Controversial ‘3-Person IVF’ Fails to Boost Fertility in Older Women

The experimental procedure is banned in the United States but is being offered at clinics abroad as a treatment for infertility

A pipette pulls out the nuclear DNA from an unfertilized egg, a key step in mitochondrial replacement therapy. Credit: OHSU

An experimental and much-hyped reproductive procedure that mixes DNA from three people is not effective at boosting the chances of having a baby for women ages 37 and older, according to doctors at a fertility clinic in Ukraine.

The technique, known as mitochondrial replacement therapy, involves taking a woman’s egg and shifting the majority of its DNA, known as the nucleus, into a hollowed-out donor egg. The shell of the donor egg contains healthy mitochondria, energy-making structures that have their own DNA. The resulting embryo ends up with DNA from the mother, father, and egg donor, so the technique is often referred to as “three-person IVF.” The procedure is controversial because many consider it a form of genetic manipulation.

Some fertility experts hoped that the younger mitochondria from the hollowed-out donor egg might rejuvenate the eggs of an infertile woman, thus increasing the chances of a successful pregnancy.

But new study results presented at a meeting of the American Society of Reproductive Medicine in Philadelphia show that might not be the case. The three-person IVF procedure was found to be ineffective at boosting the fertility of women ages 37 and older, say doctors at the Nadiya Clinic of Reproductive Medicine in Ukraine, one of two clinics worldwide conducting trials of the technique. The procedure is banned in the United States and is highly restricted in most other countries.

The doctors at the Nadiya Clinic performed mitochondrial replacement therapy on 30 women ages 37 to 47 who were seeking treatment for infertility due to advanced age. Out of 109 lab-fertilized eggs, only 33 became embryos, and just three of those embryos were healthy enough to be implanted into patients. A fetal heartbeat was confirmed in only one patient, a 42-year-old woman who gave birth to a boy in March 2018. The authors report that the child is healthy.

In light of their results, the researchers recommend that women of so-called advanced maternal age, considered age 35 and older by fertility doctors, should not undergo mitochondrial replacement to increase their chances of having a baby.

Dr. David Keefe, an obstetrician-gynecologist at NYU Langone Health, who was not involved in the study, says the results are evidence that faulty mitochondria are not to blame for the quality of a woman’s eggs or infertility. “They basically point out that it doesn’t work,” he says.

Mitochondrial replacement was performed for the first time by U.S. fertility doctor John Zhang to help a couple avoid passing a devastating mutation in the mother’s mitochondrial DNA to their child. Mitochondrial DNA makes up a tiny part of a person’s total genetic material, but mutations in it can cause serious and often fatal disorders. Zhang and the couple traveled to Mexico, where Zhang implanted the embryo created with the mother’s egg, the father’s sperm, and a donor egg. A baby boy, the first to be created using the technique, was born in 2016.

In 2017, Zhang planned to offer the procedure in Mexico or elsewhere to women ages 42 to 47 for a price between $80,000 and $120,000. He created Darwin Life, a company that advertised the procedure until the U.S. Food and Drug Administration forced him to remove some of the claims about fertility on the website. Unable to proceed in the United States, Zhang then formed Darwin Life-Nadiya with Ukrainian doctors to offer the procedure overseas. (The United Kingdom has also approved mitochondrial replacement, but only for women at high risk of having children with serious and rare conditions.)

The new study suggests an uncertain future for the procedure, but a few experts remain optimistic. Dr. Valery Zukin, director of the Nadiya Clinic and an author on the abstract, believes the procedure is still a promising option for younger women who have had trouble getting pregnant. He tells OneZero that 10 babies have so far been born from apparently infertile women under the age of 40 after undergoing mitochondrial replacement at his clinic. (Previously, Zukin had confirmed nine deliveries.) All of the women had at least three previous IVF cycles that failed.

“It may be that a subgroup of infertile patients may still benefit,” says Dr. Paula Amato, a fertility specialist at Oregon Health and Science University, where Shoukhrat Mitalipov pioneered mitochondrial replacement. She says one of the limitations of the Nadiya Clinic study was that it included relatively few women, so it’s difficult to draw meaningful conclusions.

An estimated 10% of women of childbearing age in the United States — 6.1 million people — have difficulty becoming or staying pregnant. Some of these women turn to traditional IVF, but it can often take two, three, or more cycles to have a child using the procedure, and the success rate falls off as women age.

“Not only is it not likely to work, but it is very likely to cause problems.”

There’s plenty of doubt surrounding the three-person IVF procedure. “You have to ask how many women in that age group would get spontaneously pregnant or get pregnant via another cycle of standard IVF?” says Marcy Darnovsky, director of the Center for Genetics and Society, a watchdog group based in Berkeley, California. The Ukrainian group notes in their results that a 45-year-old woman had a spontaneous pregnancy after the mitochondrial replacement technique failed.

Keefe says safer options, like egg donation and surrogacy, exist for women and couples who want to have children.

“Not only is [mitochondrial replacement] not likely to work, but it is very likely to cause problems,” he says. Mitochondria are known as the powerhouse of the cell, but Keefe says they’re also involved in metabolic, immune, neural, and psychiatric function. Earlier this year, researchers published a paper showing that mitochondrial DNA is closely tied to the DNA in the nucleus, meaning it might not be possible to use just any egg donor. A mismatch could cause health problems for the child later in life, Keefe says.

Keefe and Darnovsky worry that more fertility clinics could begin offering the experimental procedure to patients who are desperate to get pregnant.

“The swift mission creep to ‘age-related infertility’ and then to general ‘infertility’ — along with the shameless marketing push based on evidence-free claims — are signs of what’s in store if heritable genome editing is permitted,” Darnovsky 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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