Miscarriage is common. These researchers are on a mission to better understand why

Up to a million pregnancies in the United States end in miscarriage every year. For many patients, there’s no answer about why.

“This is a very common condition,” said Dr. Diana Bianchi, director of the National Institute of Child Health and Human Development. Yet in most cases, the cause is not investigated or identified until multiple pregnancy losses have occurred. As many as half of pregnancies that end in miscarriage and stillbirth have no explanation. And stigma and shame keep many people who experience miscarriage from discussing it. “It’s not something that people are willing to share. It’s often kept as a family secret,” Bianchi said.

Most miscarriages happen in the first trimester of pregnancy. While chromosomal abnormalities are the most common reason for pregnancy loss, little is known about other reasons or contributing factors. It’s difficult to study miscarriages because of how hard it can be to connect with patients in the immediate aftermath of a loss. It is also challenging to recruit patients for clinical trials for new treatments.

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Providers have also faced hurdles in miscarriage care since the Supreme Court overturned Roe v. Wade in 2022, said Dr. Debra Stulberg, a professor of family medicine at the University of Chicago. Many states have moved to restrict drugs used in medication abortion, such as mifepristone and misoprostol, which are also widely used in miscarriage management. “We still see a ton of a ton of misconceptions and fears of how policy will be applied,” Stulberg said, which can give providers pause, and can lead to patients “sometimes feeling abandoned or like you have no idea what to do.”

“Providers are fearful that to intervene without 100% certainty puts them at jeopardy of criminal or civil liability,” said Dr. Elise Boos, an OB/GYN in Tennessee.

Still, researchers and experts across the country say we’re learning more every day about why miscarriage occurs and how to better support patients experiencing it. While there’s no one-size-fits-all answer to why miscarriages occur, researchers hope these advancements help add more tools for patients and providers.

Quicker and cheaper testing

While DNA testing can help detect what led to a pregnancy loss, results can take weeks and cost thousands of dollars.

Dr. Zev Williams, chief of the Division of Reproductive Endocrinology and Infertility at Columbia University’s medical center, led a team of researchers that developed a same-day test to identify abnormal fetal chromosomes. The Short-read Transpore Rapid Karyotyping test, known colloquially as STORK, analyzes tissue from a miscarriage to identify the genetic reason for a loss. STORK, which was funded by the National Institutes of Health, has received regulatory approval, and is being used for clinical testing of miscarriage samples.

“Understanding why pregnancy loss occurs is really almost like a little bit of detective work,” Williams said. “We have patients who sometimes present with 15 or 20 losses, and the number of losses that someone has really isn’t indicative of how difficult it will be to fix the problem, so much as a reflection of how difficult it is to identify the cause of the problem.”

Genetic testing is usually only recommended after multiple miscarriages. But Williams hopes STORK, which costs roughly $200 and can give results in hours, will make chromosomal analysis more widely available — even after one miscarriage.

“Our vision is not just to help the patients at our fertility center, but to help patients around the country and around the world, but that has to happen in steps,” Williams said. “First, we have to develop the technology, then we have to validate it. Now we’re doing the study in actual clinical use. And if that looks promising, then I think it’s going to be ready to roll out more broadly, so we’re really sort of at the tail end of that long course.”

Experts like Bianchi have high hopes.

“It has tremendous potential,” she said. “It’s been shown to be accurate against conventional testing, and the thinking is that it will be rapid and relatively inexpensive. Having a diagnosis is tremendously reassuring.”

The placenta’s role

Dr. Harvey Kliman, a research scientist in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, has long advocated for more thorough investigation of placentas after miscarriage.

The placenta is understudied in part because of access and how difficult it can be to examine the placenta throughout the entire course of a pregnancy.

The NIH has invested about $100 million in the Human Placenta Project, Bianchi said, which is geared toward better understanding the placenta, including developing new tools to monitor a placenta in real time during pregnancy.

As part of a study published last year, Kliman examined more than 1,200 placentas from previously unexplained miscarriages and stillbirths. His team found that most of the miscarriages were marked by dysmorphic chorionic villi (DCV), a category that includes abnormal placental folds. Kliman’s team also found about a third of unexplained stillbirths were associated with a small placenta.

By using these two diagnostic categories, the team was able to explain the vast majority of the unexplained pregnancy losses. The study also suggests that small placentas could be detected in utero and identified as high risk during pregnancy, potentially before a loss occurs.

While most placentas will have lines and folds, placentas in pregnancies that end in loss have far more, Kliman said. But why there are more of these folds in certain placentas remains a mystery.

Now, Kliman is focused on another organ that could further miscarriage research: the heart.

Kliman wants to explore whether there is correlation between folds of the placenta and abnormalities in the heart. This could also be meaningful for children who are “ born alive, but with serious cardiac abnormalities,” he said.

“I’m interested in understanding the genes behind this,” Kliman added — it could open another door.

Mental health

More research is needed to better understand how pregnancy loss affects mental health, Bianchi said.

One 2018 study of women who miscarried in the previous four years, published in the National Library of Medicine, found that 55 percent reported symptoms of depression, and 27 percent reported symptoms of perinatal grief. Pregnancy loss is associated with higher levels of stress and depression in subsequent pregnancies.

Indiana University-Purdue University Indianapolis professors Jennifer Bute and Maria Brann are part of a team of researchers creating a mental health screening tool, known as the Reproductive Grief Screen. It’s a set of five questions for providers to screen patients experiencing a pregnancy loss for mental health issues like anxiety, depression, suicidal ideation and post-tramautic stress.

“It’s intended to work kind of like the way we screen patients for postpartum depression,” Bute said of the screening, which is still in testing. “We don’t have an equivalent of something like that for people who have experienced [pregnancy] loss.”

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Bianchi said that postpartum depression, whether the pregnancy is full-term or a miscarriage, is a critical area to study. Both Bute and Brann say physicians can struggle with how to discuss pregnancy loss with patients.

“We really want to provide a tool for providers to use to quickly assess how a patient is doing and then really use it as a tool to start the conversation,” Brann said. “A lot of times, women don’t know what to say. This gives the provider an opportunity that can initiate that conversation and provide a little more comfort for the patient.”