparable (mental development index, 79 ± 22 vs 87 ± 20; psychomotor development index, 73 ± 18 vs 81 ± 19 for air placebo and synthetic surfactant, respectively). The incidence of severe retinopathy of prematurity was significantly decreased in the surfactant group compared with the air placebo group (15% vs 34%; relative risk 0.428; 95% confidence interval 0.2 to 0.9). Overall, administration of surfactant appeared to increase the probability of a favorable outcome. Confirmation of the trends observed in this study would provide a strong rationale for the rescue use of synthetic surfactant in extremely low birth weight infants with respiratory distress syndrome even if overall mortality is not reduced. (J P EDIATR 1995;126:S53-60)