To test or not to test? A framework for counselling patients on preimplantation genetic testing for aneuploidy (PGT-A).

STUDY QUESTION: What is the treatment path and cumulative live birth (CLB) rate from a single oocyte retrieval of patients who intend to pursue PGT-A at the start of an IVF cycle compared to matched controls? SUMMARY ANSWER: The choice of PGT-A at the start of the first IVF cycle decreases the CLB per oocyte retrieval for patients <38 years of age, however patients ≥38 years of age benefit significantly per embryo transfer (ET) when live birth (LB) is evaluated. WHAT IS KNOWN ALREADY: PGT-A has been shown to reduce the practice of transferring multiple embryos and to confer a higher live birth rate per transfer. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study from December 2014 to September 2016, involving 600 patients: those intending PGT-A for their first IVF cycle (N = 300) and their matched controls. Post-hoc power calculations (alpha of 0.05, power of 0.80) indicated that our study was powered adequately to demonstrate significant differences in CLB per retrieval and LB per transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed at a large academically affiliated infertility practice where approximately 80% of patients have insurance coverage for fertility care. Patients were identified through electronic medical records, and those who intended to pursue PGT-A at the start of stimulation were assessed. Patients were matched by age, time of oocyte retrieval and oocyte yield to the same number of controls. CLB outcomes per single retrieval, including the fresh and frozen transfers arising from the initial stimulation cycle, were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: PGT-A was not beneficial when CLB rate was assessed per retrieval, however its benefits were significant when LB rate was assessed per transfer. First cycle, <38 year-old patients who intended to have PGT-A had a significantly (P < 0.001) lower CLB rate per oocyte retrieval compared to controls (49.4% vs. 69.1%). Conversely, patients ≥ 38 years in the PGT-A group had similar CLB rates compared to controls per oocyte retrieval, while LB rates per transfer were doubled compared to controls (62.1% vs. 31.7%; P < 0.001). Of the first-cycle PGT-A and control patients, 25.3% and 2.3% failed to achieve a transfer, respectively. LIMITATIONS, REASONS FOR CAUTION: This is not a true intention-to-treat study, due to its retrospective nature. Additionally, the number of patients with two or more previous miscarriages was significantly greater in the PGT-A group as compared to controls, however a sub-analysis showed that this failed to impact outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings indicate that PGT-A may be detrimental for those <38 years old undergoing their first IVF cycle. PGT-A has the greatest clinical impact when a transfer is achieved in the ≥38 years old population. This study evaluates the typical treatment path following a patient's choice to pursue PGT-A at the cycle start, and can be used as a guide for counselling patients in relation to age and cycle number. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Elevated progesterone and its impact on birth weight after fresh embryo transfers.

PURPOSE: The purpose of the study was to examine the association between serum progesterone levels on the day of hCG administration and birth weight among singleton live births after fresh embryo transfer. METHODS: This study was conducted as a retrospective cohort database analysis on patients who underwent IVF treatment cycles from January 2004 to April 2012. The study was performed at a University affiliated private infertility practice. All cycles that had achieved a singleton live birth after fresh embryo transfer and for which progesterone was measured on the day of hCG administration were examined. Generalized linear models were used to calculate mean birth weight and z-scores. RESULTS: We analyzed 817 fresh IVF embryo transfers in which birth weight, gestational age, and progesterone (ng/mL) level on day of hCG administration were documented. While there was a decrease in birth weight as progesterone quartile [≤0.54; >0.54 to ≤0.81; >0.81 to ≤1.17; >1.17 ng/mL] increased, the difference in mean birth weights among the four quartiles was not statistically significant (p = 0.11) after adjusting for maternal age and peak estradiol levels. When dichotomizing based on a serum progesterone considered clinically elevated, cycles with progesterone >2.0 ng/mL had a significantly lower mean singleton birth weight (2860 g (95% CI 2642 g, 3079 g)) compared to cycles with progesterone ≤2.0 ng/mL (3167 g (95% CI 3122 g, 3211 g) p = 0.007)) after adjusting for maternal age and estradiol. CONCLUSION: We demonstrated that caution should be exercised when performing fresh embryo transfers with elevated progesterone levels and in particular with levels (>2.0 ng/mL) as this may lead to lower birth weight.

A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T).

OBJECTIVE: To determine the optimal infertility therapy for women at the end of their reproductive potential. DESIGN: Randomized clinical trial. SETTING: Academic medical centers and private infertility center in a state with mandated insurance coverage. PATIENT(S): Couples with ≥ 6 months of unexplained infertility; female partner aged 38-42 years. INTERVENTION(S): Randomized to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. MAIN OUTCOME MEASURE(S): Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment. RESULT(S): We randomized 154 couples to receive CC/IUI (N = 51), FSH/IUI (N = 52), or immediate IVF (N = 51); 140 (90.9%) couples initiated treatment. The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatments, 110 (71.4%) of 154 couples had conceived a clinically recognized pregnancy, and 46.1% had delivered at least one live-born baby; 84.2% of all live-born infants resulting from treatment were achieved via IVF. There were 36% fewer treatment cycles in the IVF arm compared with either COH/IUI arm, and the couples conceived a pregnancy leading to a live birth after fewer treatment cycles. CONCLUSION(S): A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group. CLINICAL TRIAL REGISTRATION NUMBER: NCT00246506.

Effect of steroid and antibiotic treatment during assisted hatching on IVF outcomes.

There are limited data on the use of steroids and antibiotics in assisted reproductive technology (ART). Our aim was to evaluate the impact of these treatments on the outcome of IVF cycles in which Assisted Hatching (AH) was performed. We studied a retrospective cohort in a large university-affiliated infertility centre. Data from 1126 AH cycles performed between 2007 and 2009 were reviewed. Cycles were categorized as "treatment" (n = 640) and "no treatment" (n = 486), depending on whether they received steroids and antibiotics. The primary outcome was live birth. Secondary outcomes included implantation, spontaneous abortion, biochemical, clinical and ectopic pregnancy. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). OR were adjusted (AOR) for age, BMI, baseline FSH, peak estradiol, cycle number, number of oocytes retrieved, number of embryos that underwent AH, number of high-implantation potential embryos, number of embryos transferred and physician in charge. The AOR (95% CI) of live birth was 1.91 (1.08-3.38), of clinical pregnancy, 1.75 (1.08-2.83) and of biochemical pregnancy, 0.24 (0.07-0.85). Our study suggests that treatment with steroids and antibiotics during AH cycles significantly increases the odds of live birth.

Influence of embryo sex on development to the blastocyst stage and euploidy.

OBJECTIVE: To compare the prevalence of blastocyst development and euploidy in XX versus XY embryos. DESIGN: Retrospective cohort study. SETTING: Boston IVF, a large university-affiliated reproductive medicine practice. PATIENT(S): All patients who underwent their first preimplantation genetic screening cycle between January 1, 2006, and December 31, 2007. INTERVENTION(S): In vitro fertilization and preimplantation genetic screening. MAIN OUTCOME MEASURE(S): Proportion of embryos that developed to the blastocyst stage by day 5 and prevalence of euploidy for chromosomes 8, 13, 14, 15, 16, 17, 18, 20, 21, and 22 in XX versus XY embryos. RESULT(S): Seven hundred fifty-eight embryos from 138 cycles in 138 patients were analyzed. Three hundred sixty-six (48%) were XX, and 392 (52%) were XY. XX and XY embryos were equally likely to develop to the blastocyst stage by day 5 and were equally likely to be euploid for the analyzed chromosomes. CONCLUSION(S): Our data suggest that extending embryo culture to day 5 does not lead to sex selection and that euploidy and aneuploidy are not sex dependent.

Influence of patient age on the association between euploidy and day-3 embryo morphology.

A retrospective cohort study conducted in 138 patients undergoing their first preimplantation genetic screening (PGS) cycle between January 1, 2006, and December 31, 2007, demonstrated that embryos with good day-3 morphology were more likely to be euploid for X/Y, 8, 15, and 18 than those with poor morphology. The strength of association between euploidy and day-3 morphology was not influenced by maternal age.

A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial.

OBJECTIVE: To determine the value of gonadotropin/intrauterine insemination (FSH/IUI) therapy for infertile women aged 21-39 years. DESIGN: Randomized controlled trial. SETTING: Academic medical center associated with a private infertility center. PATIENT(S): Couples with unexplained infertility. INTERVENTION(S): Couples were randomized to receive either conventional treatment (n=247) with three cycles of clomiphene citrate (CC)/IUI, three cycles of FSH/IUI, and up to six cycles of IVF or an accelerated treatment (n=256) that omitted the three cycles of FSH/IUI. MAIN OUTCOME MEASURE(S): The time it took to establish a pregnancy that led to a live birth and cost-effectiveness, defined as the ratio of the sum of all health insurance charges between randomization and delivery divided by the number of couples delivering at least one live-born baby. RESULT(S): An increased rate of pregnancy was observed in the accelerated arm (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.00-1.56) compared with the conventional arm. Median time to pregnancy was 8 and 11 months in the accelerated and conventional arms, respectively. Per cycle pregnancy rates for CC/IUI, FSH/IUI, and IVF were 7.6%, 9.8%, and 30.7%, respectively. Average charges per delivery were $9,800 lower (95% CI, $25,100 lower to $3,900 higher) in the accelerated arm compared to conventional treatment. The observed incremental difference was a savings of $2,624 per couple for accelerated treatment and 0.06 more deliveries. CONCLUSION(S): A randomized clinical trial demonstrated that FSH/IUI treatment was of no added value.

Assessment of day-3 morphology and euploidy for individual chromosomes in embryos that develop to the blastocyst stage.

OBJECTIVE: To examine the relationship between day-3 morphology and euploidy for individual chromosomes in embryos that develop to the blastocyst stage by day 5. DESIGN: Retrospective cohort study. SETTING: Boston IVF, a large university-affiliated reproductive medicine practice. PATIENT(S): Ninety-nine patients undergoing their first preimplantation genetic screening (PGS) cycle between January 1 and December 31, 2006. INTERVENTION(S): In vitro fertilization (IVF) and preimplantation genetic screening (PGS). MAIN OUTCOME MEASURE(S): Prevalence of euploidy for chromosomes X, Y, 8, 13, 14, 15, 16, 17, 18, 20, 21, and 22 in day-3 high implantation potential (HIP) versus non-HIP embryos that grew to day-5 blastocysts. RESULT(S): Seven hundred three embryos from 99 cycles in 99 patients underwent PGS. Three hundred sixty-four (52%) embryos from 88 cycles in 88 patients developed to the blastocyst stage by day 5. High implantation potential embryos were more likely to be euploid for chromosomes X/Y, 8, 15, 16, 18, and 22 compared with non-HIP embryos, with similar trends for chromosomes 14 and 17. There were no statistically significant differences between HIP and non-HIP embryos in euploidy prevalence for chromosomes 13, 20, and 21. CONCLUSION(S): Our data suggest that PGS may detect potentially viable but detrimental chromosomal abnormalities that are not detected by embryo morphology alone.

Impact of subgroup analysis on estimates of infertility.

Conclusions regarding estimates of infertility may reflect study bias based on the definition of infertility used. Careful consideration of how the infertile population is defined, as well its use in subgroup analysis that may not be generalizable to the population of infertile women as a whole, is needed.