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Researchers are using modern experimental tools to probe the mysterious molecular pathways that lead to premature labor and birth.


Researchers are using modern experimental tools to probe the mysterious molecular pathways that lead to premature labor and birth.

 Louisa Corinne Grant just couldn’t wait to make her grand entrance into the world. My second child and first daughter was born on January 3, 2013, at 8:21 p.m., surprising me and my wife Kerry by arriving at 35 weeks of gestation, about a month before her expected due date.

Kerry had experienced an exceedingly normal pregnancy and exhibited none of the warning signs or risk factors for premature birth. At some point during her pregnancy, however, a complicated cascade of signaling and chemical crosstalk short-circuited. Something among the gene- and protein-driven pathways designed to keep Louisa wrapped in the warmth of her mother’s womb for a full 40 weeks went haywire. And the molecular confusion caused baby Louisa to depart from in utero comfort before she was fully prepared for the rigors of the outside world.

As Kerry and I watched our daughter navigate (with the help of excellent doctors and angelic neonatal intensive care unit nurses) some of the milder repercussions of preterm birth—mainly problems regulating her body temperature and eliminating waste products from her system—we wondered what compelled the untimely exit of our precious child.

We were surprised to learn that the conditions that trigger preterm birth, which is defined as any birth taking place earlier than 37 weeks of gestation, remain virtually unknown to science even though it affects 1 out of every 9 babies born in the United States, according to the Centers for Disease Control and Prevention (CDC). Knowledge of the molecular triggers for normal-term birth has proven almost equally elusive. But researchers around the world are seeking answers to these vexing questions, and, in the process, developing a fundamental understanding of human gestation and labor that could help save thousands of young lives every day.

“It is a surprise that a phenomenon such as labor is essential for the survival of our species, and yet we know very little about the mechanisms that control it,” says Roberto Romero, Wayne State University perinatologist and head of the Program for Perinatal Research and Obstetrics at the National Institutes of Health’s National Institute of Child Health and Human Development. “We need a molecular taxonomy of premature labor,” he adds. “This is an intellectual challenge that is unlike many others that have been posed by biology and medicine.”


Strange bedfellows

 From a physiological perspective, pregnancy and labor are exercises in extremes. After one sperm among hundreds of millions fertilizes an egg (itself a pretty remarkable event), the resulting embryo implants in the lining of the uterus, and the developing fetus—essentially a foreign entity—takes up residence inside the body of a host whose natural immunologic impulse would be to expel an invader as quickly as possible.

But instead of outright rejection and expulsion, a mysterious chemical conversation between mother and child ensues. Through a tangle of signaling pathways that researchers are just now beginning to tease apart, mother—her immune system modulated—ensconces baby in the serenity of a uterus that expands to 500 times its normal size, providing a retreat that allows development to progress for an average of 40 weeks in humans. But even more puzzling than the intricacies of the immune system modulation that allows mother to tolerate a pregnancy for the better part of a year is the cascade of events at the end of that period, when the process of birth, or parturition, commences.

When the time for parturition arrives, a message to contract is delivered to the smooth muscles in the wall of the uterus, a layer called the myometrium. In doing so, the organ that has stretched to such an amazing capacity becomes, for a brief time, one of the strongest muscles in the human body (by weight), exerting an incredible force downward and outward upon the infant, hell-bent on expelling it and the placenta from the body through the narrow birth canal.

The intricate steps of this process in humans are essentially mysterious to science, perhaps more so than any other physiological phenomenon our species hosts. Some of the players—hormones like progesterone and a few of its receptors—are known, but the sequence of molecular events, and many members of its cast of chemicals and cells, are as yet unidentified.

But that is beginning to change.


Prior thinking

 The insight that is propelling the field of reproductive science forward in its quest to understand the molecular roots of pregnancy and labor is a growing appreciation of the complexity of the phenomena. Much as with cancer, the terms “preterm labor” and “preterm birth” convey a simplicity that does not exist. “Preterm birth is an oddity in that it is one of the few disorders that’s defined by a calendar event rather than some pathogenesis,” says Stephen Lye, vice chair of research and professor of obstetrics and gynecology at the University of Toronto. “We’re now understanding that preterm birth is probably a whole series of different diseases. That’s exciting in that it now puts us in the position to say, ‘I’m going to focus on a fairly defined phenotype.’ ”

Previously, researchers and clinicians sought to understand normal labor and birth, and therefore addressed the problem of preterm labor and birth at the level of the uterus. The key event in labor is the contraction of that muscular organ. If uterine contractions—the rhythmic waves that represent pregnancy’s endgame—could be stopped, the reasoning went, birth could be delayed temporarily.

A class of drugs called tocolytics, which are still used today, can indeed delay a preterm birth for up to a few days by slowing or stopping contractions of the uterus that might otherwise expel a dangerously premature baby. This can buy precious time for other interventions, such as the administration of glucocorticoid drugs that can speed fetal lung development. But tocolytics come with their own suite of risks and cannot be used in many scenarios. And from a conceptual standpoint, uterine contractions—premature or otherwise—come at the end of a series of events that precede the main event of labor by weeks. If researchers can look further upstream into the molecular cascades that signal the end of pregnancy and the start of parturition, there is the potential to identify a trigger that can be targeted long before the initiation of contractions.

Out of necessity, nearly all the labs seeking to map the upstream dynamics that ultimately lead to contractions and birth root themselves in one of the few clear-cut realities regarding human gestation: the steroid hormone progesterone plays a key role in maintaining pregnancy. At the start of pregnancy and during the fertilized egg’s journey to the uterus for implantation, progesterone is produced by the corpus luteum, a temporary mass of tissue derived from the ovarian follicle that expelled the egg before fertilization. Later, the placenta pumps out progesterone, keeping systemic levels in the mother high throughout pregnancy, which decreases the contractility of uterine muscle. Seminal experiments in the 1930s and ’40s by University of Rochester Medical School anatomist George Corner—the codiscoverer of progesterone—showed that without the steroid hormone women could not become pregnant, nor could a pregnancy be maintained.

Though the link between progesterone and the maintenance of pregnancy has been thoroughly established, very little is known about how exactly the hormone works when the time comes for gestation to end. There are likely dozens of mechanisms that act to set off labor at the end of pregnancy, says Sam Mesiano, a Case Western Reserve University physiologist, but only one—with progesterone at its center—to block it. “The key is to find where all the pathways converge and attack the convergent point therapeutically as the target,” he says. And that is exactly what a bevy of research teams is seeking to do, generating some interesting models regarding the roles played by genes, the immune system, and the body’s inflammatory machinery.

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