Why is use of donor eggs not viewed as treatment failure? A call for improvements in treatments with autologous oocytes

Abstract

Based on national registry reports, after age 42, the number of IVF cycles utilizing autologous oocytes is very small; after age 43, autologous oocyte use in US IVF cycles is almost non-existent. We here argue that the in vitro fertilization (IVF) field has created a self-fulfilling prophecy by basically abandoning the utilization of autologous oocytes after ages 42–43 years. This not only resulted in almost no IVF cycles with autologous oocytes being performed but also in abandonment of research that could lead to improvements in IVF outcomes in older women when using autologous oocytes. As a consequence, IVF has largely stagnated in this area. We further argue that third-party oocyte donation in clinical IVF should be considered a treatment failure, as it requires patients to choose a second rather than a first-choice treatment. Such a redesignation of third-party egg donation would not only be appropriate but could lead to necessary changes in physician attitudes, considering that women almost exclusively prefer to conceive with their autologous oocytes.

Introduction

Routine in vitro fertilization (IVF) utilizes autologous oocytes. Donor egg cycles, in contrast, utilize oocytes of younger third parties. They offer pregnancy and miscarriage rates commensurate with donor rather than recipient ages (i.e. higher pregnancy and live birth rates as well as lower miscarriage rates). Given the choice, as long as autologous eggs still offer “reasonable” outcome chances, an overwhelming majority of infertility patient will still prefer autologous over third-party donor eggs [1]. In addition, one must also consider potential medical as well as social risks stemming from oocyte donation, such as increased risk to develop pre-eclampsia/eclampsia [2] and the psychosocial constraints of third-party motherhood [3]. In certain ways, third-party egg donation, therefore, for most patient must be viewed as treatment failure of modern fertility care.

Patients receive most information regarding treatment options and outcomes from their physicians. Physicians, therefore, ultimately define what in their patients’ eyes represents “reasonable” IVF outcomes. What represents “reasonable” expectations and/or outcomes is, of course, highly subjective. Especially over the last two decades, physicians have, however, been overly negative when advising their patients: As, after ages 42–43, autologous cycle activity almost completely ceases [4, 5], US national IVF data reported to the Center for Disease Control and Prevention (CDC) and the Society for Assisted Reproductive Technology (SART) suggest bias against utilization of autologous oocytes in older women. In 2016, only 9797 (8.47%) of egg retrievals occurred above age 42 and only 1.21% above age 44. In parallel, starting already at age 40, egg donations demonstrated a steep incline in recent years (Fig. 1).

Fig. 1.

Percentages of US embryo transfers from donor eggs in 2016 at different ages

Outside the USA, the situation is often even more complex, as egg donation in some countries is still prohibited. But instead of motivating more research on how older women’s IVF outcomes may be improved, providers of IVF services, instead, even in those countries, rather encourage utilization of third-party egg donation through medical tourism into countries where egg donation is permitted. This is, for example, how Spain evolved as a leading provider centre of IVF in Europe and the world but, for that reason, even though increasingly active in IVF research, never demonstrated interest in treating older women with autologous oocytes.

Two at times clashing motivations inform this process: First, subconsciously or consciously, fertility centers utilize referrals into egg donation as highly effective patient selection tools, and by directing poor and poorest prognosis patients into egg donation, the remaining patient pool is favourably selected toward significantly better outcomes with autologous eggs. One, however, also must acknowledge that the much better outcome chances with young donor eggs do represent a compelling argument against use of autologous oocytes. Moreover, higher pregnancy chances open the doors to a whole variety of economic arguments by physicians as well as payor organizations (insurance companies as well as governments), which then often have no coverage obligation for third-party egg donation but have a good argument to deny coverage for autologous IVF cycles. A patient’s right to self-determination, ethically, however, does offer infertility patients the absolute right to choose poorer over better pregnancy and live birth chances to satisfy the emotional need for genetic maternity.

In this figure presented data were modified from the CDC’s 2016 Assisted Reproductive Technology National Summary Reports at https://www.cdc.gov/art/reports/2016/national-summary.html.

What if treatments are considered futile?

Not everybody, however, agrees with this conclusion. Many practitioners will argue that IVF treatments in women above 42–43 are simply futile. The American Society for Reproductive Medicine (ASRM’s) ethics committee, however, defined “futility” in treatment of infertility as a live birth chance of less than 1%. “Futility” is, in addition, differentiated from “very poor prognosis”, which is defined as live birth rate between 1 and 5% [6]. The same committee also suggested that physicians are perfectly entitled to refuse fertility treatments if they consider them insufficiently warranted; but the committee also clearly indicated that in cases where personal beliefs lead to refusal of treatments, patients must be informed of alternative opinions and, if they so choose, be given referrals to providers who offer such treatment opinions [6].

“Futility” and “very poor prognosis,” moreover, refer to single cycle outcomes. Repeat cycles, of course, offer the benefit of cumulative pregnancy chances. Still, almost uniformly, current literature advocates egg donation above ages 42–43 [7].

How far does self-determination go?

Transmission of parental genes into next generations is a driving evolutionary force, explaining why most women (and their partners) favour autologous gametes. Not everybody, however, shares this opinion: Calling for further “democratization” and “de-geneticization” of human reproduction, the so-called gene-centric view of parenthood has in recent years been under increasing attack from some ethicists [8, 9]. In his book, The Age of Insight, 2010 Nobel Prize winner in Physiology and Medicine, Eric R. Kandel, however, points out that one key idea of Sigmund Freud has held up over time: “Like instincts to eat and drink, sexual striving is built into the human psyche, our genome and evident early in life” [10].

Clinical infertility practice supports Freud’s understanding of the human psyche and reveals on a daily basis how unenforceable “de-geneticization” of fertility treatments really is.

Who are the affected patients?

A large majority of donor-egg recipients are older women above age 42–43 years (Fig. 1). With oldest women in the USA being the only age group demonstrating increasing birth rates over the last decade [11, 12], this trend can be expected to continue or even to accelerate. Younger women with premature ovarian aging (POA), also called occult primary ovarian insufficiency (oPOI), represent a second major patient population. For similar reasons, they, too, are frequently prematurely directed toward egg donation. One major reason is continuous utilization at IVF centres of universal cut-offs for ovarian reserve parameters at all ages. An FSH of 10.0 mIU/mL at age 42 may, for example, be normal; yet, at age 35, it, very obviously, is not. And an AMH of 1.0 ng/mL at age 32 is definitely low; but at age 44, it is an excellent value.

In these younger patients, this is even more regrettable since, with adequate ovarian preparation, they will achieve even better pregnancy and live birth rates than older women [13]. Ovaries from older women and POA/oPOI patients share a number of characteristics: Both demonstrate low androgen levels, often relatively high sex hormone-binding globulin (SHBG) [14] and follicles that prematurely luteinize [15, 16], allowing for quite consequential treatments.

Why are there only so few studies?

During early years of IVF treatments in the early 1980s, nobody questioned that treatment outcomes had to be improved. Then in place age limits around age 38 years, therefore, quickly fell by the wayside when the field succeeded in improving outcomes especially in younger women. The early 1980s were also the time when it became apparent that by donating their eggs to older women, young egg donors transferred their much better pregnancy chances and much lower miscarriage risks to those older women. Unsurprisingly, medical providers, therefore, increasingly perceived egg donation as an attractive option for especially older patients. Excellent pregnancy and live birth rates not only discourage utilization of autologous oocytes in unfavourable patients but also further discouraged investigations to improve IVF cycle outcomes in these women with use of their own eggs. Striving for better outcomes, therefore, largely remained restricted to younger women. To this date, indeed, most clinical IVF studies intentionally exclude older patients and/or younger women with POA/oPOI, the two principal target populations for egg donation.

Acquisition of new knowledge for autologous IVF treatments of older women has, therefore, remained sparse [12, 13]. Utilization of autologous oocytes after ages 42–43, simply, no longer appears advisable to many [7]. Even socially most conscious countries have restricted IVF coverage to ages as young as 40–42 years, arguing that treatments of older women with autologous oocytes were simply not cost-effective [17–20]. The trend toward egg donation was also further advanced by the recent establishment of frozen egg banks.

As a consequence of all of these developments, women above ages 42–43 have in the USA been almost completely excluded from autologous IVF. In almost complete absence of support for autologous IVF in older women among clinicians and their often overly pessimistic representations of expected IVF outcomes, a vicious cycle has been generated that constantly reinforces itself: Absence of studies prevents generation of new knowledge, while continuing to deny older patients and younger women with POA/oPOI the opportunities to conceive with use of their own eggs. Paradoxically, this is happening while US national birth statistic demonstrate that over the last decade, only older women above age 38 have demonstrate increasing birth rates, while younger women (< age 35) have fewer and fewer offspring [21].

Why the widely expressed pessimism?

This is not the place for a detailed review of new treatment insights. Box 1, however, offers a quick summary with appropriate references for further study. As referenced studies will demonstrate, the widely expressed pessimism regarding treatment of older and other unfavourable-prognosis patients often appears exaggerated. Moreover, considering how sparse such research has been over the last two decades, one cannot but wonder where the field would be today, had third-party egg donation not existed as an alternative.

Box 1 Modifications to IVF practice which in older women and patients with POA/oPOI have been suggested to improve IVF outcomes

• With embryo numbers available for transfer representing in IVF cycles the second most important predictor of pregnancy success after female age [22], women above age 43 require availability of at least 3–4 embryos [12, 22] to be in a better prognosis group. This discovery allows for appropriate patient selection and more accurate informed consent for older patients since women with fewer transferrable embryos will only very rarely conceive. • Older ovaries require proper pharmacologic preparation before initiation of ovarian stimulation. This currently usually involves androgen [24] and/or human growth hormone supplementation [25], both exerting their beneficial effects on small growing follicles between primary and small preantral stages. Such follicles still require 6–8 weeks to reach the gonadotropin-dependent follicle stage. Supplementation, therefore, must be initiated at least 6–8 weeks before IVF cycle start. • Interventions with suppressive effects on ovaries must be avoided including hormonal contraceptives, long gonadotropin-releasing hormone agonists and antagonists [12]. • As the intrafollicular metabolism speeds up with advancing female age, oocytes must be retrieved progressively earlier, a process described as Highly Individualized Egg Retrieval (HIER) [15, 16]. • Individualization also carries over into embryology: Two recent studies, for example, clearly demonstrated that patients with small numbers of embryos may be disadvantaged in their outcomes if their embryos are cultured to blastocyst stage rather than are transferred at cleavage stages [26, 27].

Within this context, proper patient selection has been a very important new insight: Independent of number of embryos transferred, the number of embryos available for transfer was identified as the second most important predictor of pregnancy and live birth outcomes after female age [22]. Better egg and embryo numbers, therefore, denote better pregnancy chances, even if identical embryo numbers are transferred. Two studies from different IVF centres reported supporting data: A first study demonstrated that above age 43, at least three embryos were required to achieve pregnancy and live birth [12], while a second study demonstrated that above age 45, the number increased to four embryos [23]. Here described patient selection is, therefore, a very important new tool to advise older women more accurately about their outcome chances.

Among recent new insights is also treatment that should be avoided at older ages, even though at younger ages they may appear entirely appropriate. Good examples are so-called natural IVF cycles (cycles that utilize the natural cycle of a woman with no or only minimal use of fertility medications) and mild ovarian stimulations (that use less medication than standard cycles). Both, a priori, accept smaller embryo numbers and, therefore, lower pregnancy chances. Another excellent example has been preimplantation genetic testing for aneuploidy (PGT-A), until recently called preimplantation genetic screening (PGS), which for years, because aneuploidy increases in embryos with advancing maternal ages, has been considered especially indicated in older women. PGT-A was recently convincingly found ineffective but, especially at older ages [28].

What already can be achieved?

The world’s oldest patient to conceive and deliver a healthy child with use of own eggs was recently reported [12]. Two weeks shy of age 48, she received four embryos in a fresh cleavage-stage IVF transfer, utilizing HIER with ovulation trigger given at lead follicle size of only 12 mm. Separation of older patients with poorer or better prognosis can, as noted earlier, be achieved based on embryo numbers obtained [12, 23]. With only one embryo, live birth chances for completely unselected older women are only approximately 2.5%; with 3–4 embryos, they, however, start exceeding 10% and can be as high as 15–20% with 4–5 embryos. Moreover, in addition, cumulative pregnancy and live births are, of course, even higher than that. One, in older women, however, also must consider increasing miscarriage rates with advancing female age which in oldest women can be as high as ca. 50% (in our series, 12) and 82.1% (in the Cornell-group series, 23).

Conclusions

A question often asked by patients as well as colleagues is, how many unsuccessful IVF attempts are “reasonable.” We do not have an answer for this question but, in counselling patients, also do not believe that this is a decision a physician should be asked to reach. The decision to give up on genetic maternity is one of the most personal and excruciating a woman (and her partner) may ever face in life. It also is highly complex because it includes judgements (How good were their prior IVF attempts?), financial considerations (Do they have insurance coverage? What are their financial means?) and, ultimately, an individual’s (or couple’s) highly complex psychological status, religious obligations and social traditions. We, therefore, feel unqualified to reach such a decision. We, however, not only feel qualified but obliged to be fully transparent in explaining treatment options and expected outcomes, as poor as they may be. Then, it is up to the patient(s) to decide.

Considering the highly significant demographic changes infertility practice is experiencing all over the world, a change in attitude toward utilization of third-party egg donation in older women and in younger patients with POA/oPOI appears timely. Recognizing the need to refer a patient into egg donation and, by doing so, depriving her of genetic motherhood, must finally be recognized as a treatment failure. Reconsideration of egg donation as a treatment failure would represent a first step in enhancing efforts to treat older women more successfully with autologous eggs.

We, at the same time, want to reaffirm our commitment to third-party egg donation as a wonderful treatment option of last resort. For women with no other choices, egg donation has been, and will in the foreseeable future remain, a life-changing treatment option, as long as it is offered with necessary transparency.

Compliance with ethical standards

Conflict of interest

N.G. is the owner of a for-profit fertility centre, the CHR in New York, NY. He and D.H.B. are co-inventors on several pending and already awarded US patents claiming therapeutic benefits from androgen supplementation in women with low functional ovarian reserve. Both are also co-inventors on patents relating to the FMR1 gene in diagnostic functions in female fertility and to AMH as a potentially therapeutic agent in female infertility. N.G. and D.H.B. receive royalties from Fertility Nutraceuticals, LLC, in which N.G. also holds shares. Both in the past received research grants, travel funds and/or speaker honoraria from pharma and/or medical device companies, though none in any way related to hear presented materials. E.Y.A. has no conflicts to declare.