Race, ovarian responsiveness, and live birth after in vitro fertilization.

OBJECTIVE: To determine if ovarian responsiveness to gonadotropin stimulation differs by race/ethnicity and whether this predicts live birth rates (LBRs) in non-White patients undergoing in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Academic infertility center. PATIENT(S): White, Asian, Black, and Hispanic patients undergoing ovarian stimulation for IVF. INTERVENTION(S): Self-reported race and ethnicity. MAIN OUTCOME MEASURE(S): The primary outcome was ovarian sensitivity index (OSI), defined as (the number of oocytes retrieved ÷ total gonadotropin dose) × 1,000 as a measure of ovarian responsiveness, adjusting for age, body mass index, infertility diagnosis, and cycle number. Secondary outcomes included live birth and clinical pregnancy after first retrievals, adjusting for age, infertility diagnosis, and history of fibroids, as well as miscarriage rate per clinical pregnancy, adjusting for age, body mass index, infertility diagnosis, duration of infertility, history of fibroids, and use of preimplantation genetic testing for aneuploidy. RESULT(S): The primary analysis of OSI included 3,360 (70.2%) retrievals from White patients, 704 (14.7%) retrievals from Asian patients, 553 (11.6%) retrievals from Black patients, and 168 (3.5%) retrievals from Hispanic patients. Black and Hispanic patients had higher OSIs than White patients after accounting for those with multiple retrievals and adjusting for confounders (6.08 in Black and 6.27 in Hispanic, compared with 5.25 in White). There was no difference in OSI between Asian and White patients. The pregnancy outcomes analyses included 2,299 retrievals. Despite greater ovarian responsiveness, Black and Hispanic patients had lower LBRs compared with White patients, although these differences were not statistically significant after adjusting for confounders (adjusted odds ratio, 0.83; 95% confidence interval [CI], 0.63-1.09, for Black; adjusted odds ratio, 0.93; 95% CI, 0.61-1.43, for Hispanic). Ovarian sensitivity index was modestly predictive of live birth in White and Asian patients but not in Black (area under the curve, 0.51; 95% CI, 0.38-0.64) and Hispanic (area under the curve, 0.50; 95% CI, 0.37-0.63) patients. CONCLUSION(S): Black and Hispanic patients have higher ovarian responsiveness to stimulation during IVF but do not experience a consequent increase in LBR. Factors beyond differences in responsiveness to ovarian stimulation need to be explored to address the racial/ethnic disparity established in prior literature.

Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders.

STUDY QUESTION: Does the gonadotropin (GN) starting dose and the addition of clomiphene citrate (CC) during the early follicular phase influence oocyte yield in poor responders undergoing ovarian stimulation for IVF treatment? SUMMARY ANSWER: The number of retrieved oocytes was similar regardless of the starting dose of GN (150 versus 450 IU) with or without the addition of CC (100 mg from Day 3 to 7 versus placebo). WHAT IS KNOWN ALREADY: ART in poor responders is a challenge for patients and clinicians. So far, randomised controlled studies addressing interventions have shown that neither the GN dose nor the addition of oral medication has any significant effect on the clinical outcome of ART in poor responders. There is limited knowledge about the effect of GN starting dose in combination with CC during the early follicular phase of ovarian stimulation on ovarian response markers and ART outcome. STUDY DESIGN, SIZE, DURATION: This single-centre randomised double-blinded clinical trial was conducted from August 2013 until November 2017. Using the Bologna criteria, 220 of 2288 patients (9.6%) were identified as poor responders and 114 eligible participants underwent ovarian stimulation in a GnRH-antagonist protocol for ART. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were equally randomised to one of four treatment arms: Group A (n = 28) received 100 mg CC (Day 3-7) and a starting dose of 450 IU HMG, Group B (n = 29) received 100 mg CC and a starting dose of 150 IU HMG, Group C (n = 30) received placebo and a starting dose of 450 IU HMG and Group D (n = 27) received placebo and a starting dose of 150 IU HMG. Serum levels of FSH, LH, estradiol and progesterone were measured on Day 1 and 5 and on the day of ovulation induction. Available embryos were cultured up to the blastocyst stage and were always transferred in the same cycle. The primary outcome was the number of oocytes collected after ovarian stimulation. Other outcome measures were response to ovarian stimulation, embryo development and obstetrical outcome. MAIN RESULTS AND THE ROLE OF CHANCE: All study participants (n = 114) fulfilled at least two of the Bologna criteria for poor responders. Median age of the study population was 38.5 years. There were 109 patients who underwent oocyte retrieval. The number of oocytes retrieved was similar among the groups (±SD; 95% confidence intervals); A: 2.85 (±0.48; 2.04-3.98), B: 4.32 (±0.59; 3.31-5.64); C: 3.33 (±0.52; 2.45-4.54); D: 3.22 (±0.51; 2.36-4.41); P overall = 0.246. However, ovarian stimulation with 150 IU plus CC resulted in a higher number of blastocysts compared to ovarian stimulation with 450 IU plus CC (±SD; 95% confidence intervals); A: 0.83 (±0.15; 0.58-1.2), B: 1.77 (±0.21; 1.42-2.22); P overall = 0.006. Mean FSH serum levels were lower in the groups with a starting dose of 150 IU. Adding CC did not affect mean serum FSH levels. There were no differences in estradiol concentrations among the groups. Endometrial thickness was lower in the groups receiving CC. The overall live birth rate (LBR) was 12.3%, and the cumulative LBR was 14.7%. LIMITATIONS, REASONS FOR CAUTION: The trial was powered to detect differences in neither the number of blastocysts nor the LBR, which would be the preferable primary outcome of interventional trials in ART. WIDER IMPLICATIONS OF THE FINDINGS: We found that ovarian stimulation with 150 IU gonadotrophin in combination with 100 mg CC produced more blastocysts. The effect of adding CC to GN on LBR in poor responders remains to be proven in randomised trials. High GN doses (450 IU) resulted in high FSH serum levels but increased neither the estradiol levels nor the number of retrieved oocytes, implying that granulosa cell function is not improved by high FSH serum levels. Lower starting doses of GN lead to a reduction of costs of medication. The small but significant difference in blastocyst formation and the lower FSH levels in the treatment groups receiving less GN may be an indication of better oocyte quality with higher developmental competence. STUDY FUNDING/COMPETING INTEREST(S): The costs for the HMG used for ovarian stimulation were provided by IBSA Switzerland. The study was also supported by the Repronatal Foundation, Basel, Switzerland. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01577472. TRIAL REGISTRATION DATE: 13 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: August 2013.

Clinical Application of AMH Measurement in Assisted Reproduction.

Anti-Müllerian hormone reflects the continuum of the functional ovarian reserve, and as such can predict ovarian response to gonadotropin stimulation and be used to individualize treatment pathways to improve efficacy and safety. However, consistent with other biomarkers and age-based prediction models it has limited ability to predict live birth and should not be used to refuse treatment, but rather to inform counselling and shared decision making. The use of absolute clinical thresholds to stratify patient phenotypes, assess discordance and individualize treatment protocols in non-validated algorithms combined with the lack of standardization of assays may result in inappropriate classification and sub-optimal clinical decision making. We propose that holistic baseline phenotyping, incorporating antral follicle count and other patient characteristics is critical. Treatment decisions driven by validated algorithms that use ovarian reserve biomarkers as continuous measures, reducing the risk of misclassification, are likely to improve overall outcomes for our patients.

Comparison of antral follicle count and serum anti Müllerian hormone level for determination of gonadotropin dosing in in-vitro fertilization: randomized trial.

OBJECTIVE: To compare the proportion of women achieving a desired ovarian response following ovarian stimulation when gonadotropin dosing was determined based on antral follicle count (AFC) vs serum anti-Müllerian hormone (AMH) level, in women undergoing in-vitro fertilization (IVF) using the gonadotropin-releasing hormone (GnRH) antagonist protocol. METHODS: This was a randomized double-blind trial carried out in a university-affiliated assisted reproduction unit. A total of 200 women undergoing their first IVF cycle using the GnRH-antagonist protocol between April 2016 and February 2018 were randomized to determination of gonadotropin dosing based on either AFC or serum AMH level measured in the pretreatment cycle 1 month before the IVF cycle. Patients underwent IVF as per our center's standard protocol. The proportion of subjects achieving a desired ovarian response, defined as retrieval of six to 14 oocytes, was compared between the two study arms. Subgroup analysis of patients with baseline AFC > 5 and those with baseline AFC ≤ 5 was performed. Concordance in AFC and AMH categorization between the pretreatment cycle and the ovarian-stimulation cycle was assessed using Cohen's kappa (κ). RESULTS: There was no significant difference in the proportion of patients achieving a desired ovarian response between the AFC (54%) and AMH (49%) groups (P = 0.479). The median number of oocytes retrieved was nine vs seven (P = 0.070), and the median follicular output rate was 0.54 vs 0.55 (P = 0.764) in the AFC and AMH groups, respectively. Similar findings were observed on subgroup analysis of subjects with AFC ≤ 5 and AFC > 5 at the start of ovarian stimulation (P > 0.05 for all comparisons). There was moderate concordance between AFC and AMH measured in the pretreatment cycle and the stimulation cycle (κ = 0.478 and 0.587, respectively). CONCLUSION: The proportion of women achieving a desired ovarian response following ovarian stimulation using the GnRH-antagonist protocol is similar when the gonadotropin-dosing algorithm used is based on AFC or serum AMH level. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparación del recuento de folículos sinusales y el nivel de la hormona antimulleriana en el suero para la determinación de la dosis de gonadotrofina en la fecundación in vitro: ensayo aleatorizado OBJETIVO: Comparar la proporción de mujeres que logran una respuesta ovárica deseada tras la estimulación del ovario cuando se determinó la dosis de gonadotrofina en función del recuento de folículos sinusales (AFC, por sus siglas en inglés) frente al nivel de la hormona antimulleriana (HAM) en el suero, en mujeres que se sometieron a una fecundación in vitro (FIV) mediante el protocolo de antagonistas de la hormona liberadora de gonadotropina (GnRH, por sus siglas en inglés). MÉTODOS: Se trata de un ensayo aleatorizado doble ciego realizado en una unidad de reproducción asistida afiliada a una universidad. Un total de 200 mujeres que se sometieron a su primer ciclo de FIV y utilizaron el protocolo de antagonistas de la GnRH entre abril de 2016 y febrero de 2018 fueron asignadas al azar a la determinación de la dosis de gonadotrofina basada en el nivel de AFC o de HAM en suero, medidos en el ciclo de pretratamiento un mes antes del ciclo de FIV. Las pacientes se sometieron a una FIV según el protocolo estándar de nuestro centro. La proporción de mujeres que lograron una respuesta ovárica deseada, definida como la recuperación de seis a 14 ovocitos, se comparó entre las dos ramas del estudio. Se realizó un análisis de subgrupos de las pacientes con AFC de base >5 y de aquellas con AFC de base ≤5. La concordancia en la categorización del AFC y la HAM entre el ciclo de pretratamiento y el ciclo de estimulación ovárica se evaluó utilizando la medida estadística kappa de Cohen (κ). RESULTADOS: No hubo diferencias significativas en la proporción de pacientes que lograron una respuesta ovárica deseada entre los grupos de AFC (54%) y HAM (49%) (P=0,479). La mediana del número de ovocitos recuperados fue de nueve frente a siete (P=0,070), y la mediana de la tasa de producción folicular fue de 0,54 frente a 0,55 (P=0,764) en los grupos AFC y HAM, respectivamente. Se observaron hallazgos similares en el análisis de subgrupos de pacientes con AFC ≤5 y AFC >5 al comienzo de la estimulación ovárica (P>0,05 para todas las comparaciones). Se observó una concordancia moderada entre el AFC y la HAM medidos en el ciclo de pretratamiento y el ciclo de estimulación (κ=0,478 y 0,587, respectivamente). CONCLUSIÓN: La proporción de mujeres que logran una respuesta ovárica deseada después de la estimulación ovárica utilizando el protocolo de antagonistas de la GnRH es similar cuando el algoritmo de dosificación de gonadotrofina utilizado se basa en el nivel del AFC o de la HAM en suero.