CHAPTE R 10
Peripartum Cardiomyopathy
Sorel Goland1,2 and Uri Elkayam3,4
1 The Heart Institute, Kaplan Medical Center, Rehovot, Israel
2 Hebrew University and Hadassah Medical School, Jerusalem, Israel
3 Department of Medicine, Division of Cardiovascular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
4 Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
Peripartum cardiomyopathy (PPCM) is a pregnancy-
associated myocardial disease, reported to occur in different
parts of the world [1].
Historical perspective and definition
Heart failure (HF) associated with pregnancy was first
described as a definitive form of a cardiomyopathy in
1937 [2]. In 1971, Demakis et al. [3] published data on
27 patients with pregnancy-associated cardiomyopathy
(PACM) 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 (i) the development of HF in the last
month of pregnancy or within five months of delivery; (ii)
the absence of a determinable etiology for HF; and (iii) the
absence of demonstrable heart disease before the last month
of pregnancy. A workshop organized by the National Heart,
Lung, and Blood Institute and the Office of Rare Diseases
Research [4] added in 2000 an additional criterion proposed
by Hibbard et al. [5] of left ventricular (LV) systolic dysfunc-
tion demonstrated by echocardiography with left ventricular
ejection fraction (LVEF) <45%, fractional shortening <30%,
or both. Later information indicated that although the
majority of patients with PPCM are diagnosed in the peri-
partum period, early presentation during pregnancy is not
uncommon [6–8]. A study of 23 cases with PACM diagnosed
between the 17th and 36th weeks of gestation (8 before
28 weeks, 7 between 29 and 32 weeks, and 8 between 33
and 36 weeks) found them to be indistinguishable from 100
women meeting classic criteria for PPCM [7] (Figure 10.1).
These findings, supported by numerous other reports [8–11],
clearly indicated that PPCM and PACM represent a contin-
uum of the same disease [6–8]. 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
Cardiac Problems in Pregnancy, Fourth Edition. Edited by Uri Elkayam.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
128
to LV systolic dysfunction toward the end of pregnancy or
in the months following delivery, where no other cause of
heart failure is found” [12]. PPCM is therefore a diagnosis
of exclusion, and other causes of cardiac dysfunction should
be ruled out. At the same time, however, transient and unex-
pected depression of LV function typical to PPCM has been
described in women with other forms of heart disease [13].
These findings suggest that the diagnosis of PPCM should
not be excluded in patients with heart disease, which is oth-
erwise not likely to cause LV dysfunction during or after
pregnancy. In addition, overlap of PPCM and other forms of
reversible LV dysfunction such as concomitant myocarditis,
stress-induced cardiomyopathy, and LV noncompaction is
possible. Clinical course as well as imaging criteria may help
to distinguish PPCM from other acute cardiomyopathies
[14,15]. The vast majority of asymptomatic young women do
not have an echocardiogram prior to their presentation with
HF during pregnancy or the postpartum period. The absence
of preexisting heart disease is therefore assumed rather than
proven in most cases. This uncertainty may lead to differ-
ences in the results, especially of LV recovery, between stud-
ies, which may also include women with undiagnosed pre-
existing dilated cardiomyopathy (DCM) with exacerbation
during pregnancy.
Incidence and epidemiology
The incidence of PPCM varies widely between ∼1 : 100 and
1 : 300 in Africa and Haiti, to an average of 1 : 3000 in the
USA and 1 : 20 000 live births in Japan [9,16–19]. A num-
ber of studies have provided information regarding the inci-
dence of PPCM in the United States, ranging from ∼1 in
1000 to 1 in 4000 live births [20–25]. Differences in incidence
among published reports are probably not only due to vari-
ations in patient populations but also study design, sample
size, and degree of underreporting [23,26]. Mielniczuk et al.
[22] reported a trend toward an increase in incidence over
time from 1 in 4350 deliveries in 1990–1993 to 1 in 2229

100
75
Number of patients
50
25
0
≤28 29–32 33–36 37–40 1 2 3 4
Weeks Months
Figure 10.1 Time of diagnosis of cardiomyopathy in 123 patients.
Black bars represent 23 patients with early PPCM; white bars,
100 patients with traditional PPCM. Source: Adapted with
permission from Elkayam et al. 2005 [7].
in 2000–2002. Recently, Kolte et al. [25] reported a rate of
PPCM of 1 in 968 births in a study evaluating US national
databases of 64 million hospital discharge records from 1000
US hospitals in 47 states. Increased incidence of PPCM might
be related to a rise in maternal age, a substantial increase in
the rate of multifetal pregnancies due to contemporary repro-
ductive techniques, and possibly to increased recognition of
the disease. A population study in Southern California [22]
found the greatest incidence of PPCM in African-Americans
(AAs) (1 in 1421) and the lowest in Hispanics (1 in 9861). The
incidence in Caucasians was 1 in 4075, and in Asians, it was 1
in 2675. Higher incidence in AA women has been confirmed
by Gentry et al. [27], who conducted a case-control study in
Augusta, Georgia, and Memphis Tennessee and found almost
a 16-fold higher incidence of PPCM in AAs compared with
non-AA women. A recent study by Harper et al. [28] sup-
ported these findings and reported a four times higher inci-
dence of PPCM in black women in North Carolina compared
to white population. Multiple studies from the United States
reported a more severe disease and worse outcomes in AA
women with PPCM, which could be related to racial differ-
ences due to genetic predisposition and environmental dif-
ferences [23,27,29].
Etiology
The etiology of PPCM remains unclear. A number of mech-
anisms have been proposed but lack support based on
published data. These mechanisms include a low selenium
level, viral infection, stress-activated cytokines, inflamma-
tion, autoimmune reactions, and hemodynamic changes of
pregnancy [26,30–32]. Although viral genomes have been
found in endomyocardial biopsy (EMB) in PPCM patients,
similar data have been reported in matched controls; there-
fore, the role of myocarditis in PPCM remains uncertain, and
there is no indication to perform endomyocardial biopsy as
CHAPTER 10 Peripartum Cardiomyopathy 129
Relative levels Prl* and sFlt1
Relative increase in CO
Incidence PPCM
≤28 28–32 33–36 37–40 1–4 5–8 9–12 13–16 >16
Trimesters Weeks gestation Weeks postpartum
Delivery
5
Figure 10.2 Comparison of timing during and after pregnancy of
hemodynamic changes, exemplified as cardiac output (CO; in black),
elevations in prolactin, and soluble Fms-like tyrosine kinase 1 (sFlt1)
hormones (red), and incidence of peripartum cardiomyopathy
(PPCM; blue bars). *Prl levels stay elevated in women who nurse.
Source: Adapted with permission from Arany and Elkayam 2016
[26].
a part of the diagnostic workup of PPCM [33–35]. Recent
use of MRI in patients with PPCM has resulted in conflicting
information. A pattern of transient myocardial inflammation
has been described in the acute stage of PPCM in a num-
ber of small retrospective studies [36,37]. In contrast, Schel-
bert et al. [38] examined 40 of the patients who participated
in the investigation of pregnancy-associated cardiomyopathy
(IPAC) study and described late gadolinium enhancement
(LGE) in only two women at baseline and three at six months
and a pattern suggestive of myocarditis in only one case.
Low selenium blood levels have been described as a causative
factor in women with PPCM; however, its prevalence was
limited to unique geographical areas such as Nigeria [39].
Fetal microchimeric cells have been proposed as a trigger
for autoimmune reaction shortly after delivery [4]; however,
Kara et al. [40] recently reported on the beneficial role of
fetal cell traffic to the injured maternal myocardium leading
to its regeneration. Finally, abnormal response to hemody-
namic stress has been proposed as an etiologic contributor to
PPCM similar to HF exacerbation, which occurs in women
with preexisting structural disease mostly in the second and
third trimesters when maximal hemodynamic changes occur
(Chapter 1) [41]. However, since the vast majority of PPCM
patients present with symptoms in the peripartum period,
this proposed mechanism is unlikely (Figure 10.2).
Animal models of PPCM
Recent data from animal models of PACM have suggested
that PPCM could be a vascular disease triggered by the
hormonal changes associated with late-pregnancy [42].
Experimental support of this suggestion was introduced for
the first time by Hilfiker-Kleiner et al. in 2007 [43]. This
group developed a mouse model of PPCM in which the
STAT3 transcription factor was genetically deleted specifi-
cally in cardiomyocytes. Loss of STAT3 in murine hearts lead
to reduced expression of genes that protect the heart against
130 PART III Cardiac Disorders and Pregnancy
PRL
Bromocriptine
Endothelial
dysfunction,
apoptosis
Pro-angiogenics
sFLT1
Figure 10.3 Vasculohormonal hypothesis of the pathophysiology of peripartum cardiomyopathy (PPCM). Source: Adapted with permission
from Arany and Elkayam 2016 [26].
reactive oxygen species, most notably manganese super-
oxide dismutase (MnSOD), which neutralizes superoxides
generated by the robust mitochondrial activity in beating
cardiomyocytes. The consequent rise in reactive oxygen
species leads to the secretion, via a still unclear mechanism,
of cathepsin D. This extracellular peptidase then cleaves
prolactin, a hormone specific to late pregnancy, into a 16-
kDa fragment that promotes apoptosis in endothelial cells.
As a result, STAT3 cardiac knockout mice reveal significant
vascular dropout during late pregnancy and consequent
pregnancy-induced DCM (Figure 10.3). Treatment of STAT3
cardiac knockout mice with bromocriptine that blocks pro-
lactin secretion from the pituitary completely, reversed the
observed cardiomyopathy. Recent research showed that 16-
kDa prolactin fragment induced endothelial cells to package
miR-146a into exosomes, small lipid-encapsulated particles,
which are then secreted and taken up by cardiomyocytes
[44,45]. The miR-146a internalized into cardiomyocytes
then suppressed the neuregulin/ErbB pathway, thereby
promoted cardiomyocyte apoptosis. Moreover, circulating
levels of miR-146a were reported to be dramatically elevated
in women with PPCM and decreased significantly with
bromocriptine treatment, demonstrating that prolactin
drove miR-146a secretion. Based on this observation, miR-
146a may be useful as a biomarker of PPCM. In addition,
miR-146a may become a viable therapeutic target because
CathD
16Kd
ROS
MnSOD
miRNA146a
Anti-mir ERBB4
STAT3,
Cardiomyocyte PGC-1α
ischemia,
metabolic PGC-1α
insufficiency,
apoptosis
VEGFA,
VEGFB
microRNAs can be efficiently and specifically inhibited
clinically. Indeed, treatment of the STAT3 model of PPCM
with locked nucleic acid (LNA)–modified antisense oligonu-
cleotides to silence miR-146a, partially rescued cardiac
capillary density and contractile function. Moreover, LNA–
miR-146a did not inhibit lactation because the linolenic acid
acts downstream of the 16-kDa prolactin action. Thus, unlike
with bromocriptine, therapy with LNA-miR-146a, if avail-
able, would allow continued nursing of the newborn [26].
A similar vasculohormonal paradigm was recently sup-
ported in a different mouse model of PPCM with a cardiac-
specific deletion of proliferator-activated receptor-gamma
coactivator-1α (PGC-1α), a powerful transcriptional regu-
lator [46]. Similar to STAT3, PGC-1α drives the expression
of MnSOD and vascular endothelial growth factor (VEGF)
[47]. Cardiac deletion of PGC-1α thus promotes vasculotox-
icity by two pathways: the first is the activation of an antivas-
cular 16-kDa prolactin-mediated pathway (as in the STAT3
model), and the second is a loss of a proangiogenic VEGF–
mediated pathway (Figure 10.3). Accordingly, bromocriptine
and VEGF when used alone had only a partial effect, while
their combination resulted in complete LV recovery in ani-
mals with the PACM.
The observations above raised the question of what hor-
mone during pregnancy is inhibiting the VEGF pathway and
triggering DCM in the PGC-1 model. During late gestation

in placental mammals, the placenta secretes into the maternal
circulation numerous hormones, including a soluble variant
of the VEGF receptor 1, soluble Fms-like tyrosine kinase 1
(sFlt1). Most free VEGF in the maternal circulation is neu-
tralized by sFlt1 during late gestation [48]. The heart and
other organs defend themselves from this insult in part by
local secretion of VEGF, but this is diminished and insuf-
ficient in the PGC-1α model of DCM. Administering sFlt1
to nulliparous PGC-1α animals was sufficient to cause car-
diomyopathy, even in the absence of pregnancy, demonstrat-
ing that sFlt1 is a key component of the gravid state that trig-
gers pregnancy-associated cardiomyopathy in these animals.
Thus, sFlt1 and prolactin are both potentially vasculotoxic
hormones of late gestation that can trigger PPCM in sensi-
tized hosts.
The placental secretion of sFlt1 is markedly elevated in
preeclampsia and twin gestation [48,49]. The maternal heart
is thus exposed to significantly higher levels of sFlt1 in these
conditions, possibly explaining the strong epidemiological
link between preeclampsia, twin gestations, and PPCM. In
the IPAC study, higher sFlt1 levels correlated with more
severe symptoms and major adverse clinical events [50]. The
clinical application of sFlt1 removal is still under investi-
gation, but a single nonrandomized open pilot study using
extracorporeal removal of sFlt1 in preeclampsia and one
case report of plasma exchange in a patient with aggres-
sive PPCM on biventricular mechanical circulatory support
(MCS) showed promising results [51,52]. A recent study by
Goland et al. [53] described higher concentration of sFlt1
with concomitant decreased circulating endothelial progeni-
tor cell levels along with inappropriate attenuated VEGF lev-
els, which may imply an angiogenic imbalance that exists
even after recovery and may thus predispose to PPCM.
In summary, all these observations indicate that sFlt1,
secreted from the placenta in late gestation, provides a toxic
challenge to the heart and that, in the absence of appropri-
ate defense, can lead to the development of PPCM. Together
with the STAT3 model, the findings strongly support the con-
cept that PPCM is a vascular disease, triggered by the hor-
monal milieu of the peripartum (Figure 10.3). This notion
could explain the well-established epidemiological observa-
tions that PPCM is strongly associated with preeclampsia and
with multiple gestations, both of which are marked by high
secretion of sFlt1. In addition, the hormonal hypothesis if
correct, also presents diagnostic, prognostic, and future ther-
apeutic opportunities [26].
Associated conditions
Strong associations have been shown between PPCM and
older maternal age, pregnancy-associated hypertension, mul-
tiple pregnancies, AA background, and diabetes [54].
Age
Although the disease has been reported in women between
the ages of 16 and 44 years, the mean age of women with
CHAPTER 10 Peripartum Cardiomyopathy 131
PPCM in the United States has ranged from 27 to 33 years
[7,20–23], with >50% of patients reported to be >30 years of
age [7,24,25]. In the most contemporary study in the United
States (IPAC), the mean age of 100 patients with PPCM was
30 years [55], and in the first 411 patients from 43 different
countries included in the worldwide registry of PPCM, it was
31 years [1]. Other US studies, the first by Harper et al. [28]
reported a fourfold increase in incidence of PPCM in women
aged ≥35 years compared to those ≤30 years, and the sec-
ond by Kolte et al. [25] reported a 10-fold higher incidence
of PPCM in women older than 40 years compared to those
younger than 20 years.
Race
PPCM in the United States has been reported to affect
women of difference ethnic groups, including non-Hispanic
whites, AAs, Hispanics, and Asians. The incidence of the
disease is however, considerably higher among AA patients.
Gentry et al. [27] found a 16-fold higher incidence of PPCM
in black women compared to white women in a single-center
case-control study in Georgia. Harper et al. [28] reported a
fourfold higher incidence of PPCM in black women (1 : 1087
vs. 1 : 4266) and a higher five-year mortality (24% vs. 6%).
In addition, Goland et al. [29] compared 52 AA women
with PPCM to 104 white women and showed that black
patients were typically younger, had a higher prevalence of
hypertension, presented later, had a lower rate of recovery
of LVEF, and worse outcome. These findings were later
confirmed by other groups. (See also “Racial and geographic
differences in prognosis of PPCM.”)
Hypertension and preeclampsia
Hypertension, chronic, pregnancy-induced, or preeclampsia,
has been a strong associated condition to PPCM described
in 15–68% (mean 23%) of patients in the United States
[3,7,20–22,56,57], with a similar incidence reported in
women diagnosed antepartum and postpartum [7]. This
incidence is considerably higher than the 5–8% reported in
all pregnant patients [58]. A recent meta-analysis by Bello
et al. [59] of 22 studies, which included almost 1000 cases of
PPCM, described an overall prevalence of preeclampsia of
22%, and an even higher prevalence (37%) of any hyperten-
sive disorder. In addition, a recent study of hospital discharge
records in six states indicated that as many as 29% of all
cases of PPCM had preeclampsia and 47% had hypertension.
A nationwide study in Japan by Kamiya et al. [9] of 102
women with PPCM, reported on 41% with hypertension.
The presence of hypertension was independently associated
with shorter hospital stay and LV improvement in one study
in Japan. Similar findings were reported in the worldwide
registry with 30% incidence of hypertension and 23% of
preeclampsia [1]. In addition, a recent large population
study in California of clinical morbidities in women with
eclampsia have demonstrated a 12-fold increase in the risk of
developing PPCM compared to those without preeclampsia,
132 PART III Cardiac Disorders and Pregnancy
eclampsia, or preeclampsia [60]. In summary, all these stud-
ies indicate a clear association between preeclampsia and
PPCM, which may share a pathophysiological mechanism
described previously.
Symptoms of HF in patients with preeclampsia and PPCM
are often attributed to preeclampsia and hypertension in
patients with both conditions, resulting in a delay of PPCM
diagnosis and treatment. It should be noted that although
recent studies using speckle tracking, strain imaging have
described subclinical LV systolic dysfunction in women with
preeclampsia [61], this condition is not associated with a
marked decrease in LVEF seen in women with PPCM, and
the development of HF symptoms is due to exacerbation of
diastolic dysfunction by hypertension, not due to transient
systolic dysfunction [62–64]. Assessment of systolic LV
function in pregnant women with hypertension by a number
of investigators has shown it to be preserved [65–68]. A
recent report by Ntusi et al. [69] described 83 women with
pregnancy-associated HF cases diagnosed in a single referral
center in South Africa. Thirty of the patients had PPCM, and
53 had hypertension. Hypertension-associated HF typically
occurred before delivery, was associated with cardiac hyper-
trophy and preserved LVEF, and had a better prognosis.
For all these reasons, preeclampsia associated with marked
decrease in LV systolic function represents PPCM. All
patients with pregnancy-associated hypertension presenting
with HF should therefore undergo an echocardiographic
assessment of LV function [70]. Because brain natriuretic
peptide (BNP) levels are only mildly elevated [71–73] in
patients with preeclampsia, measurement of BNP levels can
also be useful for an early diagnosis of PPCM in patients
with preeclampsia who are suspected of having HF.
Multifetal pregnancies
Multigestational status has been reported in 7–14.5% of
patients with PPCM in the United States [3,21,56,57,70,74],
compared with only 3.3% in the overall population [75,76].
In the recent meta-analysis by Bello et al. [59], the average
rate of twin gestations in cases of PPCM across 16 studies
was 9% compared with the average estimated prevalence of
3% [73]. Cases of PPCM with triplet pregnancies have also
been reported [21]. These studies confirm a strong associ-
ation between multifetal pregnancies and the development
of PPCM.
Parity
Multiparity has been traditionally considered to be a risk
factor for PPCM [30], although most studies in the United
States have reported the development of PPCM in conjunc-
tion with the first or second pregnancy in >50% of patients
[7,21,56,57]. Recently published data from the worldwide
registry on PPCM by Sliwa et al. [1] showed that despite
marked differences in the sociodemographic parameters and
ethnic background of patients from around the world, the
baseline characteristics of subjects with PPCM were similar
including mean gravidity of 3.6 ± 1.9.
Diabetes mellitus
A large population-based study from Alberta, Canada
reported 194 PPCM cases (1/2418 birth events) in addition to
previously described associated conditions such as older age,
multiple gestations, and higher pregnancy-associated hyper-
tensive disorders (29.9% in PPCM and 5.9% in non-PPCM
groups; p < 0.01), identified for the first time preexisting DM
(3.6% in PPCM and 0.9% in non-PPCM groups; p < 0.01) as a
potential risk factor for PPCM [54]. The association between
PPCM and DM needs however further investigation.
Genetics of peripartum
cardiomyopathy
PPCM has been classified as a nongenetic form of DCM [77].
However, a number of studies have reported familial cluster-
ing [78–82]. Moreover, 15% of patients in a German cohort
included in a registry had a family history of cardiomyopa-
thy [10]. Two groups recently evaluated rare pedigrees of
patients affected by both PPCM and DCM and identified
variants in genes encoding myofibrillar proteins, including
TTN, the gene encoding the sarcomere protein titin [8,77].
Morales et al. [8] recently performed a systematic search of a
large DCM database for cases associated with pregnancy and
the PP period. Of 4110 women from 520 families of patients
with nonischemic DCM, they identified 45 patients with
PPCM/PACM. Nineteen of the patients had been sequenced
for genes known to be associated with DCM and six carried
mutations. This observation was further supported by a study
from van Spaendonck-Zwarts et al. [77] that found PPCM in
6% of 90 families with DCM in Europe. Screening of first-
degree relatives of three patients with PPCM with persis-
tent LV dysfunction revealed undiagnosed DCM in all three
families. Furthermore, genetic analyses showed a mutation
in the gene encoding cardiac troponin C (TNNC1) in a sin-
gle DCM family with members with PPCM. More recently,
the same group collected 18 families with PPCM and DCM
cases from various countries and applied a targeted next-
generation sequencing (NGS) approach to detect mutations
in 48 genes known to be involved in inherited cardiomy-
opathies. They identified four pathogenic mutations in four
of 18 families (22%) and six variants of unknown clinical sig-
nificance that may be pathogenic in six other families (33%).
The investigators concluded that mutations which are poten-
tially causal in cardiomyopathy-related genes are common in
families with both PPCM and DCM supporting the notion
that PPCM can be part of familial DCM [83]. Most recently,
a genetic study was undertaken with 172 patients with PPCM
who were not preselected for family history or other indexes
of genetic origin and identified the TTN-truncating vari-
ants as the most prevalent genetic predisposition in both
PPCM and DCM [84]. Twenty-six rare truncating variants
in eight genes among women with PPCM were identified.
The prevalence of truncating variants (15% vs. 4.7%) was
significantly higher than that in a reference population but

was similar to that in a cohort of patients with DCM (15%
vs. 17%, p = 0.81). Two-thirds of identified truncating vari-
ants were in TTN, and almost all TTN variants were located
in the titin A-band. Moreover, in a subgroup of clinically
well-characterized cohort of 83 women with PPCM, the pres-
ence of TTN-truncating variants was significantly correlated
with a lower EF at one-year follow-up (p = 0.005). These
results support the notion that PPCM often has a genetic
cause and that PPCM shares a genetic origin with familial and
sporadic DCM.
Clinical presentation
As previously mentioned, PPCM is diagnosed in the vast
majority women during the first weeks of the postpartum
period. A subset of patients, however, presented in the sec-
ond and third trimester of pregnancy, or later than one
month postpartum [3,7,31]. Many of the signs and symp-
toms associated with normal pregnancy are similar to those
of HF; for this reason, and because of the low incidence and
awareness of this condition, the diagnosis of PPCM is often
missed or delayed, allowing for the development of catas-
trophic complications, which otherwise are preventable [85,
86]. Most patients present with typical signs and symptoms
of HF, including dyspnea and orthopnea [21,87]. In addi-
tion, cough, chest pain, and abdominal pain are frequently
encountered and tend to confuse the initial clinical evalu-
ation [87]. 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 an increased jugular
venous pressure, displaced apical impulse, right ventricular
heave, murmurs of mitral and tricuspid regurgitation, third
heart sound, pulmonary rales, and peripheral edema. Recent
report of 12 lead electrocardiogram (ECG) in 78 consecu-
tive African women with PPCM (90%) black described sinus
tachycardia in 90% (mean heart rate 100 ± 21 beats/min).
Major ECG abnormalities were detected in 49% of the cases;
the most common being T-wave changes (59%), P wave
abnormalities (29%), and QRS axis deviation (25%). Bundle
brunch block (BBB) was seen in 12% of patients (mostly left
BBB). Repeat ECG in six months was obtained in 44 women
and showed reduction of heart rate (average of 27 beats/min)
and normalization of initial changes in 25% of cases and 75%
of those with normalization of LV function [88]. Analysis
of ECG findings at the time of diagnosis of 88 women in
the IPAC study showed sinus tachycardia in 44% of patients,
sinus bradycardia in 6%, normal QRS axis in 84%, left atrial
enlargement in 17%, left ventricular hypertrophy in 9%, ST
segment depression or elevation in 24%, T wave flattening
in 70%, and T wave inversion in 64% of patients. Conduc-
tion abnormalities included incomplete right BBB in 5% and
complete right and left BBB in 1% each [89]. Chest radio-
graphy usually shows cardiomegaly and pulmonary venous
congestion or pulmonary edema, with or without pleural
effusion [20,90]. Echocardiography shows variable degrees
CHAPTER 10 Peripartum Cardiomyopathy 133
of LV dilatation, with moderate to severe depression of sys-
tolic function, and LV apical thrombi can be seen in those
with severely depressed LV function. It should be noted that
PPCM can occur either with or without LV enlargement.
Right ventricular and bi-atrial dilatation as well as moderate
to severe mitral and tricuspid regurgitation are commonly
seen, with increased pulmonary pressures and mild pul-
monary regurgitation [5,7,20,21,90]. Cardiac MRI has been
used in a limited number of patients for the assessment of car-
diac function and the detection of mural thrombi or myocar-
dial fibrosis [80,91–94]. Although MRI is probably safe dur-
ing pregnancy [95,96], intravenous gadolinium crosses the
placenta, and the 2007 American College of Radiology doc-
ument on safe MRI practices recommended to avoid dur-
ing pregnancy and used only if absolutely essential [96]. In
a group of eight women with PPCM who were studied with
MRI, none exhibited abnormal myocardial late enhance-
ment, and no difference was found in the MRI patterns in
four patients who recovered normal LV function compared
with those who did not [97]. Recently, a number of studies
looked at LGE in women with PPCM [36–38]. In the prospec-
tive IPAC study, of 40 patients detectable by LGE was not
prevalent and was observed in only two women at baseline
and three women at six months.
Brain natriuretic peptide
Levels of BNP do not change significantly during pregnancy
or the postpartum period in healthy women and may show
a mild increase in preeclampsia [71,73,98,99]. An early mea-
surement of BNP could help in diagnosing PPCM, in which
levels of BNP have been shown to be markedly elevated [100].
Prognosis
Recovery of LV function
Rate of LV function recovery has varied in recent reports
(Table 10.1). Recent publications combining approximately
300 US patients have reported recovery of LV function
(LVEF to ≥50%) at six months in 45–78% of patients, with a
mean of 54% [31,56,57,86]. Data from Elkayam et al. [7] on
40 patients with longitudinal follow-up of 30 ± 29 months
showed that improvement usually occurred within the first
six months after the diagnosis. Amos et al. [56] demon-
strated LV recovery in 45% of 55 women, mostly occurring
within the first two months, with continued improvement
over one year. Most recently, a preliminary report from a
Utah PPCM registry described LV recovery in 62% of 58
patients, with an average time of nine months [110]. In a
recent large retrospective study including 187 patients from
South California, Louisiana, and web-based registry, the
recovery of LV function (LVEF ≥50%) at six months after
diagnosis was found in 115 patients (61%) [76]. In contrast,
Modi et al. [102] 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 AAs, the investigators suggested that race and ethnicity
134 PART III Cardiac Disorders and Pregnancy

Table 10.1 Rate of recovery of left ventricular function in patients with PPCM

Number of Rate of Mean

References Year Country patients recovery (%) follow-up (mo) Study design

Amos et al. [56] 2006 USA 55 45 41 Retrospective single center

Hu et al. [101] 2007 China 106 52 6 Prospective, multi-center
Modi et al. [102] 2009 USA 44 35 24 Retrospective
Goland et al. [70] 2011 USA 187 61 6 Retrospective, nationwide
Kamiya et al. [9] 2011 Japan 102 63 9.6 ± 6.5 Retrospective, nationwide survey
Safirstein et al. [57] 2012 USA 55 78 NA Internet survey
Biteker et al. [103] 2012 Turkey 42 30 19.3 Prospective study
Haghikia et al. [10] 2013 Germany 96 47 6±3 Prospective registry
Blauwet et al. [104] 2013 South Africa 141 21 6 Prospective
Laghari et al. [105] 2013 Pakistan 45 71 6 Retrospective
Pillarisetti et al. [106] 2014 USA 100 23 33 Retrospective
McNamara et al. [55] 2015 USA 96 72 12 Prospective
Cuenza et al. [107] 2016 Philippines 38 39 6 Retrospective
Ersboll et al. [108] 2017 Denmark 61 67 3–12 Retrospective
Hilfiker-Kleiner et al. [109] 2017 Germany 63 60 6 Prospective

might be responsible for poorer outcomes. This assumption
has been supported by a recent analysis by Goland et al.
demonstrating a significantly lower rate of LV recovery in 52
AA patients compared with 104 Caucasians (40% vs. 61%,
p = 0.02) [70]. The most recent prospective IPAC enrolled
100 women from multiple centers throughout the United
States and followed their clinical course for 12 months with
careful clinical evaluations, including repeated echocar-
diography interpreted in a central laboratory. This study
which included 30% AA women has supported the results
of previous retrospective investigations and found that 71%
of the women recovered LVEF to ≥50% and only 13% had
major events or persistent cardiomyopathy with LVEF <35%
[55] (Figure 10.4). Similar to previous reports in the United
States [7,56], recovery occurred almost uniformly by six
months, with little change in LVEF thereafter. AA women
presented with a lower LVEF (31% vs. 36%; p = 0.008) and
had a lower average LVEF at the one-year follow-up (47% vs.
56%; p = 0003) and had a lower rate of recovery (defined as
LVEF ≥50%: 59% vs. 77%; p = 0.03).
In summary, available information in the United States
demonstrates normalization of LV function in >50% of
women with PPCM, mostly occurring within two to six
months after diagnosis; later recovery, however, is possible
and occurs in some patients. The rate of LV recovery is signif-
icantly lower in AA patients compared with whites. Reports
of rate of recovery from other countries have been vari-
able. Haghikia et al. [10] in the prospective PPCM national
registry in Germany of 115 patients, described full recov-
ery in 47% at six months. A recently published retrospec-
tive study from China by Li et al. [111] of 71 PPCM subjects,
reported a full recovery in 56% of subjects at 12 months. In
a single-center study of 45 patients with PPCM in Pakistan,
71% recovered LV function within six months. In contrast,
in a larger study of 176 patients in South Africa only 21%
of the survivors had fully recovered LVEF (recovery defined
as LVEF ≥55%) [104]. Similarly, low rates of LVEF recovery
(35% at six months was reported in Turkey [103] and in Haiti
(28%) [112].
Predictors of LV recovery
A number of factors have been shown to be associated with a
higher likelihood of recovery, including LV diastolic dimen-
sion (<5.5–6.0 cm) and systolic function (LVEF 30%–35%
and fractional shortening ≥20%) at the time of diagnosis
[5,21,57,90], lack of troponin elevation [101], a lower level
of plasma BNP [100], absence of LV thrombus [56], breast-
feeding [57], diagnosis after the delivery [57], and non-
AA ethnicity [86]. In the IPAC study, only one-third of the
27 women with LVEF <30% at presentation recovered LVEF
to >50% at one year (Figure 10.4). None of the women
who also had evidence of dilation (LV end-diastolic diam-
eter >6.0 cm) recovered (Figure 10.5) compared with recov-
ery in nearly 90% of the 65 women who presented with LVEF
>30% [55]. Similarly, in the German cohort, mean present-
ing LVEF in women who recovered was significantly higher
compared to those who did not (28% vs. 17%, p < 0.0001)
[10]. Recent multivariate analysis by Goland et al. [70] in
187 patients with PPCM found LVEF >30% and LV end-
diastolic dimension <55 mm to be significantly related to LV
recovery, suggesting a relationship between the degree of ini-
tial myocardial insult and recovery. These parameters, how-
ever, have limited sensitivity in predicting recovery in indi-
vidual patients, as evidenced by full recovery found in 37% of
 CHAPTER 10 Peripartum Cardiomyopathy 135

(a) (b) Entry 6 months 12 months

0.70 Non-Black Black

0.70

0.60
0.60

0.50
0.50
Measure of LVEF

Measure of LVEF
0.40 0.40

0.30 0.30

0.20 0.20

0.10 0.10

Entry 6 months 12 months Entry 6 months 12 months

Time postpartum Time postpartum

Figure 10.4 (a) Overall cohort. LVEF at study entry, 6, and 12 months postpartum for the entire cohort. (b) By race. The LVEF was significantly
poorer in black women with PPCM at study entry (p = 0.009), 6 months (p = 0.006), and 12 months postpartum (p = 0.001). LVEF – left
ventricular ejection fraction; PPCM – postpartum cardiomyopathy. Source: Adapted with permission from McNamara et al. 2015 [55].

(a) Entry 6 months 12 months (b) Entry 6 months 12 months

LVEF ≥ 0.30 LVEF < 0.30 <6.0 cm ≥6.0 cm

0.70 0.70

0.60 0.60
Measure of LVEF

0.50 0.50
Measure of LVEF

0.40 0.40

0.30 0.30

0.20 0.20

0.10 0.10

Entry 6 months 12 months Entry 6 months 12 months

Time postpartum Time postpartum

Figure 10.5 Initial LVEF and LVEDD and LVEF over time. (a) Initial LVEF <0.30 or ≥0.30. In women with severe LV dysfunction at study entry,
poorer LV function persists at 6 months (p < 0.001) and 12 months (p < 0.001) postpartum. (b) Initial LVEDD <6.0 or ≥6.0 cm. Women with
greater LV remodeling at entry (LVEDD ≥6.0 cm) demonstrate a lower LVEF at study entry (p = 0.04) and less recovery at 6 months (p < 0.001)
and 12 months (p < 0.001) postpartum. LV – left ventricular; LVEDD – left ventricular end-diastolic diameter. Source: Adapted with permission
from McNamara et al. 2015 [55].
136 PART III Cardiac Disorders and Pregnancy
70
60
LVEF < 50%
50 LVEF < 30%
63%
Percent
40
30
32%
20
30%
10 21%
13%
0 deformation indices were reported to be sensitive indica-
Group 1 Group 2 Group 3
Figure 10.6 Failure to achieve left ventricular ejection fraction
(LVEF) of 50% and 30% at ≥6 month in different groups according
to baseline LVEF: group I: 10–19%; group II: 20–29%; and group III:
30–45%. Source: Adapted with permission from Goland et al.
(2011) [70].
patients with baseline LVEFs <20% and in 51% of those with
LVEFs <30% (Figure 10.6). Baseline parameters of LV func-
tion should therefore not be used as an indication for the pre-
mature use of devices implantation or heart transplantation.
In contrast to the aforementioned studies, LVEF at presenta-
tion in the Soweto study in South Africa did not predict out-
come in this large cohort [104]. Finally, genetic testing used
in 172 women with PPCM showed that the presence of TTN-
truncating variants was significantly correlated with a low EF
at one-year follow-up [113].
Debates related to LV recovery in PPCM
The relationship between standard HF therapy and LV recov-
ery is unclear. The rates of recovery in early studies, before
the era of contemporary HF therapy [3,114], were similar
to rates reported in recent studies, and early recovery often
occurred before achieving an optimal therapeutic doses of
standard HF medications [56]. In addition, similar to nonis-
chemic DCM [115], preliminary reports have shown no sig-
nificant difference in the use of β-blockers in recovered com-
pared with nonrecovered patients with PPCM [116,117]. A
number of studies reported on higher rates of LV recovery
with bromocriptine therapy and its potential benefit will be
discussed in detail in the following sections.
Inconsistent data have been reported regarding the role of
resolution of preeclampsia or gestational hypertension in LV
recovery. Haghikia et al. [10] in the German cohort found
that 49% of women with LVEF recovery had hypertension
compared with only 7% of those who did not (p = 0.009).
Similarly, Blauwet et al. [104] in the Soweto study showed
that blood pressure had an odds ratio of 0.97 per 1 mmHg for
poor recovery (p = 0.02). In the nationwide Japanese study,
the presence of hypertension was independently associated
with shorter hospital stay and moderately improved LVEF
at the seven-month follow-up (59% vs. 51%; p < 0.05) [9]. In
contrast, preeclampsia or hypertension was not associated
with improved outcomes in the IPAC study [55], and
moreover, a recent small retrospective study on 39 women
with PPCM including 44% with preeclampsia [118] found
significantly lower rates of LV recovery in women with
preeclampsia (25% vs. 80%, p = 0.014).
Evidence of subclinical LV dysfunction
after recovery
Introduction of 2D speckle tracking for quantification of
myocardial strain provides data on longitudinal and cir-
cumferential myocardial function and rotation [119]. These
tors of subtle changes in LV function. A recent study by
Goland et al. [53] has demonstrated a significantly impaired
LV global longitudinal and apical circumferential 2D strain in
29 women at least 12 months after presentation with PPCM
and LVEF ≥50% compared to controls (Figure 10.7). These
findings support early echocardiographic study of women
with PPCM after recovery of LV function, which revealed
decreased contractile reserve in response to dobutamine
challenge, and indicate the presence of persistent subclini-
cal dysfunction in women with a history of PPCM even after
normalization of LVEF [120].
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.
[86] described major adverse events (MAE) in 25% of 182
patients with PPCM, with 80% of these occurring during
the first six months after the diagnosis and one-third of the
survivors having residual brain damage secondary to car-
diopulmonary arrest or cerebral vascular events. Predictors
of complications were LVEF <25%, non-Caucasian ethnic
background, and delay of diagnosis (Figure 10.8). Kolte
et al. [25] reported on 14% of in-hospital MAE (defined as
in-hospital mortality, cardiac arrest, heart transplant, MCS,
acute pulmonary edema, thromboembolism, and implanta-
tion of a cardioverter defibrillator or permanent pacemaker)
in a large 2004–2011 nationwide inpatient sample database.
In the recently published prospective IPAC study, 100
women with PPCM were followed after their index presenta-
tion [55]. By one year, 13% of women had experienced major
events defined as death, transplantation, or left ventricular
assist device (LVAD) implantation or persistently severe
LV dysfunction with an LVEF <35%. The vast majority of
MAE (death, transplant, or LVAD implantation) occurred in
patients with baseline LVEF <30% (Figure 10.9) confirming
that women with severe systolic dysfunction at presentation
have the poorest outcomes. During this period, six women
developed nine major events namely four deaths, four LVAD
implantations, and one heart transplantation, and three
additional women were admitted for cardiac complications.
 CHAPTER 10 Peripartum Cardiomyopathy 137

0
Controls

PPCM
–5

P < 0.001 P = 0.02

–10

–15
–16.6 ± 4.9
–19.1 ± –3.2
–21.1 ± 7.9
–20
–22.7 ± –3.2

LG strain (%) Apical circ strain (%)

–25

Figure 10.7 Comparison two-dimensional strain values between the peripartum cardiomyopathy (PPCM) patients and controls. LG indicates
longitudinal; and circ, circumferential. Source: Adapted with permission from Goland et al. 2016 [53].

(a) 100 (b) 100

Freedom from MAE (%)

Freedom from death or

80 80
transplant (%)
60 60

40 40

0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Years Years

No. at risk No. at risk

164 83 47 30 22 15 12 164 88 49 31 22 15 12

(c) 100 (d) 100

Freedom from MAE (%)

Freedom from death or

Log rank P < 0.004

80 80
Log rank P < 0.001
transplant (%)

60 60

40 40
LVEF > 25% LVEF > 25%
LVEF ≤ 25% LVEF ≤ 25%
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Years Years
No. at risk No. at risk
81 50 28 21 16 13 10 81 51 28 21 16 13 10
83 33 19 9 6 2 2 83 37 21 10 6 2 2

Figure 10.8 (a) Kaplan–Meier survival curves demonstrating proportion of patients free from major adverse events (MAE). The numbers below
the graph represent the number subjects at risk of the event. (b) Kaplan–Meier survival curves demonstrating proportion of patients free from
death or heart transplantation. The numbers below the graph represent the number subjects at risk of the event. (c) Kaplan–Meier survival
curves demonstrating comparison of proportion of patients free from major adverse events (MAE) between those with left ventricular ejection
fraction (LVEF) ≤25% and >25%. p Value: for the comparison between the two groups. (d) Kaplan–Meier survival curves demonstrating
comparison of proportion of patients free from death or heart transplantation between those with left ventricular ejection fraction (LVEF)
≤25% and >25%. p Value: for the comparison between the two groups. Source: Adapted with permission from Goland et al. 2009 [86].
138 PART III Cardiac Disorders and Pregnancy
30
LVEF ≥ 0.30
p = 0.004
LVEF < 0.30
25
20
% Events
15
10
5 10
0 n = 52 n = 104
0 90 180 270
Days postpartum
Figure 10.9 Event rate by baseline LVEF. The percentage of women
who died or underwent LVAD implantation during the first year
postpartum. Dashed blue line – women with an initial LVEF ≥0.30;
solid red line – women with an initial LVEF <0.30. The event rate was
significantly higher in women with an LVEF <0.30, p = 0.004.
LVAD – left ventricular assist device; LVEF – left ventricular ejection
fraction. Source: Adapted with permission from McNamara et al.
2015 [55].
The event-free survival (without LVAD implantation and
heart transplantation) was 93%, and it was similar for AA and
non-AA patients. Significantly worse event-free survival was
found among women with LVEF <30% compared to those
with LVEF ≥30% (82% vs. 99%, p = 0.004, respectively).
Racial and geographic differences in
prognosis of PPCM
Racial differences in the United States
Goland et al. [29] who retrospectively analyzed the outcome
of 52 black and 104 white patients with PPCM were first to
report on worse outcomes in AA women including lower
rates of LV recovery (40% vs. 61%; p = 0.02) and a higher
incidence of mortality or cardiac transplantation (p = 0.03)
despite similar LVEF on presentation (Figure 10.10). In the
IPAC study, black patients presented with a lower LVEF
(31% vs. 36%; p = 0.008) had a lower average LVEF at the
one-year follow-up (47% vs. 56%; p = 0.003) and had a
lower rate of recovery (defined as LVEF >50%: 59% vs. 77%;
p = 0.03) (Figure 10.4). Similarly, Harper et al. [28] reported
a seven-year mortality of 24% in black patients compared
with 6% in white patients. In contrast, no difference in out-
comes was found among Hispanic women with PPCM in
the United States compared with non-Hispanic whites [121].
Most recently, Irizarry et al. from Philadelphia reported the
results of a retrospective study of 220 women with PPCM,
121 of them AAs [11]. Similar to the results published by
Goland et al. [29], AA women at this study presented at
a younger age had a higher incidence of pregnancy-related
hypertension, most of them diagnosed after the delivery and
50 p = 0.002
African-Americans
46 ± 14
45 Caucasians
39 ±17
40
35 p = 0.7
30 28 ± 10 28 ±11
LVEF (%)
25
20
15
5
n = 47 n = 89
0
360 Baseline Follow-up
Figure 10.10 Comparison of left ventricular ejection fraction (LVEF)
at the time of the diagnosis and at follow-up between
African-American and white (“Caucasian”) women with peripartum
cardiomyopathy. Source: Adapted with permission from Goland
et al. 2013 [29].
presented later in the postpartum period, and they were more
likely to present with an LVEF < 30%. African-American
women were also more likely to worsen after the initial diag-
nosis, and they were twice as likely to fail to recover, and when
they did recover, recovery took at least twice as long despite
similar and adequate medical treatment. Additional studies
are warranted to investigate potential genetic differences as
well as differences in socioeconomic resources, which may
play an important role in the causes for the differences in
outcomes in AA women with PPCM compared to non-AA
women.
National and geographic differences
Rate of PPCM-associated death varies significantly in differ-
ent parts of the world. Contemporary studies from Germany
and Japan describe the outcome of women with PPCM com-
parable to Caucasian women in the United States with a mor-
tality rate of 0–4% and LV recovery rates of ∼60% [9,10,109].
A recent single-center study from Pakistan reported no mor-
tality and LV recovery of 71% [105]. In contrast, a markedly
poor outcome has been reported from certain geographic
areas such as Turkey and Africa. High mortality of 24% and
extremely low rate of LV recovery (30%) at six months were
reported in a group of women with PPCM from two hospi-
tals in Istanbul, Turkey [103]. Two studies from South Africa
reported similarly high mortality of 13–17% and recovery
of LV function in only 21% of the survivors [104,122]. A
more recent publication describing the outcome of 96 women
with PPCM in Africa reported a six-month mortality rate
of 22% [123].
In summary, there are extreme racial and geographic varia-
tion in incidence, timing of presentation, disease severity, rate
and timing of recovery, and death rate in women with PPCM.
These differences strongly suggest that PPCM cannot be con-
sidered as “one disease,” and population-specific differences
 CHAPTER 10 Peripartum Cardiomyopathy 139

Table 10.2 Mortality of patients with PPCM in the United States

Number of Mean African- Mortality

References Year patients Study type follow-up Americans (%) (%)

Goland et al. [86] 2009 182 Multicenter retrospective 19 mo 29 7

Modi et al. [102] 2009 44 Single center retrospective 24 mo 89 16
Gunderson et al. [24] 2011 110 Population study retrospective 36 mo 29 2
Cooper et al. [126] 2012 39 Multicenter prospective 25 mo 39 0
Harper et al. [28] 2012 85 Epidemiologic study retrospective 7 yr 59 16.5
Pillarisetti et al. [106] 2014 100 Two centers retrospective 33 mo 55 11
Briasoulis et al. [127] 2015 47 Single-center retrospective 12 mo 96 11
McNamara et al. [55] 2015 100 Multicenter prospective 12 mo 30 4

need to be considered by clinicians caring for women with
this condition, by investigators designing clinical trials for
this condition and by society’s guidelines. More research is
required to determine socioeconomic and genetic reasons
for different geographical and racial characteristics of PPCM
and the need for more population specific approach to this
disease.
Durable left ventricular assist devices
Recently, two studies addressed the issue of circulatory
support devices and heart transplantation in patients with
PPCM. The recent report from INTERMACS reported out-
comes of 99 patients with PPCM who received durable
mechanically assisted circulatory support 2006–2012. Com-
pared with non-PPCM cardiomyopathy patients, PPCM
women had better survival with two-year survival of
83% because of younger age and fewer comorbidities. At
36 months, recovery was uncommon and occurred in 6% (vs.
2% in non-PPCM women), and almost one-half of women
with PPCM (48%) received cardiac transplantation [124]. A
comparison with women receiving transplantations for other
indications, outcomes of graft failure, and death were infe-
rior for recipients with PPCM, which may be partly explained
by younger age, higher allosensitization, higher pretransplant
acuity, and increased rejection [125].
Mortality or heart transplantation
Rates of mortality have varied very significantly with
important racial and geographical differences both in the
United States and other countries (Tables 10.2 and 10.3).
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%
[21–23,56,86,90,102,133] (Table 10.2). In the IPAC study,
four patients (4%) died at the one-year follow-up. Two recent
national inpatient databases reveal in-hospital mortalities of
1.3%; no information on postdischarge outcomes was avail-
able [25,121]. Harper et al. [28] reported mortality of 16% at
seven years in a population-based study from North Carolina
study. Goland et al. [86] reported mortality of 7% at mean
follow-up of 19 months with significantly higher mortality
or heart transplantation in non-Caucasian women. As low as

Table 10.3 Mortality in patients with PPCM in countries other than the United States

Number of
References Year patients Study design

Kamiya et al. [9] 2011 102 Nationwide survey

Sliwa et al. [128] 2011 80 Single center prospective
Haghikia et al. [10] 2013 115 Prospective registry
Blauwet et al. [104] 2013 176 Single center prospective
Ntusi et al. [69] 2015 30 Single center prospective
Libhaber et al. [129] 2015 206 Two centers prospective
Li et al. [111] 2016 71 Single center retrospective
Akil et al. [130] 2016 58 Three centers retrospective
Cuenza et al. [107] 2016 39 Single center retrospective
Lu et al. [131] 2017 391 Population study
Hilfiker-Kleiner et al. [132] 2017 63 Prospective
140 PART III Cardiac Disorders and Pregnancy
0–9%, two-year mortality has been described in the United
States [7,126] with higher mortality in Louisiana (16%) where
the vast majority were African-American patients. Relatively
high two-year mortality has been observed among the black
population in Africa and Haiti (28% and 15%, respectively)
[17,128]. A small number of studies have focused on two
to five year mortality rates, which varies between 0–6% in
the United States and France [22,91,97,133] and 15–30%
in China, Turkey, and South Africa [103,111,130]. The
mortality between five and nine years in the United States
has been reported to be as high as 7–16% [28,106,133], and
no death has been described during 5.8 years in Germany
[134], while consistently higher mortality rates have been
found in India (23%) [135] with similar rates of 26% at
10 years in a prospective study from Nigeria [76].
Timing and mode of death
Goland et al. [86] 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 eight years postpartum. Whitehead et al. [136] 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 one week and 87% within six months
of diagnosis, and mortality was due either to progressive HF
or to sudden cardiac death. Mortality was found by Goland
et al. [86] to be higher in women with baseline LVEFs ≤25%,
in AA patients as well as in women in whom the diagnosis of
PPCM was delayed.
Of 22 deaths reported by Yameogo et al. [123] in Africa, six
died within two weeks after diagnosis, additional 14 patients
died within three months, and the last two patients within six
months. No information was provided on the mode of death.
Risk of late mortality in PPCM has not been well defined
because of lack of long-term data [137].
Thromboembolism
PPCM is associated with increased incidence of thromboem-
bolism compared with DCM of other etiologies, and LV
thrombus has been found on initial echocardiography in
10–17% of patients [56,126]. Several reports have described
severe thromboembolic events, including embolization to
the coronary, pulmonary, peripheral, and cerebral arteries
[56,76,86,90,106,126,128,130,134,135]. Laghari et al. [105]
reported on high incidence (9%) of women experienced a
thromboembolic stroke. Sliwa et al. [1] described throm-
boembolic complications in over 5% of patients, and a recent
publication by Yaméogo et al. [123] reported thrombus for-
mation in 13 of 96 African patients with LV thrombus in
12, biventricular thrombi in two, and right atrial thrombus
in one. Increased incidence of thromboembolism is proba-
bly due to multiple reasons, including the hypercoagulable
state of pregnancy [136], cardiac dilatation and dysfunction,
endothelial injury, venous stasis, and prolonged bed rest after
commonly performed instrumental deliveries and cesarean
section.
Outcome of subsequent pregnancy
The risk of subsequent pregnancy (SSP) is the most common
question by women with a history PPCM, bearing on the
decision of the women of whether to become pregnant again.
A recent review of all posting written on an online support
group for PPCM showed that the subject of SSP was the fore-
most issue in the minds of many women [138]. Habli et al.
[139] reported on 21 patients with a mean LVEF >40% who
had SSP, with worsening of HF in 29% and in none of eight
other patients who terminated their subsequent pregnancies.
Two patients with initial LVEFs <25% (follow-up LVEFs not
provided) who had SSP and five of eight women who termi-
nated their pregnancies demonstrated clinical deterioration
requiring referral for cardiac transplantation.
Modi et al. [102] described 44 indigent patients with
PPCM and reported clinical worsening in 28% of those who
had subsequent pregnancies (number of patients not pro-
vided) but no maternal death. Elkayam et al. [140] 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 asso-
ciated with reductions in mean LVEF in the total 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% mor-
tality in group 1 women and 19% mortality in group 2
(Figure 10.11). When pregnancies that ended by abortion
50%
45% 44%
40%
35%
31%
30%
25%
25%
21% 21%
20% 19%
15% 14%
10%
5%
0%
0%
HF >20% Persistent Maternal
symptoms decreased dysfunction mortality
LVEF
Figure 10.11 Incidence of maternal complications associated with
subsequent pregnancy in women with PPCM Slate bars are group 1,
women with left ventricular ejection fraction (LVEF) ≥50% before
subsequent pregnancy. Salmon bars are group 2, women with LVEF
<50% before subsequent pregnancy. HF – heart failure. Source:
Adapted with permission from Elkayam et al. 2001 [140].
 CHAPTER 10 Peripartum Cardiomyopathy 141

80% former group (n = 93) had significant deterioration of

70% 67%
60%
50%
40%
35%
30%
17%
20%
10%
0%
<45% (N = 9) 45–54% (N = 17) >55% (N = 35)
LVEF before SSP
Figure 10.12 Rate of relapse in 61 peripartum cardiomyopathy
patients with SSP according to LVEF level before SSP. Source:
Adapted with permission from Fett et al. 2010 [141].
were excluded, the risk for unfavorable maternal and fetal
outcomes was even higher, especially in women with per-
sistent LV dysfunction. One woman in group 1 whose LV
function did not change during her first SSP had a signif-
icant decrease from 55% to 40% during her second SSP.
A publication by Fett et al. [141] 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 signif-
icantly higher rate (46%) in women with LVEFs <55% (Fig-
ure 10.12). Nine of the patients with recovered LV function
underwent stress echocardiography that demonstrated nor-
mal contractile reserve, and these patients did not experience
relapse. Although it has been suggested that normal contrac-
tile reserve in patients with PPCM with recovered LV func-
tion may ensure good outcomes during subsequent preg-
nancies [142], this concept has not been tested and should
therefore not be used to predict the risk of subsequent preg-
nancies in women with histories of PPCM. Elkayam [143]
in the most recent comprehensive review of literature sum-
marized the data on 191 recurrent pregnancies and showed
that the risk of relapse in patients with persistent LV dys-
function before their recurrent pregnancy is much higher
than in those who have normalized LV function: 48% of the
LV function and 16% died, whereas 27% of the latter
group showed deterioration, and no deaths were reported
(Tables 10.4 and 10.5). The risk of worsening PPCM with
recurrent pregnancy is thus substantial. The best predictor
for relapse and deterioration of cardiac function is prepreg-
nancy LVEF. Normalized LV function is usually associated
with good outcome but does not guarantee an uncomplicated
SSP [143,146]. The first prospective contemporary study
from Germany and South Africa from Hilfiker-Kleiner et al.
included 34 women with SSP, two-thirds of the patients were
of African origin and the rest were Caucasians [132]. The
results of this study support the findings described in pre-
vious reports demonstrating the high risk of SSP in women
with PPCM and persistent LV dysfunction. Mortality in this
group of patients was as high as 25% with one patient out of
16 dying during pregnancy and three during the six-month
follow-up period. In addition, LV recovery at follow-up was
lower compared to patients entering pregnancy after full
LV recovery. The results of the study also support previous
reports of SSP-associated reduction of LV function even in
women after full recovery of LV function. Mean group LVEF
value in these patients was reduced by 12% after delivery
(from 58 ± 5% to 51 ± 13%) with failure to show a full recov-
ery in >40% of the cases. Similar to previous studies, this
reduction in LV function in women with normal LV function
before the SSP was not associated with mortality. This study
has also tried to look at the influence of bromocriptine on
LV recovery in women with SSP concluding that addition of
bromocriptine to standard therapy appeared to be associated
with better outcome. This conclusion is premature consider-
ing the small number of patients, heterogeneity of the study
population with significant prevalence of black patients in
whom poor outcome has been shown consistently in all stud-
ies published up today, and eventually the fact that the mean
LVEF of the entire bromocriptine group immediately after
the delivery was >50% (51 ± 9% in the bromocriptine group
compared to 38 ± 16% in the standard therapy group). These
limitations emphasize the need of a large-scale and well-
design study to evaluate the efficacy of bromocriptine after
SSP before recommendation can be made for the use of these

Table 10.4 Patients with normal left ventricular function before subsequent pregnancy

Symptoms Persistently
Number of Deterioration of heart decreased LVEF
References Year pregnancies of LV function failure at follow-up Mortality

Elkayam et al. [140] 2001 23 4 (17%) 6 (20%) 2 (50%) 0 (0%)

Habli et al. [139] 2008 21 NA 6 (28%) NA 0 (0%)
Fett et al. [141] 2010 35 8 (17%) NA 1 (12%) 0 (0%)
Hilfiker-Kleiner et al. [132] 2017 18 NA NA 7 (39%) 0 (0%)
Codsi et al. [144] 2018 19 9 (47%) NA 0 (0%) 0 (0%)
Total 116 21/77 (27%) 12/44 (27%) 10/76 (13%) 0 (0%)
142 PART III Cardiac Disorders and Pregnancy

Table 10.5 Patients with persistent left ventricular function before subsequent pregnancy

Symptoms Persistently
Number of Deterioration of heart decreased LVEF
References Year pregnancies of LV function failure at follow-up Mortality

Elkayam et al. [140] 2001 12 4 (33%) 6 (50%) 5 (42%) 3 (25%)

Habli et al. [139] 2008 10 9 (53%) NA 5 (29%) 1 (6%)
Hilfiker-Kleiner et al. [43] 2007 12 5 (42%) NA 6(50%) 3 (25%)
Fett et al. [141] 2010 26 10 (46%) NA 5 (80%) 1 (0.4%)
Hilfiker-Kleiner et al. [132] 2017 16 NA NA 11 (39%) 4 (25%)
Yameogo et al. [145] 2018 23 14 (61%) 19 (83%) NA 9 (31%)
Total 115 50/99 (65%) 33/51(65%) 28/76 (39%) 23/115 (20%)

drugs in women with SSP after PPCM. The latest addition to
the literature related to SSP outcome in women with PPCM
has recently been published by Codsi et al. [144]. These inves-
tigators reported on 25 patients (80% Caucasians) with prior
PPCM, all except one had recovered left ventricular function
(>50%) before the SSP. There were 43 SSPs, 6 miscarriages,
4 terminations, and 33 (77%) live births. The rate of PPCM
relapse was similar to the previous reports [142,143] at 27%;
median decline in EF in women with relapse was 15%, and
LVEF nadir was 43%, but none of the patients with relapse
had their left ventricular LVEF decline to the level of their
index pregnancy. Relapses were diagnosed during the last
month of pregnancy in 44% of the patients and in the post-
partum period in the rest (three within a week of delivery and
one at one-month postpartum). These findings confirm the
report by Sliwa et al. in 2004 describing the outcome of SSP
in six women with previous PPCM, which resulted in reduc-
tion of EF by >10% in five. The LVEF remained unchanged at
eight months of pregnancy and showed a significant deteri-
oration at one-month postpartum. Of note, 60% of pregnan-
cies in the patients reported by Codsi et al. were complicated
by hypertensive disorder of pregnancy (gestational hyperten-
sion 12%, preeclampsia 36%, eclampsia 12%). Four patients
had (16%) preterm labor, 9 had induction of labor for hyper-
tensive disorders, and 14 (56%) underwent cesarean deliv-
ery for obstetrical reasons. There was no mortality associated
with relapses of PPCM, but three patients had to be admitted
to the intensive care unit. All patients with relapse later nor-
malized their LVEF with a median time of recovery of one
month (range 0–24 months). An additional study described
the outcome of SSP in 29 African women, two-thirds of them
with persistent LV dysfunction. The mean LVEF before preg-
nancy was 50 ± 5% and decreased significantly to 38 ± 5%
after the first SSP. Mortality was reported in 48% of the
patients including four patients who had an abortion [145].
In summary, subsequent pregnancies in women with his-
tories of PPCM in are associated with a risk for recurrent
and persistent cardiac dysfunction and even mortality. The
risk is substantially higher in patients with persistent LV dys-
function before SSP. The outcome in women with recov-
ered LV function is significantly better, and mortality in such
patients is rare. At the same time, however, marked decreases
in LV function have been reported in 20–30% of patients,
which may persist after pregnancy [140,143,147]. The most
recent study in the United States including mostly Caucasian
patients demonstrated full recovery in all patients with nor-
mal LV function who had relapse during their SSP [144].
Relapse of PPCM is usually diagnosed in the last month
of pregnancy or the first month after the delivery. Patients
should be advised on the risk of SSP and on the safest and
most effective contraceptive method by both their cardiolo-
gists and obstetricians [148].
Management of subsequent pregnancy
The main issues of management of subsequent preg-
nancy are presented in Tables 10.6 and 10.7. Patients who
Table 10.6 Suggested algorithm for management of SSP in women
with a history of PPCM and LV dysfunction
During pregnancy
qBase line echocardiography and BNP level prior to or during
the first visit
qF/U for symptoms q 1 mo for 30 wk and q 2 wk until delivery
qContinue β-blockers, switch ACEi/ARBs/Entresto to
Hydralazine/Isosorbide dinitrate
qDiuretics for volume overload
qAspirin 81 mg/daily started between 12 and 28 wk until
delivery in women at increased risk of preeclampsia
qConsider Digoxin for symptoms improvement
qTherapeutic anti coagulation for LVEF <40%
qLife Vest for LVEF ≤35%
qRepeat echocardiography and BNP at the end of first and
second trimester, 1 mo prior to estimated time of delivery, prior
to discharge after the delivery, 1-mo postpartum and at any
time if symptoms worsen
After the delivery
qStart Enalapril and Spironolactone
qContinue anticoagulation for 6 wk
qContinue Life Vest as a bridge to recovery or implantation of
implantable cardioverter defibrillator
qBreast-feeding can be allowed unless the patient is unstable
qClose follow-up for 6 mo

Table 10.7 Suggested algorithm for management of SSP in women
with a history of PPCM and recovered LV function (≥50%)
q Baseline echocardiography and BNP level prior to or at first visit
during pregnancy
q Follow-up for symptoms q 1–2 mo for 30 wk and q 2 wk until
delivery
q Discontinue ACEi/ARBs in patients who are on these medications
and continue β-blockers
q Repeat echocardiogram and BNP level 1–2 mo after
discontinuation of RAAS medication to reassess LV function
q No drug therapy in patients who are not on medications
q ASA 81 mg/d started between 12 and 28 wk until delivery in
women at increased risk of preeclampsia
q Repeat echocardiogram and BNP at the end of second trimester,
1 mo prior to estimated time of delivery, prior to discharge, 1-mo
postpartum or at any time if symptoms worsen
q Breast-feeding can be allowed
q Close follow-up for 6 mo
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 med-
ications, angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARBs), or sacubitril-valsartan
(Entresto) should be discontinued as soon as the patient
becomes pregnant. Patients with LV systolic dysfunction
(EF < 40%) with or without symptoms should be started on
isosorbide dinitrate/hydralazine combination at a starting
dose of 20 mg/25 mg tid up titrated to 40 mg/75 mg tid if
tolerated. Spironolactone and ivabradine if used should be
discontinued as well. Because of the hypercoagulable state
of pregnancy, patients with severe LV dysfunction should be
started on anticoagulation with either low-molecular-weight
heparin (LMWH) throughout pregnancy (enoxaparin
1 mg/kg q 12 hours) followed by warfarin for six to eight
weeks postpartum or sequential therapy with LMWH
during the first trimester, warfarin during the second and
third trimesters and unfractionated heparin in the last two
weeks of pregnancy in preparation for the delivery and then
warfarin for six to eight weeks postpartum. Because no
information is available regarding the safety of carvedilol
or metoprolol succinate (Toprol XL) during pregnancy, the
use of metoprolol tartrate (tid) may be considered instead.
The timing of SSP-related relapse in women with PPCM
seems to be similar to the timing of the initial PPCM. Codsi
et al. reported relapse in 45% of the patients during the
last month of pregnancy and postpartum in the rest of the
patients (during the first week in three patients and during
the first month postpartum in one) [144]. An early study by
Sliwa et al. reported on six cases of SSP following PPCM. All
patients were in the New York Heart Association functional
class 1 at the onset of SSP and remained asymptomatic until
delivery [149]. Heart failure symptoms occurred uniformly
in all patients in the postpartum period, and two patients
died within eight weeks after the delivery from severe heart
CHAPTER 10 Peripartum Cardiomyopathy 143
failure, and the remaining four patients remained symp-
tomatic. Based on this limited information, we follow
patients with recovered LV function monthly for symptoms
and repeat an echocardiogram and BNP levels at the second
trimester, in the month before the anticipated delivery,
before discharge after the delivery and one month postpar-
tum and at any time during pregnancy or following delivery
in the case of development of symptoms. Women with LV
dysfunction (LVEF <50%) are at high risk due to a high inci-
dence of relapse but also the potential detrimental effect of
the increased hemodynamic burden and should be followed
monthly including symptomatic assessment, BNP levels, and
echocardiograms for the first 30 weeks of gestation and then
every 2 weeks during the last part of gestation, before dis-
charge after the delivery and first month postpartum and at
any time during pregnancy or the postpartum period in the
event of worsening symptoms. Repeat determination of BNP
levels is helpful in differentiating between HF-like symptoms
associated with normal pregnancy and hemodynamic
deterioration [99,100]. Because relapse of PPCM is usually
diagnosed in the last month of pregnancy or early after the
delivery [144,149], patients should be closely monitored dur-
ing this time. When indicated, ACEi (captopril or enalapril
for breast-feeding women) and spironolactone should be
started after the delivery. A recent algorithm suggested in
a publication by the European society of cardiology study
group on PPCM [137] included a consideration for the use
of bromocriptine postpartum in women with SSP. These rec-
ommendations, however, are based on limited information
in human. The new 2018 ESC Guidelines for the manage-
ment of cardiovascular diseases during pregnancy defined
this indication as class IIB, level B [150]. Because the use of
bromocriptine deprives the mother and her newborn of the
important advantages of breast-feeding and the potential
thromboembolic complication associated with bromocrip-
tine, more information is needed in order to determine the
risk vs. benefit ratio of this therapy in patients with SSP post
PPCM. The benefit of using β-blockers during SSP in women
with recovered LV function is not known. In the study by
Codsi et al. [144], β-blockers were administered during 19 of
43 (44%) SSPs; of these, six (32%) pregnancies had relapse.
No patient treated with β-blockers were diagnosed with
intrauterine growth restriction during pregnancy.
As per the recommendations of the American college
of obstetrics and gynecology, the use of low-dose aspirin
(81 mg/d) should be considered during SSP in women at
high risk for the development of preeclampsia (history of
preeclampsia, multifetal gestation, renal disease, autoim-
mune disease, type 1 or type 2 diabetes, chronic hyperten-
sion, maternal age >34 years, body mass index >30, fam-
ily history of preeclampsia) started between 12 weeks and
28 weeks and continued until the time of delivery.
Early termination of an unintentional pregnancy should
be considered to prevent worsening of LV function and
potential maternal mortality in patients with persistent
LV dysfunction [143]. Special attention should be paid to
144 PART III Cardiac Disorders and Pregnancy
reproductive counseling. A recent self-reported, national,
web-based registry focused of health-related quality assess-
ment in women with PPCM 25% of patients reported not
having a discussion of contraceptive strategies to prevent
unintended pregnancy and heart failure worsening [151].
The recommendations for the use of contraceptives are
women with previous PPCM are generally similar to those
recommended for women with other forms of heart disease
[152] (Chapter 34). Women with PPCM and LV dysfunction
are at high thromboembolic risk therefore contraceptives
containing estrogen should be avoided. Progesterone-
releasing intrauterine device such as Mirena or subcutaneous
implant is preferred, tubular ligation can be used as well
when decided upon by the woman. The decision on the type
of contraception has to be taken after counseling both a gyne-
cologist and cardiologist to choose the optimal approach.
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,
sacubitril/valsartan, β-blockers, spironolactone, and digoxin
[153]. 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 vol-
ume overload and excessive and rapid reductions in intravas-
cular volume, but they should be used with caution dur-
ing pregnancy to prevent over diuresis and hypotension and
decreased uterine perfusion. Furosemide is excreted into
breast milk, but no reports of adverse effects in nursing
infants have been found, and it is listed as probably compat-
ible with breast-feeding [154].
Intravenous vasoactive medications
Vasodilators are recommended in patients with decompen-
sated HF for hemodynamic and symptomatic improvement
[153]. Among the available intravenous vasodilators, nitro-
glycerin (old 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, which is taken off the mar-
ket in the United States. There are limited data regarding the
use of inotropic agents, and these drugs should therefore be
used as recommended [153] only in patients with advanced
HF, low blood pressure, high filling pressure, and dimin-
ished peripheral perfusion due to low-output syndrome and
in patients who are unresponsive or intolerant to intravenous
vasodilators.
Dobutamine
Worse outcomes were reported in women with acute heart
failure in patients with PPCM with use of the β1-adrenergic
receptor agonist dobutamine. Stapel et al. [155] described
27 patients with severe PPCM (LVEF ≤25%). Seven patients
received dobutamine, and all of them received heart trans-
plantation or assist device. In contrast, 19 of the 20 patients
with similar left ventricular end-diastolic diameter (LVEDD)
and LVEF as well as BNP level, who did not receive dobu-
tamine, improved their cardiac function. In addition, their
animal study presented in the same article showed that
chronic β1-adrenergic receptor stimulation in STAT3 defi-
cient hearts causes deterioration of STAT3-dependent net-
work control of glucose metabolism inducing energy deficit,
oxidative stress, cardiomyocyte death, and development of
irreversible heart failure. Because reduced cardiac STAT3
was observed in PPCM patients, the authors suggested that
the cellular alteration found in their animal experiment may
underline the dobutamine-induced heart failure progression.
A recent population-based study from Denmark reported
a similar finding, but in this study, women treated with
dobutamine had significant lower LVEF, which by itself may
explain worse outcomes in these sick patients. Some investi-
gators recently recommend avoiding the use of β-adrenergic
receptor agonists and use other inotropic agents in patients
with PPCM and cardiopulmonary distress [156].
Levosimendan
Levosimendan, a calcium sensitizer used in acute decompen-
sated HF, has been applied to patients with PPCM. Based
on a recent publication from Turkey by Biteker et al. [103],
no differences on outcome has been found in a randomized,
controlled trial of 24 women with PPCM who received lev-
osimendan vs. placebo. Labbene et al. [157] reported this
year improvement in hemodynamics obtained by right heart
catheterization, EF, and decongestion in eight retrospective
cases of women with PPCM and cardiogenic shock. Levosi-
mendan which does not increase myocardial oxygen demand
has therefore been suggested to be the preferred inotrope
in cases when inotropic support is needed [156]. It should
be noted however, that levosimendan is not available in the
United States.
ACE inhibitors, ARBs (risk category C), and
angiotensin-receptor-neprilysin inhibitor (Entresto)
The use of ACE inhibitors and ARBs is contraindicated dur-
ing pregnancy because of toxic effects, mostly on the devel-
oping fetal kidneys. Other potential side effects include oligo-
hydramnios, intrauterine growth retardation, prematurity,
bony malformation, limb contractures, patent ductus arte-
riosus, pulmonary hypoplasia, respiratory distress syndrome,
hypotension, anuria, and neonatal death [158]. During preg-
nancy, the combination of organic nitrates and hydralazine
(both risk category C) should be used as a substitute for ACE
inhibitors or ARBs. Both captopril and enalapril are compat-
ible with breast-feeding.

No clinical information is available with the use of Entresto
during pregnancy or lactation. The prescribing information
by the manufacturer indicates that similar to other drugs
that act on the renin angiotensin system, Entresto can cause
fetal harm when administered to a pregnant woman. In ani-
mal reproduction studies, Entresto treatment during organo-
genesis resulted in increased embryo-fetal lethality in rats
and rabbits and teratogenicity in rabbits. When pregnancy
is detected, consider alternative drug treatment and discon-
tinue Entresto. However, if there is no appropriate alternative
to therapy with drugs affecting the renin–angiotensin system,
and if the drug is considered lifesaving for the mother, advise
a pregnant woman of the potential risk to the fetus.
There is no information regarding the presence of
sacubitril/valsartan in human milk, the effects on the breast-
fed infant, or the effects on milk production. Sacubitril/
valsartan is present in rat milk. Because of the potential for
serious adverse reactions in breast-fed infants from exposure
to sacubitril/valsartan, advise a nursing woman that breast-
feeding is not recommended during treatment with Entresto.
𝛃-Blockers (risk category C)
There is lack of human pregnancy experience with the use
of all three β-blockers approved in the United States for the
treatment of HF (carvedilol, bisoprolol, and metoprolol suc-
cinate, all risk category C), and their effects on the fetus are
therefore unknown. Metoprolol tartrate has been more com-
monly used in pregnancy for the management of hyperten-
sion, arrhythmias, mitral stenosis, and myocardial ischemia
[159]. In addition, the use of β-1-selective β-blockers is pre-
ferred during pregnancy because nonselective β-blockade
could facilitate uterine activity [159]. Carvedilol and bisopro-
lol are excreted into the breast milk of lactating rats; no infor-
mation is available on their use in lactating women [154,160].
β-Blocking agents are excreted in breast milk. Although the
milk concentration of metoprolol is three times those of that
found at the maternal serum, ingesting 200 mg/d of metopro-
lol by the mother would provide only about 225-mcg/1000 ml
of breast milk. This level is probably clinically insignificant
and the reason that no adverse effects have been observed in
nursing infants exposed to metoprolol in milk. To minimize
this exposure even further, it has been suggested to wait
three to four hours after a dose to breast-feed [154,161].
Ivabradine
Recently, Haghikia et al. [10] reported on potential clini-
cal benefit of early therapy with ivabradine (the “funny” (f)-
channel blocker) as part of the heart failure treatment regime
in 27 patients with acute PPCM including two patients with
cardiogenic shock from the subgroup analysis of the German
PPCM registry. At 24-week follow-up, 94% of the patients
showed improvement of LVEF and clinical symptoms, and
28% of the patients reached full cardiac recovery. None of the
patients received a left ventricular assist device or heart trans-
plantation or died during the follow-up period [162]. The
prescribing information provided by the manufacturer of the
CHAPTER 10 Peripartum Cardiomyopathy 145
drug, it is stated that based on findings in animals, ivabra-
dine may cause fetal harm when administered to a pregnant
woman. There are no adequate and well-controlled studies of
the drug. Women should therefore be informed on the poten-
tial risk to the fetus. There is also no information regard-
ing the presence of ivabradine in human milk, the effects of
ivabradine on the breast-fed infant, or the effects of the drug
on milk production. Animal studies have shown, however,
that ivabradine is present in rat milk. Because of the potential
risk to breast-fed infants from exposure to the drug, breast-
feeding is not recommended.
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 fetus
[154]. 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
mother’s daily dose), which seems to be insignificant [154].
The American Academy of Pediatrics classifies spironolac-
tone as compatible with breast-feeding [160].
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 [160].
Anticoagulation
Because of the high incidence of thromboembolism associ-
ated with PPCM [56,163–169], anticoagulation from the time
of the diagnosis until LV function recovers (LVEF >40%) is
advisable. Anticoagulation seems particularly important dur-
ing pregnancy and the first six to eight weeks postpartum
because of persistent hypercoagulable state [170]. In contrast
to warfarin (risk factor D), both unfractionated heparin and
LMWH (risk factor C) do not cross the placenta and are
safe during pregnancy [154]. Neither warfarin nor heparin is
secreted into breast milk, and both drugs are therefore com-
patible with breast-feeding [154].
Immune globulin
Bozkurt et al. [171] added intravenous immune globulin
to conventional HF therapy in 6 women with PPCM and
reported a significantly greater improvement in LVEFs com-
pared with 11 historical control patients who received con-
ventional therapy alone. Although the results seemed encour-
aging, a very small number of patients and the lack of a
blindly randomized, well-matched control group limited the
study.
Pentoxifylline
Sliwa et al. [172] investigated the effect of pentoxifylline, a
xanthine agent known to inhibit the production of tumor
necrosis factor and prevent apoptosis, in 30 South African
146 PART III Cardiac Disorders and Pregnancy
patients with PPCM. These patients received the drug at a
dose of 400 mg three times daily for six 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 Asso-
ciation 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. The drug is
excreted into human milk and has been defined as probably
compatible with breast-feeding [154].
Bromocriptine and the role of breast-feeding
The potential benefit of bromocriptine for the treatment of
PPCM was initially suggested in 2007 based on an animal
experimentation performed by Hilfiker-Kleiner et al. [43].
Based on the concept of enhanced oxidative stress–mediated
cleavage of the nursing hormone prolactin into an antian-
giogenic and proapoptotic 16-kDa form that may be respon-
sible for the development of PPCM [43], Sliwa et al. [91]
attempted the use of bromocriptine, a prolactin blocker, in
the treatment of 10 African patients with PPCM. The drug
was given after diagnosis at a dose of 2.5 mg twice daily for
two weeks, followed by 2.5 mg/d for six weeks, in addition
to standard HF therapy, and resulted in a significantly larger
rate of LV recovery at six months compared with a control
group of 10 women with PPCM treated with standard ther-
apy alone (31% vs. 9%, p = 0.012). In addition, there was a
lower rate of mortality in the treatment group (one vs. four
patients) and a lower rate of a combined endpoint of death,
New York Heart Association functional class III or IV, or
LVEF <35% at six months. Although the results were intrigu-
ing, 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 Europe even previously by
the same investigators in South Africa [173]. A larger African
study was provided by Yaméogo et al. [123] who reported
the results in 96 women in Burkina Faso. The study was
conducted at the Yalgado Ouedraogo teaching hospital. All
patients received heart failure treatment with furosemide and
captopril. Patients with LVEF <35% or ventricular throm-
bus received anticoagulation therapy with fluindione for six
months. Captopril dose was titrated upward as tolerated dur-
ing the first four weeks after diagnosis and then maintained
at the same dose throughout the 12-month study period.
Furosemide dose was decreased as indicated according to
clinical assessment during the study period. The 48 patients
randomized to standard therapy plus bromocriptine (Br+)
received bromocriptine 2.5 mg twice daily for four weeks.
Patients randomized to receive bromocriptine were informed
about the lactation suppression associated with the drug, and
the babies were provided artificial lactation. The mean age
Table 10.8 Effect of bromocriptine of LV size and function and
6-month mortality in 96 African patients [123]
Parameters STHF + Br STHF p Value
BL LVEDD (mm) 59 ± 3 58 ± 4 0.6
BL LVEF 37 ± 7% 37 ± 5% 0.12
6 mo LVEDD (mm) 53 ± 2 55 ± 2 0.002
6 mo LVEF 50 ± 2% 41 ± 6% 0.001
12 mo LVEDD (mm) 52 ± 2 54 ± 3 0.001
12 mo LVEF 54 ± 4% 46 ± 6% 0.001
6 mo mortality 17% 29% 0.0001
BL – baseline; LVEDD – left ventricular end diastolic dimension; LVEF – left
ventricular ejection fraction.
of the patients was 29 ± 3 years, and 2/3 had a low socioe-
conomic level, none had a medical history of hypertension.
There were no significant differences in baseline character-
istics between the two groups (Table 10.8). At six months,
cumulative death was significantly lower at the Br+ group
(16% vs. 29%, p = 0.0001), and echocardiographic findings
demonstrated better improvement in ventricular size and
function both at 6 and 12 months (Table 10.8). Because of the
high mortality in this patient population, the implications of
the results of this study for the management of patients with
PPCM in a population of patients with a significantly lower
mortality rate in North America and Europe are unclear.
The European experience with the use of bromocriptine
in women with PPCM includes a prospective, randomized,
multicenter open study, which was recently completed in
Germany and included 63 patients recruited from 2010 to
2016 [109]. The study was designed to recruit women with
PPCM with EF ≤35% and compare the effect of treatment
with bromocriptine given at 2.5 mg BID for two weeks fol-
lowed by 2.5 mg/d for six weeks in addition to standard HF
therapy on the change in LVEF from baseline to six-month
follow-up. The treatment group was compared to a control
group treated with standard HF therapy plus a low-dose
bromocriptine (2.5 mg/d) for up to one week, which was used
to stop lactation [174]. Fifty-seven women were available for
a follow-up assessment at six months after the start of treat-
ment. The LVEF increased significantly in both groups (from
a mean of 28 ± 10% at baseline to 49 ± 12% at six months in
the one week group and from 27 ± 10% to 51 ± 10% in the
eight weeks group) without a significant difference in delta
LVEF (p = 0.381). Although the study failed to show a differ-
ence between the two groups, the outcome of the two groups
was favorable with 52% of all the patients demonstrating
full functional LV recovery (LVEF ≥50%) and 21% partial
recovery (LVEF 35% <50%). Serious adverse events which
were considered to be related to bromocriptine treatment
were venous embolism in one patient and peripheral arterial
occlusion in one patient. It may be tempting to conclude
that even a small dose of bromocriptine, given for a short
period of time may have a beneficial effect; however, in the

absence of a control group not receiving bromocriptine at
all, this assumption can be viewed as hypothesis generating
rather than a conclusion based on evidence and needs to be
further investigated. A recently published population-based
study from Denmark identified 61 women with PPCM, 39%
received 0.50 mg cabergoline, a dopamine agonist for two
days for inhibition of lactation. When looking at LV recov-
ery, these authors found cabergoline as a predictor of LV
recovery with limiting significance due to conflicting results
in linear and logistic regression analyses [108]. However, a
post hoc analyses of outcome in two Danish subgroups with
baseline LVEF <30% showed no difference in full recovery
rate between 13 women who were treated with cabergoline
for two days to inhibit lactation and 23 women who did not
receive bromocriptine or cabergoline [175].
The use of bromocriptine as a therapy for PPCM has been
adopted in Germany and in other parts of the world [1]. The
uptake of this therapy, however, has lagged in the United
States as documented by the fact that only 1 of the 100
patients included in the prospective IPAC trial was treated
with bromocriptine. The IPAC study group is in the pro-
cess of submitting a study proposal to the National Institute
Health (NIH) for the performance of a randomized evalua-
tion of bromocriptine therapy in 200 women with PPCM.
The wisdom of using bromocriptine without scientifically
appropriate evidence is questionable considering the fact that
the therapy can be associated with adverse effects includ-
ing strokes and myocardial infarction and other thromboem-
bolic events [176], although such complications could hope-
fully be minimized in women with PPCM where anticoag-
ulation is recommended even in the absence of bromocrip-
tine treatment [26]. Equally important is the fact that the
use of bromocriptine is associated with lactation suppression.
The beneficial aspect of breast-feeding is multifactorial and
includes nutritional, gastrointestinal, immunological, devel-
opmental, and psychological effects [176]. These benefits are
even more profound in preterm babies, which are more com-
mon in SSP of women with a history of PPCM and reduced
LVEF, and in low- and middle-income countries [177]. In
a recently published report of the first 411 women enrolled
into the worldwide registry of PPCM, a large percentage of
the patients have been recruited in low- and middle-income
countries where the use of bromocriptine was even more
prevalent compared to the developed countries [1]. Although
the benefit of breast-feeding in low economical countries is
well recognized, its importance in high-income countries is
less well appreciated [178,179]. Considering the substantial
benefits of breast-feeding and the fact that the approval of
the use of the drug for the prevention of lactation was with-
drawn by the US Food and Drug Administration for safety
concerns [180], women with PPCM should be well informed
by their health-care providers, on the potential benefit, but
at the same time, the incomplete information available to
date on the efficacy and safety of bromocriptine therapy in
the early postpartum period [177]. Future prospective, ran-
domized and controlled trials are warranted to provide more
CHAPTER 10 Peripartum Cardiomyopathy 147
information on the efficacy and safety of bromocriptine ther-
apy in PPCM. The 2018 European cardiac society guidelines
for management of cardiovascular during pregnancy con-
cluded that the addition of bromocriptine to standard HF
therapy may improve LV recovery and clinical outcome in
women with acute severe PPCM. The guidelines recommend
that the use of bromocriptine (2.5 mg once daily) for at least
one week may be considered (class IIb, level B) in uncompli-
cated cases, whereas prolonged treatment (2.5 mg twice daily
for two weeks, then 2.5 mg once daily for six weeks) may be
considered in patients with LVEF <25% and/or cardiogenic
shock. Because of the increased risk of thromboembolic com-
plications, bromocriptine treatment must always be accom-
panied by anticoagulation with heparin (LMWH or UFH), at
least in prophylactic dosages [181].
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 avail-
able, no recommendations can be made. Amos et al. [56]
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, β-blockers
(n = 11), or both (n = 5). No MRI persistent myocardial
damage has been found in women in PPCM [97]. However,
spontaneous deterioration of LV function has been reported
in a large retrospective study in three patients after either
complete recovery (n = 2) or partial (LVEF 45%) recovery
(n = 1) 3–60 months after diagnosis [86]. An early echocar-
diographic study of women with recovered LV function
revealed decreased contractile reserve in response to dobu-
tamine challenge [120]. Recently, Goland et al. described
residual impairment of cardiac function by speckle track-
ing and tissue Doppler imaging in 29 women after recov-
ery from PPCM (LVEF ≥50%) compared with age and
parity control group indicating the presence of persistent
subclinical LV systolic dysfunction. In addition, as previously
discussed, even women with recovered LVEF remain at risk
of worsening of cardiac function with subsequent pregnan-
cies. When discontinuation of drug therapy is desired in a
patient with full recovery (LVEF ≥55%). Gradual tapering of
the medication one at the time should be done with close
clinical and echocardiographic monitoring during the first
year. Before complete discontinuation of treatment, compre-
hensive rest (including assessment by 2D strain) and stress
echo to assess LV contractility reserve should be considered.
In women with borderline LVEF (50–54%), continuation of
β-blockers would be reasonable. The University of South-
ern California protocol is to stop ACE inhibitors or ARBs
as well as spironolactone, followed by discontinuation of β-
blockers three months later provided no change in LVEF.
Annual assessment of LV function is recommended in all
women after LV recovery.
148 PART III Cardiac Disorders and Pregnancy
Devices and heart transplantation
Implantable cardioverter-defibrillators (ICDs)
There are limited data on fatal arrhythmias in patients with
PPCM. Goland et al. in a retrospective review of 182 patients
in California described sudden death as a cause of mortal-
ity in 38% of cases [86]. Nonsustained ventricular tachycar-
dia has been obtained in four patients with PPCM, out of
19 on 24-hour Holter monitoring [182]. In cases with persis-
tent ventricular tachycardia, ablation may be required [183].
A strong trend for higher incidence of appropriate ther-
apy has been found on implantable cardioverter-defibrillator
(ICD) interrogation in 19 women with PPCM compared
to those with nonischemic DCM. Duncker et al. [184] in
a recent single-center study in Germany of seven women
with severely reduced LVEF (mean 18%) who received wear-
able cardioverter/defibrillator (WCD) life vests documented
four events of ventricular fibrillation with successful shock
therapy in three of the women over a mean follow-up of
81 days. More recently, the same group reported the results
on a multicenter retrospective analysis of 49 women with
newly diagnosed PPCM and LVEF ≤35%, from 16 cen-
ters in Germany who received WCD with mean follow-up
120 ± 106 days [185]. Of 49 women, 12% presented ventric-
ular tachyarrhythmias: five episodes of VF, two of sustained
VT, and one with nonsustained VT. In contrast, a large retro-
spective registry study by Saltzberg et al. [186] of after-market
WCDs in 107 women with PPCM (average EF 22%) revealed
no shocks for ventricular tachycardia or fibrillation over an
average follow-up of four months. Only 20% of the women
underwent a permanent ICD, mostly for persistent ventricu-
lar dysfunction.
Because early sudden death is likely in high-risk patients
[7,86,136,182,184,185], it is often tempting to consider the
early implantation ICDs in such cases. Recent guidelines,
(a)
Figure 10.13 (a,b) A 18-year-old woman who developed tachycardia and hypertension with severe hypoxemia (PO2 30%) and acidosis during
C-section delivery, which was not corrected with inotropic support and 100% oxygen. LVEF was found to be 18%, and she was diagnosed
with PPCM. Extracorporeal membrane oxygenation (ECMO) was used successfully for 24 hours. Patient was extubated on day 4 and was
discharged home on day 12. One month after discharge, LVEF was 56%.
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 individ-
ual patients on the basis of initial LV function [70]. For these
reasons, and because recovery of LV function occurs in most
patients within two to six months after the diagnosis [56,187],
it may be advisable to consider the temporary use of wear-
able external defibrillators up to six months [188] or entirely
subcutaneous ICDs [189] in high-risk patients as a bridge to
recovery or to ICD implantation in patients with persistent
LV dysfunction despite an adequate trial of optimal medical
therapy. In women with LBBB and persistent LVEF≤35% in
spite of appropriate medical therapy, cardiac resynchroniza-
tion therapy implantation is recommended [190].
Mechanical circulatory devices
In patients demonstrating rapid deterioration not respond-
ing to medical therapy including vasoactive medications and
with adequate oxygenation, percutaneous (intra-aortic bal-
loon pump, Impella) or surgical devices such as CentriMag,
can be used. In cases with impaired oxygenation, extracorpo-
real membrane oxygenation (Figure 10.13) or Tandem Heart
is recommended. Assist devices (LVAD or BiVAD) have
been used successfully in cases when indicated [191–200].
A recent comprehensive search of the medical literature
through March 2017 identified 26 women with PPCM who
were treated with MCS. Seventy-four percent of them pre-
sented postpartum, and 42% of the patients received support
with more than one device. In patients who were treated
with only one device, the most common was LVAD (31%),
followed by intra-aortic balloon pump (12%), Impella (8%),
and extracorporeal membrane oxygenation (ECMO) (8%).
(b)

Complications were described in 50% of the cases with
bleeding being the most common, followed by infection
and thrombotic events, including stroke. Overall 58% of
the patients achieved recovery, 23% underwent cardiac
transplantation, 8% were listed for transplantation, and
11.5% died [201].
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 temporary devices as a bridge to recov-
ery before referral for cardiac transplantation [194,196,197].
Recently, a study of 99 patients with PPCM who received
LVAD reported that outcomes were generally better com-
pared to women with non-PPCM cardiomyopathy; however,
only a minority (6%) recovered, and almost half of them
finally received cardiac transplantation [124].
Cardiac transplantation
This procedure has been performed successfully in patients
with PPCM [202–204]. A recent multi-institutional study by
Rasmusson et al. [205] using data from a cardiac transplan-
tation research database described 69 women who under-
went 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 sim-
ilar age who did not have history of pregnancies and similar
to that of women with a history of pregnancy. The cumu-
lative risk of infections was lowest in patient with PPCM,
while freedom from allograft vasculopathy and mortality was
similar or higher compared with the other groups. Recently,
the same group compared 485 PPCM women receiving
transplantation to non PPCM patients. PPCM patients were
younger, had higher sensitization, required higher inten-
sity of cardiovascular support pretransplant, and had higher
listing status. In addition, PPCM women had more post-
transplant rejection during the index transplant hospitaliza-
tion and during the first year. Comparing PPCM with other
women and all others, graft survival was inferior, and age-
adjusted survival was lower.
Labor and delivery
The timing and mode of delivery in a patient diagnosed dur-
ing 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. Continua-
tion of pregnancy can be considered with frequent monitor-
ing, to allow fetal maturity in patients who can be stabilized
on medical or device therapy. The mode of delivery in a sta-
ble patient with PPCM should be determined jointly by the
obstetrician and the cardiologist. Vaginal delivery prevents
potential risks associated with anesthesia and surgical deliv-
ery that include hemodynamic fluctuations, larger blood loss,
pain, higher rate of infections, respiratory and thromboem-
bolic complications, damage to pelvic organs, and potential
CHAPTER 10 Peripartum Cardiomyopathy 149
unfavorable effects on future reproductive health [206]. 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 the unstable patient with PPCM who is diag-
nosed during pregnancy and allows optimization of hemody-
namic status before delivery as well as monitoring of changes
related to fluid intake and blood loss during delivery and early
hemodynamic changes as a result of increased venous return
and peripheral vascular resistance as well as fluid mobiliza-
tion after the 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 sat-
uration, ECG, and fetal heart rate should be continuously
monitored.
Psychological sequences among
PPCM survivors
Most research is focused on survival and cardiac complica-
tions of PPCM, and little is known about psychosocial out-
comes of these previously healthy young women. Rosman
et al. [207] in a nation-wide, web-based quality of life registry
revealed that 32% of 177 PPCM patients (median time since
diagnosis of 3.0 ± 4.3 years) had clinically significant symp-
toms of depression, which was associated with worse atten-
dance to medical follow-up visits. Another study showed that
women often described their initial response to the diag-
nosis of PPCM as feeling terrified, and feeling a sense of
doom, even after recovery [198]. Women had difficulty car-
ing for their newborns during the postpartum period and
recommendations to avoid additional pregnancy, had neg-
ative influence on their family relationship [208]. Another
study focused on quality of life and emotional well-being in
survivors of PPCM using a survey distributed to members of
“Peripartum Cardiomyopathy Survivors” support group on
the social networking site Facebook. Of 116 women com-
pleted the survey, more than half (56%) never returned to
their previous emotional condition and only 26% were sat-
isfied with the counseling they received from their physician.
All this information emphasizes the fact that most women
with PPCM are still worried about their long-term prognosis
and need ongoing support and education.
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