Placenta 'switch' that kickstarts labor may solve long-standing mystery

As any 40-weeks’-pregnant woman can attest, predicting when labor might start is a dark art — which is to say, basically impossible. Now, a new study suggests that a genetic “switch” in the placenta might kick off the production of the hormones that start labor.

If the findings are confirmed, they could help explain the basic biological processes that have perplexed researchers for generations. The results might also lead to ways to halt preterm birth, a problem behind more than a third of infant deaths in the United States.

“It’s 2015, and even now we don’t understand how the clock works that governs the length of pregnancy,” said study researcher Dr. Todd Rosen, chief of maternal-fetal medicine at the Rutgers University Robert Wood Johnson Medical School.

In the new study, researchers found that a protein called NF-κB switches up its activity as pregnancy progresses. This change in activity may play a role in kicking off labor, the researchers said in their findings, published today (Aug. 25) in the journal Science Signaling.

The pregnancy clock

According to the Centers for Disease Control and Prevention (CDC), one in nine births in the United States in 2012 occurred before the 37th week of pregnancy. Complications following such premature births cause 35 percent of all infant deaths, making prematurity the leading cause of death in babies.

“In the last 25 years, the problem has actually gotten worse, not better,” Rosen told Live Science. In 2015, about 11.4 percent of births were preterm, according to CDC statistics. In 1990, that number was 10.6 percent. [7 Ways Pregnant Women Affect Their Babies]

Rosen and his colleagues have been working to trace back the chain of falling dominoes that cause labor to begin. Previous researchers noticed that a substance called corticotropin-releasing hormone, or CRH, rises exponentially during pregnancy, peaking at the very end. Women with high levels of CRH at the start of pregnancy tend to deliver earliest, and women with low levels tend to remain pregnant past their due dates, implying that CRH might be part of the pregnancy “clock,” Rosen said.

CRH is also secreted in the brain, where it induces the body to produce the stress hormone cortisol. In turn, high levels of cortisol normally tamp down CRH production in the brain, creating a negative feedback loop that prevents CRH from building up.

In the placenta, it’s a different story. Instead of stopping CRH production, cortisol actually ramps up production of CRH. The picture that emerged, Rosen said, is this: As it grows, the fetus produces more and more cortisol, prompting the placenta to produce more and more CRH. But at a certain point, the placenta also begins producing COX-2, an enzyme crucial for producing prostaglandins, which are very important for starting labor.

Genetic control

All of this left a major unanswered question: Why does cortisol ramp up CRH in the placenta, when it instead ramps it down in the brain? Rosen and his team suspected the answer might lie in epigenetics, he said.

Epigenetics are like add-on programs to the genetic code — they help control when genes are activated, or inactivated. The team focused on a protein called NF-κB, which they knew to be the go-between for cortisol and the gene behind CRH production. Comparing placenta cells from the middle of pregnancy to such cells at the end of pregnancy, the researchers looked for any epigenetic changes that occurred as pregnancy advanced.

They found one: In full-term placentas, NF-κB caused epigenetic changes to the CRH gene, adding molecular “tags” that caused the gene to spring into action. In contrast, in earlier placentas, NF-κB did not add as many of the gene-promoting tags , suggesting that this epigenetic change is part of the molecular “clock” that controls the length of pregnancy, Rosen said.

“About half of all cases of preterm birth are unexplained,” Rosen said. “It’s reasonable to guess that those cases of preterm birth are caused by this clock moving too quickly.”

CRH’s exact role in starting labor remains poorly understood, Rosen said. The researchers are now honing in on the NF-κB pathway, looking for drugs that might interfere with the pathway’s work.

“What we’re trying to do is figure out, can we slow down this clock?” Rosen said. In research that has not yet been published, the team found several drugs that might do the job. To test them thoroughly, however, the researchers will have to administer the medicines to pregnant primates and see if this can delay labor.

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