Can mitochondrial transfer (three-parent technique) improve egg quality in older women?

Angelica Cheng

Active Member

Controversial ‘3-Parent Baby’ Fertility Technique Fails to Deliver for Older Women

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

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.




To determine if mitochondrial replacement theraphy (MRT) could increase blastulation rates, euploidy rates and pregnancy rate in patients of advanced maternal age (AMA).
The study period was from December 2015 to November 2018. Patients were informed and consent to possible risks and the experimental protocol was approved by ethics committee of local association of reproductive medicine. Inclusion criteria were: (1) no less than two failed previous IVF attempts, (2) low blastulation rates or recurrent embryo arrest, (3) low number or absence of euploid embryos; (4) age ≥ 37 years.
30 patients (37-47 years old, Mean age was 42±2 years) participated in this study. Five types of MRT (germinal vesicle transfer (GVT), MI spindle transfer (MIST), MII spindle transfer (MIIST), polar body 1 genome transfer (PB1GT) and pronuclear transfer (PNT)) were assisted by HVJ-E cell fusion kit. Intracytoplasmic sperm injection (ICSI) had been performed for all cases. If possible, reverse reconstitutions were done. Embryos obtained after reconstitution were cultured until blastocyst stage in time-lapse incubator, were biopsied for array comparative genomic hybridization (aCGH) or next generation sequencing (NGS) analysis and then were vitrified.
After performing various types of MRT, 109 zygotes were obtained, that resulted in 33 blastocysts (30%); 3 of which (one per patient) were euploid (2,7%). One try of elective single embryo transfer (eSET) of thawed embryo was done for each of three patients. Positive hCG level (> 100 mIU/mL) and following heartbeating were confirmed only for one patient (42 y.o., PNT group). The healthy baby boy was born on 15th of March 2018 by Caesarean section. After unsuccessful attempt of MRT, one of 30 patients (41 y.o.) had an euploid embryo from conventional aCGH cycle using donor sperm and the other patient (45 y.o.) became spontaneously pregnant and gave birth to a healthy baby at full term.
Zygotic cytoplasts of woman of AMA were competent enough to support normal embryo development when carry young karyoplasts: there were 41% blastulation rates and 70% euploidy rates for reversely reconstituted zygotes.
CONCLUSIONS: Pregnancy rate after applying MRT was lower than 1%, thereby patients of AMA should be advised not to undergone such procedures in order to increase the number of euploid embryos or pregnancy rate.