Fetal mitochondrial DNA in maternal plasma in surrogate pregnancies: Detection and topology.

OBJECTIVES: Due to the maternally-inherited nature of mitochondrial DNA (mtDNA), there is a lack of information regarding fetal mtDNA in the plasma of pregnant women. We aim to explore the presence and topologic forms of circulating fetal and maternal mtDNA molecules in surrogate pregnancies. METHODS: Genotypic differences between fetal and surrogate maternal mtDNA were used to identify the fetal and maternal mtDNA molecules in plasma. Plasma samples were obtained from the surrogate pregnant mothers. Using cleavage-end signatures of BfaI restriction enzyme, linear and circular mtDNA molecules in maternal plasma could be differentiated. RESULTS: Fetal-derived mtDNA molecules were mainly linear (median: 88%; range: 80%-96%), whereas approximately half of the maternal-derived mtDNA molecules were circular (median: 51%; range: 42%-60%). The fetal DNA fraction of linear mtDNA was lower (median absolute difference: 9.8%; range: 1.1%-27%) than that of nuclear DNA (median: 20%; range: 9.7%-35%). The fetal-derived linear mtDNA molecules were shorter than the maternal-derived ones. CONCLUSION: Fetal mtDNA is present in maternal plasma, and consists mainly of linear molecules. Surrogate pregnancies represent a valuable clinical scenario for exploring the biology and potential clinical applications of circulating mtDNA, for example, for pregnancies conceived following mitochondrial replacement therapy.

Mechanical zona pellucida removal of vitrified-warmed human blastocysts does not affect the clinical outcome.

RESEARCH QUESTION: Does complete mechanical removal of the zona pellucida modify the outcome of transfer of vitrified-warmed human blastocysts? DESIGN: In a prospective randomized controlled study, 419 couples were allocated to either zona pellucida-free (n = 209) or zona intact (n = 210) vitrified-warmed embryo transfer. Main outcome measures included clinical pregnancy, implantation and ongoing pregnancy rates. RESULTS: Transfer of zona pellucida-free blastocysts resulted in clinical pregnancy, implantation and ongoing pregnancy rates (35,9%, 33,9% and 32,1%, respectively), similar to those achieved with zona intact control embryos (39%, 36,4% and 33,1%, respectively). CONCLUSION: Total mechanical removal of the zona pellucida did not affect the tested parameters of clinical outcomes.

A multicenter, randomized, phase III study comparing the efficacy and safety of follitropin alpha biosimilar and the original follitropin alpha.

OBJECTIVE: The aim of the present study was to investigate the therapeutic equivalence between the follitropin alpha biosimilar and the reference medication in women undergoing assisted reproductive technologies (ART). STUDY DESIGN: This multicenter, randomized (1:1), embryologist-blinded, parallel-group, comparative phase III study involved 110 women aged 20-35 years old with tubal and/or male factors of infertility. All of the subjects underwent controlled ovarian hyperstimulation (COH) using a gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. Over the 5-day fixed-dose regimen, the women received 150 IU/day of follitropin alpha biosimilar (n = 55) or original follitropin alpha (n = 55), followed by dose adaptation. The primary endpoint for assessing the therapeutic equivalence was the number of retrieved oocytes using a pre-determined clinical equivalence margin of ± 3.4 oocytes. RESULTS: Similar numbers of oocytes were retrieved in both groups: 12.16 ± 7.28 in the follitropin alpha biosimilar group and 11.62 ± 6.29 in the original follitropin alpha group, with mean difference of 0.546 ± 1.297 oocytes (95% confidence interval [CI]: -2.026, 3.116), p = 0.002 (intention-to-treat [ITT] population). Additionally, no statistically significant differences were found for secondary endpoints: the onset of biochemical (34.7% and 36.7%, p = 0.883), clinical pregnancy (26.5% and 32.7%, p = 0.507), delivery (26.5% and 24.5%, p = 0.817) and take-home baby rate (28.6% and 26.5%, p = 0.816) for the follitropin biosimilar and original follitropin groups (per-protocol [PP] population). Ovarian hyperstimulation syndrome was observed in subjects with a positive pregnancy test in 0% and 3.64% of cases and after triggering ovulation in 7.27% and 3.64% for the follitropin biosimilar and original follitropin groups, respectively. CONCLUSIONS: This study demonstrated similar therapeutic equivalence and safety profiles between the follitropin alpha biosimilar and the reference follitropin in women who underwent COH in GnRH-ant cycles. TRIAL REGISTRATION NUMBER: 1. Name of the registry: ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT03088137. Date of registration: 02.03.2017, retrospectively registered. Trial conducted between 08.02.2017 and 17.08.2018, the date of enrollment of the first participant - 08.02.2017. 2. Name of the registry: Russian Ministry of Health, grls.rosminzdrav.ru. TRIAL REGISTRATION NUMBER: RCT 754. Date of registration: 26.10.2016, prospectively registered.