BioEd Online

It should be one of the happiest events in a woman's life. But for women with a rare heart disease, the first few months after giving birth can be deadly.

The disease, called postpartum cardiomyopathy, causes heart failure in affected women at the end of their pregnancy or soon after giving birth. Now, researchers have found that an aberrant breakdown of prolactin - the hormone that stimulates milk production — may be to blame. Drugs that block production of this hormone could therefore hold promise for a cure.

Postpartum cardiomyopathy is fairly rare, but is a leading cause of death soon after birth for mothers in developed countries. The frequency varies dramatically — in Haiti the disease strikes one mother for every 299 live births, whereas in the United States, it affects about one mom out of every few thousand. The disease hits otherwise healthy women within five months of giving birth, and damages the heart's left ventricle, which pumps blood to the rest of the body — proving fatal about 15% of the time.

"The women don't start out looking very sick," says Denise Hilfiker-Kleiner of the Hannover Medical School in Germany and lead author of the study. "It's hard to realize it's a severe problem until it's too late."

Cut to pieces

Hilfiker-Kleiner became interested in the disease when she and her colleagues were studying a protein called Stat3. They noticed that female mice that did not have the Stat3 gene were likely to die soon after giving birth. Although normal lab mice can produce eight to twelve litters in a lifetime, none of the mice without Stat3 survived beyond five.

They discovered that the mice with the mutant gene were producing excess amounts of a protein that breaks apart the hormone prolactin. This process produces a molecule that is known to inhibit growth of blood vessels and promote cell death, so too much of it can be bad for the heart.

The easiest way to cut down on this destructive fragment, the team reasoned, was to get rid of prolactin's source. So they treated the mice with a compound called bromocriptine, which inhibits production of prolactin. It worked, they report in Cell¹, and allowed the mice to give birth a normal number of times without their hearts failing.

Early signs

The researchers think the same mechanism is at work in people. Their research showed that in five women with the disease, levels of STAT3 protein were lower than normal. And three out of five patients were found to have prolactin fragments in their bloodstream.

The researchers joined a team in South Africa — where the frequency of the disease is one case for every thousand births — to test the effects of bromocriptine in pregnant women with a history of postpartum cardiomyopathy. "The physicians told them it was a bad idea to get pregnant again," says Hilfiker-Kleiner. "They had an almost 100% chance of getting the disease again, and potentially a more severe case than the first." But some had become pregnant anyway.

Six of these women were given bromocriptine, in addition to the normal therapy of drugs to lower blood pressure and maintain a rhythmic heart rate. None of the six developed the disease, whereas the six women in the control group that did not receive bromocriptine all had some heart failure. Three of the women in the control group died within four months of delivery.

The treatment looks promising, but the numbers so far are very small. A randomized, double-blind clinical trial involving one hundred women is currently underway in South Africa.

Milk shortage

Tiziano Scarabelli, a cardiologist at St. John Hospital and Medical Center in Detroit, Michigan, notes that successful treatment with bromocriptine does not necessarily implicate prolactin in the disease. The drug also decreases blood pressure and lowers the heart rate, he notes. Hilfiker-Kleiner says they did not see either effect in mice treated with the bromocriptine, but that could be because of the dose or the fact that the mice ate the drug rather than being given an injection.

And taking bromocriptine has disadvantages. Mothers who take it cannot produce breast milk, and the hormone may also help the uterus recover after pregnancy. "Prolactin is good — it has a lot of beneficial effects," says Hilfiker.