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Pearson GD, Veille J, Rahimtoola S, et al. Peripartum Cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) Workshop Recommendations and Review. JAMA. 2000;283(9):1183–1188. doi:10.1001/jama.283.9.1183
Author Affiliations: Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (Dr Pearson); Department of Obstetrics and Gynecology, Bowman Gray School of Medicine, Winston-Salem, NC (Dr Veille); Division of Cardiology, University of Southern California, Los Angeles (Dr Rahimtoola); Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC (Dr Hsia); Emeritus Professor of Cardiology, Imperial College Medical School, London, England (Dr Oakley); Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee (Dr Hosenpud); Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Ga (Dr Ansari); and Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md (Dr Baughman).
Clinical Cardiology Section Editors: Bruce
Brundage, MD, University of California, Los Angeles, School of Medicine; Margaret
A. Winker, MD, Deputy Editor, JAMA.
Objective Peripartum cardiomyopathy (PPCM) is a rare life-threatening cardiomyopathy
of unknown cause that occurs in the peripartum period in previously healthy
women. In April 1997, the National Heart, Lung, and Blood Institute (NHLBI)
and the Office of Rare Diseases of the National Institutes of Health (NIH)
convened a Workshop on Peripartum Cardiomyopathy to foster a systematic review
of information and to develop recommendations for research and education.
Participants Fourteen workshop participants were selected by NHLBI staff and represented
cardiovascular medicine, obstetrics, immunology, and pathology. A representative
subgroup of 8 participants and NHLBI staff formed the writing group for this
article and updated the literature on which the conclusions were based. The
workshop was an open meeting, consistent with NIH policy.
Evidence Data presented at the workshop were augmented by a MEDLINE search for
English-language articles published from 1966 to July 1999, using the terms peripartum cardiomyopathy, cardiomyopathy, and pregnancy. Articles on the epidemiology,
pathogenesis, pathophysiology, diagnosis, treatment, and prognosis of PPCM
Recommendation Process After discussion of data presented, workshop participants agreed on
a standardized definition of PPCM, a general clinical approach, and the need
for a registry to provide an infrastructure for future research.
Conclusions Peripartum cardiomyopathy is a rare lethal disease about which little
is known. Diagnosis is confined to a narrow period and requires echocardiographic
evidence of left ventricular systolic dysfunction. Symptomatic patients should
receive standard therapy for heart failure, managed by a multidisciplinary
team. If subsequent pregnancies occur, they should be managed in collaboration
with a high-risk perinatal center. Systematic data collection is required
to answer important questions about incidence, treatment, and prognosis.
Heart failure in the puerperium has been recognized since the 18th century,
but cardiomyopathy was not identified as its cause until an article by Gouley
et al was published in 1937.1 Peripartum cardiomyopathy
(PPCM) is now considered to be a cardiomyopathy of unknown cause that occurs
in the peripartum period in women without preexisting heart disease.2,3 Peripartum cardiomyopathy is relatively
rare, but can be devastating, with reported mortality rates between 18% and
may not recover completely and may require heart transplantation. Even if
left ventricular function does return to normal, exercise tolerance may remain
abnormal and the long-term sequelae, including risks of future pregnancies,
are not known.
In April 1997, the National Heart, Lung, and Blood Institute (NHLBI)
and the Office of Rare Diseases of the National Institutes of Health (NIH)
convened a Workshop on Peripartum Cardiomyopathy to foster a multidisciplinary
review. Experts in cardiovascular medicine, obstetrics, immunology, and pathology
met to discuss the available information and make recommendations (a list
of participants appears at the end of this article). The objectives for the
Workshop on PPCM, modeled on a previous NHLBI Workshop on Idiopathic Dilated
Cardiomyopathy,6 were to (1) summarize existing
information on PPCM, specifically its definition, epidemiology, cause, clinical
characteristics, treatment, and prognosis; (2) review diagnostic criteria
and discuss means of differentiating early symptoms of heart failure from
normal physiological changes associated with pregnancy, such as tachypnea
and fatigue during the third trimester of pregnancy; (3) develop recommendations
for future research on PPCM; and (4) discuss educational measures to increase
awareness of PPCM and thus facilitate prompt diagnosis. A representative subgroup
of 8 participants and NHLBI staff formed the writing group for this article
and updated the literature on which the conclusions were based. The workshop
was an open meeting consistent with NIH policy.
Data presented at the workshop were augmented with a MEDLINE literature
search (English language) for the years 1966 to July 1999 that included the
terms peripartum cardiomyopathy, cardiomyopathy, and pregnancy. The literature
search was updated following the workshop to provide the most timely references.
The bibliographies of articles identified in this fashion were searched for
additional references, and the search was further supplemented with articles
recommended by workshop participants. This review, which workshop participants
felt to be important because of the reported rarity of the condition, the
consensus that the condition may be more prevalent than reported, and because
of new data concerning cause, includes the majority of articles identified
through these processes covering epidemiology, pathogenesis, pathophysiology,
diagnosis, treatment, and prognosis of PPCM.
Peripartum cardiomyopathy is defined on the basis of 4 criteria, adapted
from work by Demakis et al3,7
and summarized in Table 1. The
importance of adhering to the interval from 1 month before delivery to 5 months
postpartum was emphasized to exclude preexisting causes of cardiomyopathy
that may be exacerbated by pregnancy rather than arising as a result of pregnancy.
For example, heart failure occurring earlier in pregnancy may be caused by
previously unsuspected dilated cardiomyopathy unmasked by the hemodynamic
or hormonal stress of pregnancy. Peripartum cardiomyopathy is defined as occuring
only in those patients with no prior history of recognizable heart disease
and can be diagnosed only in the absence of another explanation for the cardiomyopathy.
The incidence of PPCM is not known because population-based estimates
are not available, and the diagnosis of this rare disease is not always straightforward.
Incidence rates reported in individual studies are based on the experience
at a particular institution and may reflect referral bias as well as individual
practice patterns. Although the reported incidence rates range from 1 per
14858 to 1 per 15,000,9
the currently accepted estimate of incidence is approximately 1 per 3000 to
1 per 4000 live births, which would translate to between 1000 and 1300 women
affected each year in the United States.10
Risk factors for PPCM classically identified in the literature include
multiparity, advanced maternal age, multifetal pregnancy, preeclampsia and
gestational hypertension, and African American race.3
It is unclear whether race represents an independent risk factor or whether
it is the interaction of race with hypertension that increases the risk of
PPCM. Until risk factors can be delineated confidently, it is difficult to
develop recommendations for screening high-risk populations.
Workshop participants concurred that PPCM is a distinct entity, rather
than a clinically silent underlying cardiomyopathy unmasked by the hemodynamic
stresses of pregnancy, because the reported incidence is higher than the incidence
of idiopathic cardiomyopathy,6 and because
the high frequency of myocarditis would not be expected in a population presenting
with decompensation of preexisting heart disease due to hemodynamic stress.
However, reliable data comparing the incidence of cardiomyopathy in pregnant
women compared with age-matched nonpregnant women are not available. A number
of possible causes have been proposed for PPCM, including myocarditis, abnormal
immune response to pregnancy, maladaptive response to the hemodynamic stresses
of pregnancy, stress-activated cytokines, and prolonged tocolysis. In addition,
there have been a few reports of familial PPCM,11-13
raising the possibility that some cases of PPCM are actually familial dilated
cardiomyopathy unmasked by pregnancy. The key hypotheses are presented below.
There is more evidence for myocarditis as a cause of PPCM than for other
purported etiologies. Melvin and colleagues14
first reported myocarditis by endomyocardial biopsy in 3 consecutive patients
with PPCM. The incidence of myocarditis in subsequent authors' series has
varied. The variability is likely due to the inclusion of patients outside
the accepted time frame of PPCM, the inherent difficulties in establishing
the diagnosis of myocarditis by endomyocardial biopsy,15,16
the variability in the inclusion of patients with borderline myocarditis with
those with histologic myocarditis as defined by the Dallas histologic criteria,
the potential geographic variability of patient populations affected, and
the variable interval between presentation and the performance of the endomyocardial
biopsy. The highest incidence of myocarditis in PPCM (76%) was reported by
Midei and colleagues.17 This group performed
endomyocardial biopsies on patients with symptoms of congestive heart failure
at the time of presentation and included patients with histologic borderline
myocarditis as well as those with active myocarditis.
The absent or muted immune response during pregnancy may allow for unchecked
viral replication and thus a greater likelihood of myocarditis in the setting
of a viral infection. Studies in pregnant mice demonstrate enhanced susceptibility
to viral myocarditis due to coxsackieviruses and echoviruses.18,19
In the near future, electron micrography combined with molecular biological
techniques should permit not only identification of viral particles in myocardium,
but also the putative viruses implicated. The presumption is that if viral
genetic products are evident, the postviral immune response of the patient
may have been inappropriately directed against otherwise cryptic cardiac tissue
proteins, leading to ventricular dysfunction.
Several reports have documented the occurrence of chimerism of the hematopoietic
lineage cells from the fetus to the mother during pregnancy.20-23
It is postulated that fetal cells may escape into the maternal circulation
and remain there without being rejected, due to weak immunogenicity of the
paternal haplotype of the chimeric cells, or to the naturally occurring immunosuppressive
state of the mother, or both. If chimeric hematopoietic cells take up residence
in cardiac tissue during the immunosuppressed pregnant state and, following
postpartum recovery of immune competence, are recognized as nonself by the
maternal immune system, a pathologic autoimmune response may be triggered.
Prior exposure to paternal major histocompatibility complex antigens expressed
by spermatozoa or previous immunization from prior pregnancies may play a
role in inducing local tissue inflammatory response. Cytokines and similar
signaling molecules are then released, leading to nonspecific bystander myocytotoxicity
and myocarditis. The evidence (Table 2)
that PPCM is associated with high titers of autoantibodies against select
cardiac tissue proteins (eg, adenine nucleotide translocator, branched chain α-keto
acid dehydrogenase) supports abnormal immunologic activity as a possible cause
During pregnancy, blood volume (preload) and cardiac output increase
and afterload decreases. An echocardiographic assessment of cardiac hemodynamics
in normal pregnancies performed by Geva et al25
demonstrated a 10% increase in left ventricular end-diastolic volume, a 45%
increase in cardiac output, and a 26% to 28% decrease in end-systolic wall
stress, a sensitive measure of myocardial afterload. In addition, the left
ventricle remodels in response to the hemodynamics of pregnancy, resulting
in transient hypertrophy. The research by Geva et al25
and other studies26 have shown a reversible
decrease in left ventricular systolic function in the second and third trimesters
that persisted into the early postpartum period, but returned to baseline
shortly thereafter. It is possible that PPCM may be due, in part, to an exaggeration
of this decrease in systolic function, although there are no data in women
supporting this hypothesis.27
Other causes for PPCM that merit further study have been suggested and
include the following: (1) prolonged tocolysis4,28;
(2) stress-activated proinflammatory cytokines such as tumor necrosis factor α
or interleukin 1 that have been implicated in the pathophysiology of idiopathic
dilated cardiomyopathy29; (3) abnormalities
of relaxin, primarily an ovarian hormone produced during pregnancy, recently
found in cardiac atria, shown to have positive inotropic and chronotropic
properties30 and potentially involved in excessive
relaxation of the cardiac skeleton; and (4) deficiency of selenium,31 which may make the heart more susceptible to injury
from viral infection, hypertension, or hypocalcemia.
The diagnosis of PPCM rests on the echocardiographic identification
of new left ventricular systolic dysfunction during a limited period surrounding
parturition. This presents a challenge because many women in the last month
of a normal pregnancy experience dyspnea, fatigue, and pedal edema, symptoms
identical to early congestive heart failure. Peripartum cardiomyopathy may,
therefore, go unrecognized, leading to underestimation of incidence. Symptoms
and signs that might raise the suspicion of heart failure include paroxysmal
nocturnal dyspnea, chest pain, cough, neck vein distention, new murmurs consistent
with atrioventricular valve regurgitation, and pulmonary crackles. There are
no specific criteria for differentiating subtle symptoms of heart failure
from normal late pregnancy, so it is important that a high index of suspicion
be maintained to identify the rare case of PPCM.
The diagnosis of PPCM requires excluding other causes of cardiomyopathy
and is confirmed by standard echocardiographic assessment of left ventricular
systolic dysfunction, including depressed fractional shortening and ejection
fraction. Strong consideration should be given to screening family members
of PPCM patients because PPCM may be the forme fruste of a genetic predisposition
In the absence of systematic studies comparing therapeutic approaches
in PPCM, standard heart failure therapy (diuretics, vasodilators, and digoxin32 as needed) should be initiated. Careful attention
must be paid to fetal safety and to excretion of drug or drug metabolites
during breastfeeding after delivery. Collaboration among medical specialists,
including obstetricians, cardiologists, perinatologists, and neonatologists,
is essential. The discussion that follows should be considered a general guide,
rather than a specific algorithm.
Angiotensin-converting enzyme inhibitors are contraindicated during
pregnancy because of teratogenicity, but should be considered a mainstay of
treatment for PPCM after delivery. Safe alternatives during pregnancy include
hydralazine and nitrates. Calcium channel blockers can be used during pregnancy
to control blood pressure (and decrease uterine contractility), but most have
negative inotropic properties that may make them unacceptable for use in this
situation. Amlodipine, a dihydropyridine calcium channel blocker, has been
shown to improve survival in nonischemic cardiomyopathy patients33
and may have a role in management of PPCM. Plasma levels of interleukin 6,
a proinflammatory cytokine, were reduced among amlodipine recipients in the
Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial,34 providing an additional potential rationale for its
use in PPCM.
Second-generation β-adrenoreceptor antagonists have beneficial
effects in selected patients with dilated cardiomyopathy. Studies of β-adrenoreceptor
antagonists in patients with congestive heart failure have demonstrated safety
and modest clinical benefit, but conflicting results regarding survival.35 Vasodilating β-blockers such as carvedilol also
reduce afterload through α1 adrenergic blockade. Data from
the US Carvedilol Heart Failure Program suggest a potential clinical benefit,
including mortality reduction, in dilated cardiomyopathy.36
These drugs are not contraindicated in pregnancy, but as with other agents,
there are no data evaluating their use in PPCM. A reasonable approach would
be to use β-adrenoreceptor antagonists in the postpartum period in patients
who continue to have symptoms and echocardiographic evidence of left ventricular
compromise despite more than 2 weeks of standard heart failure management.
With mild left ventricular dysfunction, therapy can be initiated in
the outpatient setting. Patients with severe heart failure may require hospitalization
and more aggressive support, including intravenous inotropic agents, oxygen,
and invasive monitoring. Patients with significantly depressed left ventricular
function (ejection fraction ≤35%) may benefit from anticoagulation therapy
(heparin before delivery, warfarin afterward) to prevent thrombosis and emboli.
Arrhythmias should be treated according to standard protocols. Immunosuppressive
therapy may be considered in patients with myocarditis documented by endomyocardial
biopsy who fail to improve spontaneously within 2 weeks of initiation of standard
heart failure therapy. The Myocarditis Treatment Trial failed to demonstrate
an overall advantage for immunosuppressive therapy, but did not evaluate its
merits in women with PPCM.37 A more recent
retrospective study suggested that women with PPCM treated with intravenous
immune globulin had a greater improvement in ejection fraction during early
follow-up than patients treated conventionally.38
Women who fail maximal medical management may be candidates for cardiac transplantation.
One study of 10 PPCM patients who underwent heart transplantation reported
survival comparable to age-matched women undergoing heart transplantation
for other indications, but noted a marginally higher rate (P = .05) of biopsy-proven early rejection, necessitating increased
Salt and water restriction are important in patient management, particularly
in women with symptoms and signs of heart failure. Once heart failure symptoms
have been controlled, modest exercise may improve symptoms as well as peripheral
muscular and arterial tone. The need for early delivery and the mode of delivery
should be assessed through collaboration with cardiologists and anesthesiologists.
There is little systematic evidence that infants born to women with PPCM are
adversely affected, although one study did report a premature delivery rate
of 21% in 14 women.40
The prognosis for women with PPCM appears to depend on the normalization
of left ventricular size and function within 6 months after delivery. In one
study, approximately half of 27 women studied had persistent left ventricular
dysfunction. In this group, the cardiac mortality rate was 85% over 5 years,
compared with the group in whom cardiac size returned to normal, who experienced
no reported cardiac mortality in the same time interval.3
A more recent study corroborates these results: 50% (7/14) of patients had
dramatic improvement soon after delivery, but 6 of the 7 remaining patients
died.41 Survivors were found to have a higher
mean ejection fraction (23% vs 11%) and smaller mean left ventricular cavity
size (5.8 vs 6.9 cm) at diagnosis.
Currently, there is no consensus regarding recommendations for future
pregnancy after PPCM. Patients whose left ventricular size or function does
not return to normal should be counseled strongly to avoid subsequent pregnancy3 and treated accordingly, including adopting a heart-healthy
diet and lifestyle. Patients whose cardiomyopathy apparently resolves completely
are a more difficult group to counsel. In the long-term follow-up study reported
by Demakis et al,3 8 of 14 patients whose heart
size returned to normal after the first episode of PPCM had subsequent pregnancies.
Of the 8 patients, 2 developed PPCM with subsequent pregnancies. Sutton and
colleagues41 reported normal subsequent pregnancies
and normal left ventricular function (by echocardiography) in 4 women whose
heart size returned to normal after PPCM in a prior pregnancy. Because PPCM
has been associated with multiparity in some studies, the risk of irreversible
cardiac damage may increase with each subsequent pregnancy. In addition, even
though the left ventricular size and function return to normal, there is evidence
that contractile reserve is impaired,42 and
recurrence of PPCM despite rapid return of heart size and function to normal
in the prior affected pregnancy has been reported.43
Therefore, subsequent pregnancies, if they cannot be avoided, should be managed
in collaboration with a high-risk perinatal center.
Peripartum cardiomyopathy is a rare disease of unknown cause that strikes
women in the childbearing years, may recur, and is associated with a high
mortality rate. Hypotheses about the cause center on interactions of peripartum
physiology with infectious, inflammatory, genetic, hormonal, or metabolic
factors. Diagnosis of PPCM is challenging and requires vigilance. Once PPCM
is identified based on the workshop criteria, the primary goal of therapy
is to alleviate symptoms of congestive heart failure. If left ventricular
size returns to normal after pregnancy, the short-term prognosis is likely
to be favorable, although long-term sequelae, particularly with repeat pregnancy,
still are not known. Failure of heart size to return to normal is associated
with excess morbidity and mortality.
Based on the information presented at the workshop and on the identified
gaps in knowledge, participants made the following clinical and research recommendations:
Adherence to the criteria in Table 1, especially the timing and the necessity for echocardiographic
demonstration of left ventricular systolic dysfunction, is important in making
the diagnosis of PPCM.
Once the diagnosis is made, close collaboration between specialists
in obstetrics, perinatology, and cardiology is essential. If the diagnosis
is made before birth, the team should include anesthesiology and neonatology
as well, and transfer to a high-risk perinatal center should be considered.
For affected patients, family history may be revealing and should
Therapy should be initiated using standard heart failure protocols.
Angiotensin-converting enzyme inhibitors should be avoided prenatally, but
are a mainstay of therapy otherwise.
Immunosuppressive therapy can be considered if an endomyocardial
biopsy indicates myocarditis, and if there is no improvement after 2 weeks
of standard heart failure therapy.
Subsequent pregnancies remain controversial, but at the very least
should be managed in a high-risk perinatal center if they cannot be avoided.
Workshop participants also made recommendations about the need for additional
research and dissemination of information:
An international registry should be established to capture prospectively
all women with PPCM to facilitate the following: (1) development of better
incidence and prevalence estimates, (2) determination of risk factors and
prognostic variables, (3) ascertainment of cardiovascular risks for subsequent
pregnancies, (4) establishment of a centralized serum and tissue bank to help
facilitate identification of the cause of PPCM, and (5) evaluation of therapeutic
A review of current knowledge about PPCM should be prepared for
publication. This article fulfills that recommendation.
Because PPCM is an under-recognized obstetrical problem, an educational
brochure should be prepared for broad dissemination to individuals involved
in the care of women of childbearing age.