Immunotherapy vs No Immunotherapy

Recent years have seen the promotion of immunological therapy in conjunction with IVF, especially those who have had prior failed cycles. However, careful evaluation of the literature documents that indications for treatment are repeated pregnancy loss with anticardiolipin antibody syndrome based on abnormal anticardiolipin antibody and abnormal activated partial thromboplastin or similar test. Treatment of confirmed disease consists of aspirin and heparin therapy. The use of empiric aspirin and heparin for IVF is not supported by data.

The use of paternal leukocyte immunization is experimental for repeated pregnancy loss and not indicated for IVF. A recent large, randomized trial from Europe has shown no benefit from paternal leukocyte immunization even for repeated pregnancy loss. The use of immunoglobulin therapy is not indicated for either. Some clinicians do give aspirin alone for patients who have negative anticardiolipin antibody tests but repeated pregnancy loss or prior failed IVF, but such treatment has limited scientific basis and is empiric treatment. The ASRM/SART and CDC through the Maternal Mortality Weekly Report have both made strong statements concerning the experimental nature of immunotherapy in ART and the need for well designed prospective randomized trials before such therapy is provided and the patient charged for it.

Blastocyst Culture/Transfer vs Embryo Transfer

Blastocyst culture has become an important adjuvant to IVF therapy in the past couple of years. High multiple births are a serious problem facing the ART industry today. Blastocyst culture offers the opportunity to reduce the number of high multiple births by transferring at day 5 or 6 following oocyte retrieval a smaller number of blastocysts, each of which has a higher probability of implanting and resulting in a live birth, than embryos at day 3.

However, the promise of this technology to markedly reduce the number of high multiple births has been overstated for several reasons.

First, at the most only 40% of high order (triplet or higher) pregnancies result from ART, the majority coming from natural occurrences and controlled ovarian stimulation.

Second, the numbers of patients who can develop a large number of blastocysts represent a small percentage of the patients seen in most IVF programs. This technique is usually available to younger patients who are capable of producing sufficient embryos at day 3 following oocyte retrieval to allow them to attempt to grow the embryos into blastocysts at day 5.

Third, there are no prospective randomized trials to evaluate whether the eventual pregnancy rate is as good with blastocyst transfer as it is with day 3 embryo transfer in all populations. Such studies are difficult to perform because of limitations on human embryo research in the United States. While it is clear that transferring fewer blastocysts can be an effective technique to lower high multiple rates, it is not clear that the pregnancy rate is as high in matched populations. Studies which have been widely reported in the media have shown high pregnancy rates in populations which would be expected to have high pregnancy rates, and have still shown high multiple rates as well. It has not been demonstrated that the pregnancy rate is as high in the average patient undergoing IVF.

Fourth, most programs in the country are not having much success with frozen blastocyst transfer, so that any potential benefits of blastocyst transfer may be reduced by the loss of pregnancies usually obtained by transfer of frozen embryos following the fresh cycle.

Fifth, given the insurance coverage situation in most areas of the United States, it is likely that many patients will choose not to take the chance to grow a few embryos out to 5 days when they have healthy appearing embryos at day 3. The blastocyst development rate is approximately 30 to 50% and some patients who elect to culture the embryos to day 5 will end up having no blastocysts to transfer and will be very unhappy with their choice. In our clinic we counsel all patients about blastocyst culture, with the advantages and disadvantages. We generally recommend blastocyst culture if the couple have 6 to 8 normally developing embryos at day 3.

Number of Embryos or Blastocysts to Transfer

If the couple choose to culture to blastocyst stage, we replace two or occasionally three blastocysts depending on the patient’s age and desires. Any extra blastocysts are cryopreserved. If the couple choose not to culture the embryos to blastocyst, we replace embryos according to the SART guidelines, basically 3 good embryos for women less than 35, 4 for up to age 40 and 5 for women age 40 or over. The guidelines are likely to be changed soon to recommend that only 2 embryos be transferred for patients with especially favorable prognosis, such as women less than 35 with extra embryos available for cryopreservation. Any embryos that are not transferred are cultured to blastocysts and then cryopreserved. The 1996 SART pregnancy rates per number of embryos transferred are shown in Table I.

These results show that the pregnancy rate increases as up to three embryos are transferred and that the singleton and multiple pregnancy rate remain relatively constant following transfer of anywhere from three to seven embryos. This is likely a reflection of physicians and patients choosing to replace more embryos as their embryo quality decreases. Studies have shown that two good-quality embryos or blastocysts would be sufficient to get acceptable pregnancy rates while limiting the multiple birth rate. The results show that with two embryos the multiple birth rate is much lower, being only about 25% of that which occurs when 3 or more embryos are replaced (approximately 4% vs 16%). However the pregnancy rate is only approximately 60% as high (approximately 20% vs 35%).

The key to solving the problem of high multiples lies in being able to determine the quality of the embryo, being able to grow to blastocyst which will ensure higher quality and higher pregnancy rates per embryo/blastocyst transferred, and having adequate insurance coverage so that patients and physicians are not motivated to take unnecessary risks by transferring high numbers of good-quality embryos. Cryopreservation also enables the patient to take advantage of all of the embryos or blastocysts which develop. It must be emphasized, however, that these numbers refer to good quality embryos, and therefore the limitation of absolute numbers of embryos for transfer in all clinical situations is not acceptable. The results above show that some patients must have higher numbers of embryos transferred to have a reasonable chance for pregnancy. This is especially true for the older patient.

The issue of high multiple births is a serious one threatening our industry at this time. Highly publicized high-order multiple births result in a public perception of an unregulated industry needing regulation, of patients who are acting irrationally and of irresponsible physicians creating costly problems for families and society. Tables II through V demonstrate the high cost of high-order multiples and show how lower pregnancy rates with lower high-order multiples can actually be more cost-effective care.

Cryopreservation vs No Cryopreservation

Cryopreservation is an additional procedure which can benefit some ART patients. In 1996 approximately 20% of patients had sufficient embryos to cryopreserve. The LBR per transfer was 16.6% which compares to 27.9% for fresh embryos. However, the cost savings and markedly decreased medical care and medication make cryopreservation a very useful adjunct to ART procedures. Cryopreservation can be especially useful for the younger patient who has a large number of embryos and is at significant risk for high multiple birth if more that two or three high-quality embryos are replaced.

Multifetal Reduction vs High Order Multiple Pregnancy

Multifetal reduction (MFR), or induced reduction, is a difficult issue for most infertile patients to consider because many feel that they would be lucky to get pregnant and can hardly fathom multiple births. Yet this topic should be discussed with all patients early in the consideration of ART procedures. MFR is generally only performed for triplet or higher pregnancies and results in an improved outcome relative to the higher order multiples but does not reach the same satisfactory outcome rate of pregnancies which start out only as twins. The chance that the entire pregnancy will be lost as a result of the procedure is less than 5%. In our program we will not transfer more than 3 embryos in any patient who has not agreed in advance to consider MFR a satisfactory procedure if they have triplets or higher. Some patients do agree to undergo the procedure and later change their minds, but at least they have had the opportunity to consider all the ramifications of their decision over an extended of time and with fully informed consent.

Donor Oocytes vs Patients’ Own Oocytes

The use of donor oocytes in the older patient, the woman who has not responded well to ovarian stimulation or the woman with multiple failed ART cycles and poor quality embryos, can be an effective alternative to achieve a pregnancy. However, donor oocytes must be considered an alternative rather than treatment. Before donor oocytes are recommended to a patient, she should have appropriate testing of FSH/estradiol, possibly with a clomiphene stimulation test, or preferably have undergone ovarian stimulation with gonadotropins. The combination of increasing age over 38 with borderline or elevated FSH and/or estradiol are highly suggestive of a poor prognosis with the patient using her own eggs.

However, each couple must decide for themselves whether or not they wish to pursue an IVF cycle even with a lower chance using their own oocytes. Patients must have reasonable estimates of their prognosis and be fully counseled by the physician about options before undertaking IVF with or without use of their own eggs when the prognosis appears guarded. In our program counseling of all parties is required prior to undergoing a donor oocyte cycle to ensure that all of the issues have been addressed and that the parties are fully informed. Oocyte donors may be known or anonymous. Some programs split oocytes between one donor and two recipients or between one infertility patient and one recipient. While some programs seem to have had a satisfactory experience with this approach, many others find it problematic from ethical, social and biological perspectives. The use of donor oocytes is very successful with the 1996 SART report showing a live birth rate of 39.1% per transfer.

 

Repetitive Oocyte Donation

According to the 1997 U.S. results reported in the ASRM/SART Registry, 6,643 cycles (approximately 9% of all ART cycles) utilized donor oocytes¹. Women may choose to donate oocytes on a number of occasions. This discussion will address the issue of whether limits should be advised on the number of cycles/donations that a given oocyte donor may undergo.

Introduction

The practice of oocyte donation is not without risk. Despite stringent screening, the recipient could become infected with a communicable disease, and the offspring, who might be unaware of their genetic heritage, could potentially marry and procreate with an unrecognized half-sibling. The donor is subjected to the risks of controlled ovarian hyperstimulation and the oocyte retrieval procedure. Whereas the recipient derives a clear and tangible benefit from oocyte donation, the donor derives benefit only through a sense of altruism and/or financial compensation for her services. Thus, the question arises as to whether to limit the number of times that a given oocyte donor might donate her gametes. In the absence of definitive, long-term follow-up, there is nonetheless a motivation on the part of practitioners of ART to develop a consensus for what could be considered a prudent approach, with an understanding that unusual circumstances may be considered on an individual basis (e.g. a donor who would surpass the maximum number of donations proposed by a guideline if she were subsequently to donate oocytes to her own sister).

Inadvertent Consanguinity

The marriage of two half-siblings resulting from oocyte donation could only occur if: a) a given donor has donated to two or more families, and b) the offspring were unaware of their specific genetic heritage. Previous guidelines on therapeutic donor insemination and oocyte donation, published by the American Society for Reproductive Medicine, have advised an arbitrary limit of no more than 25 pregnancies per sperm/oocyte donor in a population of 800,000, in order to minimize risks of consanguinity ². This suggestion may require modification if the population using donor gametes represents an isolated subgroup or the specimens are distributed over a wide geographic area.

Health Risks to the Oocyte Donor

Controlled ovarian hyperstimulation entails both known and theoretical risks, which can only be obviated by the exclusive use of unstimulated cycles (which at present is an uncommon and inefficient practice). In the short-term, there is the risk of ovarian hyperstimulation syndrome (OHSS), which is reported to be associated with approximately 1% of cycles. The incidence and severity of OHSS may in fact be lower in oocyte donors³, in part due to the absence of conception in their stimulated cycles. Given the risk of recurrence in consecutive cycles, a severe episode of OHSS should generally exclude an oocyte donor from further participation.

There continues to be some concern that the use of controlled ovarian hyperstimulation might increase the long-term risk of ovarian cancer⁴. Recently published data have not demonstrated an association between the use of ovulation-inducing agents and ovarian cancer⁵, although definitive conclusions await further follow-up. The only study which specifically suggested that the repetitive use of fertility medications presented greater risk than short-term use addressed the administration of clomiphene citrate (and not exogenous gonadotropins). In that study, the risk of ovarian cancer was significantly increased only when treatment exceeded 12 cycles⁶. Limitation of the participation of a given oocyte donor to approximately six stimulated cycles would appear reasonable, particularly as the donor might herself eventually require fertility therapy (e.g. in the event of delaying child-bearing to her late reproductive years, or should a future partner have a severe male factor).

The oocyte retrieval procedure itself also poses some risks for the donor. The health risks associated with the low levels of anesthesia generally employed for oocyte retrieval in a young healthy population should be very small. However, idiopathic reactions to anesthetic agents and other anesthetic complications (e.g. aspiration) may occur. There is, at present, no documentation of any long-term sequelae of follicle aspiration. There is a real, albeit small, risk of acute complications including pelvic infection and intraperitoneal hemorrhage⁷. It is expected that the aggregate risk of any of these acute adverse events after a given number of procedures is simply additive. It is presently not known whether repetitive follicular aspirations could affect the donor’s future fertility. Lastly, oocyte donation may entail potential psychological risks (ambivalence, regret, etc.). These latter risks should be minimized by appropriate pretreatment screening and counseling.

Conclusions

There are, at this point, no clearly documented long-term risks associated with oocyte donation. However, because of the possible health risks outlined in the preceding discussion, it would seem reasonable to consider limiting the number of stimulated cycles for a given oocyte donor to approximately six, and to further restrict successful donations from a single donor to no more than 25 families per population of 800,000, given concerns regarding inadvertent consanguinity in offspring. Clearly, restrictions on the number of stimulated cycles that a given donor should undergo will in most instances be the limiting factor.

References

1. Society for Assisted Reproductive Technology, The American Society for Reproductive Medicine. Assisted reproductive technology in the United States: 1997 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry.
2. The American Society for Reproductive Medicine. Guidelines for gamete and embryo donation. Fertil Steril 1998 (Suppl. 3);70:1S-6S.
3. Sauer MV, Paulson RJ, Lobo RA. Rare occurrence of ovarian hyperstimulation syndrome in oocyte donors. Int J Gynecol Obstet 1996; 52: 259-262.
4. Whittemore AS, Harris R, Itnyre J, the Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992; 136: 1184-1203.
5. Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995; 346: 995-1000.
6. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331: 771-776.
7. Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complications of transvaginal ultrasound-directed follicle aspiration: a review of 2670 consecutive procedures. J Assist Reprod Genet 1993; 10: 72-77.