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Valvular heart disease
Original research
Pregnancy outcomes in women with significant valve disease: a systematic review and meta-analysis
  1. Robin Alexandra Ducas1,2,
  2. David A Javier2,
  3. Rohan D’Souza3,
  4. Candice K Silversides2,4,
  5. Wendy Tsang2
  1. 1 Section of Cardiology, University of Manitoba, Winnipeg, Manitoba, Canada
  2. 2 Division of Cardiology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
  3. 3 Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  4. 4 Division of Cardiology, University of Toronto Pregnancy and Heart Disease Program, Mount Sinai Hospital and Univeristy Health Network, Toronto, Ontario, Canada
  1. Correspondence to Wendy Tsang, Cardiology, University of Toronto, Toronto, ON M5G 2C4, Canada; wendy.tsang{at}uhn.ca

Abstract

Objective To perform a systematic review and meta-analysis of maternal/fetal outcomes in pregnant women with moderate/severe native valvular heart disease (VHD) from medium/higher Human Development Index (HDI) countries.

Methods OvidSP platform databases were searched (1985-January 2019) to identify studies reporting pregnancy outcomes in women with moderate/severe VHD. The primary maternal outcome was maternal mortality. The primary fetal/neonatal outcome was stillbirth and neonatal death. Pooled incidences and 95% confidence intervals (CI) of maternal/fetal outcomes could only be calculated from studies involving mitral stenosis (MS) or aortic stenosis (AS).

Results Twelve studies on 646 pregnancies were included. Pregnant women with severe MS had mortality rates of 3% (95% CI, 0% to 6%), pulmonary oedema 37% (23%–51%) and new/recurrent arrhythmias 16% (1%–25%). Their stillbirth, neonatal death and preterm birth rates were 4% (1%–7%), 2% (0%–4%), and 18% (7%–29%), respectively. Women with moderate MS had mortality rates of 1%(0%–2%), pulmonary oedema 18% (2%–33%), new/recurrent arrhythmias 5% (1%–9%), stillbirth 2% (1%–4%) and preterm birth 10%(2%–17%).

Pregnant women with severe AS had a risk of mortality of 2% (0%–5%), pulmonary oedema 9% (2%–15%), and new/recurrent arrhythmias 4% (0%–7%). Their stillbirth, neonatal death and preterm birth rates were 2% (0%–5%), 3% (0%–6%) and 14%(4%–24%), respectively. No maternal/neonatal deaths were reported in moderate AS, however women experienced pulmonary oedema (8%; 0%–20%), new/recurrent arrhythmias (2%; 0%–5%), and preterm birth (13%; 6%–20%).

Conclusions Women with moderate/severe MS and AS are at risk for adverse maternal and fetal/neonatal outcomes. They should receive preconception counseling and pregnancy care by teams with pregnancy and heart disease experience.

  • valvular heart disease
  • pregnancy
  • meta-analysis

https://doi.org/10.1136/heartjnl-2019-315859

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    Introduction

    With advances in medical and surgical care, more women with valvular heart disease (VHD) are reaching childbearing age and considering pregnancy.1 The haemodynamic changes associated with pregnancy can have a negative impact on both maternal and fetal/neonatal health. Information regarding the risk of pregnancy for the mother and fetus is necessary to help these women make informed decisions about pregnancy. While there are numerous studies on pregnancy outcomes in women with VHD, precise risk estimates are lacking. We performed a systematic review and meta-analysis on fetal and maternal pregnancy outcomes in women with moderate or severe native VHD from countries with medium or higher human development index (HDI).

    Methods

    This study protocol was registered with PROSPERO (CRD42016050733),2 and conducted according to PRISMA3 and MOOSE4 guidelines.

    Search strategy

    The literature search was performed in Medline, Medline In-Process and other non-indexed citations, EMBASE, and Cochrane Central Register of Clinical Trials (figure 1, online supplementary materials). Where available, both controlled vocabulary terms and text words (MesH and keywords) were used in the subject component blocks. The search was performed for studies published up to January 11, 2019 and limited to humans and English-language studies published after 1985. The date limitation was selected to provide a contemporary reflection of obstetric outcomes in VHD patients. Additional studies were identified by searching article reference lists and searching the grey literature with the first 200 hits on Google Scholar after entering combinations of the indexing terms.

    Supplemental material

    Figure 1
    Figure 1

    PRISMA flow diagram for systematic review. Flow diagram of included and excluded study and rationale.

    Patient and Public Involvement

    Patients were not involved in the generation of this meta-analysis.

    Study selection

    Prospective and retrospective studies describing a minimum of five completed pregnancies in women with moderate/severe VHD with maternal/fetal outcomes were included. If more than one publication was found presenting the same patient data, the most recent study was included. Studies were excluded if they only reported a case series where all patients underwent valve procedures. Such studies were felt to represent a biased cohort.

    We aimed to limit studies to those on native valve disease. However, outcomes in some aortic stenosis (AS) studies were not separated into valvular or sub-valvular and so 31 cases of sub-valvular AS were included.5–7 Additionally, for one AS study, due to outcome data aggregation, seven patients with aortic bioprosthesis and 11 with mechanical aortic valves were included.7 This study was not excluded, as it was the largest contemporary study evaluating AS in pregnancy. The total number of prosthetic valves was 10% of all patient with AS. When we performed estimate analysis with and without inclusion of this study and our estimates did not change significantly.

    We included patients with moderate/severe native valve stenosis/regurgitation. Included studies had to quantify the severity of valvular dysfunction by objective means, using either echocardiography or cardiac catheterization. Thresholds for moderate and severe valve disease were defined by the study authors as per established guidelines.8 9

    Only studies from countries with a HDI of medium/greater (score >0.55) were included for analysis. For studies with patients from multiple countries, each participating country had to meet the HDI criteria for the study to be included. Countries with low and very low HDI were excluded to minimise the potential confounding effect of poor access to healthcare resources (obstetrical and cardiac) as a cause of adverse outcomes.

    Outcomes

    Maternal and fetal pregnancy outcomes were grouped by valve lesion, namely mitral regurgitation (MR), mitral stenosis (MS), aortic regurgitation (AR), aortic stenosis (AS), tricuspid regurgitation, tricuspid stenosis, pulmonic regurgitation, and pulmonic stenosis. Where patients had mixed valve disease, we categorised them by the most hemodynamically severe lesion. Outcomes were summarised by valve severity.

    Primary outcome: The primary maternal outcome was maternal mortality (defined as death in the antenatal period, at labour and delivery or in the first 6 weeks post-partum). The primary fetal/neonatal outcome was stillbirth (defined as fetal loss after 20 weeks gestational age (GA)) and neonatal death (death of a live born infant occurring within the first 28 days of life).

    Secondary outcomes: Secondary maternal outcomes were diagnosis of New York Heart Association (NYHA) III-IV symptoms, objective evidence of pulmonary oedema (chest x-ray or crackles on auscultation), documented new/recurrent paroxysmal arrhythmias (atrial fibrillation/super-ventricular tachycardia) during pregnancy, or need for surgical/percutaneous valve intervention during pregnancy. Chronic atrial fibrillation/flutter antedating pregnancy was not included as an adverse pregnancy event. Secondary fetal outcomes included the diagnosis of small for gestational age (SGA: birth weight < 10th centile for gestational age and sex), and preterm birth (birth prior to 37 weeks of gestation).

    Data extraction and quality evaluation

    Two reviewers (RD and DJ) independently performed title and abstract screening, data extraction and risk of bias assessment. Conflicts were adjudicated by a third reviewer (CS). Authors were contacted with data requests if required information was not in the original publication. The Newcastle-Ottawa Quality Assessment Scale for cohort studies was used to assess for risk of bias.10 Risk of bias was high with a score of 0–3, moderate with a score of 4–6 and low with scores of 7–8. A maximum of eight out of nine points could only be awarded as no points could be awarded for Selection because there was no non-exposed cohort.

    Data synthesis and analysis

    Analysis was performed using OpenMetaAnalyst software.11 As considerable clinical and methodological heterogeneity between studies was expected, DerSimonian-Laird binary random effects analysis was performed with 95% confidence intervals (CIs). Estimates of pooled incidence of outcomes were presented as a percentage per 100 pregnancies. A standard correction factor of 0.5 was used. Where this resulted in clinically meaningless results, they were reported as “not applicable”. When event rates were zero, we also performed a sensitivity analysis using a very small correction factor (1×10-15) to verify that the correction factor did not change the estimate. Risk estimates were performed with and without studies with high risk of bias and with and without prosthetic valves in AS patients. Statistical heterogeneity was assessed using the I2 statistic, and a study considered to have a high degree of heterogeneity if the value was >75%.

    Results

    The literature search, reviews, and reasons for study exclusion are described in figure 1 and online supplementary table 1. Characteristics of the 12 included studies are outlined in table 1.5–7 12–20 Maternal characteristics, including age and GA at delivery were not always provided for specific lesion types or severity. Eight publications reported on MS,12–18 20 seven on AS,5–7 15–17 19 two on MR15 17 and one on AR.15 No publications on tricuspid/pulmonic stenosis/regurgitation met the inclusion criteria.

    View this table:
    Table 1

    Description of included studies

    Mitral Stenosis

    Maternal outcomes: In the severe MS group there was a 3% (0%–6%) incidence of death in pregnancy, while in the moderate MS group there was a 1% (0%–2%) incidence of death (table 2, online supplementary table 2, online supplementary figure 2A,B). Four of the six maternal deaths with severe MS had known pulmonary hypertension. In four of the six maternal deaths during pregnancy the fetus died as well.

    View this table:
    Table 2

    Maternal and fetal outcomes in mitral stenosis by severity

    In severe MS, the incidence of new/recurrent paroxysmal arrhythmias was 16% (1%–25%) compared with 5% (1%–9%) in moderate MS. New onset arrhythmia was associated with the development of pulmonary oedema, worsening functional class and cerebral vascular accident (CVA) in some cases. New CVA during pregnancy was not consistently reported. There were two CVAs reported in the severe MS group from four studies (113 pregnancies). One was in a patient with atrial fibrillation. The other had significant mitral calcification. One patient in 107 with moderate MS had a CVA.20

    Overall, 8% (2%–13%) of women with severe MS required intervention during pregnancy (two closed commissurotomy, 8 valve replacement, 14 percutaneous mitral balloon valvuloplasty (PMBV)). Three women died after intervention (2 PMBV, 1 valve replacement, online supplementary table 2) For those undergoing PMBV, two cases precipitated preterm labour (details not provided). There were at least two women with moderate MS that required PMBV during pregnancy, however due to data aggregation, the precise number of patients with moderate MS requiring intervention was not available for analysis. No woman with moderate MS required surgical intervention.

    Delivery method for women with severe MS was reported in four studies (65 pregnancies) with 23% (4%–42%) having a Caesarean delivery. For women with moderate MS, the delivery method was only described in one study with 4 of 18 women having a Caesarean delivery. The indication for delivery method was not clearly described in these studies.

    Fetal outcomes: The rate of stillbirth was 4% (1%–7%) in women with severe MS and 2% (1%–4%) in those with moderate MS (table 2, online supplementary table 2). The incidence of neonatal death for severe MS was 2% (0%–4%). Two neonatal deaths were not incorporated into the analysis as the studies did not report maternal MS severity grade.14 20

    Aortic stenosis

    Maternal outcome: There were two deaths in the severe AS group, resulting in a 2% (0%–5%) incidence of death in pregnancy (table 3, online supplementary table 3, online supplementary figure 2C,2D and 3A,B). No adverse events were attributed to complications of prosthetic valves or sub-valvular disease. No deaths were reported in the moderate AS group. Overall the majority of pulmonary oedema episodes were reported during pregnancy, however GA at onset was not consistently reported. There were two episodes of pulmonary oedema early postpartum.

    View this table:
    Table 3

    Maternal and fetal outcomes in aortic stenosis by severity

    Three aortic valve interventions were performed during pregnancy, one surgical valve replacement during the second trimester in moderate AS for endocarditis, and two percutaneous aortic balloon valvuloplasties in severe AS (first and second trimester). No post-intervention complications were reported.

    Of the five studies that described mode of delivery in severe AS (71 pregnancies), 65% (30%–99%) had a Caesarean delivery. Only three studies reported delivery method for moderate AS (75 pregnancies) with 29% (0%–60%) undergoing Caesarean deliveries. However, the indication for delivery method was not clearly reported.

    Fetal outcomes: There was one stillbirth among 103 pregnancies with severe AS (2%, 0%–5%, table 3, online supplementary table 3). There were two miscarriages in patients with moderate AS prior to 24 weeks GA, however the exact GA at death was not reported and so these deaths were not included in our analysis.7 One neonatal death was reported in a patient with severe AS.

    Mitral Regurgitation

    Only two studies met our inclusion criteria reporting on a total of 40 pregnancies with severe MR.15 17 No maternal deaths were reported. However, 30% (7%–40%) of patients experienced pulmonary oedema requiring therapy. One paper reported two neonatal deaths (6%; 1%–13%) in mothers with severe MR and pulmonary hypertension due to complications of preterm labour.

    Aortic Regurgitation

    Only one paper describing outcomes in 59 pregnancies with moderate (n=42) or severe (n=17) AR met our inclusion criteria.15 There were no maternal deaths but two mothers with severe AR required aortic valve replacement for refractory heart failure during pregnancy. There were five patients with severe AR who developed pulmonary oedema during pregnancy with three experiencing recurrence post-delivery. One neonatal death was reported due to respiratory distress after Caesarean delivery, however GA at delivery and other details for this case were not provided.

    Quality assessment of studies

    The risk of bias varied between studies. None of the studies were assigned a low risk of bias. There was one case-control study at high risk of bias and the remaining eleven cohort studies were at moderate risk. Deficiencies included, lack of control data, failing to control or report comorbidities and inadequate length of follow-up (online supplementary table 4).

    Publication bias and sensitivity analysis: As there were fewer than ten included studies per outcome, the utility of funnel plots to assess for publication bias were limited because the power of the tests would be considered too low to distinguish chance from real asymmetry (online supplementary figure 1).21 There was no major statistical difference in presented outcomes on sensitivity analysis, excluding the study with high risk of bias16 or the study with a medium HDI score.14

    Discussion

    In this systematic review and meta-analysis only risk estimates for women with MS and AS could be provided (figure 2). Pregnant women with severe MS were at high risk of adverse cardiac events including pulmonary oedema, new/recurrent arrhythmias and maternal mortality. Additionally, these women experienced high rates of stillbirth, neonatal death and preterm birth. Women with moderate MS also had an elevated risk of mortality and adverse cardiac and fetal/neonatal events during pregnancy. Pregnant women with severe AS had a mortality rate of 2% and were at risk for pulmonary oedema, new or recurrent arrhythmias and fetal or neonatal loss. In contrast, women with moderate AS had comparatively better pregnancy outcomes with no reports of maternal mortality or neonatal deaths.

    Figure 2
    Figure 2

    Maternal and fetal/neonatal outcomes by valve lesion and severity.

    Mitral Stenosis

    Moderate and severe MS are high-risk lesions for both the mother and fetus during pregnancy. In medium/higher HDI countries, women with moderate or severe MS have a maternal mortality rates that are appreciably higher than the 0.015% rate for the general pregnancy populations of Europe and North America and the 1.9% in pregnant women with cardiomyopathy.22 23 In addition, patients with severe MS experience rates of heart failure (37%) or arrhythmias (16%) that are comparable to those in patients with cardiomyopathy (29% and 15% respectively).23 Thus, pre-conception counselling, risk stratification, and cardiac management are important for these women.24

    Valvular heart disease guidelines recommend patients with moderate or greater MS be routinely evaluated with echocardiography to exclude pulmonary hypertension, and depending on the clinical situation, cardiac catheterization prior to pregnancy may be considered if echocardiography is non-diagnostic.25 Current pregnancy guidelines recommend that women with moderate/severe MS undergo or be considered for pre-pregnancy valve intervention, even if they are asymptomatic.26 Pre-conception mitral valvuloplasty may prevent the development of pulmonary hypertension, atrial fibrillation and heart failure; however, there are risks involved with valve interventions. Furthermore, there is a proportion of women with moderate/severe MS who seem to do well. Current risk stratification is reliant on clinical and echocardiographic parameters, but there may be low risk features, yet to be identified such as biomarkers, that could classify women who do not require pre-conception intervention, especially in those with moderate MS.

    CVA rates were not consistently reported however, it may be a devastating consequence of MS. Current guidelines recommend anticoagulation in women with atrial fibrillation and that anticoagulation should be considered in pregnancy with significant MS in sinus rhythm with spontaneous left atrial echo contrast, large left atrium (>60 mL/m2) or congestive heart failure.26

    Many factors are likely responsible for the adverse fetal and neonatal outcomes in women with MS including, maternal cardiac status and lesion severity. Women with heart disease may also have an inability to augment cardiac output and abnormalities in uteroplacental blood flow.27 While fetal and neonatal complication rates were highest in severe MS, both moderate and severe MS groups had rates higher than the 0.35% stillbirth, 0.3% neonatal death, and 9% preterm birth rates found in the general population in high-income countries.28 29 When compared with fetal and neonatal complications in pregnant women with cardiomyopathy (0.4% stillbirth, 1.5% neonatal death and 25% preterm birth) the rates in severe MS are higher for fetal death but comparable for neonatal death and preterm birth.23 Improvements in maternal hemodynamics, perhaps through the use of beta-blockers in women with MS, may reduce these adverse outcomes.

    Aortic Stenosis

    Maternal mortality in women with asymptomatic severe AS is low in the current era.6 7 16 We found that women with severe AS have a mortality of 2% vs no mortality in those with moderate AS. Our findings suggest that there is a subset of women with severe AS who are at risk of dying during pregnancy and that AS, whether it is moderate/severe, has a haemodynamic impact on the mother and fetus. Current guidelines recommend pre-conception risk stratification of asymptomatic women with severe AS by using exercise testing.26 Note also that there were two miscarriages in moderate AS patients that were not included in our analysis, as the exact GA at death was not reported. This may result in an underestimation of fetal risk in this population.

    Optimal mode of delivery for women with AS is debated with no evidence supporting vaginal or Caesarean delivery.26 Though Caesarean delivery was common in the AS group there was still a large percentage of women who had successful vaginal births. However, interpretation of the safety of delivery method is challenging as the indications for Caesarean delivery were not provided, and it is not possible to determine if Caesarean delivery was performed due maternal/fetal decompensation or for no other indication than a history of maternal AS.

    Limitations

    Most of the published literature on VHD in pregnancy focuses on obstructive left-sided valve lesions and there is a lack of high-quality studies on regurgitant and right-sided lesions. Additionally, in many publications, outcome data is reported in aggregate with other cardiac conditions, making it difficult to isolate specific valve type and severity data for analysis. Furthermore, included papers assessed valvular disease severity using different guidelines and did not specify when severity was assessed during pregnancy. There is also uncertainty in the data regarding VHD treatment prior to pregnancy and modes of delivery. Another limitation is the moderate-to-high risk of bias, inherent in part to the design of the included studies

    There were inconsistencies in reporting follow-up duration for maternal and neonatal outcomes, with some studies not specifying the duration of follow-up and others reporting outcomes only for the first 7 days postpartum. This may result in an under recognition of postpartum maternal and fetal adverse events. There were inconsistency between studies in defining stillbirth. It was not clear whether preterm births were spontaneous or iatrogenic and whether the iatrogenic preterm births directly related to the underlying maternal disease, or to obstetrical indications for early birth. Iatrogenic preterm birth may not reflect the effects of the maternal cardiac disease as there are multiple obstetrical indications for early delivery that are unrelated to maternal status. An effort to standardise the definition of outcomes is being developed. (online supplementary material references 31,32)

    Conclusion

    Women with left sided stenotic lesions have increased risks of adverse maternal and fetal/neonatal outcomes. These women should receive appropriate preconception risk stratification and counselling. Further research is warranted to examine outcomes in women with other valve lesions, to identify better risk predictors, and to study strategies to improve outcomes in this population.

    Key questions

    What is already known about this subject?

    • Valve disease is a common cardiac lesion in women of child-bearing age. However, there is significant variability in estimates of pregnancy complications in currently available literature, primarily due to small sample sizes in each of the individual studies. Precise estimates precise estimates are crucial for counseling and managing these patients.

    What does this study add?

    • This is the first systematic review and meta-analysis performed to address the lack of precise estimates needed to counsel these women. It also demonstrates that women with moderate or severe mitral and aortic stenoses have higher rates of adverse cardiovascular and fetal/neonatal outcomes compared to the general population.

    How might this impact on clinical practice?

    • This study provides information to support the need to refer women to centers with teams specializing in pregnancy and heart disease for preconception counseling and pregnancy care.

    Acknowledgments

    The authors would like to acknowledge Iris van Hagen and Jolien Roos-Hesselink for their assistance in providing information from the ROPAC studies and Panos Labris and Ashley Farrell for their assistance with the search strategy.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Contributors RAD Study concept, generation of search strategy, abstract review and full text review. Data extraction and analysis. Manuscript writing. Final approval. DAJ Abstract review and full text review. Data extraction and analysis. Final approval. RD’S Expert review of content. Statistical analysis and interpretation. Final approval. CKS Study concept, generation of search strategy, data evaluation and adjudication for meta-analysis. Mansucript writing.Final approval. WT Study concept, generation of search strategy, expert review of content. Data analysis. Manuscript writing. Final approval. Guarantor of the content.

    • Funding WT is supported by a Heart and Stroke Foundation of Canada National New Investigator Award.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request.

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