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BackgroundWomen of reproductive age are recommended to consume folic acid and other supplements before conception and during pregnancy. We aimed to investigate the association of the serum folate and total magnesium (Mg) and calcium (Ca) levels before ovarian stimulation with the outcomes of assisted reproductive technology (ART) in normogonadotropic women.MethodsWe used a subanalysis of data obtained from a multicentre, randomized prospective study (NCT03088137). A total of 110 normogonadotropic, non-advanced aged, non-obese women with tubal and/or male infertility factors were enrolled for the single fresh ovarian stimulation GnRH antagonist cycle. The main outcome measures were the total oocyte yield, mature oocytes, fertilization rate, biochemical, clinical pregnancy, and live birth. Multivariable generalized linear models adjusted for covariates were used with a Poisson distribution and the log link function for adjusted oocyte counts, and a binomial distribution and the log link function were used for adjusted clinical ART outcomes.ResultsThe medians (interquartile range (IQR)) were as follows: baseline serum folate, 20.55 ng/ml (10.8, 32.9); Mg, 19.4 mg/L (18.7, 20.7); Ca, 94 mg/L (91.2, 96.4); and Ca/Mg ratio, 4.78 (4.55, 5.02). Women with higher serum folate concentrations (Q4≥33.0 ng/ml) had significantly lower total numbers of oocytes retrieved (adjusted mean (95% CI) 9.2 (7.6-11.3) vs 12.9 (10.9-15.4, p-trend=0.006)) and lower odds ratios (ORs) (95% CI) of 0.12 (0.02, 0.79) for clinical pregnancy and 0.10 (0.01, 0.70) for live birth compared with women in the lowest quartile (<10.8 ng/ml), all p-trend<0.001. Women in the highest Ca/Mg ratio quartile (≥5.02) had ORs (95% CI) of 6.58 (1.31, 33.04) for biochemical pregnancy, 4.85 (1.02, 23.08) for clinical pregnancy and 4.07 (0.83, 19.9) for the live birth rate compared with women in the lowest quartile (<4.55), all p-trend<0.001.ConclusionsUsing multivariable models, we suggested that a baseline elevated serum folate level (≥33.0 ng/ml) and a lower Ca/Mg ratio were associated with worse ART outcomes in normogonadotropic women. Our findings might be useful for choosing safe dosages of folate, calcium, magnesium and complex supplementation for both fertile women and women undergoing infertility treatment. Further preconception large-scale studies with known micro- and macronutrient statuses of both parents and serum folate, Ca, Mg, and hormone levels, are needed.

Introduction. The efficacy and safety of biosimilar follitropin alpha have been demonstrated in randomized, blinded, prospective clinical trials of phases I and III. Unfortunately, there is a gap between the clinical trials and real clinical practice data. The real-world patient data helps to create an evidence-based background for successful implementation of a medicine at everyday practice in a nonselected population.Aim: to investigate the efficacy of follitropin alpha biosimilar therapy (Primapur®) in nonselected real-world population.Materials and Methods. A retrospective observational anonymized cohort study of follitropin alpha biosimilar as a pre-filled pen injector with a dose adjustment of 5 IU (Primapur®), aimed at investigate its efficacy and safety in a nonselected population with indications to assisted reproductive technologies (ART). The ovarian stimulation (OS) protocols included: monotherapy protocols with using only Primapur®; mixed protocols (recombinant and urinary-derived gonadotropins); short protocols with using antagonists gonadotropin-releasing hormone (GnRH) antagonist and long protocols with GnRH agonists. The stimulation protocols analyzed where Primapur® was applied for at least 5 days.Results. The overall clinical efficacy of ovarian stimulation cycles (N = 5484) was: oocytes retrieved – 9.5 ± 7.2, mature (MII) – 6.8 ± 6.6, fertilized (2PN) – 6.1 ± 5.8, clinical pregnancy per ET (PR) – 38.4 %. Mixed gonadotropin protocols (N = 2625) vs. monotherapy with Primapur® (N = 2859): oocytes retrieved – 8.6 ± 6.8 vs. 10.3 ± 7.4 (p < 0.001), mature (MII) – 6.7 ± 6.2 vs. 7.7 ± 6.9 (p < 0.001), fertilized (2PN) – 5.8 ± 5.2 vs. 7.2 ± 6.2 (p < 0.001). There were statistically significant differences between oocyte yields in mixed vs. monotherapy protocols due to subgroup differences, including age, body mass index (BMI) and IVF/ICSI attempts. No statistically significant differences were found for PR: 39.3 % vs. 37.6 % (p = 0.314). Monotherapy protocols with GnRH antagonist OS (N = 2183) vs. GnRH agonist (N = 676) revealed: oocytes retrieved – 10.5 ± 7.5 vs. 9.6 ± 7.0 (p = 0.032), mature (MII) – 7.6 ± 6.9 vs. 6.7 ± 5.7 (p < 0.001), fertilized (2PN) – 7.3 ± 6.3 vs. 5.7 ± 5.0 (p < 0.001). There were statistically significant differences between BMI and IVF/ICSI attempts. No statistically significant differences were found for PR: 37.9 % vs. 35.9 % (p = 0.482). All medicines were well tolerated and no serious adverse reactions were reported.Conclusion. This was the largest retrospective observational study conducted in the field of fertility in Russia and involved 5484 ovarian stimulation protocols at 35 IVF clinics. The obtained results demonstrated similar clinical efficacy for follitropin alpha biosimilar Primapur® in different OS protocols in real clinical practice.

A clinical study on the efficacy and safety of follitropin alfa has been conducted. The aim of the study was to confirm the therapeutic equivalence between the follitropin alfa biosimilar (Primapur®) and the reference medication (Gonal-f®) in controlled induction of superovulation within the assisted reproductive technologies (ART) programs. Materials and methods. This multicenter, randomized, blind at the embryological stage, in parallel groups, comparative study of phase III (RCT 754 from 26.10.16/NCT03088137) involved 110 women aged 20-35 years with established causes of infertility (tubal factor, male factor). The patients were randomized into 2 equal groups of 55 participants each. The primary end-point for assessing the therapeutic equivalence was the number of aspirated oocytes. The secondary end-points included the number of fertilized oocytes, the number of days of stimulation, the total dose of the injected drug, the occurrence rate of biochemical and clinical pregnancies. Results. In this study, the follitropin alfa biosimilar was shown to be equivalent to the original follitropin in terms of the number of aspirated oocytes. Also, no statistically significant differences were found in the number of mature and fertilized oocytes, the days of stimulation, the dose of the drug administered during the treatment, and the rate of the onset of biochemical or clinical pregnancy. Conclusion. The therapeutic equivalence between the follitropin alfa containing Primapur® and Gonal-f® has been demonstrated.

Of significant scientific and practical interest is the relationship between the blood plasma levels of folic acid at preconception and the outcome of pregnancy. A phase III clinical trial on the efficacy and safety of the biosimilar follitropin alfa has recently been completed within the ongoing assisted reproductive technology (ART) programs. The results confirmed the therapeutic equivalence of the investigational agent to the reference drug. In this trial, women with tubal infertility or male factor infertility were included. The study did not include women with endometriosis and polycystic ovary syndrome. A total of 118 patients were recruited; of those, 110 were randomized; then the 110 women underwent hormonal stimulation and 98 of them underwent embryo transfer. Blood samples were taken within a period not exceeding 28 days before the start of the stimulation; the samples were analyzed for folic acid (FA), trace elements and hormones. The results were grouped by quartiles (Q) according to the levels of FA in the blood serum: Q1 – 2.9–10.7 ng/ml, Q2 – 10.8–20.5 ng/ml, Q3 – 20.6–32.9 ng/ml, and Q4 ≥ 33.0 ng/ml. In addition, group distribution was also made according to the WHO recommendations: possible FA deficiency – 3.0–5.9 ng/ml, normal – 6.0–20.0 ng/ml, and elevated levels – more than 20 ng/ml. A significant decrease in the number of fertilized oocytes, clinical pregnancies and live births in Q4 (increased FA) compared with Q1 was found. Also, in women with high levels of FA, the number of aspirated oocytes was significantly lower than that in women with normal or decreased FA levels. We also found a significant inverse relationship between the number of aspirated oocytes and the levels of estradiol and serum FA. Plasma FA levels > 20 ng/ml detected prior to the IVF procedure may be associated with a low number of aspirated oocytes, and FA levels > 33 ng/ml – with a reduced number of fertilized oocytes, clinical pregnancies and live births. Thus, the excessive content of FA in the body can contribute to a worse outcome of IVF programs.