Effectiveness of recombinant human FSH: recombinant human LH combination treatment versus recombinant human FSH alone for assisted reproductive technology in women aged 35-40 years.

RESEARCH QUESTION: According to real-world data, is recombinant human FSH (r-hFSH) combined with recombinant human LH (r-hLH) or r-hFSH alone more effective for women of advanced maternal age (AMA) in terms of live birth? DESIGN: Non-interventional study comparing the effectiveness of r-hFSH and recombinant r-hLH (2:1 ratio) versus r-hFSH alone for ovarian stimulation during ART treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register. RESULTS: Overall clinical pregnancy (29.8%, 95% CI 28.2 to 31.6 versus 27.8%, 95% CI 26.5 to 29.2) and live birth (20.3%, 95% CI 18.7 to 21.8 versus 18.0%, 95% CI 16.6 to 19.4) rates were not significantly different between the combined r-hFSH and r-hLH group and the r-hFSH alone group (P = 0.269 and P = 0.092, respectively). Treatment effect was significantly higher for combined r-hFSH and r-hLH compared with r-hFSH alone for clinical pregnancy (33.1%, 95% CI 31.0 to 35.0 versus 28.5%, 95% CI 26.6 to 30.4; P = 0.001, not adjusted for multiplicity) and live birth (22.5%, 95% CI 20.5 to 24.2 versus 19.4%, 95% CI 17.6 to 20.9; P = 0.014, not adjusted for multiplicity) in a post-hoc analysis of women with five to 14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of combined r-hFSH and r-hLH for ovarian stimulation in women aged 35-40 years with normal ovarian reserve. CONCLUSIONS: Women of AMA with normal ovarian response benefit from treatment with combined r-hFSH and r-hLH in a 2:1 ratio versus r-hFSH alone in terms of live birth rate. The effectiveness of treatments is best assessed by RCTs; however, real-world data are valuable for examining the effectiveness of fertility treatment, especially among patient groups that are not well represented in clinical trials.

Originator recombinant human follitropin alfa versus recombinant human follitropin alfa biosimilars in Spain: A cost-effectiveness analysis of assisted reproductive technology related to fresh embryo transfers.

This study compared the cost per live birth and cost-effectiveness of the originator recombinant human follicle-stimulating hormone follitropin alfa (r-hFSH-alfa) and r-hFSH-alfa biosimilars for ovarian stimulation prior to assisted reproductive technology treatment in Spain. A decision tree model was developed, comprising pregnancy and live birth for one treatment cycle with fresh embryo transfer. Clinical inputs were based on a recent meta-analysis by Chua et al. [4]. Cost inputs were extracted from publicly available Spanish sources. The costs per live birth were lower with originator r-hFSH-alfa (€18,138) versus r-hFSH-alfa biosimilars (€20,377). The incremental cost-effectiveness ratio was €7208 for originator r-hFSH-alfa versus biosimilars. Drug acquisition costs for originator r-hFSH-alfa represented 10.5% of total costs in the base case analysis, and 6.2% in a treatment cycle resulting in live birth with one fresh embryo transfer. Results from the sensitivity analyses confirmed the robustness of the findings.

Cost-effectiveness analysis of recombinant human follicle-stimulating hormone alfa(r-hFSH) and urinary highly purified menopausal gonadotropin (hMG) based on data from a large German registry.

This was a retrospective real-world evidence analysis of the costs per live birth for reference recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG-HP), based on data from a German in vitro fertilization registry (RecDate). Pregnancy and live birth rates from the RecDate real-world evidence study over three complete assisted reproductive technology (ART) cycles using the same gonadotropin drug were used as clinical inputs. Costs related to ART treatment and to drugs were obtained from public sources. Treatment with r-hFSH-alfa resulted in higher adjusted cumulative live birth rates versus hMG-HP after one (25.3% vs. 22.3%), two (30.9% vs. 27.5%), and three (31.9% vs. 28.6%) ART cycles. Costs per live birth were lower with r-hFSH-alfa versus hMG-HP after one (€17,938 vs. €20,054), two (€18,251 vs. €20,437), and three (€18,473 vs. €20,680) ART cycles. r-hFSH-alfa was found to be a cost-effective strategy compared with hMG-HP over three cycles.

Atosiban improves the outcome of embryo transfer. A systematic review and meta-analysis of randomized and non-randomized trials.

OBJECTIVE: To estimate the effectiveness of Atosiban in improving the outcome after embryo transfer. The effectiveness of embryo transfer per cycle is still relatively low. One possible explanation might be uterine contractility that expels the transferred embryos. Atosiban improved the outcome of embryo transfer by reducing uterine contractility. METHODS: Data sources: A systematic review of papers in English using MEDLINE and EMBASE (1990-2019). Search terms included Atosiban, embryo transfer. Study selection: We included studies that compared the outcomes of embryo transfer with Atosiban and a control group. Data Extracting: Independent extraction of papers by two authors, using predefined data fields, including study quality indicators. RESULTS: All pooled analyses were based on a fixed-effect model. Four randomised controlled trials, including 1,025 women, and two non-randomised trials, including 686 patients, met our inclusion criteria. In both studies, the heterogeneity was moderate. Atosiban increased clinical pregnancy rates regardless of the indication for ART or type of embryo transferred. Pooled OR in randomized controlled trials reached 1.47 (1.18-1.82), and in non-randomised controlled trials it reached 1.50 (95% CI 1.10-2.05). CONCLUSION: Atosiban appears to increase the clinical pregnancy rates in women undergoing embryo transfer.

Assisted reproductive techniques in Latin America: The Latin American registry, 2016.

RESEARCH QUESTION: What was the utilization, effectiveness and perinatal outcome of assisted reproductive technologies (ART) performed in Latin America during 2016. DESIGN: Retrospective collection of multinational data on ART performed in 178 institutions from 15 Latin American countries. RESULTS: We are reporting 85,474 initiated cycles, 15,070 deliveries and 18,182 babies born in this period. Of all fresh autologous IVF/ICSI cycles, 40.9% were performed in women aged 35-39 years, and 31.1% in women aged ≥40 years. After removing freeze-all cycles, delivery rate per oocyte retrieval was 20.31% for ICSI and 21.85% for IVF. Fresh single embryo transfer including all age categories represented 22.96%, with a 15.35% delivery rate per transfer. Double embryo transfer represented 61.58% of transfers, with a 27.62% delivery rate per transfer. Multiple births included 18.12% twins and 0.55% triplets and higher. In oocyte donation, delivery rate per transfer was 32.89%, with a twin and triplet rate of 23.48% and 0.73%, respectively. Overall, preterm deliveries reached 17.11% in singletons, 65.69% in twins and 95.51% in triplets. Perinatal mortality was 8.0 ‰ in singletons, 19.0 ‰ in twins, and 62.3 ‰ in high-order multiples. CONCLUSIONS: The number of initiated cycles continues to increase. Compared with previous years, the number of embryos transferred decreased while the proportion of single embryo transfers increased with a drop in multiple births. It is mandatory to stimulate health care providers and consumers to continue in this trend.

Assisted reproductive techniques in Latin America: the Latin American Registry 2016.

RESEARCH QUESTION: What was the utilization, effectiveness and perinatal outcome of assisted reproductive technologies (ART) performed in Latin America during 2016? DESIGN: Retrospective collection of multinational data on ART performed in 178 institutions from 15 Latin American countries. RESULTS: This paper reports on 85,474 initiated cycles, 15,070 deliveries and 18,182 babies born in this period. Of all fresh autologous IVF/intracytoplasmic sperm injection (ICSI) cycles, 40.9% were performed in women aged 35-39 years, and 31.1% in women aged ≥40 years. After removing freeze-all cycles, delivery rate per oocyte retrieval was 20.31% for ICSI and 21.85% for IVF. Fresh single embryo transfer including all age categories represented 22.96%, with a 15.35% delivery rate per transfer. Double embryo transfer represented 61.58% of transfers, with a 27.62% delivery rate per transfer. Multiple births included 18.12% twins and 0.55% triplets and higher. In oocyte donation, delivery rate per transfer was 32.89%, with a twin and triplet rate of 23.48% and 0.73%, respectively. Overall, preterm deliveries reached 17.11% in singletons, 65.69% in twins and 95.51% in triplets. Perinatal mortality was 8.0‰ in singletons, 19.0‰ in twins, and 62.3‰ in high-order multiples. CONCLUSIONS: The number of initiated cycles continues to increase. Compared with previous years, the number of embryos transferred decreased while the proportion of single embryo transfers increased with a drop in multiple births. It is vital to motivate health care providers and consumers to continue this trend.

Assisted Reproductive Techniques in Latin America: The Latin American Registry, 2015.

RESEARCH QUESTION: What was the utilization, effectiveness and safety of assisted reproductive technologies (ART) performed in Latin American countries during 2015, and what were the regional trends? DESIGN: Retrospective collection of multinational data on assisted reproduction techniques (IVF and intracytoplasmic sperm injection [ICSI], frozen embryo transfer, oocyte donation, preimplantation genetic testing and fertility preservation), from 175 institutions in 15 Latin American countries. RESULTS: In total, 41.25% of IVF/ICSI cycles were performed in women aged 35-39 years, and 28.35% in women aged ≥40 years. After removing freeze-all cycles, delivery rate per oocyte retrieval was 21.39% for ICSI and 24.29% for IVF. Multiple births included 19.58% twins and 0.95% triplets and higher. In oocyte donation, delivery rate per transfer was 36.77%, with a twin and triplet rate of 27.65% and 1.06%, respectively. Overall, preterm deliveries reached 17.38% in singletons, 64.94% in twins and 98.41% in triplets. Perinatal mortality in 14,936 births and 18,391 babies born was 10.5 per 1000 in singletons, 17.9 per 1000 in twins, and 57.1 per 1000 in high-order multiples. Elective single embryo transfer represented 3.11% of fresh transfers, with a 31.78% delivery rate per transfer. Elective double embryo transfer represented 23.3% of transfers, with a 37.79% delivery rate per transfer. Out of 18,391 babies born, 63.22% were singletons, 34.4% twins, and 2.38% triplets and higher. CONCLUSIONS: Given the effect of multiple births on prematurity, morbidity and perinatal mortality, reinforcing the existing trend of reducing the number of embryos transferred remains mandatory.

Assisted reproductive techniques in Latin America: the Latin American Registry, 2015.

RESEARCH QUESTION: What was the utilization, effectiveness and safety of assisted reproductive technologies (ART) performed in Latin American countries during 2015, and what were the regional trends? DESIGN: Retrospective collection of multinational data on assisted reproduction techniques (IVF and intracytoplasmic sperm injection [ICSI], frozen embryo transfer, oocyte donation, preimplantation genetic testing and fertility preservation), from 175 institutions in 15 Latin American countries. RESULTS: In total, 41.25% of IVF/ICSI cycles were performed in women aged 35-39 years, and 28.35% in women aged ≥40 years. After removing freeze-all cycles, delivery rate per oocyte retrieval was 21.39% for ICSI and 24.29% for IVF. Multiple births included 19.58% twins and 0.95% triplets and higher. In oocyte donation, delivery rate per transfer was 36.77%, with a twin and triplet rate of 27.65% and 1.06%, respectively. Overall, preterm deliveries reached 17.38% in singletons, 64.94% in twins and 98.41% in triplets. Perinatal mortality in 14,936 births and 18,391 babies born was 10.5 per 1000 in singletons, 17.9 per 1000 in twins, and 57.1 per 1000 in high-order multiples. Elective single embryo transfer represented 3.11% of fresh transfers, with a 31.78% delivery rate per transfer. Elective double embryo transfer represented 23.3% of transfers, with a 37.79% delivery rate per transfer. Out of 18,391 babies born, 63.22% were singletons, 34.4% twins, and 2.38% triplets and higher. CONCLUSIONS: Given the effect of multiple births on prematurity, morbidity and perinatal mortality, reinforcing the existing trend of reducing the number of embryos transferred remains mandatory.

DHEA use to improve likelihood of IVF/ICSI success in patients with diminished ovarian reserve: A systematic review and meta-analysis.

The aim of this review is to determine if the use of DHEA increases the likelihood of success in patients with POR. We searched MEDLINE and EMBASE using the terms "DHEA and diminished ovarian reserve", "DHEA and poor response", "DHEA and premature ovarian aging". A fixed effects model was used and Peto's method to get the odds ratio (OR) with 95% confidence intervals (CI 95%). For quantitative variables, Cohen's method was used to present the standardized mean differences (SMD) with their corresponding confidence intervals. Only five studied fulfilled the selection criteria. DHEA was administered in 25 mg doses, three times a day. In all studies, the authors corrected for the presence of confounding variables such as partner's age, infertility diagnosis and number of transferred embryos. The meta-analysis of the five selected studies assessed a total of 910 patients, who underwent IVF/ICSI, of which 413 had received DHEA. DHEA use was associated with a significant increase in pregnancy likelihood (OR 1.8, CI 95% 1.29 to 2.51, p=0.001). When analyzing the association between DHEA use and the likelihood of abortion, we found low heterogeneity between studies (I2=0.0%) and the use of DHEA to be associated to a significant reduction in the likelihood of abortion (OR 0.25, CI 0.07 to 0.95; p=0.045). Analysis of the association of DHEA with average oocyte retrieval showed high variability between studies (I2=98.6%), as well as no association between DHEA use and the number of oocytes retrieved (SMD -0.01, CI 95% -0.16 to 0.13; p<0.05).

Does acupuncture the day of embryo transfer affect the clinical pregnancy rate? Systematic review and meta-analysis.

The effects of acupuncture on IVF outcomes is still unknown. We carried out a systematic review and meta-analysis of RCT to determine whether acupuncture performed at the time of ET improves outcomes. We searched Medline and Embase from January 1990 to June 2017, for the following terms): (acupuncture; acupuncture therapy) and (reproductive techniques, assisted; in vitro fertilization; embryo transfer). We selected RCT that compared acupuncture with sham acupuncture or no treatment. We included only trials in which acupuncture involved the insertion of needles into traditional meridian points. We evaluated the methodological quality of the trials using the Cochrane risk of bias tool. The measure of treatment effect was the pooled odds ratio of achieving a clinical pregnancy, ongoing pregnancy, or live birth for women in the acupuncture group compared with women in the control group. For pooled data, summary test statistics were calculated using the Mantel-Haenszel method, using the Rev-Man software, version 5.1. We analyzed six studies, including 2,376. In all trials, there were no significant differences between the groups concerning the mean numbers of embryos transferred, the mean age of the women undergoing the procedure, diagnose and use of ICSI. Acupuncture performed the day of ET was associated with a reduced risk of clinical pregnancy (0.87, 95% confidence interval 0.77 to 0.98). The pooled rate difference was -0.06 (-0.12 to -0.01) for clinical pregnancy. None of the trials reported significant adverse effects of acupuncture.

Is the risk of preeclampsia higher in donor oocyte pregnancies? A systematic review and meta-analysis.

OBJECTIVE: Preeclampsia (PE) occurs in 4.6% of pregnancies worldwide. The social phenomenon of increasing maternal age has raised the demand for donor oocytes. Egg donation has allowed women with poor ovarian reserve, premature ovarian failure, genetic disorders or surgical menopause to get pregnant. Recipients provide a unique model of immune response because of the differences in the genetic makeup of mothers and fetuses. In PE, immune tolerance may be impaired as a result of having non-autologous eggs implanted. Egg donation is a highly successful assisted reproductive technology, despite the significant number of issues arising from the implantation of non-autologous eggs. This study aimed to determine whether there is an association between egg donation and preeclampsia. METHODS: A systematic review of the literature available in PubMed and Google Scholar was carried out from January of 1995 to August of 2016 using the terms 'oocyte donation, preeclampsia', 'oocyte donation, in vitro fertilization, preeclampsia', 'oocyte donation, preeclampsia, outcomes pregnancies', 'oocyte donation, obstetric outcome.' Only six retrospective cohort studies met the selection criteria. RESULTS: The meta-analysis revealed a statistically significant association between egg donation and onset of preeclampsia (OR 4.50; 95% CI: 3.28-6.19; p<0.0001). CONCLUSION: Oocyte donation is associated with increased risk of preeclampsia in singleton pregnancies. Therefore, it is crucial to properly record and assess this finding when egg donation is the chosen assisted reproductive technology to attain pregnancy.

There is no association between the presence of anti-thyroid antibodies and increased reproductive loss in pregnant women after ART: a systematic review and meta-analysis.

Women submitted to ART treatments represent a select subgroup of individuals. Several studies have described the relationship between TAI and pregnancy outcomes as a result of ART, with contradictory results. The purpose of this systematic review was to determine the association between TAI and the risk of miscarriage in pregnancies resulting from ART. MEDLINE via PubMed, LILACS and Embase were searched for studies published in peer-reviewed journals from 1999 to 2017. The studies were summarized using the fixed effects model and the Peto's method to calculate RR in order to flesh out the association between TAI and spontaneous abortion. Only four papers were included in this systematic review and meta-analysis. Thirty-one miscarriages were observed in 210 clinical pregnancies of women with antithyroid antibodies; and 158 miscarriages were seen in 1,371 pregnancies without antithyroid antibodies. The meta-analysis failed to find an association between TAI and higher risk of reproductive loss, RR=0.94 95% confidence interval: 0.71-1.24; p=0.879. In conclusion, the presence of antithyroid antibodies was not associated with increased reproductive loss in patients submitted to ART treatments. It is our opinion that the presence of antithyroid antibodies should be considered as a secondary biomarker of autoimmune disease, rather than an actual cause of miscarriage in patients undergoing ART. Due to the small amount of evidence on the matter, the determination of TAI before the initiation of ART should be limited to research contexts.

Assisted reproductive techniques in Latin America: The Latin American Registry, 2014.

Multinational data on assisted reproduction techniques undertaken in 2014 were collected from 159 institutions in 15 countries in Latin America. Treatments included IVF/ ICSI, FET, OD, PGD and fertility preservation (FP). 41.34% of IVF/ICSI cycles were performed in women aged 35 to 39 years and 23.35% in women aged 40 and older. After removing cases with total freezing, delivery rate per oocyte retrieval was 25.05% for ICSI and 27.41% for IVF. Multiple births included 20.78% twins and 0.92 % triplets and over. In OD, twins reached 28.93% and triplets 1.07 %. Preterm deliveries reached 16.4% in singletons, 55.02% in twins and 76% in triplets. Perinatal mortality in 18,162 births was 23 per 1000 in singletons, 35 per 1000 in twins, and 36 per 1000 in high-order multiples. Elective single embryo transfer (eSET) represented only 2.63 % of fresh transfers, with a delivery rate of 32.15% per transfer. Elective double embryo transfer (eDET) represented 23.74% of transfers, with a delivery rate of 41.03% per transfer. Among babies born during this period 11,373 (62.6%) were singletons; 6,398 (35.2%) twins, and 391 (2.2%), triplets and more. Given the effect of multiple births on prematurity, morbidity and perinatal mortality, reinforcing the existing trend of reducing the number of embryos transferred is mandatory.

Are children born from singleton pregnancies conceived by ICSI at increased risk for congenital malformations when compared to children conceived naturally? A systematic review and meta-analysis.

Since 1992, the development of intra-cytoplasmic sperm injection (ICSI) has allowed infertile couples and couples affected by severe male factor infertility in particular, many of which with a history of failed traditional IVF, to become parents. This has generated considerable controversy over the safety of the procedure for the offspring. This systematic review seeks to determine whether evidence indicates that the use of ICSI increases the risk of congenital malformation in children born from singleton pregnancies versus naturally conceived children. Twenty-one of the 104 publications listed in the literature search were included in the analysis. Observational studies reported mostly an increased risk for congenital malformation; the risk of congenital malformations is 7.1% in ICSI and 4.0% in the general population (OR 1.99 (95% CI [1.87 - 2.11]). However, attributing higher risk solely to ICSI might seem far-fetched, as in vitro and simulation procedures, patient diseases, and ICSI indication may also be associated with higher risk of malformation.

Assisted reproduction techniques in Latin America: the Latin American Registry, 2014.

Multinational data on assisted reproduction techniques (IVF and intractytoplasmic sperm injection [ICSI], frozen embryo transfer, oocyte donation, preimplantation genetic diagnosis and fertility preservation) were collected from 159 institutions in 15 Latin American countries. A total of 41.34% of IVF-ICSI cycles were conducted in women aged 35-39 years and 23.35% in women aged 40 years and older. After removing freeze-all cases, delivery rate per oocyte retrieval was 25.05% for ICSI and 27.41% for IVF. Multiple births included 20.78% twins and 0.92% triplets and over. In oocyte donation, twins reached 28.93% and triplets 1.07%. Preterm deliveries reached 16.4% in singletons, 55.02% in twins and 76% in triplets. Perinatal mortality in 18,162 births was 23 per 1000 in singletons, 35 per 1000 in twins, and 36 per 1000 in high-order multiples. Elective single embryo transfer represented 2.63% of fresh transfers, with a 32.15% delivery rate per transfer. Elective double embryo transfer represented 23.74% of transfers, with a 41.03% delivery rate per transfer; 11,373 babies (62.6%) were singletons; 6398 (35.2%) twins, and 391 (2.2%), triplets and more. Given the effect of multiple births on prematurity, morbidity and perinatal mortality, reinforcing the existing trend of reducing the number of embryos transferred is mandatory.

Outcome of assisted reproductive technology in overweight and obese women.

OBJECTIVE: The main objective of this study was to assess the prevalence of overweight and obesity among patients undergoing assisted reproductive technology (ART) in Latin America and its consequences on treatment outcomes. METHODS: We used the Latin American Registry of ART to obtain women's age and body mass index (BMI), cancellation rate, number of oocytes retrieved and embryos transferred, clinical pregnancy, live birth and miscarriage rates from 107.313 patients undergoing autologous IVF and ICSI during four years; a multivariable analysis was performed to determine the effect of BMI on cancellation, oocytes retrieved, pregnancy, live birth and miscarriage, adjusting for age, number of embryos transferred and embryo developmental stage upon embryo transfer, when appropriate. RESULTS: The prevalence of overweight and obesity was 16.1% and 42.4%, respectively; correcting for age of female partner, overweight and obesity were associated to an increase in the odds of cancellation and to a lower mean number of oocytes retrieved; after adjusting for age, number of embryos transferred and stage of embryo development at transfer, we found that the BMI category was not associated to a change in the likelihoods of pregnancy, live birth and miscarriage. CONCLUSIONS: The prevalence of obesity among women seeking ART in Latin America is surprisingly high; however, BMI does not influence the outcome of ART performed in these women.

Do women offered assisted reproduction technologies have a higher incidence of gynecologic cancer? A systematic review and meta-analysis.

The last two decades have seen an increase in the number of women diagnosed with infertility. The consequent growth in the use of assisted reproductive technologies (ART) calls for the determination of its long-term effects, including the risk of cancer. Many studies have attempted to answer this question, albeit with contradictory results. This review aimed to assess whether assisted reproductive technologies are associated with an increased risk of gynecological cancer. A search for papers in the literature was carried out on MEDLINE, TRIP DATABASE and NICE, resulting in 11 studies enrolling 3,900,231 patients altogether. Of these, 118,320 were offered ART. The incidence of gynecological cancer in the group offered ART was 0.6%, while the incidence in the group not offered ART was 2.1%. Taking all the studies into consideration, women offered ART were not at greater risk of having gynecological cancer; instead, a protective association was found.