Pre-Implantation Genetic Testing Shows No Birth Rate Benefit in IVF

Trial included only women with good prognosis for live birth

In women with a good prognosis for a live birth, in vitro fertilization (IVF) with pre-implantation genetic testing for aneuploidy (PGT-A) did not improve the cumulative live-birth rate over conventional IVF, a randomized clinical trial found.

Of 1,212 women age 20 to 37 randomized to pre-implantation genetic testing or conventional IVF with up to three single embryo transfers, live births occurred in 468 (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional IVF group (absolute difference −4.6, 95% CI −9.2 to 0.0, P<0.001), reported Zi‑Jiang Chen, MD, PhD, of Shandong University in China, and colleagues.

The cumulative frequency of clinical pregnancy loss was 8.7% with PGT-A and 12.6% for IVF (absolute difference −3.9, 95% CI −7.5 to −0.2), they reported in The New England Journal of Medicine. Obstetric and neonatal complications and other adverse events were similar for both groups.

The results “showed that the cumulative live-birth rate after conventional IVF alone was not only noninferior to the rate with PGT-A, but was numerically higher (81.8% vs 77.2%),” Chen and co-authors wrote.

The researchers conducted their study from July 2017-June 2018 at 14 academic fertility centers in China. They identified an inferiority margin of 7% greater cumulative live-birth rate for PGT-A.

All couples were diagnosed with subfertility. Good prognosis for live birth was defined by inclusion and exclusion criteria; women 20 to 37 years old who had three or more good-quality blastocysts were included, while women with uterine malformation, adenomyosis, submucous myoma, endometrial polyps, or intrauterine adhesions were excluded.

Controlled ovarian hyperstimulation was conducted with the use of a gonadotropin-releasing hormone (GnRH) agonist on the basis of a long or short protocol or with a GnRH antagonist at the discretion of local investigators. Intracytoplasmic sperm injection was used in all IVF procedures, since randomization was not performed until day five of embryo culture. All embryos were cultured to the blastocyst stage. All blastocysts were assessed with morphologic criteria (expansion, inner cell mass, and trophectoderm development), and all embryos were cryopreserved for single frozen-embryo transfer.

On day five, patients with three or more good-quality blastocysts were randomized to conventional IVF (n=606) or pre-implantation genetic testing (n=606). Those randomized to IVF were implanted, while those randomized to PGT-A had trophectoderm biopsy to identify a euploid blastocyst for implantation.

If live birth was not achieved after initial implantation, additional frozen-embryo transfers to a maximum of three were performed. Only transfers within one year of randomization were included in the analysis.

The primary outcome was the cumulative live birth rate from up to three embryo transfers performed within one year of randomization. Mean age of the women was about 29. Indication for IVF was mostly tubal factor (51.8% and 56.9% in the PGT-A and IVF groups, respectively), as well as male factor (15.2% and 15.5%), and combined factors (20.1% and 17.8%).

Of 1,809 embryos analyzed by pre-implantation genetic testing, 69.8% were euploid, 17.2% aneuploid, 11.7% mosaic, and 1.4% uncertain. Of the 606 women in the PGT-A group, 2.8% had only abnormal embryos.

Mean number of embryos transferred per live birth was 1.2 for the PGT-A group and 1.3 in the IVF group. Second embryo-transfers were done in 192 women in the IVF group and 119 in the PGT-A group; for a third cycle, transfers were 49 and five, respectively.

Incidence of moderate or severe ovarian hyperstimulation syndrome, ectopic pregnancy, obstetrical or perinatal complications, and congenital anomalies were similar in the groups.
“There are two possible explanations for the inferior outcome after PGT-A,” Chen and colleagues wrote. First, the decision not to transfer mosaic embryos and the possibility of false positive or negative results for all embryos may be a factor, they pointed out. Mosaic embryos may develop into viable euploid newborns with a live-birth rate that can vary from 30 to 47%, but were excluded from the study (six mosaic transfers were performed on patient request). This and related technical limitations “unavoidably cause false positive or negative results, resulting in embryo waste or false embryo transfer,” the researchers noted.

Second, the pre-implantation genetic testing procedure involves trophectoderm biopsy, which may be harmful and by design was done only in women in the PGT-A group, they added.

“The aim of PGT-A is to help achieve a healthy child and reduce the related burden of implantation failures and miscarriages,” Chen and co-authors wrote. “In our trial, the results of a prespecified intention-to-treat analysis showed a lower rate of early pregnancy loss with PGT-A, which is consistent with the findings in the two trials involving women of advanced maternal age.”

“The frequency of biochemical loss was similar in the two trial groups, which suggests that embryos that are selected by morphologic criteria may be as likely as those selected by PGT-A to begin implantation but PGT-A does a better job of selecting embryos that continue through the first trimester,” they observed.

“Although some randomized trials have shown a higher frequency of ongoing pregnancy with PGT-A than with conventional IVF, two recent trials showed that PGT-A did not improve the frequency of ongoing pregnancy or live birth among women under 35 years of age,” Chen and colleagues noted.

The cohort included only women with a good prognosis for a live birth, the researchers acknowledged. “Thus, the results may not be generalizable to women who do not have a good prognosis (e.g., those with recurrent miscarriage or recurrent implantation failure) or to situations in which more embryos are available for testing and transfer,” they wrote.

  1. In women with a good prognosis for a live birth, in vitro fertilization (IVF) with pre-implantation genetic testing for aneuploidy (PGT-A) did not improve the cumulative live-birth rate over conventional IVF.

  2. Obstetric and neonatal complications and other adverse events were similar for both groups.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The trial was funded by the National Natural Science Foundation of China, the National Key Research and Development Program, and the Taishan Scholars Program for Young Experts of Shandong Province, with no commercial support.

Chen had no disclosures to report.

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Topic ID: 495,496,496,497,730,191,40,41,192,925

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