新冠病毒感染与母婴炎症反应、不良妊娠结局有关
创作:Epi汪 审核:Epi汪 2022年06月10日
  • 纳入306名孕妇,包括新冠阳性组、COVID-19疫苗接种组和阴性对照组,对母婴的样本进行多种炎症因子检测;
  • 疫苗组女性TNF-α水平较低,而新冠阳性组IL-6水平较高;
  • 新冠阳性组婴儿的脐带血中IL-10水平增高,而疫苗组未观察到变化;
  • 未观察到母亲炎症因子水平与子痫前期或血管灌注不良结局存在关联;
  • TNF-α水平与早产风险呈正相关;
  • 新冠阳性组女性胎盘血管灌注不良、早产的风险增高。
主编推荐语
Epi汪
COVID-19感染,即使是轻微的,也与母体的炎症反应有关。但这个过程在怀孕期间尚未得到很好的描述。COVID-19与早产、先兆子痫 、胎盘血管病变等相关,其中是否是炎症反应导致的,并不清楚。而疫苗接种也会导致与免疫反应增强相关的轻微病毒症状,但尚不清楚这种免疫反应是否会导致炎症细胞因子通路激活。基于这些问题,本研究开展了人群的研究。
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延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!

Impact of COVID-19 disease and COVID-19 vaccination on maternal or fetal inflammatory response, placental pathology, and perinatal outcomes

COVID-19和疫苗接种对母体/胎儿炎症反应、胎盘病理学和围产期结果的影响

10.1016/j.ajog.2022.05.049

2022-05-28, Article

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OBJECTIVE: COVID-19 disease, even mild, is associated with a host inflammatory response1, which has not been well delineated in pregnancy. COVID-19 disease is associated with preterm birth2, preeclampsia2, and placental vascular pathology3. While COVID-19 vaccination does result in mild viral-type symptoms associated with a heighted immune response, it is not known whether this immune response results in inflammatory cytokine pathway activation. Our objective is to evaluate the impact of COVID-19 disease and vaccination on the maternal-fetal unit through study of inflammatory cytokine panel at delivery, placental pathology, and perinatal outcomes.
STUDY DESIGN: This is a retrospective cohort study of pregnant patients who delivered at Thomas Jefferson University Hospital from March 2020-July 2021 and consented to an ongoing delivery sample biorepository. With our convenience sample of ~300 we anticipated at least 15% rate of COVID disease or vaccination, or N≥50 in each group. The cohort was categorized as 1) Control- no COVID-19 disease or vaccination history; 2) COVID-19 disease (PCR) during pregnancy, and 3) COVID-19 mRNA vaccination during pregnancy (patient report). Those with both COVID-19 disease and vaccination were excluded. Placental histopathology was sent for standard clinical criteria. Cytokine paneling completed on those with maternal or cordblood samples available and without a diagnosis of clinical triple-I. Cytokine analysis was done using the Mesoscale Diagnostics (MSD) platform using the 10-plex human pro-inflammatory panel kit (IL1β, IL8, IL2, IL4, IL6, IL10, IL12p70, IL13, IFNγ, TNFα) and read on a QuickPlex SQ120 (Mesoscale, Gaithersburg, MD).
RESULTS: 306 were included, Control (N=198), COVID+ (N=59) and COVID vaccine (N=49). There were significant differences in age, BMI, and race between groups (Supplemental table 1). Mean latency to delivery was similar between COVID vaccine and COVID positive groups (89.5±46.6 days vs 71.0 ± 78.6 days respectively, p=0.14), although more in the COVID-vaccine group had latency >30 days from delivery compared to COVID disease (91.7% vs 60.7%, p<0.001). Of those with COVID, 54 (91.5%) were mild, none were severe. Maternal cytokine analysis included N=142 control, N=58 COVID disease, and N=42 COVID vaccine. COVID-19 vaccination had lower median TNFα concentrations than COVIDdisease or control (p=0.001), while COVID-disease had higher median IL-6 compared to control (p=0.04) (Figure 1a, supplemental Figure 1). IL-6 and TNFα levels were not correlated with latency from exposure to delivery (> or <30 days) among those with COVID-19 disease (Pearson correlation coefficient r=0.10, p=0.48 and r=0, p>0.99 respectively) or among those with COVID-19 vaccination (r=0.12, p=0.46 and r=0.14, p=0.40 respectively). Among cordblood samples, COVID-19 disease, but not vaccination, was associated with elevated cord blood IL-10 compared to control (p=0.04), although this did not remain significant after Bonferroni correction (p=0.14) (Figure 1a, supplemental Figure 2). Correlation matrices were generated to assess differences in the cytokine environment between groups. Significant correlation between IL12/IL13/IL-2 was seen in control maternal samples and IL12/IL13/IL4 in COVID-vaccine maternal serum samples. These relationships suggest a balanced Th1/Th2 profile without a pro-inflammatory tendency. Samples from COVID-19 positive maternal serum samples shows a strong correlation between IL10/TNFα/IL1β/IL8 indicating a pro-inflammatory milieu (Figure 1b). Cytokine milieu in cord blood samples were similar across cohorts (Figure 1c). There was a positive correlation betweencertain maternal and cord blood Th1 and Th2 markers (IL-12, IL-13, IL-2, IL-4, and TNFα) (Supplemental Figure 3). Using multivariable logistic regression we evaluated association of cytokines with the outcomes of preeclampsia, preterm birth, and placental maternal vascular malperfusion (MVM). No maternal cytokines were associated with preeclampsia or MVM. TNFα was positively associated with preterm birth (B= 1.58 (1.15-2.15, p=0.004) (Supplemental table 4a-c). Similar findings were noted in the subgroup of those with documented COVID-19 infection (Supplemental Table 5a-c); TNFα remained significantly associated with preterm birth risk (B=3.77 (1.34-10.61), p=0.01)). COVID-19 disease, but not vaccination, was associated with a significantly higher rate of placental MVM (55.8% vs 35.8%, aOR 2.34 (1.16-4.73)) and preterm birth (15.3% vs 6.6%, aOR 4.54 (1.61-12.78)) compared to control (Table 1). Among those with COVID-19 during pregnancy and placental pathology available (N=52), 19 reported aspirin use. The rate of placental MVM was lower with aspirin, although not statistically significant (42.5% vs 63.6%, p=0.13). In contrast, among N=95 control, the rate of placental MVM was higher in the aspirin group (48.5% vs 29.0%, p=0.06), as expected based on baseline risk factors prompting aspirin use. There was no correlation between placental MVM and COVID-19 latency (greater or less than 30 days) (r= -0.10, p=0.51).
CONCLUSION: COVID-19 disease, but not vaccination, in pregnancy is associated with increased inflammatory cytokines, placental vascular pathology, and preterm delivery. This inflammatory signature, specifically TNFα, was correlated with preterm birth risk but not placental vascular pathology, suggesting potentially divergent pathways related to these downstream consequences.19 vaccination, despite mild viral-like symptoms, did not elicit the same pathological effects, providing both pathophysiological and clinical evidence of safety of mRNA vaccines in pregnancy. Compared to a smaller study4, we did not identify a fetal inflammatory signature associated with COVID-19. It is likely there was undocumented COVID-19 disease exposure in the control or vaccine groups3, although it would not be possible to determine if this exposure were prior to or during pregnancy, and if anything this would lead to Type 1 error. Further research is needed to elaborate on the pathophysiological basis for adverse perinatal outcomes following maternal COVID-19, timing of infection and risk of these outcomes, and how therapies, such as aspirin, may mitigate these downstream perinatal effects5.

First Authors:
Rupsa C Boelig

Correspondence Authors:
Rupsa C Boelig

All Authors:
Rupsa C Boelig,Zubair H Aghai,Sidhartha Chaudhury,Adina S Kazan,Joanna S Y Chan,Elke Bergmann-Leitner

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