Severe maternal morbidity is associated with an increased risk of hospitalization and mortality in the postpartum period.1–3 Severe maternal morbidity includes life threatening complications such as eclampsia and renal failure during pregnancy or within 42 days of delivery.4–6 Current data suggest that up to 88% of maternal deaths are preceded by severe maternal morbidity.1 Risk of death within 42 days has been shown to increase with the number of severe morbidities.3 However, the long-term risk of mortality after the postpartum period is not known as the association of severe maternal morbidity with mortality has been studied mainly for the first 42 days, with little attention to the risk of death past this period.
Severe maternal morbidity has the potential to affect the risk of mortality beyond the immediate postpartum period. Pregnancy complications are known to be associated with poor long-term health outcomes.7,8 In a study of 1,670 pregnant women in the United Kingdom, women with severe maternal morbidity had higher risks of physical, mental, and sexual dysfunction within 6–12 months of delivery compared with women without severe morbidity.8 Similarly, women with severe maternal morbidity had lower scores on physical and general wellbeing up to 5 years later in a cross-sectional study in Brazil.7 Severe maternal morbidity is associated with a two-fold increased rate of hospital readmission in the first year of delivery compared with uncomplicated pregnancies.9 These studies suggest that women who experience severe maternal morbidity may be at risk of long-term sequelae, including premature mortality. We examined the long-term risk of in-hospital mortality after severe maternal morbidity, compared with no morbidity. We hypothesized that severe maternal morbidity was associated with an accelerated long-term risk of mortality.
We performed a longitudinal cohort study of 1,229,306 women who delivered a liveborn neonate or stillborn fetus from 1989 through 2016 in Quebec, Canada. For women with more than one pregnancy, we focused the analysis on the last pregnancy because we were interested in mortality at the end of childbearing, when severe maternal morbidity may be more likely. We extracted data from the Maintenance and Use of Data for the Study of Hospital Clientele registry, which includes 99% of deliveries in Quebec.10 Quebec provides universal health coverage for the population, except for temporary visitors, tourists, and undocumented residents. We excluded 22,573 (1.8%) deliveries with missing health insurance numbers, as these women could not be tracked over time. Follow-up began at delivery and continued until death or the end of follow-up on March 31, 2018.
The main exposure measure was severe maternal morbidity, coded using diagnostic and procedure codes in the International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revisions the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures; and the Canadian Classification of Health Interventions. As a secondary exposure measure, we included severe maternal morbidity in previous pregnancies. We identified women with severe maternal morbidity using the criteria of the Canadian Perinatal Surveillance System, which defines severe morbidity as life threatening conditions during pregnancy or within 42 days of delivery.1 Mortality was not included in the exposure.
Components of severe maternal morbidity included severe preeclampsia or eclampsia, severe hemorrhage (peripartum hemorrhage or placental abruption with a coagulation defect, and transfusion for intrapartum hemorrhage, postpartum hemorrhage, placenta previa, or complications of curettage), cardiac complications (cardiomyopathy, cardiac arrest and resuscitation, myocardial infarction, pulmonary edema and heart failure, complications of anesthesia), cerebrovascular accidents, acute renal failure or dialysis, embolism, shock, disseminated intravascular coagulation, sepsis, uterine rupture, hysterectomy, surgical complications (Appendix 1, available online at http://links.lww.com/AOG/C154), assisted ventilation, intensive care unit admission, and other serious disorders (acute fatty liver, hepatic failure, cerebral edema or coma, and similar conditions).1 We included a composite variable for any severe maternal morbidity, and examined subtypes of morbidity separately (not mutually exclusive). Women without severe maternal morbidity comprised the comparison group.
The outcome included in-hospital deaths up to three decades after delivery. We identified deaths that occurred within 42 days of delivery compared with 43 days or later. According to the World Health Organization, maternal mortality refers to death during pregnancy or within 42 days of the end of gestation.11 We categorized long-term deaths as between 43 days and 11 months, 1–4 years, 5–9 years, or 10–29 years after delivery. We could not account for deaths out of hospital. The majority of deaths are recorded in hospital data, although deaths due to intentional or unintentional injuries, including homicides and accidents, may be missed.
We assessed the underlying cause of death, as recorded by the physician in the hospital dossier. Causes of death became available in 2006 and were documented using diagnostic codes in the ICD-10. Causes included obstetric, cardiovascular, pulmonary, neurologic, sepsis, shock, organ failure, neoplastic, suicide, gastrointestinal, endocrine, renal, injury, and other remaining conditions (Appendix 1, http://links.lww.com/AOG/C154). Obstetric deaths were deaths within 42 days of delivery with obstetric causes in the ICD. Although most causes of death became available in 2006, codes for deaths due to obstetric conditions and suicide were available from the start of the study in 1989.
We accounted for potential confounders of the association between severe maternal morbidity and mortality.1,12 We measured age (younger than 20, 20–24, 25–29, 30–34, 35 years or older), parity (one, two, three, four or more deliveries), multiple birth (yes, no), pre-existing comorbidity (myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, liver disease, hemiplegia or paraplegia, renal disease, malignancies other than skin cancer, metastatic solid tumor, human immunodeficiency virus (HIV) disease, hypertension, obesity, type 1 or 2 diabetes, alcohol, tobacco or substance use),10,12,13 socioeconomic deprivation (disadvantaged quintile, not disadvantaged), and time period (1989–1999, 2000–2009, 2010–2016) at the last pregnancy. Socioeconomic status was measured using a composite score from a principal component analysis of Census data on mean neighborhood income, education level, and employment in Quebec.10
We calculated mortality rates per 1,000 person-years and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CI for the association of severe maternal morbidity with in-hospital mortality. We adjusted models for age, parity, multiple birth, pre-existing comorbidity, socioeconomic deprivation, and time period. We also examined models adjusted only for age and pre-existing comorbidity. The time scale was the number of days between the last delivery and death or the study end. Women who did not die before study end were censored. We examined the risk of mortality overall and by time interval, including 0–42 days, 43 days–11 months, 1–4 years, 5–9 years, and 10–29 years. We assessed specific causes of death separately. Except for obstetric conditions and suicide, we restricted the analysis of specific causes to women who delivered after 2006 when the cause of death became available. We verified the proportional hazards assumption using time interaction terms and by stratifying models by follow-up period.
In secondary analyses, we assessed how severe maternal morbidity in previous pregnancies was associated with the risk of mortality. To do so, we separated women who were multiparous (severe maternal morbidity in last pregnancy only, severe maternal morbidity in previous and last pregnancies, severe maternal morbidity in previous pregnancies only, no morbidity) from women who were nulliparous (severe maternal morbidity, no morbidity). In sensitivity analyses, we tested models with follow-up for severe maternal morbidity beginning at the first pregnancy. We also determined whether associations changed when we excluded 108,200 women with pre-existing comorbidity, 232,418 women with socioeconomic deprivation, and 243,460 women who had their first delivery after 2010 and may not have completed childbearing. We carried out the analysis using SAS version 9.4. We complied with Tri-Council Policy requirements for research in Canada and obtained a waiver for ethics review from the institutional review board of the University of Montreal Hospital Centre.
The study cohort comprised 1,229,306 women who delivered from 1989 through 2016 (Table 1). A total of 36,079 women (2.9%) had severe maternal morbidity in their last pregnancy. Compared with no morbidity, women with severe maternal morbidity were more likely to be 35 years or older (23.5% vs 20.0%), primiparous (54.9% vs 43.4%), socioeconomically deprived (22.5% vs 18.8%), and have multiple births (5.4% vs 1.8%), or pre-existing comorbidity (17.0% vs 9.7%).
There were 7,533 deaths during the study, corresponding to a mortality rate of 0.42 per 1,000 person-years (95% CI 0.41–0.43). Women with severe morbidity had a mortality rate of 0.86 per 1,000 person-years compared with 0.41 per 1,000 person-years for no morbidity (Table 2). Median time to death was 6.8 years for severe maternal morbidity compared with 15.1 years for no morbidity. Women with cardiac complications and cerebrovascular accidents in their last pregnancy had substantially elevated mortality rates compared with no morbidity. In fully adjusted models, severe maternal morbidity was associated with increased risk of mortality any time after delivery. Over the entire duration of follow-up, women with severe maternal morbidity had two times the risk of mortality any time after their last pregnancy (95% CI 1.81–2.20), compared with no morbidity. Risks of mortality in the immediate postpartum period were elevated for all types of severe morbidity.
Severe maternal morbidity was associated with mortality 42 days after delivery, and associations persisted several years later (Table 3 and Appendices 2 and 3 [Appendixes 2 and 3 are available online at http://links.lww.com/AOG/C154]). Risks of mortality after 42 days were particularly elevated for morbidity due to cardiac complications (HR 7.00, 95% CI 4.94–9.91), cerebrovascular accidents (HR 4.03, 95% CI 2.17–7.48), acute renal failure (HR 4.35, 95% CI 2.66–7.10), and hysterectomy (HR 2.26, 95% CI 1.46–3.50). However, the association of severe maternal morbidity with mortality weakened over time. Compared with no morbidity, severe maternal morbidity was associated with 6.73 times the risk of mortality from 43 days to 11 months (95% CI 4.48–10.1), 1.91 times the risk from 1 to 4 years (95% CI 1.45–2.52), 1.77 times the risk from 5 to 9 years (95% CI 1.38–2.26), and 1.18 times the risk from 10 to 29 years after delivery (95% CI 1.02–1.38). Women with cardiac complications (HR 2.62, 95% CI 1.25–5.51), severe hemorrhage (HR 1.73, 95% CI 1.19–2.51), and severe preeclampsia or eclampsia (HR 1.38, 95% CI 1.05–1.82) had particularly elevated risks of mortality after 10 years, compared with no morbidity.
Severe maternal morbidity was more strongly associated with death due to cardiovascular, pulmonary, sepsis, shock and organ failure, and neurologic causes any time after delivery (Table 4 and Appendix 4 [Appendix 4 is available online at http://links.lww.com/AOG/C154]). Although the number of deaths was low, severe maternal morbidity was associated with 28.7 times the risk of cardiovascular death (95% CI 9.67–85.0), 38.3 times the risk of neurologic death (95% CI 8.87–165.6), and 21.7 times the risk of death due to sepsis, shock, or organ failure (95% CI 4.72–100.1) within 1 year of delivery. Severe maternal morbidity was associated with pulmonary mortality (HR 5.60, 95% CI 1.56–20.0) and cardiovascular mortality (HR 4.97, 95% CI 1.66–14.8) 1–4 years after delivery, and neurologic mortality (HR 8.19, 95% CI 1.62–41.5) 5 years or more after delivery.
Women with severe maternal morbidity in previous pregnancies had an increased risk of mortality (Table 5 and Appendix 5 [Appendix 5 is available online at http://links.lww.com/AOG/C154]). Among multiparous women, severe maternal morbidity in both the previous and last pregnancies was associated with 2.36 times the risk of death (95% CI 2.00–2.78), compared with no morbidity. Severe maternal morbidity in the last pregnancy only was associated with 2.88 times the risk of death (95% CI 1.96–4.24). However, severe maternal morbidity in a previous but not the last pregnancy was associated with a less pronounced risk of death (HR 1.20, 95% CI 0.99–1.45).
In sensitivity analyses (Appendix 6, available online at http://links.lww.com/AOG/C154), we obtained similar associations when follow-up began at the first pregnancy. Excluding women with pre-existing comorbidities or socioeconomic deprivation, and women who had their first delivery after 2010, did not substantially affect the results.
In this longitudinal study with 17.9 million person-years of follow-up, women with severe maternal morbidity at their last pregnancy had a persistently increased risk of mortality after the postpartum period. The risk of mortality was strongest within 6 weeks of delivery but remained elevated several years later. The risk of mortality in the first year after delivery was highest for women who experienced cardiac complications, cerebrovascular accidents, and acute renal failure. Severe maternal morbidity was associated with increased risks of death due to cardiovascular and pulmonary causes. Women with severe maternal morbidity in previous pregnancies had an elevated risk of death if severe morbidity was also present in their last pregnancy. These findings suggest that severe maternal morbidity may be an important determinant of mortality later in life.
Very few studies have evaluated the association of severe maternal morbidity with long-term outcomes. The few existing studies focus on quality of life measures,7,8 and risk of re-hospitalization within the first year.9 In an analysis of 685,228 deliveries in the United States, severe maternal morbidity was associated with 2.5 times the risk of hospital readmission within 6 weeks of delivery and two times the risk 1 year after delivery, compared with no morbidity.9 Although the reasons for admission were unspecified, the findings suggest that the association of severe maternal morbidity with long-term sequelae may be grossly underestimated. Other studies have shown that pregnant women with severe morbidity have increased risks of physical, mental, and sexual dysfunction up to 1 year later.7,8
Severe maternal morbidity comprises heterogeneous life-threatening conditions, including disorders associated with end-organ damage in the cardiovascular, renal, and hepatic systems. The pathways leading to mortality may vary by organ system. Cardiac complications or cerebrovascular accidents in pregnancy may influence longer-term cardiovascular mortality, as there may be permanent sequelae on the cardiovascular system.14 Severe preeclampsia and disorders associated with hemorrhage such as placental abruption may be markers of endothelial dysfunction and stress that persist after pregnancy, which may carry implications for cardiovascular mortality.15,16 Severe preeclampsia is associated with a two-fold increase in the risk of cardiovascular disease,16,17 which resembles the risks of cardiovascular mortality that we observed. The long-term risk of mortality in our study may reflect incomplete recovery of normal organ function after pregnancy complications.15,16
Severe maternal morbidity was strongly associated with cardiovascular mortality. Cardiovascular disease is the leading cause of death in women.18 Pregnancy-related conditions such as preeclampsia, preterm birth, and gestational diabetes are increasingly recognized determinants of cardiovascular morbidity and mortality,19 but the association with severe maternal morbidity has received limited attention. In our study, severe maternal morbidity was associated with cardiovascular mortality several years after delivery. Severe maternal morbidity was also associated with mortality due to pulmonary causes, neurologic causes, and sepsis, shock and organ failure, although the number of deaths from these causes was low.
Severe maternal morbidity in the last pregnancy was more strongly associated with mortality than severe morbidity in previous pregnancies. Women with a normal last pregnancy who had severe morbidity in previous pregnancies did not have as great a risk of mortality. These women had a similar risk of death as primiparous women with normal pregnancies. However, multiparous women without severe morbidity in any pregnancy had the lowest risk. This is consistent with prior literature indicating that primiparous women tend to have higher mortality than multiparous women,20,21 and perhaps also multiparous women with previous pregnancy complications.22 Although women with adverse outcomes may be less likely to have another pregnancy, it is possible that having another pregnancy indicates better health in general compared with having only one pregnancy in total.22 Some primiparous women may have had complications that were not serious enough to be classified as severe maternal morbidity.
There are study limitations. We used the definition of severe maternal morbidity from the Canadian Perinatal Surveillance System which is validated for Canada.1,4 This definition may not capture all severe morbidities, and findings could differ with alternate definitions. We were limited to in-hospital mortality which may exclude some deaths due to suicide, homicide, or accidents. We had data on obstetric causes and suicide before 2006, but not other causes. The methods in our study were not causative analyses. We cannot confirm that severe maternal morbidity was the cause of mortality. Women with pregnancy complications may already be predisposed to chronic conditions that are either revealed during pregnancy or manifest at a later date. Further, a failure to completely recover after severe maternal morbidity may later lead to chronic disorders. Nonetheless, the findings suggest that severe maternal morbidity may help identify women at risk of premature mortality. The results do not generalize to patients who died out of hospital or migrated out of the province. However, out-of-province migration is not common in Quebec.23
In this study, severe maternal morbidity was associated with mortality several years after delivery. Cardiac complications, cerebrovascular accidents, and acute renal failure were the leading morbidities associated with the risk of death, both in the short and long term. Women with severe maternal morbidity may benefit from continued surveillance and preventative interventions to reduce the risk of premature mortality.
1. Dzakpasu S, Deb-Rinker P, Arbour L, Darling EK, Kramer MS, Liu S, et al. Severe maternal morbidity surveillance: monitoring pregnant women at high risk for prolonged hospitalisation and death. Paediatr Perinat Epidemiol 2020;34:427–39. doi: 10.1111/ppe.12574
2. Koblinsky M, Chowdhury ME, Moran A, Ronsmans C. Maternal morbidity and disability and their consequences: neglected agenda in maternal health. J Health Popul Nutr 2012;30:124–30. doi: 10.3329/jhpn.v30i2.11294
3. Ray JG, Park AL, Dzakpasu S, Dayan N, Deb-Rinker P, Luo W, et al. Prevalence of severe maternal morbidity and factors associated with maternal mortality in Ontario, Canada. JAMA Netw Open 2018;1:e184571. doi: 10.1001/jamanetworkopen.2018.4571
4. Dzakpasu S, Deb-Rinker P, Arbour L, Darling EK, Kramer MS, Liu S, et al. Severe maternal morbidity in Canada: temporal trends and regional variations, 2003-2016. J Obstet Gynaecol Can 2019;41:1589–98.e16. doi: 10.1016/j.jogc.2019.02.014
5. American College of Obstetricians and Gynecologists, the Society for Maternal–Fetal Medicine, Kilpatrick SK, Ecker JL. Severe maternal morbidity: screening and review. Am J Obstet Gynecol 2016;215:B17–22. doi: 10.1016/j.ajog.2016.07.050
6. Say L, Pattinson RC, Gülmezoglu AM. WHO systematic review of maternal morbidity and mortality: the prevalence of severe acute maternal morbidity (near miss). Reprod Health 2004;1:3. doi: 10.1186/1742-4755-1-3
7. Angelini CR, Pacagnella RC, Parpinelli MA, Silveira C, Andreucci CB, Ferreira EC, et al. Quality of life after an episode of severe maternal morbidity: evidence from a cohort study in Brazil. Biomed Res Int 2018;2018:9348647. doi: 10.1155/2018/9348647
8. Waterstone M, Wolfe C, Hooper R, Bewley S. Postnatal morbidity after childbirth and severe obstetric morbidity. BJOG 2003;110:128–33. doi: 10.1046/j.1471-0528.2003.02151.x
9. Harvey EM, Ahmed S, Manning SE, Diop H, Argani C, Strobino DM. Severe maternal morbidity at delivery and risk of hospital encounters within 6 weeks and 1 year postpartum. J Womens Health (Larchmt) 2018;27:140–7. doi: 10.1089/jwh.2017.6437
10. Auger N, Potter BJ, Bilodeau-Bertrand M, Paradis G. Long-term risk of cardiovascular disease in women who have had infants with heart defects. Circulation 2018;137:2321–31. doi: 10.1161/CIRCULATIONAHA.117.030277
11. Alkema L, Chou D, Hogan D, Zhang S, Moller AB, Gemmill A, et al. Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Maternal Mortality Estimation Inter-Agency Group. Lancet 2016;387:462–74. doi: 10.1016/S0140-6736(15)00838-7
12. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. doi: 10.1016/0021-9681(87)90171-8
13. Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005;43:1130–9. doi: 10.1097/01.mlr.0000182534.19832.83
14. Law MR, Watt HC, Wald NJ. The underlying risk of death after myocardial infarction in the absence of treatment. Arch Intern Med 2002;162:2405–10. doi: 10.1001/archinte.162.21.2405
15. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974. doi: 10.1136/bmj.39335.385301.BE
16. Neiger R. Long-term effects of pregnancy complications on maternal health: a review. J Clin Med 2017;6:76. doi: 10.3390/jcm6080076
17. Brown MC, Best KE, Pearce MS, Waugh J, Robson SC, Bell R. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol 2013;28:1–19. doi: 10.1007/s10654-013-9762-6
18. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017;70:1–25. doi: 10.1016/j.jacc.2017.04.052
19. Grandi SM, Filion KB, Yoon S, Ayele HT, Doyle CM, Hutcheon JA, et al. Cardiovascular disease-related morbidity and mortality in women with a history of pregnancy complications. Circulation 2019;139:1069–79. doi: 10.1161/CIRCULATIONAHA.118.036748
20. Doblhammer G. Reproductive history and mortality later in life: a comparative study of England and Wales and Austria. Popul Stud (Camb) 2000;54:169–76. doi: 10.1080/713779087
21. Grundy E, Kravdal O. Fertility history and cause-specific mortality: a register-based analysis of complete cohorts of Norwegian women and men. Soc Sci Med 2010;70:1847–57. doi: 10.1016/j.socscimed.2010.02.004
22. Skjaerven R, Wilcox AJ, Klungsøyr K, Irgens LM, Vikse BE, Vatten LJ, et al. Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study. BMJ 2012;345:e7677. doi: 10.1136/bmj.e7677
23. Girard C. La migration interprovinciale au Québec, 2000-2009. Institut de la Statistique du Québec; 2010.