Peripartum Cardiomyopathy: Underdiagnosed Cardiovascular Killer

The most common cardiovascular killer in maternal medicine is also among the most misdiagnosed. Peripartum cardiomyopathy (PPCM), a systolic dysfunction that occurs either in late pregnancy or in the early postpartum stage, is often misdiagnosed in the obstetric and primary care settings, according to experts.

“I’ve looked at why people die during pregnancy and postpartum, and the single largest cause is a late referral or late diagnosis, or not being able to refer to a tertiary level care center,” said Garima Sharma, MD, who directs cardio-obstetrics and cardiovascular women’s health at Inova Health System in Falls Church, Virginia.

Sharma is the lead author of a paper published in the Journal of the American Heart Association, aimed at improving workforce competencies in cardio-obstetrics.

Symptoms and Misdiagnosis

PPCM’s most common presentations, such as shortness of breath and edema, mimic symptoms of late-stage pregnancy. Patients who are postpartum and present with fatigue, another common symptom of PPCM, are often told it is due to lack of sleep, typical of life with an infant.

That’s according to Michael Givertz, MD, medical director of Heart Transplant and Mechanical Circulatory Support Program at Brigham and Women’s Hospital in Boston, and a professor of cardiovascular medicine at Harvard Medical School, Boston.

“That confusion in the diagnosis often happens,” Givertz told Medscape Medical News. “We’ll see patients postpartum who have been to the emergency room two or three times, or who’ve been to urgent care or back to see their obstetrician or primary care provider with some of these symptoms. They get diagnosed with bronchitis or asthma, or worse — anxiety, before ultimately someone makes the diagnosis that they have significant heart failure,” he said.

Other symptoms of PPCM are congestion — including dyspnea on exertion — orthopnea, and paroxysmal nocturnal dyspnea, according to a paper published in the Journal of the American College of Cardiology.

PPCM Diagnostic Criteria

Diagnosis of PPCM is on the rise, but awareness among primary care clinicians and Ob/gyns is still not very high, said Givertz and Afshan Hameed, MD, a clinical professor of obstetrics and gynecology and cardiology at the UC Irvine School of Medicine.

“The diagnosis of peripartum cardiomyopathy is generally made more often now that we have a better understanding of the disease process associated with it,” Hameed said. “But pregnancy stresses the body and can adversely impact the cardiovascular system. This is why it is important for primary care and obstetricians to be aware of it.”

Givertz said that for a clinician to suspect PPCM, the presentation must meet these three criteria:

● Patient is pregnant, typically in the last trimester or patient was recently pregnant, usually within the previous 5 months.

● The patient exhibits typical signs and symptoms of heart failure and has left ventricular ejection fractions (LVEFs)

● There is no other explanation for the symptoms.

“Data suggest that PPCM occurs about once in every 1000 births in the US,” Givertz said. “That’s pretty rare, right?” 

The odds of encountering a patient with PPCM may be even lower, according to the National Heart, Lung, and Blood Institute, which states on its website that PPCM occurs anywhere between 1 in 1000 to 1 in 4000 births.

And yet, it is the most common cause of cardiovascular-related maternal mortality in the United States, according to Hameed, who is also the director of obstetrical services and patient safety and quality at UC Irvine.

“In my work, especially with writing maternal mortality reviews, this is one of the most common causes of cardiovascular-related maternal death I see,” Hameed said. “We need primary care physicians and obstetricians to be suspicious. They need to keep that question in mind if someone comes to see them with shortness of breath.”

Cardiovascular and Other Risk Factors

Maternal mortality data collected by the US Centers for Disease Control and Prevention show that there were 33.2 pregnancy-related deaths per 100,000 live.

More than a quarter of those deaths was due to cardiovascular diseases, according to a practice bulletin from the American College of Obstetrics and Gynecologists of which Hameed is a co-author.

Risk factors for PPCM include preeclampsia, advanced maternal age, and multiple gestation pregnancy, according to Givertz, co-author of a PPCM literature review in The BMJ. Black women, especially those from Nigeria and Haiti, are particularly at risk, according to the review.

Lactation Hormone Possible Cause

The exact etiology of PPCM is still unknown. In patients who are diagnosed with it, there may or may not be a preexisting cardiovascular concern. Givertz said some have suggested it is due to viral inflammation or an autoimmune dysfunction. Current popular thinking based on animal models is that peripartum hormonal changes create some sort of vascular insult directly to the heart.

“The hypothesis is that the lactation hormone prolactin somehow becomes altered and then becomes dangerous to the cardiac muscle, causing apoptosis,” said Hameed. “Prolactin is at much higher levels in pregnancy and also postpartum.”

The REBIRTH clinical trial (NCT05180773) is a multi-site, phase 4, randomized, placebo-controlled study of the effect of the prolactin suppressant bromocriptine in women newly diagnosed with PPCM. Both Givertz and Hameed are REBIRTH principal investigators at their respective research facilities.

“The thought is that bromocriptine stops the ongoing destruction of the heart and then gives the body a chance to heal,” Hameed said.

The study’s primary analysis will compare LVEF at 6 months in the cohort receiving standard heart failure therapy plus bromocriptine with those on standard therapy plus placebo, controlling for initial baseline LVEF. Investigators aim to enroll 200 women in the study.

Genetic Predisposition

There also has been investigation into whether some women are genetically predisposed to this cardiovascular condition.

Givertz and colleagues in a study published in TheNew England Journal of Medicine found that 15% of 172 women with PPCM had a genetic profile similar to that in persons with dilated cardiomyopathy compared with 4% of population level controls that matched the dilated cardiomyopathy group.

“That’s kind of the first hit. Then there’s a second hit, which is the actual pregnancy and perhaps the biology related to pregnancy,” Givertz said.

Confirming Suspicions

If PPCM is suspected in a patient, Sharma, Hameed, and Givertz all recommended ordering an echocardiogram to examine left ventricular size and function as part of the differential.

Sometimes, such as when a patient presents to the emergency department (ED), an echocardiogram is not the first test ordered, said Givertz.

“If you asked which is more common at the end of pregnancy or immediately following delivery, PPCM or an embolism, it’s a pulmonary embolism,” he said. “The ED physician is going to order chest x-rays.”

If a chest x-ray rules out blood clots but indicates fluid on the lungs and an enlarged heart, Givertz said the next test will be for N-terminal pro-brain natriuretic peptide, a hormonal marker of heart failure. And that, at least in the ED, typically will lead to an echocardiogram, which will help to get to the correct diagnosis, which is important, Givertz said, because delays in starting therapy can lead to adverse events.

PPCM Management

Treatment for PPCM is about the same as for heart failure, although women who are breastfeeding need modifications to their regimen because the angiotensin receptor-neprilysin inhibitor combination, sacubitril with valsartan, does not have safety data on breastfeeding, according to Givertz. Instead, he said this cohort is given an ace inhibitor, a beta blocker, and the neuromodulator isoallopregnolone, which is also used to mitigate stress in premenstrual dysphoric disorder.

“Ninety percent or more of these women will actually get better, have improvement in their cardiac function over 6-12 months, and then at some point in the future may be able to come off of medications and even have another baby safely,” Givertz said.

“That’s 90% compared with up to 50% of them dying, which is what it used to be. Now most of them will get better, but not on their own.”

Givertz received research support from the National Institutes of Health National Heart Lung, and Blood Institute. Hameed and Sharma had not relevant disclosures.

Whitney McKnight is a freelance medicine and health policy reporter based near Lexington, Kentucky.