The fetus aggressively "plunders" the mother's resources. What is the solution to preeclampsia?

Leviathan Press:

Despite a large amount of experimental data, the "paternal sperm immunity" theory is still a hypothesis, and there is still a lot of controversy in the academic community. But no matter what, combined with existing research, this hypothesis seems to make sense - because we have too many concerns about preeclampsia.

The condition can lead to placental abruption and/or premature birth, increasing the risk of health problems for the fetus shortly after birth. In addition, pregnant women may experience swelling in their hands, feet, and neck, and if preeclampsia is severe and untreated, they may experience seizures (eclampsia) or organ damage. If it is understood as an excessive immune defense against the fetus in a first-time pregnancy, then how do we explain the symptoms of preeclampsia that can occur in a second, third, or even fourth pregnancy?

So, it is indeed a bit embarrassing... According to the logic of this hypothesis, it is possible to reduce the probability of preeclampsia by having multiple unprotected sexual intercourses before pregnancy (which can be understood as... adaptive exercises to relieve the maternal immune system alarm)? This sounds incredible.

In the early 1990s, Pierre-Yves Robillard was studying preeclampsia in Guadeloupe when he made a discovery that seemed to shake the foundations of his field.

Preeclampsia is a pregnancy complication that causes approximately 500,000 fetal and 70,000 maternal deaths worldwide each year and, for decades, has been considered the most common condition among first-time mothers because their bodies are launching an inappropriate attack on their first fetus[1].

© Live Action

Robiard, now a neonatologist and epidemiologist at the Centre Hospitalier Universitaire de La Réunion, noticed that the condition also occurred during the second, third, or fourth pregnancy , a pattern that has been documented in other studies but has not yet been fully explained. [2]

Then Robiard noticed something else. “These women had switched fathers,” he told me. He eventually surmised that the catalyst was not the unfamiliarity of a first pregnancy but unfamiliarity with the father’s genetic material —perhaps the mother had not been sufficiently exposed to it.

Robiard’s idea was unusual not only because it challenged contemporary thinking but also because it suggested some evolutionary consequences. Preeclampsia seemed to exist only in humans (or almost only in humans) and might be the result of the fetus exploiting the mother’s resources in a particularly aggressive way.[3]

So perhaps, Robiard and his colleagues suggest, the dangers it posed forced humans to develop a strange trait: relative inefficiency in reproducing offspring.

Humans, by this logic, are not very fertile, and therefore need to have lots of sex; frequent sex exposes a mother to her partner’s semen, accustoming her to the molecular makeup of her future offspring. If preeclampsia is an exaggerated immune response,[4] then unprotected sex might be the world’s most unusual allergy vaccine.

At least, that’s the view advocated by Robiard and his colleagues—an idea that’s “a little controversial and a little embarrassing,” Inkeri Lokki, an immunologist and reproductive biologist at the University of Helsinki, told me. She remembers a senior researcher in the field once stating the conclusion of the hypothesis as “choose your partner early and practice a lot.”

© Los Angeles Times

In addition to foreign genetic material, the mother’s body has good reason to be wary of the fetus. Pregnancy is an intergenerational struggle, with the fetus trying to plunder all nutrients from the mother’s tissues, while the mother tries to retain some resources for herself.[5]

In most mammals, it would be easy for the two sides to settle into a protracted stalemate. In humans, however, the fetus “has the upper hand” from the start, says Amy Boddy, an evolutionary biologist at the University of California, Santa Barbara.

Whether due to the extreme nutritional demands of our energy-hungry brains or simply the constraints of evolution in our primate lineage,[6] no other developing mammal invades as vigorously as the human embryo,[7] in two rounds of invasion,[8] where placental cells bury themselves deep into the endometrium, penetrating its muscle layer, where they stretch, melt, and rewire an entire set of blood vessels until they dilate and relax.

Embryo implantation process. The blastula implants into the maternal endometrium after a series of stages: apposition, adhesion and invasion. © ResearchGate

During this process, tissues liquefy and cells are forced apart, all in the interest of pumping large amounts of “blood to the placenta,” Julienne Rutherford, a biological anthropologist at the University of Arizona’s College of Nursing, told me.

The fetus thrives under these conditions, but the demands on the mother’s body are so great that they are almost immune-inducing. Therefore, preeclampsia, which occurs at least before 34 weeks of gestation, can be seen as a manifestation of the human maternal self-protection mechanism becoming aware of placental invasion and then initiating an over-defense.[9]

Haley Ragsdale, a biological anthropologist at Northwestern University, told me that when researchers examine tissue samples from early-onset preeclampsia cases, they often find that the placenta has failed to fully invade the uterus. At risk of starvation, the fetus tries to get more nutrients from the mother, in part by raising the mother’s blood pressure, a classic symptom of preeclampsia. (Although high blood pressure in the last few weeks of pregnancy can signal late-onset preeclampsia, researchers generally agree that the cause is different.)

Semen may be the answer[10]: it is full of the father’s genetic material, and once it enters the vagina, there are a lot of immune cells and molecules hanging around. It also contains signaling molecules that may be able to soothe the mother’s immune system[11]. Gustaaf Dekker, head of obstetrics and gynecology at the North Adelaide Local Health Network in Australia, who has worked with Robillard for many years, says that repeated contact without causing harm sends a clear message: I am safe.

Over the past 30 years, Decker, Robiard, and their colleagues have accumulated a wealth of evidence to support this view.[12] In multiple populations, the risk of early preeclampsia appears to be higher among couples experiencing their first pregnancy.[13] It is also higher among couples using donor eggs and sperm.[14]

In some studies, the risk of pre-eclampsia also appears to be lower in women who have had a lot of sex before pregnancy, at least if they avoid using condoms.[15] There is even evidence that repeated exposure to semen can make female mice more tolerant to cells collected from their mates.[16]

© Dribbble

From an evolutionary perspective, the theory goes a step further. If priming the maternal immune system with sperm is important, then “there was a strong selective pressure for humans to adopt a set of behaviors that promoted this exposure,” says Bernard Crespi, an evolutionary biologist at Simon Fraser University in Canada who has collaborated with Robillard.

The way our bodies fight over the placenta may help explain the nature of our semi-monogamous relationships: relatively low fertility rates among mammals, and relatively large testicles that provide an abundant supply of sperm. It may even influence the unusual ways in which the female body hides its fertility.

Unlike other mammals, we don’t go into regular, well-defined estrus or give clear signals about when we’re ovulating—the lack of both of these traits encourages more frequent sex to ensure reproduction. We hypothesize that repeated matings are just a habit of ours, perhaps because they make our pregnancies safer.

The paternal immunity hypothesis is not the only possible explanation for early-onset preeclampsia, and for some researchers it is far from the most compelling one. Fathers may play a different role in the condition.[17] Some evidence suggests that the DNA passed down by some men may predispose their offspring to slightly different implantations in the womb.

Carlos Galaviz Hernández, a geneticist at CIIDIR Unidad Durango in Mexico, told me that immune compatibility may also be important: the mother may be able to tolerate some partners better, similar to how organ transplants are more successful if certain molecular markers match. In some cases, the mother’s DNA may be the dominant force. For example, some women seem genetically predisposed to developing a disease regardless of who they partner with.[18]

Jimmy Espinoza, a maternal-fetal medicine specialist at McGovern Medical School at UTHealth in Houston, also pointed out to me that the idea Robiard advocates has its own scientific problems. In particular, in recent years, other research groups have found evidence that seems to directly contradict this idea[19]—in some cases[20], suggesting that some people may have a lower risk of preeclampsia if they choose a different partner for their next child (Decker and Robiard argue[21] that some of these studies have problems, including possible misdiagnosis and failure to adequately distinguish between early-onset and late-onset preeclampsia).

© iStock / Getty Images

Andrea Edlow, a maternal-fetal medicine specialist at Massachusetts General Hospital, said all of these ideas may have some merit, in part because preeclampsia, like cancer, is an umbrella term for different disease pathways that behave similarly at the end. Despite evidence to the contrary, “I still support this hypothesis,” Decker told me. In his view, “no one has come up with a better hypothesis yet.”

Even if the semen hypothesis turns out to be correct, it’s hard to know what to do with that information. Breakthroughs are desperately needed: Despite thousands of years of documented history of preeclampsia, diagnosis, treatment, and prevention are limited. Perhaps a better understanding of paternal immunity could one day lead to preconception vaccines or immunotherapies for high-risk individuals.

Today, however, the feasibility of this concept is very limited.

In Robiard’s ideal world, clinicians would recommend at least six months of active sex, or at least 100 intercourses, before pregnancy; pregnant women would also regularly disclose their sexual history with their partners to their doctors, and changes in partners would be recorded in the medical record.[21] Needless to say, conveying these practice ideas to colleagues “has been an uphill battle,” Decker told me.

Edlow, for one, supports the idea of ​​the paternal immunity hypothesis. But “it’s not something I would talk to my patients about,” she told me. Sarah Kilpatrick, chair of obstetrics and gynecology at Cedars-Sinai Hospital in Los Angeles, feels similarly. She told me that there’s not enough evidence to make recommendations yet, and that designing a large clinical trial to rigorously test these ideas is difficult, especially for a disease with such serious risks.

Moreover, the practice of encouraging more sex before conception to reduce the risk of preeclampsia only works for a very specific population. It assumes heterosexual, monogamous relationships. Even the amount of sex Robiyard advocates for can be challenging for couples who meet those criteria. Heterosexual, monogamous couples are hardly representative of the entire population of pregnant women—which includes single parents, those who conceive through intrauterine insemination or in vitro fertilization, those seeking donor sperm or embryos, and those whose pregnancies may be unplanned.

Although the odds of preeclampsia may be slightly increased in some of these populations, overall, “we just don’t know why X gets preeclampsia and Y doesn’t,” Kilpatrick told me. Moreover, biological anthropologist Rutherford told me, such a change in clinical strategy would legitimize long-term monogamy, which puts medical professionals in the position of offering a very specific and limited view of human sexuality.

“Frankly, I don’t want to attribute this disease that affects pregnancy entirely to male sperm,” Edlow told me. Perhaps there are other ways to trigger tolerance or keep the mother’s immune system stable. Whatever the reason, preeclampsia may be an evolutionary trap that our species has fallen into.

But to solve it, or even eliminate it, people don't necessarily need to fully cater to the randomness of evolution.

References:

[1]www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.118.313276

[2]www.sciencedirect.com/science/article/abs/pii/016503789390032D?via%3Dihub

[3]pubmed.ncbi.nlm.nih.gov/23266291/

[4]www.frontiersin.org/articles/10.3389/fimmu.2018.02630/full

[5]www.jstor.org/stable/3037249

[6]www.pnas.org/doi/10.1073/pnas.0511344103

[7]www.ncbi.nlm.nih.gov/pmc/articles/PMC5121266/

[8]www.ncbi.nlm.nih.gov/pmc/articles/PMC1891950/

[9]pubmed.ncbi.nlm.nih.gov/21909154/

[10]www.frontiersin.org/articles/10.3389/fphys.2018.01870/full

[11]www.explorationpub.com/Journals/ei/Article/100322

[12]www.sciencedirect.com/science/article/abs/pii/S0165037807001982

[13]www.sciencedirect.com/science/article/abs/pii/S0165037899000406

[14]www.sciencedirect.com/science/article/abs/pii/S0301211598002504

[15]www.sciencedirect.com/science/article/abs/pii/S0140673694916381

[16]pubmed.ncbi.nlm.nih.gov/19164169/

[17]www.frontiersin.org/articles/10.3389/fphys.2018.01870/full

[18]academic.oup.com/aje/article/178/11/1611/83552

[19]pubmed.ncbi.nlm.nih.gov/11679788/

[20]pubmed.ncbi.nlm.nih.gov/11821338/

[21]www.sciencedirect.com/science/article/abs/pii/S0165037822002765?via%3Dihub

By Katherine J. Wu

Translated by tamiya2

Proofreading/tim

Original article/www.theatlantic.com/health/archive/2023/10/preeclampsia-pregnancy-semen/675658/

This article is based on the Creative Commons License (BY-NC) and is published by tamiya2 on Leviathan

The article only reflects the author's views and does not necessarily represent the position of Leviathan