Why pregnancies fail

In an era of high-profile debates and legislation surrounding abortion, it can be easy to overlook another widespread but less talked-about reproductive issue: the many obstacles some people face trying to get and stay pregnant. Among women of childbearing age, as many as 1 in 4 have trouble either becoming pregnant or carrying a pregnancy to term.

That figure translates into a lot of miscarriages. About 20% of the 5 million or so pregnancies that occur each year in the United States end in miscarriage at or before 20 weeks. Losses that happen past the 20th week of pregnancy are called stillbirths; these add another 20,000 to the total. One in 10 women will miscarry during their lives.

“These are just the losses where there was a heartbeat,” said Harvey Kliman, MD, PhD, a research scientist in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine (YSM). Kliman is also the director of the Reproductive and Placental Research Unit.

In addition to miscarriages and stillbirths, another 1 to 2 million pregnancies too small to detect on an ultrasound also end spontaneously before the fifth week.

Pregnancy loss can result in anguish as well as grief borne in isolation, as the losses are often written off as unavoidable by the general culture. This pain is magnified when the losses recur. And about half the time, such standard diagnostic measures as placental inspection and/or genetic testing after a miscarriage do not provide a clear explanation—which is all the more distressing for potential parents who often blame themselves.

The vast majority of early pregnancy losses are due to genetic abnormalities. But hearing that is often no consolation, Kliman said.

“On an emotional level, almost 100% of the women I take care of with pregnancy loss feel it’s their fault,” he said. “[They hear things like] ‘You need to take more vitamins. Maybe you need more sun. Maybe you’re eating [wrong].’”

Part of the problem is that it’s usually a mystery how the genetic factors went askew.

Evidence of many abnormalities does not show up on such routine prenatal tests as the 10-week blood test of fetal DNA that screens for chromosomal anomalies like Down syndrome.

Likewise, if genetic testing is performed after a miscarriage, it only “scratches the surface,” said Reshef Tal, MD, PhD, an assistant professor of obstetrics, gynecology, and reproductive sciences at YSM, who is an expert on reproductive endocrinology and infertility. Tal is also a principal investigator of an NIH-funded basic science research lab.

“We think that there are many subtle genetic abnormalities—even variants in single genes—that can lead to recurrent pregnancy loss. These are things we are not currently testing for as part of the workup for recurrent pregnancy loss,” Tal said.

Kliman and Tal are among a group of Yale researchers seeking to better understand miscarriage by studying how genetic factors influence pregnancy, as well as how genetic changes affect the placenta and its role in pregnancy. What they’re discovering suggests not only such potential future therapies as bone marrow transplant but also finer-grained genetic checks before in vitro fertilization and closer monitoring of high-risk pregnancies.

An intricate genetic dance

Pregnancy proceeds step by step. A fertilized egg begins dividing and becomes a blastocyst, which travels to the uterus and begins to settle there—a key event called implantation. Then begins what Tal calls “cross-talk” between the embryo and the endometrium, or lining of the uterus. Cells in the endometrium adapt in response to the embryo in part by engaging new cells from far afield in the mother’s body that help support the pregnancy.

Over many years of research published in journals that include PLoS Biology, Biology of Reproduction, and most recently JCI Insight, Tal has painstakingly demonstrated that a pregnancy recruits cells from maternal bone marrow, summoning them to the pregnant uterus via a molecule called CXCR4. There, the bone marrow cells differentiate into cells involved in embryonic implantation.

In their recent study, Tal and his colleagues showed that adult mice without a functioning CXCR4 receptor have such problems as smaller litter sizes and miscarriages. Their placentas have immune cell abnormalities and develop inflammation and abnormal blood vessels. Pregnancies proceed normally, though, in knockout mice that receive a bone marrow transplant from other mice with normal CXCR4 function. The bone marrow transplant introduces normal immune cells into the placental microenvironment. These cells are able to correct the abnormal placental inflammation and blood vessels, thus rescuing the pregnancy.

It’s too soon to say how this finding translates to human pregnancy losses. If the gene for CXCR4 is involved, it isn’t the only one. But the notion that a bone marrow transplant can rescue placental function in mothers with abnormal pregnancy genes is an important proof of concept, Tal said: “That’s definitely something that we foresee as a future therapy for patients.”

A “check engine” light in the placenta

Kliman is taking a different approach to the mystery, scrutinizing placentas from both healthy pregnancies and miscarriages under a microscope to look for telltale differences.

In a 2023 study published in Reproductive Sciences, which examined 1,256 placentas from previously unexplained miscarriages and stillbirths, Kliman reported that an abnormality that could explain the pregnancy loss emerged in nearly 92% of cases. Most of the miscarried placentas contained a type of abnormal folding that is a red flag for genetic abnormalities.

Placentas from stillbirths, meanwhile, were usually very small. That insight could allow for preventive efforts. Kliman has developed a formula to estimate placental volume from easily measured parameters during prenatal ultrasound. If used routinely, estimated placental volume might allow obstetricians to flag higher-risk pregnancies for closer monitoring and treatments that could reduce the risk of stillbirth.

These results underscore the importance of a more thorough inspection of the placenta after pregnancy loss—something Kliman has advocated for years.

The abnormalities Kliman sees in placentas from miscarriages are called trophoblastic inclusions. Under a magnified cross-section of the placenta, these microscopic anomalies resemble circular islands of cells, but they are actually infoldings—as if you were to poke a finger deep into a ball of clay, then remove your finger and slice across the tube-shaped space left behind.

Trophoblastic inclusions are harmless per se. Some are found in every placenta, but there are far more in placentas from miscarriages. Large numbers of them are also associated with such abnormalities as low birthweight and swelling of the placenta.

When many inclusions show up in the placenta, they are “the ‘check engine’ light that is saying there’s a problem in the pregnancy,” Kliman said.

An explanation from evolution?

Kliman’s findings have led him to hypothesize that evolutionary pressures that favor increased brain folding in human beings might also be driving vast numbers of pregnancy losses.

Broadly speaking, building a baby from a cell involves basic developmental processes or tools.

For one, there is proliferation; one cell must become many. In addition, there is migration: cells must travel to and develop in new locations in the embryo or fetus. Cell death also needs to occur in the right spots—so that, say, fingers emerge from a webbed proto-hand.

Another crucial tool is folding. That includes both infolding, as with the finger hole poked into clay; and branching, as if one were to mold protrusions from the clay. A host of anatomical structures develop using this tool, including the lung, kidney, brain, and heart.

Folding is a complex process involving many genes, so there are many ways it can go wrong. If it does, the developing fetus winds up with anomalous tissues or organs. The consequences vary in severity: misfolding of the brain may result, for example, in developmental disabilities.

During evolution, human beings have developed more complex brains than those of our primate cousins; the evidence is visible in our highly folded cortex. Nature increases cognitive capacity in part by increasing these deep folds, possibly because this may allow a larger cortex to fit into a head small enough to pass through the birth canal. If intelligence can confer a survival advantage, there may likewise be an advantage to genes that result in revved-up folding during development in the womb.

But folding also illustrates the Goldilocks principle; it needs to be “just right.” Genes that promote a little extra folding may well result in a more highly folded brain. But too much can result in an unwelcome side effect: a malformed and nonfunctional heart. While a fetus can survive to term with a variety of organ defects, a nonfunctional heart is lethal.

Trophoblastic inclusions are not only more common in pregnancy losses, they also appear in large numbers in the placentas of children on the autism spectrum, whose brains have been found in some studies to exhibit extra folding. Kliman is now searching for the inclusions in the placentas of children with congenital heart disease—who, perhaps not incidentally, also have a higher incidence of brain abnormalities.

More light on genetics

So far, Kliman’s explanation remains a hypothesis that requires more research. Yale’s Genomic Predictors of Recurrent Pregnancy Loss (GPRPL) study is currently recruiting 1,000 couples with unexplained recurrent pregnancy loss and scrutinizing their genomes, as well as the genomes of the miscarried fetuses. This analysis allows fine genetic detail to emerge, including errors that correlate with pregnancy loss.

The study should shed more light on the genes that are essential to early embryonic development and implantation—and it should translate immediately to prenatal care, Tal said.

That is because, at least for in vitro fertilization, a technology called preimplantation genetic testing is already used in the clinic to screen for chromosomal abnormalities and single-gene disorders to help clinicians select unaffected embryos. A more complete understanding of gene abnormalities associated with miscarriage will allow providers to better screen embryos before implantation for maximal chances of a successful pregnancy.

For a doctor specializing in infertility, that success is deeply gratifying, he said.

“I cherish the opportunity to be involved in the journey of the couples that I treat, helping them navigate what is a frustrating journey at the beginning, but then ultimately witnessing those miracles of life and the patients’ joy of starting or expanding their family,” Tal said. “You are really dealing with the secrets of life, the very origins of humankind.”

Kliman for his part hopes that for people coping with the loss of a wanted pregnancy, understanding the genetics of miscarriage—and the ways in which it might exist within our very humanity—could help ease the anguish.

The work, he says, is “an effort to be able to give grieving would-be parents a more satisfying explanation than ‘These things just happen.’”