Journal of the American College of Cardiology

2011 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 58, No. 7, 2011

ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.03.047

STATE-OF-THE-ART PAPER

Clinical Characteristics of
Peripartum Cardiomyopathy in the United States
Diagnosis, Prognosis, and Management
Uri Elkayam, MD
Los Angeles, California
Peripartum cardiomyopathy is a pregnancy-associated myocardial disease characterized by the development of
heart failure due to marked left ventricular systolic dysfunction. Although the disease is relatively uncommon, its
incidence is increasing, and it can be associated with important and lasting morbidity and with mortality. Peripartum cardiomyopathy seems to affect women in different parts of the world but with considerable differences in clinical presentation. The purposes of this review are to describe the clinical profile of peripartum
cardiomyopathy in the United States and to provide recommendations for the diagnosis and the management of this disease. (J Am Coll Cardiol 2011;58:65970) 2011 by the American College of Cardiology
Foundation

Peripartum cardiomyopathy (PPCM) is a pregnancyassociated myocardial disease, reported to occur in different

parts of the world (1). The disease is heterogeneous and
seems to have important phenotypic variations in different
geographical regions; for this reason as well as differences in
the availability and delivery of care, it is difficult to formulate
uniform recommendations throughout different parts of the
world. The purposes of this review are therefore to describe
the clinical characteristics of PPCM in the United States
and to provide recommendations for the diagnosis and
treatment of this condition.
Historical Perspective and Definition
Heart failure (HF) associated with pregnancy was first
described as a definitive form of cardiomyopathy in 1937
(2). In 1971, Demakis et al. (3) published data on 27
patients with pregnancy-associated cardiomyopathy who
presented in the peripartum period. These investigators
coined the term peripartum cardiomyopathy and defined diagnostic criteria on the basis of their patients
characteristics and available diagnostic tools at the time.
These criteria included: 1) the development of HF in the
last month of pregnancy or within 5 months of delivery;
2) the absence of a determinable etiology for HF; and 3) the
absence of demonstrable heart disease before the last
From the Division of Cardiology, Department of Medicine and the Department of
Obstetrics and Gynecology, University of Southern California Keck School of
Medicine, Los Angeles, California. Dr. Elkayam has reported that he has no
relationships to disclose.
Manuscript received January 6, 2011; revised manuscript received March 2, 2011,
accepted March 21, 2011.

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month of pregnancy. A workshop organized by the

National Heart, Lung, and Blood Institute and the Office
of Rare Diseases Research in 1997 (4) added an additional criterion proposed by Hibbard et al. (5) of left
ventricular (LV) systolic dysfunction demonstrated by
echocardiography with left ventricular ejection fraction
(LVEF) !45%, fractional shortening !30%, or both.
Additional information has indicated that although the
majority of patients with PPCM are diagnosed in the
peripartum period (Fig. 1), early presentation during
pregnancy is not uncommon (6,7). A recent study of 23
cases with pregnancy-associated cardiomyopathy diagnosed between the 17th and 36th weeks of gestation
found them to be indistinguishable from 100 women
meeting classic criteria for PPCM (8). These findings,
supported by numerous other reports (6,9 15), clearly
indicate that PPCM and pregnancy-associated cardiomyopathy represent a continuum of the same disease (7,8).
A recent position statement from a European Society of
Cardiology working group on PPCM has therefore
expanded the definition of PPCM to an idiopathic
cardiomyopathy presenting with HF secondary to LV
systolic dysfunction towards the end of pregnancy or in
the months following delivery, where no other cause of
heart failure is found (16). The majority of patients who
are diagnosed during pregnancy present in the third
trimester, with a few in the second trimester (8).
PPCM is a diagnosis of exclusion, and other causes of
cardiac dysfunction should be ruled out. At the same time,
however, transient and unexpected depression of LV function typical to PPCM has been described in women with
other forms of heart disease (6). These findings therefore

660

Elkayam
Peripartum Cardiomyopathy

ARB ! angiotensin
receptor blocker

suggest that the diagnosis of

PPCM should not be excluded in
patients with heart disease,
which is otherwise not likely to
cause LV dysfunction during or
after pregnancy.

BNP ! brain natriuretic

peptide

Incidence

Abbreviations
and Acronyms
ACE ! angiotensinconverting enzyme

DCM ! dilated
cardiomyopathy

A number of recent studies have

provided information regarding
HF ! heart failure
the incidence of PPCM in the
ICD ! implantable
United States, ranging from 1 in
cardioverter-defibrillator
1,149 to 1 in 4,350 live births
LV ! left ventricular
(11,1719), with a mean of 1 in
LVEF ! left ventricular
3,186 live births (Table 1). Difejection fraction
ferences in incidence among
MRI ! magnetic resonance
published reports are probably
imaging
due to variations in patient popPPCM ! peripartum
ulations but also study design,
cardiomyopathy
sample size, and degree of underreporting (20). Mielniczuk et al.
(18) reported a trend toward an increase in incidence over
time from 1 in 4,350 in 1990 to 1993 to 1 in 2,229 in 2000 to
2002 (Fig. 2). This suggested increase in the incidence of
PPCM in the U.S. might be related to a rise in maternal
age, a substantial increase in the rate of multifetal pregnancies due to contemporary reproductive techniques, and
possibly to increased recognition of the disease. A population study in Southern California (19) found the greatest

Figure 1

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incidence of PPCM in African Americans (1 in 1,421) and

the lowest in Hispanics (1 in 9,861). The incidence in
Caucasians was 1 in 4,075 and in Asians was 1 in 2,675.
Higher incidence in African American women has recently
been confirmed by Gentry et al. (21), who conducted a
case-control study in Augusta, Georgia, and Memphis
Tennessee, and found almost a 16-fold higher incidence of
PPCM in African American compared with nonAfrican
American women.
In summary, the incidence of PPCM in the U.S. seems to
be increasing and is estimated to be approximately 1 in 3,200
deliveries, with a significantly higher incidence in African
American women and possibly lower incidence in Hispanics
compared with non-Hispanic whites. Because the number of
live births in the United States is "4,300,000 per year (22), the
estimated annual number of new patients with PPCM in the
U.S. is approximately 1,350.
Etiology
The etiology of PPCM is still unknown, and many potential
causes have been proposed but not proven (1,16,23). These
include viral myocarditis, abnormal immune response to
pregnancy, abnormal response to increased hemodynamic
burden of pregnancy, hormonal abnormalities, malnutrition,
inflammation, and apoptosis. Most recently, experimental
work has suggested a novel and specific pathogenic mechanism by demonstrating the development of PPCM in
female mice with a cardiomyocyte-specific deletion of the
transcription factor signal transducer and activator of tran-

Time of Diagnosis of PPCM in 123 Patients

Red bars represent 23 patients with diagnosis before the last month of pregnancy. Green bars represent 100 patients diagnosed in the last month of pregnancy or the 5-month
postpartum. PP # postpartum; PPCM # peripartum cardiomyopathy. Adapted from Elkayam et al. (8).

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661

Incidence
PPCM in the
UnitedinStates
Table 1 of Incidence
of PPCM
the United States
First Author
(Year)
(Ref. #)

Study Design

Age (yrs),
Range (Mean)

Ethnic Background

Period of
Study

Rate

Witlin et al.
(1997) (11)

Prospective, single institution

28 of 67,369 deliveries

2935 (32)

African American 75%;

white 21%; Asian 0.5%

19881994

1 in 2,406

Chapa et al.
(2005) (17)

Retrospective, single institution

35 of 40,200 deliveries

1638 (27 $ 6)

African American 80%;

white 20%

19882001

1 in 1,149

Brar et al.
(2006) (19)

Retrospective review,
Southern California Kaiser
Permanente

60 of 241,497 deliveries

33 $ 7

African American 28%;

white 27%; Hispanic
20%; Asian 17%;
others 8%

19962005

All patients 1 in 4,025;

whites 1 in 4,075;
African Americans
1 in 1,421;
Hispanics 1 in 9,861;
Asians 1 in 2,675

Mielniczuk
(2006) (18)

National hospital discharge

16,296 patients among

51,966,561 live births

NA (29.7)

African American 32%;

white 42%

19902002

1 in 3,189

NA # not available; PPCM # peripartum cardiomyopathy.

scription 3 (STAT3) protein (24). Absence of cardiomyocyte STAT3 in the postpartum heart resulted in increased
oxidative stress secondary to blunted induction of the
antioxidant enzyme manganese superoxide dismutase, leading to increased expression and proteolytic activity of cardiac
cathepsin D and resulting in cleavage of the nursing
hormone prolactin into an antiangiogenic and proapoptotic
16-kDa form with a detrimental effect on the myocardial
microvasculature resulting in myocardial hypoxemia and
apoptosis and the development of PPCM. Preliminary data
in human demonstrating a favorable effect of bromocriptine,
a pharmacological inhibitor of prolactin in a limited number
of patients with PPCM, may support this mechanism of
PPCM (25).
Associated Conditions
Strong associations have been shown between PPCM and
older maternal age, history of hypertension, multiple pregnancies, and African American background.
Age. Although the disease has been reported in women
between the ages of 16 and 44 years, the mean age of
women with PPCM in the United States has ranged from
27 to 33 years (8,11,1719) (Table 1), with "60% of
patients reported in 1 study to be "30 years of age (8).

Figure 2

Change in the Incidence of PPCM Over Time

PPCM # peripartum cardiomyopathy. Data derived from Mielniczuk et al. (18).

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Race. PPCM in the United States has been reported to

affect women of different ethnic groups, including nonHispanic whites, African Americans, Hispanics, and
Asians. However, the incidence of the disease seems to be
considerably higher among African American patients
(19,21).
Hypertension. Hypertension chronic, pregnancy induced,
or preeclampsia has been described in 15% to 68% (mean
23%) of patients with PPCM in the United States
(3,8,11,17,18,26,27), with a similar incidence reported in
women diagnosed antepartum and postpartum (8). This incidence is considerably higher than the 8% reported in all
pregnant patients (28,29). Symptoms of HF in patients with
PPCM are often attributed to preeclampsia and hypertension
in patients with both conditions, resulting in a delay of PPCM
diagnosis and treatment. Although one can argue that LV
dysfunction is not truly idiopathic in the setting of severe
hypertension, chronic hypertension is not likely to cause
marked LV systolic dysfunction in young women, and hypertensive pulmonary edema is due mostly to exacerbation of
diastolic dysfunction by hypertension, not to transient systolic
dysfunction (31). In fact, assessment of systolic LV function in
pregnant women with hypertension by a number of investigators has shown it to be preserved (3234). Preeclampsia can
also present with signs and symptoms of HF, but systolic
function is usually preserved or even improved (33,3537). For
all these reasons, as well as similar rates of LV recovery in
patients with PPCM with and without histories of gestational
hypertension (38), the latter does not seem to be a cause of LV
systolic dysfunction but a strong associated condition to
PPCM. Because brain natriuretic peptide (BNP) levels
are only mildly elevated (36,39,40) in patients with
preeclampsia, echocardiographic evaluation and measurement of BNP levels are advisable for the early diagnosis
of PPCM in patients with preeclampsia who are suspected of having HF.
Multifetal pregnancies. Multiple births have been reported in 7% to 14.5% of patients with PPCM in the
United States (3,17,26,27,38), compared with only 3% in

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Elkayam
Peripartum Cardiomyopathy

the overall population (41), confirming a strong association

between multifetal pregnancies and the development of
PPCM.
Parity. Multiparity has been traditionally considered to be
a risk factor for PPCM (1). However, most studies in the
United States have reported the development of PPCM in
conjunction with the first or second pregnancy in "50% of
patients (8,17,26,27). Therefore, these data do not support
a strong association between multiparity and PPCM in the
United States.
Genetics of Peripartum Cardiomyopathy
PPCM has been classified as a nongenetic form of dilated
cardiomyopathy (DCM) (10). However, a number of studies have reported familial clustering (42 45). Morales et al.
(9) recently performed a systematic search of 110 women
from 520 families of patients with nonischemic DCM and
identified 45 patients with PPCM. Nineteen of the patients
had been sequenced for genes known to be associated with
DCM. This observation was further supported by a European study that found PPCM in 6% of 90 families with
DCM (10). Screening of first-degree relatives of 3 patients
with PPCM with persistent LV dysfunction revealed undiagnosed DCM in all 3 families. Furthermore, genetic
analyses showed a mutation in the gene encoding cardiac
troponin C (TNNC1) in 1 DCM family with members with
PPCM. These findings may suggest that in a proportion of
patients, PPCM is due to genetic causes (7) or represents
cases of familial DCM that was unmasked or first recognized in pregnancy.
Clinical Presentation
Many of the signs and symptoms of normal pregnancy are
similar to those of HF; for this reason, and because of the
low incidence of this condition, the diagnosis of PPCM is
often missed or delayed, allowing the development of
preventable complications (15,30). Most patients present
with typical signs and symptoms of HF, including dyspnea
and orthopnea (6,17); in addition, cough, chest pain, and
abdominal pain are frequently encountered and tend to
confuse the initial clinical evaluation (6). Physical examination often reveals tachycardia and tachypnea, blood pressure
may be elevated or reduced, and patients are often not able
to lie down flat because of shortness of breath. There is
usually increased jugular venous pressure, displaced apical
impulse, right ventricular heave, murmurs of mitral and
tricuspid regurgitation, third heart sound, pulmonary rales,
and peripheral edema. Electrocardiography usually shows
sinus tachycardia with nonspecific ST-T wave changes. LV
hypertrophy can be found as well as left atrial enlargement
and, occasionally, conduction abnormalities including left
bundle brunch block (11). Chest radiography usually shows
cardiomegaly and pulmonary venous congestion or pulmonary edema, with or without pleural effusion (11,46). Echocardiography shows variable degrees of LV dilatation, with
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moderate to severe depression of systolic function. Right

ventricular and biatrial dilatation as well as moderate to
severe mitral and tricuspid regurgitation are commonly seen,
with increased pulmonary pressures and mild pulmonary
regurgitation (5,8,11,17,46). Cardiac magnetic resonance
imaging (MRI) has been used in a limited number of
patients for the assessment of cardiac function and the
detection of mural thrombi or myocardial fibrosis (25,48 51).
Although MRI is probably safe during pregnancy (52,53),
intravenous gadolinium crosses the placenta, and the 2007
American College of Radiology document on safe MRI
practices recommends that it be avoided during pregnancy
and used only if absolutely essential (53). Although only
0.04% of the maternal dose of gadolinium passes into the
breast milk, it has been recommended to discontinue
breast-feeding for 24 h after intravenous administration
(53). In a group of 8 women with PPCM who were studied
with MRI, none exhibited abnormal myocardial late enhancement, and no difference was found in the MRI
patterns in 4 patients who recovered normal LV function
compared with those who did not (47).
Brain natiuretic peptide. Levels of BNP do not change
significantly during normal pregnancy or in the postpartum
period (36,40,54,55). An early measurement of BNP could
help in diagnosing PPCM, in which levels of BNP have
been shown to be markedly elevated (56).
Prognosis
Recovery of LV function. Recent publications combining
close to 300 U.S. patients have reported recovery of LV
function (LVEF to !50%) at 6 months in 45% to 78% of
patients, with a mean of 54% (26,27,30). Data from my
group (8) in 40 patients with longitudinal follow-up of 30 $
29 months showed that improvement usually occurred
within the first 6 months after the diagnosis (Fig. 3). Amos

Figure 3

Pattern of Recovery of Left Ventricular Function

in 40 Patients With PPCM

There was a significant increase in left ventricular ejection fraction (LVEF)

between time of diagnosis and 6 months (*p ! 0.0001), with only a small and
statistically insignificant further increase after 6 months. F/U # follow-up.
Adapted from Elkayam et al. (8).

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Figure 4

Trend in LVEF According to Final Outcome

EF # ejection fraction; LV # left ventricular.

Adapted, with permission, from Amos et al. (26).

et al. (26) demonstrated LV recovery in 45% of 55 women,

mostly occurring within the first 2 months, with continued
improvement over 1 year (Fig. 4). Most recently, a preliminary report from a Utah PPCM registry described LV
recovery in 62% of 58 patients, with an average time of 9
months (57). In contrast, Modi et al. (58) reported recovery
of LV function in only 35% of 40 indigent patients, with a
median time to recovery of 54 months. Because 87.5% of
the patients in this group were African Americans, the
investigators suggested that race and ethnicity might be
responsible for poorer outcomes. This assumption is supported by a recent analysis by my group demonstrating a
significantly lower rate of LV recovery in 52 African
American patients compared with 104 Caucasians (40% vs.
61%, p # 0.02; Elkayam et al., unpublished data, 2011). In
summary, the majority of available information in the U.S.
demonstrates normalization of LV function in "50% of
women with PPCM, mostly occurring within 2 to 6 months
after diagnosis; later recovery, however, is possible and
occurs in some patients. The rate of LV recovery seems to
be significantly lower in African American patients compared with whites. More information will be needed to
determine potential genetic and environmental causes for
this difference.
Predictors of LV recovery. A number of factors have been
shown to be associated with a higher likelihood of recovery,
including LV diastolic dimension (!5.5 to 6.0 cm) and
systolic function (LVEF "30% to 35% and fractional
shortening !20%) at the time of diagnosis (5,11,17,27),
lack of troponin elevation (59), a lower level of plasma BNP
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663

(56), absence of LV thrombus (26), breast-feeding (27),

diagnosis after the delivery (27), and non-African American
ethnicity (30). Recent multivariate analysis by Goland et al.
in 187 patients with PPCM (38) found LVEF "30% and
LV end-diastolic dimension !55 mm to be significantly
related to LV recovery, suggesting a relationship between
the degree of initial myocardial insult and recovery. These
parameters, however, have limited sensitivity in predicting
recovery in individual patients, as evidenced by full recovery
found in 37% of patients with baseline LVEFs !20% and in
51% of those with LVEFs !30%. Baseline parameters of
LV function should therefore not be used as an indication
for the premature use of devices or heart transplantation.
Is LV recovery related to medical therapy? The relationship between standard HF therapy and recovery is not
completely clear. The rates of recovery in early studies,
before the era of contemporary HF therapy (3,60), were
similar to rates reported in recent studies, and early recovery
often occurred before up-titration of drugs to optimal
therapeutic doses (26). In addition, similar to nonischemic
DCM (61), preliminary reports have shown no significant
difference in the use of beta-blockers in recovered compared
with nonrecovered patients with PPCM (62,63).
Complications
PPCM can be associated with important and lasting complications, including severe HF, cardiogenic shock, cardiopulmonary arrest secondary to HF or arrhythmias, thromboembolic complications, and death. Goland et al. (30)
recently described major adverse events in 25% of 182
patients with PPCM, with 80% of these occurring during
the first 6 months after the diagnosis and one-third of the
survivors having residual brain damage secondary to cardiopulmonary arrest or cerebral vascular events. Predictors of
complications were LVEF !25%, non-Caucasian ethnic
background, and delay of diagnosis.
Thromboembolism. PPCM is associated with increased
incidence of thromboembolism compared with DCM of
other etiologies, and LV thrombus has been found on initial
echocardiography in 10% to 17% of patients (26,64). Several
reports have described severe thromboembolic events, including embolization to the coronary, pulmonary, peripheral, and cerebral arteries (11,26,30,64 70). Increased incidence of thromboembolism is probably due to multiple
reasons, including the hypercoagulable state of pregnancy
(71), cardiac dilatation and dysfunction, endothelial injury,
venous stasis, and prolonged bed rest after commonly
performed instrumental deliveries and cesarean section in
patients diagnosed during pregnancy.
Mortality and heart transplantation. Reported mortality
rates associated with PPCM in the United States have
varied widely between 0% and 19%, while rates of cardiac
transplantation have ranged from 6% to 11% (11,1719,26,
30,58,72) (Table 2). Substantial differences in the reported

NA

NA

LVEF !25%, delay of

diagnosis "1 week

NA

NA

NA

NA

LVEF
0%
Retrospective, single center
Modi et al. (2009) (58)

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*Studies with mortality reports.

LV # left ventricular; LVEDD # left ventricular end-diastolic diameter; LVEF # left ventricular ejection fraction; other abbreviations as in Table 1.

15.9%

Retrospective, nationwide
Goland et al. (2009) (30)

54 months

Retrospective, Southern California

Kaiser Permanente
Brar et al. (2007) (19)

40

35%

6%
7%
49% at 6 months

National Hospital Discharge Survey

Mielniczuk (2006) (18)

19 months

60

Retrospective, single center

Amos et al. (2006) (26)

4.7 yrs

NA
16,296

Retrospective, single center

Chapa et al. (2005) (17)

182

NA
3.2%
NA

NA

NA
LVEDD !5.6 cm, nonAfrican
American race, no LV
thrombus

NA

In hospital total
2.5%

NA
LVEDD !6.0 cm, LVEF "20%

10%

6.5%
9.6%

0%
45%
55

41% at 3 months
NA

43 $ 43 months

32

NA

LV stroke volume index

NA
7%

NA
18%

7%
NA

NA
NA

Retrospective, single center

42

Prospective, single center

28

Figure 5

Timing of Mortality After Diagnosis

in Patients With PPCM

PPCM # peripartum cardiomyopathy. Data derived from Whitehead et al. (74).

Felker et al. (2000) (72)

8.6 yrs

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Witlin et al. (1997) (11)

Mortality
Recovery of LV Function
(LVEF >50%)
Mean Follow-Up
Period
n
Study Design
First Author (Year) (Ref. #)

Outcomes
Patients With
PPCM in
thePPCM
UnitedinStates*
Table 2 ofOutcomes
of Patients
With
the United States*

11%

Predictors of Death
and Transplantation
Predictors of LV Recovery

Elkayam
Peripartum Cardiomyopathy

Heart
Transplantation

664

incidence of these complications are probably due to variations in patient populations, diagnostic criteria, and treatments, as well as reporting bias. Felker et al. (72), in a
retrospective review of cardiomyopathies of various etiologies, reported markedly lower mortality in PPCM compared
with other forms of myocardial disease. At the same time,
however, PPCM has become an increasingly recognized
cause of pregnancy-related maternal mortality (73,74).
Timing and mode of death. Goland et al. (30) provided
detailed information regarding mortality in 13 patients,
most of whom died either suddenly (38%) or of progressive
HF (45%) between the day of delivery and 8 years postpartum. Whitehead et al. (74) reported on 17 cases of death
due to PPCM between 1991 and 1997. Mortality increased
with maternal age, in women with live birth order of !4,
and in black women, who were 6.4 times more likely to die
compared with whites. Eighteen percent of deaths occurred
within 1 week and 87% within 6 months of diagnosis (Fig. 5),
and mortality was due either to progressive HF or to sudden
cardiac death. Mortality was found by Goland et al. (30) to
be higher in women with baseline LVEFs "25% as well as
in women in whom the diagnosis of PPCM was delayed.
Outcome of Subsequent Pregnancy
Habli et al. (75) reported on 21 patients with a mean
LVEF "40% who had subsequent pregnancy, with worsening of HF in 29% and in none of 8 other patients who
terminated their subsequent pregnancies. Two patients with
initial LVEFs !25% (follow-up LVEFs not provided) who
had subsequent pregnancy and 5 of 8 women who terminated their pregnancies demonstrated clinical deterioration
requiring referral for cardiac transplantation.
Modi et al. (58) described 44 indigent patients with
PPCM and reported clinical worsening in 28% of those who
had subsequent pregnancies (number of patients not provided) but no maternal death. Elkayam et al. (76) reported
on the outcomes of 60 subsequent pregnancies in 44
women, 28 after recovery of LV function (group 1) and 16
with LV dysfunction (group 2). Subsequent pregnancies
were associated with reductions in mean LVEF in the total

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Figure 6

Incidence of Maternal Complications Associated

With Subsequent Pregnancy in Women With PPCM

Red bars represent women with recovered left ventricular (LV) function before
subsequent pregnancy; green bars represent women with persistent LV dysfunction. HF # heart failure; LVEF # left ventricular ejection fraction. Data
derived from Elkayam et al. (76).

cohort from 49 $ 12% to 42 $ 13% (p ! 0.001) and from

56 $ 7% and 36 $ 9% to 49 $ 10% and 32 $ 11% in
groups 1 and 2, respectively. Reductions "20% in LVEFs
were seen in 21% of group 1 and 44% of group 2, and there
was 0% mortality in group 1 women and 19% mortality in
group 2 (Fig. 6). When pregnancies that ended by abortion
were excluded, the risk for unfavorable maternal and fetal
outcomes was even higher, especially in women with persistent LV dysfunction. One woman in group 1 whose LV
function did not change during her first subsequent pregnancy had a significant decrease from 55% to 40% during
her second subsequent pregnancy. A recent publication by
Fett et al. (77) reported on 61 post-PPCM pregnancies,
with data mostly obtained from an Internet support group
in the United States, and described relapses of PPCM in
29% of the entire group, with a significantly higher rate
(46%) in women with LVEFs !55%. Nine of the patients
with recovered LV function underwent stress echocardiography that demonstrated normal contractile reserve, and
these patients did not experience relapse. Although it has
been suggested that normal contractile reserve in patients
with PPCM with recovered LV function may ensure good
outcomes during subsequent pregnancies (78), this concept
has not been tested and should therefore not be used to
predict the risk of subsequent pregnancies in women with
histories of PPCM.
In summary, subsequent pregnancies in women with
histories of PPCM in the U.S. are associated with a risk for
recurrent and persistent cardiac dysfunction and even mortality. The risk is substantially higher in patients with
persistent LV dysfunction before subsequent pregnancy. At
the same time, however, recovery of LV systolic function
does not guarantee an uncomplicated subsequent pregnancy.
Although mortality in such patients is rare, marked decreases in LV function have been reported in approximately
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665

20% of patients, with persisting dysfunction after pregnancy

in about one-half (76,79). Patients should be advised on the
risk of subsequent pregnancy and on the safest and most
effective contraceptive method by both their cardiologists
and obstetricians (80). Patients who decide to become
pregnant again should undergo baseline echocardiography
before or early in pregnancy, as well as determination of
serum BNP level. In patients on HF medications, baseline
LVEF prior to subsequent pregnancy should be determined 3
months after the discontinuation of angiotensin-converting
enzyme (ACE) inhibitors or angiotensin receptor blockers
(ARBs), which cannot be used during pregnancy. In patients
with LV dysfunction, ACE inhibitors or ARBs should be
substituted with isosorbide dinitrate-hydralazine combination.
Because no information is available regarding the safety of
carvedilol during pregnancy, the use of metoprolol may be
considered instead. Patients should be followed with repeat
echocardiography during the early second and third trimesters,
during the last gestational month, and early after delivery and
at any time if new symptoms of HF develop. Repeat determination of BNP levels should be helpful in differentiating
between HF-like symptoms associated with normal pregnancy
and hemodynamic deterioration (55,56). Early termination of
an unintentional pregnancy should be considered to prevent
worsening of LV function and potential maternal mortality,
especially in patients with persistent LV dysfunction.
Breast-Feeding
Breast milk is associated with health, nutritional, immunologic, physical, cognitive, and emotional developmental
benefits to the infant (81). The American Academy of
Pediatrics recommends human milk for all infants in whom
breast-feeding is not specifically contraindicated. As shown
in the following paragraphs, most drugs used for the
management of HF are compatible with breast-feeding; in
addition, a recent study reported breast-feeding in 67% of
55 patients with PPCM without adverse effects to the
mothers (27). Moreover, the rate of recovery of LV function
was significantly higher in lactating women. For all these
reasons, clinically stable women with PPCM should not be
discouraged from breast-feeding their infants.
Treatment
Drugs. Standard drug therapy for acute and chronic HF
includes the potential use of diuretic agents, intravenous and
oral vasodilators, intravenous inotropes, ACE inhibitors or
ARBs, beta-blockers, spironolactone, and digoxin (82). In
general, the treatment of HF in patients with PPCM should
follow recent guideline recommendations, except during
pregnancy and lactation, when drug therapy may need to be
altered because of potential detrimental effects on the fetus
or the lactating infant.
Diuretic agents. Loop diuretic agents are indicated for the
correction of volume overload and excessive and rapid
reductions in intravascular volume, but they should be used

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with caution during pregnancy to prevent hypotension and

decreased uterine perfusion. Furosemide (risk category C) is
excreted into breast milk, but no reports of adverse effects in
nursing infants have been found, and it is listed as probably
compatible with breast-feeding (83).
Intravenous vasoactive medications. Vasodilators are recommended in patients with decompensated HF for hemodynamic and symptomatic improvement (82). Among the
available intravenous vasodilators, nitroglycerin (risk category B) is preferred during pregnancy because nitroprusside
(risk category C) may be associated with thiocyanate toxicity, and no information is available regarding the safety of
nesiritide. There are only limited data regarding the use of
inotropic agents, including dopamine (risk category C),
dobutamine (risk category B), and milrinone (risk category C),
and these drugs should therefore be used as recommended
(82) only in patients with advanced HF, low blood pressure,
high filling pressure, and diminished peripheral perfusion
due to low-output syndrome and in patients who are
unresponsive or intolerant to intravenous vasodilators.
ACE inhibitors and ARBs. The use of these drugs (both
risk category C) is contraindicated during pregnancy because of toxic effects, mostly on the developing fetal kidneys.
Other potential side effects include oligohydramnios, intrauterine growth retardation, prematurity, bony malformation, limb contractures, patent ductus arteriosus, pulmonary
hypoplasia, respiratory distress syndrome, hypotension, anuria, and neonatal death (84). During pregnancy, the
combination of organic nitrates and hydralazine (both risk
category C) should be used as a substitute for ACE
inhibitors or ARBs.
Beta-blockers. There is lack of human pregnancy experience with the use of all 3 beta-blockers approved in the U.S.
for the treatment of HF (carvedilol, bisoprolol, and metoprolol succinate, all risk category C), and their effects on the
fetus are therefore unknown. Metoprolol tartrate has been
more commonly used in pregnancy for the management of
hypertension, arrhythmias, mitral stenosis, and myocardial
ischemia (85). In addition, the use of beta-1-selective
beta-blockers is preferred during pregnancy, because nonselective beta-blockade could facilitate uterine activity (85).
Carvedilol and bisoprolol are excreted into the breast milk
of lactating rats; no information is available on their use in
lactating women (83). Metoprolol is secreted into breast
milk, with a milk/plasma concentration ratio of 2 to 4, but
the amount of drug estimated to be ingested by the infant is
negligible, and the drug has been classified as compatible
with breast-feeding (86).
Spironolactone (risk category C). There is no report of a
teratogenic effect in humans, but there is concern regarding
the antiandrogenic effect of the drug in humans and
feminization reported in male rat fetuses (83). The rate of
excretion of spironolactone in breast milk is unknown. Its
principal metabolite, canrenone, is excreted into breast milk
in a small amount (approximately 0.2% of the mothers daily
dose), which seems to be insignificant (83). The American
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Academy of Pediatrics (86) classifies spironolactone as

compatible with breast-feeding.
Digoxin (risk category C). This drug has been used in
pregnancy for both maternal and fetal indications without
causing fetal harm. It is excreted into breast milk, but no
adverse effects have been reported, and the drug is compatible with breast-feeding (86).
Anticoagulation. Because of the high incidence of thromboembolism associated with PPCM (26,64 70), anticoagulation from the time of the diagnosis until LV function
recovers (LVEF "35%) is advisable. Anticoagulation seems
particularly important during pregnancy and the first 6 to 8
weeks postpartum because of persistent hypercoagulable
state (71). In contrast to warfarin (risk factor D), both
unfractionated heparin and low-molecular-weight heparin
(risk factor C) do not cross the placenta and are safe during
pregnancy (83). Because of a high prevalence of premature
labor and a possible need for urgent delivery because of
maternal or fetal instability, the use of unfractionated
heparin is preferred during pregnancy because of its shorter
half-life and reversible effect. Neither warfarin nor heparin
is secreted into breast milk, and both drugs are therefore
compatible with breast-feeding (83).
Experimental drug therapy. IMMUNE GLOBULIN. Bozkurt
et al. (87) added intravenous immune globulin to conventional HF therapy in 6 women with PPCM and reported a
significantly greater improvement in LVEFs compared with
11 historical control patients who received conventional
therapy alone. Although the results seemed encouraging, a
very small number of patients and the lack of a blindly
randomized, well-matched control group limited the study.
Sliwa et al. (88) investigated the effect of
pentoxifylline, a xanthine agent known to inhibit the production of tumor necrosis factor and prevent apoptosis, in
30 South African patients with PPCM. These patients
received the drug at a dose of 400 mg 3 times daily for 6
months in addition to standard HF therapy and were
compared with 29 patients with PPCM who received
standard therapy alone. The results of the study demonstrated a significant improvement in a combined endpoint
including death, failure to improve LVEF by 10 absolute
points, or persistence of New York Heart Association
functional class III to IV at the last follow-up (52% vs. 27%,
p # 0.03). Despite these positive results, no further studies
have been conducted, and this therapy has not been widely
used. In addition, the safety of pentoxifylline during pregnancy and lactation has not been established; it is excreted
into human milk and has been defined as probably compatible with breast-feeding (83).

PENTOXIFYLLINE.

On the basis of the concept of enhanced

oxidative stressmediated cleavage of the nursing hormone
prolactin into an antiangiogenic and proapoptotic 16-kDa
form that may be responsible for the development of PPCM
(24), Sliwa et al. (25) attempted the use of bromocriptine, a
prolactin blocker, in the treatment of 10 African patients
BROMOCRIPTINE.

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with PPCM. The drug was given after diagnosis at a dose of

2.5 mg twice daily for 2 weeks, followed by 2.5 mg/day for
6 weeks, in addition to standard HF therapy and resulted in
a significantly larger rate of LV recovery at 6 months
compared with a control group of 10 women with PPCM
treated with standard therapy alone (31% vs. 9%, p #
0.012). In addition, there was a lower rate of mortality in the
treatment group (1 vs. 4 patients) and a lower rate of a
combined endpoint of death, New York Heart Association
functional class III or IV, or LVEF !35% at 6 months.
Although the results are intriguing, the study suffered from
important limitations, including a very small number of
patients, excessive mortality and a lower recovery rate in the
control group compared with rates reported in the United
States and even previously by the same investigators in
South Africa (89). In addition, the use of bromocriptine is
associated with suppression of breast milk production and
potential complications to the mother (90), and its approval
for the prevention of lactation was withdrawn by the U.S.
Food and Drug Administration for safety concerns (91). For
all these reasons, further studies aimed at clearly establishing
the efficacy and safety of bromocriptine are needed before it
can be recommended for the treatment of PPCM.
Should drug therapy be stopped in women with PPCM
after recovery? This is a commonly asked question by
patients with PPCM who are eager to stop taking medications after recovery. Because only limited long-term, prospective data are available, no recommendations can be
made. Amos et al. (26) reported a lack of deterioration of
LV function during an average follow-up period of 29
months in 15 patients with full recovery who stopped taking
ACE inhibitors, beta-blockers (n # 11), or both (n # 5).
When discontinuation of drug therapy is desired, it should
be done gradually, with repeated echocardiographic evaluations of cardiac function. Because the spontaneous deterioration of LV function was reported by my group in 3
patients after either complete recovery (n # 2) or partial
(LVEF 45%) recovery (n # 1) 3 to 60 months after
diagnosis (30), annual echocardiographic examinations are
advisable in all patients with histories of PPCM.
Implantable cardioverter-defibrillators. Because early
sudden death is likely in high-risk patients (8,30,74) and
arrhythmias are common in the postpartum period (92), it is
often tempting to consider the early implantation of implantable cardioverter-defibrillators (ICDs) in such cases.
Recent guidelines, however, recommend consideration of
ICDs only in patients with persistent LV dysfunction
despite optimal drug therapy. These recommendations are
especially applicable to patients with PPCM, in whom the
improvement of LV function is likely, and failure to
improve cannot be predicted in individual patients on the
basis of initial LV function (38). For these reasons, and
because recovery of LV function occurs in most patients
within 2 to 6 months after the diagnosis (8,26), it may be
advisable to consider the temporary use of wearable external
defibrillators (93) or entirely subcutaneous ICDs (94) in
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667

high-risk patients as a bridge to recovery or to ICD

implantation in patients with persistent LV dysfunction
despite adequate trials of optimal medical therapy.
Cardiac assist devices. In patients demonstrating rapid
deterioration not responding to medical therapy including
vasoactive medications, intra-aortic balloon pumps, extracorporeal membrane oxygenation, and LV assist devices
have been used successfully and should be considered
(95101). Because the rate of recovery in patients with
PPCM is higher than in those with other forms of DCM,
an attempt should be made to use such devices as a bridge
to recovery before referral for cardiac transplantation
(98,100,101).
Cardiac transplantation. This procedure has been performed successfully in patients with PPCM (102104). A
recent multi-institutional study by Rasmusson et al. (105)
using data from a cardiac transplantation research database
described 69 women who underwent heart transplantation
for PPCM in 29 institutions in the United States. The risk
for rejection was somewhat higher in patients with PPCM
compared with men or women of similar age who did not
have history of pregnancies and similar to that of women
with histories of pregnancy. The cumulative risk for infections was lowest in patients with PPCM, while freedom
from allograft vasculopathy and mortality was similar or
higher compared with the other groups. These data indicate, therefore, that the overall outcome of heart transplantation in women with PPCM is comparable with that of
transplantation for other reasons.
Labor and Delivery
The timing and mode of delivery in a patient diagnosed
during pregnancy should be determined by the clinical
status of the mother and the fetus. Termination of pregnancy or early delivery may result in improvement of both
symptoms and cardiac function and should be considered in
patients with deteriorating symptoms or cardiac function.
Continuation of pregnancy can be allowed, with frequent
monitoring, to allow fetal maturity in patients who can be
stabilized on medical therapy. The mode of delivery in a
stable patient with PPCM should be determined jointly by
the obstetrician and the cardiologist. Vaginal delivery prevents potential risks associated with anesthesia and surgical
delivery that include hemodynamic fluctuations, larger
blood loss, pain, infections, respiratory and thromboembolic
complications, damage to pelvic organs, and potential unfavorable effects on future reproductive health (106). At the
same time, an elective cesarean section is more rapid and
allows better planning of the time of delivery as well as the
presence of the most experienced medical team during the
delivery. Hemodynamic monitoring for labor and delivery is
desirable in a patient with PPCM who is diagnosed during
pregnancy and allows optimization of hemodynamic status
before delivery as well as monitoring of changes related to
fluid intake and blood loss during delivery and early hemo-

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Peripartum Cardiomyopathy

dynamic changes as a result of increased venous return and

peripheral vascular resistance after delivery. In case of
vaginal delivery, assisted second stage is recommended to
reduce maternal efforts and shorten labor. Maternal vital
signs as well as oxygen saturation, electrocardiogram, and
fetal heart rate should be continuously monitored.
Ongoing Research
The IPAC (Investigation in Pregnancy Associated Cardiomyopathy) study is currently under way in the United States
(107). This is a National Institutes of Healthsponsored
multicenter study and the first prospective trial in the
United States aiming to enroll 100 patients with newly
diagnosed PPCM and evaluate systemic immune activation
as the etiology of this disease and the relationship between
autoimmunity and LV dysfunction and recovery and in
addition investigate the frequency of myocardial injury or
inflammation on cardiac MRI and the ability of tissue
characteristics to predict subsequent recovery of LVEF.
Reprint requests and correspondence: Dr. Uri Elkayam, LAC/
USC Medical Center, 2020 Zonal Avenue, Los Angeles, California
90033. E-mail: elkayam@usc.edu.

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Key Words: cardiomyopathy y heart failure y pregnancy.