Anxiety and depression among pregnant women undergoing IVF-ET and WeChat group peer support during the COVID-19 pandemic: Study protocol for a randomized controlled trial.

INTRODUCTION: The psychological well-being of pregnant women following assisted reproductive has increasingly gained attention in recent years. Anxiety and depression may be associated to pregnancy outcomes. This study aims to determine whether peer support and the WeChat group platform will reduce anxiety and depression among in vitro fertilization and embryo transfer (IVF-ET) women. METHODS AND ANALYSIS: In the present randomized controlled study, 296 patients with confirmed clinical pregnancy following IVF-ET will be randomly assigned to receive standard intervention support or WeChat peer support on a 1:1 basis. The levels of anxiety and depression are the primary endpoints. Assessments will be performed at baseline measurements, first trimester, second trimester, and third trimester, and data will be collected. ETHICS AND DISSEMINATION: This study has been approved as ethical by the affiliated hospital of Shandong University of Traditional Chinese Medicine's Reproductive Ethics Committee. Each patient will sign a written statement of informed permission. All information and biological samples will be legally protected. A peer-reviewed academic journal will publish the findings of this investigation. DISCUSSION: Given the inconvenience of visits due to the current pandemic of COVID-19, this study addresses the patient's visit needs by combining WeChat, the most widely used social software in China, with peer support, while helping improve maternal anxiety, depression, and pregnancy outcomes following IVF-ET.

Antibodies to SARS-CoV-2 in follicular fluids and their association with assisted reproduction.

Introduction: Every second woman suffering from infertility asks for medical help. There is public concern that vaccination-induced antibodies (Ab) are negatively associated with fertility. A recent study has demonstrated an association between SARS-CoV-2 vaccination and a lower pregnancy rate in the subsequent 60 days. Consequently, Ab could affect fertility success in assisted reproduction. Methods: To address this question, we compared fertilization outcomes of vaccinated (n=35) and nonvaccinated (n=34) women. Paired serum samples and multiple follicular fluids (FF) (up to 10 from the same donor) were collected during the course of assisted reproduction and characterized for oocyte quality, the presence of Ab and trace element concentrations. Results: The results showed a positive correlation of vaccination-induced neutralizing activity of SARS-CoV-2-Ab in serum and FF. On average, Ab concentrations in serum were higher than in the corresponding FF. However, wide variations in SARS-CoV-2 Ab titers were observed between different FF, correlating to trace element levels, even when retrieved from the same donor. Discussion: Overall, FF contents are highly variable, but no negative association was observed between Ab in serum or FF and fertilization success and oocyte development, supporting the safety of SARS-CoV-2 vaccination during assisted reproduction.

The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF.

STUDY QUESTION: Is the total number of oocytes retrieved with dual ovarian stimulation in the same cycle (duostim) higher than with two consecutive antagonist cycles in poor responders? SUMMARY ANSWER: Based on the number of total and mature oocytes retrieved in women with poor ovarian response (POR), there is no benefit of duostim versus two consecutive antagonist cycles. WHAT IS KNOWN ALREADY: Recent studies have shown the ability to obtain oocytes with equivalent quality from the follicular and the luteal phase, and a higher number of oocytes within one cycle when using duostim. If during follicular stimulation smaller follicles are sensitized and recruited, this may increase the number of follicles selected in the consecutive luteal phase stimulation, as shown in non-randomized controlled trials (RCT). This could be particularly relevant for women with POR. STUDY DESIGN, SIZE, DURATION: This is a multicentre, open-labelled RCT, performed in four IVF centres from September 2018 to March 2021. The primary outcome was the number of oocytes retrieved over the two cycles. The primary objective was to demonstrate in women with POR that two ovarian stimulations within the same cycle (first in the follicular phase, followed by a second in the luteal phase) led to the retrieval of 1.5 (2) more oocytes than the cumulative number of oocytes from two consecutive conventional stimulations with an antagonist protocol. In a superiority hypothesis, with power 0.8 alpha-risk 0.05 and a 35% cancellation rate, 44 patients were needed in each group. Patients were randomized by computer allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with POR, defined using adjusted Bologna criteria (antral follicle count ≤5 and/or anti-Müllerian hormone ≤1.2 ng/ml) were randomized, 44 in the duostim group and 44 in the conventional (control) group. HMG 300 IU/day with flexible antagonist protocol was used for ovarian stimulation, except in luteal phase stimulation of the duostim group. In the duostim group, oocytes were pooled and inseminated after the second retrieval, with a freeze-all protocol. Fresh transfers were performed in the control group, frozen embryo transfers were performed in both control and duostim groups in natural cycles. Data underwent intention-to-treat and per-protocol analyses. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference between the groups regarding demographics, ovarian reserve markers, and stimulation parameters. The mean (SD) cumulative number of oocytes retrieved from two ovarian stimulations was not statistically different between the control and duostim groups, respectively, 4.6 (3.4) and 5.0 (3.4) [mean difference (MD) [95% CI] +0.4 [-1.1; 1.9], P = 0.56]. The mean cumulative numbersof mature oocytes and total embryos obtained were not significantly different between groups. The total number of embryos transferred by patient was significantly higher in the control group 1.5 (1.1) versus the duostim group 0.9 (1.1) (P = 0.03). After two cumulative cycles, 78% of women in the control group and 53.8% in the duostim group had at least one embryo transfer (P = 0.02). There was no statistical difference in the mean number of total and mature oocytes retrieved per cycle comparing Cycle 1 versus Cycle 2, both in control and duostim groups. The time to the second oocyte retrieval was significantly longer in controls, at 2.8 (1.3) months compared to 0.3 (0.5) months in the duostim group (P < 0.001). The implantation rate was similar between groups. The cumulative live birth rate was not statistically different, comparing controls versus the duostim group, 34.1% versus 17.9%, respectively (P = 0.08). The time to transfer resulting in an ongoing pregnancy did not differ in controls 1.7 (1.5) months versus the duostim group, 3.0 (1.6) (P = 0.08). No serious adverse events were reported. LIMITATIONS, REASONS FOR CAUTION: The RCT was impacted by the coronavirus disease 2019 pandemic and the halt in IVF activities for 10 weeks. Delays were recalculated to exclude this period; however, one woman in the duostim group could not have the luteal stimulation. We also faced unexpected good ovarian responses and pregnancies after the first oocyte retrieval in both groups, with a higher incidence in the control group. However, our hypothesis was based on 1.5 more oocytes in the luteal than the follicular phase in the duostim group, and the number of patients to treat was reached in this group (N = 28). This study was only powered for cumulative number of oocytes retrieved. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT comparing the outcome of two consecutive cycles, either in the same menstrual cycle or in two consecutive menstrual cycles. In routine practice, the benefit of duostim in patients with POR regarding fresh embryo transfer is not confirmed in this RCT: first, because this study demonstrates no improvement in the number of oocytes retrieved in the luteal phase after follicular phase stimulation, in contrast to previous non-randomized studies, and second, because the freeze-all strategy avoids a pregnancy with fresh embryo transfer after the first cycle. However, duostim appears to be safe for women. In duostim, the two consecutive processes of freezing/thawing are mandatory and increase the risk of wastage of oocytes/embryos. The only benefit of duostim is to shorten the time to a second retrieval by 2 weeks if accumulation of oocytes/embryos is needed. STUDY FUNDING/COMPETING INTERESTS: This is an investigator-initiated study supported by a research Grant from IBSA Pharma. N.M. declares grants paid to their institution from MSD (Organon France); consulting fees from MSD (Organon France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. I.A. declares honoraria from GISKIT and support for travel and meetings from GISKIT. G.P.-B. declares Consulting fees from Ferring and Merck KGaA; honoraria from Theramex, Gedeon Richter, and Ferring; payment for expert testimony from Ferring, Merck KGaA, and Gedeon Richter; and support for travel and meetings from Ferring, Theramex, and Gedeon Richter. N.C. declares grants from IBSA pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. E.D. declares support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Ferring, Gedeon Richter, Theramex, and General Electrics. C.P.-V. declares support for travel and meetings from IBSA Pharma, Merck KGaA, Ferring, Gedeon Richter, and Theramex. M.Pi. declares support for travel and meetings from Ferring, Gedeon Richetr, and Merck KGaA. M.Pa. declares honoraria from Merck KGaA, Theramex, and Gedeon Richter; support for travel and meetings from Merck KGaA, IBSA Pharma, Theramex, Ferring, Gedeon Richter, and MSD (Organon France). H.B.-G. declares honoraria from Merck KGaA, and Gedeon Richter and support for travel and meetings from Ferring, Merck KGaA, IBSA Pharma, MSD (Organon France), Theramex, and Gedeon Richter. S.G. and M.B. have nothing to declare. TRIAL REGISTRATION NUMBER: Registration number EudraCT: 2017-003223-30. ClinicalTrials.gov identifier: NCT03803228. TRIAL REGISTRATION DATE: EudraCT: 28 July 2017. ClinicalTrials.gov: 14 January 2019. DATE OF FIRST PATIENT'S ENROLMENT: 3 September 2018.

Does mRNA COVID-19 vaccination in oocyte donors impact ovarian stimulation parameters or IVF outcomes for recipients?

RESEARCH QUESTION: What is the effect of mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in young oocyte donors in terms of ovarian response to stimulation, fertilization rate, embryo development and clinical outcomes in recipients? DESIGN: This retrospective, multicentre cohort study evaluated 115 oocyte donors who had undergone at least two ovarian stimulation protocols (before and after complete SARS-CoV-2 vaccination) between November 2021 and February 2022. Comparisons were made of the primary outcomes of days of stimulation, total dose of gonadotrophins and laboratory performance in ovarian stimulation in oocyte donors before and after vaccination. A total of 136 cycles in matched recipients were analysed as secondary outcomes and, from those, 110 women received a fresh single-embryo transfer, with analysis of biochemical ß-human chorionic gonadotrophin concentrations and rates of clinical pregnancy with heartbeat. RESULTS: Longer stimulation was required in the post-vaccination than pre-vaccination group (10.31 ± 1.5 versus 9.51 ± 1.5 days; P < 0.001) along with higher gonadotrophin consumption (2453.5 ± 740 versus 2235.5 ± 615 IU; P < 0.001) with a similar starting dose of gonadotrophins in both groups. More oocytes were retrieved in the post-vaccination group (16.62 ± 7.1 versus 15.38 ± 7.0; P = 0.02). However, the number of metaphase II (MII) oocytes was similar between groups (pre-vaccination 12.61 ± 5.9 versus post-vaccination 13.01 ± 6.6; P = 0.39) and the ratio of MII/retrieved oocytes favoured the pre-vaccination group (0.83 ± 0.1 versus 0.77 ± 0.2 post-vaccination; P = 0.019). In recipients with a similar number of provided oocytes, the fertilization rate, total number of obtained blastocysts, number of top-quality blastocysts, and rates of biochemical pregnancy and clinical pregnancy with heartbeat were not significantly different between groups. CONCLUSIONS: This study shows no adverse influence of mRNA SARS-CoV-2 vaccination on ovarian response in a young population.

Past COVID-19: The Impact on IVF Outcomes Based on Follicular Fluid Lipid Profile.

Follicular fluid is an important component of follicle growth and development. Negative effects of COVID-19 on follicular function are still open. The aim of this work was to study the features of the lipid profile of follicular fluid and evaluate the results of the in vitro fertilization (IVF) program in women after COVID-19 to identify biomarkers with prognostic potential. The study involved samples of follicular fluid collected from 237 women. Changes in the lipid composition of the follicular fluid of patients who underwent COVID-19 in mild and severe forms before entering the IVF program and women who did not have COVID-19 were studied by mass spectrometry. Several lipids were identified that significantly changed their level. On the basis of these findings, models were developed for predicting the threat of miscarriage in patients who had a severe course of COVID-19 and models for predicting the success of the IVF procedure, depending on the severity of COVID-19. Of practical interest is the possibility of using the developed predictive models in working with patients who have undergone COVID-19 before entering the IVF program. The results of the study suggest that the onset of pregnancy and its outcome after severe COVID-19 may be associated with changes in lipid metabolism in the follicular fluid.

Safety of COVID-19 vaccination in women undergoing IVF/ICSI treatment - Clinical study and systematic review.

Background: It was suggested that vaccination in general might affect reproductive health. Safety of COVID-19 vaccination in women undergoing assisted reproductive techniques (ART) treatment is not well established. Methods: We performed a retrospective study including 536 women undergoing fresh embryo transfer after IVF/ICSI treatment in a huge IVF center in southern China to investigate the effect of COVID-19 vaccination on oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate and miscarriage rate. In addition, we performed a systematic review of existing studies on the safety of COVID-19 vaccination in women undergoing ART treatment. Results: In our study, 268 women received inactivated or recombinant COVID-19 vaccination and 268 controls were enrolled based on propensity score matching. We observed a decreased fertilization rate and signs for impaired oocyte maturation in vaccinated women. Besides our study, there were 15 studies analyzing the safety of COVID-19 vaccination in women undergoing ART treatment. For the mRNA vaccines, no adverse signals were reported concerning oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate and miscarriage rate. In women being vaccinated with an inactivated vaccine, implantation rate, clinical pregnancy rate and miscarriage rate were not affected, whereas oocyte maturation and fertilization rate were impaired. Conclusions: Vaccination against COVID-19 in women undergoing ART treatment seems to be safe especially for women getting mRNA vaccines. The effects on oocyte maturation and fertilization rate of inactivated and recombinant COVID-19 vaccinations might be a safety signal and need further investigation and independent confirmation.

Previous infection with SARS-CoV-2 impacts embryo morphokinetics but not clinical outcomes in a time-lapse imaging system.

The goal for the present study was to investigate whether previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may compromise embryo morphokinetics and implantation. For that, a historical cohort study was performed in a private university-affiliated in vitro fertilization center. The study included 1628 embryos from 88 patients undergoing intracytoplasmic sperm injection (ICSI) cycles. Patients were age-matched in a 1:3 ratio to either a coronavirus disease (COVID) group, including patients with a positive SARS-CoV-2 immunoglobulin test (n = 22 patients, 386 embryos), or a control group, including patients with a negative SARS-CoV-2 immunoglobulin test (n = 66, 1242 embryos). The effect of previous infection with SARS-CoV-2 on morphokinetic events and ICSI outcomes was evaluated. Embryos derived from patients in the COVID group presented longer time to pronuclei appearance and fading, time to form two, three, four and five cells, and time to blastulation. The durations of the third cell cycle and to time to complete synchronous divisions were also significantly increased in the COVID group compared with the control group, whereas known implantation diagnosis score Day 5 ranked significantly lower in the COVID group. No differences were observed between the COVID and control groups on clinical outcomes. In conclusion, patients planning parenthood, who have recovered from COVID-19 infection, must be aware of a possible effect of the infection on embryo development potential.

Association Between Time Interval from COVID-19 Vaccination to In Vitro Fertilization and Pregnancy Rate After Fresh Embryo Transfer.

Importance: There is a lack of information regarding the need to postpone conception after COVID-19 vaccination. Objective: To investigate the time interval between the first dose of inactivated COVID-19 vaccine and in vitro fertilization (IVF) treatment as well as the rate of pregnancy after a fresh embryo transfer. Design, Setting, and Participants: This cohort study was conducted at a single public IVF center in China. Female patients aged 20 to 47 years and undergoing IVF treatment were consecutively registered from May 1 to December 22, 2021, with follow-up until March 31, 2022. Patients with SARS-CoV-2 infection before or during IVF treatment and those who underwent 2 or more IVF treatments, received the noninactivated or unknown COVID-19 vaccine, or did not have a fresh embryo transfer were excluded from this study. Exposures: The vaccinated group (subdivided into 4 subgroups of time interval from first vaccination to fertilization treatment: ≤30 days, 31-60 days, 61-90 days, and ≥91 days) and nonvaccinated group. Main Outcomes and Measures: Risk ratios (RRs) for the association between the time interval and ongoing pregnancy (pregnancy continued at least 12 weeks). Results: A total of 3052 female patients (mean [SD] age, 31.45 [3.96] years) undergoing IVF treatment were analyzed in this study. There were 667 vaccinated patients receiving IVF (35 were vaccinated ≤30 days, 58 were vaccinated 31-60 days, 105 were vaccinated 61-90 days, and 469 were vaccinated ≥91 days before fertilization treatment), and 2385 unvaccinated patients receiving treatment. The ovarian stimulation and laboratory parameters were similar among all groups. Ongoing pregnancy was significantly lower in the 30 days or less subgroup (34.3% [12 of 35]; adjusted RR [aRR], 0.61; 95% CI, 0.33-0.91) and the 31 to 60 days' subgroup (36.2% [21 of 58]; aRR, 0.63; 95% CI, 0.42-0.85). A slightly but not statistically lower rate was found in the 61 to 90 days' subgroup, and no reduced risk for ongoing pregnancy in the 91 days or more subgroup was observed (56.3% [264 of 469]; aRR, 0.96; 95% CI, 0.88-1.04) compared with the unvaccinated group (60.3% [1439 of 2385], as reference). Conclusions and Relevance: Findings of this study suggest that receipt of the first inactivated COVID-19 vaccine dose 60 days or less before fertilization treatment is associated with a reduced rate of pregnancy. In patients undergoing IVF treatment with a fresh embryo transfer, the procedure may need to be delayed until at least 61 days after COVID-19 vaccination.

Impact of the first wave of the COVID-19 pandemic on birth rates in Europe: a time series analysis in 24 countries.

STUDY QUESTION: Did the first wave of the COVID-19 pandemic have an impact on monthly birth rates in Europe? SUMMARY ANSWER: Using datasets on live births per month in Europe, collected from the Human Fertility Database, we found a -14.1% decline in live births in January 2021 (i.e. 9-10 months after the epidemic peaks and first lockdowns), compared to the average number of live births in January 2018 and 2019. WHAT IS KNOWN ALREADY: Previous pandemics in the 20th and 21st centuries have been associated with a decline in birth rates 9 months after their peak, and a rebound in births over time. Lockdowns were necessary to control the first wave of the COVID-19 pandemic and may have had an impact on subsequent birth rates. STUDY DESIGN, SIZE, DURATION: Monthly time series data on live births from January 2018 to March 2021 were extracted to provide a time-series analysis of birthrates during and after the first wave of the COVID-19 pandemic in 24 European countries. PARTICIPANTS/MATERIALS, SETTING, METHODS: We conducted a random-effect generalized least squares regression to assess the seasonality of births from January 2018 to March 2021, and to identify potential differences in monthly live births after the first wave of the COVID-19 pandemic, considering the seasonality of births. To quantify these potential differences, we estimated the variation rate between the monthly live births observed during 2020 and 2021 and the mean of the 2018-2019 monthly live births in Europe. Factors potentially associated with a variation in monthly birth rates were assessed using univariable and multivariable generalized linear regressions. MAIN RESULTS AND THE ROLE OF CHANCE: When considering the seasonality of births, January 2021 was the only month with a significant difference in live births. A drop of -14.1% was observed compared to the average number of live births in January 2018 and 2019. At the national level, this drop was observed 9-10 months after the epidemic peaks in 13 countries. The duration of lockdowns was the variable that had the stronger association with this decrease, whereas higher incomes per capita could be a factor limiting this decline. A rebound in births compared to the previous years occurred in March 2021 in 13 countries. LIMITATIONS, REASONS FOR CAUTION: Our data are based on national data, limiting the power in the multivariable models used and the identification of other potential factors contributing to a decrease or an increase in birth rates. In addition, we collected only live births up to April 2021, which precludes the identification of a difference in births seasonality in 2021. WIDER IMPLICATIONS OF THE FINDINGS: As with previous pandemics, the COVID-19 outbreak was associated with a decline in births 9 months after its first wave. This trend may be associated with the duration of the lockdowns. Although there was a rebound in births in the following months, it does not seem to compensate for this decline. STUDY FUNDING/COMPETING INTEREST(S): The authors receive no external funding and have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Inactivated Covid-19 vaccine did not undermine live birth and neonatal outcomes of women with frozen-thawed embryo transfer.

STUDY QUESTION: Does inoculation with inactivated vaccines against coronavirus disease 2019 (Covid-19) before frozen-thawed embryo transfer (FET) affect live birth and neonatal outcomes? SUMMARY ANSWER: Inactivated Covid-19 vaccines did not undermine live birth and neonatal outcomes of women planning for FET. WHAT IS KNOWN ALREADY: Accumulating reports are now available indicating the safe use of mRNA vaccines against Covid-19 in pregnant and lactating women, and a few reports indicate that they are not associated with adverse effects on ovarian stimulation or early pregnancy outcomes following IVF. Evidence about the safety of inactivated Covid-19 vaccines is very limited. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis from Reproductive Medical Center of a tertiary teaching hospital. Clinical records and vaccination record of 2574 couples with embryos transferred between 1 March 2021 and 30 September 2021 were screened for eligibility of this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical and vaccination data of infertile couples planning for FET were screened for eligibility of the study. The reproductive and neonatal outcomes of FET women inoculated with inactivated Covid-19 vaccines or not were compared. The primary outcomes were live birth rate per embryo transfer cycle and newborns' birth height and weight. Secondary outcomes included rates of ongoing pregnancy, clinical pregnancy, biochemical pregnancy and spontaneous miscarriage. Multivariate logistical regression and propensity score matching (PSM) analyses were performed to minimize the influence of confounding factors. Subgroup analyses, including single dose versus double dose of the vaccines and the time intervals between the first vaccination and embryo transfer, were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: Vaccinated women have comparable live birth rates (43.6% versus 45.0% before PSM, P = 0.590; and 42.9% versus 43.9% after PSM, P = 0.688), ongoing pregnancy rates (48.2% versus 48.1% before PSM, P = 0.980; and 52.2% versus 52.7% after PSM, P = 0.875) and clinical pregnancy rate (55.0% versus 54.8% before PSM, P = 0.928; and 54.7% versus 54.2% after PSM, P = 0.868) when compared with unvaccinated counterparts. The newborns' birth length (50.0 ± 1.6 versus 49.0 ± 2.9 cm before PSM, P = 0.116; and 49.9 ± 1.7 versus 49.3 ± 2.6 cm after PSM, P = 0.141) and birth weight (3111.2 ± 349.9 versus 3030.3 ± 588.5 g before PSM, P = 0.544; and 3053.8 ± 372.5 versus 3039.2 ± 496.8 g after PSM, P = 0.347) were all similar between the two groups. Neither single dose nor double dose of vaccines, as well as different intervals between vaccination and embryo transfer showed any significant impacts on reproductive and neonatal outcomes. LIMITATIONS, REASONS FOR CAUTION: The main findings might be limited by retrospective design. Besides, inoculations of triple dose of Covid-19 vaccines were not available by the time of data collection, thus the results cannot reflect the safe use of triple dose of inactivated Covid-19 vaccines. Finally, history of Covid-19 infection was based on patients' self-report rather than objective laboratory tests. WIDER IMPLICATIONS OF THE FINDINGS: Eligible individuals of inactivated vaccines against Covid-19 should not postpone vaccination plan because of their embryo transfer schedule, or vice versa. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Medical Key Discipline of Guangzhou (2021-2023). All authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Inactivated COVID-19 vaccination does not affect in vitro fertilization outcomes in women.

STUDY QUESTION: Do inactivated coronavirus disease-2019 (COVID-19) vaccines affect IVF outcomes among the vaccine recipients? SUMMARY ANSWER: The receipt of inactivated COVID-19 vaccines before ovarian stimulation has little effect on the outcomes of IVF, including ovarian stimulation outcomes, embryo development and pregnancy rates. WHAT IS KNOWN ALREADY: Limited studies have reported that COVID-19 vaccines do not affect ovarian function, embryo development or pregnancy outcomes. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study performed at the Third Affiliated Hospital of Guangzhou Medical University on 240 women vaccinated with either CoronaVac or Sinopharm COVID-19 before ovarian stimulation in the exposed group and 1343 unvaccinated women before ovarian stimulation in the unexposed group. All participants received fresh embryo transfers between 1 March 2021 and 15 September 2021. The included women were followed up until 12 weeks of gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Vaccination information of all subjects was followed up by a nurse, and the IVF data were obtained from the IVF data system. The following aspects were compared between the vaccinated and the unvaccinated groups: parameters of ovarian stimulation, embryo development and pregnancy rates. Regression analyses were performed to control for confounders of embryo development and pregnancy rates. Propensity score matching (PSM) was performed to balance the baseline parameters of the two groups. The primary outcome was the ongoing pregnancy rate. MAIN RESULTS AND THE ROLE OF CHANCE: Liner regression analysis revealed that the number of oocytes retrieved (regression coefficient (B) = -0.299, P = 0.264), embryos suitable for transfer (B = -0.203, P = 0.127) and blastocysts (B = -0.250, P = 0.105) were not associated with the status of vaccination before ovarian stimulation, after adjusting for the confounders. The ongoing pregnancy rate in the women of the vaccinated group was not significantly lower than that in the unvaccinated group (36.3% vs 40.7%, P = 0.199) (adjust odd ratio = 0.91, 95% CI = 0.68-1.22, P = 0.52). After PSM, the rates of ongoing pregnancy (36.0% vs 39.9%, P = 0.272), implantation (35.4% vs 38.3%, P = 0.325), biochemical pregnancy (47.3% vs 51.6%, P = 0.232), clinical pregnancy (44.4% vs 47.4%, P = 0.398) and early miscarriage (15.0% vs 12.1%, P = 0.399) were not significantly different between the vaccinated and the unvaccinated groups. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study of women with infertility. The results from the present study warrant confirmation by prospective studies with a larger cohort. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study with a large sample size on the effect of inactivated COVID-19 vaccines on ongoing pregnancy rates of women undergoing IVF. The present results showed that vaccination has no detrimental effect on IVF outcomes. Therefore, women are recommended to receive COVID-19 vaccines before undergoing their IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (No. 2018YFC1003803 to J.L.), the Guangzhou Science and Technology Plan Project (No. 202102010076 to H.L.) and the Medical Key Discipline of Guangzhou (2021-2023), as well as the Sino-German Center for Research Promotion Rapid Response Funding Call for Bilateral Collaborative Proposals between China and Germany in COVID-19 Related Research (No. C-0032 to Xingfei Pan). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Effects of COVID-19 vaccination status, vaccine type, and vaccination interval on IVF pregnancy outcomes in infertile couples.

PURPOSE: This study aimed to explore whether the coronavirus disease (COVID-19) vaccination of both partners in infertile couples, different types of COVID-19 vaccines, and the interval between complete vaccination and oocyte retrieval or embryo transfer (ET) affect the quality of embryos and pregnancy rates in in vitro fertilization (IVF). METHODS: This was a prospective cohort study, comprising 735 infertile couples conducted between December 6, 2021, and March 31, 2022, in a single university hospital-based IVF center. The patients were divided into different groups according to the vaccination status of both partners in infertile couples, type of vaccine, and interval between complete vaccination and IVF treatment. The embryo quality and pregnancy rates were compared among different groups. RESULTS: The results showed that embryo quality and pregnancy rates had no significant differences among different groups. The multivariate regression model showed that the vaccination status of both infertile couples, types of vaccines, and intervals had no significant effects on the clinical pregnancy rate. CONCLUSIONS: The vaccination status of both partners in infertile couples, different types of vaccines, and time intervals have no effect on embryo quality and pregnancy rates in IVF. This is the first study to compare the vaccination status of both partners in infertile couples and the impact of different vaccine types on pregnancy rates and embryo quality in detail. Our findings provide evidence of vaccine safety for infertile couples wishing to undergo IVF treatment. This evidence is crucial for decision-making by clinicians and policymakers involved in IVF cycles.

Investigate the effect of COVID-19 inactivated vaccine on sperm parameters and embryo quality in in vitro fertilization.

Since the reproductive toxicity of COVID-19 vaccines have not been assessed in previous clinical trials, and studies have shown that SARS-CoV-2 is associated with a decrease in sperm parameters. Although it has been reported that the mRNA SARS-CoV-2 vaccines do not adversely affect semen parameters, whether this conclusion applies to inactivated vaccines remains unclear. Here, we conducted a study among patients who accepted in vitro fertilization (IVF) at the reproductive centre between June and August of 2021. In the enrolled cases, men who have completed two doses of COVID-19 inactivated vaccine were included in "vaccine group" (N = 105), and those who were not vaccinated were included in "control group" (N = 155). In this study, we compare the sperm parameters and embryo quality between these two groups. Our data showed that the sperm parameters were similar in terms of volume, sperm concentration, sperm count, progressive motility, total motility and total motile sperm count between these two groups. Similarly, no significant differences were observed in IVF outcomes. The mean number of 2PN, cleavage-stage embryos, blastocysts, and good-quality blastocysts was 8.59 ± 4.47, 5.06 ± 3.17 and 2.08 ± 1.79 in vaccine group, 7.75 ± 4.14, 4.34 ± 3.06 and 1.74 ± 1.54 in control group, respectively. The high-quality blastocyst rate was 41.05% (218 of 531) in vaccine group and 40.03% (269 of 672) in control group (p > 0.05). In addition, no differences were observed in biochemical and clinical pregnancy rates between the two groups. In summary, our results revealed that COVID-19 inactivated vaccine administration exhibited no negative effect on sperm parameters and embryo quality in IVF.

Impact of Protocol Adjustments Due to the COVID-19 Pandemic on Infertility Treatment Outcomes.

As a result of the COVID-19 pandemic, our centre made adjustments that reduced the number of patient visits, ultrasound scans, laboratory investigations, and face-to face instructions. The objective of this study was to evaluate whether these changes had any effect on the pregnancy rate for patients undergoing infertility treatment. The primary outcome was clinical pregnancy rates from intrauterine insemination and frozen embryo transfer. Clinical pregnancy rates were not statistically different between patients who underwent either procedure before and after the protocols were put in place. It is reassuring to know our pandemic protocol adjustments did not have a negative impact on infertility treatment outcomes.

Investigating the impact of SARS-CoV-2 infection on basic semen parameters and in vitro fertilization/intracytoplasmic sperm injection outcomes: a retrospective cohort study.

BACKGROUND: This study aimed to evaluate the influences of SARS-CoV-2 infection on semen parameters and investigate the impact of the infection on in vitro fertilization (IVF) outcomes. METHODS: This retrospective study enrolled couples undergoing IVF cycles between May 2020 and February 2021 at Tongji Hospital, Wuhan. Baseline characteristics were matched using propensity score matching. Participants were categorized into an unexposed group (SARS-COV-2 negative) and exposed group (SARS-COV-2 positive) based on a history of SARS-CoV-2 infection, and the populations were 148 and 50 after matching, respectively. IVF data were compared between the matched cohorts. Moreover, semen parameters were compared before and after infection among the infected males. The main measures were semen parameters and IVF outcomes, including laboratory and clinical outcomes. RESULTS: Generally, the concentration and motility of sperm did not significantly differ before and after infection. Infected males seemed to have fewer sperm with normal morphology, while all values were above the limits. Notably, the blastocyst formation rate and available blastocyst rate in the exposed group were lower than those in the control group, despite similar mature oocytes rates, normal fertilization rates, cleavage rates, and high-quality embryo rates. Moreover, no significant differences were exhibited between the matched cohorts regarding the implantation rate, biochemical pregnancy rate, clinical pregnancy rate, or early miscarriage rate. CONCLUSIONS: The results of this retrospective cohort study suggested that the semen quality and the chance of pregnancy in terms of IVF outcomes were comparable between the males with a history of SARS-CoV-2 infection and controls, although a decreased blastocyst formation rate and available blastocyst rate was observed in the exposed group, which needs to be reinforced by a multicenter long-term investigation with a larger sample size.

IVF under COVID-19: treatment outcomes of fresh ART cycles.

STUDY QUESTION: Does prior severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in women undergoing fertility treatments affect the outcomes of fresh ART cycles? SUMMARY ANSWER: SARS-CoV-2 infection does not affect fresh ART treatment outcomes, except for a possible long-term negative effect on oocyte yield (>180 days postinfection). WHAT IS KNOWN ALREADY: A single previous study suggested no evidence that a history of asymptomatic or mild SARS-CoV-2 infection in females caused impairment of fresh ART treatment outcomes. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study, including all SARS-CoV-2 infected women who underwent fresh ART cycles within a year from infection (the first cycle postinfection), between October 2020 and June 2021, matched to non-diagnosed controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients from two large IVF units in Israel who were infected with SARS-CoV-2 and later underwent fresh ART cycles were matched by age to non-diagnosed, non-vaccinated controls. Demographics, cycle characteristics and cycle outcomes, including oocyte yield, maturation rate, fertilization rate, number of frozen embryos per cycle and clinical pregnancy rates, were compared between groups. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and twenty-one infected patients and 121 controls who underwent fresh ART cycles were included. Oocyte yield (12.50 versus 11.29; P = 0.169) and mature oocyte rate (78% versus 82%; P = 0.144) in all fresh cycles were similar between groups, as were fertilization rates, number of frozen embryos per cycle and clinical pregnancy rates (43% versus 40%; P = 0.737) in fresh cycles with an embryo transfer. In a logistic regression model, SARS-CoV-2 infection more than 180 days prior to retrieval had a negative effect on oocyte yield (P = 0.018, Slope = -4.08, 95% CI -7.41 to -0.75), although the sample size was small. LIMITATIONS, REASONS FOR CAUTION: A retrospective study with data that was not uniformly generated under a study protocol, no antibody testing for the control group. WIDER IMPLICATIONS OF THE FINDINGS: The study findings suggest that SARS-CoV-2 infection does not affect treatment outcomes, including oocyte yield, fertilization and maturation rate, number of good quality embryos and clinical pregnancy rates, in fresh ART cycles, except for a possible long-term negative effect on oocyte yield when retrieval occurs >180 days post-SARS-CoV-2 infection. Further studies are warranted to support these findings. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: 0010-21-HMC, 0094-21-ASF.

Does mRNA SARS-CoV-2 vaccine in the follicular fluid impact follicle and oocyte performance in IVF treatments?

PROBLEM: The COVID-19 pandemic has many clinical manifestations. Rapid vaccine development raised concerns and speculations about future fertility outcomes and vaccine safety. We evaluated the effect of Pfizer-BioNTech mRNA SARS-CoV-2 vaccine on IVF treatment, oocyte and embryo quality, and pregnancy outcomes. METHOD OF STUDY: This prospective, observational cohort study was conducted in a referral IVF Unit, 3/2021-5/2021. We aimed to recruit all women undergoing IVF/ICSI cycles from 3/1-4/30/2021, 2-8 weeks after the second vaccination, and to analyze 50-60 samples in the 2-month period. Patients were categorized according to serum antibody levels: positive for spike (S), positive for nucleotide (N), or negative for both. On the day of ovum pick-up, follicular fluid and blood samples were analyzed for anti-nucleotide (anti-N) antibodies, and anti-spike (anti-S) antibodies, hormonal profile, C-reactive protein (CRP) and other metabolic parameters. RESULTS: Of 59 women enrolled, 37 reported being vaccinated and 22 were not. We found 97% correlation between anti-S and anti-N in the blood and the follicular fluid. Follicular fluid was analyzed based on antibody categorization. All IVF treatment parameters in the follicular fluids and serum were comparable, except CRP was significantly elevated among patients with anti-N antibodies (2.29 [1.42-6.08] vs. 4.11 [1.62-5.75] vs. 1.44 [.36-8.33]; p < .001). Pregnancy outcomes were comparable (44% vs. 33% vs. 50%; p = .97). CONCLUSION: mRNA SARS-CoV-2 vaccine did not appear to affect treatment outcomes or ovarian reserves in the subsequent IVF cycle.

Different CO2 settings (6.0% vs 7.0%) do have an impact on extracellular pH of culture medium (pHe) and euploidy rates rather than on blastocyst development: a sibling oocyte study.

OBJECTIVE: To determine whether euploidy rates and blastocyst development differ in a continuous culture medium under different CO2 concentrations. DESIGN AND METHOD: A single-center retrospective study was performed from July 2018 to October 2019 including 44 fresh cycles with at least four fresh mature oocytes (MII) without severe male factor infertility. Sibling MII were injected and cultured in Global®Total®LP under 6.0% (pHe = 7.374 ± 0.014) or 7.0% (pHe = 7.300 ± 0.013) CO2, 5.0% O2, and 89.0% or 88.0% N2. Analyzed variables were normally fertilized oocytes (2PN), cleavage rate, blastulation rate on day 5/2PN, usable blastocyst (blastocysts biopsied/2PN), and euploidy rates. Blastocyst's trophectoderm biopsy was performed on day 5, 6, or 7 for genetic testing and mitochondrial DNA (mtDNA) quantification by next-generation sequencing. RESULTS: Women's mean age was 33.0 ± 6.6 years old. From a total of 604 MII, no differences were found in normal fertilization and cleavage rates on day 3 between 6.0 and 7.0% CO2 (72.3% vs 67.1%, p = 0.169 and 96.6% vs 96.3%, p = 0.897, respectively). Blastulation rate on day 5/2PN was comparable between 6.0 and 7.0% CO2 (68.1% vs 64.2%, p = 0.409). Although usable blastocyst rate was not different (54.3% vs 55.3%, p = 0.922), total euploidy rates differed significantly (58.7% vs 42.8%, p = 0.016) between 6.0% and 7.0% CO2, respectively. The mean blastocyst mtDNA content was significantly lower in 6.0% CO2 (30.4 ± 9.1 vs 32.9 ± 10.3, p = 0.037). CONCLUSION: Blastocyst development is not affected when embryos are cultured in vitro at 6.0% or 7.0% CO2, while euploidy rates are significantly decreased at a higher CO2 concentration, therefore at a lower pHe.

Impact of the COVID-19 Pandemic on Access to Fertility Care: A Retrospective Study at a University-Affiliated Fertility Practice.

OBJECTIVE: To elucidate the impact of the COVID-19 pandemic on access to fertility services. METHODS: A retrospective quality improvement study was conducted at a university-affiliated fertility practice in southwestern Ontario. Annual procedural volumes for intrauterine and donor inseminations (IUI/DI), in vitro fertilization and intracytoplasmic sperm injections (IVF/ICSI), and frozen embryo transfers (FET) during the COVID-19-affected year were compared with mean annual volumes from the 2 preceding years. In addition, volumes for the same procedures were compared between the first quarter of 2021 and mean first quarter volumes from 2018 to 2019. Piecewise linear regressions were conducted to evaluate whether any changes in monthly procedural volume were attributable to the COVID-19 pandemic. RESULTS: In 2020, our fertility practice attained the mean annual volumes of 89.7% for IUI/DI, 69.0% for IVF/ICSI, and 60.6% for FET. In contrast, in 2021, we performed mean first quarter volumes of 130.1% for IUI/DI, 164.3% for IVF/ICSI, and 126.8% for FET. The slopes of the pre- and post-COVID-19 segments of the piecewise linear regressions were significantly different for IUI/DI (P < 0.001) and IVF/ICSI (P = 0.001), but not for FET (P = 0.133). CONCLUSION: The COVID-19 pandemic resulted in decreased annual volumes of medically assisted reproductive procedures at a university-affiliated fertility practice in southwestern Ontario. Impact on monthly procedural volume was confirmed for IUI/DI and IVF/ICSI by linear regression. Local adaptations helped compensate and exceed expected volumes in 2021. As a result, the COVID-19 pandemic resulted in a short-lived limitation in access to fertility care.

Development of Optimized Vitrification Procedures Using Closed Carrier System to Improve the Survival and Developmental Competence of Vitrified Mouse Oocytes.

The open carrier system (OC) is used for vitrification due to its high efficiency in preserving female fertility, but concerns remain that it bears possible risks of cross-contamination. Closed carrier systems (CC) could be an alternative to the OC to increase safety. However, the viability and developmental competence of vitrified/warmed (VW) oocytes using the CC were significantly lower than with OC. We aimed to improve the efficiency of the CC. Metaphase II oocytes were collected from mice after superovulation and subjected to in vitro fertilization after vitrification/warming. Increasing the cooling/warming rate and exposure time to cryoprotectants as key parameters for the CC effectively improved the survival rate and developmental competence of VW oocytes. When all the conditions that improved the outcomes were applied to the conventional CC, hereafter named the modified vitrification/warming procedure using CC (mVW-CC), the viability and developmental competence of VW oocytes were significantly improved as compared to those of VW oocytes in the CC. Furthermore, mVW-CC increased the spindle normality of VW oocytes, as well as the cell number of blastocysts developed from VW oocytes. Collectively, our mVW-CC optimized for mouse oocytes can be utilized for humans without concerns regarding possible cross-contamination during vitrification in the future.