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n vitro fertilization has been a huge success story in reproductive medicine. In just the last three decades it’s gone from a highly experimental treatment to one over 60,000 women in the U.S. use to conceive every year.

But it’s not perfect. Data have shown that infants conceived via IVF are at a slightly higher risk for some birth defects and genetic disorders, and are more likely to be born at low birth weight. One possible cause for these differences is epigenetics — that is, the markers that turn genes on and off. Scientists have noticed that IVF embryos have subtly different epigenetic patterns than naturally conceived embryos.

And one of the prime differences between the process of IVF and natural conception is the early embryonic environment. So, researchers trying to improve IVF have begun looking at how to make the Petri dish environment more like that of the fallopian tubes.

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Pilar Coy and her colleagues at the University of Murcia in Spain are some of those researchers. Their hypothesis: That fluids in the female reproductive tract have an effect on the early embryo. Studies in animals have supported that idea, and now the team is launching a pilot study in humans in which women’s eggs will be cultured in a dish containing fluid from her own reproductive tract — and Coy will watch and see if those fluids make for a healthier embryo.

Genetic differences

The term “test tube baby” is a misnomer. For children conceived by in vitro fertilization, their story actually begins in a Petri dish. In that dish, an egg and a sperm cell meet and begin to divide. The resulting ball of cells stays bathed in fluid in that dish for about five days before it’s developed enough to be transferred into a uterus.

In the early days of an embryo’s development, methyl groups are added or removed from DNA. These groups can change the degree to which a gene is expressed or if the gene is expressed at all.

Something about IVF may be affecting this process. One paper published in 2015 estimated that as much as 67 percent of the methylation differences seen in the DNA of placentas from children fertilized in vitro versus those conceived naturally could be chalked up to the procedure itself.

The absolute magnitude of the changes was small, and there’s no clear connection between these methylation differences and health outcomes in the child. But a few of the genes affected have been associated with increased risks of cancer, some neurological disorders, and low birth weight.

One obvious candidate for the source of this impact? The environment in which eggs are fertilized and embryos begin to grow, including the culture medium.

Many different things in IVF culture media help an embryo grow, including sugars, salts, proteins, and vitamins. Most of that media is produced commercially, and some companies and scientists have tried to mimic the fluid found naturally in fallopian tubes — where fertilization usually happens — with limited success.

One way to get culture media to more closely resemble human tubal fluid, of course, is to add actual human tubal fluid. For Coy’s experiment, planned to begin in September, she and a team at local IVF clinics will culture half of the eggs a woman has had collected in a medium supplemented with fluid from the mother’s reproductive tract — also known as oviductal fluid — after it’s tested to ensure there isn’t anything that might harm the embryo. The other half will be cultured by a conventional IVF procedure, and researchers will watch to see if or how they grow differently than the other group. (“Embryologists will decide what is the best embryo to transfer, independently of the fluid supplementation or not,” Coy said.)

Human tests

Preliminary research that Coy and her group have done indicates promise. A paper they published in eLife in February compared gene expression patterns in three groups of pig embryos: those fertilized through artificial insemination, those conceived in a conventional IVF culture medium, and another conceived in culture medium supplemented with oviductal fluid. Nearly 30 genes showed significantly different expression patterns between conventional IVF embryos and those supplemented with oviductal fluid. And culturing with oviductal fluid resulted in embryos that were more similar to embryos that developed in utero.

Still, whether that means human IVF could benefit from a similar approach is an open question, said Dr. Christos Coutifaris, chief of the reproductive endocrinology and infertility division at the University of Pennsylvania Health System, who is not involved with Coy’s research. “All this information is going to help us make the in vitro environment more optimal. I wouldn’t jump to the conclusion and say — as they were implying in the paper — that we should be extracting tubal fluid to add to the media.”

A 2015 paper from Coy’s own lab flagged some of these translational difficulties. Of 10 proteins found in the oviductal fluid of various animals, one protein seen in humans wasn’t found at all in pigs and the genetic sequences that coded for the rest ranged from 60 to 99 percent similar. And even in humans, fluid from different parts of the reproductive tract will have slightly different protein concentrations.

Still, Coy and her colleagues are hopeful that they could someday launch a bank of fluid from human donors, which could then be given to women undergoing IVF, akin to an off-the-shelf blood transplant. They’ve already banked the first of those human samples — though regulatory approval for a study using donor fluid is at least two to three years away, Coy estimated.

She even envisions drawing together an encyclopedic look at human embryos’ epigenomes, potentially shedding some light on the murky role of epigenetics in development.

“That is one of the most important endpoints in the near future to help develop healthier individuals,” Coy said.

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