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

• Type of Material: Article
• Authors: Annemarie Stroustrup, Hofstra University; Xueying Zhang, Icahn School of Medicine at Mount Sinai; Emily Spear, Icahn School of Medicine at Mount Sinai; Sanjukta Bandyopadhyay, University of Rochester; Srinivasan Narasimhan, Icahn School of Medicine at Mount Sinai; Anil K. Meher, Icahn School of Medicine at Mount Sinai; Jaeun Choi, Albert Einstein College of Medicine; Gao Qi, Albert Einstein College of Medicine; Brenda Poindexter, Emory University; Susan L. Teitelbaum, Icahn School of Medicine at Mount Sinai; Syam S. Andra, Icahn School of Medicine at Mount Sinai; Chris Gennigns, Icahn School of Medicine at Mount Sinai; Judy L. Aschner, Hackensack Meridian School of Medicine
• Language: English
• Date: 2023-07-26
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2023 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016/j.envint.2023.108117
• Title of Journal or Parent Work: Environment International
• Volume: 178
• Start Page: 108117
• Grant/Funding Information: This work was supported by the National Institutes of Health [K23ES022268, UG3OD023320, UH3OD023320, P30ES023515, R35ES030435, U2CES030859, U01HL101456).
• Keywords: Bronchopulmonary dysplasia; Neonatal intensive care; Chronic lung disease of prematurity; Phthalate; DEHP; Preterm birth
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Toxicology; Health Sciences, Public Health

Abstract

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.