Research
Open Access

Maternal cardiovascular disease after twin pregnancies complicated by hypertensive disorders of pregnancy: a population-based cohort study

Liran Hiersch, Joel G. Ray, Jon Barrett, Howard Berger, Michael Geary, Sarah D. McDonald, Christina Diong, Sima Gandhi, Jun Guan, Beth Murray-Davis and Nir Melamed; for the DOH-NET (Diabetes, Obesity and Hypertension in Pregnancy Research Network)
CMAJ September 20, 2021 193 (37) E1448-E1458; DOI: https://doi.org/10.1503/cmaj.202837

Abstract

Background: People whose singleton pregnancy is affected by hypertensive disorders of pregnancy (HDP) are at risk of future cardiovascular disease. It is unclear, however, whether this association can be extrapolated to twin pregnancies. We aimed to compare the association between HDP and future cardiovascular disease after twin and singleton pregnancies.

Methods: We conducted a population-based retrospective cohort study that included nulliparous people in Ontario, Canada, 1992–2017. We compared the future risk of cardiovascular disease among pregnant people from the following 4 groups: those who delivered a singleton without HDP (referent) and with HDP, and those who delivered twins either with or without HDP.

Results: The populations of the 4 groups were as follows: 1 431 651 pregnant people in the singleton birth without HDP group; 98 631 singleton birth with HDP; 21 046 twin birth without HDP; and 4283 twin birth with HDP. The median duration of follow-up was 13 (interquartile range 7–20) years. The incidence rate of cardiovascular disease was lowest among those with a singleton or twin birth without HDP (0.72 and 0.74 per 1000 person-years, respectively). Compared with people with a singleton birth without HDP, the risk of cardiovascular disease was highest among those with a singleton birth and HDP (1.47 per 1000 person-years; adjusted hazard ratio [HR] 1.81 [95% confidence interval (CI) 1.72–1.90]), followed by people with a twin pregnancy and HDP (1.07 per 1000 person-years; adjusted HR 1.36 [95% CI 1.04–1.77]). The risk of the primary outcome after a twin pregnancy with HDP was lower than that after a singleton pregnancy with HDP (adjusted HR 0.74 [95% CI 0.57–0.97]), when compared directly.

Interpretation: In a twin pregnancy, HDP are weaker risk factors for postpartum cardiovascular disease than in a singleton pregnancy.

Cardiovascular disease has been shown to be the leading cause of death among women.1–3 Classic risk factors for cardiovascular disease include obesity, diabetes mellitus, hypertension and family history of cardiovascular disease. 3 More recently, an association has been established between a history of hypertensive disorders of pregnancy (HDP) — gestational hypertension and pre-eclampsia — and future risk of cardiovascular disease.1,4–11 Consequently, some recommend using a history of HDP for cardiovascular disease risk stratification in women.3,12

The leading hypothesis for the pathogenesis of HDP is that it results from abnormal placentation due to impaired trophoblast invasion,13–16 resulting in reduced placental perfusion.17–19 This, in turn, leads to abnormal secretion of the angiogenic factors soluble FMS-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng),20 which induce endothelial dysfunction and the clinical manifestations of HDP.19,21–24 The mechanisms underlying the association between HDP and future cardiovascular disease are under debate.25 One hypothesis is that HDP are merely a marker of underlying subclinical or clinical vascular risk factors that predispose a person to both HDP and future cardiovascular disease.

A person who is pregnant with twins is at about 3–4 times higher risk of HDP than a person with a singleton pregnancy,26–33 with rates of 14% and 5%, respectively.34 The higher risk of HDP in twin pregnancies may be due to higher circulating sFlt1 and sEng owing to greater placental mass in twin pregnancies, 35–37 and less related to the classic vascular risk factors for HDP in a singleton pregnancy. Therefore, a logical question is whether the established higher risk of future cardiovascular disease after singleton pregnancies with HDP also occurs in twin pregnancies with HDP. Limited data are available to answer this question.38 In the current study, we aimed to test the hypothesis that the association between HDP and future cardiovascular disease is less pronounced in twin versus singleton pregnancies.

Methods

Study design and participants

We conducted a population-based retrospective cohort study using linked administrative health databases for the province of Ontario, Canada, in which hospital and physician care is publicly funded for all residents. Eligible participants were nulliparous people aged 18–45 years who had a singleton or twin hospital live birth between Apr. 1, 1992, and Mar. 31, 2017. If a person had more than 1 pregnancy, we considered only the first.

We excluded pregnancies with invalid or missing data on gestational age, infant birth weight or infant sex; non-Ontario residents, or people not eligible for the Ontario Health Insurance Plan (OHIP) at the time of delivery; people who died or lost OHIP eligibility within 120 days after the delivery date; and a pregnancy complicated by a stillbirth of 1 or both fetuses. Furthermore, in order to avoid the inclusion of people with pre-existing cardiovascular disease before the index pregnancy, we also excluded those with any recognized form of cardiovascular disease within 2 years before the conception date of the index pregnancy. We present the list of diagnostic and billing codes used to identify cardiovascular disease before the index pregnancy in Appendix 1, Appendix A (available at www.cmaj.ca/lookup/doi/10.1503/cmaj.202837/tab-related-content). Those codes are used by caregivers at both inpatient and outpatient settings.

Data sources

We obtained data from Ontario health care administrative databases held at ICES.39 These databases contain data on health service utilization by residents of the province and include the Registered Persons Database, which records demographic information for all residents of Ontario, including deaths; and the Ontario Health Insurance Plan provider service claims database, which records all fee-for-service billing and shadow-billing claims submitted by Ontario physicians for inpatient or ambulatory consultations, assessments and diagnostic or therapeutic procedures.40 All in-hospital deliveries in Ontario are included in the ICES MOMBABY data set with 98% deterministic linkage of newborn and maternal hospital records. We obtained all hospital discharges from the Canadian Institutes of Health Information Discharge Abstract Database. We identified all emergency department records using the National Ambulatory Care Reporting System. We used Immigration, Refugees and Citizenship Canada’s Permanent Resident Database to obtain immigration information. Records from the administrative databases are deterministically linked using a patient’s encrypted health card number.

We used the International Classification of Diseases (ICD) coding system (9th Revision [ICD-9] before 2002 and the Canadian version, 10th Revision [ICD-10-CA] thereafter) to identify previously validated study exposures41 and outcomes.42,43 We based residential area income quintile and rurality on Statistics Canada Census data.44

Exposures

The primary exposure was 1 of 4 mutually exclusive states in the index (first) pregnancy: i) singleton birth, no HDP; ii) singleton birth, with HDP; iii) twin birth, no HDP; iv) twin birth, with HDP. We defined HDP as either pre-eclampsia (ICD-9 codes 642.4 or 642.7, and ICD-10 codes O11, O14 or O15) or gestational hypertension (ICD-9 codes 642.3 or 642.9, and ICD-10 code O13) at the index birth, ascertained from the Canadian Institute for Health Information Discharge Abstract Database. For the primary analysis, we chose people with a first singleton birth without HDP as the reference group, as they provide a large sample of pregnant people who are likely representative of the population at large. For those with a twin pregnancy and HDP, we also estimated the risk of future cardiovascular disease relative to singleton pregnancies and HDP in order to provide a direct comparison between the 2 groups.

As people with pre-eclampsia may have a more pronounced risk of cardiovascular disease than those with gestational hypertension, especially when pre-eclampsia arises preterm, we further considered 2 secondary exposures: any pre-eclampsia, and pre-eclampsia with a preterm birth before 34 weeks’ gestation. As gestational age at birth is available only from April 2002 onward, we limited the analysis to births starting Apr. 1, 2002.

Outcomes

We defined the primary outcome as a cardiovascular disease composite of any future hospital admission for heart failure, cardiac dysrhythmia, coronary artery disease, cerebrovascular disease or peripheral artery disease (Appendix 1, Appendix B). Secondary study outcomes included the individual components of the primary outcome, as well as all-cause mortality. To minimize the immediate effect of HDP and other factors related to pregnancy and delivery on the risk of cardiovascular disease, we assessed study outcomes starting at 120 days after the index birth date.

Statistical analysis

We used standard descriptive statistics to present the baseline characteristics of the 4 exposure groups. We expressed time-to-event analyses for each study outcome as incidence rates per 1000 person-years, with 95% confidence intervals (CIs), starting 120 days after the index birth date. We used Cox proportional hazards models to generate unadjusted and adjusted hazard ratios (HRs), and censored on death, outmigration from the province, or reaching the end of the study period of Mar. 31, 2018. If a person had more than 1 cardiovascular disease event, we counted the first event. A priori, we adjusted HRs for the pregnant person’s age at the index birth, neighbourhood income quintile, world region of origin, assisted reproductive technology use, and cardiovascular risk factors present before pregnancy, including diabetes mellitus, chronic hypertension, obesity, dyslipidemia, tobacco use or drug dependence, and kidney disease (Appendix 1, Appendix C). We generated time-to-event curves using the Kaplan–Meier procedure and compared exposure groups using the log-rank test.

We analyzed data using the SAS Enterprise Guide statistical software Version 6.1 (Cary, NC).

Ethics approval

The use of data in this project was authorized under section 45 of Ontario’s Personal Health Information Protection Act, in accordance with the Sunnybrook Research Ethics Board.

Results

There were 3 267 689 births during the study period. Of the 1 555 611 nulliparous people who met the study inclusion criteria, 25 329 (1.6%) had a twin gestation (Figure 1). The proportions of pregnancies complicated by HDP in the singleton and twin groups were 6.4% (98 631/1 530 282) and 16.9% (4283/25 329), respectively (Figure 1).

Figure 1:
Figure 1:

Description of the study groups. Note: HDP = hypertensive disorders of pregnancy, OHIP = Ontario Health Insurance Plan. *For the term “birth,” the unit of analysis is newborn rather than pregnancy. Thus, a delivery of twins is counted as 2 births.

The baseline characteristics of the study groups at the time of the index (first) pregnancy are presented in Table 1. Most people lived in a city and had no prepregnancy morbidity.

View this table:
Table 1:

Baseline characteristics of the study groups

The median (interquartile range) duration of follow-up was 13 (7–20) years. The cumulative probability of the cardiovascular disease composite outcome was lowest among people without HDP, either in a singleton or twin pregnancy (incidence rate 0.72 and 0.74 per 1000 person-years, respectively), highest in those with a singleton birth and HDP (1.47 per 1000 person-years), and intermediate in those with a twin birth and HDP (1.07 per 1000 person-years) (Figure 2 and Table 2). Relative to a singleton birth without HDP, the corresponding adjusted HRs were 1.81 (95% CI 1.72–1.90) in singleton pregnancies with HDP and 1.36 (95% CI 1.04–1.77) in twin pregnancies with HDP (Table 2, Figure 3). When we compared the risk of the primary outcome in the twin pregnancy with HDP group versus the singleton pregnancy with HDP group, the adjusted HR was 0.74 (95% CI 0.57–0.97) (Appendix 1, Appendix D).

Figure 2:
Figure 2:

Cumulative probability of the composite primary outcome by plurality and hypertensive disorders of pregnancy (HDP; gestational hypertension or pre-eclampsia) in a first pregnancy. Note: The cumulative probability curves of the composite cardiovascular outcome are presented for twin and singleton pregnancies with and without HDP. *n = number at risk at each 5-year interval shown. Differences between the 4 groups were statistically significant (p < 0.001, log-rank test).

View this table:
Table 2:

Risk of the primary composite outcome in relation to plurality and the hypertensive disorders of pregnancy using people with a singleton birth with no hypertensive disorders as the reference group*

Figure 3:
Figure 3:

Incidence rate of cardiovascular morbidity or death by plurality and hypertensive disorders of pregnancy (HDP; gestational hypertension or pre-eclampsia) in the first pregnancy. The incidence rates of the composite cardiovascular outcome are presented for people with twin and singleton pregnancies with and without HDP. Values are presented as rate per 1000 person-years (PYs) with 95% confidence intervals (CI).

Hypertensive disorders of pregnancy were associated with all the secondary outcomes in singleton pregnancies, but not in twin pregnancies (Table 3). For instance, relative to a singleton birth without HDP, the corresponding adjusted HRs for heart failure, coronary artery disease and cerebrovascular disease were 2.20 (95% CI 1.92–2.51), 1.91 (95% CI 1.80–2.03) and 2.13 (95% CI 1.88–2.42), in singleton pregnancies with HDP and 1.74 (95% CI 0.87–3.48), 1.37 (95% CI 0.98–1.91) and 1.51 (95% CI 0.76–3.04) in twin pregnancies with HDP, respectively (Table 4).

View this table:
Table 3:

Risk of the secondary outcomes in relation to plurality and the hypertensive disorders of pregnancy using people with a singleton birth with no hypertensive disorders as the reference group

View this table:
Table 4:

Risk of the primary composite outcome in relation to plurality and the hypertensive disorders of pregnancy using people with a singleton birth with no hypertensive disorders as the referent, stratified by age of the pregnant person at delivery*

When we calculated the risk of the secondary outcomes in the twin pregnancy with HDP group using the singleton pregnancy with HDP group as the reference, the effect size ranged from 0.36 to 0.83 (indicating a lower risk of the secondary outcomes in twin pregnancy with HDP compared with the reference group), but none of these associations were statistically significant (Appendix 1, Appendix E).

In both singleton and twin gestations, the associations between either pre-eclampsia or pre-eclampsia with preterm birth before 34 weeks and the primary cardiovascular disease composite were similar in direction and magnitude to those observed for the primary exposure of HDP (Table 2; Appendix 1, Appendices D and F).

Finally, to determine whether age during pregnancy modifies the associations described above, we stratified the analysis for the primary outcome by age (Table 4). Although the incidence rates were higher among people aged 35 years or older than those younger than 35 years, the risk of the primary outcome in each of the groups in relation to the referent group (singleton pregnancies without HDP) remained similar (Table 4).

Interpretation

Main findings

In agreement with our hypothesis, we found that those with a history of HDP in a twin pregnancy were at an intermediate risk of the primary composite cardiovascular disease outcome, with the risk being lower than in those with HDP in a singleton pregnancy, but higher than in people with a twin pregnancy without HDP. The association was not affected by the severity of hypertensive complications.

Comparison with other studies

The association of HDP with future cardiovascular disease is well established.1,4,6–10,46,47 In a recent meta-analysis, women with a history of pre-eclampsia had a relative risk of 2.5 for future coronary artery disease, 4.2 for heart failure, and 2.2 for cardiovascular death.47 Given the relatively high prevalence of HDP in twin pregnancies (16.9% in the current study, which is in agreement with previous reports34), it is important to determine whether this association can be extrapolated to people who experienced HDP in a twin pregnancy. As previous studies were either limited to people with singleton gestations48,49 or did not differentiate between people with singleton and twin gestations, our findings add to the literature by qualifying the relationship between HDP and future cardiovascular disease among people who have a twin pregnancy.4,6,7,9,11 A recently published cohort study reported that pre-eclampsia in women with multifetal pregnancy was not associated with a higher risk of future cardiovascular disease.38 However, that study addressed only pre-eclampsia (and not gestational hypertension) as the exposure variable, and did not adjust for known cardiovascular risk factors such as diabetes mellitus and kidney disease. Our results confirm previous findings regarding the association of HDP in singleton gestations with future maternal cardiovascular disease but suggest that the magnitude of this association is lower in those who experienced HDP during a twin pregnancy. Although the adjusted hazard ratio for future cardiovascular disease in the twin pregnancy with HDP group did not differ significantly from that found in the singleton pregnancy with HDP group (as reflected by the overlapping CIs), this is likely to be due to insufficient power, given the considerable differences in the point estimates of the hazard ratios, and as demonstrated by the differences in the incidence rates and the survival curves (Figure 2) between the twin pregnancy with HDP and singleton pregnancy with HDP groups. Furthermore, the risk of the primary outcome in twin pregnancies with HDP was significantly lower than in singleton pregnancies with HDP (adjusted HR 0.74 [95% CI 0.57–0.97]).

The mechanisms underlying the association between HDP and future cardiovascular disease remain unclear.1 One explanation is that HDP is associated with a release of inflammatory and anti-angiogenic factors,50 and although these changes usually resolve postpartum, some patients experience sustained vascular damage and endothelial dysfunction, which may predispose them to future cardiovascular disease.1,46,51,52 The differences in the associations between HDP and future cardiovascular disease between twin and singleton pregnancies identified in our study argues against a direct causal relationship between HDP and future maternal cardiovascular disease, however, because the association between HDP and future cardiovascular disease would be expected to be similar in people who had delivered twins and singletons, respectively, if that was the case. Furthermore, the lack of a “dose–response” relationship between the severity of HDP and future cardiovascular disease, as we observed, further argues against a direct causal relationship between HDP and future cardiovascular disease.

A second explanation for the association between HDP and future cardiovascular disease attributes this association to the presence of underlying clinical or subclinical maternal vascular risk factors that predispose patients to both HDP and future cardiovascular disease (Appendix 1, Appendix G). Our observation of a lower association of HDP with future cardiovascular disease in people who had delivered twins compared with singletons provides support for this explanation. In people who have delivered twins, where the pathogenesis of HDP is heterogeneous and some of it likely attributed to transient factors such as increased placental mass rather than to vascular predisposition, the association between HDP with future maternal cardiovascular disease would be expected to be weaker than in people who have delivered singletons (Appendix 1, Appendix G). This explanation is further supported by previous studies reporting that the risk of recurrence of HDP in subsequent pregnancies is greater for people with a history of HDP in a singleton gestation (where HDP is likely to reflect vascular predisposition) than for those with a history of HDP in a twin gestation (where HDP is more likely to be the result of the transient risk factor such as increased placental mass).53

Limitations

The main limitations of our study are those inherent to the use of administrative databases that are based on diagnostic or billing codes to determine outcomes. Thus, cases with mild cardiovascular disease may not have been recorded. In addition, although we adjusted the analysis for multiple confounding variables, we could not rule out residual confounding, as data on certain cardiovascular risk factors, such as family history of cardiovascular disease and maternal body mass index, were not available. Furthermore, given the observational nature of the study, data on preventive interventions and risk reduction measures in those with a history of HDP were not available.3,12,54 Finally, despite the large sample size, the current study was underpowered to detect associations with the secondary outcomes in the twin group.

Conclusion

We found that compared with HDP in singleton pregnancies, HDP in twin pregnancies is less likely to be associated with future cardiovascular disease. This suggests that HDP in twin gestations is a weaker risk factor for future cardiovascular disease than HDP in singleton pregnancies. This has important implications for the counselling and risk stratification of cardiovascular risk, given the relatively high prevalence of HDP in twin gestations, as well as for the understanding of the mechanisms underlying HDP in twin compared with singleton pregnancies. Future studies should focus on the pathophysiology of HDP in twin compared with singleton pregnancies, and on the mechanisms underlying the association between HDP and future cardiovascular disease in these 2 groups.

Acknowledgement

The authors thank Ms. Negar Bagheri for assistance in project coordination. Parts or whole of this material are based on data and/or information compiled and provided by Immigration, Refugees and Citizenship Canada (IRCC) current to March 31, 2017. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of IRCC.

Footnotes

  • Competing interests: Jon Barrett reports receiving fees for giving expert testimony on behalf of the Canadian Medical Protective Association. Howard Berger reports receiving human placenta growth factor (PLGF) analysis kits from Roche Diagnostics for a quality improvement study on PLGF use in obstetrics. No other competing interests were declared.

  • This article has been peer reviewed.

  • Contributors: Nir Melamed, Liran Hiersch, Joel Ray and Jon Barrett contributed to the conception and design of the work and the acquisition, analysis, and interpretation of data. All of the authors drafted the manuscript. Howard Berger, Michael Geary, Sarah McDonald, Christina Diong, Sima Gandhi, Jun Guan and Beth Murray-Davis revised it critically for important intellectual content. All of the authors gave final approval of the version to be published.

  • Funding: This study was funded by Canadian Institute of Health Research (CIHR) (Grant#146442; Non-communicable Diseases in Obstetrics: Improving Quality of Care and Maternal-infant Outcomes Through an Obstetrical Research Network). Dr. Melamed holds the Waugh Family Chair in Twin Fetal Medicine Research at the Sunnybrook Health Sciences Center and the University of Toronto. Dr. McDonald is supported by a Tier II Canada Research Chair (950-229920). The funders had no roles in the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the article for publication. We confirm the independence of the study researchers from the funders; and we confirm that all authors, external and internal, had full access to all the data in the study (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the analysis.

  • Data sharing: The data set from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., health care organizations and government) prohibit ICES from making the data set publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at https://www.ices.on.ca/DAS (email: das{at}ices.on.ca). The full data set creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

  • Disclaimer: No endorsement by ICES or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information. However, the analyses, conclusions, opinions, and statements expressed herein are those of the authors and not necessarily those of the Canadian Institute for Health Information.

  • Accepted June 17, 2021.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

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Canadian Medical Association Journal: 193 (37)
CMAJ
Vol. 193, Issue 37
20 Sep 2021

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Maternal cardiovascular disease after twin pregnancies complicated by hypertensive disorders of pregnancy: a population-based cohort study
Liran Hiersch, Joel G. Ray, Jon Barrett, Howard Berger, Michael Geary, Sarah D. McDonald, Christina Diong, Sima Gandhi, Jun Guan, Beth Murray-Davis, Nir Melamed
CMAJ Sep 2021, 193 (37) E1448-E1458; DOI: 10.1503/cmaj.202837
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