Howard W. Kilbride

Pulmonary function and exercise capacity for ELBW survivors in preadolescence: effect of neonatal chronic lung disease☆

OBJECTIVE To assess pulmonary function and exercise capacity of apparently asymptomatic children who were born extremely preterm. STUDY DESIGN Pulmonary function and treadmill testing were performed on 50 children 9 to 15 years old who had birth weight <801 g (extremely low birth weight [ELBW]) and without apparent neurodevelopmental or pulmonary disabilities, compared with 25 children born at term with normal birth weight (NBW). Medical history and physical activity levels were assessed by parent questionnaire. Group differences were determined by two-sample t test. Secondary analysis was performed to assess significant influence of neonatal chronic lung disease (CLD) on outcome measures. RESULTS Twenty percent of ELBW subjects but no subjects with NBW had clinically abnormal pulmonary function (>2 SD from norms, P=.026). All significant pulmonary function differences except peak expiratory flow rate percentages were accounted for by ELBW subjects who had CLD. Oxygen consumption measurements were significantly lower for subjects with ELBW (30.3+/-6.9 and 38.5+/-5.2 mL/kg/min, P=.000), independent of CLD status. CONCLUSION Pulmonary function abnormalities consistent with obstructive lung disease were more frequently detected in ELBW children who had neonatal CLD. Low oxygen consumption measurements suggest a lower level of fitness for ELBW children compared with children with NBW.

Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

BACKGROUND Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants. METHODS We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large childrens hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq. FINDINGS 20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3-153) and median time to STATseq report was 23 days (5-912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis. INTERPRETATION In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes. FUNDING Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.

Thirty-six-month outcome of prenatal cocaine exposure for term or near-term infants: impact of early case management.

&NA; Gestational cocaine use is associated with serious pregnancy complications having fetal and neonatal implications. However, many cocaine‐abusing women deliver uneventfully at term. The purpose of this study was to assess the neurodevelopmental outcome for term or near‐term infants after prenatal cocaine exposure and to determine whether that outcome would be modified by early, intensive family case management. Cocaine‐exposed infants identified after delivery at an urban hospital were alternately assigned to receive case management (n = 70) or routine follow‐up (n = 48). A matched, non‐drug‐exposed group of infants was identified for comparison (n = 41). Infants aged up to 36 months were serially evaluated in a multidisciplinary clinic with cognitive, psychomotor, and language testing. Group comparisons were performed using one‐way analysis of variance. There were no statistical differences in mean cognitive, psychomotor, or language quotients between cocaine‐exposed and non‐drug‐exposed infant groups aged up to 36 months. At 6 months of age, case‐managed cocaine‐exposed infants had a significantly higher mean Bayley Mental Developmental Index score than those who were routinely managed. However, no differences were present at subsequent assessments. Among cocaine‐exposed infants who remained with their mothers at 36 months, verbal scores were significantly higher for case‐managed compared with routine‐managed infants. The negative effects of urban, low socioeconomic status may overshadow the impact of prenatal cocaine exposure on early childhood outcome for those infants born without prenatal complications.

Haploinsufficiencies of FOXF1 and FOXC2 Genes Associated With Lethal Alveolar Capillary Dysplasia and Congenital Heart Disease

Neonatal deaths account for about 67% of all deaths during the first year of life in the USA. Genetic defects are important factors contributing to neonatal deaths and congenital anomalies. Here we report on the identification of a 1.37 Mb de novo deletion of chromosome 16q24.1‐q24.2 by microarray‐based comparative genomic hybridization (aCGH) technique in a newborn boy with lethal severe alveolar capillary dysplasia and multiple congenital anomalies who died of irreversible pulmonary hypertension, respiratory failure and cor pulmonale at three days of age. The phenotypic findings and causal genes (FOXF1 and FOXC2) involved in producing this unusual syndrome are detailed. Our findings independently confirm the results in a previous publication describing multiple patients with similar clinical and genetic observations, and highlight the importance of scanning human genomes at high resolution for identifications of micro‐imbalances as pathogenic causes in neonates with unexplained congenital anomalies.

NEONATAL COMPLICATIONS OF PRETERM PREMATURE RUPTURE OF MEMBRANES, PATHOPHYSIOLOGY AND MANAGEMENT

Midtrimester PROM is an infrequent, yet potentially disastrous complication of pregnancy. The most likely neonatal complication is preterm delivery with associated morbidity and mortality risks. Unique neonatal complications following PPROM include skeletal deformations and pulmonary hypoplasia related to prolonged oligohydramnios exposure. A systematic approach to an infant with respiratory insufficiency following PPROM delivery is possible with an understanding of the pathophysiology of pulmonary hypoplasia. Neonatal management should include immediate resuscitation including surfactant replacement, with careful attention to techniques of mechanical ventilation to avoid early volutrauma. Adjunctive therapies directed at pulmonary hypertension may now permit survival of some infants with less severe forms of pulmonary hypoplasia.

Developmental care teams in the neonatal intensive care unit: survey on current status.

Developmental Care Teams (DCT) have evolved in Neonatal Intensive Care Units (NICUs) in response to mounting evidence that developmental care is cost-effective and improves outcomes of critically ill newborns. Lack of national practice guidelines and standardized roles for DCT members prompted formulation and distribution of a questionnaire to obtain information regarding staff membership of DCTs, budgeting for DCTs, utilization of developmental care in practice, and education and developmental training of NICU staff.Questionnaires were sent to 50 NICUs in 30 states, with a return rate of 62% (31 of 50), representing 18 different states. Of those who responded, 64% had a DCT, and an additional 24% were in various phases of starting a team. Forty-three percent of the teams meeting on a regular basis did so monthly. Only 30% of those with a DCT had a dedicated budget to cover operating costs of their developmental program. Fifty-two percent of respondents had Neonatal Individualized Developmental Care and Assessment Program (NIDCAP)-certified staff at their institutions; however, nine other types of developmental specialists were also listed. Only four respondents indicated utilization of set criteria for initiation of a DCT consult, and 74% of those with DCTs initiated consults “when the need arises.” NIDCAP assessments were used for parent teaching (54%), care plans (69%), care recommendations (46%), and at caregiver “discretion” (39%).The results of the survey validated an intense interest in developmental care. Approach to developmental care is variable between NICUs and implementation as outlined by NIDCAP is unusual. Practical guidelines for utilization and funding of DCTs are needed.

School-age outcome of children with prenatal cocaine exposure following early case management

ABSTRACT. The impact of prenatal cocaine exposure on neurodevelopmental outcome in childhood continues to be in question. Objectives of this study were to determine if there are differences in growth, behavioral, cognitive or verbal functioning or caregiver-child dyad interactions for inner-city, school-aged children with and without prenatal cocaine exposure, and if these measures would be affected by early family case management. From an initial sample of 118 cocaine-exposed children who were evaluated to 36 months of age, 47 were able to be contacted and 39 (83%) completed a follow-up evaluation at 84 ± 11 months of age. Subjects had been assigned at birth to early case management (CM, 24) and routine care (RC, 15). Eighteen children from the initial non-cocaine-exposed comparison sample of 41 children were able to be contacted and 12 (67%) were evaluated at 85 ± 16 months of age. Evaluation included growth measurements, Stanford-Binet IQ, receptive and expressive language quotients, parent-reported Child Behavior Checklists (CBCL), and assessment of caregiver-child interactions by scored videotaped free-play sessions. No differences were found in growth, mean IQ, language quotients, CBCL scores or videotaped caregiver-child play interactions as a function of cocaine exposure. Within the cocaine-exposed group, there were no outcome differences between CM and RC children. However, during the play sessions, CM caregivers had more positive affect in interactions with the child than RC. Within the RC dyads, birthmothers had significantly more positive interactions than non-birthmothers. In summary, no differences in growth, behavioral, cognitive, or language function were evident for inner-city, school-aged children related to prenatal cocaine exposure or early case management. CM caregivers demonstrated more positive interactions during a play session than RC; within the RC group, non birthmothers had the least positive affective interactions. Further study of influences on caregiver-child interactions may lead to effective intervention strategies for drug-exposed infants.

Use in Newborn Infants A Controlled Trial

The heparin lock technique has been available for parenteral access in older children and adults but has not yet been described for use in newborns. We randomized 39 newborns who needed parenteral medication in the intermediate care nursery to receive a heparin lock catheter (17) or an intravenous line kept patent by continuous low infusion rate (22). There were no differences between study groups with regard to birthweight, gestational age, or distribution of diagnoses. Infants in the heparin lock group were enrolled in the study on average 1 day longer than the continuous intravenous group (p < 0.05). Subcutaneous infiltration occurred twice as frequently with the continuous intravenous line (p = 0.0015), and the life span was significantly less than heparin lock (1.0 ± 0.5 days versus 2.1 ± 1.0 days, p = 0.0003). Infants with continuous intravenous lines received approximately 20 ml/kg/day greater quantity of fluid (p < 0.0001). There was no difference between groups with regard to mean heparin activity level. None of the infants developed hemorrhagic complications, thrombophlebitis, or documented nosocomial infection. Nurses significantly favored heparin locks over continuous intravenous lines for ease of use. The heparin lock technique is a safe and reasonable alternative to a continuous low infusion intravenous line for administering parenteral medications to intermediate care newborns.

Prognostic neurodevelopmental testing of preterm infants: do we need to change the paradigm?

Longitudinal follow-up with assessment of developmental status at about 2 years of age is routine for high-risk newborns. The results of these assessments can be used for many purposes, including helping physicians, parents, and teachers plan educational or developmental interventions. These assessments also provide outcome measures for clinical research studies. Outcome results may also serve as a source of information for clinicians when counseling parents regarding provision of care for extreme preterm infants. Consideration should be given to use of different outcome metrics based on the purpose for testing. Categorization of composite cognitive, motor and neurosensory findings to define levels of impairment should be limited to research. Planning for individual interventions is better guided by descriptive findings. Current tools for assessing neurodevelopmental status at 2 years of age have important limitations. First, outcomes at early ages do not always predict function later in life. They are, at best, an estimate of longer-term outcomes, with important individual variation. For infants without severe neurologic injury, postnatal environmental factors play a predominant role in determining long-term cognitive and academic outcomes. Further investigations should assess quality of life and other considerations that are important for parents when making decisions about neonatal intensive care unit care for their infant.

Does diagnosis influence end-of-life decisions in the neonatal intensive care unit?

Objective:To determine the influence of physiological status and diagnosis at the time of death on end-of-life care.Study Design:Retrospective descriptive study in a regional referral level IV neonatal intensive care unit (NICU) of infants who died from 1 January 1999 to 31 December 2008. Infants were categorized based on diagnosis (very preterm, congenital anomalies or other) and level of stability. Primary outcome was level of clinical service provided at end of life (care withheld, care withdrawn or full resuscitation).Result:From 1999 to 2008, there were 414 deaths in the NICU. Congenital anomaly was the leading diagnosis at the time of death, representing 45% of all deaths. Comparing mode of death, very preterm newborns were more likely than infants with congenital anomalies to have received cardio-pulmonary resuscitation (CPR) at the time of death (26% vs 13%, P<0.01) and were significantly more unstable (75% vs 52%, P<0.01). Infants aged 22 to 24 weeks were mostly unstable and significantly more likely to receive CPR than infants with any other diagnosis.Conclusion:Over the 10-year period, very preterm infants were more likely to be physiologically unstable and to receive CPR at the time of death than infants with any other diagnosis. This finding was especially true for infants at the edge of viability (22 to 24 weeks). These differences in end-of-life care suggest that the quality of life and medical futility may be viewed differently for the least mature infants.