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Sources of clinically significant neonatal intensive care unit phthalate exposure

Journal of Exposure Science & Environmental Epidemiology volume 30, pages 137–148 (2020)Cite this article

Abstract

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.

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References

  1. Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007;261:412–7.

    CAS  PubMed  Google Scholar 

  2. Meredith RM. Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a framework for neurodevelopmental disorders. Neurosci Biobehav Rev. 2015;50:180–8.

    CAS  PubMed  Google Scholar 

  3. Mueller CA, Eme J, Burggren WW, Roghair RD, Rundle SD. Challenges and opportunities in developmental integrative physiology. Comp Biochem Physiol A Mol Integr Physiol. 2015;184:113–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Stroustrup A, Teitelbaum SL, Aschner JL. The value of preterm infant environmental health cohorts: the canary in the coal mine. JAMA Pediatr. 2017;171:1139–40.

    PubMed  PubMed Central  Google Scholar 

  5. Kraft AD, Aschner M, Cory-Slechta DA, Bilbo SD, Caudle WM, Makris SL. Unmasking silent neurotoxicity following developmental exposure to environmental toxicants. Neurotoxicol Teratol. 2016;55:38–44.

    CAS  PubMed  Google Scholar 

  6. Mundy WR, Padilla S, Breier JM, Crofton KM, Gilbert ME, Herr DW, et al. Expanding the test set: chemicals with potential to disrupt mammalian brain development. Neurotoxicol Teratol. 2015;52(Pt A):25–35.

    CAS  PubMed  Google Scholar 

  7. Aarnoudse-Moens CS, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics. 2009;124:717–28.

    PubMed  Google Scholar 

  8. Scharf RJ, Stroustrup A, Conaway MR, DeBoer MD. Growth and development in children born very low birth weight. Arch Dis Child Fetal Neonatal Ed. 2016;101:F433–8.

    PubMed  Google Scholar 

  9. Delobel-Ayoub M, Arnaud C, White-Koning M, Casper C, Pierrat V, Garel M, et al. Behavioral problems and cognitive performance at 5 years of age after very preterm birth: the EPIPAGE Study. Pediatrics. 2009;123:1485–92.

    PubMed  Google Scholar 

  10. Treyvaud K, Ure A, Doyle LW, Lee KJ, Rogers CE, Kidokoro H, et al. Psychiatric outcomes at age seven for very preterm children: rates and predictors. J Child Psychol Psychiatry. 2013;54:772–9.

    PubMed  Google Scholar 

  11. Andrews B, Lagatta J, Chu A, Plesha-Troyke S, Schreiber M, Lantos J, et al. The non-impact of gestational age on neuro-developmental outcome for ventilated survivors born at 23–28 weeks gestation. Acta Paediatr. 2012;101:574–8.

    PubMed  PubMed Central  Google Scholar 

  12. Conrad AL, Richman L, Lindgren S, Nopoulos P. Biological and environmental predictors of behavioral sequelae in children born preterm. Pediatrics. 2010;125:e83–9.

    PubMed  Google Scholar 

  13. Calafat AM, Needham LL, Silva MJ, Lambert G. Exposure to di-(2-ethylhexyl) phthalate among premature neonates in a neonatal intensive care unit. Pediatrics. 2004;113:e429–34.

    PubMed  Google Scholar 

  14. Green R, Hauser R, Calafat AM, Weuve J, Schettler T, Ringer S, et al. Use of di(2-ethylhexyl) phthalate-containing medical products and urinary levels of mono(2-ethylhexyl) phthalate in neonatal intensive care unit infants. Environ Health Perspect. 2005;113:1222–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Latini G, De Felice C, Del Vecchio A, Barducci A, Ferri M, Chiellini F. Di-(2-ethylhexyl)phthalate leakage and color changes in endotracheal tubes after application in high-risk newborns. Neonatology. 2009;95:317–23.

    CAS  PubMed  Google Scholar 

  16. Latini G, Ferri M, Chiellini F. Materials degradation in PVC medical devices, DEHP leaching and neonatal outcomes. Curr Med Chem. 2010;17:2979–89.

    CAS  PubMed  Google Scholar 

  17. Weuve J, Sanchez BN, Calafat AM, Schettler T, Green RA, Hu H, et al. Exposure to phthalates in neonatal intensive care unit infants: urinary concentrations of monoesters and oxidative metabolites. Environ Health Perspect. 2006;114:1424–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Department of Health and Human Services, Centers for Disease Control and Prevention. Fourth National Report on Human Exposure to Environmental Chemicals. Atlanta, GA; 2009.https://www.cdc.gov/exposurereport/index.html.

  19. Calafat AM, Ye X, Silva MJ, Kuklenyik Z, Needham LL. Human exposure assessment to environmental chemicals using biomonitoring. Int J Androl. 2006;29:166–71. discussion 81–5.

    CAS  PubMed  Google Scholar 

  20. Ventrice P, Ventrice D, Russo E, De Sarro G. Phthalates: European regulation, chemistry, pharmacokinetic and related toxicity. Environ Toxicol Pharmacol. 2013;36:88–96.

    CAS  PubMed  Google Scholar 

  21. Anderson WA, Castle L, Hird S, Jeffery J, Scotter MJ. A twenty-volunteer study using deuterium labelling to determine the kinetics and fractional excretion of primary and secondary urinary metabolites of di-2-ethylhexylphthalate and di-iso-nonylphthalate. Food Chem Toxicol. 2011;49:2022–9.

    CAS  PubMed  Google Scholar 

  22. Kessler W, Numtip W, Volkel W, Seckin E, Csanady GA, Putz C, et al. Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP. Toxicol Appl Pharmacol. 2012;264:284–91.

    CAS  PubMed  Google Scholar 

  23. Koch HM, Angerer J. Di-iso-nonylphthalate (DINP) metabolites in human urine after a single oral dose of deuterium-labelled DINP. Int J Hyg Environ Health. 2007;210:9–19.

    CAS  PubMed  Google Scholar 

  24. Koch HM, Bolt HM, Preuss R, Angerer J. New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP. Arch Toxicol. 2005;79:367–76.

    CAS  PubMed  Google Scholar 

  25. Leng G, Koch HM, Gries W, Schutze A, Langsch A, Bruning T, et al. Urinary metabolite excretion after oral dosage of bis(2-propylheptyl) phthalate (DPHP) to five male volunteers--characterization of suitable biomarkers for human biomonitoring. Toxicol Lett. 2014;231:282–8.

    CAS  PubMed  Google Scholar 

  26. Engel SM, Zhu C, Berkowitz GS, Calafat AM, Silva MJ, Miodovnik A, et al. Prenatal phthalate exposure and performance on the Neonatal Behavioral Assessment Scale in a multiethnic birth cohort. Neurotoxicology. 2009;30:522–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ferguson KK, Peterson KE, Lee JM, Mercado-Garcia A, Blank-Goldenberg C, Tellez-Rojo MM, et al. Prenatal and peripubertal phthalates and bisphenol A in relation to sex hormones and puberty in boys. Reprod Toxicol. 2014;47:70–6.

    CAS  PubMed  Google Scholar 

  28. Tellez-Rojo MM, Cantoral A, Cantonwine DE, Schnaas L, Peterson K, Hu H, et al. Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age. Sci Total Environ. 2013;461–2:386–90.

    Google Scholar 

  29. Cho SC, Bhang SY, Hong YC, Shin MS, Kim BN, Kim JW, et al. Relationship between environmental phthalate exposure and the intelligence of school-age children. Environ Health Perspect. 2010;118:1027–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim Y, Ha EH, Kim EJ, Park H, Ha M, Kim JH, et al. Prenatal exposure to phthalates and infant development at 6 months: prospective Mothers and Children’s Environmental Health (MOCEH) study. Environ Health Perspect. 2011;119:1495–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 2008;108:177–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ejaredar M, Nyanza EC, Ten Eycke K, Dewey D. Phthalate exposure and childrens neurodevelopment: a systematic review. Environ Res. 2015;142:51–60.

    CAS  PubMed  Google Scholar 

  33. Yolton K, Xu Y, Strauss D, Altaye M, Calafat AM, Khoury J. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior. Neurotoxicol Teratol. 2011;33:558–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Park S, Kim BN, Cho SC, Kim Y, Kim JW, Lee JY, et al. Association between urine phthalate levels and poor attentional performance in children with attention-deficit hyperactivity disorder with evidence of dopamine gene-phthalate interaction. Int J Environ Res Public Health. 2014;11:6743–56.

    PubMed  PubMed Central  Google Scholar 

  35. Testa C, Nuti F, Hayek J, De Felice C, Chelli M, Rovero P, et al. Di-(2-ethylhexyl) phthalate and autism spectrum disorders. ASN Neuro. 2012;4:223–9.

    CAS  PubMed  Google Scholar 

  36. Factor-Litvak P, Insel B, Calafat AM, Liu X, Perera F, Rauh VA, et al. Persistent associations between maternal prenatal exposure to phthalates on child IQ at age 7 years. PLoS ONE. 2014;9:e114003.

    PubMed  PubMed Central  Google Scholar 

  37. Fischer CJ, Bickle Graz M, Muehlethaler V, Palmero D, Tolsa JF. Phthalates in the NICU: is it safe? J Paediatr Child Health. 2013;49:E413–9.

    PubMed  Google Scholar 

  38. Mallow EB, Fox MA. Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks. J Perinatol. 2014;34:892–7.

    CAS  PubMed  Google Scholar 

  39. Santos J, Pearce SE, Stroustrup A. Impact of hospital-based environmental exposures on neurodevelopmental outcomes of preterm infants. Curr Opin Pediatr. 2015;27:254–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Stroustrup A, Bragg JB, Andra S, Curtin P, Spear EA, Sison DB, et al. Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance. PLoS ONE. 2018;13:e0193835.

    PubMed  PubMed Central  Google Scholar 

  41. Boukydis CF, Bigsby R, Lester BM. Clinical use of the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics. 2004;113(3 Pt 2):679–89.

    PubMed  Google Scholar 

  42. Lester BM, Tronick EZ. History and description of the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics. 2004;113(3 Pt 2):634–40.

    PubMed  Google Scholar 

  43. Lester BM, Tronick EZ, Brazelton TB. The Neonatal Intensive Care Unit Network Neurobehavioral Scale procedures. Pediatrics. 2004;113(3 Pt 2):641–67.

    PubMed  Google Scholar 

  44. Lester BM, Tronick EZ, LaGasse L, Seifer R, Bauer CR, Shankaran S, et al. Summary statistics of Neonatal Intensive Care Unit Network Neurobehavioral Scale scores from the maternal lifestyle study: a quasinormative sample. Pediatrics. 2004;113(3 Pt 2):668–75.

    PubMed  Google Scholar 

  45. Tronick E, Lester BM. Grandchild of the NBAS: the NICU Network Neurobehavioral Scale (NNNS): a review of the research using the NNNS. J Child Adolesc Psychiatr Nurs. 2013;26:193–203.

    PubMed  Google Scholar 

  46. Tronick EZ, Olson K, Rosenberg R, Bohne L, Lu J, Lester BM. Normative neurobehavioral performance of healthy infants on the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics. 2004;113(3 Pt 2):676–8.

    PubMed  Google Scholar 

  47. Liu J, Bann C, Lester B, Tronick E, Das A, Lagasse L, et al. Neonatal neurobehavior predicts medical and behavioral outcome. Pediatrics. 2010;125:e90–8.

    PubMed  Google Scholar 

  48. Lester BM, Tronick EZ, LaGasse L, Seifer R, Bauer CR, Shankaran S, et al. The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants. Pediatrics. 2002;110:1182–92.

    PubMed  Google Scholar 

  49. Montirosso R, Del Prete A, Bellu R, Tronick E, Borgatti R. Neonatal Adequate Care for Quality of Life Study G. Level of NICU quality of developmental care and neurobehavioral performance in very preterm infants. Pediatrics. 2012;129:e1129–37.

    PubMed  PubMed Central  Google Scholar 

  50. Smith JR, McGrath J, Brotto M, Inder T. A randomized-controlled trial pilot study examining the neurodevelopmental effects of a 5-week M Technique intervention on very preterm infants. Adv Neonatal Care. 2014;14:187–200.

    PubMed  PubMed Central  Google Scholar 

  51. Sampson J, de Korte D. DEHP-plasticised PVC: relevance to blood services. Transfus Med. 2011;21:73–83.

    CAS  PubMed  Google Scholar 

  52. Carrico C, Gennings C, Wheeler D, Factor-Litvak P. Characterization of a weighted quartile sum regression for highly correlated data in a risk analysis setting. J Agric Biol Environ Stat. 2014;20:100–20.

    PubMed  PubMed Central  Google Scholar 

  53. Lester BM, Andreozzi-Fontaine L, Tronick E, Bigsby R. J Vis Exp. 2014 Aug 25;(90). Assessment and evaluation of the high risk neonate: the NICU Network Neurobehavioral Scale. https://doi.org/10.3791/3368. PMID:25177897. PMCID: PMC4828009.

  54. Textor J, Hardt J, Knuppel S. DAGitty: a graphical tool for analyzing causal diagrams. Epidemiology. 2011;22:745.

    PubMed  Google Scholar 

  55. Parry G, Tucker J, Tarnow-Mordi W, Group UKNSSC. CRIB II: an update of the clinical risk index for babies score. Lancet. 2003;361:1789–91.

    PubMed  Google Scholar 

  56. Van Vliet ED, Reitano EM, Chhabra JS, Bergen GP, Whyatt RM. A review of alternatives to di (2-ethylhexyl) phthalate-containing medical devices in the neonatal intensive care unit. J Perinatol. 2011;31:551–60.

    PubMed  PubMed Central  Google Scholar 

  57. Su PH, Chang YZ, Chang HP, Wang SL, Haung HI, Huang PC, et al. Exposure to di(2-ethylhexyl) phthalate in premature neonates in a neonatal intensive care unit in Taiwan. Pediatr Crit Care Med. 2012;13:671–7.

    PubMed  Google Scholar 

  58. Whyatt RM, Liu X, Rauh VA, Calafat AM, Just AC, Hoepner L, et al. Maternal prenatal urinary phthalate metabolite concentrations and child mental, psychomotor, and behavioral development at 3 years of age. Environ Health Perspect. 2012;120:290–5.

    CAS  PubMed  Google Scholar 

  59. Demirel A, Coban A, Yildirim S, Dogan C, Sanci R, Ince Z. Hidden toxicity in neonatal intensive care units: phthalate exposure in very low birth weight infants. J Clin Res Pediatr Endocrinol. 2016;8:298–304.

    PubMed  PubMed Central  Google Scholar 

  60. Frederiksen H, Kuiri-Hanninen T, Main KM, Dunkel L, Sankilampi U. A longitudinal study of urinary phthalate excretion in 58 full-term and 67 preterm infants from birth through 14 months. Environ Health Perspect. 2014;122:998–1005.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Strømmen K, Lyche JL, Blakstad EW, Moltu SJ, Veierød MB, Almaas AN, et al. Increased levels of phthalates in very low birth weight infants with septicemia and bronchopulmonary dysplasia. Environ Int. 2016;89-90:228–34.

    PubMed  Google Scholar 

  62. Johnson S, Marlow N. Preterm birth and childhood psychiatric disorders. Pediatr Res. 2011;69(5 Pt 2):11R–8R.

    PubMed  Google Scholar 

  63. Montagna A, Nosarti C. Socio-emotional development following very preterm birth: pathways to psychopathology. Frontiers in Psychology. 2016;7:80. https://doi.org/10.3389/fpsyg.2016.00080.

  64. Services DoHaH. Fourth national report on human exposure to environmental chemicals. Atlanta, GA; 2009.

  65. Koch HM, Muller J, Angerer J. Determination of secondary, oxidised di-iso-nonylphthalate (DINP) metabolites in human urine representative for the exposure to commercial DINP plasticizers. J Chromatogr B Anal Technol Biomed Life Sci. 2007;847:114–25.

    CAS  Google Scholar 

  66. Madlinger-Lewis L, Reynolds L, Zarem C, Crapnell T, Inder T, Pineda R. The effects of alternative positioning on preterm infants in the neonatal intensive care unit: a randomized clinical trial. Res Dev Disabil. 2014;35:490–7.

    PubMed  Google Scholar 

  67. Donauer S, Chen A, Xu Y, Calafat AM, Sjodin A, Yolton K. Prenatal exposure to polybrominated diphenyl ethers and polyfluoroalkyl chemicals and infant neurobehavior. J Pediatr. 2015;166:736–42.

    CAS  PubMed  Google Scholar 

  68. Yolton K, Xu Y, Sucharew H, Succop P, Altaye M, Popelar A, et al. Impact of low-level gestational exposure to organophosphate pesticides on neurobehavior in early infancy: a prospective study. Environ Health. 2013;12:79.

    PubMed  PubMed Central  Google Scholar 

  69. Bernard L, Decaudin B, Lecoeur M, Richard D, Bourdeaux D, Cueff R, et al. Analytical methods for the determination of DEHP plasticizer alternatives present in medical devices: a review. Talanta. 2014;129:39–54.

    CAS  PubMed  Google Scholar 

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Acknowledgements

A.S. is supported by a career development award, K23ES022268, from the National Institutes of Environmental Health Sciences (NIEHS) and a cooperative agreement, UG3OD023320, from the National Institutes of Health for the Environmental Influences on Child Health Outcomes (ECHO) program. Additional funding for the investigators and this project came through pilot grants from the Passport Foundation, the Mount Sinai Children’s Environmental Health Center, and an NIEHS center grant P30ES023515.

Funding

A.S. is supported by a career development award, K23ES022268, from the National Institutes of Environmental Health Sciences (NIEHS) and a cooperative agreement, UG3OD023320, from the National Institutes of Health for the Environmental Influences on Child Health Outcomes (ECHO) program. Additional funding for the investigators and this project came through pilot grants from the Passport Foundation, the Mount Sinai Children’s Environmental Health Center, and an NIEHS center grant P30ES023515.

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Authors and Affiliations

  1. Division of Newborn Medicine, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Annemarie Stroustrup & Jennifer B. Bragg

  2. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Annemarie Stroustrup, Stefanie A. Busgang, Syam S. Andra, Paul Curtin, Emily A. Spear, Allan C. Just, Manish Arora & Chris Gennings

  3. Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Annemarie Stroustrup

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Appendix 3

Directed acyclic graphs depicting covariate selection. Models based on WQS regressions involving NNNS subscales included covariates representing severity of illness at birth (base deficit on central blood sampling in the first 12 h of life), gestational age at birth, a variable representing composite medical illness in the NICU, and gender. For models based on DEHP exposure that did not take into accounte neurodevelopmental outcome (i.e., NNNS performance), gestational age at birth, status as a small for gestational age at birth, and infant gender were included as covariates in the model.

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Stroustrup, A., Bragg, J.B., Busgang, S. et al. Sources of clinically significant neonatal intensive care unit phthalate exposure. J Expo Sci Environ Epidemiol 30, 137–148 (2020). https://doi.org/10.1038/s41370-018-0069-2

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