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Medical News & Perspectives
December 5, 2018

Unraveling the Mysteries of the Human Placenta

JAMA. Published online December 5, 2018. doi:10.1001/jama.2018.18200

Diana Bianchi, MD, has referred to the placenta as the Rodney Dangerfield of organs because it’s typically given little thought during pregnancy and discarded after delivery. The late Dangerfield, a comedian and actor, was best-known for his catchphrase, “I don’t get no respect.”

Linda Huynh/Eunice Kennedy Shriver National Institute of Child Health and Human Development

However the scientific community is increasingly paying more attention to what the Human Placenta Project (HPP) calls the least-understood human organ. The HPP was created by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which Bianchi directs.

The project aims to improve current technologies and develop new ones to assess the placenta during pregnancy, develop noninvasive markers for the prediction of adverse pregnancy outcomes, understand the contribution of the placenta to long-term maternal and child health, and develop interventions to prevent placental abnormalities.

JAMA spoke with Dr Bianchi about the HPP shortly before its most recent conference. The following is an edited version of that conversation.

JAMA:Why does the placenta deserve respect and why hasn’t it received more attention?

Dr Bianchi:Many people don't even know what the placenta is. They've never seen one, unless they've been at a delivery, and most women are too busy with their newborns if they've just given birth to take a look at the placenta. But it's really an amazing organ. It is an organ, because an organ is defined as a collection of tissues with specific functions that has to be self-contained, and certainly the placenta fulfills all of those criteria.

But it most certainly deserves respect because it's critical to the health of the developing fetus. It delivers oxygen and nutrients, it removes wastes, it protects the fetus from external threats. And an improperly functioning placenta can have very serious consequences for the fetus and for the pregnancy overall. It can lead to long-term adverse health consequences for both the mother and the child. I would think that such an important organ would seem worthy of respect, but by the time the baby is delivered its role is complete.

JAMA:Is this dearth of knowledge about the placenta due to a lack of interest in studying it?

Dr Bianchi:There's always been a lot of interest and a lot of research in the placenta after delivery, and there's also been interest in animal models, but each animal has a completely different type of placenta. The guinea pig is the animal model that has the most similar placenta to the human, but the mouse model is quite different from the human placenta. The Human Placenta Project was specifically created to develop new ways to study the human placenta noninvasively and in real time. Because if you wait until after the placenta is delivered, then it's too late. We need to be able to identify problems that are occurring during the pregnancy, so we can intervene in real time.

JAMA:What are some of the tools that scientists are testing or already using to look at the placenta in real time?

Dr Bianchi:There have been some major advances in imaging and being able to study how oxygen flows across the placenta. Oxygen is a major nutrient that the fetus needs to grow and thrive. There also have been advances in various omics technologies for studying genes in the placenta that are expressed at different points in time. Here's where artificial intelligence is also playing a role, because artificial intelligence allows us to learn from certain patterns. There have been major advances in all of these areas that have already allowed us in just 2 to 3 short years to see some of the successes of the Human Placenta Project.

JAMA:What are some of the biggest questions that the Human Placenta Project is hoping to answer?

Dr Bianchi:One of the biggest questions is why do some placentas fail to function properly? Is it the mother's underlying health? High blood pressure may result in an abnormal formation of the placenta. Is it the mother's genetics? Is it a combination of the mother's and the father's genetics? Is it something in the environment that the mother's exposed to? Is it some aspect of the immune system or the mother's microbiome, or is it something else altogether? We really don't know why some placentas are healthy and others are not, so if we can follow the placenta's development and function from early stages in the pregnancy, we can get an early sense of the potential for adverse outcomes that are not clinically apparent to the obstetrician-gynecologist. If we can understand high-risk pregnancies by studying the placenta, then that allows us to intervene, whether it's treating the mother or some other type of intervention. But right now, all that we can do is try to deliver the baby early to mitigate an adverse outcome.

JAMA:Do you hope that the Human Placenta Project might give rise to treatments targeting the placenta that could prevent pregnancy complications?

Bianchi:There are quite a number of things that potentially will come out of this. One of our grantees, Dr. Ellen Grant, has developed a technique where she can actually show the flow of oxygen across the placenta, particularly in twin pregnancies. The amount of oxygen that an individual fetus gets is correlated with both brain growth and growth of the fetus, so in twin pregnancies the fetus that gets more oxygen is actually bigger and has a bigger brain. Understanding this transport of oxygen helps us understand factors that may result in an outcome that might be associated with developmental disabilities later on.

JAMA:What is known about the impact of the placenta on a child's health throughout life?

Dr Bianchi:The most important time of your life is the first 9 months, and the placenta plays a critical role in that. There's a whole field of investigation called developmental origins of health and disease that correlates experiences and events that happen in the womb with later health outcomes. For example, if you were born on time, not premature, but your birth weight is under 6 pounds, that's associated with having a thrifty metabolism. The placenta was not working normally, and those babies were essentially deprived of nutrients, so they develop a metabolism that hangs on to every calorie. That doesn't stop once the baby's born, so those babies have a lifelong propensity to obesity. Studies in the United Kingdom have shown that these growth-restricted babies who were born on time had a much higher incidence of dying prematurely of myocardial infarction.

JAMA:Are pregnant women interested in enrolling in research studies of the placenta?

Dr Bianchi:We find that pregnant women in general are very interested in participating in research. This is a time when they do have a lot of contact with the health care system, but there's a lot of curiosity about the growing person inside of them. Just by following the mommy blogs you can see how much interest and discussion there is. The Human Placenta Project features studies that are noninvasive, so many of them are related to ultrasound imaging or MRI [magnetic resonance imaging]. Some involve blood testing, but pregnant women are already undergoing blood testing, and I'm sure the investigators are trying to coordinate the research blood samples with the regular blood samples that are taken as part of clinical care. The investigators are well on track in terms of recruiting pregnant women.

JAMA:Might something show up in a study that could affect participants’ treatment during their pregnancy?

Dr Bianchi:That's always a possibility but the focus here is really on the womb. I think the one area where there might be more of a possibility is in some of the studies that are looking at detecting circulating molecules in maternal blood that provide clues to how the placenta is functioning. The placenta releases small, membrane-coated particles known as extracellular vesicles that contain DNA, RNA, lipids, and other markers. We know from studying circulating DNA in the maternal blood that we can detect conditions that affect the mother as well, so there is that possibility. With the imaging studies that are going on in the uterus, you could perhaps find a benign uterine tumor that might subsequently affect the mother's care, but that's really not going to be a big deal.

JAMA:What are some of the specific projects funded by the Human Placenta Project?

Dr Bianchi:We have some investigators who are part of our intramural branch who are in a group called translational biophotonics. They are taking advantage of electronic miniaturization of spectroscopy, and they're using artificial intelligence to come up with a miniaturized placental oximeter. It's about the size of an iPhone and straps onto the woman's abdomen, and it allows easy, noninvasive monitoring of placental oxygenation. This is something that could be done at home. It's small and battery-operated with wireless capability, so there is potential to be remotely monitoring the health of the placenta. It's not clinically available yet, but you could imagine that women who are at high risk for a placental complication would be the first to get this kind of device. Their physicians or their health care providers could be tracking exactly what is going on in real time in that pregnancy.

When you look at the difference between the resolution of ultrasound imaging even 5 years ago and what is possible now, particularly in terms of visualizing the vessels of the placenta, the fact that you can see the architecture of the vessels now is truly an advance. Some of our funded investigators are trying to identify what normal placental vessels look like. If you have vessels that are constricted or are anatomically abnormal, that would tell you quite early on to be worried about a potential problem, so that is very exciting work. And the implementation of artificial intelligence, which is what a number of our investigators are doing, is truly novel, so these are really exciting times.

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