Li Yanping, Lu Xuan, Fu Jing, Yang Fan, Mao Zenghui, Liao Hongqing, Zhang Juan, Huang Xianghong, Zhang Qiong
Center for Reproductive Medicine, Xiang-Ya hospital, Central South University, Changsha City, Hunan Province, China.
Center for Reproductive Medicine, Chenzhou No 1 People's Hospital East Hospital, Chenzhou City, Hunan Province, China.
PLoS One. 2025 Sep 11;20(9):e0328743. doi: 10.1371/journal.pone.0328743. eCollection 2025.
Extensive research has demonstrated the detrimental effects of COVID-19 on maternal-fetal outcomes. However, few studies have examined the impact of SARS-CoV-2 infection before and during organogenesis on human embryo implantation and subsequent development. Additionally, the influence of SARS-CoV-2 on the endometrial microenvironment, which is critical for embryo implantation, remains poorly understood. This study seeks to address these gaps in knowledge.
We prospectively enrolled 971 participants undergoing frozen-thawed embryo transfer (FET) during the final two months of 2022, coinciding with the nationwide COVID19 outbreak following the end of China's Zero-Covid policy. Patients undergoing FET during this period were at high risk of SARS-CoV-2 infection before and during organogenesis. Based on self-reported symptoms and nucleic acid testing, 520 individuals were confirmed to have SARS-CoV-2 infection, while 451 were uninfected. Consistent with existing literature, our study reinforced that SARS-CoV-2 infection negatively impacted pregnancy outcomes, as evidenced by reduced clinical pregnancy (52.69% vs. 76.50%, RR = 60.506, [95%CI, 0.259 ~ 0.452]) and live birth rates (46.54% vs. 60.09%, RR = 17.865, [95%CI, 0.448 ~ 0.746]), alongside an increase in obstetric complications (35.89% vs. 27.37%, RR = 4.380, [95%CI, 1.055 ~ 2.223]). Seven fetal congenital heart defects (CHDs) were observed in the infected group versus one in uninfected population. Bioinformatic analysis of endometrial mRNA profiles showed SARS-CoV-2 infection significantly downregulated key endometrial receptivity molecules, increased natural killer cell and mast cell infiltration, and disrupted the balance of cytokine and chemokine. Moreover, our findings demonstrated that SARS-CoV-2 infection downregulated the transcriptional activity of endometrial SLC6A, a serotonin transporter, and ErbB-2, a mediator of serotonin-regulated differentiation in cardiac development. This disruption in serotonin signaling may underlie the pathogenesis of congenital heart disease.
SARS-CoV-2 infection before and during organogenesis negatively impacts embryo implantation and development, primarily through mechanisms involving compromised endometrial receptivity and disruption of the local immune microenvironment.
广泛的研究已经证明了新冠病毒病对母婴结局的有害影响。然而，很少有研究考察严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染在器官发生之前及期间对人类胚胎着床及后续发育的影响。此外，SARS-CoV-2对子宫内膜微环境（对胚胎着床至关重要）的影响仍知之甚少。本研究旨在填补这些知识空白。
我们前瞻性地纳入了971名在2022年最后两个月接受冻融胚胎移植（FET）的参与者，这一时期恰逢中国结束“动态清零”政策后全国范围内的新冠疫情爆发。在此期间接受FET的患者在器官发生之前及期间有感染SARS-CoV-2的高风险。根据自我报告症状和核酸检测，520人被确诊感染SARS-CoV-2，451人未感染。与现有文献一致，我们的研究进一步证实SARS-CoV-2感染对妊娠结局有负面影响，临床妊娠率降低（52.69%对76.50%，RR = 60.506，[95%CI，0.259～0.452]）、活产率降低（46.54%对60.09%，RR = 17.865，[95%CI，0.448～0.746]）以及产科并发症增加（35.89%对27.37%，RR = 4.380，[95%CI，1.055～2.223]）均证明了这一点。感染组观察到7例胎儿先天性心脏病（CHD），未感染组观察到1例。子宫内膜mRNA谱的生物信息学分析显示，SARS-CoV-2感染显著下调关键的子宫内膜容受性分子，增加自然杀伤细胞和肥大细胞浸润，并破坏细胞因子和趋化因子的平衡。此外，我们的研究结果表明，SARS-CoV-2感染下调了子宫内膜中血清素转运体SLC6A和心脏发育中血清素调节分化的介质ErbB-2的转录活性。血清素信号传导的这种破坏可能是先天性心脏病发病机制的基础。
器官发生之前及期间的SARS-CoV-2感染对胚胎着床和发育有负面影响，主要通过涉及子宫内膜容受性受损和局部免疫微环境破坏的机制。
