Long-term mortality in mothers of infants with neonatal abstinence syndrome: A population-based parallel-cohort study in England and Ontario, Canada

Autoři: Astrid Guttmann aff001;  Ruth Blackburn aff006;  Abby Amartey aff001;  Limei Zhou aff001;  Linda Wijlaars aff007;  Natasha Saunders aff001;  Katie Harron aff007;  Maria Chiu aff001;  Ruth Gilbert aff007
Působiště autorů: ICES, Toronto, Ontario, Canada aff001;  Hospital for Sick Children, Toronto, Ontario, Canada aff002;  Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada aff003;  Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada aff004;  Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada aff005;  UCL Institute of Health Informatics, London, United Kingdom aff006;  UCL Great Ormond Street Institute of Child Health, London, United Kingdom aff007
Vyšlo v časopise: Long-term mortality in mothers of infants with neonatal abstinence syndrome: A population-based parallel-cohort study in England and Ontario, Canada. PLoS Med 16(11): e32767. doi:10.1371/journal.pmed.1002974
Kategorie: Research Article
doi: 10.1371/journal.pmed.1002974



Opioid addiction is a major public health threat to healthy life expectancy; however, little is known of long-term mortality for mothers with opioid use in pregnancy. Pregnancy and delivery care are opportunities to improve access to addiction and supportive services. Treating neonatal abstinence syndrome (NAS) as a marker of opioid use during pregnancy, this study reports long-term maternal mortality among mothers with a birth affected by NAS in relation to that of mothers without a NAS-affected birth in 2 high-prevalence jurisdictions, England and Ontario, Canada.

Methods and findings

We conducted a population-based study using linked administrative health data to develop parallel cohorts of mother–infant dyads in England and Ontario between 2002 and 2012. The study population comprised 13,577 and 4,966 mothers of infants with NAS and 4,205,675 and 929,985 control mothers in England and Ontario, respectively. Death records captured all-cause maternal mortality after delivery through March 31, 2016, and cause-specific maternal mortality to December 31, 2014. The primary exposure was a live birth of an infant with NAS, and the main outcome was all deaths among mothers following their date of delivery. We modelled the association between NAS and all-cause maternal mortality using Cox regression, and the cumulative incidence of cause-specific mortality within a competing risks framework. All-cause mortality rates, 10-year cumulative incidence risk of death, and crude and age-adjusted hazard ratios were calculated. Estimated crude 10-year mortality based on Kaplan–Meier curves in mothers of infants with NAS was 5.1% (95% CI 4.7%–5.6%) in England and 4.6% (95% CI 3.8%–5.5%) in Ontario versus 0.4% (95% CI 0.41%–0.42%) in England and 0.4% (95% CI 0.38%–0.41%) in Ontario for controls (p < 0.001 for all comparisons). Survival curves showed no clear inflection point or period of heightened risk. The crude hazard ratio for all-cause mortality was 12.1 (95% 11.1–13.2; p < 0.001) in England and 11.4 (9.7–13.4; p < 0.001) in Ontario; age adjustment did not reduce the hazard ratios. The cumulative incidence of death was higher among NAS mothers than controls for almost all causes of death. The majority of deaths were by avoidable causes, defined as those that are preventable, amenable to care, or both. Limitations included lack of direct measures of maternal opioid use, other substance misuse, and treatments or supports received.


In this study, we found that approximately 1 in 20 mothers of infants with NAS died within 10 years of delivery in both England and Canada—a mortality risk 11–12 times higher than for control mothers. Risk of death was not limited to the early postpartum period targeted by most public health programs. Policy responses to the current opioid epidemic require effective strategies for long-term support to improve the health and welfare of opioid-using mothers and their children.

Klíčová slova:

Death rates – England – Infants – Labor and delivery – Neonates – Ontario – Opioids – Pregnancy


1. Gomes T, Tadrous M, Mamdani MM, Paterson JM, Juurlink DN. The burden of opioid-related mortality in the United States. JAMA Netw Open. 2018;1(2):e180217. doi: 10.1001/jamanetworkopen.2018.0217 30646062

2. Statistics Canada. Changes in life expectancy by selected causes of death, 2017. Ottawa: Statistics Canada; 2019 [cited 2019 Oct 24]. https://www.150.statcan.gc.ca/n1/daily-quotidien/190530/dq190530d-eng.htm.

3. International Narcotics Control Board. Narcotic drugs: estimated world requirements for 2019; statistics for 2017. Vienna: International Narcotics Control Board; 2018 [cited 2019 Oct 24]. https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2018/INCB-Narcotics_Drugs_Technical_Publication_2018.pdf.

4. Weisberg DF, Becker WC, Fiellin DA, Stannard C. Prescription opioid misuse in the United States and the United Kingdom: cautionary lessons. Int J Drug Policy. 2014;25(6):1124–30. doi: 10.1016/j.drugpo.2014.07.009 25190034

5. Gemmill A, Kiang MV, Alexander MJ. Trends in pregnancy-associated mortality involving opioids in the United States, 2007–2016. Am J Obstet Gynecol. 2019;220(1):115–6. doi: 10.1016/j.ajog.2018.09.028 30273587

6. McQueen K, Murphy-Oikonen J. Neonatal abstinence syndrome. N Engl J Med. 2016;375(25):2468–79. doi: 10.1056/NEJMra1600879 28002715

7. Norgaard M, Nielsson MS, Heide-Jorgensen U. Birth and neonatal outcomes following opioid use in pregnancy: a Danish population-based study. Subst Abuse. 2015;9(Suppl 2):5–11. doi: 10.4137/SART.S23547 26512202

8. 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(24):2320–31. doi: 10.1056/NEJMoa1005359 21142534

9. 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(4):e20173520. doi: 10.1542/peds.2017-3520 29572288

10. Filteau J, Coo H, Dow K. Trends in incidence of neonatal abstinence syndrome in Canada and associated healthcare resource utilization. Drug Alcohol Depend. 2018;185:313–21. doi: 10.1016/j.drugalcdep.2017.12.019 29486420

11. Davies H, Gilbert R, Johnson K, Petersen I, Nazareth I, O’Donnell M, et al. Neonatal drug withdrawal syndrome: cross-country comparison using hospital administrative data in England, the USA, Western Australia and Ontario, Canada. Arch Dis Child Fetal Neonatal Ed. 2016;101(1):F26–30. doi: 10.1136/archdischild-2015-308948 26290479

12. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000–2009. JAMA. 2012;307(18):1934–40. doi: 10.1001/jama.2012.3951 22546608

13. Kozhimannil KB, Graves AJ, Levy R, Patrick SW. Nonmedical use of prescription opioids among pregnant U.S. women. Womens Health Issues. 2017;27(3):308–15. doi: 10.1016/j.whi.2017.03.001 28408072

14. O’Donnell M, Nassar N, Leonard H, Hagan R, Mathews R, Patterson Y, et al. Increasing prevalence of neonatal withdrawal syndrome: population study of maternal factors and child protection involvement. Pediatrics. 2009;123(4):e614–21. doi: 10.1542/peds.2008-2888 19336352

15. Doggett C, Burrett SL, Osborn DA. Home visits during pregnancy and after birth for women with an alcohol or drug problem. Cochrane Database Syst Rev. 2005;(4):CD004456. doi: 10.1002/14651858.CD004456.pub2 16235364

16. Maeda A, Bateman BT, Clancy CR, Creanga AA, Leffert LR. Opioid abuse and dependence during pregnancy: temporal trends and obstetrical outcomes. Anesthesiology. 2014;121(6):1158. doi: 10.1097/ALN.0000000000000472 25405293

17. Whiteman VE, Salemi JL, Mogos MF, Cain MA, Aliyu MH, Salihu HM. Maternal opioid drug use during pregnancy and its impact on perinatal morbidity, mortality, and the costs of medical care in the United States. J Pregnancy. 2014;2014:906723. doi: 10.1155/2014/906723 25254116

18. Wolfe EL, Davis T, Guydish J, Delucchi KL. Mortality risk associated with perinatal drug and alcohol use in California. J Perinatol. 2005;25(2):93–100. doi: 10.1038/sj.jp.7211214 15496968

19. Hunt RW, Tzioumi D, Collins E, Jeffery HE. Adverse neurodevelopmental outcome of infants exposed to opiate in-utero. Early Hum Dev. 2008;84(1):29–35. doi: 10.1016/j.earlhumdev.2007.01.013 17728081

20. Kahila H, Gissler M, Sarkola T, Autti-Ramo I, Halmesmaki E. Maternal welfare, morbidity and mortality 6–15 years after a pregnancy complicated by alcohol and substance abuse: a register-based case-control follow-up study of 524 women. Drug Alcohol Depend. 2010;111(3):215. doi: 10.1016/j.drugalcdep.2010.04.014 20627617

21. Aldridge RW, Story A, Hwang SW, Nordentoft M, Luchenski SA, Hartwell G, et al. Morbidity and mortality in homeless individuals, prisoners, sex workers, and individuals with substance use disorders in high-income countries: a systematic review and meta-analysis. Lancet. 2018;391(10117):241–50. doi: 10.1016/S0140-6736(17)31869-X 29137869

22. Hser YI, Kagihara J, Huang D, Evans E, Messina N. Mortality among substance-using mothers in California: a 10-year prospective study. Addiction. 2012;107(1):215. doi: 10.1111/j.1360-0443.2011.03613.x 21831178

23. Dannenberg AL, Carter DM, Lawson HW, Ashton DM, Dorfman SF, Graham EH. Homicide and other injuries as causes of maternal death in New York City, 1987 through 1991. Am J Obstet Gynecol. 1995;172(5):1557–64. doi: 10.1016/0002-9378(95)90496-4 7755071

24. Hardt N, Wong TD, Burt MJ, Harrison R, Winter W, Roth J. Prevalence of prescription and illicit drugs in pregnancy-associated non-natural deaths of Florida mothers, 1999–2005. J Forensic Sci. 2013;58(6):1536–41. doi: 10.1111/1556-4029.12219 23879385

25. Oates M. Perinatal psychiatric disorders: a leading cause of maternal morbidity and mortality. Br Med Bull. 2003;67(1):219–29. doi: 10.1093/bmb/ldg011 14711766

26. Bogdanowicz KM, Stewart R, Broadbent M, Hatch SL, Hotopf M, Strang J, et al. Double trouble: psychiatric comorbidity and opioid addiction-all-cause and cause-specific mortality. Drug Alcohol Depend. 2015;148:85. doi: 10.1016/j.drugalcdep.2014.12.025 25578253

27. Degenhardt L, Bucello C, Mathers B, Briegleb C, Ali H, Hickman M, et al. Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies. Addiction. 2011;106(1):32. doi: 10.1111/j.1360-0443.2010.03140.x 21054613

28. Degenhardt L, Larney S, Randall D, Burns L, Hall W. Causes of death in a cohort treated for opioid dependence between 1985 and 2005. Addiction. 2014;109(1):90. doi: 10.1111/add.12337 23961881

29. Veldhuizen S, Callaghan RC. Cause-specific mortality among people previously hospitalized with opioid-related conditions: a retrospective cohort study. Ann Epidemiol. 2014;24(8):620. doi: 10.1016/j.annepidem.2014.06.001 25084705

30. Mc Grath-Lone L, Dearden L, Harron K, Nasim B, Gilbert R. Factors associated with re-entry to out-of-home care among children in England. Child Abuse Negl. 2017;63:73–83. doi: 10.1016/j.chiabu.2016.11.012 27907847

31. Wijlaars L, Herbert A, Zylbersztejn A, Hardelid P, Cromwell D. Data resource profile: Hospital Episode Statistics Admitted Patient Care (HES APC). Int J Epidemiol. 2017;46(4):1093–1093i. doi: 10.1093/ije/dyx015 28338941

32. Patrick SW, Dudley J, Martin PR, Harrell FE, Warren MD, Hartmann KE, et al. Prescription opioid epidemic and infant outcomes. Pediatrics. 2015;135(5):842. doi: 10.1542/peds.2014-3299 25869370

33. Healthcare Cost and Utilization Project. Trends in neonatal abstinence sydrome births in the United States. Rockville (MD): Agency for Healthcare Research and Quality; 2018 [cited 2019 Oct 24]. https://www.hcup-us.ahrq.gov/reports/Trends_NeonatalAbstinenceSyndrome_Births_UnitedStates.pdf.

34. Harron K, Gilbert R, Cromwell D, van der Meulen J. Linking data for mothers and babies in de-identified electronic health data. PLoS ONE. 2016;11(10):e0164667. doi: 10.1371/journal.pone.0164667 27764135

35. Mortality Analysis Team. Review of avoidable mortality definition. London: Office for National Statistics; 2015 [cited 2019 Oct 24]. https://www.ons.gov.uk/aboutus/whatwedo/statistics/consultationsandsurveys/allconsultationsandsurveys/reviewofavoidablemortalitydefinition.

36. Aoyama K, D’Souza R, Inada E, Lapinsky SE, Fowler RA. Measurement properties of comorbidity indices in maternal health research: a systematic review. BMC Pregnancy Childbirth. 2017;17(1):372. doi: 10.1186/s12884-017-1558-3 29132349

37. Austin SR, Wong Y-N, Uzzo RG, Beck JR, Egleston BL. Why summary comorbidity measures such as the Charlson comorbidity index and Elixhauser score work. Med Care. 2015;53(9):e65–72. doi: 10.1097/MLR.0b013e318297429c 23703645

38. Therneau T, Grambsch P. Modeling survival data: extending the Cox model. New York: Springer-Verlag; 2000.

39. Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug Alcohol Depend. 2009;105(1–2):9–15. doi: 10.1016/j.drugalcdep.2009.05.021 19608355

40. Arendt M, Munk-Jorgensen P, Sher L, Jensen SO. Mortality among individuals with cannabis, cocaine, amphetamine, MDMA, and opioid use disorders: a nationwide follow-up study of Danish substance users in treatment. Drug Alcohol Depend. 2011;114(2–3):134–9. doi: 10.1016/j.drugalcdep.2010.09.013 20971585

41. Herbert A, Gilbert R, Cottrell D, Li L. Causes of death up to 10 years after admissions to hospitals for self-inflicted, drug-related or alcohol-related, or violent injury during adolescence: a retrospective, nationwide, cohort study. Lancet. 2017;390(10094):577–87. doi: 10.1016/S0140-6736(17)31045-0 28552365

42. Broadhurst K, Shaw M, Kershaw S, Harwin J, Alrouh B, Mason C, et al. Vulnerable birth mothers and repeat losses of infants to public care: is targeted reproductive health care ethically defensible? J Soc Welf Fam Law. 2015;37(1):84–98. doi: 10.1080/09649069.2015.998007

43. Canfield M, Radcliffe P, Marlow S, Boreham M, Gilchrist G. Maternal substance use and child protection: a rapid evidence assessment of factors associated with loss of child care. Child Abuse Negl. 2017;70:11–27. doi: 10.1016/j.chiabu.2017.05.005 28551458

44. Cornford CS, Close HJ, Bray R, Beere D, Mason JM. Contraceptive use and pregnancy outcomes among opioid drug-using women: a retrospective cohort study. PLoS ONE. 2015;10(3):e0116231. doi: 10.1371/journal.pone.0116231 25739018

45. Downe S, Finlayson K, Walsh D, Lavender T. ‘Weighing up and balancing out’: a meta-synthesis of barriers to antenatal care for marginalised women in high-income countries. Br J Obstet Gynaecol. 2009;116(4):518–29. doi: 10.1111/j.1471-0528.2008.02067.x

46. D’Souza L, Garcia J. Improving services for disadvantaged childbearing women. Child Care Health Dev. 2004;30(6):599–611. doi: 10.1111/j.1365-2214.2004.00471.x 15527471

47. Wall-Wieler E, Roos LL, Bolton J, Brownell M, Nickel N, Chateau D. Maternal mental health after custody loss and death of a child: a retrospective cohort study using linkable administrative data. Can J Psychiatry. 2018;63(5):322–8. doi: 10.1177/0706743717738494 29082774

48. Miller WR. A collaborative approach to working with families. Addiction. 2003;98:5–6. doi: 10.1046/j.1360-0443.2003.00305.x 12492750

49. Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. Br J Obstet Gynaecol. 2009;116(5):665–71. doi: 10.1111/j.1471-0528.2008.02073.x

50. Fajemirokun-Odudeyi O, Sinha C, Tutty S, Pairaudeau P, Armstrong D, Phillips T, et al. Pregnancy outcome in women who use opiates. Eur J Obstet Gynecol Reprod Biol. 2006;126(2):170–5. doi: 10.1016/j.ejogrb.2005.08.010 16202501

51. Goel N, Beasley D, Rajkumar V, Banerjee S. Perinatal outcome of illicit substance use in pregnancy—comparative and contemporary socio-clinical profile in the UK. Eur J Pediatr. 2011;170(2):199–205. doi: 10.1007/s00431-010-1284-6 20827558

52. Lejeune C, Simmat-Durand L, Gourarier L, Aubisson S, Groupe d’Etudes Grossesse et Addictions. Prospective multicenter observational study of 260 infants born to 259 opiate-dependent mothers on methadone or high-dose buprenophine substitution. Drug Alcohol Depend. 2006;82(3):250–7. doi: 10.1016/j.drugalcdep.2005.10.001 16257138

53. Mc Grath-Lone L, Dearden L, Nasim B, Harron K, Gilbert R. Changes in first entry to out-of-home care from 1992 to 2012 among children in England. Child Abuse Negl. 2016;51:163–71. doi: 10.1016/j.chiabu.2015.10.020 26585214

54. Faherty LJ, Matone M, Passarella M, Lorch S. Mental health of mothers of infants with neonatal abstinence syndrome and prenatal opioid exposure. Matern Child Health J. 2018;22(6):841–8. doi: 10.1007/s10995-018-2457-6 29417369

55. Blackburn R, Wijlaars L, Harron K, Guttmann A, Gilbert R. Maternal mortality of women with opioid-use during pregnancy in England: investigating bias in a cohort of linked mother-baby hospital records. Int J Popul Data Sci. 2018;3(4):Conference Proceedings for PIDLC 2018. doi: 10.23889/ijpds.v3i4.895

56. Klinger G, Merlob P. Selective serotonin reuptake inhibitor induced neonatal abstinence syndrome. Isr J Psychiatry Relat Sci. 2008;45(2):107–13. 18982836

57. Maalouf FI, Cooper WO, Stratton SM, Dudley JA, Ko J, Banerji A, et al. Positive predictive value of administrative data for neonatal abstinence syndrome. Pediatrics. 2019;143(1):e20174183. doi: 10.1542/peds.2017-4183 30514781

58. Wong S, Ordean A, Kahan M. Substance use in pregnancy. J Obstet Gynaecol Can. 2011;33(4):367–84. doi: 10.1016/S1701-2163(16)34855-1 21501542

59. Motz M, Leslie M, Pepler D, Moore T, Freeman PA. Breaking the cycle: measures of progress 1995–2005. J FAS Int. 2006;4(Suppl):e22.

60. O’Brien C. Mothering Project—effective prevention with vulnerable families. Ottawa: Canadian Centre for Policy Alternatives; 2015 [cited 2019 Oct 24]. https://www.policyalternatives.ca/sites/default/files/uploads/publications/Manitoba%20Office/2015/12/Mothering_Project.pdf.

61. Ordean A, Kahan M. Comprehensive treatment program for pregnant substance users in a family medicine clinic. Can Fam Physician. 2011;57(11):e430–5. 22084472

62. Pepler DJ, Motz M, Leslie M, Jenkins J, Espinet SD, Reynolds W. The Mother-Child Study: evaluating treatments for substance-using women—a focus on relationships. Toronto: Mothercraft Press; 2014 [cited 2019 Oct 24]. http://www.mothercraft.ca/index.php?q=837.

63. Poole N. Evaluation report of the Sheway Project for high-risk pregnant and parenting women. Vancouver: British Columbia Centre of Excellence for Women’s Health; 2000 [cited 2019 Oct 24]. http://bccewh.bc.ca/wp-content/uploads/2012/05/2000_Evaluation-Report-of-the-Sheway-Project.pdf.

64. Sword W, Niccols A, Fan A. “New Choices” for women with addictions: perceptions of program participants. BMC Public Health. 2004;4:10. doi: 10.1186/1471-2458-4-10 15086957

65. Feder KA, Letourneau EJ, Brook J. Children in the opioid epidemic: addressing the next generation’s public health crisis. Pediatrics. 2019;143(1):e20181656. doi: 10.1542/peds.2018-1656 30514782

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PLOS Medicine

2019 Číslo 11

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