Fertility treatment, not mother's age, increases risk of genetic disorders and rare diseases among babies, says study

The study found that fertility treatments caused epigenetic changes associated with Beckwith-Wiedemann, Silver-Russell, and Angelman syndromes in mouse embryos; Surprisingly, the research team says maternal age itself had no such effect


                            Fertility treatment, not mother's age, increases risk of genetic disorders and rare diseases among babies, says study

Fertility treatments, and not the mother's age could be responsible for the high risk of genetic disorders in babies, according to researchers. 

A team from the Magee-Womens Research Institute (MWRI) and the University of Pittsburgh wanted to understand why children born to older women with the help of assisted reproductive technologies such as in-vitro fertilization (IVF) have a higher risk of rare diseases such as Down syndrome.

The researchers found that though epigenetic disorders — diseases caused by faulty gene expression — are still rare overall, babies born using fertility treatments have up to 11-fold higher risk of inheriting them.

The findings, which are based on a study conducted on mice, states that the problem likely lies with the technology, not the mother's age.

The study found that fertility treatments caused epigenetic changes associated with Beckwith-Wiedemann, Silver-Russell, and Angelman syndromes in mouse embryos. Surprisingly, the research team says maternal age itself had no such effect.

According to researchers, while fertility treatments have come a long way since the first "test-tube baby" was born over 40 years ago, the study highlights that there is still room for improvement.

"Women of advanced maternal age might have one less thing to worry about. We need clinical studies to back that up, but this is a promising animal model that clinical studies could be based on," says lead author Audrey Kindsfather, a medical student researcher at MWRI.

Assisted Reproductive Technology

Assisted reproductive technology (ART) is used to to treat infertility include IVF or the use of an egg donor, sperm donor, or adopted embryo. 

"Assisted reproductive technology (ART), including IVF, involves procedures in which both eggs and sperm are handled, and may be recommended when other techniques have not been successful. In IVF, an egg is combined with sperm outside the body in vitro — in glass," says Penn Medicine experts.

Assisted reproductive technology (ART) to treat infertility include IVF or the use of an egg donor, sperm donor, or adopted embryo (Getty Images)

Over the last several decades, the average age of first-time mothers has risen steadily. Experts say that with increasing maternal age comes a decrease in fertility, which, in turn, has led to an increase in the use of assisted reproductive technologies by these women.

While the odds of conception go down as a woman ages, the odds of genetic disorders, such as Down syndrome, go up.

"Birth rates have significantly increased among women 35–55 years of age, which is considered advanced maternal age, labeling the current decade as an "epidemic of age-related infertility".

This increase in maternal age has contributed in part to the tripling of infertility rates since 1984 (approximately 5% to 15%). After the age of 35, a woman's fertility declines, and in the likelihood that a pregnancy is achieved, the risk of adverse outcomes increases.

"Thus, it is crucial to understand the molecular consequences of advanced maternal age in gametes and embryos," says the study published in Clinical Epigenetics.

It adds, "In response to the age-related fertility decline, women of advanced maternal age frequently turn to ARTs as medical treatments for subfertility, which often represent the best recourse for achieving a pregnancy."

IVF is the most common fertility treatment used: an estimated one million babies were born in the US between 1987 and 2015 through the use of IVF or other assisted reproductive technologies, according to a national report on assisted reproductive technology. 

"The number of ART cycles performed in the US has increased by 32%, from 138,198 cycles in 2006 to 182,154 in 2015. The number of live-birth deliveries in 2015 (59,348) was almost one-and-a-half times higher than in 2006 (41,343)," states the report.

"The number of infants born who were conceived using ART increased from 54,656 in 2006 to 71,169 in 2015. Because more than one infant can be born during a live-birth delivery (for example, twins), the total number of infants born is greater than the number of live-birth deliveries," it adds.

The mouse study

Before conducting their research, the team reasoned that maternal age might increase the odds of epigenetic disorders, too, which could explain the higher incidence of these rare diseases among children born through fertility treatments, since women using these technologies tend to be older.

To understand and separate these factors, the scientists turned to mice. The team grouped female mice by age, ranging from adolescence to the mouse equivalent of a 45-year-old woman.

Some of the mice in each age group had "hormone injections to kick ovulation into high gear or their embryos cultured in a Petri dish" — procedures commonly involved in fertility treatments — while control mice conceived naturally.

The team grouped female mice by age, ranging from adolescence to the mouse equivalent of a 45-year-old woman (Getty Images)

To quantify epigenetic changes in the embryos of mouse mothers, the experts measured the amount of DNA methylation — molecular locks — clasped around genes associated with epigenetic disorders, preventing them from being expressed.

"Hormone therapy and embryo culture both disrupted DNA methylation in these critical spots. When these two procedures were used in combination, the effects were even stronger. Maternal age, on the other hand, had no impact on DNA methylation patterns around these genes," says the study. 

The results were unexpected, says the research team. "We know that as a woman ages, there are a lot of molecular changes happening to her eggs, so we thought that these changes could be leading to abnormal DNA methylation. We were quite surprised that it didn't," says senior author Dr. Mellissa Mann, principal investigator with MWRI and associate professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh. 

According to Kindsfather, these are "wonderful technologies, but not the same as spontaneously conceiving," adding that more research needs to be done to improve fertility treatments.

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