Does a Popular Form of In Vitro Fertilization Cause Autism?

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SCIENCE JULY 4, 2013

Does a Popular Form of In Vitro Fertilization Cause Autism?

There’s been a lot of chatter these past few weeks about an Atlantic article by Jean Twenge called “How Long Can You Wait to Have a Baby?” In it she debunks some of the research underlying the claim that women’s fertility declines steeply after 35. (The killer point: the main data set is “French birth records from 1670 to 1830.”) Good for her! Would that there were more biostatisticians out there holding studies up to scrutiny, doing God’s work. Living as I do in the world headquarters of older parenting—the Upper West Side of Manhattan—I can’t say that I believe that women in their late thirties can now blithely ignore the risks of diminishing fertility, because I hear about little else whenever we start talking about how hard it was for us to have our children. But I’ll admit I haven’t replicated Twenge’s impressive literature review.

I will say, though, that she ignores what’s actually new and interesting about fertility research right now, which isn’t its findings on would-be mothers and their fertility. It’s what we’re learning about would-be fathers and their fertility—as well as its treatment. When couples can’t conceive, the man is just as likely as the women to be the infertile party (one-third of the time it’s the man, one-third of the time it’s the woman, and one-third some combination of both). Age ups the odds of infertility for men as well as women. A man’s fecundity weakens more slowly than a woman’s, but after 50, the number of healthy, wiggly sperm he makes goes way down. Over the past decade, several studies have turned up links  between the sperm of older fathers and neurological problems, including schizophrenia and autism. (It should be said that other causes of male infertility include genetic inheritance, obesity, exposure to toxins such as pesticides and endocrine disruptors, obsessive overexercising, alcoholism, pot-smoking, and yes, tight underpants.)

So it’s not just women who should worry (or decide not to worry) about their deteriorating reproductive material, and it’s not just women who get treated for infertility. In vitro fertilization or IVF is a catchall-term for all the ways doctors take eggs and sperm out of bodies and turn them into embryos. Most people think of IVF as pumping a woman full of hormones and harvesting her eggs. But about half the time, these days, IVF also involves a procedure in which a single sperm is injected directly into an egg, instead of letting it fight its way into the egg as sperm usually do. Intracytoplasmic injection, or ICSI, has become enormously popular since it was first added to IVF in 1992. It was originally intended just to treat male infertility, but its use has expanded because, unlike IVF alone, you can count on it working: ICSI fertilizes 50-80% of the eggs it shoots sperm into. 

The biggest study done so far on the neurological profile of IVF babies  came out Tuesday in the Journal of the American Medical Association. It’s based on 2.5 million Swedish birth records spanning 25 years, from 1982 and 2007, and it’s both reassuring and worrisome. The reassuring part is that when the researchers compared all IVF babies with babies conceived naturally, they found no increased risk for autism, and only a small risk for “intellectual disability” (what used to be called mental retardation)—and that  seemed to vanish when the researchers figured in another risk factor: being a multiple (a twin or triplet and so on). The worrisome part is that when the researchers broke down all the procedures lumped together under IVF, they found that adding ICSI to the mix heightens the risk of child’s having neurological deficits to a meaningful degree.

Supplementing IVF with ICSI increased by 51% the chance that a child would have an “intellectual disability”; that number spiked if the child was born prematurely. If the sperm used in ICSI happened to have been surgically removed from the man rather than ejaculated (extraction is done when the man’s sperm is blocked for some reason or when there just isn’t enough of it), and if it was then implanted into a fresh embryo, then the risk of “intellectual disability” rose by 66% and the risk of autism went up 360%. For some reason, the risk is lower with frozen eggs, though still present. (Some of those risks also disappeared when researchers factored in multiple births—probably, the authors speculate, because once they took multiples out of the equation, they didn’t have enough singletons to draw conclusions from.)

Still, ICSI looks to be a real problem. “Our study shows that treatments developed to manage male infertility are associated with an increased risk for developmental disorders in the offspring,” said one of the authors of the study, Avi Reichenberg of Mount Sinai Hospital in New York and King’s College in London. An Australian study published last year also tied ICSI to autism and neurodevelopmental delay. Why would ICSI transmogrify the architecture of the fetal brain if IVF alone doesn’t? One obvious possibility is that injecting spermatozoa into the ovum lets the defective ones bypass a test that evolution devised for them: being able to break down the outer membrane of the egg so as to fertilize it. (Weak or misshapen sperm can’t do that.) Another possibility is that men who use ICSI are likely to have problematic sperm to begin with, so the problem is not with the procedure, it’s with the men who use it.

What alarms researchers about ICSI and, it must be said, about IVF in general, is that these procedures involve handling embryos at the very earliest stage of cell division, when a zygote (a fertilized egg) first starts cleaving itself. That’s precisely when maternal and paternal genetic information are being merged and the new organism is sorting out which epigenetic instructions—that is, which patterns of gene expression—will survive and prevail. It cannot be overstated how big a role this delicate negotiation plays in all future development, prenatal and postnatal, because epigenetic markings determine the ultimate shape and workings of the body.  And what directs the entire process are hormonal cues, triggered by whatever the sperm or egg happens to be experiencing at the moment. 

So there are some big questions out there yet to be answered. What does it mean for the egg to have its outer membrane penetrated like that? (The wall is called the “zona pellucida,” and it is made of a protein that may have its role to play in the fertilization process.) What does it mean for the sperm to be plopped inside the egg, along with the chemical “medium” they were cultured in beforehand? One recent mouse study offered some not-very-comforting hints. This study found that while the brains, kidneys, and livers of certain mouse pups conceived through IVF alone were epigenetically identical to those of naturally conceived pups, the same organs in pups conceived by ICSI were markedly different—three to five percent of their genes had strong epigenetic variations.

Ironically, doctors have lately been calling for ICSI to become a standard part of IVF treatment, on the theory that it boosts success rates and lowers the high emotional and financial toll of artificial fertilization. The American Society of Reproductive Medicine, to its credit, published a paper in 2012 rejecting that notion. But the deepening concern about ICSI proves that, pace Twenge, we all—men as well as women—have to worry about infertility, age-related as well as stemming from other causes, because if we don’t, we may find ourselves doing things to our bodies, and our future children’s bodies, that cost a lot more than money.  

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