IVF Add-Ons Don't Improve Birth Rates

Donavyn Coffey

November 15, 2019

Procedures and medications often added on to IVF cycles in hopes of improving the chance of having a baby are not worth the price tag, according to a series of reviews published in Fertility and Sterility. Three different research groups looked at the evidence for add-ons used in the lab, in the clinic, and for the endometrium. All ultimately concluded that there is not sufficient evidence these techniques work.

The number of add-ons coming onto the scene also seems to be getting "a bit out of control," said Sarah Lensen, PhD, a researcher in obstetrics and gynecology at the University of Auckland in New Zealand and lead author of the review of add-ons targeting the endometrium.

Lensen's review of endometrial add-on procedures, also called adjunct procedures, included immune therapies, endometrial scratching, endometrial receptivity array, uterine artery vasodilation, and human chorionic gonadotropin. All of these techniques attempt to improve uterine receptivity to embryos, but the review authors found no robust evidence to support the efficacy or safety of any of the procedures.

The series of reviews presents a laundry list of add-ons that are widely used but unsupported. Researchers reviewing clinical add-ons, including growth hormones, aspirin, heparin, testosterone, and male and female antioxidants, found they were not backed by robust evidence.

Similarly, other scientists who reviewed in-lab add-ons, such as time-lapse embryo imaging, hyaluronic acid, and measurement of sperm DNA fragmentation, concluded none improved live birth rate.

"If we don't know if it's beneficial, we also don't know if it's harmful," Lensen told Medscape Medical News. "Your patient is paying for that risk."

Part of the appeal of add-ons, Lensen says, stems from the low success rate of IVF procedures. Only 30% to 40% of IVF cycles end in a live birth, and that's "a difficult thing for both physicians and patients to deal with. So there's all this energy that gets put into new techniques in hope that it might boost the chances of conceiving."

The typical cost of a single round of IVF in the United States is $10,000 and $15,000, according to Penn Medicine. Some add-ons, like aspirin, are of negligible expense, but others can cost thousands of dollars per cycle. That's money that could be used to help pay for another round of IVF, Lensen notes.

In addition, some of the add-ons, like immune therapies that are supposed to suppress the mother's immune system in hopes of making the uterus more hospitable to the implanted embryo, aren't really based in biological sciences at all, Lensen told Medscape. There's no high-quality evidence that the maternal immune system is damaging in early pregnancy, the review authors wrote in their paper. Starting at $2,000, intravenous immunoglobulin treatments, which are used after women suffer multiple implantation failures and aim to dampen the immune system, are the most expensive add-on Lensen and her colleagues assessed.

Other add-ons targeting the endometrium that Lensen and her colleagues reviewed do have some biological basis. They're "noble" ideas, said Richard Paulson, MD, director of fertility at the University of Southern California, Los Angeles, but "marketing is now ahead of the science."

He notes that startups and clinics can offer add-on interventions before proving their worth in clinical trials. The US Food and Drug Administration only requires a full benefit and risk analysis when interventions on human cellular and tissue-based products manipulate human tissues to a "more than minimal" degree — a criterion no fertility add-on has met.

Starting at a cost of $800, the endometrial receptor assay (ERA) is the second most expensive endometrial procedure that Lensen's team reviewed. The test measures gene expression in the endometrium to determine exactly when the uterus will be most receptive to an embryo transfer. Igenomix, the New Jersey-based company that patented ERAs and markets them directly to patients, claims to have already completed 55,000 assays and the company website boasts that 33 publications back ERA technology. But Lensen and her colleagues concluded the test lacks "any robust evidence of benefit" from randomized controlled trials, and that independent evaluation from external researchers is required.

Igenomix maintains that they don't have any tests on the market that aren't supported by peer-reviewed studies. The company has just completed a randomized controlled trial, and four papers from outside experts support the ERA's use, Nassar Piñar, PhD, a scientific adviser at Igenomix, told Medscape in an interview. "What on the market has more support than this?" he said.

The prevalence of add-ons depends on a country's healthcare system. They are far less common in countries like the Netherlands where health insurers determine how IVF will be administered. But in markets with a private sector, add-ons abound. There's not a robust measure of how frequently they are used in the United States, but an estimate suggests that at least 74% of women undergoing IVF in the United Kingdom had one or more add-on procedure. Last December, the UK's IVF regulatory body released a statement calling for a culture change in IVF treatment and reiterating that "patients deserve evidence-based treatment."

Fertility practitioners and IVF clinics offer promising but unproven treatments because the field is relatively new and still looking for a lot of answers, Paulson said. Patients, desperate to make sure they are doing everything they can often ask for the add-ons. Doctors are also motivated to ensure the patient feels like clinicians are doing everything they can. And on top of that, clinicians get paid for providing the add-ons. "This is fueled by everyone," Paulson said.

Lensen hopes that her review will equip doctors with the evidence they need to steer vulnerable patients away from unproven techniques. Defenders of add-ons claim that rigorous scientific studies are paternalistic, delaying access to patients in need. But as Lensen sees it, doctors have "a duty not to offer patients things that don't work."

Fertil Steril. Published online November 5, 2019. Abstract

Donavyn Coffey is an editorial intern for Medscape. Follow Medscape on Facebook, Twitter, Instagram, and YouTube. Here's how to send Medscape a story tip.

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