Heartbreak and elation battle it out for control of my emotional state as I perch on the cusp of sending my daughter to college. I remember the first movie I ever brought her to (Curious George) in which she literally slapped her knee she was laughing so hard, and think: I can’t live without her. And then I remember the very first friend-for-life I made at college, and am filled with excitement for her to make her own strong connections. I haven’t been so overcome by feelings since I brought this same baby girl home from the hospital. While it’s miraculous to have gotten to this point–especially since that baby was born with a life threatening heart condition–a potentially bigger miracle was that I got pregnant at all, and then, as if that weren’t enough, turned an egg and a sperm into a living, breathing human inside the confines of my body. The number of steps involved and the precise timing required to make this transformation happen is staggering–and that’s just the steps we know about. There are plenty of details missing in our understanding of gestation–a fact that’s unavoidable if you don’t glide, seamlessly, into reproduction. Uncovering these unknown facts could have dramatic repercussions on generations to come.
These facts are hard to nail down in part because pregnancy is an elaborate magic trick. One of the elements that makes it magic is that the mother’s immune system “allows” sperm (completely unrelated to her), and then eventually the fetus (only half related) to exist inside her body, despite the fact that most “foreign” elements that enter the body face destruction at the hands of the immune system. When pregnancy works, these foreign elements are not attacked, but fostered. It never occured to me to question how these contradictory goals–protecting my body from disease and providing a hospitable space for my next generation–were balanced.
Today doctors believe that problems with immune function might be at the heart of infertility, miscarriage, preeclampsia and premature birth. These issues are relevant for a large number of couples. The CDC estimates that roughly ten percent of couples experience infertility. (here) Among other industrialized nations, the US has one of the highest incidences of preterm births. Using the most recent data from the WHO (2014), the US is ranked 67th out of 184 countries in terms of preterm birth rate, just edging out Venezuela, but not quite as successful as Benin. (here) Babies who arrive too early have the physiology and chemistry of a fetus–which suits them to the world of the womb, not the world outside it. Preterm birth is associated with higher rates of infant mortality, has potentially long term developmental consequences for the baby, and can be wildly expensive to treat. In 2018 approximately 1 in 10 babies were born prematurely in the United States. (here) That rate, 1 in 10, is an average that conceals the significant racial disparity in outcomes: black women in the US face a much higher rate of prematurity than any other racial group–a finding that persists even when studies control for income and education.(!!) (here)
Initially, attention paid to this relationship was not born of an interest in pregnancy. It arrived, in 1953, in response to a question posed by a famous scientist in search of ways to improve the success of organ transplantation. Peter Medawar, a British zoologist who would go on to share the Nobel Prize in 1960, noted in a speech to the British Society for Experimental Biology that pregnancy was an instance in which the body tolerated foreign material (in the form of a fetus), seemingly without an immune reaction. Wasn’t pregnancy an example of a successful transplant, he wondered? Could whatever deal the fetus cut with its mother be used to advantage in organ transplantations?
Once Medawar identified the maternal fetal relationship as a grail for transplantation biology, many scientists were drawn into the quest to discover how it worked. Likening a fetus to an organ transplant dramatically shaped how researchers thought about pregnancy. Numerous hypotheses were formed to answer the question: how does the fetus thwart the mother’s immune system to survive in her body? It turns out this is not a great analogy, and accordingly, none of the hypotheses were validated. But this search uncovered some of the very special rules that govern a woman’s body during pregnancy. It turns out to be one hell of a trick.
These hypotheses can broadly be grouped into three categories. The first idea was that during pregnancy the mother’s immune system was shut down by the release of hormones like progesterone, effectively eliminating her body’s ability to attack a growing fetus. A side effect was that she also couldn’t fend off an infection. While the developing embryo and the growing placenta do in fact produce progesterone and other chemical signals, the goal is to temper the activity of immune cells in the vicinity of the fetus, not to shut the immune system down entirely. Experiments in pregnant mice showed that progesterone didn’t prevent immune cell attacks in other parts of the mother’s body. And epidemiological evidence suggests that pregnant women are not more susceptible than other women to infections in general. That the mother’s immune system functions during pregnancy makes sense for long term survival of the species. Population growth would be seriously disadvantaged if pregnant women were routinely getting picked off by every passing Flu.
It turns out there is no need to shut down the mother’s ability to fight infection because immunity during pregnancy, like politics and real estate, is a local endeavor. Although different types of immune cells play a part in successful pregnancies, Natural Killer (NK) cells provide an example. As their name implies, these cells kill other cells, in particular abnormal cells. NK cells that circulate throughout the body continue to do this very job. But instead of killing things, NK cells that situate themselves in the lining of the uterus (aka uNK) play an entirely different role. They facilitate implantation (the very early stages of pregnancy) and contribute to the growth and differentiation of other cells. (here) The special assignment seems to be critical to success. Researchers have found that smaller populations of uNK cells are correlated with spontaneous abortions and infertility. (here)
Idea two was that a physical barrier separated mother from young. Although the fetus was inside the mother’s body, it was sealed in its own compartment, an inaccessible passenger on the mothership. According to this theory, maternal immune cells didn’t react to the fetus because they couldn’t sense its presence. This view held sway until about 1980. Research shows that fetal cells and maternal cells are, in fact, in contact with one another. When the fetus is just a ball of cells it sends out fingerlike projections embedding it in the mother’s uterine lining. These inroads are the initial foray into the creation of the placenta–an organ that allows for exchange between the two worlds; the mother passes oxygenated blood and nutrients to the developing fetus, and the fetus gets rid of waste. That maternal immune cells are well aware of the massive changes going on around them became irrefutable once antibodies to the fetus were found in blood samples from pregnant women. (here) Other mechanisms, including the re-casting of additional immune cell roles near the uterus and the gathering of cells that dampen inflammatory tendencies, are in place to keep these antibodies at bay.
We weren’t privy to any of these findings when we were trying to get pregnant. Our difficulty getting pregnant wasn’t attributed to anything in particular; ditto to my miscarriage. And just as inexplicably, more than a year after setting out to start a family, we got pregnant. For the first few months we truly believed that we’d outrun the mysterious obstacle that kept us from growing our family, accepting the proposition that pregnancy was an intricate and not fully knowable process.
The third theory makes the first two seem like warm up pitches by making use of what was known at the time about organ transplants. Donor organs were rejected because the recipient’s immune system could sniff out the presence of something foreign. What the immune system recognized was a protein on the surface of almost all cells that uniquely identified individuals, one from another. This protein was made by a gene, first discovered in mice in the 1940s. That gene, called the major histocompatibility complex (MHC) in mice, has a human analog called the HLA. In theory, the HLA would be relevant for a partially foreign fetus trying to stay on the good side of it’s mother’s immune cells. Scientists conjectured that the fetus avoided attack because it might be “underdeveloped”, and as such had no way to uniquely identify itself (here); either it didn’t have this distinguishing protein on its cells, or the protein existed, but couldn’t be recognized by the mother’s immune cells.(here)
The surprising answer to this question is that HLA proteins are present on fetal cells, but it’s an entirely different kind of protein from the one present on most adult cells. (here) It was first identified in 1982, and covers the surface of cells that line the sensitive border between mother and fetus. This is where the action seems to be, where the truce between immune cells and the fetus is continually renewed. Current theories suggest that this special HLA gene modulates the activity of immune cells, in particular uNK cells, by discouraging destructive behavior. This version of the HLA is also credited with sweet talking other types of immune cells by the border, tempering their interest in attack. Understandably, your specific copy of this gene is important for many immune related functions, including maintaining a successful pregnancy. Experiments show that differences in genetic instructions for this set of proteins are associated with preeclampsia and premature birth, miscarriage and recurrent spontaneous abortion. (here)
Although my HLA genes didn’t steer us to preeclampsia or premature birth, these genes likely predisposed me to the autoimmune problem that tried to crash my pregnancy. In the second trimester, once my antibodies made their way into the fetal bloodstream, they attacked the fetal heart, destroying the nerve that sets the heart’s rate. My husband and I quickly learned the high cost of a bad relationship between my immune system and our developing baby. Our high risk doctors were confident the baby wouldn’t survive. Given the damage caused by my antibodies, they didn’t understand why her heart continued to beat. Our only hope was that pregnancy had many overlapping systems in place to manage the failure of any one system–maybe one of these redundancies could prop up the fetal heart. What that mechanism would be and how it would work were unknown. We were just guessing, and hoping.
It’s not clear that pregnancy, a process that’s undergone hundreds of thousands of years of evolution in humans, has shortcuts to a good relationship with a foreign immune system that can be lifted for tranplantation. Unlike transplantation, pregnancy requires immune system involvement and is not a singular event, but one that undergoes different stages which call for varying levels of immune system participation. In the first trimester there is a dramatic need for immune cells to help the embryo anchor to the wall of the uterus and grow both itself and the placenta. The second trimester is one of relatively less need for inflammation. In the third trimester immune cells are recruited to nudge open the cervix, stimulate uterine contractions and initiate birth.
Consistent with this dynamic environment, in 2017 researchers at Stanford set out to establish an “immune clock” which would allow them to determine which populations of immune cells should be present at different stages of fetal development for pregnancy success. With this clock doctors could conceivably test blood samples to predict if preeclampsia or premature birth posed an imminent threat. (here) With advance warning preeclampsia can be managed, and perhaps the factors that contribute to premature birth could be manipulated to delay the birth.
Our problem struck without warning; a perfect storm of unlikely events. At twenty four weeks the fetal heart rate was normal, and at twenty five it had dropped from 140 beats per minute to 90. Two days later it hovered at 50. At her birth, our baby was whisked from my body–and immediately installed in the Neonatal Intensive Care Unit. Most of the other patients in the unit were preemies–fragile looking babies with eyes tightly shut, working on regulating their temperature or developing the pliable lungs they needed outside their mother’s bodies. Some of them would graduate to the general newborn ward and eventually to their own homes. Some would not. In 2017 prematurity was the second leading cause of death for infants in the US. We got lucky. Despite my uncontrollable autoimmune problem and the absence of a rigorously tested way to manage my slowly sinking pregnancy, our baby made it–out of the NICU and into a full life.
With continued research pregnancy will become a trick we understand more completely. The drastically high preterm birth rate among black mothers has been attributed to many influences, both genetic and environmental. Ultimately, many of these influences are expressed in the body through changes in immune activity which upsets the delicate balance between a mother’s immune system and and her pregnancy. (here) Truly pinning down how this agreement works when it works, and what goes wrong when it doesn’t work could have a profound impact on the future, making a normal pregnancy a miracle that is commonplace.