Abstract
The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.
Similar content being viewed by others
Data availablity
Data is available from the author on request.
References
Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) https://heal.nih.gov/research/infants-and-children/act-now Accessed 29 April 2023
Anbalagan S, Mendez MD (2023) Neonatal abstinence syndrome. StatPearls Publishing, Treasure Island. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551498/. Accessed 30 April 2023
Baldo BA (2021) Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity. Arch Toxicol 95:2627–2642. https://doi.org/10.1007/s00204-021-03068-2
Baldo BA, Pham NH (2021) Drug allergy: clinical aspects, diagnosis, mechanisms, structure-activity relationships, 2nd edn. Springer Nature, Cham, pp 411–438. https://doi.org/10.1007/978-3-030-51740-3
Baldo BA, Rose MA (2022) Mechanisms of opioid-induced respiratory depression. Arch Toxicol 96:2247–2260. https://doi.org/10.1007/s00204-022-03300-7
Bauer IE, Soares JC, Nielsen DA (2015) The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: a systematic review. Am J Addict 24:15–23. https://doi.org/10.1111/ajad.12172
Beyeler SA, Naidoo R, Morrison NR et al (2023) Maternal opioids age-dependently impair neonatal respiratory control networks. Front Physiol 14:1109754. https://doi.org/10.3389/fphys.2023.1109754
Boggess T, Risher WC (2022) Clinical and basic research investigations into the long-term effects of prenatal opioid exposure on brain development. J Neurosci Res 100:396–409. https://doi.org/10.1002/jnr.24642
Buck SA, Torregrossa MM, Logan RW et al (2021) Roles of dopamine and glutamate co-release in the nucleus accumbens in mediating the actions of drugs of abuse. FEBS J 288:1462–1474. https://doi.org/10.1111/febs.15496
CDC for disease control and prevention. NVSS vital statistics rapid release overdose death counts. Update 2/16/2022. https://www.cdc.gov/nchs/nvss/vsrr/drugoverdose-data.htm. Accessed June 1, 2023
Conradt E, Crowell SE, Lester BM (2018) Early life stress and environmental influences on the neurodevelopment of children with prenatal opioid exposure. Neurobiol Stress 9:48–54. https://doi.org/10.1016/j.ynstr.2018.08.005
Coyle DT, Pratt CY, Ocran-Appiah J et al (2018) Opioid analgesic dose and the risk of misuse, overdose, and death: a narrative review. Pharmacoepidemiol Drug Saf 27:464–472. https://doi.org/10.1002/pds.4366
Cui Y, Kam K, Sherman D et al (2016) Defning preBötzinger complex rhythm- and pattern-generating neural microcircuits in vivo. Neuron 91:602–614. https://doi.org/10.1016/j.neuron.2016.07.003
D’Apolito KC (2014) Assessing neonates for neonatal abstinence. J Perinat Neonat Nurs 28:220–231. https://doi.org/10.1097/JPN.0000000000000056
Del Negro CA, Funk GD, Feldman JL (2018) Breathing matters. Nat Rev Neurosci 19:351–367. https://doi.org/10.1038/s41583-018-0003-6
Dennis BB, Bawor M, Thabane L et al (2014) Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone metabolism, dose and treatment response in patients with opioid addiction: A systematic review and meta-analysis. PLoS ONE. 9:e86114. https://doi.org/10.1371/journal.pone.0086114
Devlin LA, Young LW, Kraft WK et al (2022) Neonatal opioid withdrawal syndrome: a review of the science and a look toward the use of buprenorphine for affected infants. J Perinatol 42:300–306. https://doi.org/10.1038/s41372-021-01206-3
Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278. https://doi.org/10.1073/pnas.85.14.5274
Di Lullo E, Kriegstein AR (2017) The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci 18:573–584. https://doi.org/10.1038/nrn.2017.107
Doberczak TM, Kandall SR, Friedmann P (1993) Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal. Obstet Gynecol 81:936–940
D’Souza MS (2015) Glutamatergic transmission in drug reward: implications for drug addiction. Front Neurosci 9:404. https://doi.org/10.3389/fnins.2015.00404
Epstein RA, Bobo WV, Martin PR et al (2013) Increasing pregnancy-related use of prescribed opioid analgesics. Ann Epidemiol 23:498–503. https://doi.org/10.1016/j.annepidem.2013.05.017
Fältmarch S, Perttilä I, Tuomi U et al (2019) Use of opioids during pregnancy and effects of pregnancy outcomes. Pharmacoepidemiol Drug Saf 28:1239–1245. https://doi.org/10.1002/PDS.4848
Farid WO, Dunlop SA, Tait RJ et al (2008) The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: Review of human and animal data. Curr Neuropharmacol 6:125–150. https://doi.org/10.2174/157015908784533842
FDA news release: FDA announces safety labeling changes and post-market study requirements for extended-release and long-acting opioid analgesics—new boxed warning to include neonatal opioid withdrawal syndrome. 2013 http://wayback.archiveit.org/7993/20170112130229/http:/www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm367726.htm. Accessed June 1, 2023
FDA prescribing information, morphine sulfate (2016). Adverse reactions. Available from: https://www.accessdata.fda.gov/drugs atfda_docs/label/2017/208603s000lbl.pdf. Accessed 20 May 2023
Finnegan LP, Kron RE, Connaughton JF et al (1975) Assessment and treatment of abstinence in the infant of the drug-dependent mother. Int J Clin Pharmacol Biopharm 12:19–32
Garcia AJ, Dashevskiy T, Khuu MA et al (2017) (2017) Chronic intermittent hypoxia differentially impacts different states of inspiratory activity at the level of the preBötzinger complex. Front Physiol 8:571. https://doi.org/10.3389/fphys.2017.00571
Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet. 6:521–532. https://doi.org/10.1038/nrg1635
Gourevitch B, Cai J, Mellen N (2017) Cellular and network-level adaptations to in utero methadone exposure along the ventral respiratory column in the neonate rat. Exper Neurol 287:288–297. https://doi.org/10.1016/j.expneurol.2016.03.020
Gray PA, Rekling JC, Bocchiaro CM et al (1999) Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex. Science 286:1566–1568. https://doi.org/10.1126/science.286.5444.1566
Griffiths SK, Campbell JP (2015) Placental structure, function and drug transfer. Cont Edu Anaesth Crit Care Pain. 15:84–89. https://doi.org/10.1093/bjaceaccp/mku013
Hall ES, Wexeblatt SL, Crowley M et al (2014) A multicenter cohort study of treatments and hospital outcomes in neonatal abstinence syndrome. Pediatrics 134:e527–e534. https://doi.org/10.1542/peds.2013-4036
Hauser KF, Knapp PE (2018) Opiate drugs with abuse liability hijack the endogenous opioid system to disrupt neuronal and glial maturation in the central nervous system. Front Pediatr 23(5):294. https://doi.org/10.3389/fped.2017.00294
Heinsbroek JA, De Vries TJ, Peters J (2021) Glutamatergic systems and memory mechanisms underlying opioid addiction. Cold Spring Harb Perspect Med. 11:a039602. https://doi.org/10.1101/cshperspect.a039602
Hirai AH, Ko JY, Owens PL et al (2021) Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2000–2017. JAMA 325:146–155. https://doi.org/10.1001/jama.2020.24991
Hocker AD, Morrison NR, Selby ML et al (2021) Maternal methadone destabilizes neonatal breathing and desensitizes neonates to opioid-induced respiratory frequency depression. Front Physiol. 12:604593. https://doi.org/10.3389/fphys.2021.604593
Hudak ML, Tan RC (2012) Neonatal drug withdrawal. Pediatrics 129:e540–e560. https://doi.org/10.1542/peds.2011-3212
Isaac L, van den Hoogen NJ, Habib S et al (2022) Maternal and iatrogenic neonatal opioid withdrawal syndrome: differences and similarities in recognition, management, and consequences. J Neurosci Res 100:373–395. https://doi.org/10.1002/jnr.24811
Jansson LM (2023) UpToDate Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes. https://www.uptodate.com/contents/prenatal-substance-exposure-and-neonatal-abstinence-syndrome-nas-management-and-outcomes Accessed June 30, 2023
Jansson LM, Velez M, Harrow C (2009) The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag 5:47–55
Jarvis MA, Wu-Pong S, Kniseley JS et al (1999) Alterations in methadone metabolism during late pregnancy. J Addict Dis 18:51–61. https://doi.org/10.1300/J069v18n04_05
Jilani SM, Giroir BP (2020) Neonatal abstinence syndrome: leveraging health information technology to develop a data-driven national policy approach. Public Health Rep 135:173–176. https://doi.org/10.1177/0033354920902476
Jilani SM, Jordan CJ, Jansson LM et al (2021) Definitions of neonatal abstinence syndrome in clinical studies of mother and infants: an expert literature review. J Perinatol 41:1364–1371. https://doi.org/10.1038/s41372-020-00893-8
Jilani SM, Jones HE, Grossman M et al (2022) Standardizing the clinical definition of opioid withdrawal in the neonate. J Pediatr 243:33–39. https://doi.org/10.1016/j.jpeds.2021.12.021
Jones HE, Kaltenbach K, Heil SH et al (2010a) Neonatal abstinence syndrome after methadone or buprenorphine exposure. New Engl J Med 363:2320–2331. https://doi.org/10.1056/NEJMoa1005359
Jones HE, O’Grady KE, Johnson RE et al (2010b) Infant neurobehavior following prenatal exposure to methadone or buprenorphine: results from the neonatal intensive care unit network neurobehavioral scale. Subst Use Misuse 45:2244–2257. https://doi.org/10.3109/10826084.2010.484474
Jones HE, Jansson LM, O’Grady KE et al (2013) The relationship between maternal methadone dose at delivery and neonatal outcome: methodological and design considerations. Neurotoxicol Teratol 39:110–115. https://doi.org/10.1016/j.ntt.2013.05.003
Kaltenbach K, Holbrook AM, Coyle MG et al (2012) Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication. Addiction 107(Suppl 1):45–52. https://doi.org/10.1111/j.1360-0443.2012.04038.x
Kendler KS, Karkowski LM, Neale MC et al (2000) (2000) Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Arch Gen Psychiatry 57:261–269. https://doi.org/10.1001/archpsyc.57.3.261
Ko JY, D’Angelo DV, Haight SC et al (2020) Vital signs: prescription opioid pain reliever use during pregnancy – 34 US jurisdictions. Morb Mortal Wkly Rep 69:897–903
Kocherlakota P (2014) Neonatal abstinence syndrome. Pediatrics 134:e547–e561. https://doi.org/10.1542/peds.2013-3524
Kraft WK, Stover MW, Davis JM (2016) Neonatal abstinence syndrome: pharmacologic strategies for the mother and infant. Semin Perinatol 40:203–212. https://doi.org/10.1053/j.semperi.2015.12.007
Kushnir A, Garretson C, Mariappan M et al (2022) Use of phenobarbital to treat neonatal abstinence syndrome from exposure to single vs. multiple substances. Front Pediatr. 9:752854. https://doi.org/10.3389/fped.2021.752854
Lee LA, Caplan RA, Stephens LS et al (2015) Postoperative opioid induced respiratory depression: a closed claims analysis. Anesthesiology 122:659–665. https://doi.org/10.1097/ALN.0000000000000564
Lewis T, Erfe BL, Ezell T et al (2015) Pharmacoepidemiology of opiate use in the neonatal ICU: Increasing cumulative doses and iatogenic opiate withdrawal. J Opioid Manag 11:305–312. https://doi.org/10.5055/jom.2015.0279
Lipsitz PJ (1975) A proposed narcotic withdrawal score for use with newborn infants: a pragmatic evaluation of its efficacy. Clin Pediatr (phila) 14:592–594. https://doi.org/10.1177/000992287501400613
Logan BA, Brown MS, Hayes MJ (2013) Neonatal abstinence syndrome: treatment and pediatric outcomes. Clin Obstet Gynacol 56:186–192. https://doi.org/10.1097/GRF.ObO13e31827feea4
Lugo RA, Satterfield KL, Kern SE (2005) Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 19:13–24. https://doi.org/10.1080/J354v19n04_05
MacMullen NJ, Samson LF (2018) Neonatal abstinence syndrome: an uncontrollable epidemic. Crit Care Nurs Clin N Am 30:585–596. https://doi.org/10.1016/j.cnc.2018.07.011
Mactier H, McLaughlin P, Gillis C et al (2017) Variations in infant CYP2B6 genotype associated with the need for pharmacological treatment for neonatal abstinence syndrome in infants of methadone-maintained opioid-dependent mothers. Am J Perinatol 34:918–921. https://doi.org/10.1055/s-0037-1600917
Mague SD (2010) Blendy JA (2010) OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend 108:172–182. https://doi.org/10.1016/j.drugalcdep.2009.12.016
Mangat AK, Schmolzer GM, Kraft WK (2019) Pharmacological and non-pharmacological treatments for the neonatal abstinence syndrome (NAS). Sem Fetal Neonatal Med 24:133–141. https://doi.org/10.1016/j.siny.2019.01.009
McLaughlin P, Mactier H, Gillis C et al (2017) Increased DNA methylation of ABCB1, CYP2D6, and OPRM1 genes in newborn infants of methadone-maintained opioid-dependent mothers. J Pediatr 190:180-184.e1. https://doi.org/10.1016/j.jpeds.2017.07.026
McPhail BT, Emoto C, Butler D et al (2021) Opioid treatment for neonatal opioid withdrawal syndrome: current challenges and future approaches. J Clin Pharmacol 61:857–870. https://doi.org/10.1002/jcph.1811
McQueen K, Murphy-Oikonen J (2016) Neonatal abstinence syndrome. New Engl J Med 375:2468–2479. https://doi.org/10.1056/NEJMra1600879
Mills-Huffnagle S, Nyland JE (2023) Potential problems and solutions of opioid-based treatment in neonatal opioid withdrawal syndrome (NOWS): a scoping review protocol. BMJ Open. 13:e067883. https://doi.org/10.1136/bmjopen-2022-067883
Montandon G, Horner R (2014) Cross talk proposal: the preBötzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics. J Physiol 592:1159–1162. https://doi.org/10.1113/jphysiol.2013.261974
Montandon G, Qin W, Liu H et al (2011) PreBötzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression. J Neurosci 31:1292–1301. https://doi.org/10.1523/JNEUROSCI.4611-10.2011
National Institute on Drug Abuse. Overdose Death Rates. January 20, 2022. https://nida.nih.gov/drug-topics/trends-statistics/overdose-death-rates. Accessed 1 May, 2023.
Nielsen DA, Yuferov V, Hamon S et al (2009) Increased OPRM1 DNA methylation in lymphocytes of methadone-maintained former heroin addicts. Neuropsychopharmacology 34:867–873. https://doi.org/10.2217/pgs.1294
Nielsen DA, Utrankar A, Reyes JA et al (2012) Epigenetics of drug abuse: predisposition or response. Pharmacogenomics 13:1149–1160. https://doi.org/10.2217/pgs.12.94
NIH Heal Initiative Research Plan https://heal.nih.gov/about/research-plan. Accessed 29 April 2023
Nutt DJ, Lingford-Hughes A, Erritzoe D et al (2015) (2015) The dopamine theory of addiction: 40 years of highs and lows. Nat Rev Neurosci 16(5):305–312. https://doi.org/10.1038/nrn3939
Nygaard E, Slinning K, Moe V et al (2017) Cognitive function of youths born to mothers with opioid and poly-substance abuse problems during pregnancy. Child Neuropsychol 23:159–187. https://doi.org/10.1080/09297049.2015.1092509
Nygaard E, Slinning K, Moe V et al (2018) Neuroanatomical characteristics of youths with prenatal opioid and poly-drug exposure. Neurotoxicol Teratol 68:13–26. https://doi.org/10.1016/j.ntt.2018.04.004
Oei JL, Melhuish E, Uebel H et al (2017) Neonatal abstinence syndrome and high school performance. Pediatrics. 139(2):e20162651. https://doi.org/10.1542/peds.2016-2651
Pagliardini S, Ren J, Greer JJ et al (2003) Ontogeny of the pre-Botzinger complex in perinatal rats. J Neurosci 23:9575–9584. https://doi.org/10.1523/jneurosci.23-29-09575,2003
Pang G, Wu X, Tao X et al (2016) Blockade of serotonin 5-HT2A receptors suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-treated mice. Front Pharmacol 7:514. https://doi.org/10.3389/fphar.2016.00514
Patriquin MA, Bauer IE, Jair C et al (2015) Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system. Psychiatr Genet 25:181–193. https://doi.org/10.1097/YPG.0000000000000095
Pattinson KTS (2008) Opioids and the control of respiration. Br J Anaesth 100:747–758. https://doi.org/10.1093/bja/aen094
Peng J, Sarkar S, Chang SL (2012) Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Dependence 124:2230228. https://doi.org/10.1016/j.drugalcdep.2012.01.013
Piccotti L, Voigtman B, Vongsa R et al (2019) Neonatal opioid withdrawal syndrome: a developmental care approach. Neonatal Netw 38:160–169. https://doi.org/10.1891/0730-0832.38.3.160
Rana D, McLeod AR, Gaston PK et al (2023) Assessing neonatal opioid withdrawal syndrome severity as a function of maternal buprenorphine dose and umbilical cord tissue concentrations. Ann Pharmacother 57:892–898. https://doi.org/10.1177/10600280221134643
Reddy UM, Davis JM, Ren Z et al (2017) Opioid use in pregnancy, neonatal abstinence syndrome, and childhood outcomes: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, American College of Obstetricians and Gynecologists, American Academy of Pediatrics, Society for Maternal-Fetal Medicine, Centers for Disease Control and Prevention, and the March of Dimes Foundation. Obstet Gynecol 130:10–28. https://doi.org/10.1097/AOG.0000000000002054
Sanlorenzo LA, Cooper WO, Dudley JA et al (2019) Increased severity of neonatal abstinence syndrome associated with concomitant antenatal opioid and benzodiazepine exposure. Hosp Pediatr 9:569–575. https://doi.org/10.1542/hpeds.2018-0227
Schiff DM, Grossman MR (2019) Beyond the Finnegan scoring system: Novel assessment and diagnostic techniques for the opioid-exposed infant. Semin Fetal Neonatal Med 24:115–120. https://doi.org/10.1016/j.siny.2019.01.003
Sirnes E, Oltedal L, Bartsch H et al (2017) Brain morphology in school-aged children with prenatal opioid exposure: a structural MRI study. Early Hum Dev 106–107:33–39. https://doi.org/10.1016/j.earlhumdev.2017.01.009
Smith JC, Ellenberger HH, Ballanyi K et al (1991) Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254:726–729. https://doi.org/10.1126/science.1683005
Stover MW, Davis JM (2015) Opioids in pregnancy and neonatal abstinence syndrome. Semin Perinatol 39:561–565. https://doi.org/10.1053/j.semperi.2015.08.013
Sutter MB, Leeman L, Hsi A (2014) Neonatal opioid withdrawal syndrome. Obstet Gynecol Clin North Am 41:317–334. https://doi.org/10.1016/j.ogc.2014.02.010
Swift RM, Dudley M, DePetrillo P et al (1989) Altered methadone pharmacokinetics in pregnancy: implications for dosing. J Substance Abuse 1:453–460. https://doi.org/10.1016/S0899-3289(20)30008-0
Tan W, Janczewski WA, Yang P et al (2008) Silencing preBotzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat Neurosci 11:538–540. https://doi.org/10.1038/nn.2104
Vassoler FM, Byrnes EM, Pierce RC (2014) The impact of exposure to addictive drugs on future generations: physiological and behavioral effects. Neuropharmacology. 76:269–275. https://doi.org/10.1016/j.neuropharm.2013.06.016
Wachman EM, Farrer LA (2019) The genetics and epigenetics of neonatal abstinence syndrome. Semin Fetal Neonatal Med 24:105–110. https://doi.org/10.1016/j.siny.2019.01.002
Wachman EM, Hayes MJ, Brown MS et al (2013) Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA 309:1821–1827. https://doi.org/10.1001/jama.2013.3411
Wachman EM, Hayes MJ, Lester BM et al (2014) Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome. J Pediatr 165:472–478. https://doi.org/10.1016/j.jpeds.2014.05.040
Wachman EM, Hayes MJ, Sherva R et al (2015) Variations in opioid receptor genes in neonatal abstinence syndrome. Drug Alcohol Depend 155:253–259. https://doi.org/10.1016/j.drugalcdep.2015.07.001
Wachman EM, Hayes MJ, Shreatha J et al (2018) Epigenetic variation in OPRM1 gene in opioid-exposed mother-infant dyads. Genes Brain Behav. 17:e12476. https://doi.org/10.1111/gbb.12476
Ward SLD, Schuetz S, Krishna V et al (1986) Abnormal sleeping ventilatory pattern in infants of substance-abusing mothers. Am J Dis Child 140:1015–1020. https://doi.org/10.1001/archpedi.1986.02140240061028
Ward SL, Bautista DB, Woo MS et al (1992) Responses to hypoxia and hypercapnia in infants of substance-abusing mothers. J Pediatr 121:704–709. https://doi.org/10.1016/s0022-3476(05)81896-81897
Weller AE, Crist RC, Reiner BC et al (2021) Neonatal opioid withdrawal syndrome (NOWS): A transgenerational echo of the opioid crisis. Cold Spring Harb Perspect Med. 11(3):a039669. https://doi.org/10.1101/cshperspect.a039669
Wiles JR, Isemann B, Ward LP et al (2014) Current management of neonatal abstinence syndrome secondary to intrauterine opioid exposure. J Pediatr 165:440–446. https://doi.org/10.1016/j.jpeds.2014.05.010
Wilson GS, McCreary R, Kean J et al (1979) The development of preschool children of heroin-addicted mothers: a controlled study. Pediatrics 63:135–141. https://doi.org/10.1542/peds.63.1.135
Winkelman TNA, Villapiano N, Kozhimannil KB et al (2018) Incidence and costs of neonatal abstinence syndrome among infants with Medicaid: 2004–2014. Pediatrics. 141:e20173520. https://doi.org/10.1542/peds.2017-3520
Wise RA, Robbie MA (2020) Dopamine and addiction. Annu Rev Psychol 71:79–106. https://doi.org/10.1146/annurev-psych-010418-103337
Yeoh SL, Eastwood J, Wright IM et al (2019) Cognitive and motor outcomes of children with prenatal opioid exposure: a systematic review and meta-analysis. JAMA Netw Open. 2(7):e197025. https://doi.org/10.1001/jamanetworkopen.2019.7025
Young LW, Hu Z, Annett RD et al (2021) Site-level variation in the characteristics and care of infants with neonatal opioid withdrawal. Pediatrics. 147:e2020008839. https://doi.org/10.1542/peds.2020-008839
Yuan Q, Rubic M, Seah J et al (2014) Do maternal opioids reduce neonatal regional brain volumes? A pilot study. J Perinatol 34:909–913. https://doi.org/10.1038/jp.2014.111
Zahorodny W, Rom C, Whitney W (1998) The neonatal withdrawal inventory: a simplified score of newborn withdrawal. J Dev Behav Pediatr 19:89–93. https://doi.org/10.1097/00004703-199804000-00005
Funding
No funding was received to assist in the preparation of this review.
Author information
Authors and Affiliations
Contributions
The author undertook the literature review, wrote and reviewed the draft, prepared the final manuscript, and agrees to be accountable for all aspects of the work.
Corresponding author
Ethics declarations
Conflict of interest
The author declares no known competing financial interests or personal relationships that influenced the work reported here.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The author is retired. The positions and affiliations are those prior to retirement.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Baldo, B.A. Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression. Arch Toxicol 97, 2575–2585 (2023). https://doi.org/10.1007/s00204-023-03563-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-023-03563-8