Discordance in neonatal risk factors and early childhood outcomes of very low birth weight (<1.5 kg) twins.

OBJECTIVE: To examine the rates of discordance in neonatal risk factors and neurodevelopmental outcomes within very low birth weight twin pairs and the factors associated with discordant outcomes. STUDY DESIGN: Rates of neonatal risk factors and neurodevelopmental outcomes, and discordance in outcomes were examined for 88 very low birth weight twin pairs born between 1990 and 2005 and followed through 20 months' corrected age. RESULT: Discordance rates ranged from 17 to 42% for neonatal risk factors and from 18 to 31% for neurodevelopmental outcomes. In regression analysis, affected co-twins were significantly more likely to have had an abnormal cerebral ultrasound than their unaffected co-twins in pairs discordant for cerebral palsy (odds ratio (OR): 13.00, 95% confidence interval (CI): 2.22 to 76.03)) and in pairs discordant for neurodevelopmental impairment (OR: 4.00, 95% CI: 1.13 to 14.18). Outcomes and discordance in outcomes were similar for monochorionic and dichorionic pairs. CONCLUSION: Despite shared genetics and risk factors, twins may have discordant outcomes. Information on discordant neonatal and neurodevelopmental outcomes is important for counseling families of twins.

Prematurity and programming: contribution of neonatal Intensive Care Unit interventions.

Contemporary clinical practice for the care of the prematurely born babies has markedly improved their rates of survival so that most of these babies are expected to grow up to live a healthy functional life. Since the clinical follow-up is of short duration (years), only limited data are available to relate non-communicable diseases in adult life to events and interventions in the neonatal period. The major events that could have a programming effect include: (1) intrauterine growth restriction; (2) interruption of pregnancy with change in redox and reactive oxygen species (ROS) injury; (3) nutritional and pharmacological protocols for clinical care; and (4) nutritional care in the first 2 years resulting in accelerated weight gain. The available data are discussed in the context of perturbations in one carbon (methyl transfer) metabolism and its possible programming effects. Although direct evidence for genomic methylation is not available, clinical and experimental data on impact of redox and ROS, of low protein intake, excess methionine load and vitamin A, on methyl transfers are reviewed. The consequences of antenatal and postnatal administration of glucocorticoids are presented. Analysis of the correlates of insulin sensitivity at older age, suggests that premature birth is the major contributor, and is compounded by gain in weight during infancy. We speculate that premature interruption of pregnancy and neonatal interventions by affecting one carbon metabolism may cause programming effects on the immature baby. These can be additive to the effects of intrauterine environment (growth restriction) and are compounded by accelerated growth in early infancy.

Improved weight attainment of extremely low-gestational-age infants with bronchopulmonary dysplasia.

OBJECTIVE: To determine whether changes in neonatal practice and morbidity since 2000 have improved the growth attainment of infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: We compared the respective z-scores of the weight, length and head circumference of extremely low-gestational-age infants (aged <28 weeks) with BPD at birth, 40 weeks and 20 months corrected age (CA) during two time periods, namely period I, 1996-1999 (n=117) and period II, 2000-2003 (n=105), and examined the effects of significant changes in neonatal practice, morbidities and neurosensory outcome on 20-month growth outcomes. RESULT: During the most recent period (2000-2003), there was a significant increase in mean weight z-scores (-1.60 vs -1.22) and decrease in rates of subnormal weight (40 vs 21%), P<0.05 at 20 months CA but not in those of length or head circumference. Significant predictors of the 20-month weight z-score included time period (period I vs II), duration of ventilator dependence and 20-month neurosensory abnormality (all P<0.05). CONCLUSION: Despite an improvement in weight since 2000, poor growth attainment remains a major problem among infants with BPD.

The early use of minimal enteral nutrition in extremely low birth weight newborns.

OBJECTIVE: To gather information regarding the efficacy of early minimal enteral nutrition on overall feeding tolerance in extremely low birth weight infants. STUDY DESIGN: Prospective randomized controlled trial comparing the early use of minimal enteral nutrition in extremely low birth weight infants from day 2 to day 7 vs control infants. On day 8, feeding volume in both groups were advanced by 10 ml kg(-1) day(-1) until full enteral feedings were reached. Time to full feeds, number of intolerance episodes, anthropometric measurements, peak total bilirubin levels, incidence of necrotizing enterocolitis and incidence of sepsis were compared between the two groups with t-test and chi (2) test. RESULT: Eighty-four infants were enrolled in the study but only 61 infants completed the feeding protocol. No statistically significant differences were found between the groups with regards to growth patterns, feeding tolerance, mortality, length of hospital stay and incidence of sepsis and necrotizing enterocolitis. CONCLUSION: Early minimal enteral nutrition use in extremely low birth weight infants did not improve feeding tolerance.

Accuracy of the 7-8-9 Rule for endotracheal tube placement in the neonate.

OBJECTIVE: To determine accuracy of the 7-8-9 Rule in a cohort of neonates. STUDY DESIGN: This study was cross-sectional in design. Seventy-five consecutive neonates who required oral intubation from June 2004 to November 2004 for cardiopulmonary failure, respiratory distress, or surfactant administration were the subjects of this study. The initial endotracheal tube (ETT) depth of insertion was determined using either an estimated birth weight or actual weight in the 7-8-9 Rule calculation followed by auscultation and subsequent adjustment if necessary. Midtracheal position was identified as the point halfway between the inferior clavicle and carina on a chest radiograph. The initial depth was compared to the midtracheal depth to determine clinical accuracy of the 7-8-9 Rule. The depth predicted by the 7-8-9 Rule was also calculated using only actual weights. This predicted depth was compared to the midtracheal depth to determine true accuracy of the 7-8-9 Rule. Accuracy was determined using mean paired differences with 95% confidence intervals (CI) between initial or predicted depth and ideal, midtracheal ETT depth. Linear regression was used to adjust for confounding variables. RESULTS: Mean (range) gestational age was 32 weeks (23 to 44 weeks) and weight was 2001 g (490 to 4400 g). Eighteen (24%) infants weighed 1000 g or less, 20 (27%) weighed between 1001 and 2000 g, 21 (28%) weighed between 2001 and 3000 g, 15 (20%) weighed between 3001 and 4000 g, and one (1%) weighed more than 4000 g. Thirteen of the 18 extremely low birth weight infants weighed <750 g. The initial depth of insertion was 0.004 cm above midtracheal position (95% CI -0.13 to 0.14, P = 0.96). After controlling for head position, the initial depth did not significantly differ from the midtracheal position among weight groups. Predicted depth using the 7-8-9 Rule placed the ETT 0.12 cm above midtracheal position (95% CI -0.30 to 0.06, P = 0.20). However, after controlling for head position, the 7-8-9 Rule positioned the ETT significantly below midtracheal position in infants weighing <750 g (mean 0.62 cm; 95% CI 0.30 to 0.93, P=0.002). CONCLUSIONS: The 7-8-9 Rule appears to be an accurate clinical method for endotracheal tube placement in neonates weighing more than 750 g. When the 7-8-9 Rule is applied to infants weighing <750 g, caution is warranted. The current rule may lead to an overestimated depth of insertion and potentially result in clinically significant consequences.

Risk factors for neurologic impairment among very low-birth-weight infants.

Although cerebral palsy is the most common neurologic impairment among very low-birth-weight survivors, its etiology remains uncertain. Current research supports the role of both antenatal and neonatal factors in the pathogenesis of cerebral palsy among these extremely premature infants. Important antenatal risk factors include chorioamnionitis and multiple placental lesions. Maternal preeclampsia may provide neuroprotection. The major neonatal risk factors include severe cranial ultrasound abnormalities, chronic lung disease, hyperbilirubinemia, and possibly hypothyroxinemia.

Neurodevelopment and predictors of outcomes of children with birth weights of less than 1000 g: 1992-1995.

OBJECTIVE: To examine the neurosensory and cognitive status of extremely low-birth-weight (ELBW; < 1,000 g) children born from January 1, 1992, through December 31, 1995, and to identify the significant predictors of outcome. DESIGN: An inception cohort of ELBW infants admitted to the neonatal intensive care unit (NICU) and observed to 20 months' corrected age. SETTING: A tertiary level urban NICU and follow-up clinic at a university hospital. POPULATION: Of 333 ELBW infants without major congenital malformations admitted to the NICU, 241 (72%) survived to 20 months' corrected age. We studied 221 children (92%) at a mean of 20 months' corrected age. The mean birth weight was 813 g; mean gestational age, 26.4 weeks. MAIN OUTCOME MEASURES: Assessments of cognitive and neurosensory development. RESULTS: Major neurosensory abnormality was present in 54 children (24%), including 33 (15%) with cerebral palsy, 20 (9%) with deafness, and 2 (1%) with blindness. The mean (+/- SD) Bayley-Mental Developmental Index (MDI) score was 74.7 +/- 17. Ninety-two children (42%) had a subnormal MDI score (<70). Neurodevelopmental impairment (neurosensory abnormality and/or MDI score <70) was present in 105 children (48%). Multiple stepwise logistic regression analysis that considered sex, social risk, birth weight, and neonatal risk factors revealed significant predictors of a subnormal MDI score to be male sex (odds ratio [OR], 2.73; 95% confidence interval [CI], 1.52-4.92), social risk (OR, 1.48; 95% CI, 1.09-2.00), and chronic lung disease (OR, 2.18; 95% CI, 1.20-3.94). Predictors of neurologic abnormality were a severely abnormal finding on cerebral ultrasound (OR, 8.09; 95% CI, 3.69-17.71) and chronic lung disease (OR, 2.46; 95% CI, 1.12-5.40); predictors of deafness were male sex (OR, 2.79; 95% CI, 1.02-7.62), sepsis (OR, 3.15; 95% CI, 1.05-9.48), and jaundice (maximal bilirubin level, >171 micromol/L [>10 mg/dL]) (OR, 4.80; 95% CI, 1.46-15.73). CONCLUSION: There is an urgent need for research into the etiology and prevention of neonatal morbidity.

The relationship between placental and other perinatal risk factors for neurologic impairment in very low birth weight children.

Placental abnormalities reflect antenatal disease processes that may interact with other perinatal risk factors to affect long-term outcome. We performed a nested case control analysis of placental and clinical risk factors associated with neurologic impairment (NI) at 20-mo corrected age (60 cases and 59 controls) using data collected in a prospective study of very low birth weight (less than 1500 g) infants born between 1983 and 1991. In a preliminary analysis we explored the relationship between clinical infection and histologic chorioamnionitis (CA). Only histologic CA with a fetal vascular response correlated with either clinical CA or early onset neonatal sepsis. We then assessed the relative contribution of the nine risk factors (four placental and five clinical) associated with NI at the univariate level by multiple logistic regression. Three risk factors were independent predictors of NI: severe cranial ultrasound abnormalities (odds ratio 13.6, 95% confidence intervals 4.5-66.7), multiple placental lesions (odds ratio 13.2, 95% confidence intervals 1.3-137.0), and oxygen dependence at 36 wk (odds ratio 4.2, 95% confidence intervals 1.2-14.6). Finally, a series of logistic regressions was conducted with the dependent variable changing as we moved back along the causal chain to explore the relationships between risk factors operating at different stages. This analysis suggested that antenatal variables that were not independent predictors of NI by multiple logistic regression exerted their effects through the following intermediate pathways: fetal grade 3 histologic CA via chorionic vessel thrombi, clinical CA via grade 3 villous edema, and grade 3 villous edema via severe cranial ultrasound abnormalities.

Chronic peripheral separation of placenta. The significance of diffuse chorioamnionic hemosiderosis.

Diffuse nonmeconium-related pigment was observed in the chorioamnion of 36 of 1,023 placentas over 4 years and evaluated by iron staining. Stains were negative in 13 cases and positive in chorionic plate and membranes (diffuse chorioamnionic hemosiderosis [DCH]) in 23 cases (3/1,000 deliveries; 25/1,000 placentas). Gestational age at delivery was lower in DCH and was inversely proportional to the magnitude of iron staining. Placentas with DCH were more likely to show circumvallation, old peripheral blood clots, increased chorionic-villous macrophages, and green discoloration. To evaluate demographic, obstetric, and perinatal factors associated with DCH, 2 gestational age-matched controls were selected for each DCH case. Multiparity, smoking, and chronic vaginal bleeding all were increased significantly with DCH, while intrauterine growth retardation and oligohydramnios were increased but did not achieve statistical significance. Gestational hypertension and advanced maternal age were significantly decreased with DCH, and cocaine abuse was uncommon (3 cases). Long-term neurologic sequelae of DCH were evaluated in a separate series of gestational age-matched very-low-birth-weight infants with and without neurologic impairment at 2 years of age. No increased risk of neurologic impairment was found in patients with DCH.

Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants.

OBJECTIVE: Systematic placental examination has the potential to shed light on poorly understood antenatal processes that may increase the risk of neurologic impairment and cerebral palsy. DESIGN: Using data from a retrospective case-control study, we analyzed placentas from 60 inborn, singleton, very low-birth-weight (<1.5 kg) infants delivered between 1983 and 1991 who had subsequent neurologic impairment at 20 months corrected age (42 with cerebral palsy and 18 with other neurologic abnormalities) and 59 control infants of comparable gestational age, birth weight, sex, and race. Three a priori hypotheses based on previous studies were that neurologic impairment would be increased with fetal vascular lesions with or without coexisting chorioamnionitis, decreased with chronic maternal vascular underperfusion, and increased when multiple placental abnormalities were seen in the same case. RESULTS AND CONCLUSIONS: We found 2 types of fetal placental vascular lesions to be associated with neurologic impairment, namely, recent nonocclusive thrombi of chorionic plate vessels (P < .04) and severe villous edema (P < .01). Chorionic plate thrombi were seen only with chorioamnionitis and accounted for the increased risk of neurologic impairment seen with chorioamnionitis. Maternal vascular lesions showed a biphasic relation to neurologic impairment in the subgroup of patients without chorioamnionitis. Mild lesions were increased in controls (inadequate vascular remodeling, P=.03, and accelerated maturation, P=.004). A more severe lesion, multiple villous infarcts, although not reaching significance, was increased in the neurologically impaired cases. Finally, in a test of 9 selected placental lesions, cases with cerebral palsy were more likely to have 2 or more lesions (P < .0001) and were less likely to have no lesions (P < .04) than control infants.

Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children.

BACKGROUND AND OBJECTIVE: The etiology of neurologic impairments among very low birth weight (VLBW, <1.5 kg) children is poorly understood. We sought to investigate the perinatal predictors of major neurologic impairment, including cerebral palsy, among VLBW children. METHODS: Antenatal, intrapartum, and neonatal events and therapies were compared between 72 singleton inborn VLBW children born between 1983 to 1991 who had neurologic impairment at 20 months corrected age (including 50 with cerebral palsy and 22 with other neurologic impairments) and 72 neurologically normal VLBW children matched by birth weight, gestational age, race, and sex via a retrospective case-control method. Multiple logistic regression was conducted, entering only those variables found to be significant at the bivariate level. RESULTS: There were no significant differences in the rates of pregnancy-induced hypertension, maternal tocolytic use including magnesium, or antenatal steroid therapy. Higher rates of clinical chorioamnionitis were found among the mothers of the neurologically impaired children as compared with controls (31% vs 11%), but not among the subgroup of mothers of children with cerebral palsy (22% vs 12%). Significant differences in neonatal factors among the total neurologically-impaired group (n = 72) versus controls included oxygen dependence at 36 weeks (31% vs 15%), septicemia (53% vs 31%), severe cranial ultrasound abnormality (50% vs 17%), and hypothyroxinemia (43% vs 25%). In the subgroup with cerebral palsy (n = 50), significant differences included days on the ventilator (23 vs 14 days), septicemia (54% vs 33%), and severe cranial ultrasound abnormality (52% vs 12%). Multivariate analysis controlling for birth weight, gestational age, race, sex, and the birth period (before 1990 versus 1990 and after) revealed direct and independent effects of clinical chorioamnionitis [odds ratio (OR), 3. 79; confidence interval (CI), 1.34-10.78], severe cranial ultrasound abnormality (OR, 9.97; CI, 3.84-25.87), and septicemia (OR, 2.46; CI, 1.10-5.52) on total neurologic impairment. Consideration of the 50 cases with cerebral palsy revealed direct and independent effects of severe cranial ultrasound abnormality only (OR, 15.01; CI, 4.34-51. 93). CONCLUSIONS: Both antenatal and neonatal risk factors contribute to the development of severe neurologic impairment, including cerebral palsy among VLBW children. Because prevention of chorioamnionitis may not be feasible in the near future, attempts to decrease neonatal risk factors such as severe cranial ultrasound abnormalities and sepsis may be most feasible at this time.

Radiation exposure from diagnostic radiographs in extremely low birth weight infants.

OBJECTIVE: We sought to examine radiation doses received by infants of less than 750 g birth weight from radiographs. METHODS: We examined the radiology records, including radiograph films, of all 25 surviving infants with birth weight less than 750 g admitted to our center during 1991. The standard method of neonatal radiation dose calculation was modified to consider the body size, postnatal growth, and extramedullary hematopoiesis of the extremely low birth weight infant. To determine overall radiation exposure, we calculated an effective dose equivalent, which is the sum of weighed organ dose equivalents. RESULTS: The infants had a mean of 31 radiographys performed, including 17 chest radiographs, 5 babygrams, and 9 abdominal radiographs. The majority of chest radiographs and babygrams were performed in the first month, whereas abdominal radiographs increased during the second month of life. Total-body radiation dose and total effective dose equivalent by the standard and modified methods, respectively, for single exposures ranged from 0.01 to 0.02 millisieverts (mSv) for a chest radiograph, from 0.02 to 0.04 mSv for a babygram, and from 0.02 to 0.03 mSv for an abdominal radiograph. Surface organs icluding the skin, breast, and thyroid received the largest radiation doses. The effective dose equivalent per infant for all radiographs was 0.72 mSv according to the modified method, compared to a total-body dose of 0.40 mSv using the standard method. However, infants with chronic lung disease or necrotizing enterocolitis received up to 1.5 mSv total-body dose, including 3.3 mSv to the breast, 2.5 mSv to the thyroid, and 2.3 mSv to the testes. CONCLUSIONS: Radiation doses received by infants of less than 750 g birth weight are small in comparison with the range of doses that form the basis of risk estimates for cancer.