Copeptin levels in hospitalized infants and children with suspected vasopressin-dependent disorders: a case series.

OBJECTIVES: There have been recent advances assessing copeptin levels in adults with suspected disorders of vasopressin release. Very limited data exits on copeptin levels in children and infants, especially in a critically-ill hospitalized population where hyper- and hypo-natremia are very common. Our objective is to describe the institutional experience assessing copeptin levels in hospitalized infants and children with hyper- or hypo-natremia. METHODS: We performed a single-center retrospective case series of all infants, children, and adolescents who had an ultrasensitive plasma copeptin level obtained between 2019-2021. RESULTS: A total of 29 critically ill patients (6 infants) were identified with 38 % of patients having copeptin levels after neurosurgical procedures for tumors or trauma. Approximately 13/17 children with hypernatremia had central diabetes insipidus (central diabetes insipidus) to diagnose CDI, A copeptin level ≤ 4.9 pmol/L resulted in an 88 % sensitivity (95 % CI 47-99 %), and 66 % specificity (95 % CI 30-93 %). Amongst those with hyponatremia levels were more variable, 8/12 children had syndrome of inappropriate antidiuresis (SIAD) with copeptin levels ranging 4.7-72.6 pmol/L. CONCLUSIONS: While difficult to conclude due to multiple limitations, this case series highlights that typical copeptin cutoffs used to diagnose DI in adults in an ambulatory setting may also translate to a critically-ill pediatric population. Large prospective studies are needed to confirm this observation. In addition, postoperative copeptin levels could potentially be utilized as an additional marker to predict permanent from transient DI, but much larger studies are needed. Further work is needed to establish normative copeptin levels in infants and patients with SIAD.

Online clinical tool to estimate risk of bronchopulmonary dysplasia in extremely preterm infants.

OBJECTIVE: Develop an online estimator that accurately predicts bronchopulmonary dysplasia (BPD) severity or death using readily-available demographic and clinical data. DESIGN: Retrospective analysis of data entered into a prospective registry. SETTING: Infants cared for at centres of the United States Neonatal Research Network between 2011 and 2017. PATIENTS: Infants 501-1250 g birth weight and 23 0/7-28 6/7 weeks' gestation. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Separate multinomial regression models for postnatal days 1, 3, 7, 14 and 28 were developed to estimate the individual probabilities of death or BPD severity (no BPD, grade 1 BPD, grade 2 BPD, grade 3 BPD) defined according to the mode of respiratory support administered at 36 weeks' postmenstrual age. RESULTS: Among 9181 included infants, birth weight was most predictive of death or BPD severity on postnatal day 1, while mode of respiratory support was the most predictive factor on days 3, 7, 14 and 28. The predictive accuracy of the models increased at each time period from postnatal day 1 (C-statistic: 0.674) to postnatal day 28 (C-statistic 0.741). We used these results to develop a web-based model that provides predicted estimates for BPD by postnatal day. CONCLUSION: The probability of BPD or death in extremely preterm infants can be estimated with reasonable accuracy using a limited amount of readily available clinical information. This tool may aid clinical prognostication, future research, and center-specific quality improvement surrounding BPD prevention. TRIAL REGISTRATION NUMBER: NCT00063063.

The relationship of neurodevelopmental impairment to concurrent early childhood outcomes of extremely preterm infants.

OBJECTIVE: Determine how neurodevelopmental impairment (NDI) relates to concurrent outcomes for children born extremely preterm. STUDY DESIGN: Retrospective cohort study children born 22 0/7-26 6/7 weeks' gestation at NICHD Neonatal Research Network hospitals. Outcomes were ascertained at 18-22 months' corrected age. RESULT: Of 6562 children, 2618 (40%) died and 441 (7%) had no follow-up. Among the remaining 3483 children, 825 (24%), 1576 (45%), 657 (19%), and 425 (12%) had no, potential/mild, moderate, and severe NDI, respectively. Rehospitalization, respiratory medications, surgery, and medical support services were associated with greater NDI severity but affected >10% of children without NDI. Rehospitalization occurred in 40% of children with no NDI (mean (SD): 1.7 (1.3) episodes). CONCLUSION: Medical, functional, and social outcomes at 18-22 months' corrected age were associated with NDI; however, many children without NDI were affected. These data should contribute to counseling families and the design of studies for childhood outcomes beyond NDI.

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior. RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05). CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

Birth weight discordance in very low birth weight twins: mortality, morbidity, and neurodevelopment.

OBJECTIVE: Examine outcomes among birth weight concordant and discordant 401-1500 g twins. STUDY DESIGN: Twins (n = 8,114) at NICHD Neonatal Research Network (1994-2011) were studied. Discordance (birth weight difference/larger twin birth weight x 100%) was categorized into: ≤ 14, > 14-20, > 20-30, and > 30%. Separate logistic regression models for the smaller and larger infants assessed the adjusted association between discordance and outcomes. RESULTS: Compared with the smaller twin with ≤ 14% discordance, mortality, necrotizing enterocolitis, severe retinopathy of prematurity, bronchopulmonary dysplasia, and neurodevelopmental impairment or death were highest among the smaller twins with discordance > 30%. The larger twins with discordance > 30% had higher odds of patent ductus arteriosus, moderate-to-severe cerebral palsy, blindness, cognitive and motor scores < 70. Odds of cerebral palsy and blindness were also higher among the larger twins with discordance > 14-20%. CONCLUSIONS: Discordance > 30% was associated with higher mortality in the smaller twin and higher morbidities among the smaller and larger twins.

The changing relationship between bronchopulmonary dysplasia and cognition in very preterm infants.

AIM: To characterise the relationship between bronchopulmonary dysplasia (BPD) severity and cognition in the post-surfactant era. METHODS: This was a single-centre retrospective analysis of a cohort of infants born 2009-2012. Inclusion criteria were as follows: admission within 48 hours of birth, gestational age 22-0/7-31-6/7 weeks, birthweight 400-1500 g and Bayley Scales of Infant and Toddler Development-III testing at 18-26 months corrected age. Infants (n = 151) were classified by BPD severity with the NIH Workshop definition. Generalised linear modelling and multivariate logistic regression were performed. RESULTS: Bayley cognitive score was not associated with BPD severity in univariate (p = 0.053) or multivariate (p = 0.503) analysis. About 27% of infants with no/mild BPD, 33% of infants with moderate BPD and 40% of infants with severe BPD had a cognitive score <85. There was no difference in the odds of cognitive score <85 based on BPD severity in univariate (p = 0.485) or multivariate analysis (p = 0.225). All infants with cognitive score <70 had severe BPD, although the association between cognitive score <70 and BPD severity was not significant. CONCLUSION: We found no independent effect of BPD severity level on cognition. The likelihood of a cognitive score <85 was not associated with BPD severity.

Neurodevelopmental and Behavioral Outcomes in Extremely Premature Neonates With Ventriculomegaly in the Absence of Periventricular-Intraventricular Hemorrhage.

Importance: Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective: To characterize the outcomes of extremely preterm neonates younger than 27 weeks' gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks' postmenstrual age. Design, Setting, and Participants: This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks' gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks' postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures: The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results: Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance: Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Efficacy of pharmacologic closure of patent ductus arteriosus in small-for-gestational-age extremely preterm infants.

BACKGROUND: Optimal management of the patent ductus arteriosus (PDA) in preterm infants remains controversial. Therefore, studies identifying infants who are most likely to benefit from PDA treatment are needed. AIM: We sought to examine if significant intrauterine growth restriction, defined by birth weight z-score, reduces the efficacy of PDA closure with indomethacin or ibuprofen and thereby increases the need for surgical closure of PDA after pharmacologic treatment. STUDY DESIGN, SUBJECTS, AND OUTCOME MEASURES: We studied infants 23-28weeks' gestation born 2006-2013 at NICHD Neonatal Research Network centers. We examined the responses to PDA treatment with indomethacin and/or ibuprofen and whether the PDA was subsequently closed surgically. Logistic regression generated adjusted odds ratios (ORs) for the associations between the z-score groups (<-2, -2 to -0.5, and >-0.5) and PDA surgery following pharmacologic treatment. RESULTS: 5606 infants were diagnosed with PDA; 3587 (64.0%) received indomethacin or ibuprofen or both, and 909 (25.3%) underwent PDA surgery. Mothers of infants with PDA non-closure were less likely to have hypertension (19% vs. 28%). Infants with non-closure were more likely to be female (53% vs. 49%), have lower gestational age and birth weight and to develop sepsis (42% vs. 31%). Compared to infants with z-score>-0.5, PDA surgery was increased among infants with z-score -2 to -0.5 (OR=1.23; 95% CI 1.02-1.47) but not among infants with z-score<-2. CONCLUSION: Infants with birth weight z-score -2 to -0.5 are more likely than normally grown infants to require PDA surgery following pharmacologic treatment.

Congenital nephrotic syndrome in an infant with ALG1-congenital disorder of glycosylation.

Congenital nephrotic syndrome (NS) in the newborn is most frequently related to mutations in genes specific for structural integrity of the glomerular basement membrane and associated filtration structures within the kidney, resulting in massive leakage of plasma proteins into the urine. Occurrence of congenital NS in a multi-system syndrome is less common. We describe the case of an infant with deteriorating neurological status, seizures, edema, and proteinuria who was found to have a mutation in gene ALG1 and a renal biopsy consistent with congenital NS. Furthermore, we briefly review rare existing case reports documenting congenital NS in patients with mutations in ALG1, and treatment strategies, including novel use of peritoneal dialysis.