Previous studies have explored the impact of COVID-19 infection on pregnancy outcomes, with some focusing on the recovery period post-infection and its effects on oocyte maturation, embryo quality and ART outcomes [8]. Our study aimed to investigate the potential effect of COVID-19 infection on embryo implantation and early development, and uniquely, concentrated on women who received FET and were not infected prior to oocyte retrieval, thereby excluding the effect of COVID-19 infection on oocytes. This study benefited from the clear timeline of both FET and COVID-19 infection, ensuring precise categorization of infected individuals. The infection rate in our study population was notably high (78.28%), allowing for a comprehensive analysis of the impact of COVID-19 infection at various periods.
In this study, no significant differences were found in embryo implantation and early development, including biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate, among the four groups (uninfected, ≥ 60 days before FET, < 60 days before FET, 0–14 days after FET). These findings suggest that even asymptomatic or mild COVID-19 infection, occurring during the critical period of embryo implantation (0–14 days after transplantation), does not significantly impact embryo implantation into the endometrium. Moreover, it implies that such infections do not affect early embryo development or maternal endometrial receptivity [10]. Multivariable logistic regression analysis reinforced these findings, revealing that ongoing pregnancy rate was significantly correlated with factors such as maternal age, stage of transferred embryos, and the number of transferred embryos, while COVID-19 infection did not exhibit a significant correlation. It is consistent with the outcomes of related studies [11, 12]. Additionally, our study indicated that asymptomatic or mild COVID-19 infection did not increase the occurrence of early pregnancy adverse reactions, such as severe morning sickness or vaginal bleeding, following the establishment of early clinical pregnancy.Comparison with prior studies highlights the unique aspects of our research.
A study from Israel with a smaller sample size (n = 82) assessed the impact of COVID-19 infection on pregnancy rates in FET. It reported a lower clinical pregnancy rate for women who underwent embryo transfer within 60 days post-infection compared to those who waited longer. Therefore, the authors recommended to delay embryo transfer for at least 60 days after COVID-19 recovery in FET cycles for women with limited embryo number [13]. However, our study, conducted during a concentrated outbreak period, featured a larger sample size and a higher population infection rate. Notably, the lowest clinical pregnancy rate in infected individuals in our study was 48.1%, substantially higher than the rates reported in previous studies. This discrepancy led us to speculate that asymptomatic or mild COVID-19 infection at various periods before and after FET does not significantly impair the pregnancy rate of FET. Consequently, delaying pregnancy plans for prior infection might not be necessary. However, these conclusions are preliminary and require cautious interpretation, urging further research for clarification.
During the global COVID-19 pandemic, various studies have explored the relationship between COVID-19 infection and pregnancy outcomes, presenting diverse findings. A prospective cohort study in the UK demonstrated an increased risk of early abortion in women infected with COVID-19 before 13 weeks’ gestation [14]. However, a retrospective cohort study in New York City did not find an elevated rate of pregnancy failure within the first trimester among women infected with COVID-19 who achieved pregnancy through ART [4]. Similarly, a single-center study in Iran found no negative impact on ART outcomes despite symptoms of infection occurring before or after the ART cycle [5]. In India, a retrospective analysis showed no differences in pregnancy outcomes between the pre-pandemic and pandemic periods of COVID-19, suggesting that the virus did not significantly affect pregnancy results [6].
Our study, encompassing a larger participant pool with a higher infection rate, aligned with these findings, indicating that COVID-19 infection in early pregnancy around the FET cycle did not significantly adversely affect early pregnancy outcomes. Notably, the study also suggested that COVID-19 may not cross the placenta readily, reducing the likelihood of vertical transmission in mid- to late pregnancy [2, 15], and there is no evidence that the virus infects embryos in early pregnancy. These findings are consistent with previous research and are in line with current knowledge of the effects of COVID-19 on pregnancy.
A comprehensive analysis of existing literature, including 148 papers collected from PUBMED/MEDLINE and the COVID-19 database of the World Health Organization, indicated that due to the increased time of waiting for fertility treatment and the suspension of fertility services, the pandemic's psychological burden on couples seeking fertility treatment was substantial [10]. The pandemic also had a profound impact on ART live births in the United States, with an estimated loss of approximately 25,143 live births due to the suspension of ART activities and the economic recession associated with the pandemic [16]. Considering these factors, there has been an ongoing debate about the optimal interval between COVID-19 infection and ART treatment to achieve the best pregnancy outcome. The stratified analysis of our study showed that no significant differences were observed in the effects on early embryo implantation and development as well as early pregnancy adverse reactions, between individuals infected with COVID-19 at different periods and uninfected individuals. We believe that there is no need to delay pregnancy plans for possible asymptomatic or mild COVID-19 infections.
Our study, characterized by its large sample size, high population infection rate, and clear infection timeline, stands as a robust contribution to this discussion. By closely examining critical periods related to FET and pregnancy establishment, it provides substantial statistical evidence supporting the notion that asymptomatic or mild COVID-19 infections, even during different periods before and after FET as well as in early pregnancy, do not significantly impact early pregnancy outcomes. This finding holds even in the context of the pandemic when the virus's virulence weakens. Consequently, individuals with asymptomatic or mild infections can confidently pursue pregnancy through natural conception or ART.
Our study has some limitations. The study may be affected by retrospective bias, and there might be limitations in the quality and scope of the available data. In addition, this study has limitations regarding the response of individuals of Asian ethnicity to viral infection. There are no quantitative data on the effect of viral infection, such as measurement of virus titer, assessment of reproductive biological samples (eg follicular fluid, endometrium, etc.). Therefore, more related detailed characteristics should be collected and well-designed studies are needed in the future.