背景:怀孕期间SARS-CoV-2感染与死产风险增加有关,先兆子痫和早产。然而,这似乎不是由于胎儿宫内感染,垂直传播很少报道。有关胎盘SARS-CoV-2组织病理学及其与感染时间和严重程度的关系的数据很少。
目的:确定母体SARS-CoV-2感染是否与胎盘损伤的特定模式相关,以及这些发现是否因感染时间或疾病严重程度的胎龄而不同。
方法:一项回顾性队列研究于2020年3月至2021年2月在加州大学圣地亚哥分校进行。将SARS-CoV-2测试阳性的妊娠胎盘与两组对照进行匹配:一组按分娩日期进行时间匹配,并送至病理学以进行常规临床指征,另一个是从先前为研究目的而收集的胎盘队列中选择的,在SARS-CoV-2爆发之前没有临床指征进行病理检查。根据标准标准定义胎盘病理性病变,包括母体和胎儿血管灌注不良,和急性和慢性炎性病变。采用独立的Studentt检验和Pearson卡方进行双变量分析。Logistic回归用于控制相关协变量。在GeoMx平台上使用基于蛋白质的数字空间分析(DSP)测定法进一步研究了SARS-CoV-2相关的绒毛炎区域,通过免疫组织化学验证,并与感染性绒毛炎和病因不明的绒毛炎病例进行了比较。进行差异表达分析以鉴定这些绒毛膜组之间的蛋白质表达差异。
结果:我们包括272例SARS-CoV-2阳性病例,272个时间匹配控件,和272个历史控件。受SARS-CoV-2影响的受试者的平均年龄为30.1±5.5岁,大多数是西班牙裔(53.7%)和帕罗斯人(65.7%)。SARS-CoV-2胎盘显示出四种主要胎盘损伤的频率较高(所有p<.001),与历史控制相比。与时间匹配的对照组相比,SARS-CoV-2胎盘也显示出更高的慢性绒毛炎(CV)和严重CV(两者的p=.03)频率。在分娩时控制胎龄后仍然显着(分别为aOR1.52,95%CI1.01-2.28;aOR2.12,95%CI1.16-3.88)。DSP显示,在SARS-CoV-2(logFC0.47,调整p值=0.002)和VUE(logFC0.58,调整p值=0.003)的绒毛组织阳性区域,程序性死亡配体1(PD-L1)增加。但相反,感染性绒毛组的绒毛炎阳性区域降低(logFC-1.40,adjp值<0.001)。
结论:CV似乎是与SARS-CoV-2母体感染相关的最具体的组织病理学发现。CV涉及绒毛膜绒毛的血管合胞体膜的损伤,参与气体/营养交换,提示胎盘(也许是新生儿)损伤的潜在机制,即使在没有垂直传输。令人惊讶的是,SARS-CoV-2相关绒毛炎的蛋白质表达变化似乎与VUE更相似,而不是感染性绒毛炎。
BACKGROUND: SARS-CoV-2 infection during pregnancy is associated with an increased risk for stillbirth, preeclampsia, and preterm birth. However, this does not seem to be caused by intrauterine fetal infection because vertical transmission is rarely reported. There is a paucity of data regarding the associated placental SARS-CoV-2 histopathology and their relationship with the timing and severity of infection.
OBJECTIVE: This study aimed to determine if maternal SARS-CoV-2 infection was associated with specific patterns of placental injury and if these findings differed by gestational age at time of infection or disease severity.
METHODS: A retrospective cohort study was performed at the University of California San Diego between March 2020 and February 2021. Placentas from pregnancies with a positive SARS-CoV-2 test were matched with 2 sets of controls; 1 set was time-matched by delivery date and sent to pathology for routine clinical indications, and the other was chosen from a cohort of placentas previously collected for research purposes without clinical indications for pathologic examination before the SARS-CoV-2 outbreak. Placental pathologic lesions were defined based on standard criteria and included maternal and fetal vascular malperfusion and acute and chronic inflammatory lesions. A bivariate analysis was performed using the independent Student t test and Pearson chi-square test. A logistic regression was used to control for relevant covariates. Regions of SARS-CoV-2-associated villitis were further investigated using protein-based digital spatial profiling assays on the GeoMx platform, validated by immunohistochemistry, and compared with cases of infectious villitis and villitis of unknown etiology. Differential expression analysis was performed to identify protein expression differences between these groups of villitis.
RESULTS: We included 272 SARS-CoV-2 positive cases, 272 time-matched controls, and 272 historic controls. The mean age of SARS-CoV-2 affected subjects was 30.1±5.5 years and the majority were Hispanic (53.7%) and parous (65.7%). SARS-CoV-2 placentas demonstrated a higher frequency of the 4 major patterns of placental injury (all P<.001) than the historic controls. SARS-CoV-2 placentas also showed a higher frequency of chronic villitis and severe chronic villitis (P=.03 for both) than the time-matched controls, which remained significant after controlling for gestational age at delivery (adjusted odds ratio, 1.52; 95% confidence interval, 1.01-2.28; adjusted odds ratio, 2.12; 95% confidence interval, 1.16-3.88, respectively). Digital spatial profiling revealed that programmed death-ligand 1 was increased in villitis-positive regions of the SARS-CoV-2 (logFC, 0.47; adjusted P value =.002) and villitis of unknown etiology (logFC, 0.58; adjusted P value =.003) cases, but it was conversely decreased in villitis-positive regions of the infectious villitis group (log FC, -1.40; adjusted P value <.001).
CONCLUSIONS: Chronic villitis seems to be the most specific histopathologic finding associated with SARS-CoV-2 maternal infection. Chronic villitis involves damage to the vasculosyncytial membrane of the chorionic villi, which are involved in gas and nutrient exchange, suggesting potential mechanisms of placental (and perhaps neonatal) injury, even in the absence of vertical transmission. Surprisingly, changes in protein expression in SARS-CoV-2-associated villitis seem to be more similar to villitis of unknown etiology than to infectious villitis.