As demand for in vitro fertilization (IVF) has grown, fertility clinics have developed supplementary procedures, or "add-ons," that are purported to increase the odds of success—but there's little evidence these add-ons actually work, Sharon Begley reports for STAT News.

Cheat sheets: Evidence-based medicine 101

What the research says

One add-on that received closer scrutiny earlier this year is "endometrial scratching," Begley reports. The theory behind the procedure is that using a pipette to scratch the endometrium could trigger a hormonal response to make the tissue more receptive to the implantation of an embryo.

Fertility practices started using the procedure about 20 years ago, after doctors in Israel observed that women who underwent a biopsy of their uterine lining seemed to have higher pregnancy rates.

Since then, a handful of case reports showed that some patients who underwent the procedure gave birth at a higher rate than those who didn't. But a large randomized controlled study of 1,364 women published in the New England Journal of Medicine earlier this year found that endometrial scratching had no effect on live birth rates.

"Assisted hatching" is another common IVF add-on that has been shown to have little effect on birth rates, Begley reports. In this procedure, embryologists use acid, lasers, or other tools to poke a hole in a woman's zona pellucida, which covers the ova, to increase the chances of embryo fertilization.

But an analysis in 2016 found that, while the procedure may increase pregnancy rates, it had no effect on live birth rates because it came with higher miscarriage rates.

Other add-ons have a bit more evidence behind them, Begley reports. For example, research on "artificial egg activation," in which clinicians cover fertilized eggs in chemicals called calcium ionophores to induce the embryo development process, has shown that it may improve fertilization rates once sperm is injected into an egg. However, other research has found the procedure has no benefit, Begley reports.

Similarly, some clinics add hyaluronan, known as "embryo glue," to a lab dish to increase implantation chances. The practice has been found to increase the chances of live birth by about 10% in the United States, which translates to 39% of IVF cycles resulting in a live birth, Begley reports.

Meanwhile, some IVF add-ons have been shown to be counterproductive and may even increase the risk of miscarriage, Begley reports. For example a 2019 analysis, found that time-lapse systems to monitor IVF embryos had miscarriage rate of 4% to 14%, compared to 4% through traditional incubation.

Moreover, an add-on called preimplantation genetic testing for aneuploidy (PGT-A) "indisputably hurt women's chances of giving birth," Begley writes. In this add-on, embryos are tested for aneuploidy, a chromosomal anomaly, and those that show an anomaly are not implanted and are typically discharged.

However, a large randomized controlled trial published last year by the European Society of Human Reproduction and Embryology said that PGT-A, which usually costs around $5,000, "makes no difference to live birth rates," meaning that embryos discarded through PGT-A potentially could have been viable.  

According to Jack Wilkinson, a biostatistician at the University of Manchester in England, who led one of four analyses on IVF add-ons published in the journal Fertility and Sterility, there is "at best, extremely weak or contradictory evidence of benefit" for IVF add-ons. "At worst, there is good evidence that some of the add-ons lower the chance" of conception through IVF.

'You want to throw everything you've got at it'

Lax regulation of fertility clinics could be one reason why add-ons are easily incorporated into a treatment plan, Begley reports. FDA requires a safety and efficacy assessment of procedures that manipulate human cells "more than minimally," but fertility procedures do not rise to that standard. That means FDA doesn't require any proof that IVF procedures benefit patients, Begley reports.

Pamela Mahoney Tsigdinos, co-author of Wilkinson's paper and a former IVF patient, said, "Patients are given the impression that the procedures have been studied and shown to be effective. But in most cases, they haven't been. You're on your own at a time when you're in no position to be objective."

Meanwhile, Alan Penzias, a Massachusetts-based fertility doctor and chair of the American Society for Reproductive Medicine practice committee, said doctors use add-ons typically when the core procedure doesn't work. He noted, "Patients and providers have the same interests. … A pregnancy with a healthy singleton baby as soon as possible."

He continued, "Sometimes, when you're down to your last hurrah" with a patient who doesn't have much money, time, or emotional or physical strength left for IVF, "you want to throw everything you've got at it" (Begley, STAT News, 11/5).