Organ of Change

IT WASN’T CLEAR WHY BLOOD BEGAN HEMORRHAGING INTO THE VENTRICLES of the newborn’s brain, causing seizures. The baby, at Stanford University’s Lucile Packard Children’s Hospital, was a first child, but the delivery wasn’t premature, there was no sign of infection, and there had been no obvious risk factors.

The biggest clue lay in the placenta. A microscopic examination revealed that the villi (fingerlike projections, covering one side of the placenta, that embed themselves in the uterine wall) were chock-full of lymphocytes. Those white blood cells, says Stanford University neonatologist Anna Penn, belonged to the mother and showed that her immune system had been attacking the placenta.

This complication isn’t hard to understand. Half the genetic makeup of the placenta (which forms from embryonic cells during the earliest days of pregnancy) comes from the father, and because of those paternal genes, placental cells are covered in proteins that the mother’s immune system registers as foreign. Normally the placenta can counteract that response, but sometimes things go awry. “What happened in this pregnancy was essentially a graft vs. host reaction,” Penn says. It was as if an organ recipient’s body had rejected a transplant.

Knowing what went wrong couldn’t reverse the bleeding, and only time will tell about any permanent damage to the baby. But because unwanted immune responses often recur, the diagnosis should help this mother during future pregnancies. She’ll be closely monitored by an obstetrician who specializes in high-risk cases. “If we hadn’t looked at the placenta, we would have had no explanation of the problem and no way to prevent it from happening again,” says Penn.

In the vast majority of U.S. hospitals, no one would have looked; most placentas are dumped into a biohazard bucket. This lack of attention is partly a problem of timing: By the time anyone sees the placenta, its job is over and it seems irrelevant. More important, placentas are overlooked because, until recently, we didn’t understand much of what their work entails.

Scientists have long grasped the core function of this organ—to act as an intermediary between maternal and fetal blood circulation systems by transporting oxygen and nutrients to the fetus and carrying away waste. Research has also linked the health of the placenta to the health of the baby. A placenta of abnormally low volume, for example, may signal such complications as restricted fetal growth. Yet science has generally thought of the placenta as a passive conduit with no capacity to act independently.

Now, however, Penn and other scientists have helped usher in a very different view of the spongy, veiny placenta. It has turned out to be an active, even aggressive orchestrator of the events of pregnancy and fetal development. Interrupting the placenta in that job has serious consequences for mother and baby alike. And though the organ (like no other in the body) has an ephemeral existence, the molecules it produces, its tissues and other features provide essential information about the pregnancy and the fetus that is available from no other source. While researchers are still learning how to interpret and use much of that information, studies have already yielded compelling conclusions that argue for a deeper appreciation of the placenta’s role.

STUDYING A PLACENTA AT WORK HAS NEVER BEEN EASY—in part because many important steps of its development happen during the first weeks after conception, before many women even know they’re pregnant. What’s more, some imaging techniques, such as CT scans, are not ideal for use during pregnancy because of the risk of irradiating the fetus. Other ways of getting an instructive early look at the placenta may become possible—ultrasound resolution is improving, and there’s growing evidence that MRIs are safe for fetuses.

In the meantime, one work-around is to use animal models. To study placental hormones and the fetal brain, Penn creates mice whose placentas are hindered in producing particular hormones. She starts with mouse blastocysts, early-stage embryos comprising a ball of fetal cells surrounded by a ring of cells beginning to develop into the placenta, and then exposes the blastocysts to a virus carrying genetic material. Because the virus Penn uses penetrates only a single layer of cells, she is able to alter the genetics of the placental ring selectively without changing the fetus’s own DNA. The technique lets her create placentas that produce lower-than-normal levels of specific hormones or reduce the enzymes that make steroid hormones. That, in turn, leads to a deficiency in key hormones, such as neurosteroids, that normally pass to the fetus and the mother.

After letting the mice fetuses come almost to term, Penn examines their brain tissue. The genetically altered placentas have a powerful effect. “Our preliminary results show that mice with decreased neurosteroids have striking, abnormal changes in cell numbers in the subventricular zone of the cortex, which is where progenitor cells proliferate,” she says. (Progenitor cells are more highly developed forms of stem cells that will eventually differentiate into specialized brain cells and form connections among neurons.)

These findings strongly suggest that placental hormones are essential for normal fetal brain development and that insufficient hormone levels could have damaging effects. Previous studies have suggested that high levels of one such neurosteroid, allopregnanolone, may protect against the death of brain cells when fetuses are deprived of oxygen, as they may be during difficult deliveries. This steroid is also a powerful anticonvulsant, so lower levels of it in the developing brain may create children prone to seizures. Penn’s laboratory is testing such hypotheses in transgenic mice.

Penn wasn’t surprised that suppressing a placental hormone had such a noticeable effect on neural development, because research had already linked several disorders of early brain wiring—including cognitive delays, autism and schizophrenia—to imbalances in such hormones as allopregnanolone and oxytocin (which her lab is also studying).

Penn’s latest work, which is being readied for publication, supports an increasingly persuasive scientific hypothesis that the placenta shapes the development of a fetus and its organs. A recent study found that serotonin, a neurotransmitter that is critical for neurodevelopment, is not made in the early developing brain but instead is made and transmitted to the fetus by the placenta. Other studies have offered evidence that corticotropin-releasing hormone—which the placenta produces in exponentially increasing amounts as pregnancy progresses—stimulates the fetus’s adrenal glands to manufacture cortisol, which many fetal organs require to mature.

Yet according to Penn, the dogma that the placenta serves only as a passive filter between mother and baby still dominates most doctors’ thinking. “Medical students are taught that the endocrinology of the placenta itself doesn’t actively change the development of the internal organs of the fetus,” she says. “I think placental hormones will prove to be an extremely important piece of the puzzle of fetal neurodevelopment. And because we’re very good at creating medications, that may be the piece we can fix most easily”—with new drugs that, for example, provide an adequate substitute for missing allopregnanolone or oxytocin. More than 12% of births in this country occur prematurely, adding up to more than half a million infants annually who might benefit from this branch of placental research.

THE MOLECULAR STRATEGIES A PLACENTA USES TO ESTABLISH ITSELF during pregnancy have also attracted increasing scientific scrutiny, and some are proving to have implications that go beyond fetal development. The placenta must transform maternal tissues to support its own and the fetus’s needs, and a growing body of research suggests that placental cells and cancer cells use the same set of molecular tools to channel blood their way.

According to Susan Fisher, a developmental biologist at the University of California, San Francisco, the central requirement for both successful pregnancies and “successful” cancers is the ability to establish a sufficient supply of blood, and thus of oxygen and nutrients, to the placenta or the tumor. Unlike most tumors, however, the placenta accomplishes this in a very organized manner. Early-stage placental cells differentiate into specialized invasive cells that then proliferate, migrate into the uterine wall and implant themselves there—attaching the placenta to the uterus and providing it with a blood supply. At that point, the cells stop proliferating and their invasive activity is reined in.

To study this process, Fisher and other researchers cultivate placental cells, watching to see how they switch their production of particular molecules on and off. That, by extension, also helps them learn about invasive mechanisms that could have implications for cancer therapy. One of those may be “vascular mimicry,” a process by which epithelial cells—normally lacking a blood supply—start to act like endothelial cells, which line the inner surfaces of blood vessels. A placenta uses that trick as it implants itself in the womb, sending out “fake” endothelial cells that swarm into uterine arteries, replace their existing linings and reshape them to channel blood toward the placenta’s own cells.

Studying the molecular profile of placental activities may also help physicians intervene sooner in cases of preeclampsia, a sudden, severe complication of pregnancy characterized by the mother’s extremely high blood pressure. The condition occurs when the placenta’s tumorlike invasion of maternal blood vessels fails and the organ is deprived of sufficient blood and oxygen. That triggers the release of chemicals from the placenta that cause hypertension—the placenta may force up maternal blood pressure to draw more blood and oxygen to itself.

The potentially dire results of preeclampsia, which can develop in just a few hours, may be eased if the condition is identified earlier. “Right now the screening protocols we have to offer a pregnant woman are unbelievably primitive,” says Fisher. “We test blood pressure, check for protein in the urine and look for swelling. But studying the abnormal molecules that the placenta produces when things go wrong should help us develop blood tests that will warn if a woman is at risk for preeclampsia or preterm birth.” Fisher is testing many placental molecules to find early biomarkers for preeclampsia.

MICROSCOPIC PLACENTAL ABNORMALITIES ARE ALSO EMERGING as early markers of disease. Among the most intriguing are the ones that involve specialized placental cells known as trophoblasts. The cells make up the two layers of the placental surface—the outer, syncytial trophoblast layer and the inner, cytotrophoblast layer—and as they multiply, the two layers normally fuse, causing bulges in the placental surface that become new villi connecting the placenta to the uterus. What interests Harvey J. Kliman, director of the Reproductive and Placental Research Unit at the Yale University School of Medicine, is the abnormality that occurs when the multiplying cells in the inner layer mostly fail to fuse with the outer layer. That causes the placental surface to curl inward, forming divots called trophoblast inclusions.

Although trophoblast inclusions don’t affect the way the placenta functions, there seems to be a powerful association between those mistaken folds and several genetic disorders—suggesting that the same genetic anomalies cause both the inclusions and problems in cell and tissue formation elsewhere in the body. It has been known for some time, for instance, that trophoblast inclusions show up more often in the placentas of babies with Down and Turner syndromes, genetic diseases marked by physical abnormalities, than in those of normal infants. But recently Kliman discovered that placentas belonging to children who were later diagnosed with a more subtle neurological anomaly—autism spectrum disorder—had three times more trophoblast inclusions than normal.

Such placental irregularities aren’t considered definitive signs of disease. But Kliman is working with Irva Hertz-Picciotto of the University of California, Davis, to determine whether they can predict autism. Hertz-Picciotto is conducting a prospective investigation of expectant couples in which at least one parent already has a biological child with autism. Kliman will collect and screen placentas from their current pregnancies and, based on the frequency of trophoblast inclusions, try to predict which babies are likely to develop the disorder. The children will be followed for several years to see whether they show signs of autism. If it turns out that the screening results correctly predict who will develop the condition, making placental exams part of standard postdelivery practice could be a simple, cost-effective way to test for autism years before it’s usually diagnosed, giving physicians and families a head start on interventions.

BECAUSE PLACENTAL RESEARCH IS AN EMERGING SCIENCE, many of its potential applications (such as autism screening) are still being investigated, and much of its significance has yet to be definitively established. But research is advancing along multiple fronts, and many findings, if still tentative, are beginning to change conventional thinking.

For example, cerebral palsy, a group of neurological disorders that typically show up in infancy or early childhood, has long been linked to birth asphyxia—an acute period of oxygen deprivation before, during or just after delivery. But Karin B. Nelson, who has studied cerebral palsy and other neurological disorders of children for more than 40 years and who recently retired from the National Institute of Neurological Disorders and Stroke, believes that the placenta may play a role in brain development and sometimes in fetal brain injury.

Working with Australian colleagues, Nelson mined data from a large cerebral palsy registry created in Western Australia that had placental measurements taken soon after birth. Upon analysis, they discovered clear signs of trouble—including indications of inflammation and abnormal-looking blood vessels (investigators studying a Danish registry arrived at similar results). Nelson’s work, added to recent studies reporting high rates of placental abnormalities in babies born with brain injuries, suggests that cerebral palsy is actually associated with such events as perinatal stroke.

Meanwhile, other placental research is already paying off in clinical applications. With his mathematician father, Kliman has worked out a simple formula for estimating placental volume by measuring the organ’s width, height and thickness during routine ultrasounds. Low placental volume is a major warning sign of complications ahead, and when a patient was recently admitted to the hospital because her fetus had stopped moving, Kliman used the formula to measure the placenta. Its volume was extremely low, and the patient was given intravenous fluids. “We literally saw the placenta inflate,” Kliman says. “Two weeks later, she delivered a perfectly normal kid. If we hadn’t known what was wrong, this would have been an intrauterine fetal demise.”

Such successes argue that close attention be paid to this temporary organ—and, certainly, against its routine disposal after birth. At Stanford every placenta is now stored for at least a few days to facilitate the kind of analysis that helped the parents of the infant who developed seizures. And the university is building one of the country’s most comprehensive placental tissue banks, a stockpile of samples for research and education. Such resources, common in other areas, such as oncology, in which tissue samples have been an invaluable research tool, could prove indispensable in helping scientists confirm that the influence of the placenta extends far beyond the womb.