By Robert W. Rebar, MD
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: Cumulative live-birth rates were more than 65% after the sixth cycle of in vitro fertilization.
SOURCE: Smith AD, et al. Live-birth rates associated with repeat in vitro fertilization treatment cycles. JAMA 2015;314:2654-2662.
In vitro fertilization (IVF) has permitted previously infertile women without hope of pregnancy to build families. It has been more successful than anyone ever imagined. Now, investigators have used data involving ovarian stimulation cycles initiated between January 2003 and Dec. 31, 2010, with live-birth outcome data collected up to June 2012 to determine the extent to which repeat IVF cycles continue to increase the likelihood of a live birth (defined as an infant born alive after 24 weeks’ gestation and surviving longer than 1 month) for women undergoing IVF in the United Kingdom. A cycle was defined as the initiation of treatment with ovarian stimulation and all resulting separate fresh or frozen embryo transfers.
The cohort consisted of 156,947 women of median age 35 years at start of treatment with a median duration of infertility of 4 years undergoing 257,398 IVF ovarian stimulation cycles. The live-birth rate for the first cycle was 29.5%. The overall cumulative live-birth rate after the sixth cycle was 65.3% (95% confidence interval [CI], 64.8-65.8%) and continued to increase up to the ninth cycle. As expected, live-birth rates decreased with age, with women
< 40 years of age achieving a cumulative prognosis-adjusted live-birth rate of 68.4% after six cycles and those aged 40-42 years achieving a cumulative live-birth rate of 31.5% with six cycles. For women > 42 years of age, live-birth rates within each cycle were < 4%. The authors suggested that the data support extending the number of IVF cycles undertaken beyond three or four.
COMMENTARY
I chose to review this article as an introduction to a discussion about the current status of IVF. I was actually surprised that this study was accepted for publication in a major journal. It is true that data collected by the CDC on a per-cycle rather than a per-patient basis do not permit easy calculation of cumulative data in the United States, but we would anticipate that such calculations would result in at least similar cumulative pregnancy rates for IVF in the United States. However, I believe that the technological advances that have occurred in this field will lead to this study being of historical interest only.
I say that because the physical, emotional, and financial demands of IVF make most women unwilling to endure more than a couple of cycles of IVF. However, it soon should be possible to achieve the kinds of cumulative pregnancies detailed in this study without enduring so many IVF cycles. What advances should make this possible?
First and foremost has been the improvement in live-birth rates in any given IVF cycle itself. There have been significant improvements in both ovarian stimulation and culture techniques. The use of ultrasound-guided embryo transfer has no doubt had an effect as well. Live-birth rates have increased slowly but significantly since the birth of the first IVF baby in 1978.
Second has been the development of successful techniques for embryo cryopreservation. Embryo cryopreservation allows excess embryos to be replaced in cycles removed in time from the initial ovarian stimulation cycle. One recent study noted that transfer of single vitrified and then warmed blastocysts maximizes live-born children while obviously minimizing multiple pregnancies as well as preterm births.1
Third has been advances in preimplantation genetic testing (PGT). Comprehensive chromosome screening (CCS) can now utilize any of several genetic platforms, including metaphase comparative genomic hybridization (mCGM), array comparative genomic hybridization (aCGH), single-nucleotide polymorphism (SNP) microarray, quantitative polymerase chain reaction (qPCR), and most recently next-generation sequencing (NGS), to test the genetic complement of single blastomeres obtained on day 5-6 of embryo development. Typically, the blastocysts are frozen and those that are genetically normal are then thawed and transferred in subsequent cycles. Currently, the major use of this technology is to identify aneuploid embryos. Remember that aneuploidy increases with increasing maternal age and accounts for the increasing rate of miscarriage with maternal age. Thus, the intent of such testing is to identify and transfer only genetically normal embryos. A recent meta-analysis suggested that transferring euploid embryos does in fact increase the rate of live births.2
The meta-analysis focused on implantation rate because the three randomized, controlled trials included did not report live-birth rates. Sustained implantation of transferred euploid embryos beyond 20 weeks’ gestation was significantly higher after PGT-CCS compared to embryos selected for transfer on the basis of normal morphological characteristics and development (relative risk [RR], 1.39; 95% CI, 1.21-1.60). The authors noted that this suggests that PGT confers a 21% to 60% chance of improved sustained implantation (and presumably live birth). Analysis of data from seven observational studies included in the meta-analysis suggested a similarly increased sustained implantation rate (RR, 1.75; 95% CI, 1.48-2.07). Moreover, the data analyzed suggested that there is no detrimental effect of blastocyst biopsy on subsequent embryo development. While it will take years to determine if tested embryos result in truly normal children, there is no reason to think that this will not be the case.
IVF programs using PGT-CCS must have experience with extended embryo culture and biopsy, a successful program of embryo cryopreservation, and experience with a validated and tested CCS platform. The genetic test used must have a low false detection rate so that normal embryos are not inappropriately excluded from transfer. Another study indicating that selective transfer of euploid embryos after aCGH will result in equal implantation and pregnancy rates in women of all ages up to 42 years also suggests that this technology can increase live-birth rates in older women undergoing IVF.3 Thus, this technology can be coupled with elective single embryo transfer to result in high live-birth rates and low rates of multiple births.
These advances in IVF technology lead me to conclude that we should see increasing rates of live births and ever decreasing rates of multiple births. I think that I first personally realized the power of IVF when we first used IVF with donor oocytes in women with premature ovarian failure from varied causes. More than 70% of our patients took home babies after no more than two ovarian stimulations of the donors, counting all fresh and frozen-thawed transfers.4 We really are allowing women without prior hope to deliver babies and build families.
REFERENCES
- Devine K, et al. Single vitrified blastocyst transfer maximizes liveborn children per embryo while minimizing preterm birth. Fertil Steril 2015;103:1454-1460.
- Dahdouh EM, et al. Comprehensive chromosome screening improves embryo selection: A meta-analysis. Fertil Steril 2015;104:1503-1512.
- Harton GL, et al. Diminished effect of maternal age on implantation after preimplantation diagnosis with array comparative genomic hybridization. Fertil Steril 2013;100:1695-1703.
- Lydic ML, et al. Success of donor oocyte IVF-ET in recipients with and without premature ovarian failure. Fertil Steril 1996;65:98-102.
Cumulative live-birth rates were more than 65% after the sixth cycle of in vitro fertilization.
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