Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance

Stroustrup A, Bragg JB, Andra SS, Curtin PC, Spear EA, Sison DB, Just AC, Arora M, Gennings C. Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance. PLoS One. 2018 Mar 5;13(3):e0193835. 

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193835

Abstract

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.

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From the article 

Every year in the United States, more than 300,000 infants are admitted to neonatal intensive care units (NICUs) where, in addition to experiencing life-saving treatments, they are exposed to a chemical-intensive hospital environment during a developmentally vulnerable period.[1–5] Prematurity, particularly birth at gestational age < 32 weeks and weight < 1500g, is associated with a particular behavioral phenotype characterized by inattention, anxiety, and socialization difficulties[6] that can be measured as early as the toddler years.  Alterations in the developmental trajectory of the cerebral cortex—as opposed to focal brain injury—are thought to lead to behavioral morbidities associated with preterm birth.[6, 8] Prematurity-related impairments such as cognitive dysfunction, fine and gross motor impairments, attention deficit, hyperactivity, and autism spectrum disorders  are only partially explained by degree of prematurity or severity of illness in infancy.  Traditional perinatal risk factors such as gestational age are not as strongly prognostic of neurodevelopmental outcome as previously thought.  Exposure to chemical toxicants during early development, notably exposure to phthalates, is implicated in alterations in neurodevelopment in term-born human and animal studies. Phthalates, chemical plasticizers known to leach out of medical equipment used to care for infants,  are known to be present in biospecimens taken from NICU inpatients.  Whether hospital-based exposure to phthalates influences behavioral development of NICU graduates has not been evaluated previously…

Associations between prenatal or early childhood exposure to phthalates and alterations in multiple domains of neurodevelopment have been reported in non-NICU populations.  Elevated in utero exposure to phthalate mixtures has been associated with poorer infant executive function, attention, and motor reflexes.  In utero exposure to DEHP, the phthalate most commonly associated with polyvinyl chloride (PVC) plastic medical equipment, has been associated independently with childhood impairments in cognitive, motor, and executive function, as well as with hyperactivity, poor attention, and autism spectrum behaviors in term-born cohorts.  No biomarker-based study of preterm infants or preterm animal models during the “third trimester” developmental period between birth and term-equivalent has assessed the impact of phthalate exposure on neurodevelopmental outcomes.

We hypothesize that NICU-based exposure to phthalates contributes to altered behavioral development in preterm infants. This hypothesis draws on noted similarities between abnormal attention and social interaction phenotypes that have been linked to in utero phthalate exposure in term cohorts and the characteristic “preterm behavioral phenotype” described by Montagna and Nosarti.  Additionally, through data gathered in this study we preliminarily explore the hypothesis first investigated by Green et al.  that clinically-relevant phthalate exposure can be linked to specific NICU equipment…

This study is the first to relate NICU-based phthalate exposure to neurobehavioral outcome. As a biomarker-based prospective study designed from its inception as an environmental health cohort of premature infants, it is unique in its population and approach. The primary finding, that NICU-based phthalate exposure was associated with improved performance on specific NNNS summary scales was unexpected, but consistent across analyses focused only on DEHP metabolites and on agnostically derived phthalate mixtures…

Although unexpected, our findings are biologically plausible and may provide insight into the sometimes inconsistent data on the relationship between phthalate exposure during early development and neurodevelopmental outcomes. Our outcome measure, the NNNS, is a measure of neurobehavioral development, not a measure of static cognitive ability or behavior. As NNNS performance improves with maturity, improved summary scale scores can be interpreted as either improved ability compared to PMA-matched peers, or attainment of neurodevelopmental milestones earlier than expected. Commonly proposed mechanisms of action of phthalate neurotoxicity involve endocrine disruption via interference with androgen synthesis and thyroid function—two pathways known to be critically important to neurodevelopment. Additionally, phthalate exposure is linked to epigenetic modification which could alter neurodevelopmental velocity during times of neuronal plasticity.  If phthalates prevented the development of normal inhibitory responses that protect the nervous system from excess stimulation, infants with greater phthalate exposure would demonstrate elements of the pattern seen in our cohort: hyper-attention, hyperreflexia, and difficulty being soothed. The sensitivity of premature infants to hyperstimulation has been long recognized; multiple established care practices (low lighting, covered incubators, clustered cares) aimed at reducing environmental stimulation have been shown to improve preterm brain development and motor function…

In this first phase of a prospective cohort study of the neurodevelopmental impact of NICU-based phthalate exposure on very low birth weight infants, specific mixtures of phthalate biomarkers were associated with improved attention and social response on the NICU Network Neurobehavioral Scale. The long-term impact of this association between phthalate exposure and neurobehavior needs to be evaluated as our preterm cohort ages.

Courtesy of:  https://www.medpagetoday.com/neurology/generalneurology/71561