Peripartum cardiomyopathy: A systematic review of the literature

Abstract

Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure. It is defined as cardiomyopathy that develops in the last month of pregnancy or within 5 months of the postpartum period without an identifiable cause. We conducted a systematic review of literature of prospective studies with a focus on echocardiographic and long‐term clinical outcomes in PPCM. We searched MEDLINE and Embase up to October 1, 2017. Prospective studies (sample size ≥20) reporting all‐cause mortality and follow‐up duration of ≥1 year were included. Of the 956 studies identified, 7 met the inclusion criteria. A total of 445 patients with a mean age of 30 years (range, 27–32 years) were included. The mean follow‐up duration was 41 months (range, 12–61 months). The majority of patients had New York Heart Association class III or IV symptoms at the time of diagnosis. Only 3 studies reported data on ethnicity where the majority of patients were non‐Caucasian. Most of the patients (81%–93%) were on guideline‐directed medical therapy, except 1 study (41%). Left ventricular ejection fraction at baseline ranged from 24% to 35% (mean, 28%) and at follow‐up from 31% to 53% (mean, 44%). Recovery in systolic function was noted in 20% to 82% (mean, 50%) of patients. All‐cause mortality ranged from 0% to 28% (mean, 16%). This systematic review summarizes the evidence to date on the clinical characteristics and outcomes of patients with PPCM. Multicenter registries with long‐term follow‐up will help shed further light on characteristics and outcomes of patients with this rare disease.

1. INTRODUCTION

Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure (HF). Its incidence ranges from 1 in 300 live births in Haiti to 1 in 1300 to 4000 live births in the United States.1, 2, 3, 4 It is defined as cardiomyopathy that develops in the last month of pregnancy or within 5 months of the postpartum period without an identifiable cause.5 Data on clinical outcomes and natural history of PPCM are very diverse. Most of the women recover completely, but a few develop progressively worsening HF and, ultimately, death. Most of the reports on clinical outcomes are limited to single‐center studies, case series, and retrospective studies with small sample size and short duration of follow‐up. Therefore, we conducted a systematic review of literature of prospective studies with a focus on echocardiographic and long‐term clinical outcomes of women with PPCM. The intent was to synthesize the available clinical literature on this rare disease to gain a better understanding of the disease characteristics and echocardiographic/clinical outcomes.

2. METHODS

We searched MEDLINE and Embase databases accessed by Ovid. The search was performed on October 1, 2017, and the terms included the subject headings or keywords exploded to include all the subheadings: “cardiomyopathies” or “cardiomyopathy” and “peripartum period” or “peripartum” or “postpartum period” or “postpartum” or “puerperal disorders” or “puerperal.” The search was limited to articles in English and to studies done on humans. Two independent reviewers screened titles, abstracts, and, wherever necessary, full articles of all 956 studies with their references to identify relevant studies; disagreements were resolved by consensus and discussion with a third independent reviewer. The reference lists of all included studies were also scanned.

We included prospective studies if they fulfilled the following inclusion criteria: (1) prospective study design, (2) long‐term follow‐up reported (≥1 year), (3) reported outcomes that included all‐cause mortality and/or echocardiographic characteristics, and (4) written in the English language. The exclusion criteria were (1) case reports, case series, retrospective studies, or cross‐sectional study design; (2) follow‐up duration <1 year; and (3) sample size ≤20.

A predefined extraction sheet was used for data gathering, which included the name of the first author, year and journal of publication, number of patients studied, and a checklist for inclusion criteria. Whenever available, the following information was extracted from each study: demographic characteristics such as age, ethnicity, comorbidities, and medications used to manage HF; the duration of follow‐up; echocardiographic parameters; and the reported mortality. The included studies were evaluated according to the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines.6 The primary outcome of interest was all‐cause mortality 1 year after follow‐up in PPCM patients. A secondary outcome of interest was a change in left ventricular ejection fraction (LVEF) and other echocardiographic characteristics at the end of the follow‐up duration.

3. RESULTS

The search yielded 956 studies, out of which 65 were duplicates and 864 were excluded after screening the titles and abstracts in the databases because they were either retrospective studies, case reports or case series, letter to editors, or review articles, or they did not meet the inclusion criteria. Out of the 27 studies with full‐text articles screened, 7 met the full inclusion criteria listed above.4, 7, 8, 9, 10, 11, 12 A detailed search strategy is given in the Figure 1 .

Figure 1.

Search strategy for the systematic review of literature on PPCM. Abbreviations: PPCM, peripartum cardiomyopathy

A total of 445 patients in 7 prospective studies with a mean age of 30 years (range, 27–32 years) were included in this systematic review. The mean follow‐up duration was 41 months (range, 12–61 months). The majority of the patients had New York Heart Association (NYHA) class III or IV symptoms at the time of diagnosis. Only 3 studies reported data on the ethnicities of patients, and the majority of the patients in those studies were non‐Caucasian. Only 6 studies reported the time of onset of symptoms, and the majority of those patients were diagnosed in the postpartum period. Most of the studies did not report any associated comorbidities except hypertension (HTN), which was reported in 3 studies with a prevalence of 15% to 45%. Only 5 studies reported data on medication use; the majority of patients were managed with β‐blockers, angiotensin‐converting enzyme inhibitors (ACEIs), or angiotensin II receptor blockers and diuretics (81%–93%), except 1 study (41%). Table 1 summarizes the demographic features and the clinical characteristics.

Table 1.

Baseline demographic and clinical characteristics of the selected patients

Author and Year	McNamara 7	Ntusi 8	Biteker 9	Cooper 2011	Sliwa 11	Mishra 12	Fett 4
No. of patients	100	30	42	39	80	56	98
Duration of follow‐up, mo	12	42	39 ±  15	48	24	61	60
Mean age, y	30 ±  6	32 ± 8	27 ± 5	30 ± 7	30 ± 7	31 ± 5	32
NYHA class
I	12	11	0	—	—	—	0
I–II	—	—	—	—	11	—	—
II	46	12	17	—	—	32	2
III	25	36	31	—	—	43	31
III–IV	—	—	—	31	89	—	—
IV	17	30	52	—	—	25	67
DM	11	—	5	—	—	—	—
AF	—	—	12	—	—	—	—
HTN	45	—	17	—	—	—	15
Preeclampsia	—	—	0	—	—	—	4
Race
White	65	—	—	64	—	—	—
Black	30	60	—	36	—	—	—
Other	5	40	—	—	—	—	—
Smoking	34	30	—	—	—	—	—
Onset of PPCM	Postpartum	Postpartum	Prepartum (29), postpartum (71)	Postpartum		Prepartum (37), postpartum (63)	Postpartum
SBP, mm Hg	112 ±  17	106 ±  16	—	110 ±  18	113 ±  19	—	—
DBP, mm Hg	71 ±  13	64 ±  10	—	72 ±  14	75 ±  12	—	—
Medications
ACEI/ARB	81	100	81	87	—	53.5	—
β‐Blocker	88	93	90	85	—	41.1	—
Diuretic	—	100	100	74	—	100	—
Digitalis	—	77	36	—	—	100	—

Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; DBP, diastolic blood pressure; DM, diabetes mellitus; HTN, hypertension; NYHA, New York Heart Association; PPCM, peripartum cardiomyopathy; SBP, systolic blood pressure; SD, standard deviation.

Data are presented as % or mean ±  SD.

All‐cause mortality was reported by all the studies included in this systematic review, and it ranged from 0% to 28%, with a mean mortality of 16%. Studies with a follow‐up duration >12 months had a higher mortality. All studies included in this systematic review reported the LVEF at entry; it ranged from 24% to 35%, with a mean LVEF of 28%. Only 6 studies reported LVEF after follow‐up, which ranged from 31% to 53% with a mean LVEF of 44%. Recovery in the LVEF was reported in 5 studies, with 20% to 82% of the patients (mean, 50%) having a partial or full recovery at the end of follow‐up.

4. DISCUSSION

Our systematic review provides the most comprehensive overview of contemporary prospective studies of PPCM and elaborates on the clinical characteristics, echocardiographic follow‐up, and outcomes. Our study design is unique in that strict inclusion and exclusion criteria were utilized and only prospective studies with a minimum follow‐up of 1 year were included. Our review demonstrated a great disparity in the reporting of clinical characteristics, treatment patterns, and data pertaining to patterns of left ventricular recovery. The studies reported a wide range of mortality, ranging from 0% to 28% as shown in Table 2.

Table 2.

Echocardiographic characteristics and mortality

Author and Year	McNamara 2015	Ntusi 2015	Biteker 9	Cooper 2011	Sliwa 9	Mishra 12	Fett 4
Duration of follow‐up, mo	12	42	39 ± 15	48	24	61	60
LVEF at entry	35 ± 10	24 ± 8	26 ± 6	27 ± 7	30 ± 9	31 ± 7	24
LVEF at follow‐up	53 ± 10	31	—	45 ± 14	50 ± 14	43 ± 8	44
LVEDD at entry, cm	5.5 ± 0.07	7.4 ± 1.1	6.6 ± 0.6	—	5.66 ± 0.6	6.4 ± 1.25	5.9a
LVEDD at follow‐up, cm	—	—	—	—	5 ±  0.9	5 ± 0.7	5.9a
Recovered LVEF	72	20	48	82	—	—	28
Mortality	4	17	24	0	28	23	15

Abbreviations: LVEDD, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction; SD, standard deviation.

Data are presented as % or mean ± SD.

^aSD not available.

PPCM is a rare cause of HF and continues to remain a diagnosis of exclusion in the late part of pregnancy and early postpartum period (first 5 months). Due to the rarity of the disease, specific geographical and socioeconomic differences, and a complex heterogeneous presentation, the disease continues to be underdiagnosed and incompletely characterized. Classic criteria for the diagnosis of PPCM, as established by Demakis et al., limited the diagnosis to the last gestational month through the first 5 months after delivery.13 There has been a dearth of comprehensive data reporting in studies involving patients with PPCM. Our systematic review was designed to synthesize the available data from prospective studies.

Medical therapies form the cornerstone of treatment for HF. Current HF guidelines endorse an aggressive approach to utilization and up‐titration of guideline‐driven medical therapies. Our review suggests that most of the patients in the included studies were managed with guideline‐directed medical therapy for HF. Prescription rates for commonly used HF therapies, such as ACEIs or angiotensin receptor blockers and β‐blockers, ranged from 53% to 100% to 41% to 93%, respectively. The reasons for lower‐than‐expected utilization of standard HF therapies are not outlined in the study by Mishra et al.12 All the other studies report a > 80% utilization of guideline‐driven therapies. Utilization of diuretics was reported in 3 of the 7 studies, in which they documented a near 100% use, likely attesting to the increased prevalence of systemic vascular congestion at the time of diagnosis. Bromocriptine is emerging as a useful adjunct therapy in PPCM.14 Our current analysis does not provide information on the utilization rate of this therapy. The worldwide registry of PPCM very recently published its very first analysis of the first cohort of enrolled subjects and sheds light on the global utilization patterns of guideline‐directed therapies. In this registry, the utilization of therapies such as ACEIs and β‐blockers was >80%. Global utilization of bromocriptine was 20%, digoxin ~38%, and mineralocorticoid receptor antagonists 45% to 50%. Certain regional differences were noted in the utilization of the aforementioned therapies.

African American race has been proposed as a risk factor for development of PPCM in several studies.1, 3 In a large case–control study from the United States, the odds ratio for development of PPCM among African American women was 15.7.15 Similarly, regions of the world with large proportions of women from African descent, such as Nigeria, Haiti, and South Africa, have high prevalence of PPCM.4, 16, 17 Similarly, 2 of the studies included in our systematic review reported low LVEF at entry and a low LVEF at follow‐up among African Americans with PPCM.7, 8

The role of HTN in PPCM has been unclear; some consider it a risk factor for development of PPCM, whereas others propose that PPCM should be a diagnosis of exclusion.18, 19 Ntusi et al., in their case‐comparison study of hypertensive HF of pregnancy and PPCM, showed that there were significant differences in symptoms, echocardiographic characteristics, and mortality over long‐term follow‐up of 6 years.8 Only 3 of our included studies provided data on prevalence of HTN and preeclampsia among PPCM patients, and McNamara et al. in their univariate analysis did not find HTN as a predictor of recovery in LVEF.4, 7, 10

The timing of recovery in LVEF after starting optimal medical therapy is important in determining the need for implantable cardioverter‐defibrillator therapy for prevention of sudden cardiac death. Current consensus statements from the European Society of Cardiology and the US National Heart, Lung, and Blood Institute suggest that most patients recover LVEF within 6 months of diagnosis. If LVEF does not recover in this time frame, it indicates worse prognosis, which is consistent with the large prospective study by McNamara et al… included in our analysis, according to which 50% of patients recover their LVEF within 6 months of diagnosis.5, 7, 20 However, the study by Ntusi et al reported that 60% of patients recovered their LVEF after 6 months, and 73% of patients had recovery of LVEF after 12 months in the study by Fett et al.8, 21 This delayed recovery of LVEF after 6 months of diagnosis is clinically important when recommending implantable cardioverter‐defibrillator therapy, and further studies should focus on long‐term follow‐up of these patients to address this question of delayed recovery.

Mortality associated with PPCM was quite variable in the included studies, ranging from 0% to as high as 28%. It is interesting that Cooper et al., despite having a mean follow‐up of 36 months, demonstrated a 0% mortality rate.10 The likely explanation could be a very high left ventricular systolic function recovery rate in 82% of the included patients. Not surprisingly, among the included studies that reported data on both recovery in left ventricular function and mortality, there seemed to be an inverse relationship between mortality and recovery. Most patients with PPCM demonstrate a very early recovery in systolic function, and previous studies have demonstrated certain clinical characteristics and echocardiographic parameters that are associated with recovery in systolic function.7

4.1. Study limitations

Currently available data about clinical characteristics, treatments, and outcomes are very scattered and heterogeneous, and this systematic review provides the most up‐to‐date overview of the clinical aspects of PPCM. Given that this disease is rare, the sample size of the studies is low; due to the lack of availability of comprehensive data, a meaningful meta‐analysis could not be undertaken. The current systematic analysis does not provide insights into the utilization of advanced HF therapies, such as left ventricular assist devices and heart transplantation, among patients with PPCM. In addition, data on subsequent pregnancies and the contribution of subsequent pregnancies to systolic function recovery were not reported in the included studies. Future studies including the currently ongoing international PPCM registry will shed light on the various deficiencies that have been outlined in this analysis.

5. CONCLUSION

Our systematic review of prospective studies summarizes the evidence to date on the clinical characteristics and outcomes of patients with PPCM. Multicenter registries with long‐term follow‐up, like the international PPCM registry, will help shed further light on optimal medical characteristics and outcomes of patients with this rare disease.

Conflicts of interest

The authors declare no potential conflicts of interest.

Asad ZUA, Maiwand M, Farah F, Dasari TW. Peripartum cardiomyopathy: A systematic review of the literature. Clin Cardiol. 2018;41:693–697. 10.1002/clc.22932