Eric Wang, Senior Photographer

In a study released last month, Yale researchers found that accurately examining placentas and their pathologies can explain over 90 percent of unaccounted pregnancy losses. 

Harvey Kliman, a research scientist in obstetrics, gynecology and reproductive sciences and senior author of the study, developed a new classification system for pregnancy losses based on examining the placentas of babies who passed away. Of the millions of pregnancy losses each year, 40 percent are classified as “unexplained,” leaving families uncertain about the cause. Kliman said he seeks to use his research to help families understand what caused their loss.

“If you don’t know why it happened, invariably, these women feel that they must be responsible,” Kliman said. “Guilt is an understatement. They feel devastatingly responsible for the loss. They are already the mother of this child, and they feel they failed their child.”

The researchers found that the causes of pregnancy loss depend on the phase of the pregnancy, according to Parker H. Holzer GRD ’21, a Yale data science doctoral student and an author of the paper, wrote to the News. With the study, Holzer said the authors hope that doctors can now know what signals to look for at each stage of pregnancy, allowing doctors to hopefully further decrease the rate of pregnancy loss.

To uncover these signals, the researchers analyzed 1,256 placentas from 922 patients. All of these patients’ pregnancies had ended in loss and were referred to Yale’s consult service for evaluation. Of the pregnancies, 70 percent were miscarriages, while 30 percent were stillbirths. 

The researchers attributed the deaths to placental complications including cord accidents, abruptions, thrombotic issues and infections. They attributed other cases to two new categories, which they introduced — “placenta with abnormal development” and “small placenta,” which are placentas below the 10th percentile for gestational age.

  As director of volunteer organization Measure the Placenta, Ann O’Neill works to promote using the Estimated Placental Volume test placenta in prenatal care. The organization is comprised of parents who experienced stillbirths due to an undetected very small or large placenta. She told the News about the guilt she experienced when her baby, Elijah, was born still in 2018. 

“The pressing question that at first I was terrified to ask was ‘Why did he die?’” O’Neill said. “How could this seemingly healthy baby out of nowhere just die?”

When O’Neill turned to pathologists to find answers, she said they provided little help. They labeled Elijah’s passing as unexplained, but his pathology report had one oddity: Elijah, a large baby, had a small placenta. The size difference was so pronounced, according to O’Neill, that pathologists told her the placenta might not be Elijah’s. Though later genetic tests revealed it was his, O’Neill told the News that the pathologists initially wondered whether it might have accidentally been swapped with another placenta. 

O’Neill said she left the meeting with the pathologist feeling disappointed and still seeking answers. Later, O’Neill listened to a podcast in which Kliman discussed the possibility that a small placenta may cause stillbirths. Hoping to find an answer, O’Neill sent Elijah’s physical placenta to Kliman, who attributed Elijah’s death to his small placenta.

“Getting an answer from Kliman was huge in so many ways,” O’Neill said. “Number one, the self-blaming doesn’t happen.”

The study offers additional findings on a larger scale. The study suggests that placental examination can identify the cause behind approximately 99 percent of stillborn cases. The researchers noted that over 60 percent of unexplained stillbirths are due to “placental insufficiency,” or that the placenta is too small in proportion to the baby’s size. Another cause is placental dysmorphia, which describes the placenta’s shape or weight. 

Though the research may help provide closure to these families, Kliman said it will be difficult to translate into clinical changes. The American College of Obstetricians and Gynecologists sets clinical practices in this field. The ACOG requires direct scientific proof that changes to standard treatment, such as measuring the placenta, will result in different outcomes. 

In this case, Kliman said, it is nearly impossible to meet ACOG’s standards. Scientists can never be certain that a treatment will prevent a stillbirth, according to Kliman. Further, he said, it is difficult to change clinical practices because healthcare professionals are not trained in using the EPV test during their residency and fellowship programs. Consequently, Kliman said, some doctors might question the need to incorporate the EPV into their established routines. 

The study encourages clinicians to adopt the EPV tests to manage high-risk pregnancies and make informed decisions about the timing of delivery. If they identify a small placenta, along with other factors, early delivery may mitigate the risk of fetal loss before birth.

Still, the researchers said that the study has limitations. The study lacked comprehensive data on maternal demographics, such as race or ethnicity. Nevertheless, the researchers told the News they recognized that this could be an important point for further research. 

“This study will need to be confirmed by others, however it is likely to change our ability to diagnose the cause of pregnancy loss and potentially help to prevent this tragedy,” Hugh Taylor ’83, a professor of obstetrics, gynecology and reproductive science, wrote to the News. 

Following the study, Kliman said he hopes to explore the genomics underlying pregnancy losses and to delve deeper into the mechanisms that link dysmorphic placentas to pregnancy complications. 

Kliman and Taylor are now conducting an NIH-funded trial that sequences the entire genome of patients who have experienced more than one miscarriage. 

“It’s terrifying to find an answer, but when you do, the emotional guilt is relieved,” O’Neill said. “You have the weight off your shoulders. For future medical care, it’s crucial to understand what caused the previous loss so that in any future pregnancies you can be monitored for those things.”

Stillbirth affects one of every 175 births in the United States.

Omar Ali covers science, technology and academics for the News. Originally from Lahore, Pakistan, he is a sophomore in Berkeley College majoring in Economics with Mathematics and Molecular, Cellular & Developmental Biology.
Carlos Salcerio covers the Yale School of Medicine and the Yale School of Nursing for the SciTech desk. Originally from Cuba, he is a prospective pre-medical student majoring in Molecular Biophysics and Biochemistry in Jonathan Edwards College.