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Maternal pregnancy outcomes in women with cardiomyopathy: a systematic review and meta-analysis

Open AccessPublished:May 21, 2022DOI:https://doi.org/10.1016/j.ajog.2022.05.039

      Objective

      This study aimed to systematically assess the impact of cardiomyopathy on maternal pregnancy outcomes.

      Data Sources

      PubMed, Ovid Embase, Ovid MEDLINE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to April 24, 2022.

      Study Eligibility Criteria

      Observational cohort, case-control, and case-cohort studies in human populations were included if they reported predefined maternal outcomes for pregnant women with cardiomyopathy (any subtype) and for an appropriate control population (pregnant women with no known heart disease or pregnant women with noncardiomyopathy heart disease).

      Methods

      Two reviewers independently assessed the articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Data were extracted and synthesized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analyses of Observational Studies in Epidemiology guidelines.

      Results

      A total of 14 studies (n=57,539,306 pregnancies) were eligible for inclusion. Women with cardiomyopathy were more likely to deliver by cesarean delivery than women with no heart disease (odds ratio, 2.96; 95% confidence interval, 2.47–3.55; I2=95%; P≤.00001) or women with noncardiomyopathy heart disease (odds ratio, 1.90; 95% confidence interval, 1.62–2.22; I2=91%; P<.00001). Having cardiomyopathy conferred a greater risk for experiencing severe maternal adverse cardiovascular events during pregnancy when compared with not having any heart disease (odds ratio, 206.64; 95% confidence interval, 192.09–222.28; I2=73%; P<.0001) or having noncardiomyopathy heart disease (odds ratio, 7.09; 95% confidence interval; 6.08–8.27; I2=88%; P<.00001). In-hospital mortality was significantly higher among women with cardiomyopathy than among women with no heart disease (odds ratio, 126.67; 95% confidence interval, 43.01–373.07; I2=87%; P<.00001) or among women with noncardiomyopathy heart disease (odds ratio, 4.30; 95% confidence interval, 3.42–5.40; I2=0%; P<.00001).

      Conclusion

      Pregnant women with cardiomyopathy have increased risks for adverse maternal outcomes, including maternal death, when compared with both women with no heart disease and women with noncardiomyopathy heart disease. Our results highlight the importance of preconception risk assessments to allow for informed decision-making before pregnancy. Pregnancies affected by cardiomyopathy are high risk and should be managed by expert, multidisciplinary obstetrical and cardiology teams.

      Key words

      Why was this study conducted?

      Women with heart disease are at increased risk for adverse pregnancy outcomes. However, the magnitude of the risk associated with cardiomyopathy during pregnancy when compared with healthy pregnancies and pregnancies with other forms of heart disease is not known.

      Key findings

      All major adverse cardiovascular complications are considerably more likely in women with cardiomyopathy than in healthy women. Cardiomyopathy confers a 7-fold greater risk of experiencing severe maternal adverse cardiovascular events and a 4-fold greater risk of dying in hospital than other forms of heart disease during pregnancy.

      What does this add to what is known?

      We highlight the extremely high-risk nature of pregnancies among women with cardiomyopathy. These data are important to allow women to make informed choices about the risk associated with pregnancy. Pregnancies complicated by cardiomyopathy should be managed by specialist, multidisciplinary services when possible.

      Introduction

      Pregnancy requires significant physiological adaptations in the maternal cardiovascular system that augment maternal cardiac output to meet the demands of the developing maternal-fetal-placental unit.
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      Ventricular tachyarrhythmia during pregnancy in women with heart disease: data from the ROPAC, a registry from the European Society of Cardiology.
      The poor tolerance of pregnancy in some women with cardiac disease may be caused by limited cardiovascular reserve preventing adaptation to the increased demands of pregnancy, in particular, reduced total peripheral resistance, increased circulating volume, and increased cardiac output.
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      • et al.
      Prospective multicenter study of pregnancy outcomes in women with heart disease.
      Maternal cardiac disease has been highlighted as the single most common cause of indirect maternal deaths with 1.66 deaths per 100,000 maternities in the United Kingdom.
      Globally, the magnitude of this risk is likely to be much higher, and in the United States, cardiomyopathy is among the leading causes of pregnancy-related deaths among all age groups.
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      ,

      Building U.S. Capacity to Review and Prevent Maternal Deaths. 2018. Report from nine maternal mortality review committees. Available at: https://reviewtoaction.org/national-resource/report-nine-mmrcs. Accessed June 6, 2022.

      Cardiomyopathy is a disorder characterized by structural and functional abnormalities of the ventricular myocardium in the absence of other disease that is sufficient to cause myocardial abnormality.
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      • et al.
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      A large cross-sectional study from the United States estimated that the rate of hospitalization owing to cardiomyopathy was 0.46 per 1000 deliveries, highlighting the significant impact this condition has during pregnancy.
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      It was reported in the International Registry of Pregnancy and Cardiac Disease (ROPAC) study that maternal mortality, heart failure, and ventricular arrhythmias occurred more frequently in women with cardiomyopathy than in women with other forms of heart disease, emphasizing the need for close monitoring of pregnancies complicated by cardiomyopathy.
      • Roos-Hesselink J.W.
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      • et al.
      Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology.
      However, despite widespread acceptance that women with cardiomyopathy are at increased risk for adverse maternal outcomes, there is a lack of systematic evidence synthesis across studies to define the specific risks and to contextualize the magnitude of these risks for women and their healthcare providers. A better understanding of the risks associated with cardiomyopathy during pregnancy would allow for more informed preconception risk stratification, counseling, and provision of high-quality care during pregnancy.
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      • et al.
      Pregnancy outcomes in women with heart disease: the CARPREG II study.
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      • Gatzoulis M.
      A time for greater investment into care for pregnancy and heart disease.
      The management of pregnancy and delivery in women with cardiomyopathy is a complex clinical challenge, compounded by the current lack of systematic evidence to inform optimal management strategies.

      Objective

      To fully assess the maternal implications of pregnancy in women with cardiomyopathy, we aimed to perform a systematic review of the literature with a meta-analysis specifically focusing on maternal pregnancy outcomes, including mode of delivery, major adverse cardiovascular events (MACEs), 30-day readmission rates, length of hospital stay postdelivery, and intensive therapy unit (ITU) admission. The key study aim was to provide information regarding the risks associated with cardiomyopathy compared with both healthy populations and women with other forms of heart disease during pregnancy. These data will assist in counseling women with cardiomyopathy who are considering pregnancy and will help to optimize risk management by their clinical teams.

      Materials and Methods

      This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines.
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      The PRISMA checklist is detailed in Appendix A. The systematic review protocol was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42021276218) (Appendix B).

      Eligibility criteria, information sources, search strategy

      To identify eligible studies, systematic literature searches were performed using predefined search terms (Appendix C) in PubMed (June 1997 to April 24, 2022), Ovid Embase (1974 to February 21, 2022), Ovid MEDLINE (1946 to April 24, 2022), Cochrane Library (database inception to April 24, 2022), and ClinicalTrials.gov (database inception to April 24, 2022). No filters, language, or location restrictions were applied to the searches.
      Primary studies in the form of cohort, case-control, and case-cohort studies in human populations were included. Studies were eligible for inclusion if they reported outcomes for a group of pregnant women with cardiomyopathy and a control group of either (1) pregnant women with no known heart disease (designated healthy) or (2) pregnant women with heart disease other than cardiomyopathy. Cardiomyopathy was defined as any form of cardiomyopathy, whether arising during pregnancy or preexisting, including but not limited to dilated cardiomyopathy, hypertrophic cardiomyopathy, peripartum cardiomyopathy, restrictive cardiomyopathy, ischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or idiopathic cardiomyopathy. Studies were excluded if the control group was not clearly identified as excluding women with cardiomyopathy. Studies were excluded if they did not report the pre-identified maternal outcomes. Conference abstracts were excluded. A complete list of the inclusion and exclusion criteria is available in Table A.1.
      Table 1Summary of the meta-analysis of delivery methods of (1) women with cardiomyopathy and healthy women and (2) women with cardiomyopathy and women with other heart disease
      Method of deliveryComparisonOdds ratio [95% CI]Number of studies (patients)P valueI2 (%)
      Spontaneous vaginal deliveryCardiomyopathy vs healthy0.28 [0.23–0.36]3 (17,528,082)<.00001
      P<.05.
      77
      Cardiomyopathy vs heart disease0.61 [0.37–1.01]4 (34,976).0572
      Induction of laborCardiomyopathy vs healthy1.46 [0.63–3.40]1 (105).38
      Cardiomyopathy vs heart disease0.91 [0.40–2.09]1 (102).83
      Instrumental deliveryCardiomyopathy vs healthy1.71 [1.30–2.25]2 (2,280,954).0001
      P<.05.
      41
      Cardiomyopathy vs heart disease0.81 [0.61–1.07]4 (4,359).1431
      Cesarean deliveryCardiomyopathy vs healthy2.96 [2.47–3.55]5 (57,439,222)<.00001
      P<.05.
      95
      Cardiomyopathy vs heart disease1.90 [1.62–2.22]6 (121,268)<.00001
      P<.05.
      91
      Elective cesarean deliveryCardiomyopathy vs healthy
      Cardiomyopathy vs heart disease1.05 [0.63–1.74]1 (753).860
      Emergency cesarean deliveryCardiomyopathy vs healthy1.49 [0.60–3.71]1 (105).39
      Cardiomyopathy vs heart disease1.33 [0.22–8.10]2 (955).7688
      CI, confidence interval.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.
      a P<.05.
      When there was insufficient information for assessment in published studies, the authors were contacted. Two of the 5 authors that were contacted for further information responded. One author kindly provided clarification on the number of women in the overall sample and cardiomyopathy group.
      • Roos-Hesselink J.W.
      • Ruys T.P.E.
      • Stein J.I.
      • et al.
      Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology.

      Study selection

      Two reviewers (E.J.E. and K.J.M.) independently assessed each study using predetermined inclusion and exclusion criteria (Table A.1). A third reviewer (C.E.A.) was available to resolve any conflicts. An initial screen of the title and abstract was performed, followed by a thorough full-text analysis.

      Data extraction

      Data extraction from eligible studies was performed independently by 2 reviewers (E.J.E. and K.J.M.). The predefined maternal outcome measures were delivery methods (spontaneous vaginal delivery [SVD], induction of labor, instrumental delivery, cesarean delivery, elective cesarean delivery, emergency cesarean delivery), left ventricular ejection fraction, MACEs (any of in-hospital mortality, cardiac arrest, heart failure, myocardial infarction, arrhythmia, cerebrovascular event, pulmonary embolism, obstetrical pulmonary embolism, cardiac complications of anesthesia or sedation during labor and delivery, cardiorespiratory failure or shock, respiratory failure, dissection of aorta or another artery), and non-MACE outcomes (30-day readmission, length of hospital stay postdelivery, ITU admission).

      Risk of bias of included studies

      Each study was independently assessed by 2 reviewers (E.J.E. and K.J.M.) using the Newcastle-Ottawa Risk of Bias tool for quality and validity. All 9 domains were considered relevant and used to assess each study. Each study was classified as either achieving or failing each domain. All risk-of-bias assessments were performed at the study level. Each study was given a quality rating of good, fair, or poor (Table B.1). A third reviewer (C.E.A.) was available to resolve any conflicts in the bias assessment of studies.

      Data synthesis

      The summary measures used for this systematic review were difference in means for continuous data and unadjusted odds ratios (ORs) for dichotomous data. The meta-analysis was performed using Review Manager (RevMan) version 5.4 (Nordic Cochrane Centre, Copenhagen, Denmark) and the “metafor” package in R version 4.1.1 (R Core Team, Vienna, Austria). Funnel plots were created to assess publication bias (Fig A.1) and outcome measures that were reported by 5 or more studies and were subjected to Egger test. Heterogeneity between studies was assessed using the I2 statistic. Studies were assessed using fixed-effects models, except for outcomes with significant interstudy heterogeneity, which were analyzed using random-effects models. A sensitivity analysis was performed using leave-one-out analysis for individual studies and conducting relevant subgroup analyses (studies with low numbers, defined as <100 women in intergroup comparisons, and studies with a high risk of bias, defined as receiving a poor classification in risk-of-bias assessment). Where P values are reported, an alpha level of <.05 was considered statistically significant.
      Figure thumbnail gr1
      Figure 1PRISMA flow diagram of study inclusion and exclusion
      PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.

      Results

      Study selection

      Electronic searching of the specified databases yielded a total of 23,377 studies. No additional studies were found by manual searching. After the removal of duplicates, title and abstract screening was performed for 13,611 studies. A total of 76 studies underwent full-text analysis. After applying the eligibility criteria, a total of 14 studies remained eligible for inclusion, including 57,539,306 pregnancies. The results from each stage of the selection process are presented in Figure 1.

      Study characteristics

      The 14 studies comprised women with varying types of cardiomyopathies and heart disease.
      • Owens A.
      • Yang J.
      • Nie L.
      • Lima F.
      • Avila C.
      • Stergiopoulos K.
      Neonatal and maternal outcomes in pregnant women with cardiac disease.
      ,
      • Roos-Hesselink J.W.
      • Ruys T.P.E.
      • Stein J.I.
      • et al.
      Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology.
      ,
      • Koutrolou-Sotiropoulou P.
      • Parikh P.B.
      • Miller C.
      • Lima F.V.
      • Butler J.
      • Stergiopoulos K.
      Impact of heart disease on maternal and fetal outcomes in pregnant women.
      ,
      • Meyer N.L.
      • Mercer B.
      • Khoury A.
      • Sibai B.
      Pregnancy complicated by cardiac disease: maternal and perinatal outcome.
      • Avila W.S.
      • Rossi E.G.
      • Ramires J.A.F.
      • et al.
      Pregnancy in patients with heart disease: experience with 1,000 cases.
      • Thanajiraprapa T.
      • Phupong V.
      Pregnancy complications in women with heart disease.
      • Yaghoubi A.
      • Mirinazhad M.
      Maternal and neonatal outcomes in pregnant patients with cardiac diseases referred for labour in Northwest Iran.
      • Hu J.
      • Ye Y.
      • Lu A.
      • et al.
      Pregnancy outcomes in patients with heart disease in China.
      • Huang G.Y.
      • Zhang L.Y.
      • Bai T.F.
      • Wang R.K.
      • Zhang X.S.
      Effect of inflammation and autoimmunity in peripartum cardiomyopathy.
      • Isogai T.
      • Matsui H.
      • Tanaka H.
      • Kohyama A.
      • Fushimi K.
      • Yasunaga H.
      Clinical features and peripartum outcomes in pregnant women with cardiac disease: a nationwide retrospective cohort study in Japan.
      • Lewis N.L.
      • Dob D.P.
      • Yentis S.M.
      UK registry of high-risk obstetric anaesthesia: arrhythmias, cardiomyopathy, aortic stenosis, transposition of the great arteries and Marfan’s syndrome.
      • Lima F.
      • Nie L.
      • Yang J.
      • et al.
      Postpartum cardiovascular outcomes among women with heart disease from A nationwide study.
      • Lima F.V.
      • Yang J.
      • Xu J.
      • Stergiopoulos K.
      National trends and in-hospital outcomes in pregnant women with heart disease in the United States.
      • Liu H.
      • Huang T.T.
      • Lin J.H.
      Risk factors and risk index of cardiac events in pregnant women with heart disease.
      The characteristics of women included in each study are displayed in Table C.1.

      Assessment of quality of evidence

      The 14 studies were from a range of countries globally, including the United States, United Kingdom, China, and Brazil (Table C.1). There was considerable variation in the size, quality, and design of the studies. The risk of bias was low in the majority of studies included. In total, 8 studies had a low risk of bias, 1 had a moderate risk of bias, and 5 had a high risk of bias (Table B.1). A leave-one-out sensitivity analysis was performed to identify single studies with a significant influence on the overall results (Table D.1). In the majority of cases, the results of the meta-analyses were unaffected by the omission of single studies. Subgroup meta-analyses were performed by excluding studies that were considered to have an overall high risk of bias (low-quality studies). The removal of low-quality studies did not alter the overall outcome of the meta-analysis in any of the outcomes assessed (Table D.1). Therefore, all studies were included. A subgroup meta-analysis was performed with exclusion of studies with low numbers. Excluding studies with low numbers did not alter the overall outcomes of the meta-analysis (Table D.1). Funnel plots were visually assessed for all outcomes (Fig A.1). The visual inspection confirmed that there was no reason to consider significant publication bias in any of the outcomes studied and all outcomes that were subjected to the Egger test passed (Table D.1).

      Synthesis of results

      Modes of delivery

      There was considerable variation in the reporting of mode of delivery between studies (Table 1). SVD rates were reported in 3 studies (n=17,528,082) in which women with cardiomyopathy were compared with healthy controls and in 4 studies (n=34,976) in which women with cardiomyopathy were compared with women with other forms of heart disease. Women with cardiomyopathy were 72% less likely to have an SVD than healthy controls (OR, 0.28; 95% confidence interval [CI], 0.23–0.36; I2=77%; P<.00001) (Table 1). The difference in the rates of SVD between women with cardiomyopathy and women with other forms of heart disease was of borderline significance (OR, 0.61; 95% CI, 0.37–1.01; I2=72%; P=.05) (Table 1).
      There was no significant difference in the rates of induction of labor between women with cardiomyopathy and healthy controls (OR, 1.46; 95% CI, 0.63–3.40; P=.38) (Table 1) or women with other forms of heart disease (OR, 0.91; 95% CI, 0.40–2.09; P=.83) (Table 1); however, this outcome was sparsely reported (1 study with n=105 and 1 study with n=102, respectively) (Table 1).
      Two studies (n=2,280,954) reported rates of instrumental delivery among women with cardiomyopathy in comparison with healthy controls. Overall, women with cardiomyopathy were 71% more likely to have an instrumental delivery (OR, 1.71; 95% CI, 1.31–2.25; I2=41%; P=.0001) (Table 1). Four studies (n=4359) reported data on instrumental delivery rates among women with cardiomyopathy compared with women with other forms of heart disease. There was no significant difference between these groups (OR, 0.81; 95% CI, 0.61–1.07; I2 =31%; P=.14) (Table 1).
      Five studies (n=57,439,222) reported rates of any cesarean delivery among women with cardiomyopathy compared with healthy controls, and 6 studies (n=121,268) reported cesarean delivery rates among women with cardiomyopathy compared with women with other forms of heart disease. The cardiomyopathy group were approximately 3 times more likely to have a cesarean delivery than the healthy group (OR, 2.96; 95% CI, 2.47–3.55; I2=95%; P≤.00001) (Table 1) and 90% more likely to have a cesarean delivery than the noncardiomyopathy heart disease group (OR, 1.90; 95% CI, 1.62–2.22; I2=91%; P<.00001) (Table 1).
      Data comparing the rates of elective and emergency cesarean delivery between groups were sparse (Table 1). The few studies that were available suggested that women with cardiomyopathy were not at increased risk for emergency cesarean delivery when compared with healthy women or women with other forms of heart disease.

      Left ventricular ejection fraction

      Three studies reported left ventricular ejection fraction as an echocardiographic parameter. In 2 studies, this was measured in early pregnancy,
      • Koutrolou-Sotiropoulou P.
      • Parikh P.B.
      • Miller C.
      • Lima F.V.
      • Butler J.
      • Stergiopoulos K.
      Impact of heart disease on maternal and fetal outcomes in pregnant women.
      ,
      • Yaghoubi A.
      • Mirinazhad M.
      Maternal and neonatal outcomes in pregnant patients with cardiac diseases referred for labour in Northwest Iran.
      and in 1 study, it was unspecified when left ventricular ejection fraction was measured.
      • Huang G.Y.
      • Zhang L.Y.
      • Bai T.F.
      • Wang R.K.
      • Zhang X.S.
      Effect of inflammation and autoimmunity in peripartum cardiomyopathy.
      Two studies (n=287) reported the left ventricular ejection fraction among women with cardiomyopathy in comparison with a healthy control group. As expected, the left ventricular ejection fraction among women with cardiomyopathy was significantly lower by approximately 25% (mean difference, –25.17; 95% CI, –38.98 to –11.35; I2=96%; P=.0004) (Figure 2, A) when compared with healthy controls. The left ventricular ejection fraction among women with cardiomyopathy was also significantly lower when compared with those with other forms of heart disease, which was reported in 2 studies (n=296). The mean difference was approximately 14% less among women with cardiomyopathy (mean difference, –14.15; 95% CI, –16.70 to –11.59; I2=72%; P<.00001) (Figure 2, B) when compared with women with other forms of heart disease.
      Figure thumbnail gr2
      Figure 2Meta-analysis of left ventricular ejection fraction
      The black diamond represents the overall effect. A, Cardiomyopathy vs healthy controls, expressed as the mean difference (random-effects model) with 95% CIs. B, Cardiomyopathy vs heart disease controls, expressed as the mean difference (fixed-effects model) with 95% CIs.
      CI, confidence interval; IV, inverse variance; SD, standard deviation.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.

      Major adverse cardiovascular events

      Four studies included a composite MACE outcome for cardiomyopathy in comparison with healthy women (n=57,439,040). Women with cardiomyopathy had a significantly higher likelihood of experiencing a MACE than healthy women (OR, 206.64; 95% CI, 192.09–222.28; I2=73%; P<.00001) (Figure 3, A). Five studies compared the MACE outcomes for women with cardiomyopathy with the group of women with other heart diseases (n=119,949). Overall, women with cardiomyopathy were approximately 7 times more likely to experience a MACE (OR, 7.09; 95% CI, 6.08–8.27; I2=88%; P<.00001) (Figure 3, B) during pregnancy than women with other forms of heart disease.
      Figure thumbnail gr3
      Figure 3Meta-analysis of combined major adverse cardiovascular events
      The black diamond represents the overall effect. A, Cardiomyopathy vs healthy controls, expressed as ORs (random-effects model) with 95% CIs. B, Cardiomyopathy vs heart disease controls, expressed as ORs (random-effects model) with 95% CI.
      CI, confidence interval; M-H, Mantel-Haenszel; OR, odds ratio.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.
      Four studies (n=57,439,040) reported in-hospital mortality for women with cardiomyopathy compared with healthy women. There were significantly higher rates of in-hospital mortality in the cardiomyopathy group than in the healthy group (OR, 126.67; 95% CI, 43.01–373.07; I2=87%; P<.00001) (Figure 4, A). A total of 13 studies (n=125,431) reported in-hospital mortality for women with cardiomyopathy in comparison with those with other forms of heart disease. Women with cardiomyopathy were more than 4 times more likely to die in hospital during pregnancy than those with other forms of heart disease (OR, 4.30; 95% CI, 3.42–5.40; I2 =0%; P<.00001) (Figure 4, B).
      Figure thumbnail gr4
      Figure 4Meta-analysis of in-hospital mortality rates
      The black diamond represents the overall effect. A, Cardiomyopathy vs healthy controls, expressed as ORs (random-effects model) with 95% CIs. B, Cardiomyopathy vs heart disease controls, expressed as ORs (fixed-effects model) with 95% CIs.
      CI, confidence interval; M-H, Mantel-Haenszel; OR, odds ratio.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.
      Women with cardiomyopathy were more likely than either healthy controls or women with other forms of heart disease to experience cardiac arrest, heart failure, myocardial infarction, arrhythmias, pulmonary embolism, complications of anesthesia, cardiorespiratory or respiratory failure during pregnancy (Table 2). There was no significant difference in the rates of aortic dissection between women with cardiomyopathy and either of the control groups, although only 2 studies (1 with each control group) reported this outcome (Table 2). The risk for cerebrovascular events was elevated in women with cardiomyopathy when compared with healthy controls, but not when compared with women with other forms of heart disease (Table 2).
      Table 2Summary of meta-analysis of major adverse cardiovascular events among (1) women with cardiomyopathy and healthy women and (2) women with cardiomyopathy and women with other heart disease
      Major adverse clinical eventComparisonOdds ratio [95% CI]Number of studies (patients)P valueI2 (%)
      Cardiac arrestCardiomyopathy vs healthy193.08 [51.89–718.44]3 (17,528,082)<.00001
      P<.05.
      88
      Cardiomyopathy vs heart disease16.44 [4.62–58.54]4 (4873)<.0001
      P<.05.
      0
      Heart failureCardiomyopathy vs healthy2804.35 [2218.89–3544.30]4 (57,439,040)<.00001
      P<.05.
      95
      Cardiomyopathy vs heart disease7.06 [4.58, 10.88]8 (121,653)<.00001
      P<.05.
      96
      Myocardial infarctionCardiomyopathy vs healthy436.34 [258.26–737.21]4 (57,439,040)<.00001
      P<.05.
      87
      Cardiomyopathy vs heart disease7.63 [6.20–9.39]5 (119,949)<.00001
      P<.05.
      0
      ArrhythmiaCardiomyopathy vs healthy48.91 [44.60–53.64]4 (57,439,040)<.00001
      P<.05.
      67
      Cardiomyopathy vs heart disease2.35 [1.99–2.78]6 (121,257)<.00001
      P<.05.
      78
      Cerebrovascular eventCardiomyopathy vs healthy34.57 [11.09–107.77]4 (57,439,040)<.00001
      P<.05.
      93
      Cardiomyopathy vs heart disease1.27 [0.50–3.25]5 (119,949).6284
      Pulmonary embolismCardiomyopathy vs healthy141.86 [37.39–538.25]2 (17,527,997)<.00001
      P<.05.
      80
      Cardiomyopathy vs heart disease3.19 [1.73–5.89]4 (39,393).0002
      P<.05.
      19
      Obstetrical pulmonary embolismCardiomyopathy vs healthy56.71 [50.79–63.32]3 (57,438,935)<.00001
      P<.05.
      0
      Cardiomyopathy vs heart disease2.33 [2.03–2.67]3 (118,994)<.00001
      P<.05.
      0
      Cardiac complications of anesthesia or sedation during labor and deliveryCardiomyopathy vs healthy66.62 [53.54–82.90]2 (42,191,807)<.00001
      P<.05.
      0
      Cardiomyopathy vs heart disease7.55 [5.22–10.91]2 (85,166)<.00001
      P<.05.
      0
      Cardiorespiratory failure or shockCardiomyopathy vs healthy1248.72 [238.73–6531.66]3 (57,438,935)<.00001
      P<.05.
      99
      Cardiomyopathy vs heart disease19.96 [6.52–61.13]3 (118,994)<.00001
      P<.05.
      89
      Respiratory failureCardiomyopathy vs healthy290.12 [250.86–335.53]3 (57,438,935)<.00001
      P<.05.
      90
      Cardiomyopathy vs heart disease9.15 [8.61–9.72]3 (118,994)<.00001
      P<.05.
      45
      Dissection of aorta or another arteryCardiomyopathy vs healthy0.13 [0.01–2.27]1 (2956).16-
      Cardiomyopathy vs heart disease0.11 [0.01–1.90]1 (3871).13-
      CI, confidence interval.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.
      a P<.05.

      Nonmajor adverse cardiovascular events

      One study (n=105) reported on ITU admission among women with cardiomyopathy and healthy controls. Women with cardiomyopathy were significantly more likely to be admitted to the ITU than healthy women (OR, 12.22; 95% CI, 2.51–59.51; P<.002). Four studies (n=2166) reported on ITU admission among women with cardiomyopathy in comparison with women with other forms of heart disease. Women with cardiomyopathy were approximately 4 times more likely to be admitted to the ITU than women with other heart disease (OR, 4.02; 95% CI, 1.57–10.32; I2=82%; P=.004).
      One study (n=2,289,849) reported on 30-day readmission rates among women with cardiomyopathy in comparison with healthy women and women with other forms of heart disease. Women with cardiomyopathy were significantly more likely to be readmitted than either healthy women (OR, 9.18; 95% CI, 7.11–11.86; P<.00001) or women with other forms of heart disease (OR, 3.36; 95% CI, 2.43–4.65; P<.00001).
      Length of hospital stay postdelivery among women with cardiomyopathy and healthy women was reported in 2 studies (n=2,280,954). The length of hospital stay among women with cardiomyopathy was 4.7 days longer than that of healthy women (mean difference, 4.70; 95% CI, 3.86–5.53; I2=0%; P<.00001) (Figure 5, A). Two studies (n=3973) compared the length of hospital stay postdelivery among women with cardiomyopathy and those with other forms of heart disease. The length of hospital stay among women with cardiomyopathy was approximately 5 days longer than that among women with other heart disease (mean difference, 5.18; 95% CI, 0.70–9.65; I2=77%; P=.02) (Figure 5, B).
      Figure thumbnail gr5
      Figure 5Meta-analysis of mean length of hospital stay postdelivery
      The black diamond represents the overall effect. A, Cardiomyopathy vs healthy controls, expressed as the mean difference (fixed-effects model) with 95% CIs. B, Cardiomyopathy vs heart disease controls (random-effects model) with 95% CIs.
      CI, confidence interval; IV, inverse variance; SD, standard deviation.
      Eggleton. Maternal pregnancy outcomes in women with cardiomyopathy. Am J Obstet Gynecol 2022.

      Comment

      Principal findings

      A total of 14 studies from diverse global settings, including the United States, United Kingdom, China, Japan, Brazil, Thailand, and Iran, were available for inclusion in this quantitative synthesis of the maternal outcomes of pregnancies among women with cardiomyopathy. We found that all adverse maternal outcomes studied, with the exception of induction of labor, emergency cesarean delivery, and aortic dissection, were considerably more likely among women with cardiomyopathy than among women with no known heart disease. Women with cardiomyopathy were more likely to deliver by cesarean delivery than women with other forms of heart disease. Of key concern is that our results show that women with cardiomyopathy are more than 4 times more likely to die in hospital during pregnancy than those with other forms of heart disease. The likelihood of a woman with cardiomyopathy suffering a MACE during pregnancy is 7-fold higher than that among women with other forms of heart disease, in particular cardiac arrest, heart failure, and cardiorespiratory failure. There is a 4-fold increased risk for ITU admission among women with cardiomyopathy than among women with other forms of heart disease in pregnancy. These results contextualize the extremely high risk for maternal mortality and morbidity posed by cardiomyopathy in the context of pregnancy.

      Comparison with existing literature

      Our results show a markedly increased risk for both cardiac and respiratory failure in women with cardiomyopathy when compared with both healthy women and women with other forms of heart disease. The increase in circulating blood volume and the consequent increase in preload during pregnancy may not be tolerated in women with cardiomyopathy. This can cause decompensation because of the associated increased fluid load and inability to adapt to an increasingly hyperdynamic circulation.
      • Ruys T.P.
      • Roos-Hesselink J.W.
      • Hall R.
      • et al.
      Heart failure in pregnant women with cardiac disease: data from the ROPAC.
      ,
      • Bright R.A.
      • Lima F.V.
      • Avila C.
      • Butler J.
      • Stergiopoulos K.
      Maternal heart failure.
      We hypothesize that decompensation and limited cardiovascular reserve is also the likely causal mechanism for the higher risk for admission to intensive care, cardiac arrest, and in-hospital mortality among women with cardiomyopathy when compared with women with other forms of heart disease. However, the direct causes of these rare outcomes are not directly discernible from the available studies. In addition to the challenges that the delivery period holds for mothers with cardiomyopathy, there is also a significant risk for complications in the postpartum period.
      • Mogos M.F.
      • Piano M.R.
      • McFarlin B.L.
      • Salemi J.L.
      • Liese K.L.
      • Briller J.E.
      Heart failure in pregnant women: a concern across the pregnancy continuum.
      Mortality data suggest that women with cardiomyopathy are at increased risk for pregnancy-related deaths that occur after 42 days postpartum, however, there is no information in the included studies about events that may have occurred beyond 42 days postpartum.
      • Petersen E.E.
      • Davis N.L.
      • Goodman D.
      • et al.
      Vital signs: pregnancy-related deaths in the United States 2011-2015, and strategies for prevention, 13 states, 2013-2017.
      This highlights the need for large-scale, population-based studies to be supplemented with detailed narrative maternal death reviews to maximize future learning.
      ,

      Building U.S. Capacity to Review and Prevent Maternal Deaths. 2018. Report from nine maternal mortality review committees. Available at: https://reviewtoaction.org/national-resource/report-nine-mmrcs. Accessed June 6, 2022.

      Left ventricular ejection fraction was only reported in 3 included studies but was considerably lower among women with cardiomyopathy than among either healthy women or women with other forms of heart disease. Previous work suggests that a left ventricular ejection fraction <40% predicts immediate adverse events in pregnancy,
      • Siu S.C.
      • Sermer M.
      • Colman J.M.
      • et al.
      Prospective multicenter study of pregnancy outcomes in women with heart disease.
      ,
      • Grewal J.
      • Siu S.C.
      • Ross H.J.
      • et al.
      Pregnancy outcomes in women with dilated cardiomyopathy.
      but may also be associated with late adverse maternal outcomes.
      • Grewal J.
      • Siu S.C.
      • Ross H.J.
      • et al.
      Pregnancy outcomes in women with dilated cardiomyopathy.
      This may account for the increased risk for 30-day readmission among women with cardiomyopathy than among women with other forms of heart disease. It was specified in 1 study that readmission among women with cardiomyopathy was related to cardiovascular events.
      • Lima F.
      • Nie L.
      • Yang J.
      • et al.
      Postpartum cardiovascular outcomes among women with heart disease from A nationwide study.
      Understanding the late adverse sequelae of maternal cardiomyopathy is an underexplored but important area for future research.
      The time of delivery is considered the most dangerous period of the pregnancy for many women with heart disease, because of the potential for extreme shifts in fluid balance, vascular resistance, and significant increases in cardiac output, all of which may be poorly tolerated.
      • Chattopadhyay R.
      • Olwell B.
      • Bhagra C.J.
      Maternal cardiac disease in pregnancy.
      Current guidelines recommend that vaginal delivery is appropriate for the majority of women with heart disease because of the reduced risk for heavy blood loss and avoidance of major surgery.
      • Regitz-Zagrosek V.
      • Roos-Hesselink J.W.
      • Bauersachs J.
      • et al.
      2018 ESC guidelines for the management of cardiovascular diseases during pregnancy.
      ,
      • Ruys T.P.E.
      • Roos-Hesselink J.W.
      • Pijuan-Domènech A.
      • et al.
      Is a planned caesarean section in women with cardiac disease beneficial?.
      We show that women with cardiomyopathy were more likely to deliver by cesarean delivery than both healthy women and women with other forms of heart disease. The ROPAC study reported that 44% of cesarean delivery among women with heart disease were for cardiac reasons,
      • Ruys T.P.E.
      • Roos-Hesselink J.W.
      • Pijuan-Domènech A.
      • et al.
      Is a planned caesarean section in women with cardiac disease beneficial?.
      but this information is not available in most other studies and there is considerable heterogeneity between studies in the likelihood of women with cardiomyopathy delivering by cesarean delivery. It may be that changing guidance related to the clinical management of women with heart disease in different global regions contributed to a changing picture of delivery methods and other clinician-dependent outcomes over time. Although other evidence suggests that this might be the case,
      • Silversides C.K.
      • Grewal J.
      • Mason J.
      • et al.
      Pregnancy outcomes in women with heart disease: the CARPREG II study.
      ,
      • Magun E.
      • DeFilippis E.M.
      • Noble S.
      • et al.
      Cardiovascular care for pregnant women with cardiovascular disease.
      it was not possible to evaluate this systematically using the available data.
      Further work should focus on determining the risk vs benefit balance of cesarean delivery in different contexts (eg, stratified by cardiomyopathy type or by left ventricular ejection fraction), and providing further insight into optimizing the mode of delivery for women with cardiomyopathy. There is potentially significant variation in the timing of diagnosis between subtypes of cardiomyopathy, in particular, the diagnosis of peripartum cardiomyopathy may not be made until the postpartum period.
      • Sliwa K.
      • Hilfiker-Kleiner D.
      • Petrie M.C.
      • et al.
      Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy.
      Ideally, a sensitivity analysis that exclude women with no diagnosis of cardiomyopathy at the time of delivery should be performed, however, sufficient information was not available.

      Strengths and limitations

      Although previous individual studies have highlighted the risks of cardiomyopathy in pregnancy,
      • Roos-Hesselink J.W.
      • Ruys T.P.E.
      • Stein J.I.
      • et al.
      Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology.
      ,
      • Hu J.
      • Ye Y.
      • Lu A.
      • et al.
      Pregnancy outcomes in patients with heart disease in China.
      a major strength of our study is the ability to provide a cross-context systematic overview of the magnitude of maternal risk posed by cardiomyopathy. We have been able to include studies from a variety of global contexts with differing availability of obstetrical and cardiology resources to provide as complete an overview as possible of the impact of cardiomyopathy in pregnancy. A strength of our study design is that it utilizes 2 distinct control groups, namely women with no known heart disease and women with noncardiomyopathy heart disease. These dual comparisons enable us to contextualize the likelihood of adverse outcomes associated with cardiomyopathy as much as possible and aid in the interpretation of the magnitude of risk. Cardiomyopathy is a relatively uncommon disease and therefore not often encountered in pregnancy outside of specialist joint obstetrical-cardiology services.
      • McKenna W.J.
      • Maron B.J.
      • Thiene G.
      Classification, epidemiology, and global burden of cardiomyopathies.
      ,
      • Schaufelberger M.
      Cardiomyopathy and pregnancy.
      Our results provide a systematic overview of the magnitude of the risk that women with cardiomyopathy face and make the case for careful counseling and specialist pregnancy care.
      The ability to draw definitive conclusions from this meta-analysis is limited both by the quantity and size of the studies available for inclusion, which is itself a consequence of the relative rarity of cardiomyopathy in pregnancy.
      • McKenna W.J.
      • Maron B.J.
      • Thiene G.
      Classification, epidemiology, and global burden of cardiomyopathies.
      ,
      • Schaufelberger M.
      Cardiomyopathy and pregnancy.
      There is a potential risk for overrepresentation of a small number of patients within studies that may contain some degree of population overlap,
      • Owens A.
      • Yang J.
      • Nie L.
      • Lima F.
      • Avila C.
      • Stergiopoulos K.
      Neonatal and maternal outcomes in pregnant women with cardiac disease.
      ,
      • Lima F.
      • Nie L.
      • Yang J.
      • et al.
      Postpartum cardiovascular outcomes among women with heart disease from A nationwide study.
      ,
      • Lima F.V.
      • Yang J.
      • Xu J.
      • Stergiopoulos K.
      National trends and in-hospital outcomes in pregnant women with heart disease in the United States.
      however, because of the nature of the data, we were unable to exclude the potential overlap. We aimed to address this by carrying out further extensive sensitivity analyses showing that the reported effect sizes were robust to inclusion or exclusion of all studies (Appendix D).
      In total, 5 of 14 studies included in this review originated from the United States,
      • Owens A.
      • Yang J.
      • Nie L.
      • Lima F.
      • Avila C.
      • Stergiopoulos K.
      Neonatal and maternal outcomes in pregnant women with cardiac disease.
      ,
      • Koutrolou-Sotiropoulou P.
      • Parikh P.B.
      • Miller C.
      • Lima F.V.
      • Butler J.
      • Stergiopoulos K.
      Impact of heart disease on maternal and fetal outcomes in pregnant women.
      ,
      • Meyer N.L.
      • Mercer B.
      • Khoury A.
      • Sibai B.
      Pregnancy complicated by cardiac disease: maternal and perinatal outcome.
      ,
      • Lima F.
      • Nie L.
      • Yang J.
      • et al.
      Postpartum cardiovascular outcomes among women with heart disease from A nationwide study.
      ,
      • Lima F.V.
      • Yang J.
      • Xu J.
      • Stergiopoulos K.
      National trends and in-hospital outcomes in pregnant women with heart disease in the United States.
      which may limit the generalizability of our results and highlights the need for further large global studies of maternal outcomes in women with cardiomyopathy. Had sufficient data been available, it would have been valuable to perform a subgroup analysis in our review based on cardiomyopathy subtype. It has been suggested that hypertrophic cardiomyopathy is relatively well tolerated in pregnancy,
      • Bright R.A.
      • Lima F.V.
      • Avila C.
      • Butler J.
      • Stergiopoulos K.
      Maternal heart failure.
      ,
      • Pieper P.G.
      Pre-pregnancy risk assessment and counselling of the cardiac patient.
      ,
      • Probst V.
      • Langlard J.M.
      • Desnos M.
      • Komajda M.
      • Bouhour J.B.
      Familial hypertrophic cardiomyopathy. French study of the duration and outcome of pregnancy.
      whereas peripartum cardiomyopathy is associated with a greater risk of decompensation, obstetrical complications, and readmission rates.
      • Lima F.
      • Nie L.
      • Yang J.
      • et al.
      Postpartum cardiovascular outcomes among women with heart disease from A nationwide study.
      ,
      • Lima F.V.
      • Parikh P.B.
      • Zhu J.
      • Yang J.
      • Stergiopoulos K.
      Association of cardiomyopathy with adverse cardiac events in pregnant women at the time of delivery.
      We hypothesize that the risk for adverse maternal outcomes may be directly related to the magnitude of left ventricular systolic dysfunction and that women with different types of cardiomyopathies may not all be at equal risk. However, there were insufficient primary studies available to interrogate this hypothesis in detail. A future research priority is large-scale international studies with sufficient power to compare the frequency of adverse maternal outcomes between cardiomyopathy subtypes.
      A further limitation was a high level of heterogeneity between the included studies. This might reflect the variability in disease phenotypes included, both within the cardiomyopathy groups and the heart disease control groups. Furthermore, the included studies represent global populations of women with varying levels of provision of antenatal and prepregnancy cardiology care, which was not possible to control for in our analysis.
      Our analysis included a number of observational studies based on large administrative databases that rely on diagnosis and billing codes for the identification of study populations.
      • Owens A.
      • Yang J.
      • Nie L.
      • Lima F.
      • Avila C.
      • Stergiopoulos K.
      Neonatal and maternal outcomes in pregnant women with cardiac disease.
      ,
      • Hu J.
      • Ye Y.
      • Lu A.
      • et al.
      Pregnancy outcomes in patients with heart disease in China.
      ,
      • Isogai T.
      • Matsui H.
      • Tanaka H.
      • Kohyama A.
      • Fushimi K.
      • Yasunaga H.
      Clinical features and peripartum outcomes in pregnant women with cardiac disease: a nationwide retrospective cohort study in Japan.
      ,
      • Lima F.
      • Nie L.
      • Yang J.
      • et al.
      Postpartum cardiovascular outcomes among women with heart disease from A nationwide study.
      ,
      • Lima F.V.
      • Yang J.
      • Xu J.
      • Stergiopoulos K.
      National trends and in-hospital outcomes in pregnant women with heart disease in the United States.
      Such studies carry inherent limitations because of the possibility of coding errors, including ascertainment bias, although previous work suggests that this error rate may be low.
      • Lima F.V.
      • Yang J.
      • Xu J.
      • Stergiopoulos K.
      National trends and in-hospital outcomes in pregnant women with heart disease in the United States.
      These studies also lack detailed echocardiographic data, for example, left ventricular ejection fraction, which would be useful to aid further risk stratification.

      Conclusion and implications

      This was a systematic synthesis of the maternal risks associated with pregnancy among women with cardiomyopathy. We showed that women with cardiomyopathy are at increased risk for severe adverse maternal outcomes, including death, when compared with healthy women and women with other forms of heart disease. We also identified a lack of data to assist with detailed risk stratification, which is essential to optimize care for this high-risk patient group. Our results highlight the importance of prenatal counseling to ensure that women with cardiomyopathy make informed choices about the risks associated with pregnancy and to emphasize the need for close antenatal surveillance by experienced, multidisciplinary maternal cardiology teams in view of the increased likelihood of severe adverse maternal outcomes.

      Supplementary Data

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