The Role Of Subclinical Infection And Cytokines In Preterm Parturition

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

SARS-CoV-2 infection during pregnancy and the risk of preeclampsia. Preeclampsia, a multisystem syndrome that complicates about 5% of pregnancies, is one of the leading causes of maternal mortality worldwide, accounting for approximately 14% of all maternal deaths. During the current pandemic, epidemiological studies have shown that pregnant women with SARS-CoV-2 infection have a significant increase in the risk of maternal death, admission to the intensive care unit, preterm birth, and stillbirth as compared to those without SARS-CoV-2 infection. Hence, we performed a systematic review and meta-analysis to assess whether SARS-CoV-2 infection during pregnancy also increases the risk of preeclampsia. A total of 28 studies that included 790,954 pregnant women, among which 15,524 were diagnosed with SARS-CoV-2 infection, met the inclusion criteria. Overall, meta-analyses of unadjusted and adjusted risk estimates showed that pregnant women with SARS-CoV-2 infection had a significantly increased risk of preeclampsia as compared to pregnant women without SARS-CoV-2 infection. Moreover, there was a significant increase in the odds of preeclampsia with severe features, eclampsia, and HELLP syndrome among pregnant women with SARS-CoV-2 infection, as compared to those without the infection. Both asymptomatic and symptomatic SARS-CoV-2 infections significantly increased the odds of preeclampsia, although it was higher among patients with symptomatic illness than among those with asymptomatic illness. We concluded that SARS-CoV-2 infection during pregnancy is associated with higher odds of preeclampsia and hypothesized that this relationship may be causal. The findings of our study have clear implications for patient care, public health policy, and future research (2). Clinical chorioamnionitis implications for clinical care Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. We found that: (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% vs. 38%; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40-58%); (7) neonatal bacteremia was diagnosed in 4.9% of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% of cases. These observations have implications for the diagnosis, treatment, and optimal management of the neonate born to mothers with the most common infection in obstetrics (14). Resolution of acute cervical insufficiency after antibiotics. Cervical insufficiency generally refers to a condition in which there is mid-trimester cervical dilatation or protruding chorioamniotic membranes in the absence of uterine contractions. Such condition is a risk factor for mid-trimester spontaneous abortion or early preterm birth, and is associated with adverse neonatal outcomes. Both intra-amniotic infection and inflammation ascertained by amniocentesis have been identified in patients with cervical insufficiency, and are poor prognostic factors. A subset of patients with intra-amniotic inflammation will have no demonstrable microorganisms detected via cultivation or molecular methods, and therefore represent cases of sterile intra-amniotic inflammation. Amniotic fluid sludge (free-floating hyperechogenic material within the amniotic fluid in close proximity to the uterine cervix) identified on sonography is a biomarker for intra-amniotic infection and inflammation. Recent evidence suggests that intra-amniotic infection, as well as sterile intra-amniotic inflammation can be treated successfully using antimicrobial agents. We reported a unique case in which administration of antibiotics in the presence of mid-trimester cervical insufficiency, sterile intra-amniotic inflammation, and amniotic fluid sludge was associated with resolution of the cervical findings (as demonstrated on both sonographic and speculum examination). The patient successfully underwent elective cesarean delivery at 36 2/7 weeks of gestation. This case illustrates that antibiotic therapy may be effective despite the presence of several high-risk pregnancy conditions, and that successful outcome is possible (17). The amniotic fluid cell-free transcriptome in spontaneous preterm labor. Amniotic fluid cell-free RNA was shown to reflect physiological and pathological processes in pregnancy, but its value in the prediction of spontaneous preterm delivery is unknown. We therefore profiled cell-free RNA in amniotic fluid samples collected from women who underwent transabdominal amniocentesis after an episode of spontaneous preterm labor and subsequently delivered within 24h or later in gestation. Expression of known placental single-cell RNA-Seq signatures was quantified in amniotic fluid cell-free RNA and compared between the groups. Random forest models were applied to predict time-to-delivery after amniocentesis. We found 2385 genes differentially expressed in samples of women who delivered within 24 h of amniocentesis compared to gestational age-matched samples from women who delivered after 24 h of amniocentesis. Genes with cell-free RNA changes were associated with immune and inflammatory processes related to the onset of labor, and the expression of placental single-cell RNA-Seq signatures of immune cells was increased with imminent delivery. Transcriptomic prediction models captured these effects and predicted delivery within 24 h of amniocentesis (area under the ROC=0.81). These results may inform the development of biomarkers for spontaneous preterm birth (1).