Whole-genome risk prediction of common diseases in human preimplantation embryos.

Preimplantation genetic testing (PGT) of in-vitro-fertilized embryos has been proposed as a method to reduce transmission of common disease; however, more comprehensive embryo genetic assessment, combining the effects of common variants and rare variants, remains unavailable. Here, we used a combination of molecular and statistical techniques to reliably infer inherited genome sequence in 110 embryos and model susceptibility across 12 common conditions. We observed a genotype accuracy of 99.0-99.4% at sites relevant to polygenic risk scoring in cases from day-5 embryo biopsies and 97.2-99.1% in cases from day-3 embryo biopsies. Combining rare variants with polygenic risk score (PRS) magnifies predicted differences across sibling embryos. For example, in a couple with a pathogenic BRCA1 variant, we predicted a 15-fold difference in odds ratio (OR) across siblings when combining versus a 4.5-fold or 3-fold difference with BRCA1 or PRS alone. Our findings may inform the discussion of utility and implementation of genome-based PGT in clinical practice.

Pregnancy outcomes from more than 1,800 in vitro fertilization cycles with the use of 24-chromosome single-nucleotide polymorphism-based preimplantation genetic testing for aneuploidy.

OBJECTIVE: To measure in vitro fertilization (IVF) outcomes following 24-chromosome single‒nucleotide-polymorphism (SNP)-based preimplantation genetic testing for aneuploidy (PGT-A) and euploid embryo transfer. DESIGN: Retrospective. SETTING: Fertility clinics and laboratory. PATIENT(S): Women 20-46 years of age undergoing IVF treatment. INTERVENTION(S): Twenty-four-chromosome SNP-based PGT-A of day 5/6 embryo biopsies. MAIN OUTCOME MEASURE(S): Maternal age-stratified implantation, clinical pregnancy, and live birth rates per embryo transfer; miscarriage rates; and number of embryo transfers per patient needed to achieve a live birth. RESULT(S): An implantation rate of 69.9%, clinical pregnancy rate per transfer of 70.6%, and live birth rate per transfer of 64.5% were observed in 1,621 nondonor frozen cycles with the use of SNP-based PGT-A. In addition, SNP-based PGT-A outcomes, when measured per cycle with transfer, remained relatively constant across all maternal ages; when measured per cycle initiated, they decreased as maternal age increased. Miscarriage rates were ∼5% in women ≤40 years old. No statistically significant differences in pregnancy outcomes were found for single-embryo transfers (SET) versus double-embryo transfers with SNP-based PGT-A. On average, 1.38 embryo transfers per patient were needed to achieve a live birth in nondonor cycles. CONCLUSION(S): Our findings that SNP-based PGT-A can mitigate the negative effects of maternal age on IVF outcomes in cycles with transfer, and that pregnancy outcomes from SET cycles are not significantly different from those of double-embryo transfer cycles, support the use of SET when transfers are combined with SNP-based PGT-A.

Transfer of blastocysts and morulae on day 5.

OBJECTIVE: To limit the number of embryos transferred and reduce high-order multiple pregnancies without compromising a patient's opportunity to become pregnant. DESIGN: Retrospective, nonrandomized analysis of embryo development and patient outcome when embryos were transferred on day 5. SETTING: Private practice. PATIENT(S): Women undergoing in vitro fertilization (IVF) treatment. INTERVENTION(S): Extend embryo culture to day 5 before embryo transfer (ET) to reduce the number of embryos transferred and minimize high-order multiple pregnancies. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR), implantation rate (IR), and live born rate (LBR) from expanding (expanded blastocysts and blastocysts) and nonexpanding (early blastocysts and morulae) embryos transferred on day 5. RESULT(S): Approximately 60% of patients had expanding embryos (EXE) on day 5. Forty percent of patients having an ET had transferable non-expanding embryos (NEE). Patients with EXE had higher CPR and LBR compared to patients with NEE. Implantation rate and multiple pregnancy rate (MPR) were also higher for patients with EXE. The miscarriage rate (MCR) for patients with EXE and NEE was not different. Approximately 5.5% of patients did not have an ET, with most (>98%) of the ET failures from patients with <==3 two pronuclei (2PN) embryos. The number of 2PN embryos had an effect on CPR, LBR, MPR, and the number of patients having cryopreservation. CONCLUSION(S): Day 5 ET allows for the selection of embryos with the highest implantation potential as evidenced by acceptable pregnancy rates for patients with either EXE or NEE, without the need to transfer more than two embryos.

Integration of blastocyst transfer for all patients.

OBJECTIVE: To evaluate the efficacy of using day-5 embryo transfer (ET) for all patients. DESIGN: Retrospective, non-randomized comparison of day-3 ET versus day-5 ET. SETTING: Private practice. PATIENT(S): Women having in vitro fertilization and receiving either day-3 ET or day-5 ET. INTERVENTION(S): Extended embryo culture through embryonic genome activation to select those embryos with higher implantation potential. MAIN OUTCOME MEASURE(S): The following parameters were compared for day-3 ET and day-5 ET: clinical and ongoing pregnancy rates, implantation rates, patients having cryopreservation, and liveborn rates. RESULT(S): Blastocyst embryo transfer (day-5 ET) increased the clinical and ongoing pregnancy rate for patients <35 years of age and for the total program. The risk of high order multiple pregnancy was reduced by a decrease in the number of embryos transferred (2.0 vs. 2.7; day-5 ET vs. day-3 ET, respectively). However, the multiple pregnancy rate was not different due to an increase in the implantation rate (day-5 ET 43% vs. day-3 ET 27%). There was no difference in the percent of patients not having an ET (day-5 ET 2.8%; day-3 ET 1.3%). CONCLUSION(S): Blastocyst ET increased the clinical and ongoing pregnancy rate for patients <35 years of age and for the total program, with a concomitant decrease in the number of embryos transferred. However, the decrease in the number of embryos transferred did not decrease the multiple rate, but did reduce the incidence of high order multiples. Most patients (97%) had an embryo transfer. Therefore, culturing embryos an additional 48 hours through embryonic genome activation allows for selection of the most viable embryos without compromising the patient's opportunity to become pregnant.