This study provides a clinical reference for physicians in reproductive medicine to continue oocyte retrieval surgery when treating patients with COVID-19 infection. The results of the present study suggest that asymptomatic or mild COVID-19 infection in women prior to oocyte retrieval may not has a significant negative impact on ovulation induction outcomes or embryo laboratory results. It is not necessary to cancel the oocyte retrieval procedure due to infection with COVID-19, but it is worth noting that the number of stimulation days and dose of Gn may increase. To our knowledge, this is the first study to investigate whether preretrieval COVID-19 infection has an impact on ovulation induction outcomes and laboratory embryo outcomes in women.

At the beginning of the outbreak, the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE) issued guidelines recommending that all assisted reproductive treatment (ART) be postponed as much as possible except in emergencies. With the effective control of the epidemic in some countries and regions, these medical societies recommend that reproductive health care be fully restarted on the premise of ensuring the safety of medical staff [11]. However, it is not clear whether previous infection of the parent with the novel coronavirus infection has a significant negative effect on gametes or embryos. In particular, if an infertile woman faces many obstacles in her attempt to complete the process of COH, before oocyte retrieval reveals COVID-19 infection, should she proceed with oocyte retrieval surgery, or cancel the surgery and negate all her efforts those of the physicians? This is a difficult decision for both doctors and patients.

The ovarian reserve and ovarian response are common indicators of ovarian function, among which AMH is considered the most sensitive marker of the ovarian reserve [12]. In one study the serum AMH levels in women infected with COVID-19 were reported to be significantly decreased, and the testosterone/prolactin (T/PRL) ratio was found to be significantly increased [13], indicating that the ovarian reserve function of these patients was significantly reduced; however, the validity of this conclusion remains to be confirmed, as the findings may have been influenced by differences in sample collection times between the infection and control groups. Other studies have shown that there are no significant difference in sex hormones, including FSH, LH and AMH, between patients with COVID-19 infection and patients in the control group [14, 15]. This finding is consistent with the results of this study; compared with those in the non-infection group, there were no significant differences in basal hormone levels, AMH levels, AFC or trigger day hormone levels in either the infection group or the recovery group, suggesting that COVID-19 infection may has a limited impact on the ovarian reserve of female patients.

In this study, we found, for the first time, that the Gn dose and duration of Gn treatment were significantly higher in the infection group than in the other two groups. At present, there have been no studies confirming that infection with COVID-19 increases the number of days and dose of Gn stimulation. A 2024 study revealed that the COVID-19 infection group had lower Gn doses and shorter Gn durations than did non-infection group. This may be because the study included a greater proportion of patients receiving antagonist therapy, favoring short-term ovulation induction regimens during pandemics to minimize hospital visits, reduce the risk of nosocomial infections, and improve treatment efficiency [16]. The ovulation induction protocols of the subjects included in this study were all EFLL protocol, thereby excluding the influence of the ovulation induction protocol on Gn use. The reason that COVID-19 infection increased the number of days and dose of Gn stimulation has not been clarified. The study sample size is limited, so this gap in knowledge will need further clarification in future studies. Additionally, in some studies, the effects of the COVID-19 vaccine were evaluated only in terms of female reproductive function, but their conclusions were controversial. Specifically, Aránzazu Bosch et al. reported that oocyte donors who were vaccinated with the COVID-19 mRNA vaccine required longer ovarian stimulation times and higher Gn dosages than did those who were not vaccinated [17]. However, Antonio Requena et al. reported that there was no significant difference in the number of days or dose of Gn, regardless of the vaccine administered, and that it had no measurable harmful effects on reproductive outcomes [18]. Surprisingly, in this study, despite the use of more Gn stimulation, there was no significant increase in the number of oocytes recovered in the infection group. In addition, COVID-19 infection had no significant effect on subsequent oocyte maturation, embryo fertilization, embryo cleavage or blastocyst formation.

In a retrospective study from Wuhan, the authors reported that although the blastocyst formation rate in the case group decreased slightly, the final laboratory and clinical outcomes did not significantly differ from those in the non-infection group [15]. The results of this study revealed that the number of blastocysts, rate of blastocyst formation, rate of high-quality blastocyst formation and number of high-quality blastocysts in the recovery group were significantly lower than those in the non-infection group. Even the blastocyst formation rate and high-quality blastocyst formation rate were also significantly lower in the recovery group than in the infection group; however, there was no significant difference between the infection group and non-infection group (P > 0.05). This suggests that when infertile women are unfortunately infected with asymptomatic or mildly symptomatic COVID-19 prior to oocyte retrieval, there may not be a significant negative impact on embryo laboratory results, which is consistent with the results of a multicenter prospective cohort study led by Shandong University [19]. Therefore, there is no need to cancel oocyte retrieval due to COVID-19 infection, but infertile women who recover from COVID-19 infection need to be aware of the impact of infection on blastocyst formation, especially with regard to the significant reduction in the number of high-quality blastocysts. Multivariate regression analysis also revealed a 0.599-fold increase in the number of high-quality blastocysts obtained from women who had recovered from COVID-19 infection compared to uninfected women, again confirming the disadvantage of COVID-19 infection to the subsequent formation of high-quality blastocysts. The reason may be that the microenvironment of oocyte development after COVID-19 infection is abnormal, which has a long-term negative effect. If ART is used before the recovery period, embryo quality may be affected, especially as the number of high-quality blastocysts decreases. In addition, COVID-19 can also cause a decline in male semen quality, as well as embryo quality.

Unfortunately, data on the minimum time interval required between recovery from COVID-19 infection and ART treatment are not available at this stage [20]. Some authors recommend a 3-month interval between recovery from COVID-19 infection and ART treatment, primarily to allow men to enter a new spermatogenic cycle [21]. The shortest interval between recovery from COVID-19 infection and ART treatment among the subjects included in the Wuhan retrospective study was 4 months [15], whereas the interval between recovery from COVID-19 infection and ART treatment among the subjects in the recovery group included in this study was no more than 2 months. At this stage, there is no consensus on the appropriate interval between recovery from COVID-19 infection and initiation of fertility treatment, so further research is needed and is the focus of our team’s future research.

This study has three major limitations. First, this was a single-center retrospective study with a limited sample size, and we were unable to classify subgroups to study the effects of different characteristics (e.g., severity, complications, recovery time), and a multicenter study with a larger sample size is needed to support the conclusions of this study to eliminate the limitations of sample size and study design. Second, only the effects of COVID-19 infection on ovarian function and laboratory outcomes in women were studied, and the effects of COVID-19 infection on pregnancy outcomes, especially the live birth rate, were not evaluated. The impact of COVID-19 infection on the clinical outcomes of ART and offspring should be further studied via follow-up of infected patients. Finally, most of the patients included were asymptomatic or had mild disease, so the conclusions of this study may not be applicable to all patients with COVID-19 infection, especially those with severe disease.