Despite Calls for a Moratorium, More ‘Three-Parent’ Babies Expected Soon

Clinics in Europe say they will continue offering a controversial IVF procedure

Human embryo from IVF. Credit: K. Hardy/CC BY

At least 10 babies have been born to apparently infertile women as a result of a controversial in vitro fertilization procedure that involves combining a mother’s egg with a donor one. The technique is often referred to as “three-person IVF” because the baby ends up with DNA from three people — the mother, the father, and an egg donor.

One of the births was reported in April by a Greek clinic performing the procedure, also known as mitochondrial replacement therapy, or mitochondrial donation. Now, fertility experts in Europe are calling for a moratorium on using the technique for women who have struggled to conceive.

The European Society of Human Reproduction and Embryology (ESHRE) has issued a statement urging “extreme caution” on the use of mitochondrial replacement for cases of infertility. The organization, which represents 8,000 clinicians and scientists, says there’s not enough evidence to show that it produces higher birth rates than conventional IVF. However, OneZero has learned that despite the group’s recommendation, the Greek clinic, as well as another center in Ukraine, will continue to offer the procedure — and that more “three-parent” babies are likely on the way.

“The current lack of solid scientific evidence providing safety reassurance requires more study and continued vigilance,” the ESHRE statement says. “At the present stage, and until this technology has been proven to be effective and safe, ESHRE strongly discourages the use of mitochondrial donation to alleviate an infertility condition.”

In IVF, an egg from the mother is combined with sperm from the father and fertilized outside the body, with the resulting embryos transferred to the uterus of the mother. In mitochondrial replacement therapy, an embryo is made using two eggs plus sperm. The technique involves taking the mother’s egg and extracting its nucleus — where the majority of DNA is located — and swapping it into a hollowed-out donor egg that has had its own nucleus removed. The shell of the donor egg retains healthy mitochondria, the cell’s energy-making structures that float around outside the nucleus. Mitochondria have their own DNA, so the resulting egg ends up with DNA from the mother as well as a tiny amount of DNA from the donor.

Mitochondrial DNA accounts for less than 1% of a person’s total genetic makeup, but inherited mutations in this DNA can cause serious and sometimes life-threatening mitochondrial diseases. Mitochondrial replacement therapy was originally developed as a way to help couples who carry these mutations have healthy, biologically related children. But so far, only one baby has been born using the procedure specifically for this purpose. That was in 2016, after New York-based fertility doctor John Zhang traveled to Mexico, where he also has a clinic, to implant the modified embryo into a carrier of a fatal mitochondrial disorder called Leigh syndrome.

Since then, at least 10 babies have been born using mitochondrial replacement specifically as a fertility treatment. One baby was born in April to a 32-year-old patient at the Institute of Life in Athens who previously had four unsuccessful IVF cycles. Nuno Costa-Borges, the chief scientific officer and co-founder of Embryotools, a Barcelona company that collaborated with the Institute of Life, tells OneZero that the clinic has achieved additional pregnancies but did not want to provide more details at this time. Nine more babies have been delivered after their mothers underwent mitochondrial replacement for infertility at the Nadiya Clinic in Kyiv, Ukraine, according to Dr. Valery Zukin, the center’s director. And another four patients at his clinic are pregnant as a result of the procedure.

As women age, the number and quality of their eggs decline, which affects fertility. Experts like Costa-Borges and Zukin believe that faulty or fewer mitochondria are a cause of poor-quality eggs, so they reason using a younger egg with healthy mitochondria will boost the chances of a successful pregnancy. They say mitochondrial donation should be an option for couples who want to have a child that is genetically similar to both parents and for mothers who want to carry their own baby.

Some reproductive specialists, though, say there’s not enough evidence to know whether mitochondria are responsible for all cases of age-related fertility. “In this super-technological world, sometimes there is a tendency to propose novel techniques to patients without having solid evidence supporting their efficacy and safety,” says Cristina Magli, an Italian embryologist who chairs the ESHRE.

Mitochondrial replacement therapy is also controversial because some experts consider it a form of genetic modification. The procedure alters the germline — the traits that can be passed on from one generation to the next — and it’s unknown whether it could cause unexpected health problems later in a child’s life.

Whether the ESHRE statement will act as a deterrent to other clinics wishing to offer mitochondrial replacement therapy is yet to be seen.

Until recently, scientists had thought that mitochondria were readily interchangeable and thus could be replaced with those from a donor with no consequences. But a recent study in Science suggests that may not be the case. Researchers looked at more than 1,500 mother and child pairs and found subtle connections between their mitochondrial DNA and their nuclear DNA. This suggests that mitochondrial donors might need to have a similar genetic makeup to the woman undergoing the procedure.

“Swapping mitochondria might not be as straightforward as just changing the batteries in a device,” says Patrick Chinnery, a professor at the University of Cambridge who investigates mitochondria and human diseases and is one of the authors of the Science study.

The first baby born from an egg-swapping technique in 2016 appeared healthy, but the parents don’t want the child to be followed by researchers throughout his life. Zukin says the oldest baby born after mitochondrial donation at the Nadiya Clinic is a healthy two-year-old. “Our follow-up of the born babies did not demonstrate any harmful effects for their health,” Zukin says. Still, that might not be long enough to determine whether health problems will develop.

Zukin has formed a company, Darwin Life-Nadiya, with Zhang to offer the service to women outside Ukraine who are willing to travel there to get the procedure.

In the United States, mitochondrial replacement therapy is effectively banned, which is why Zhang went to Mexico initially and why he’s partnering with a clinic in Ukraine. The ban stems from a bill passed by Congress in December 2015, which contains text prohibiting the Food and Drug Administration (FDA) from considering a human clinical trial “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Any use of mitochondrial replacement therapy in the United States would fall under FDA’s purview, but for now it remains illegal.

In the 1990s, a fertility doctor in New Jersey pioneered a technique that involved injecting cytoplasm from donor eggs (the gel-like substance that contains mitochondria) into the eggs of infertile women. More than 30 babies worldwide were born as a result. But the FDA banned the procedure in 2001 due to safety concerns.

The United Kingdom made mitochondrial replacement therapy legal in 2015, but only for couples at high risk of having a child with a life-threatening mitochondrial disease. Even then, couples need to apply through the U.K. Human Fertilisation and Embryology Authority, which regulates fertility technology, and applications are considered on a case-by-case basis. Only one clinic, Newcastle Fertility of Life, has been licensed to perform the procedure. A spokesperson said the agency has so far received 15 applications for mitochondrial donation, 14 of which have been approved. No pregnancies resulting from the procedure have been reported yet.

Costa-Borges and Zukin have both seen the ESHRE statement but say they will continue offering mitochondrial replacement as part of research studies. Both clinics say they have gotten approval from their respective governments to conduct clinical trials and for now are only using the procedure on women under 40 who have had prior failed IVF attempts.

“In general, we agree that this is still an experimental technique and thus we need to keep on with our research to provide all evidence about the effectiveness and safety of the procedure for infertility problems,” Costa-Borges says. “Only groups with demonstrated experience should be conducting this type of research, as regular IVF centers usually do not have the equipment and expertise needed.”

Whether the ESHRE statement will act as a deterrent to other clinics wishing to offer mitochondrial replacement therapy is yet to be seen, says César Palacios-González, a bioethicist at the University of Oxford who has studied mitochondrial replacement therapy. He agrees that extreme caution is needed with this procedure because it’s not yet known how safe or effective it is. However, he says he wouldn’t see a reason for concern if the trials are well-designed. But until the clinics publish data on their methods and outcomes, “we don’t know,” he notes.

Zukin says countries should develop regulations around how it can be used since its legality is murky in many places. But even if other countries allow mitochondrial replacement therapy, it’s still unclear how many women would be able to benefit and whether it’s any better than conventional IVF. Zukin estimates that 1% to 3% of patients who would otherwise turn to IVF could be helped with the procedure. “We think that it is not ethical to refuse patients the right to have their own genetic children,” he says.

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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