Medical News

An Awkward Evolutionary Theory for One of Pregnancy’s Biggest Complications

In the early 1990s, while studying preeclampsia in Guadeloupe, Pierre-Yves Robillard hit upon a realization that seemed to shake the foundations of his field. Preeclampsia, a pregnancy complication that causes some 500,000 fetal deaths and 70,000 maternal deaths around the world each year, had for decades been regarded as a condition most common among new mothers, whose bodies were mounting an inappropriate attack on a first baby. But Robillard, now a neonatologist and epidemiologist at Centre Hospitalier Universitaire de La Réunion, on Réunion Island in the Indian Ocean, kept seeing the condition crop up during second, third, or fourth pregnancies—a pattern that a few other studies had documented, but had yet to fully explain. Then, Robillard noticed something else. “These women had changed the father,” he told me. The catalyst in these cases of preeclampsia, he eventually surmised, wasn’t the newness of pregnancy. It was the newness of paternal genetic material that, maybe, the mother hadn’t had enough exposure to before.

Robillard’s idea was unconventional not only because it challenged the dogma of the time, but because it implied certain evolutionary consequences. Preeclampsia appears to be exclusive (or almost exclusive) to humans, and may have arisen as a by-product of the particularly aggressive ways in which our fetuses pillage their mother’s body for resources. So, Robillard and his colleagues posited, maybe the dangers it poses then pressured humans into developing a bizarre trait: being rather inefficient at conceiving offspring. Maybe, if humans aren’t terribly fertile, they need to have a lot of sex; maybe having a lot of sex repeatedly exposes a mother to her partner’s semen, inuring her to the molecular makeup of future offspring. If preeclampsia is a kind of immune overreaction, then perhaps unprotected sex is the world’s most unconventional allergy shot.

That, at least, is what Robillard and his colleagues contend—a notion that’s “a bit controversial, and a bit awkward,” Inkeri Lokki, an immunologist and reproductive biologist at the University of Helsinki, told me. She remembers a senior researcher in the field once framing the upshot of the hypothesis as “pick your partner early, and practice.”

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Foreign genetic material aside, a mother’s body has every reason to be wary of a fetus. Pregnancy is an intergenerational struggle in which the fetus tries to pillage all the nutrients it can from the mother’s tissues, while the mother tries to keep some of her own resources in reserve.

For most mammals, the two parties easily reach a lasting stalemate. Among humans, though, the fetus starts “with the upper hand,” Amy Boddy, an evolutionary biologist at UC Santa Barbara, told me. Whether it’s because of the extreme nutritional demands of our energy-guzzling brain, or just a constraint of how the primate lineage evolved, no other developing mammal invades quite as vigorously as the human embryo does: Through two waves of invasion, our placental cells burrow so deeply into the lining of the uterus that they breach its muscular layer, where they unfurl, melt, and rewire an entire set of blood vessels until they widen and relax. In the process, tissues liquify, and cells are forced apart, all to get an enormous amount of “blood delivered to the placenta,” Julienne Rutherford, a biological anthropologist at the University of Arizona College of Nursing, told me.

The fetus thrives in these conditions—but it also asks so much of the mother’s body that it almost invites pushback. Preeclampsia, then, at least when it appears prior to 34 weeks of gestation, is arguably a manifestation of a human mother’s defenses wising up to the invasion, then kicking into overdrive. When researchers examine tissue samples in early-onset preeclampsia cases, they tend to find that the placenta has been prevented from invading the uterus thoroughly enough, Haley Ragsdale, a biological anthropologist at Northwestern University, told me. Now at risk of starving, the fetus tries to juice more from mom—in part by raising maternal blood pressure, preeclampsia’s hallmark symptom. (High blood pressure that arises in the last few weeks of pregnancy can signal late-onset preeclampsia, but researchers generally think the causes are distinct.)

Why exactly the placenta’s invasion flags in early-onset cases remains contentious, Offer Erez, an ob-gyn at Soroka University Medical Center, in Israel, told me. One possibility, as Robillard and others argue, is that a mother’s immune system, unaccustomed to her partner’s particular blend of molecules, codes the fetus as foreign, and dispatches a fleet of defenses to waylay the threat. If that’s indeed the case, a logical workaround might involve familiarizing her body with those foreign substances—and nipping her overreaction in the bud.

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Semen could do the trick: It’s chock-full of paternal material, and introduced into the vaginal tract, where a legion of immune cells and molecules roam. It also contains signaling molecules that might be able to mollify the maternal immune system. Repeat exposures with no harm send a clear message: I am safe, says Gustaaf Dekker, who leads the department of obstetrics and gynecology at Northern Adelaide Local Health Network, in Australia, and who has collaborated for years with Robillard.

In the past three decades, Dekker, Robillard, and their colleagues have amassed a large amount of evidence to support that idea. Across several populations, the risk of early-onset preeclampsia seems to be higher among couples conceiving for the first time; it’s also higher among people using donor sperm and eggs. The risk also seems lower among couples who have a lot of penetrative or oral sex before they get pregnant—at least, if they skip the condoms, some studies suggest. There’s even evidence that repeat exposures to seminal fluid can make female mice more tolerant of cells sampled from their mates.

From an evolutionary perspective, the theory goes even further. If it is important to indoctrinate the maternal immune system with semen, “that is a strong selective pressure” for humans to adopt a suite of behaviors to facilitate that exposure, says Bernard Crespi, an evolutionary biologist at Simon Fraser University, in Canada, who’s collaborated with Robillard. Our bodies’ combative approach to placentation could help to explain our semi-monogamous nature, our comparably low fertility among mammals, and our comparatively large testes, which can provide a generous supply of sperm. It may even have influenced the unusual ways in which the female human body conceals its own fertility. Unlike other mammals, we don’t regularly enter an obvious period of heat, or visibly signal when we ovulate—both traits that encourage more frequent sex in pursuit of reproduction. If repeat couplings are just kind of our thing, maybe it’s because they make our pregnancies that much safer.

The paternal-immunity hypothesis is not the only possible explanation for early-onset preeclampsia, and for some researchers, it is far from the strongest one. Fathers could be playing a different role in the condition. Some evidence suggests that certain males pass down DNA that predisposes their offspring to implant a bit differently in the womb, Laura Schulz, a women’s-health researcher at the University of Missouri School of Medicine, pointed out to me. And Carlos Galaviz Hernández, a geneticist at CIIDIR Unidad Durango, in Mexico, told me that immune compatibility may matter too: The mother might be able to better tolerate some partners, analogous to the way that organ transplants are more successful if certain molecular signatures match. In some cases, the mother’s DNA may be the dominant force. Certain women, for instance, seem genetically predisposed to developing the condition, regardless of whom they partner with.

Jimmy Espinoza, a maternal-fetal-medicine specialist at UTHealth Houston’s McGovern Medical School, also pointed out to me that the idea Robillard has championed has its own scientific issues. In recent years, especially, other teams of researchers have found evidence that seems to directly contradict it—in some cases, finding that some people may reduce their chances of preeclampsia if they switch to a different partner for a subsequent child. (Dekker and Robillard argue that several of these studies had issues, including possible misdiagnoses and not distinguishing enough between early- and late-onset preeclampsia.)

All of these ideas may have some truth to them—in part because preeclampsia, like cancer, is a catchall term for different disease pathways that manifest similarly at their tail end, Andrea Edlow, a maternal-fetal-medicine specialist at Massachusetts General Hospital, told me. And despite evidence to the contrary, “I still support the hypothesis,” Dekker told me. In his opinion, “nobody has come up with a better one.”

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: Although preeclampsia has been documented for millennia, diagnostics, treatments, and preventives are scant. Maybe better understanding paternal exposures will someday lead to preconception vaccines, or targeted immunotherapies for people deemed high risk. Today, though, the idea’s most actionable takeaways are very limited. In Robillard’s ideal world, clinicians would recommend at least six months of sexually active cohabitation, or at least 100 sexual encounters, before conception; pregnant people would also routinely disclose their sexual history with their partner to their doctor, and changes in partners would be noted in medical charts. Unsurprisingly, “it’s been an uphill battle” to sell some of those ideas to colleagues, Dekker told me.

Edlow, for one, generally supports the idea of paternal tolerance. But “it’s not something I would talk to patients about,” she told me. Sarah Kilpatrick, the chair of the department of obstetrics and gynecology at Cedars-Sinai, in Los Angeles, feels similarly. There’s just not quite enough evidence to build a recommendation, she told me—and designing a large clinical trial to rigorously test these ideas is difficult, especially for a condition with such serious risks.

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Plus, a pre-pregnancy injunction to have more sex to lower the risk of preeclampsia can only really apply to a very specific audience. It assumes heterosexuality; it implies monogamy. Even the amount of sex that Robillard advocates for could pose a challenge for some couples who meet those criteria. And heterosexual, monogamous couples hardly represent the full universe of people who are getting pregnant—among them people who are pursuing single parenthood, who get pregnant through intrauterine insemination or in vitro fertilization, who are seeking donor sperm or embryos, and who get pregnant quickly or perhaps unintentionally. And although the chances of preeclampsia may be slightly elevated in some of those cohorts, in the broadest terms, “why person X gets it, and why person Y doesn’t get it, we just don’t know,” Kilpatrick told me. Plus, a clinical strategy that pushes for, or even seems to justify, long-term sexual monogamy puts medical professionals in the position of actively prescribing a very specific and limited vision of human sexuality, Rutherford, the biological anthropologist, told me.

Frankly, Edlow told me, “I don’t want to take this condition that affects pregnancy and make it all about men’s sperm.” There may yet be other ways to trigger tolerance, or keep the maternal immune system in check. Preeclampsia, for whatever reason, may be an evolutionary snarl our lineage got tangled up in. But to address it, or even solve it, people may not need to bend to evolution’s whims.