placenta
Understanding Childbirth Through a Single-Cell Atlas of the Placenta
Posted on by Dr. Monica M. Bertagnolli
While every birth story is unique, many parents would agree that going into labor is an unpredictable process. Although most pregnancies last about 40 weeks, about one in every 10 infants in the U.S. are born before the 37th week of pregnancy, when their brain, lungs, and liver are still developing.1 Some pregnancies also end in an unplanned emergency caesarean delivery after labor fails to progress, for reasons that are largely unknown. Gaining a better understanding of what happens during healthy labor at term may help to elucidate why labor doesn’t proceed normally in some cases.
In a recent development, NIH scientists and their colleagues reported some fascinating new findings that could one day give healthcare providers the tools to better understand and perhaps even predict labor.2 The research team produced an atlas showing the patterns of gene activity that take place in various cell types during labor. To create the atlas, they examined tissues from the placentas of 18 patients not in labor who underwent caesarean delivery and 24 patients in labor. The researchers also analyzed blood samples from another cohort of more than 250 people who delivered at various timepoints. This remarkable study, published in Science Translational Medicine, is the first to analyze gene activity at the single-cell level to better understand the communication that occurs between maternal and fetal cells and tissues during labor.
The placenta is an essential organ for bringing nutrients and oxygen to a growing fetus. It also removes waste, provides immune protection, and supports fetal development. The placenta participates in the process of normal labor at term and preterm labor. Problems with the placenta can lead to many issues, including preterm birth. To create the placental atlas, the study team used an approach called single-cell RNA sequencing. Messenger RNA molecules transcribed or copied from DNA serve as templates for proteins, including those that send important signals between tissues. By sequencing RNAs at the single-cell level, it’s possible to examine gene activity and signaling patterns in many thousands of individual cells at once. This method allows scientists to capture and describe in detail the activities within individual cell types along with interactions among cells of different types and in immune or other key signaling pathways.
Using this approach, the researchers found that cells in the chorioamniotic membranes, which surround the fetus and rupture as part of the labor and delivery process, showed the greatest changes. They also found cells in the mother and fetus that were especially active in generating inflammatory signals. They note that these findings are consistent with previous research showing that inflammation plays an important role in sustaining labor.
Gene activity patterns and changes in the placenta can only be studied after the placenta is delivered. However, it would be ideal if these changes could be identified in the bloodstream of mothers earlier in pregnancy—before labor—so that health care providers can intervene if necessary. The recent study showed that this was possible: Certain gene activity patterns observed in placental cells during labor could be detected in blood tests of women earlier in pregnancy who would later go on to have a preterm birth. The authors note that more research is needed to validate these findings before they can be used as a clinical tool.
Overall, these findings offer important insight into the underlying biology that normally facilitates healthy labor and delivery. They also offer preliminary proof-of-concept evidence that placental biomarkers present in the bloodstream during pregnancy may help to identify pregnancies at increased risk for preterm birth. While much more work and larger studies are needed, these findings suggest that it may one day be possible to identify those at risk for a difficult or untimely labor, when there is still opportunity to intervene.
The research was conducted by the Pregnancy Research Branch part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and led by Roberto Romero, M.D., D.Med.Sci., NICHD; Nardhy Gomez-Lopez, Ph.D., Washington University School of Medicine in St. Louis; and Roger Pique-Regi, Ph.D., Wayne State University, Detroit.
References:
[1] Preterm Birth. CDC.
[2] Garcia-Flores V, et al., Deciphering maternal-fetal crosstalk in the human placenta during parturition using single-cell RNA sequencing. Science Translational Medicine DOI: 10.1126/scitranslmed.adh8335 (2024).
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Visualizing The Placenta, a Critical but Poorly Understood Organ
Posted on by Diana W. Bianchi, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development
The placenta is the Rodney Dangerfield of organs; it gets no respect, no respect at all. This short-lived but critical organ supports pregnancy by bringing nutrients and oxygen to the fetus, removing waste, providing immune protection, and producing hormones to support fetal development.
It also influences the lifelong health of both mother and child. Problems with the placenta can lead to preeclampsia, gestational diabetes, poor fetal growth, preterm birth, and stillbirth. Although we were all connected to one, the placenta is the least understood, and least studied, of all human organs.
What we do know about the human placenta largely comes from studying it after delivery. But that’s like studying the heart after it’s stopped beating. It doesn’t help us predict complications in time to avert a crisis.
To fill these knowledge gaps, NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) developed the Human Placenta Project (HPP) to noninvasively study the placenta during pregnancy. Since 2014, this approximately $88 million collaborative research effort has been developing ultrasound, magnetic resonance imaging (MRI), and blood-based biomarker methods to study how the placenta functions in real time and in greater detail.
As illustrated in the image above, advanced ultrasound tools allowed HPP researchers at Eastern Virginia Medical School, Norfolk, and the University of Texas Medical Branch, Galveston, to gain a detailed look at the placenta’s intricate arrangement of blood vessels, or vasculature. By evaluating both fetal (left panel) and maternal (right panel) placental vasculature in 610 pregnant people starting at 13 weeks of gestation, the investigators aimed to identify early changes that predicted later complications.
They observed that such changes can start in the first trimester and affect both the vasculature and placental tissue. While further research is needed, these findings suggest that placental ultrasound monitoring can inform efforts to prevent and treat pregnancy complications.
Another HPP team led by Boston Children’s Hospital is developing an MRI strategy to monitor blood flow and oxygen transport through the placenta during pregnancy. Interpreting and visualizing MRI data of the placenta is challenging because of its variable shape, the tendency of muscles in the uterus to begin tightening or contracting well before labor [1], and other factors.
As shown in the video above, the researchers developed a way to account for the motion of the uterus and “freeze” the placenta to make it easier to study (left two panels of video) [2]. They also developed algorithms to better visualize the complex patterns of placental oxygen content during contractions (center panel) [3]. The scientists then carried out initial visualizations of blood flow through the placenta shortly after delivery (second panel from right) [4].
They now intend to map these MRI findings to the placenta itself after delivery (far right panel), which will allow them to explore how additional factors such as gene expression patterns and genetic variants contribute to placental function. Ultimately, they plan to apply these MRI techniques to monitor the placenta in real time during pregnancy and identify changes that indicate compromised function early enough to adjust maternal management as needed.
Other HPP efforts focus on identifying components in maternal blood that reflect the status of the placenta. For example, an HPP research team led by scientists at the University of California, Los Angeles, adapted non-invasive prenatal testing methods to analyze genetic material shed from the placenta into the maternal bloodstream. Their findings suggest that distinctive patterns in this genetic material detected early in pregnancy may indicate risk for later complications [5].
Another HPP team, led by investigators at Columbia University, New York, helped establish that extracellular RNAs (exRNAs) released by the placenta into maternal circulation reflect the placenta’s status at a cellular level beginning in the first trimester. To harness the potential of exRNA biomarkers, the investigators are optimizing methods to isolate, sequence, and analyze exRNAs in maternal blood.
These are just a few examples of the cutting-edge work being funded through the HPP, which complements NICHD’s longstanding investment in basic research to unravel the physiology of and real-time gene expression in the placenta. Unlocking the secrets of the placenta may one day help us to prevent and treat a range of common pregnancy complications, while also providing insights into other areas of science and medicine such as cardiovascular disease and aging. NICHD is committed to giving this important organ the respect it deserves.
References:
[1] Placental MRI: Effect of maternal position and uterine contractions on placental BOLD MRI measurements. Abaci Turk E, Abulnaga SM, Luo J, Stout JN, Feldman H, Turk A, Gagoski B, Wald LL, Adalsteinsson E, Roberts DJ, Bibbo C, Robinson JN, Golland P, Grant PE, Barth, Jr WH. Placenta. 2020 Jun 1; 95: 69-77.
[2] Spatiotemporal alignment of in utero BOLD-MRI series. Turk EA, Luo J, Gagoski B, Pascau J, Bibbo C, Robinson JN, Grant PE, Adalsteinsson E, Golland P, Malpica N. J Magn Reson Imaging. 2017 Aug;46(2):403-412.
[3] Volumetric parameterization of the placenta to a flattened template. Abulnaga SM, Turk EA, Bessmeltsev M, Grant PE, Solomon J, Golland P. IEEE transactions on medical imaging. 2022 April;41(4):925-936.
[4] Placental MRI: development of an MRI compatible ex vivo system for whole placenta dual perfusion. Stout JN, Rouhani S, Turk EA, Ha CG, Luo J, Rich K, Wald LL, Adalsteinsson E, Barth, Jr WH, Grant PE, Roberts DJ. Placenta. 2020 Nov 1; 101: 4-12.
[5] Cell-free DNA methylation and transcriptomic signature prediction of pregnancies with adverse outcomes. Del Vecchio G, Li Q, Li W, Thamotharan S, Tosevska A, Morselli M, Sung K, Janzen C, Zhou X, Pellegrini M, Devaskar SU. Epigenetics. 2021 Jun;16(6):642-661.
Links:
Human Placenta Project (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)
Preeclampsia (NICHD)
Understanding Gestational Diabetes (NICHD)
Preterm Labor and Birth (NICHD)
Stillbirth (NICHD)
Abuhamad Project Information (NIH RePORTER)
Grant Project Information (NIH RePORTER)
Devaskar Project Information (NIH RePORTER)
Williams Project Information (NIH RePORTER)
Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 10th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Studies Confirm COVID-19 mRNA Vaccines Safe, Effective for Pregnant Women
Posted on by Dr. Francis Collins
Clinical trials have shown that COVID-19 vaccines are remarkably effective in protecting those age 12 and up against infection by the coronavirus SARS-CoV-2. The expectation was that they would work just as well to protect pregnant women. But because pregnant women were excluded from the initial clinical trials, hard data on their safety and efficacy in this important group has been limited.
So, I’m pleased to report results from two new studies showing that the two COVID-19 mRNA vaccines now available in the United States appear to be completely safe for pregnant women. The women had good responses to the vaccines, producing needed levels of neutralizing antibodies and immune cells known as memory T cells, which may offer more lasting protection. The research also indicates that the vaccines might offer protection to infants born to vaccinated mothers.
In one study, published in JAMA [1], an NIH-supported team led by Dan Barouch, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, wanted to learn whether vaccines would protect mother and baby. To find out, they enrolled 103 women, aged 18 to 45, who chose to get either the Pfizer/BioNTech or Moderna mRNA vaccines from December 2020 through March 2021.
The sample included 30 pregnant women,16 women who were breastfeeding, and 57 women who were neither pregnant nor breastfeeding. Pregnant women in the study got their first dose of vaccine during any trimester, although most got their shots in the second or third trimester. Overall, the vaccine was well tolerated, although some women in each group developed a transient fever after the second vaccine dose, a common side effect in all groups that have been studied.
After vaccination, women in all groups produced antibodies against SARS-CoV-2. Importantly, those antibodies neutralized SARS-CoV-2 variants of concern. The researchers also found those antibodies in infant cord blood and breast milk, suggesting that they were passed on to afford some protection to infants early in life.
The other NIH-supported study, published in the journal Obstetrics & Gynecology, was conducted by a team led by Jeffery Goldstein, Northwestern’s Feinberg School of Medicine, Chicago [2]. To explore any possible safety concerns for pregnant women, the team took a first look for any negative effects of vaccination on the placenta, the vital organ that sustains the fetus during gestation.
The researchers detected no signs that the vaccines led to any unexpected damage to the placenta in this study, which included 84 women who received COVID-19 mRNA vaccines during pregnancy, most in the third trimester. As in the other study, the team found that vaccinated pregnant women showed a robust response to the vaccine, producing needed levels of neutralizing antibodies.
Overall, both studies show that COVID-19 mRNA vaccines are safe and effective in pregnancy, with the potential to benefit both mother and baby. Pregnant women also are more likely than women who aren’t pregnant to become severely ill should they become infected with this devastating coronavirus [3]. While pregnant women are urged to consult with their obstetrician about vaccination, growing evidence suggests that the best way for women during pregnancy or while breastfeeding to protect themselves and their families against COVID-19 is to roll up their sleeves and get either one of the mRNA vaccines now authorized for emergency use.
References:
[1] Immunogenicity of COVID-19 mRNA vaccines in pregnant and lactating women. Collier AY, McMahan K, Yu J, Tostanoski LH, Aguayo R, Ansel J, Chandrashekar A, Patel S, Apraku Bondzie E, Sellers D, Barrett J, Sanborn O, Wan H, Chang A, Anioke T, Nkolola J, Bradshaw C, Jacob-Dolan C, Feldman J, Gebre M, Borducchi EN, Liu J, Schmidt AG, Suscovich T, Linde C, Alter G, Hacker MR, Barouch DH. JAMA. 2021 May 13.
[2] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in pregnancy: Measures of immunity and placental histopathology. Shanes ED, Otero S, Mithal LB, Mupanomunda CA, Miller ES, Goldstein JA. Obstet Gynecol. 2021 May 11.
[3] COVID-19 vaccines while pregnant or breastfeeding. Centers for Disease Control and Prevention.
Links:
COVID-19 Research (NIH)
Barouch Laboratory (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston)
Jeffery Goldstein (Northwestern University Feinberg School of Medicine, Chicago)
NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institute of Child Health and Human Development; National Center for Advancing Translational Sciences; National Institute of Biomedical Imaging and Bioengineering
Preeclampsia: Study Highlights Need for More Effective Treatment, Prevention
Posted on by Dr. Francis Collins
It’s well known that preeclampsia, a condition characterized by a progressive rise in a pregnant woman’s blood pressure and appearance of protein in the urine, can have negative, even life-threatening impacts on the health of both mother and baby. Now, NIH-funded researchers have documented that preeclampsia is also taking a very high toll on our nation’s economic well-being. In fact, their calculations show that, in 2012 alone, preeclampsia-related care cost the U.S. health care system more than $2 billion.
These findings are especially noteworthy because preeclampsia rates in the United States have been steadily rising over the past 30 years, fueled in part by increases in average maternal age and weight. This highlights the urgent need for more research to develop new and more effective strategies to protect the health of all mothers and their babies.
Morning Sickness Associated with Lower Miscarriage Risk
Posted on by Dr. Francis Collins
During the first trimester of pregnancy, many women experience what’s commonly known as “morning sickness.” As distressing as this nausea and vomiting can be, a team of NIH researchers has gathered some of the most convincing evidence to date that such symptoms may actually be a sign of something very positive: a lower risk of miscarriage.
In fact, when the researchers studied a group of women who had suffered one or two previous miscarriages, they found that the women who felt nauseous during their subsequent pregnancies were 50 to 75 percent less likely to miscarry than those without nausea. While it’s not yet exactly clear what’s going on, the findings lend support to the notion that morning sickness may arise from key biological factors that reflect an increased likelihood of a successful pregnancy.
Not Sterile, After All: The Placenta’s Microbiome
Posted on by Dr. Francis Collins
When thinking about your health, or the health of your children, you’re probably not thinking of the placenta. This often neglected, yet vital, pancake-shaped organ develops during pregnancy. It adheres to the inside surface of the uterus and guides development; partly maternal, partly fetal, it delivers food and oxygen to the growing fetus via the umbilical cord and removes waste products—among other vital functions. Yet, the placenta may be even more important to the health of mother and child than we’ve previously imagined.
Until recently, the uterus and the placenta were thought to be germ-free and sterile—to keep the baby safe from infection. But at just one week old, babies have a complex collection of microbes in their guts. Where do those bacteria come from? It was thought that a baby received its first dose of bacteria as it passed through the vagina—or from the mother’s skin, if the child was born via C-section. But Kjersti Aagaard, a 2007 recipient of a NIH Director’s New Innovator Award and an obstetrician and associate professor of gynecology at Baylor and the Texas Children’s Hospital, began to suspect there was more to the story.