Assisted reproductive technologies in Africa: The African Network and Registry for ART, 2020.

RESEARCH QUESTION: What were the utilization, effectiveness and safety of assisted reproductive technology (ART) in Africa during 2020? DESIGN: Cross-sectional, cycle-based and retrospective summary data were collected from voluntarily participating ART centres. RESULTS: During 2020, 37,063 ART procedures were reported by 67 centres in 15 countries. Autologous fresh transfers were predominant at 65.0%, whereas autologous frozen embryo transfers (FET) represented 26.2% and oocyte donation cycles remained less than 10%. Women undergoing autologous fresh embryo transfer had a mean age of 34.9 years and received a mean number of 2.4 embryos per transfer. The clinical pregnancy rate (CPR) per embryo transfer was 37.3% after fresh embryo transfer and 37.8% after frozen embryo transfer. The cumulative CPR per aspiration was 41.9% in autologous cycles. Most ART procedures resulted in a multiple delivery rate above 20%. After autologous ART, multiples were predominantly born preterm (twin and triplet deliveries 59.5% versus singleton 21.9% born before 37 weeks), with a substantially increased perinatal mortality compared with ART singletons (59.0‰ versus 22.2‰). Cycle-based data documented that elective single embryo transfer (eSET) provides the optimal balance of effectiveness (eSET CPR per embryo transfer 36.7%) and safety. CONCLUSION: This fourth report of the African Network and Registry for ART provides real-world evidence of ART utilization, practices and outcomes in Africa, which is relevant to many stakeholders. It critically informs and represents regional ART development based on national, regional and global cooperation.

Assisted reproductive technologies in Africa: The African Network and Registry for ART, 2018 and 2019.

RESEARCH QUESTION: What were the utilization, practices and outcomes of assisted reproductive technology (ART) in Africa in 2018 and 2019? DESIGN: Cycle-based data (CBD) and retrospective summary data were collected cross-sectionally from voluntarily participating ART centres. RESULTS: During 2018, 43,958 ART procedures were reported by 67 centres in 16 countries, increasing to 45,185 procedures reported by 70 centres in 18 countries in 2019. Autologous fresh procedures predominated at 70%, whereas autologous frozen embryo transfers (FET) increased from 21.2% to 23.1% and oocyte donation cycles remained below 10%. In 2019, the mean age of women undergoing autologous fresh embryo transfer was 33.9 years and received a mean number of 2.4 embryos per transfer. The clinical pregnancy rate (CPR) per fresh embryo transfer was 42.8% in 2018 and 38.4% in 2019, with corresponding rates of 38.3% and 31.8% after FET. In both years, most ART procedures, excluding single embryo transfer (SET), were associated with a multiple delivery rate above 20%, reaching over 30% after elective dual embryo transfer in autologous cycles and after fresh oocyte donation. Multiples were predominantly born preterm with a substantially increased perinatal mortality rate. The CBD for both years showed that elective SET (eSET) achieved a high CPR without compromising safety. CONCLUSION: This third report of The African Network and Registry for Assisted Reproductive Technology documents the prevailing practice of multiple embryo transfers in a cohort of relatively young women while highlighting the importance of disaggregating eSET, non-eSET and double embryo transfer. The high CPR after eSET and the increase in cryopreservation cycles are encouraging trends towards decreasing the number of embryos transferred without compromising effectiveness. Improved follow-up of ART pregnancies is required.

The novel incorporation of aromatase inhibitor in hormonal replacement therapy cycles: a randomized controlled trial.

RESEARCH QUESTION: Does the incorporation of the aromatase inhibitor, letrozole, in hormone replacement therapy (HRT) improve the pregnancy outcome in vitrified-warmed blastocyst transfer cycles? DESIGN: A randomized controlled trial; HRT was used in all cycles. Exogenous oestradiol, 6 mg daily started on day 2 or day 3 of the cycle. Tri-laminar endometrium 9 mm or thicker was the targeted cut-off. Thereafter, participants were randomized into two groups. Group A (HRT plus letrozole): 2.5 mg oral letrozole was given twice daily for 5 days only with continuation of daily oestradiol. Then, daily intramuscular progesterone was started with continuation of oestradiol. Group B (HRT only): daily intramuscular progesterone was administered in addition to daily oestradiol. In both groups, good-quality day-5 blastocyst transfer was planned on the sixth progesterone day with continuation of oestradiol and progesterone. Ongoing pregnancy rate was the primary outcome. RESULTS: A total of 112 patients were randomized, 56 in each group. Three participants did not have good-quality blastocyst after warming (one in group A and two in group B) and were excluded from the study. Group A and B included 55 and 54 participants, respectively. Ongoing pregnancy rate was significantly higher in group A than group B (RR 1.39, 95% CI 1.04 to 1.86, P = 0.023). Additionally, clinical pregnancy rate was significantly higher in group A (RR 1.31, 95% CI 1.02 to 1.68, P = 0.030). CONCLUSIONS: A new protocol of incorporating letrozole in HRT cycles seems to significantly increase probability of pregnancy, compared with HRT alone.

Endometrial scratching for women with previous IVF failure undergoing IVF treatment.

The purpose of this study was to find out whether endometrial scratching could improve live birth rate in women with previous IVF failure undergoing fresh IVF cycle. In a randomized controlled trial, 387 women with previous IVF failure were divided into two groups. Group A (193 women) was subjected to endometrial biopsy procedure twice. Group B (194 women) was subjected to a placebo procedure. Our results showed no difference in live birth rate between the two groups of women (47.2% versus 38.1%, p = 0.08). However, regression analysis revealed that endometrial scratching was an independent predictor of live birth in the subgroup of women with two or more previous failure after control of other independent predictors (odds ratio (OR) 3.4, p = 0.005). We conclude that endometrial scratching does not improve live birth rate in women undergoing IVF treatment with previous one IVF failure. Nevertheless, it may improve live birth in women with two or more previous IVF failures.

Common Beverage Consumption and Benign Gynecological Conditions.

The purpose of this article is to review the effects of four commonly consumed beverage types-sugar-sweetened beverages (SSBs), caffeinated beverages, green tea, and alcohol-on five common benign gynecological conditions: uterine fibroids, endometriosis, polycystic ovary syndrome (PCOS), anovulatory infertility, and primary dysmenorrhea (PD). Here we outline a plethora of research, highlighting studies that demonstrate possible associations between beverage intake and increased risk of certain gynecological conditions-such as SSBs and dysmenorrhea-as well as studies that demonstrate a possible protective effect of beverage against risk of gynecological condition-such as green tea and uterine fibroids. This review aims to help inform the diet choices of those with the aforementioned conditions and give those with uteruses autonomy over their lifestyle decisions.

International Committee for Monitoring Assisted Reproductive Technology world report: assisted reproductive technology, 2015 and 2016.

OBJECTIVE: To report utilization, effectiveness, and safety of assisted reproductive technologies in 2015 and 2016. DESIGN: A retrospective, cross-sectional survey of 3,103 assisted reproductive technology clinics in 74 countries in 2015 and 3,249 clinics in 79 countries in 2016 that submitted cycle and pregnancy outcome data through national and regional registries. SETTING: Seventy-nine countries and >3,000 assisted reproductive technology clinics. PATIENT(S): Patients undergoing assisted reproductive technology procedures. INTERVENTION(S): Assisted reproductive technology. MAIN OUTCOME MEASURE(S): Outcomes on country, regional, and global levels. RESULT(S): Reported for 2015: 2,358,239 cycles with 548,652 infants born; for 2016: 2,807,963 cycles with 647,188 infants born. Estimated in 2015, ≥2,683,677 cycles resulted in >675,134 infants; in 2016, ≥3,100,448 cycles resulted in ≥723,026 infants. Reported cycles represent approximately 80% of global utilization. In 2015 and 2016, 27.6% and 27.8%, respectively, of women undergoing fresh autologous treatment cycles were aged ≥40 years. Frozen-thawed embryo transfer (ET) cycles accounted for 47.0% and 51.9%, respectively, of all ETs in 2015 and 2016. Oocyte donation cycles accounted for 6.7% and 7.1% of all ETs in 2015 and 2016. Intracytoplasmic sperm injection was performed in 57.7% and 56.4% of autologous aspiration cycles in 2015 and 2016, respectively. The cumulative delivery rate per aspiration cycle for fresh and frozen-thawed ET was 32.4% in 2015 and 33.1% in 2016, respectively. The average number of transferred embryos was 1.70 in 2015 and 1.69 in 2016. The proportion of single ETs in fresh autologous cycles increased from 42.1% in 2015 to 44.0% in 2016. The twin delivery rate decreased from 16.0% in 2015 to 14.7% in 2016, and the triplet rate decreased from 0.6% in 2015 to 0.4% in 2016. The proportion of single ETs in frozen-thawed ET autologous treatment cycles was 62.2% in 2015 and 64.2% in 2016, with twin and triplet rates of 10.1% and 0.3% in 2015 and 10.0% and 0.2% in 2016, respectively. CONCLUSION(S): Utilization of assisted reproductive technology treatment and births per cycle increased from 2015 to 2016, although multiple births were reduced. An increasing proportion of frozen-thawed ET cycles, continuing wide variation in use of intracytoplasmic sperm injection, and an increase in single ET rates are reported.

Day 5 expanded blastocysts transferred on same day have comparable outcome to those left for more extended culture and transferred on day 6.

OBJECTIVE: To study the outcome of blastocysts showing expansion on day 5 and transferred on day 5 or 6, in comparison with those unexpanded and transferred on day 6. STUDY DESIGN: Prospective cohort of 221 women prepared for BET classified into three groups according to timing of blastocyst expansion and day of embryo transfer. Group I; with expanded blastocysts on day 5 having day 5 transfer, group II; with expanded blastocysts on day 5 having day 6 transfer and group III ; with delayed expansion undergoing day 6 BET. RESULTS: Implantation rates, pregnancy rates, ongoing pregnancy rates, and live birth rates in the first 2 groups were almost double the rates in the third group. The figures for implantation rates were 40 % in the first two groups vs. 19 % in the third group (P < 0.05). Pregnancy rates were 60.9 % and 64 % vs. 31.8 % (P < 0.05) and ongoing pregnancy/ live-birth rates were 52.3 % & 56 % vs. 27.3 %. CONCLUSION: The current study reports better implantation and pregnancy rates with earlier expanding blastocysts regardless of the time of transfer.

Blastocyst-stage versus cleavage-stage embryo transfer in women with high oestradiol concentrations: randomized controlled trial.

This prospective, randomized, controlled trial tested the hypothesis that delaying embryo transfer to the blastocyst stage can increase the probability of clinical pregnancy and live birth in women with high oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) undergoing intracytoplasmic sperm injection using the long protocol. A total of 200 women with oestradiol >3000 pg/ml on the HCG day with four or more good-quality, day-3 embryos were randomized in a 1:1 ratio to undergo day-3 or day-5 embryo transfer. Clinical pregnancy rates (CPR; 41% versus 59%; relative risk 0.70, 95% CI 0.52­0.93) and ongoing pregnancy/live-birth rates (35% versus 52%; relative risk 0.67, 95% CI 0.46­0.93) were lower in women undergoing cleavage-stage than blastocyst-stage embryo transfer. Using receiver operating characteristic curves, among women undergoing cleavage-stage embryo transfer, a detrimental cut-off value for not achieving pregnancy for oestradiol was 4200 pg/ml, with lower CPR and ongoing pregnancy/live-birth rates (P = 0.006 and 0.02, respectively). No detrimental cut-off value for oestradiol was identified among women undergoing blastocyst-stage embryo transfer. Delaying embryo transfer to the blastocyst stage can increase the probability of pregnancy in women with high oestradiol on the HCG day

N-acetyl cysteine: could it be an effective adjuvant therapy in ICSI cycles? A preliminary study.

This randomized controlled trial tested the hypothesis that addition of N-acetyl cysteine (NAC) can increase the probability of pregnancy in intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol. Women undergoing ICSI cycles due to male factor were randomly assigned to receive either long protocol (group A, 38 women) or long protocol plus NAC (group B, 38 women). Clinical pregnancy was the primary outcome. Granulosa cell apoptosis, fertilization rate, number of grade-one embryos and ongoing pregnancy were the secondary outcomes. Clinical pregnancy rate was insignificantly higher in NAC group (52.6%) than control (47.4%). Early and late apoptosis were also insignificantly lower in group B than in group A. Irrespective of the used protocol, there was significant negative correlation between both early and late apoptosis and fertilization rate (both P<0.001) and the number of good-quality embryos (P=0.007 and P<0.001, respectively). Pregnant patients had significantly lower early and late apoptosis than those who didn't achieve pregnancy (P<0.001). In conclusion, NAC supplementation did not significantly increase the probability of pregnancy in ICSI cycles using long agonist protocol. It appears that granulosa cell apoptosis may be an important prognosticator for ICSI cycle outcome.

Protecting Ovaries During Chemotherapy Through Gonad Suppression: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate whether gonadotropin-releasing hormone (GnRH) analog administration during chemotherapy can protect against development of ovarian toxicity. DATA SOURCES: MEDLINE (1966 to present), EMBASE (1980 to present), Cochrane Central Register of Controlled Trials (CENTRAL), World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched through March 2015 using the phrases: "gonadotropin-releasing hormone," "chemotherapy," and "premature ovarian failure." Hand-search on conference abstracts, SCOPUS, and ISI Web of Science were also searched. METHODS OF STUDY SELECTION: Published English-language randomized controlled trials comparing resumption of ovarian function between GnRH analogs plus chemotherapy with chemotherapy without GnRH analogs were included. Studies including women with pelvic metastases or recent history of receiving chemotherapy were excluded. Accordingly, 10 eligible trials (907 women) were analyzed. TABULATION, INTEGRATION, AND RESULTS: Our primary outcome was the proportion of women with resumed ovarian function (defined as resumption of menstruation, prevention of chemotherapy-induced ovarian failure, or both) at the longest follow-up after the end of chemotherapy. Secondary outcomes were evaluating ovarian reserve parameters and pregnancy. Risk ratio was used to integrate qualitative results and mean difference was used for quantitative data. Gonadotropin-releasing hormone analog cotreatment did not significantly increase ovarian function resumption (320/468 [68.4%] in GnRH analog arm and 263/439 [59.9%] in the chemotherapy alone arm; risk ratio 1.12, 95% confidence interval [CI] 0.99-1.27). No protective effect existed after subgroup analyses (type of malignancy [P=.31], age [P=.14], and GnRH analog type [P=.44]). Gonadotropin-releasing hormone analogs did not protect any of ovarian reserve parameters, whether follicle-stimulating hormone (mean difference -2.63, 95% CI -7.33 to 2.07), antral follicle count (mean difference 1.66, 95% CI -0.69 to 4.01), or anti-Müllerian hormone (mean difference 0.31, 95% CI -0.41 to 1.03). Spontaneous pregnancy was also comparable (risk ratio 1.63, 95% CI 0.94-2.82). CONCLUSION: Gonadotropin-releasing hormone analog administration during chemotherapy does not appear to protect the ovaries from gonadal toxicity. It is not a reliable method for fertility preservation.

Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial.

OBJECTIVE: To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy. METHODS: One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes. RESULTS: Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months. CONCLUSION: GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257. LEVEL OF EVIDENCE: I.

Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy.

OBJECTIVE: To identify if there are certain cutoff levels for P and or the P/E(2) ratio on the day of hCG that would be defined as detrimental for occurrence of pregnancy in women with normal ovarian reserve undergoing cleavage-stage embryo transfer (ET). Secondarily, to determine if these same cutoffs might have the same potential negative effect in women undergoing blastocyst ET. DESIGN: Prospective cohort study including two randomized cohorts. SETTING: Private and university fertility centers. PARTICIPANT(S): A total of 240 women undergoing long agonist protocol with at least four grade 1 day 3 embryos. INTERVENTION(S): Women were randomized in a 1:1 ratio to undergo day 3 or day 5 embryo transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) was the primary outcome. RESULT(S): Using receiver operator characteristics, cutoffs for P and P/E(2) ratio were 1.5 ng/mL and 0.55, respectively. Patients with P ≤ 1.5 ng/mL and P/E(2) ≤ 0.55 undergoing cleavage-stage ET had higher CPR. Using multiple regression, P/E(2) ratio was the only independent predictor for pregnancy. The P and P/E(2) cutoffs were not correlated with CPR in blastocyst transfers. CONCLUSION(S): Progesterone >1.5 ng/mL and P/E(2) >0.55 affect the CPR in women undergoing cleavage-stage, but not blastocyst ET. P/E(2) ratio is the only independent prognosticator for cycle outcome in women undergoing cleavage-stage ET.

Does luteal estradiol supplementation have a role in long agonist cycles?

OBJECTIVE: To test the hypothesis that the addition of 6 mg estradiol (E2) valerate either orally or vaginally to progesterone (P) for luteal support, can increase the probability of pregnancy in intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol. DESIGN: Prospective open-labeled randomized controlled trial. SETTING: Private and university fertility centers. PARTICIPANT(S): Women undergoing ICSI cycles, with controlled ovarian hyperstimulation using long agonist protocol. INTERVENTION(S): On embryo transfer day, participants were randomized to receive, only P (group A, n = 90), P along with 6 mg E(2) valerate either orally (group B, n = 90), or vaginally (group C, n = 90) for luteal support. MAIN OUTCOME MEASURE(S): Clinical pregnancy was the main outcome. luteal serum E(2) and P profiles were the secondary outcomes. RESULT(S): Highest pregnancy rate was achieved in group C (45.56%), it was significantly higher than A (relative risk 1.52, 95% CI: 1.03 to 2.24). Day 0 (hCG day) E2 levels were similar in the three groups. Group A had lower E2 levels on days 7, 10, and 13 and a higher magnitude of E2 decline on days 7 and 10. Similar levels of luteal E2 were documented in groups B and C. P levels were similar in the three groups. CONCLUSIONS(S): Addition of 6 mg E(2) valerate to P support may encumber the sharp decline in luteal E(2) level. It may enhance the probability of pregnancy if administered vaginally.

Anti-Müllerian hormone: correlation of early follicular, ovulatory and midluteal levels with ovarian response and cycle outcome in intracytoplasmic sperm injection patients.

OBJECTIVE: To measure serum anti-Müllerian hormone (AMH) during different phases of the menstrual cycle and to correlate the measurements with ovarian response and clinical-pregnancy rates in intracytoplasmic sperm injection cycles. DESIGN: Prospective cohort study. SETTING: University IVF unit. PATIENT(S): Thirty-three patients undergoing their first intracytoplasmic sperm injection treatment cycle with a long protocol. INTERVENTION(S): On day 3 of the menstrual cycle, measurements of AMH, FSH, and LH and ultrasound evaluation of mean ovarian volume and antral follicle count were performed. Anti-Müllerian hormone was remeasured at ovulation and 7-8 days later (midluteal). MAIN OUTCOME MEASURE(S): Poor response and number of oocytes were primary outcomes. Clinical pregnancy was a secondary outcome. RESULT(S): Levels of AMH were lower in poor ovarian responders than in normal responders. Number of oocytes retrieved was statistically significantly correlated with midluteal AMH, day 3 AMH, antral follicle count, ovulatory AMH, mean ovarian volume (r = 0.89, 0.88, 0.88, 0.86, 0.66, respectively) and with day 3 FSH (r = -0.41). Midluteal, day 3, and ovulatory AMH showed a good discriminatory potential for prediction of poor response (area under the receiver operating characteristics curves, 0.977, 0.9, and 0.89, respectively). Midluteal and early AMH were statistically significant predictors of clinical pregnancy. CONCLUSION(S): A strong association exists between midluteal, early follicular, ovulatory AMH levels and number of oocytes retrieved. Midluteal and early follicular AMH may offer good prognostic value for clinical pregnancy.