Conflict on the Maternal-Fetal Front
In her line of work, Yalda Afshar, MD (FEL ’19), PhD, sometimes has to deliver difficult news. A maternalfetal medicine physician, she works collaboratively with other sub-specialists to manage high-risk pregnancies, such as patients with cardiovascular disease, high blood pressure or organ transplantations who take multiple immune suppressants. At her first meeting with every patient, she issues a caution: “I say to them, ‘I may look you in the eyes and tell you that I am worried that this pregnancy can harm you. And if this happens, I will tell you what I think needs to be done about it.’ For some of my very, very sick patients, that pregnancy can become a risk to their life.”
Dr. Afshar’s goal as a clinician is to care for the patient in front of her and to optimize care for the fetus developing within her womb. But what happens when the interests of mother and fetus conflict? Such biological quarrels are not always a matter of life and death. But even in the healthiest patients, pregnancy is not purely the harmonious biological process that we often think it to be. In fact, maternal-fetal conflict is a feature of pregnancy, not a bug; the genetic divergence between a fetus, whose DNA comes from two distinct individuals, and the mother creates the potential for a host of pregnancy complications and adverse outcomes for both parties.
Yet the causes of even common pregnancy afflictions (such as pre-eclampsia, which occurs in 12% of pregnancies, or gestational diabetes, which affects 2-to-10% of pregnancies in the United States) are still not well-understood. Research by Dr. Afshar and other UCLA faculty is yielding new insights into the hows and whys of the maternal-fetal conflict, and its costs and benefits for the health of women and their children.
HAVING A NUMBER OF ROBUST TOTS, EVEN IF THAT IS A MOTHER’S DREAM COME TRUE, does not necessarily support her long-term health. “Evolution doesn’t promote health and happiness and longevity; it promotes reproductive success. Sometimes, that reproductive success comes at the cost of health or happiness or longevity,” says Molly Fox, PhD, a biological anthropologist and assistant professor in the UCLA Department of Anthropology and the Department of Psychiatry and Biobehavioral Sciences in the UCLA Semel Institute for Neuroscience and Human Behavior. “In the case of reproduction, there are costs to the mother’s body and health that play out over the course of her life, and those costs are balanced against the adaptive benefit of passing on her genes,” says Dr. Fox, who studies the evolutionary context and role of family environments in transgenerational transmission of health and disease.
To understand why this is, it helps to look more closely at the mechanisms of pregnancy itself. Pregnancy in certain species of mammals, such as primates and mice, features a unique interaction between the placenta, an organ that develops during pregnancy to deliver nutrients and oxygen from the mother’s blood to the growing embryo, and the endometrium, or the lining of the uterus. Responding to hormonal signals, the placental cells enlarge the blood vessels on the endometrial surface to secure maximum blood supply. Unlike in other mammals, a human mother has limited control over this process. You might say that the fetus and its placental cells are in the driver’s seat, sending hormonal messages that steer the vehicle that is the mother’s body. Some of this hormonal signaling occurs through what’s called genomic imprinting, in which genes are either expressed or suppressed depending on whether they are inherited from the mother or father.
The maternal body has its own, albeit more limited, way of pushing back. From the outset of a pregnancy, the mother’s immune system treats the embryo, with its partially foreign DNA, as an intruder. It has evolutionary reasons for doing so: The mother may have existing children, or she may be early in her reproductive years, with the potential for many more children, possibly by other partners. If she is going to invest her energies in gestating this particular embryo, the embryo itself has to give her body a reason to do so by proving it is healthy. The first test is implantation: An embryo must send a continual stream of hormones to the endometrial tissues to convince the endometrium to let it implant. (The Harvard evolutionary biologist David Haig has described this interaction as a “job interview.”)
Then the mother and fetus must work out how they’re going to allocate resources, such as nutrients and calories. Most female mammals keep their own blood supply separate from that of the fetus, and control over what nutrients are filtered to the fetus remains with the mother. In humans, the mother is at a disadvantage, as an implanted embryo not only can access all the blood and nutrients it needs but also sends its own hormones into the mother’s bloodstream. In a healthy pregnancy, this exchange reaches a balance, so that the fetus can grow at an appropriate pace with the nutrients, blood and sugars it needs, while the mom’s health remains intact. Unfortunately, that’s not always the case.
GROUND ZERO FOR THIS LOWINTENSITY BIOLOGICAL BATTLE OF WILLS BETWEEN MOTHER AND FETUS is the placenta. “It’s this organ that’s, in essence, created to sustain the pregnancy, and it is truly where the cellular crosstalk from the fetus and the mother happens,” Dr. Afshar says. The placenta contains a number of different cell types: endothelial (or vascular) cells, de - cidual cells, trophoblast cells and immune cells, among others. Dr. Afshar believes that a better understanding of normal pregnancy biology and physiology throughout the 280 or so days a pregnancy normally lasts would shed light on the range of eventual pregnancy and maternal-health outcomes.
But it’s not enough to study only the placenta. She and her colleagues observe development of the embryo and the fetus par - allel to the dynamic changes of the placenta throughout the pregnancy in order to gain a better understanding of the relationship between placental abnormalities (such as placenta accreta, in which the placenta at - taches too deeply into the uterine wall) and outcomes such as heart disease or genetic abnormalities of the fetus. “I think about how the placenta develops concomitantly with the embryology of the fetus,” Dr. Afshar says. “I’m really interested in the cellular signaling and the crosstalk, and what is happening at the cell level, especially in the vascular cells in the placenta.”
How does one tune into the conversations between cells? Dr. Afshar eavesdrops, as it were, using a range of diagnostic and monitoring tools to observe and sample the fetal-placental unit throughout the pregnancy. These include observation of the fetus, usually via a handheld Doppler and an ultrasound, and an MRI in some instances, throughout the pregnancy; monitoring the fetal heart rate and rhythm and observing the fetus’ anatomy; and maternal blood draws, chorionic villus sampling (biopsy of the placenta) or amniocentesis (sampling the amniotic fluid). She and her team then use a multi-step process to isolate placental DNA, RNA or cells circulating within the maternal blood. “Those isolated DNA, RNA, proteins or whole cells are our window into what’s going on in the placenta,” Dr. Afshar says.
One study Dr. Afshar co-authored and published in 2022 found that key placental functions that shape maternal and fetal pregnancy outcomes vary based on fetal sex. This is because male and female fetuses control the expression of microRNA (or miRNA), which regulates gene expression and mediates communication between cells, differently. Another line of her research, done in collaboration with UCLA colleagues Yazhen Zhu, MD, PhD, assistant professor of molecular and medical pharmacology and member of the Crump Institute of Molecular Imaging, and Hsian-Rong Tseng, PhD, pro - fessor of molecular medical pharmacology and member of the Crump Institute and the UCLA Jonsson Comprehensive Cancer Center, uses a nanostructure-embedded microchip to detect circulating trophoblasts (cTBs). Trophoblasts are the cells on the outer layer of a developing embryo that help it attach to the wall of the uterus; during implantation, cTBs are shed into the mother’s bloodstream. Their presence may indicate placental accreta spectrum disorders. “What are the genetic changes at the level of the placenta that differ - entiate disease versus no disease?” Dr. Afshar asks. “What are the changes that happen as a function of gestational age?”
An increase in cTBs floating around the mother’s blood can indicate that this process has somehow gone awry. Tracking the concen - tration of cTBs throughout pregnancy can help doctors screen for various placental abnormal - ities, some which cause severe hemorrhage at the time of birth. Current diagnostic tools such as MRIs or ultrasounds are either unavailable in low-resource settings or fail to capture onethird to one-half of placental accreta spectrum disorders. The capacity to continually monitor cTB levels could help prevent emergency hys - terectomies, blood transfusions or intensive care unit admissions that accompany such placental disorders.
SLEEP-DEPRIVED PARENTS LAYING OUT A SUBSTANTIAL PORTION OF THEIR TAKEHOME PAY FOR DIAPERS AND CHILDCARE will be the first to tell you that reproduction has costs. But what about the biological costs? If Dr. Afshar’s findings have given us a better picture of how the mother and fetus “talk” in real time through gene regulation and expression and hormonal signaling, the lingering effect of these conversations is still being worked out. “The interplay between the maternal and fetal systems is understood during pregnancy, but it’s not well-character - ized in terms of long-term effects.”
Dr. Fox’s research looks at the long-term health effects of pregnancy on both the mother and the fetus. She is investigating both how reproductive activity alters women’s risk of various diseases, and also seeking to under - stand how women’s experience of pregnancy might affect fetal development of certain traits that predispose their children to the risk of chronic disease. Like Dr. Afshar, she and her colleagues have a range of observational and measurement tools at their disposal: cogni - tive testing, assessments of oxidative stress, tracking the levels of certain cells responsible for suppressing inflammation.
But because women in general have been a neglected population throughout decades — if not centuries — of scientific research, Dr. Fox cautions that knowledge in this field is still in its infancy, so to speak. What’s more, certain areas are marked by significant disagreement. Dr. Fox gives the example of research on Alzheimer’s disease and pregnancy. “Some people say that having more pregnancies is helpful to your brain health, and some people say having more pregnancies is harmful. And some people say it has no effect at all,” she says. “There have been a lot of studies in all of these different directions. It’s really hard to reconcile.”
One reason these studies have conflicting findings may be a lack of consensus on how to even characterize women’s reproductive histories. Incomplete pregnancies, meaning miscarriages and elective abortions “have been totally neglected,” Dr. Fox points out, so they are typically not included in the count of pregnancies. “You have these wonderful long-term studies of health and disease, but they often don’t include that kind of nuanced information that may not have even been part of the person’s medical record. Yet, this kind of information is crucial to accurately counting their pregnancies or documenting the age at first pregnancy.”
Similarly, she observes, “lactation also has profound physiological effects on a woman’s body, and the variation in breastfeeding du - ration is really massive,” with some women spending years of their lives engaged in it and others no time at all.
If these variations in the experience of pregnancy and lactation influence wom - en’s health outcomes over the long-term, how does the fetus then manifest its own experience of pregnancy as a child or adult? One of Dr. Fox’s research projects, looking at the health of U.S.-born Latinos, seeks to answer these questions by understanding how women’s experiences of pregnancy map onto their children’s health. Her findings could go some way toward explaining what’s known as the “Hispanic health paradox,” in which the children of immigrants to the U.S. tend to have worse health outcomes than their parents, even though their parents are of the generation that uprooted themselves from their home countries, experienced the stress and trauma of setting up lives in a new country, and potentially struggled financially as well.
Why would their children, who were born in the U.S. and never experienced the loss of social ties or homesickness, fare worse? Dr. Fox’s hypothesis is that the trauma expe - rienced by the pregnant mothers may affect fetal development, such that the second gen - eration of children are “prenatally built in a way that makes them maybe more sensitive to the exposures that they face.” She cites obesity risk as an example. “A person who’s born with more of a predisposition towards obesity can eat the same diet as someone who is not, and they’ll be more likely to become obese,” she explains. “Everyone’s eating the same, crappy American diet, but the second generation has a higher risk of suffering as a result.”
THAT INTERPLAY BETWEEN ENVIRONMENTAL AND BIOLOGICAL FACTORS had long been the subject of speculation about why women were far more susceptible than men to autoimmune diseases such as lupus and multiple sclerosis (MS). In the early years of MS research, this was often attributed to differences in lifestyle — for example, women are more exposed to viruses because they’re the ones doing school pick-up and drop-off — or sometimes women’s complaints were simply dismissed as excessive.
Rhonda R. Voskuhl, MD, Jack H. Skirball Chair for Multiple Sclerosis Research and director of the UCLA Multiple Sclerosis Program, noticed another way that women differed from men in their experience of MS, the symptoms of which can include intense paralysis, visual loss and numbness.
Like many clinicians, she began to appre - ciate that relapses among her patients with MS seemed to be fewer during pregnancy.
Then, in 1998, a study in the New England Journal of Medicine showed a 75% reduction in relapses for pregnant people. At the time, that improvement was more than twice as powerful as what the most effective MS drug on the market had been able to achieve. “It was like, my goodness, this effect of pregnancy is stronger than anything else we have,” Dr. Voskuhl recalls.
She wanted to understand what it was about pregnancy that had such a potent effect on her patients. Through experiments on mice, she traced the beneficial effects to the hormone estriol, which in humans starts to be produced in the first trimester of pregnancy and peaks in the third trimester, before falling off dramatically after delivery. Since then, she and others have documented a beneficial effect on MS disease mechanisms of the increase in blood levels of this estrogen during pregnancy both in mice and in humans. (The fact that female mice with the relapsing form of disease are also more susceptible than male mice to MS debunks the theories about lifestyle or excessive complaints in humans, Dr. Voskuhl notes.)
Dr. Voskuhl highlights the role estriol plays in influencing the immune system during pregnancy. Rather than attacking the male proteins that have been introduced thanks to the father’s genetic material via a cellular response, the way an immune system might attack a localized infection, a pregnant per - son’s immune system shifts to responding less with cellular infiltration and more with anti - bodies. Dr. Voskuhl believes decreasing the cellular immune attack is beneficial for fetal survival. (Antibodies can be passed through the placenta, which is why pregnant women are given vaccines in order to provide passive immunity to the fetus.)
This, incidentally, benefits a pregnant mother with a cell-mediated autoimmune disease by reducing those types of immune responses during pregnancy. “An immune attack on those foreign male proteins on the fetus would be bad,” Dr. Voskuhl says. “I think women have been selected, evolutionarily, to shift their immune systems to where they don’t attack the fetus in deleterious ways. They go more for an antibody-mediated response, which is good for the fetus.”
Estriol is not only anti-inflammatory but also neuroprotective. That means it helps protect the fetus’s developing neural system in the case of maternal insults — an event such as hypoxia (low oxygen) or an infection in the mother. Both of these maternal changes, the shift from a cellular immune response to an antibody response, as well as the presence of a neuroprotective estrogen in the blood, con - tribute to the amelioration of MS symptoms in the mother.
Dr. Voskuhl notes that women with MS used to be told to avoid pregnancy; now it is clear that pregnancy offers health benefits both in the short-term and over the long-term. Other research has shown that having more pregnancies compared to fewer or none seems to align with having less long-term disability over the subsequent decades.
All of the researchers agree that we will need a better understanding of these dynamics as countries around the world undergo demo - graphic transition and women globally have fewer and later pregnancies. “In a very short period of time, the average age at first birth has shot up; it’s now extremely delayed compared to even one generation ago,” Dr. Fox notes.
At the same time, fertility rates have also fallen dramatically in the course of a generation in nearly all rich and middle-income countries. From a public-health or epidemiological stand - point, this mass shift in reproductive behavior is going to have consequences for many areas of women’s health that are still barely understood. Whichever way the data cuts, it’s imperative to get a better grasp on it, the UCLA scientists assert. That means teasing apart why some women gain physiological benefits from preg - nancy or lactation while others pay a cost in the form of accelerated aging or other degrading effects on the body.
“If we don’t understand how the number of pregnancies or the age of first pregnancy or how long you breastfeed — and all these other aspects of health — relate to one another, then we’re going to be woefully unprepared for the epidemiological environment in which we’re going to find ourselves, especially as popula - tions age,” Dr. Fox says. “Some of the effects will be immediate, and some of them will manifest only decades later.”
This article was written by Anna Louie Sussman and originally appeared in the Fall 2022 edition of U Magazine.