Phthalate exposure in the neonatal intensive care unit is associated with development of bronchopulmonary dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious yet common morbidity of preterm birth. Although prior work suggests a possible role for phthalate exposure in the development of BPD, no study has rigorously evaluated this. Our objective was to determine whether hospital-based phthalate exposure is associated with the development of BPD and to identify developmental windows sensitive to exposure. STUDY DESIGN: This is a prospective multicenter cohort study of 360 preterm infants born at 23-33 weeks gestation participating in the Developmental Impact of NICU Exposures (DINE) cohort. 939 urine specimens collected during the NICU stay were analyzed for biomarkers of phthalate exposure by liquid chromatography with tandem mass spectrometry. The modified Shennan definition was used to diagnose bronchopulmonary dysplasia. Reverse distributed-lag modeling identified developmental windows sensitive to specific phthalate exposure, controlling for relevant covariates including sex and respiratory support. RESULTS: Thirty-five percent of participants were diagnosed with BPD. Exposure to specific phthalate mixtures at susceptible points in preterm infant development are associated with later diagnosis of BPD in models adjusted for use of respiratory support. The weighted influence of specific phthalate metabolites in the mixtures varied by sex. Metabolites of di(2-ethylhexyl) phthalate, a phthalate previously linked to neonatal respiratory support equipment, drove this association, particularly among female infants, at 26- to 30-weeks post-menstrual age. CONCLUSIONS: This is the largest and only multi-site study of NICU-based phthalate exposure and clinical impact yet reported. In well-constructed models accounting for infant sex and respiratory support, we found a significant positive association between ultimate diagnosis of BPD and prior exposure to phthalate mixtures with DEHP predominance at 26- to 30-weeks PMA or 34-36-weeks PMA. This information is critically important as it identifies a previously unrecognized and modifiable contributing factor to BPD.

Application of growth modeling to assess the impact of hospital-based phthalate exposure on preterm infant growth parameters during the neonatal intensive care unit hospitalization.

In this study, we use advanced growth modeling techniques and the rich biospecimen and data repositories of the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) study to assess the impact of NICU-based phthalate exposure on extrauterine growth trajectories between birth and NICU discharge. Repeated holdout weighed quantile sum (WQS) regression was used to assess the effect of phthalate mixtures on the latency to first growth spurt and on the rate of first growth spurt. Further, we assessed sex as an effect modifier of the relationship between a phthalate mixture and both outcomes. Nine phthalate metabolites, mono-ethyl phthalate (MEP), mono-benzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-(3-carboxypropyl) phthalate (MCPP), mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were measured in weekly urine specimens from 101 NICU-HEALTH participants between birth and the first growth spurt. Phthalate levels varied by species but not by infant sex, and decreased over the course of the NICU hospitalization as presented in detail in Stroustrup et al., 2018. There was evidence of nonlinearity when assessing the effect of phthalates on latency to first growth spurt. Above a threshold level, a higher phthalate mixture with dominant contributors MCPP, MBzP, and MEP predicted a shorter latency to the first inflection point, or an earlier growth spurt. A higher phthalate mixture with dominant contributors MECPP, MEHHP, and MEOHP was associated with an increased rate of growth. Results of both models were clearly different for boys and girls, consistent with other studies showing the sexually dimorphic impact of early life phthalate exposure. These results suggest that growth curve modeling facilitates evaluation of discrete periods of rapid growth during the NICU hospitalization and exposure to specific phthalates during the NICU hospitalization may both alter the timing of the first growth spurt and result in more rapid growth in a sexually dimorphic manner.

NICU-based stress response and preterm infant neurobehavior: exploring the critical windows for exposure.

BACKGROUND: Exposure to maternal stress in utero negatively impacts cognitive and behavioral outcomes of children born at term. The neonatal intensive care unit (NICU) can be stressful for preterm infants during a developmental period corresponding to the third trimester of gestation. It is unknown whether stress in the NICU contributes to adverse neurodevelopment among NICU graduates. The aim was to examine the association between salivary cortisol and early neurodevelopment in preterm infants. METHODS: We examined the association between cortisol levels during the NICU hospitalization and subsequent performance on the NICU Network Neurobehavioral Scales (NNNS), estimating time-specific associations and considering sex differences. RESULTS: Eight hundred and forty salivary cortisol levels were measured from 139 infants. Average cortisol levels were inversely associated with NNNS Regulation scores for both male and female infants (ß = -0.19; 95% CI: -0.44, -0.02). Critical developmental windows based on postmenstrual age were identified, with cortisol measured <30 weeks PMA positively associated with Habituation and Lethargy scores (ß = 0.63-1.04). Critical developmental windows based on chronological age were identified, with cortisol measured in the first week of life inversely associated with Attention score (ß = -1.01 for females; -0.93 for males). CONCLUSIONS: Stress in the NICU at specific developmental time points may impact early preterm infant neurodevelopment. IMPACT: Stress in the neonatal intensive care unit can impact the neurodevelopmental trajectory of premature infants. The impact of stress is different at different points in development. The impact of stress is sexually dimorphic.

Neighborhood characteristics associated with COVID-19 burden-the modifying effect of age.

BACKGROUND: Neighborhood characteristics have been linked to community incidence of COVID-19, but the modifying effect of age has not been examined. OBJECTIVE: We adapted a neighborhood-wide analysis study (NWAS) design to systematically examine associations between neighborhood characteristics and COVID-19 incidence among different age groups. METHODS: The number of daily cumulative cases of COVID-19 by zip code area in Illinois has been made publicly available by the Illinois Department of Public Health. The number of COVID-19 cases was reported for eight age groups (under 20, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80+). We reviewed this data published from May 23 through June 17, 2020 with complete data for all eight age groups and linked the data to neighborhood characteristics measured by the American Community Survey (ACS). Geographic age-specific cumulative incidence (cases per 1000 people) of COVID-19 was calculated by dividing the number of daily cumulative cases by the population of the same age group at each zip code area. The association between individual characteristics and COVID-19 incidence was examined using Poisson regression models. RESULTS: At the zip code level, neighborhood socioeconomic status was a more important risk factor of COVID-19 incidence in children and working-age adults than in seniors. Social demographics and housing conditions were important risk factors of COVID-19 incidence in older age groups. We additionally observed significant associations between transportation-related variables and COVID-19 incidences in multiple age groups. SIGNIFICANCE: We concluded that age modified the association between neighborhood characteristics and COVID-19 incidence.

Renal insufficiency in children born preterm: examining the role of neonatal acute kidney injury.

OBJECTIVE: To identify the prevalence of renal insufficiency (RI) in children with a history of prematurity and acute kidney injury (AKI). STUDY DESIGN: This prospective cohort study evaluated renal function in children born preterm at 5-9 years of age. Univariable analyses compared perinatal and follow-up data from subjects with and without AKI history, and with and without current RI. Regression analyses were attempted to model RI as a function of AKI and other clinical risk factors. RESULTS: Fifteen of 43 (35%) participants had previously undiagnosed RI. Only children with no AKI history or neonatal stage 1 AKI presented for follow-up. Children born preterm with a history of stage 1 AKI had higher serum creatinine (sCr) at follow-up, but were not more likely to have RI compared to children without stage 1 AKI history (RI prevalence 30% and 36% in AKI and non-AKI group, respectively). CONCLUSION: The high prevalence of RI in this preterm cohort at middle childhood follow-up highlights the need for routine kidney health assessments in this population. Large multicenter studies are needed to further characterize the impact of premature birth and mild AKI on renal function throughout childhood.

The association of prenatal exposure to intensive traffic with early preterm infant neurobehavioral development as reflected by the NICU Network Neurobehavioral Scale (NNNS).

INTRODUCTION: Traffic-related air pollution has been shown to be neurotoxic to the developing fetus and in term-born infants during early childhood. It is unknown whether there is an increased risk of adverse neurobehavioral outcome in preterm infants exposed to higher levels of air pollution during the fetal period. OBJECTIVE: To assess the association between prenatal exposure to traffic-related air pollution on early preterm infant neurobehavior. METHODS: Air pollution exposure was estimated by two methods: density of major roads and density of vehicle-miles traveled (VMT), each at multiple buffering areas around residential addresses. We examined the association between prenatal exposure to traffic-related air pollution and performance on the Neonate Intensive Care Unit (NICU) Network Behavioral Scale (NNNS), a measure of neurobehavioral outcome in infancy for 240 preterm neonates enrolled in the NICU-Hospital Exposures and Long-Term Health cohort. Linear regression analysis was conducted for exposure and individual NNNS subscales. Latent profile analysis (LPA) was applied to classify infants into distinct NNNS phenotypes. Multinomial logistic regression analysis was conducted between exposure and LPA groups. Covariates included gestational age, birth weight z-score, post-menstrual age at NNNS assessment, socioeconomic status, race, delivery type, maternal smoking status, and medical morbidities during the NICU stay. RESULTS: Among all 13 NNNS subscales, hypotonia was significantly associated with VMT (104 vehicle-mile/km2) in 150 m (ß = 0.01, P-value<0.001), 300 m (ß = 0.01, P-value = 0.003), and 500 m (ß = 0.01, P-value = 0.002) buffering areas, as well as with road density in a 500 m buffering area (ß = 0.03, P-value = 0.03). We identified three NNNS phenotypes by LPA. Among them, high density of major roads within 150 m, 300 m, and 500 m buffers of the residential address was significantly associated with the same phenotype (P < 0.05). CONCLUSION: Prenatal exposure to intensive air pollution emitted from major roads may impact early neurodevelopment of preterm infants. Motor development may be particularly sensitive to air pollution-related toxicity.

Sources of clinically significant neonatal intensive care unit phthalate exposure.

In the United States each year, more than 300,000 infants are admitted to neonatal intensive care units (NICU) where they are exposed to a chemical-intensive hospital environment during a developmentally vulnerable period. Although multiple studies have demonstrated elevated phthalate biomarkers in NICU patients, specific sources of NICU-based phthalate exposure have not been identified.In this study, premature newborns with birth weight <1500 g were recruited to participate in a prospective environmental health cohort during the NICU hospitalization. Exposure to specific NICU equipment was recorded daily during the NICU hospitalization. One hundred forty-nine urine specimens from 71 infants were analyzed for phthalate metabolites using high-performance liquid chromatography/tandem mass spectrometry.In initial analyses, exposure to medical equipment was directly related to phthalate levels, with DEHP biomarkers 95-132% higher for infants exposed to specific medical equipment types compared to those without that equipment exposure (p < 0.001-0.023). This association was mirrored for clinically relevant phthalate mixtures whether composed of DEHP metabolites or not (p = 0.002-0.007). In models accounting for concurrent equipment use, exposure to respiratory support was associated with DEHP biomarkers 50-136% higher in exposed compared to unexposed infants (p = 0.007-0.036). Phthalate mixtures clinically relevant to neurobehavioral development were significantly associated with non-invasive respiratory support (p = 0.008-0.026). Feeding supplies and intravenous lines were not significantly associated with clinically important phthalate mixtures.Respiratory support equipment may be a significant and clinically relevant NICU source of phthalate exposure. Although manufacturers have altered feeding and intravenous supplies to reduce DEHP exposure, other sources of exposure to common and clinically impactful phthalates persist in the NICU.

Clinical validation of the Neonatal Infant Stressor Scale with preterm infant salivary cortisol.

BACKGROUND: Preterm infants face unique stress states in early life. Early-life stress has been associated with changes in cortisol reactivity and behavioral abnormalities later in childhood in non-preterm populations. The Neonatal Infant Stressor Scale (NISS) has been used to estimate infant stress in the neonatal intensive care unit (NICU) but has not been biomarker validated. The relationship between NISS scores and salivary cortisol is unknown. The aim of this study is to test the association between NISS scores and salivary cortisol in the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) preterm birth cohort. METHODS: Three hundred and eighty-six salivary cortisol specimens were collected from 125 NICU-HEALTH participants during the NICU hospitalization. NISS scores were calculated to represent the infant's experience in the 6 hours prior to specimen collection. Adjusted mixed-effect regression models were used to assess the association between each NISS score and salivary cortisol. RESULTS: Acute and total NISS scores were significantly associated with salivary cortisol level (P = 0.002 and 0.05, respectively). The chronic NISS score was not associated with salivary cortisol levels. Caffeine treatment and postmenstrual age of the infant were important covariates in all models. CONCLUSION: Acute and total NISS score are associated with salivary cortisol level in hospitalized moderately preterm infants.

Cohort profile: the Neonatal Intensive Care Unit Hospital Exposures and Long-Term Health (NICU-HEALTH) cohort, a prospective preterm birth cohort in New York City.

PURPOSE: The Neonatal Intensive Care Unit Hospital Exposures and Long-Term Health (NICU-HEALTH) longitudinal preterm birth cohort studies the impact of the NICU exposome on early-life development. NICU-HEALTH collects multiple biospecimens, complex observational and survey data and comprehensive multisystem outcome assessments to allow measurement of the impact of modifiable environmental exposures during the preterm period on neurodevelopmental, pulmonary and growth outcomes. PARTICIPANTS: Moderately preterm infants without genetic or congenital anomalies and their mothers are recruited from an urban academic medical centre level IV NICU in New York City, New York, USA. Recruitment began in 2011 and continues through multiple enrolment phases to the present with goal enrolment of 400 infants. Follow-up includes daily data collection throughout the NICU stay and six follow-up visits in the first 2 years. Study retention is 77% to date, with the oldest patients turning age 8 in 2019. FINDINGS TO DATE: NICU-HEALTH has already contributed significantly to our understanding of phthalate exposure in the NICU. Phase I produced the first evidence of the clinical impact of phthalate exposure in the NICU population. Further study identified specific sources of exposure to clinically relevant phthalate mixtures in the NICU. FUTURE PLANS: Follow-up from age 3 to 12 is co-ordinated through integration with the Environmental Influences on Child Health Outcomes (ECHO) programme. The NICU-HEALTH cohort will generate a wealth of biomarker, clinical and outcome data from which future studies of the impact of early-life chemical and non-chemical environmental exposures can benefit. Findings from study of this cohort and other collaborating environmental health cohorts will likely translate into improvements in the hospital environment for infant development. TRIAL REGISTRATION NUMBERS: This observational cohort is registered with ClinicalTrials.gov (NCT01420029 and NCT01963065).

Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance.

Every year in the United States, more than 300,000 infants are admitted to neonatal intensive care units (NICU) where they are exposed to a chemical-intensive hospital environment during a developmentally vulnerable period. The neurodevelopmental impact of environmental exposure to phthalates during the NICU stay is unknown. As phthalate exposure during the third trimester developmental window has been implicated in neurobehavioral deficits in term-born children that are strikingly similar to a phenotype of neurobehavioral morbidity common among children born premature, the role of early-life phthalate exposure on the neurodevelopmental trajectory of premature infants may be clinically important. In this study, premature newborns with birth weight <1500g were recruited to participate in a prospective environmental health cohort study, NICU-HEALTH (Hospital Exposures and Long-Term Health), part of the DINE (Developmental Impact of NICU Exposures) cohort of the ECHO (Environmental influences on Child Health Outcomes) program. Seventy-six percent of eligible infants enrolled in the study. Sixty-four of 81 infants survived and are included in this analysis. 164 urine specimens were analyzed for phthalate metabolites using high-performance liquid chromatography/tandem mass spectrometry. The NICU Network Neurobehavioral Scale (NNNS) was performed prior to NICU discharge. Linear and weighted quantile sum regression quantified associations between phthalate biomarkers and NNNS performance, and between phthalate biomarkers and intensity of medical intervention. The sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP) was associated with improved performance on the Attention and Regulation scales. Specific mixtures of phthalate biomarkers were also associated with improved NNNS performance. More intense medical intervention was associated with higher ∑DEHP exposure. NICU-based exposure to phthalates mixtures was associated with improved attention and social response. This suggests that the impact of phthalate exposure on neurodevelopment may follow a non-linear trajectory, perhaps accelerating the development of certain neural networks. The long-term neurodevelopmental impact of NICU-based phthalate exposure needs to be evaluated.

Evaluation of the Affymetrix CytoScan(®) Dx Assay for developmental delay.

The goal of molecular cytogenetic testing for children presenting with developmental delay (DD) is to identify or exclude genetic abnormalities that are associated with cognitive, behavioral and/or motor symptoms. Until 2010, chromosome analysis was the standard first-line genetic screening test for evaluation of patients with DD when a specific syndrome was not suspected. In 2010, The American College of Medical Genetics and several other groups recommended chromosomal microarray as the first-line test in children with DDs, multiple congenital anomalies and/or autism. This test is able to detect regions of genomic imbalances at a much finer resolution than G-banded karyotyping. Until recently, no chromosomal microarray testing had been approved by the US FDA. This article focuses on the use of the Affymetrix CytoScan(®) Dx Assay (Santa Clara, CA, USA), the first chromosomal microarray to receive FDA approval for the genetic evaluation of individuals with DD.