By Deborah Borfitz

November 14, 2024 | Perinatal pathologists are calling for placental pathology to be incorporated into prospective clinical trials so they can start telling clinical providers what the findings in their reports mean. For want of funding and the relevant diagnostic expertise, the placenta has long been a woefully under-investigated organ that could be providing critical insights on pregnancy-related conditions like preeclampsia and preterm birth that are currently defined solely based on a clinical diagnosis, according to Mana Parast, M.D., Ph.D., professor of pathology at University of California San Diego School of Medicine and director of the perinatal pathology service at UC San Diego Health.  

Parast helped make the case in a recently published opinion piece in Trends in Molecular Medicine (DOI: 10.1016/j.molmed.2024.08.002) proposing that placental evaluation be part and parcel of the routine delivery of obstetric and neonatal care. The move would mirror what happened in the cancer field over 50 years ago when pathologists and oncologists worked together to come up with a staging system that incorporates clinical presentation and microscopic diagnosis, says Parast. 

Pathologists these days grade resected tumors (based on how abnormal the cells look under the microscope) to improve clinical staging (size of tumors and how far cancer has spread) to help oncologists determine the best treatment and estimate a patient's prognosis. “That is the integration of clinical and pathological information that needs to happen for obstetrics,” she says. 

For women at risk for preeclampsia or preterm birth, insights gleamed from the placental pathology of a previous pregnancy might answer the basic question of whether they should be put on preventive aspirin therapy, continues Parast. Which patients respond to aspirin, and what the dose should be, are currently debated only with regard to pharmacogenetic testing, but placental pathology could play a more primary role. 

The type of preeclampsia a patient has can also be deciphered based on placental pathology, Parast says. The presence of dead and damaged tissue is indicative of vascular preeclampsia that more often occurs preterm, as opposed to inflammatory preeclampsia that more often happens closer to term and is signaled by the presence of pro-inflammatory cells in the placental tissue. “Then there’s the mixtures,” she adds, “and the question of what this means, prospectively, for any single patient is something that is incompletely understood.” 

The Bottlenecks

The holdups in including placental pathology in clinical care and research have been numerous, says Parast, starting with the perinatal pathology community itself. It wasn’t until 2015, at a gathering of perinatal pathologists in Amsterdam, that consensus was reached on how to go about sampling the placenta and the general criteria for diagnosing four major patterns of placental injury. 

Another big bottleneck is the shortage of trained perinatal pathologists, making the quality of placental pathology “highly variable” across the country and globally, she says. Obstetricians (OBs) will often say they don’t find placental pathology reports clinically useful either because they’re too brief or contain details they don’t understand. The American College of Obstetricians and Gynecologists and other professional associations publishing clinical practice guidelines for OBs and neonatologists have therefore issued few statements on the proper role of placental pathology other than in the setting of stillbirth. 

An additional institutional roadblock is the expense of processing placentas at a fast enough pace for the clinical diagnosis to be meaningful, especially for a baby in the neonatal intensive care unit, says Parast. The bigger overarching issue is a failure to appreciate the significance of placental pathology, as exemplified by a 2022 opinion article published in the prominent Obstetrics & Gynecology journal questioning the utility of placental pathology since OBs don’t understand its significance.  

If the same were said of oncologists having trouble interpreting a pathology report, the idea of abandoning the evaluation of tumor tissue would sound “ludicrous,” Parast says, as it should be for inspecting placentas for obstetrical conditions. OBs have the option of learning what a pathology report means, which any fellowship-trained perinatal pathologist could readily help them do. “I feel like we’re making a lot of excuses.” 

First Step

Literally all the clinical research involving placental pathology is retrospective studies, Parast notes, getting back to the core problem. Papers on common acute chorioamnionitis, which is evidence of an impending amniotic fluid infection, will report on the percentage of affected placentas infected with a particular bacterium, she offers as an example. But they won’t help guide the decision-making of practicing clinicians looking to produce a good outcome for a mom and her baby. 

In one of the few examples where clinical guidelines were put forth several years ago, placental pathologists were advised when diagnosing placenta accreta syndrome to look for muscle fibers that are attached to the maternal surface of the placenta, Parast says. “This is a horrible complication where the placenta doesn’t separate from the uterus” and oftentimes requires an emergency hysterectomy after a Cesarean delivery (C-section), leaving no possibility of the mother having more babies. 

Among the predisposing factors are multiple C-sections and prior “uterine instrumentation,” a method used for removing fibroids, she continues. Occasionally, a placenta is delivered where those muscle fibers can be seen, and the amount gets documented per the guidelines. 

But when the practice was adopted at UC San Diego Health, she recalls, people began asking, “What does this mean?” Her response was that standardization of placental pathology is the necessary first step and that meaning will come in time from ongoing clinical studies. A retrospective study at Northwestern found that the presence of muscle fibers in a placenta appears to put a woman at increased risk for full-on accreta in a subsequent pregnancy and “definitely bears paying attention to.” 

Change Agents

As to who will fund and conduct these prospective clinical trials, Parast points to the Maternal-Fetal Medicine Unit (MFMU) network and Neonatal Research Network (NRN), both funded by the National Institute of Child Health and Human Development, which receive input from academic medical centers regarding the studies that need to happen. She hopes that by working closely with clinical colleagues in obstetrics and neonatology, showing them the importance and relevance of placental pathology to patient care, they can together argue for the inclusion of placental pathology in ongoing trials. 

In addition to Parast’s collaborative ambitions with the MFMU and NRN, many patient advocacy groups are also promoting the importance of placental pathology, she says. Parast sits on the Perinatal Practice Committee for the Society for Pediatric Pathology, which is creating a standard placental pathology report form. It will be used in a planned educational campaign that will initially target general surgical pathologists so that they can better diagnose lesions in the placenta. 

It will thereafter be used to educate OB-GYNs and neonatologists about the meaning of the reports, says Parast. Patient advocacy groups have pledged their support in getting the word out nationwide, which should facilitate acceptance and adoption of the report form. 

This won’t solve the funding problem, which helps explain why placenta pathology is also routinely ignored in preclinical research involving pregnancy complications, Parast says. A PubMed search of better-favored organs like the heart, brain, and liver reveals exponential growth in the number of associated publications since the 1970s and 1980s, while the placenta continues flatlining. The amount of money put into the BRAIN Initiative ($3 billion) is almost 30 times more than what has been funneled to the Human Placenta Project ($101 million), although both launched in 2014.  

“The number of people who do basic placental biology research is abysmal,” she says, and the reason technology can’t be applied to women’s health. “You can’t apply technology to knowledge that isn’t there.” 

Parast says she uneasily laughs when watching science fiction movies depicting a future where women are still experiencing pain during labor. “Is that what it is going to be like 200 years from now, [with] no improvement between now and then?” 

Be Proactive

Her parting advice is for pregnant women: “Ask about your placenta. ... A lot of babies are born small but that doesn’t necessarily mean the baby has fetal growth restriction. The placenta can give a lot of insight into that. 

“If you had preeclampsia,” she continues, “ask your OB, ‘Are you going to send my placenta to pathology?’ Then follow up with that and read your report and inquire whether the person who reviewed your placenta was a trained perinatal or placental pathologist and, if not, you can always seek a consult.” 

Many women only realize after experiencing a bad outcome that they didn’t get the kind of information they should have received, Parast says. “Unfortunately, advocating for yourself is required in a lot of healthcare settings in this country, especially when it comes to pregnancy care.”