By Deborah Borfitz
November 26, 2019 | Of the long list of pregnancy-related questions OB-GYNs most want to unambiguously answer, “Is everything OK with my baby?” would probably be in the top spot. The reality is that there is no definitive yes-or-no test allowing doctors to confidently reassure all moms-to-be, says David Weinberg, lead of the Human Placenta Project of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Pregnancy complications can be diagnostically murky.
In the absence of clear indicators of trouble, such as spiking blood pressure or a chromosomal abnormality detected by amniocentesis, pregnancy is a bit of a “black box,” says Weinberg. The literature is filled with important studies showing associations at the population level, but diagnostic signals from individual patients often fall in the overlap region between the all-clear and oh-no ends of the distribution curve, he says.
“It’s very challenging because there’s a lot we don’t know,” Weinberg continues, including what constitutes a “normal” pregnancy. And neither doctors nor researchers want to do anything more invasive than a blood draw in the search for clues, due to an abundance of concern for the developing fetus.
Ultrasound and magnetic resonance imaging are among the diagnostic staples when dealing with pregnant women with a suspected medical problem, and they’re getting progressively better at dealing with maternal and fetal motion artifacts that can degrade image quality, says Weinberg. These imaging modalities might be more widely utilized during prenatal visits if there was convincing evidence of their value in the early diagnosis of pregnancy complications and some sort of risk index to gauge who would most benefit from such studies.
Researchers at the University of California, Los Angeles, recently took a step in that direction with a new imaging technique called pseudo-continuous arterial spin labeling magnetic resonance imaging (pCASL MRI), which tracks maternal blood flow to the placenta, Weinberg says. In a study (DOI: 10.1002/jmri.26944) that recently published in the Journal of Magnetic Resonance Imaging, they demonstrated the potential of pCASL MRI to help diagnose several common complications in early pregnancy.
The study involved scanning the placentas of 69 women, first at 14 to 18 weeks of pregnancy and again at 19 to 24 weeks and then following those pregnancies to term. Ultimately, 15 pregnancies were identified as having at least one ischemic placental disease (IPD)—preeclampsia, intrauterine growth restriction (IUGR) and preterm birth—and those women tended to have lower blood supply to the placenta, especially at the earlier time point.
A 2014 review (DOI: 10.1053/j.semperi.2014.03.004) finds the incidence of IPD is shockingly common, says Weinberg. The rate is 2% to 8% for preeclampsia, about 10% for preterm birth and 3% to 5% for IUGR (aka “small for gestational age”).
As the paper points out, the problems of pregnancy are heterogeneous and the placenta may be differently affected based on the stage of the disease, says Weinberg. The pathology and clinical manifestations are different for early- and late-onset IUGR, for example, but only a few studies have addressed them as separate conditions.
IPD is a collection of placental insufficiency conditions that are themselves highly variable clinically, notes Weinberg, adding that the preliminary data are encouraging. “It would be interesting to see if they can be confirmed in a larger study for specific IPDs.”
Gray Areas
Weinberg spent nearly 20 years in translational research at a pharmaceutical company before becoming a review officer in the area of women’s reproductive health at the NICHD and, six years ago, being tapped to lead the Human Placenta Project. Surprisingly little is known about the role of the placenta in health and disease, he says.
The ability to safely study the placenta during pregnancy wasn’t even possible until about a decade ago, thanks to advances in nanotechnology, microfluidics, sequencing, omics and imaging technology, says Weinberg. These advances were big reasons the Human Placenta Project got launched in the spring of 2014, when scientific and clinical thought leaders in and outside the U.S. agreed “now’s the time.”
Most people picture the placenta as it appears at delivery, a unique vasculature organ roughly the size of a dinner plate, says Weinberg. “But it doesn’t start that way. It follows a complex developmental pathway from early pregnancy all the way up to term. It’s not a trivial thing to figure out at any given point along the pregnancy how things are going. It would be like taking 50 marriages and trying to tell which ones will end in divorce.”
Key diagnostic goals are to noninvasively determine if the placenta is keeping up with the growth rate of the fetus and how well it is delivering oxygen and nutrients. A blood test would be great, Weinberg says, but “you have to know what you’re looking for, when to measure it and what that means.”
That gets back to known influencers of poor outcomes, such as placenta size. Studies demonstrate a placental weight to birth weight ratio below the 10th percentile or above the 90th percentile can signal trouble, says Weinberg, but most women fall in the gray area between those two extremes.
In the recent study using pCASL MRI, researchers were able to plot a “pretty good” separation between normal and IPD pregnancies at 16 weeks, Weinberg notes, but the differences were much less only four weeks later. Study authors offered “compensatory mechanisms” during the second trimester as a potential explanation. “It would be logical that the placenta would physiologically adapt as best it could to meet the needs of the fetus,” Weinberg says.
Marking Progress
In addition to investigator-initiated studies, the Human Placenta Project periodically issues funding opportunity announcements for specific areas of science. An announcement for outside-of-the-box technologies, for example, has advanced research aimed at isolating placenta-specific vesicles in the bloodstream, he says.
Most early funding applications specific to the Human Placenta Project, while not limited to imaging, were for studies involving ultrasound and MRI because those modalities have established safety boundaries when used with pregnant women, Weinberg continues. Evolving research in proteomics, transcriptomics and lipidomics should eventually enable the development of a signature of normal and quantify variation in various dysfunctions across pregnancies, he adds.
Weinberg says he imagines the day women get an MRI or ultrasound and blood test, and possibly also a urinalysis, during the first well visit with their OB-GYN to either learn all is well or that more frequent checkups are warranted.
Long before the Human Placenta Project launched, the NICHD was already funding a large amount of basic research to learn more about how the placenta works, says Weinberg. That work continues and is expected to generate a “mechanistic understanding of why sometimes things go wrong” so potential new treatments for IPD conditions get developed in parallel with tests for detecting them.
One of the biggest achievements of the Human Placenta Project to date has been “galvanizing the research community to make research on human placenta development and function a priority,” says Weinberg. In addition to novel methods for isolating placental vesicles, notable breakthroughs include “advanced MRI for measuring placenta oxygenation and perfusion and advanced ultrasound for looking in detail at placental blood flow.”