Does mild stimulation offer advantages over regular stimulation for IVF?

Does mild stimulation perform better than regular IVF? The answer to this question is a clear no, and here is why: Like every sphere of life, medical practice is, at times, being “taken over” by myths. Nobody knows where they came from, but in most instances the source can be found in prominent leaders in the profession who, simply, expressed somewhere an opinion orally or in writing that is then slowly turned into “medical folklore,” unfortunately leading to clinical practice changes without prior validation studies.

There is a reason why in classifications of evidence “expert opinions” are always ranked lowest among all formats of evidence. As we elsewhere in this issue discuss of a very telling example (Are fertility drugs safe?), not all experts are necessarily experts on the subject they are commenting on and not all experts are really adequately knowledgeable. Just because someone is alleged to be an expert in a field does not necessarily mean she/he is a competent expert in every small subspecialty area of the field: Very smart people, therefore, frequently express very uninformed opinions.

But, as smart people are often far more convinced of their own abilities to form opinions correctly than less established individuals who may be more careful, it should not surprise that very smart people quite often express incredibly stupid opinions. A poster boy for this conclusion has been Nobel Prize Winner and U.S. biologist, James Watson, PhD, who, along with British physicist, Francis Crick, PhD, was awarded a Nobel in medicine and physiology for discovery of the double helix structure of DNA. He later also won acclaim for his book, The Double Helix, which Modern Library listed as number 7 among 100 best non-fiction books of the 20th century. Though holding highly prestigious appointments in science since, Watson expressed at times astonishingly uninformed opinions in various areas of biology, including IVF. Examples abound: Some of the fears he expressed about IVF in the early days of the procedure were more reflective of a horror movie aficionado than a Nobel laureate in biology, and his more recent comments on racially driven genetic influences on human intelligence almost made him an outcast in the biology community.

Despite many studies proving the concept to be spectacularly non-sensical and practically greatly inferior to alternative treatments, a long-surviving myth has been that mild ovarian stimulation has significant outcome advantages over standard high-dose stimulations. Like most myths that mix facts and fiction, at first glance, some of the arguments may sound believable. Those include:

  1. Less medication is always better than more for health but also for pocket book.
  2. “Natural” sounds always better than “artificial” or “medicated.” The closer cycles are to “natural,” therefore, the better.
  3. Too much medication changes the cycle hormonally and, therefore, reduces chances for implantation.
  4. Embryo quality suffers from high-dose stimulation. Therefore, low-dose ovarian stimulation improves embryo quality.

Though superficially sounding logical, they present only one problem: They all have been proven wrong!

After age, numbers of eggs and embryos obtained in an IVF cycle are the best predictors of pregnancy and live birth chances. To intentionally produce fewer eggs and embryos than one safely can with other forms of ovarian stimulation, therefore, makes absolutely no logical sense. Innumerable studies have demonstrated that mild stimulation uniformly reduces pregnancy chances in comparison to standard stimulations, and it does so without offering any compensatory benefits. Even many proponents of mild stimulation nowadays acknowledge that it significantly reduces pregnancy and live birth rates. They, however, counter-argue that compensatory benefits, like lower costs and more patient satisfaction, make up for lower pregnancy and live birth rates.

This, of course, does not mean that all mild stimulations should be abandoned. Patients, of course, have an absolute right to choose treatments they prefer. Their choices of treatments, however, are usually greatly dependent on what data are presented to them by their physicians. Representations to patients, therefore, must be fully transparent and clearly state how much lower pregnancy chances are in such mild stimulation cycles and what that means for treatment costs due to the need for more cycles to achieve similar cumulative pregnancy and live birth chances.

It is, simply, not enough to say that a cycle of mild stimulation is less costly than a full stimulation (in itself, of course, a correct statement because of much higher medication costs) because what matters is not the cost per cycle start but the cost per baby at home. So, for example, if a mild-stimulation cycle only results in one-third the pregnancy chance of a full-stimulation cycle, costs of three mild-stimulation cycles must be compared to one full-stimulation cycle in order to make a valid cost comparison. If this is done, mild stimulation, likely, will no longer look like such a bargain.

That this is not only hypothetical is best demonstrated by the recent 10 years of IVF experience in the nation of Japan, where, based on the so-called Kato protocol (a protocol developed at the Kato Institute in Tokyo that was based on ovarian stimulation with clomiphene citrate and only very low dosages of gonadotropins on alternative days), mild stimulation over that time period had become the dominant protocol at most IVF centers. Over that time period, live birth rates in Japan fell by two-thirds, while cycle starts tripled. This, of course, represents a development that one cannot view as cost-effective.

It is difficult to combat the emotional attraction of doing something in “natural” rather than more “artificial,” ways. The truth, however, is that standard stimulations with gonadotropin hormones are much more “natural” than the treatments sold as “more natural.” Most of “mild” stimulation protocols use clomiphene citrate and/or letrozole, both synthetic and, therefore, “artificial” hormones. In contrast, gonadotropins are natural hormones–indeed the same hormones our bodies are producing to stimulate gonads. When patients receive full ovarian stimulations with gonadotropins, they only receive supplementations of their own identical hormone production. Their bodies, therefore, do not have to deal with new synthetic chemicals like clomiphene citrate or letrozole.

That full-stimulation cycles have poorer implantation rates or that embryo quality deteriorates with increasing gonadotropin dosages are additional mini-myths within the larger all-encompassing myth of mild ovarian stimulation. Both have also been largely debunked in a number of recent studies. In principle, the harder ovaries are stimulated, the more eggs and embryos will they produce. (This applies more to younger than older women, and, obviously, only up to a maximum effective dosage of gonadotropins.) CHR’s and other investigators have in recent years also convincingly demonstrated, that the more embryos are available for transfer, the better pregnancy and live birth chances are achieved. Finally, studies have demonstrated that there is no truth to the allegation that higher stimulation dosages of gonadotropins cause more embryo aneuploidy.

In short, mild stimulation never offers best pregnancy chances. It is also important to note that every patient survey ever performed on IVF patients, uniformly demonstrated that pregnancy and live birth chances represent the by far most important single outcome parameter in IVF.

The best possible outcome in defining “patient friendliness,” therefore, is an IVF cycle leading to pregnancy and live birth. Why anybody would offer mild stimulations to IVF patients is, therefore, unclear, unless, of course, there are specific clinical reasons, or it is a personal preference of a patient. These are the only indications at CHR when mild ovarian stimulation may be considered.

This is a part of the January 2019 CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.