We would like to acknowledge EpigenDx (Ashland, MA; epigendx.com) who performed the DNA methylation studies; the research assistants who assisted with patient enrollment, sample collection, and data collection; and the BMC RESPECT NOWS Research Group.
Author contributions
EMW and AW contributed to the conception and design of the study; HS and JAB organized the database; EMW wrote the first draft of the manuscript; BCI wrote sections of the manuscript; JAB and AH performed the data analysis; HS and BCI performed the subject enrollment, sample and data collection; AW performed the DNA isolation; JAB, CB, and HZ contributed to the analysis and interpretation of the data. All authors contributed to the manuscript revision, read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical approval
The study was approved by the Boston University Medical Campus Institutional Review Board.
Consent to participate
Written consent was obtained from those subjects in the opioid cohort as part of a more extensive study protocol. Informed consent was waived for those subjects in the control cohort due to the collection of discarded placental tissue only for these subjects.
Consent to publication
Not applicable.
Availability of data and materials
All relevant data is contained within the manuscript. The dataset used for this manuscript will not be made publicly available due to the confidentiality issues and the sensitive nature of the data related to maternal substance use disorder.
Funding
This project was supported by the Boston University Genome Science Institute, Boston University Clinical and Translational Science Institute (1UL1TR001430), and a Young Clinical Scientist grant from FAMRI (Flight Attendant Medical Research Institute).
Winkelman TNA, Villapiano N, Kozhimannil KB, Davis MM, Patrick SW. Incidence and costs of neonatal abstinence syndrome among infants with Medicaid: 2004–2014. Pediatrics.2018;141:e20173520. [DOI] [PubMed] [PMC]
Tolia VN, Patrick SW, Bennett MM, Murthy K, Sousa J, Smith PB, et al. Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Engl J Med.2015;372:2118–26. [DOI]
Patrick SW, Davis MM, Lehman CU, Cooper WO. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012. J Perinatol.2015;35:667. [DOI]
Brogly SB, Saia KA, Walley AY, Du HM, Sebastiani P. Prenatal buprenorphine versus methadone exposure and neonatal outcomes: systematic review and meta-analysis. Am J Epidemiol.2014;180:673–86. [DOI]
Wachman EM, Warden AH, Thomas Z, Thomas-Lewis JA, Shrestha H, Nikita FNU, et al. Impact of psychiatric medication co-exposure on neonatal abstinence syndrome severity. Drug Alcohol Depend.2018;192:45–50. [DOI]
Jones HE, Heil SH, Tuten M, Chisolm MS, Foster JM, O’Grady KE, et al. Cigarette smoking in opioid-dependent pregnant women: neonatal and maternal outcomes. Drug Alcohol Depend.2013;131:271–7. [DOI]
Wachman EM, Schiff DM, Silverstein M. Neonatal abstinence syndrome: advances in diagnosis and treatment. JAMA.2018;319:1362–74. [DOI]
Wachman EM, Farrer LA. The genetics and epigenetics of neonatal abstinence syndrome. Semin Fetal Neonatal Med.2019;24:105–10. [DOI]
Wachman EM, Hayes MJ, Sherva R, Brown MS, Shrestha H, Logan BA, et al. Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity. Am J Addict.2017;26:42–9. [DOI]
Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, et al. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA.2013;309:1821–7. [DOI]
Wachman EM, Hayes MJ, Sherva R, Brown MS, Davis JM, Farrer LA, et al. Variations in opioid receptor genes in neonatal abstinence syndrome. Drug Alcohol Depend.2015;155:253–9. [DOI]
Wachman EM, Hayes MJ, Lester BM, Terrin N, Brown MS, Nielsen DA, et al. Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome. J Pediatr.2014;165:472–8. [DOI]
Wachman EM, Hayes MJ, Shrestha H, Nikita FNU, Nolin A, Hoyo L, et al. Epigenetic variation in OPRM1 gene in opioid-exposed mother-infant dyads. Genes Brain Behav.2018;17:e12476. [DOI] [PubMed]
Cardenas A, Lutz SM, Everson TM, Perron P, Bouchard L, Hivert MF. Mediation by placental DNA methylation of the association of prenatal maternal smoking and birth weight. Am J Epidemiol.2019;188:1878–86. [DOI]
Novakovic B, Saffery R. The ever growing complexity of placental epigenetics – role in adverse pregnancy outcomes and fetal programming. Placenta.2012;33:959–70. [DOI]
Januar V, Desoye G, Novakovic B, Cvitic S, Saffery R. Epigenetic regulation of human placental function and pregnancy outcome: considerations for causal inference. Am J Obstet Gynecol.2015;213Suppl 4:S182–96. [DOI] [PubMed]
Vlahos A, Mansell T, Saffery R, Novakovic B. Human placental methylome in the interplay of adverse placental health, environmental exposure, and pregnancy outcome. PLoS Genet.2019;15:e1008236. [DOI] [PubMed] [PMC]
Palma-Gudiel H, Córdova-Palomera A, Eixarch E, Deuschle M, Fañanás L. Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis. Epigenetics.2015;10:893–902. [DOI] [PubMed] [PMC]
Appleton AA, Murphy MA, Koestler DC, Lesseur C, Paquette AG, Padbury JF, et al. Prenatal programming of infant neurobehaviour in a healthy population. Paediatr Perinat Epidemiol.2016;30:367–75. [DOI] [PubMed] [PMC]
van Otterdijk SD, Binder AM, Michels KB. Locus-specific DNA methylation in the placenta is associated with levels of pro-inflammatory proteins in cord blood and they are both independently affected by maternal smoking during pregnancy. Epigenetics.2017;12:875–85. [DOI] [PubMed] [PMC]
Conradt E, Fei M, LaGasse L, Tronick E, Guerin D, Gorman D, et al. Prenatal predictors of infant self-regulation: the contributions of placental DNA methylation of NR3C1 and neuroendocrine activity. Front Behav Neurosci.2015;9:130. [DOI] [PubMed] [PMC]
Paquette AG, Lester BM, Lesseur C, Armstrong DA, Guerin DJ, Appleton AA, et al. Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics.2015;7:767–79. [DOI] [PubMed] [PMC]
Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addict Dis.1975;2:141–58.[PubMed]
Davis JM, Shenberger J, Terrin N, Breeze JL, Hudak M, Wachman EM, et al. Comparison of safety and efficacy of methadone vs. morphine for treatment of neonatal abstinence syndrome: a randomized clinical trial. JAMA Pediatr.2018;172:741–8. [DOI] [PubMed] [PMC]
Wachman EM, Saia K, Humphreys R, Minear S, Combs G, Philipp BL. Revision of breastfeeding guidelines in the setting of maternal opioid use disorder: one institution’s experience. J Hum Lact.2016;32:382–7. [DOI] [PubMed]
Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res.2001;125:279–84. [DOI] [PubMed]
Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med.2010;363:2320–31. [DOI] [PubMed] [PMC]
Saia K, Bagley SM, Wachman EM, Patel PP, Nadas MD, Brogly SB. Prenatal treatment for opioid dependency: observations from a large inner-city clinic. Addict Sci Clin Pract.2017;12:5. [DOI] [PubMed] [PMC]
Levran O, Yuferov V, Kreek MJ. The genetics of the opioid system and specific drug addictions. Hum Genet.2012;131:823–42. [DOI] [PubMed] [PMC]
Nielsen DA, Yuferov V, Hamon S, Jackson C, Ho A, Ott J, et al. Increased OPRM1 DNA methylation in lymphocytes of methadone-maintained former heroin addicts. Neuropsychopharmacology.2009;34:867–73. [DOI] [PubMed] [PMC]
Nielsen DA, Utrankar A, Reyes JA, Simons DD, Kosten TR. Epigenetics of drug abuse: predisposition or response. Pharmacogenomics.2012;13:1149–60. [DOI] [PubMed] [PMC]
Zhang H, Herman AI, Kranzler HR, Anton RF, Simen AA, Gelernter J. Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence. J Hum Genet.2012;57:670–5. [DOI] [PubMed] [PMC]
Ebrahimi G, Asadikaram G, Akbari H, Nematollahi MH, Abolhassani M, Shahabinejad G, et al. Elevated levels of DNA methylation at the OPRM1 promoter region in men with opioid use disorder. Am J Drug Alcohol Abuse.2018;44:193–9. [DOI] [PubMed]
Chidambaran V, Gang Y, Pilipenko V, Ashton M, Ding L. Systematic review and meta-analysis of genetic risk of developing chronic postsurgical pain. J Pain.2019;[Epub ahead of print].[DOI]
Banik A, Kandilya D, Ramya S, Stünkel W, Chong YS, Dheen ST. Maternal factors that induce epigenetic changes contribute to neurological disorders in offspring. Genes.2017;8:150. [DOI]
Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ. The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics.2013;8:1321–9. [DOI] [PubMed] [PMC]
Paquette AG, Lester BM, Koestler DC, Lesseur C, Armstrong DA, Marsit CJ. Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort. PLoS One.2014;9:e104913. [DOI] [PubMed] [PMC]
Zhang H, Herman AI, Kranzler HR, Anton RF, Zhao H, Zheng W, et al. Array-based profiling of DNA methylation changes associated with alcohol dependence. Alcohol Clin Exp Res.2013;37Suppl 1:E108–15. [DOI] [PubMed] [PMC]
Spence JP, Liang T, Foroud T, Lo D, Carr LG. Expression profiling and QTL analysis: a powerful complementary strategy in drug abuse research. Addict Biol.2005;10:47–51. [DOI] [PubMed] [PMC]
Xu H, Wang F, Liu Y, Yu Y, Gelernter J, Zhang H. Sex-biased methylome and transcriptome in human prefrontal cortex. Hum Mol Genet.2014;23:1260–70. [DOI] [PubMed] [PMC]
