Neurodevelopmental outcome of extremely low birth weight infants with Candida infection.

OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.

Extracorporeal photopheresis for the treatment of severe, refractory steroid dependent pediatric Crohn's Disease.

Crohn's disease is a chronic, inflammatory disease of the gastrointestinal tract, affecting both children and adults. Extracorporeal photopheresis (ECP) has been used in steroid dependent adults with moderate to severely active Crohn's disease, with response rates up to 50%, with up to 25% complete responses. A 12-year-old male patient had severe unremitting Crohn's disease for one year, despite treatment with anti-inflammatory, immunosuppressive, and biologic agents. He failed elemental enteral nutrition and required total parenteral nutrition (TPN). A diverting colostomy for perforation was required. He required frequent hospitalizations and required homebound schooling. Endoscopy revealed severe inflammation and ulcerations of the entire colon. ECP was begun twice weekly for 4 weeks, then twice per week every 14 days for a total of 28 weeks. ECP was well tolerated and prednisone was gradually discontinued. He continued daily azathioprine and infliximab at 6 week intervals. TPN was weaned as enteral intake improved. Disease abatement allowed a return to school and normal activities. Endoscopy at completion of ECP course revealed normal upper tract, normal ano-rectum, and decreased, although significant, colonic disease. This response has continued for at least 16 months since completion of ECP. We conclude that ECP is useful for pediatric patients with steroid dependent Crohn's disease and prospective evaluation is warranted.

Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes.

OBJECTIVES: To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development's Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2). STUDY DESIGN: Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates. RESULTS: Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001). CONCLUSION: Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.

Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide.

OBJECTIVES: We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group. STUDY DESIGN: Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness. RESULTS: Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43). CONCLUSIONS: In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990-2000: a retrospective cohort study.

BACKGROUND: It is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23-27 weeks gestation) are changing over time. METHODS: Study infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness. RESULTS: Survival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2. CONCLUSION: The probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990's in this regionally based sample of ELGANs.

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study.

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.

Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain.

Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer's disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 µg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 µg/ml compared to 27.60 µg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 µg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD.

Maternal and infant characteristics associated with human milk feeding in very low birth weight infants.

This study identified maternal and infant characteristics predicting human milk (HM) feeding in very low birth weight (VLBW) infants whose mothers (n = 184) participated in a study of lactation counseling and initiated milk expression. Data were collected prospectively, by maternal interview and medical record review. During hospitalization, 159 (86%) infants received at least 50% HM proportion of feedings in the first 2 weeks of life, and 114 (62%) received some HM until the day of hospital discharge. Analysis showed plan to breastfeed was the strongest predictor of initiation and duration of HM feeding. Greater than 12 years of education, respiratory distress syndrome, Apgar score >6, and female gender were significant predictors, and no perinatal hypertensive disorder, white race, and mechanical ventilation were marginal predictors of HM feeding. Women with a high-risk pregnancy should be provided education about the benefits of breastfeeding for infants who are likely to be born prematurely.

Human milk consumption and full enteral feeding among infants who weigh

OBJECTIVE: Establishing enteral feeding is an important goal in the care of very low birth weight infants. In such infants, receipt of >/=50 mL/kg per day human milk during hospitalization has been associated with shorter time to full enteral feeding. The objective of this study was to determine whether high proportions (>/=50%) of human milk during feeding advancement are associated with shorter time to full enteral feeding and improved feeding tolerance. METHODS: This was a prospective cohort study of very low birth weight infants (n = 127) who were grouped into low (<50%; n = 34) and high (>/=50%; n = 93) human milk consumption groups according to their human milk proportion of enteral feeding during the time of feeding advancement. The primary outcomes of interest were ages at which 100 and 150 mL/kg per day enteral feedings were achieved. RESULTS: The high human milk group reached 100 mL/kg per day enteral feeding 4.5 days faster than the low human milk group. The high human milk group reached 150 mL/kg per day enteral feeding 5 days faster than the low human milk group. After adjustment for gestational age, gender, and respiratory distress syndrome, times to reach 100 and 150 mL/kg per day were significantly shorter for those in the high human milk group. Infants in the high human milk group had a greater number of stools per day; other indicators of feeding tolerance were not statistically different. CONCLUSION: In infants who weighed

Appropriate calibration curve fitting in ligand binding assays.

Calibration curves for ligand binding assays are generally characterized by a nonlinear relationship between the mean response and the analyte concentration. Typically, the response exhibits a sigmoidal relationship with concentration. The currently accepted reference model for these calibration curves is the 4-parameter logistic (4-PL) model, which optimizes accuracy and precision over the maximum usable calibration range. Incorporation of weighting into the model requires additional effort but generally results in improved calibration curve performance. For calibration curves with some asymmetry, introduction of a fifth parameter (5-PL) may further improve the goodness of fit of the experimental data to the algorithm. Alternative models should be used with caution and with knowledge of the accuracy and precision performance of the model across the entire calibration range, but particularly at upper and lower analyte concentration areas, where the 4- and 5-PL algorithms generally outperform alternative models. Several assay design parameters, such as placement of calibrator concentrations across the selected range and assay layout on multiwell plates, should be considered, to enable optimal application of the 4- or 5-PL model. The fit of the experimental data to the model should be evaluated by assessment of agreement of nominal and model-predicted data for calibrators.

Follow-up care for infants with chronic lung disease: a randomized comparison of community- and center-based models.

OBJECTIVES: Premature infants with chronic lung disease benefit from comprehensive care, which typically is based in tertiary medical centers. When such centers are not easily accessible, alternative models of care are needed. The purpose of this work was to compare community-based follow-up, provided via telephone contacts, to traditional center-based follow-up of premature infants with chronic lung disease. PATIENTS AND METHODS: After discharge from neonatal intensive care, 150 premature infants with chronic lung disease were randomly assigned to either community-based (n = 75) or center-based (n = 75) follow-up. In community-based follow-up, a nurse specialist maintained telephone contact with the infant's primary caregiver and health care providers. Center-based follow-up consisted of visits to a medical center-based multidisciplinary clinic staffed by a neonatologist, a nurse specialist, and a social worker. The outcomes of interest were Bayley Scales of Infant Development mental developmental index and psychomotor developmental index, Vineland Adaptive Behavioral Composite, and growth delay (weight for length <5th percentile) at 1-year adjusted age and respiratory rehospitalizations through 1-year adjusted age. RESULTS: In each randomization group, 73 infants survived, and 69 were evaluated at 1-year adjusted age. The median mental development index (corrected for gestational age) was 90 for both groups. The median psychomotor developmental index was 82 for the center-based group and 81 for the community-based group. The median Vineland Adaptive Behavioral Composite was 100 and 102 for the center-based and community-based groups, respectively. In the center-based and community-based groups, respectively, the proportions with growth delay were 13% and 26%, and the proportions rehospitalized for respiratory illness were 33% and 29%. CONCLUSIONS: Infants randomly assigned to community-based, as compared with those randomly assigned to center-based follow-up, had similar developmental and health outcomes. The former approach might be a preferred alternative for families in rural settings or families for whom access to a tertiary care medical center is difficult.

Lactation counseling for mothers of very low birth weight infants: effect on maternal anxiety and infant intake of human milk.

OBJECTIVE: Although it is well documented that breastfeeding promotes health and development of very low birth weight (VLBW) infants, lactation initiation among mothers of VLBW infants is low. Mothers are anxious about the health of their children, and medical staff may be reluctant to promote breastfeeding out of concern for increasing that anxiety. Therefore, the purpose of this study was to examine whether mothers of VLBW infants who initially planned to formula feed were different in terms of their level of anxiety and maternal stress compared with mothers who had planned to breastfeed their infants. The aims of this study were to (1) determine whether counseling mothers of VLBW infants who had initially planned to formula feed on the benefits of breast milk would increase their stress and anxiety levels, (2) assess whether mothers who initially had not planned to breastfeed changed their plans after counseling to provide breast milk, and (3) measure the amount of breast milk expressed by mothers who initially planned to formula feed. Their results were compared with those of mothers of VLBW infants who initially planned to breastfeed. METHODS: Initial plan to breastfeed (initial breastfeed group [IBG]; n = 115) or formula feed (initial formula feed group [IFG]; n = 81) was determined before counseling. All participants received counseling on infant health benefits, collection and storage of breast milk, and breast pump procurement. Maternal anxiety was measured using the State-Trait Anxiety Inventory (STAI), which was administered to mothers before and after counseling and every 2 weeks until infant discharge. Maternal stress was measured after counseling with the Parental Stressor Scale: NICU. Infant breast milk intake was measured throughout hospitalization. An exit questionnaire that pertained to the perceived benefits and efforts of expressing milk was administered close to the time of infant discharge. RESULTS: After lactation counseling, 100% of the IBG and 85% of the IFG initiated breast milk expression (used the electric breast pump in the hospital) for a total lactation initiation rate of 94%. After adjustment for the mothers who initiated milk expression but did not provide any breast milk, the lactation initiation rate for the entire group was 84%. Non-Hispanic black mothers and Non-Hispanic white mothers initiated milk expression at similarly high rates (95% vs 93%). Also, milk expression initiation was similar for low-income and non-low-income mothers (95% vs 92%). IFG and IBG STAI and Parental Stressor Scale: NICU scores were not significantly different, and there were no significant differences between groups in the change in anxiety after counseling. In addition, the mean difference scores (after counseling - before counseling) for STAI anxiety "state" were not significantly different between groups, even when controlling for "trait" anxiety. State anxiety declined during the first 6 weeks of infant hospitalization in a similar manner for both groups. Maternal trait but not state anxiety scores were inversely correlated with total infant breast milk intake. Breast milk intake (mL/kg per day) was greater in the infants of mothers in the IBG compared with the IFG at each week during the first month and for their entire hospital stay. Infant breast milk intake increased from weeks 1 to 3 in both groups and continued to rise in the fourth week for the IBG. However, breast milk intake declined at week 4 for the IFG. IBG infants received breast milk for 83% of the total fed hospital days (days that feedings were given) compared with 44% of total fed days for the IFG. The proportion of enteral intake that was breast milk was also greater for the IBG compared with IFG during the first 4 weeks and for the total hospitalization. However, the mothers in IFG were able to provide at least 50% of their infants' enteral intake for the first 3 weeks, 48.8% for the fourth week, and 32.8% of the enteral intake for the entire hospitalization. Infants of low-income women received significantly lower amounts of breast milk than did infants of non-low-income mothers. Race and income accounted for 36% of the variance in breast milk intake. Of the 184 mothers who initiated breast milk expression, 72 (39%) completed the exit questionnaire. Infant health benefits were the most common reasons cited by both groups for expressing milk. The most common reasons that both groups reported for ceasing milk expression were (1) low milk supply, (2) returning to work or school, and (3) inability to pump as often as needed. Almost all of the mothers reported that pumping was worth the effort (IBG 100%, IFG 87%), and 100% said that they were glad that the staff helped them with milk expression. CONCLUSION: Counseling mothers of VLBW infants increases the incidence of lactation initiation and breast milk feeding without increasing maternal stress and anxiety.

Bioanalytical method validation for macromolecules in support of pharmacokinetic studies.

The development and validation of ligand binding assays used in the support of pharmacokinetic studies has been the focus of various workshops and publications in recent years, all in an effort to establish a guidance document for standardization of these bioanalytical methods. This summary report of the workshop from 2003 focuses on the issues discussed in presentations and notes points of discussion and areas of consensus among the participants.