Advances in Infertility Treatment: Oocyte Cryopreservation and Comprehensive Chromosome Screening

Since the birth of the first in vitro fertilization (IVF) baby in 1978,1 IVF has allowed many infertile couples and individuals to build families. Still, the likelihood of achieving a live birth with any single IVF cycle remains low (about 40% in women younger than 35 and only 4.5% in women older than 42).2

A study in the U.K. of repeated IVF cycles showed that cumulative live-birth rates continued to increase up to the ninth cycle, with >65% of women achieving a live birth by the sixth cycle (NEJM JW Womens Health Jan 2016 and JAMA 2015; 314:2654). However, the emotional and physical tolls associated with so many IVF cycles (as well as the improved pregnancy rates associated with intrauterine transfer of cryopreserved embryos3) make the success of multiple IVF cycles of historical interest. Now, two technologic advances — oocyte cryopreservation and preimplantation genetic testing with comprehensive chromosome screening — promise to augment IVF's utility in diverse circumstances.

Oocyte Cryopreservation

The large size and high water content of oocytes (as opposed to fertilized embryos) initially slowed the development of suitable techniques for their successful cryopreservation; however, the ultra-rapid cooling associated with vitrification of oocytes has improved cell survival and subsequent fertilization, embryonic development, likelihood of pregnancy, and live birth rates.4 Thus, in 2013, the American Society for Reproductive Medicine (ASRM) concluded that cryopreservation of mature oocytes should no longer be considered experimental.5

In randomized controlled trials, clinical pregnancy rates per thawed oocyte ranged from 4.5% to 12%, not appreciably different from those achieved with fresh oocytes. No increases in chromosomal abnormalities, birth defects, or developmental deficits have been noted in the children born from cryopreserved oocytes (although only about 2000 such births have been reported in the literature to date).5

Although oocyte cryopreservation is most beneficial for women who may lose their fertility because of cancer therapy or the need for extirpative ovarian surgery, this technology has value in other circumstances because it obviates the need to cryopreserve embryos and then determine the fate of extra stored embryos. More recently, interest has grown in oocyte cryopreservation as an option for women who simply wish to delay childbearing. The ASRM urges caution about this strategy for guarding against the effects of age on the reproductive potential of healthy women. The optimal maternal age for oocyte cryopreservation has not been determined, and significant risks and expenses are associated with ovarian stimulation, oocyte retrieval, and cryopreservation. Perhaps more importantly, there is no guarantee that oocyte cryopreservation will ultimately result in a live-born infant. In a decision-tree modeling study, oocyte cryopreservation compared with no action provided the greatest difference in probability of live birth when performed at age 37, although live birth rates were still relatively low with both approaches (52% vs. 22%). The highest probability of live birth (>70%) was calculated for oocyte cryopreservation before age 34, with little benefit before age 30.6

Preimplantation Genetic Testing with Comprehensive Chromosome Screening (PGT-CCS)

This technology permits testing for genetic abnormalities through analysis of the entire chromosomal complement of single cells obtained by preimplantation biopsy of the embryo on day 5 to 6. Any of several genetic platforms can be used, including metaphase comparative genomic hybridization, array comparative genomic hybridization, single-nucleotide polymorphism microarray, quantitative polymerase chain reaction, and next-generation sequencing. Typically, embryos are frozen and those selected are transferred in subsequent cycles.

A key application of this technology is to identify aneuploid embryos, particularly in older women, as aneuploidy rates rise with maternal age (thereby accounting in part for increasing miscarriage rates). If only normal embryos are transferred, then live birth rates theoretically should not decline with advancing maternal age. A meta-analysis of three randomized controlled trials (RCTs) and seven observational studies suggests so, but this remains controversial. Because live birth rates were not reported in the RCTs, the authors focused on implantation rate (IR). Likelihood of sustained implantation (beyond 20 weeks' gestation) of transferred embryos was significantly higher after PGT-CCS compared with conventional embryo selection based on morphologic characteristics (relative risk, 1.4; 95% confidence interval, 1.2–1.6). This suggests that PGT-CCS confers a 21% to 60% greater chance of sustained implantation. Analysis of combined data from the observational studies indicates that sustained IRs are similarly increased (RR, 1.8; 95% CI, 1.5–2.1). Overall, this meta-analysis suggests that blastocyst biopsy has no detrimental effect on subsequent embryo development and implantation.7 Randomized controlled trials are still required to prove that PGT-CCS is beneficial.

Recent data indicate that selective transfer of euploid embryos after array comparative genomic hybridization results in similar rates of implantation and pregnancy in younger women as well as those up to age 42.8 This finding implies that such technology can be coupled with elective single embryo transfer with resulting high live-birth rates.

Clearly, these methods are not simple; they require experience with extended embryo culture and biopsy, validated and tested CCS platforms, and an established and effective program of embryo cryopreservation. Moreover, the chosen genetic test must have a low false-positive rate to minimize the exclusion of normal embryos misdiagnosed as aneuploid or otherwise abnormal. These techniques are not yet widely utilized or available, and they increase the costs of IVF substantially. We will continue to follow the development of CCS in refining embryo selection and identifying abnormal embryos in families known to carry potentially harmful mutations.

Conclusion

Together, oocyte cryopreservation and PGT-CCS continue to augment the utility of IVF in various settings, manifested in higher live-birth rates, lower multiple-birth rates, and preservation of fertility potential.