Perinatal Outcomes Among Patients With Sepsis During Pregnancy.

Importance: Rates of maternal sepsis are increasing, and prior studies of maternal sepsis have focused on immediate maternal morbidity and mortality associated with sepsis during delivery admission. There are no data on pregnancy outcomes among individuals who recover from their infections prior to delivery. Objective: To describe perinatal outcomes among patients with antepartum sepsis who did not deliver during their infection hospitalization. Design, Setting, and Participants: This retrospective cohort study was conducted using data from August 1, 2012, to August 1, 2018, at an academic referral center in San Francisco, California. Included patients were all individuals with nonanomalous, singleton pregnancies who delivered after 20 weeks' gestation during the study period. Data were analyzed from March 2020 through March 2021. Exposures: Antepartum admission for infection with clinical concern for sepsis and hospital discharge prior to delivery. Main Outcomes and Measures: The primary outcome was a composite of perinatal outcomes associated with placental dysfunction and consisted of 1 or more of the following: fetal growth restriction, oligohydramnios, hypertensive disease of pregnancy, cesarean delivery for fetal indication, child who is small for gestational age, or stillbirth. Results: Among 14 565 patients with nonanomalous singleton pregnancies (mean [SD] age at delivery, 33.1 [5.2] years), 59 individuals (0.4%) were in the sepsis group and 14 506 individuals (99.6%) were in the nonsepsis group; 8533 individuals (59.0%) were nulliparous. Patients with sepsis, compared with patients in the reference group, were younger (mean [SD] age at delivery, 30.6 [5.7] years vs 33.1 [5.2] years; P < .001), were more likely to have pregestational diabetes (5 individuals [8.5%] vs 233 individuals [1.6%]; P = .003), and had higher mean (SD) pregestational body mass index scores (26.1 [6.1] vs 24.4 [5.9]; P = .03). In the sepsis group, the most common infections were urinary tract infections (24 patients [40.7%]) and pulmonary infections (22 patients [37.3%]). Among patients with sepsis, 5 individuals (8.5%) were admitted to the intensive care unit, the mean (SD) gestational age at infection was 24.6 (9.0) weeks, and the median (interquartile range) time from infection to delivery was 82 (42-147) days. Antepartum sepsis was associated with higher odds of placental dysfunction (21 patients [35.6%] vs 3450 patients [23.8%]; odds ratio, 1.77; 95% CI, 1.04-3.02; P = .04). On multivariable logistic regression analysis, antepartum sepsis was an independent factor associated with placental dysfunction (adjusted odds ratio, 1.88; 95% CI, 1.10-3.23; P = .02) after adjusting for possible confounders. Conclusions and Relevance: This study found that pregnancies complicated by antepartum sepsis were associated with higher odds of placental dysfunction. These findings suggest that increased antenatal surveillance should be considered for these patients.

The KRAS-variant and its impact on normal breast epithelial cell biology.

MicroRNA (miRNA)-binding site variants in 3' untranslated regions (3'UTRs) are a novel class of germ-line, functional mutations, which are now recognized as powerful biomarkers of human cancer risk and biology. The first mutation discovered in this class is the KRAS-variant, a let-7-binding site mutation in the 3'UTR of the KRAS oncogene. The KRAS-variant predicts increased cancer risk for certain populations, is a predictive biomarker of cancer treatment response across cancer types, leads to conserved tumor biology and elevated AKT signaling in KRAS-variant patient tumors, and was recently found to predict elevated TGF-ß and immunosuppression in cancer patients. Based on the functional biology of the KRAS-variant in cancer patients, here we chose to investigate altered normal cellular biology in the presence of the KRAS-variant, through interrogation of an isogenic normal breast epithelial cell line model with and without the KRAS-variant. We find that KRAS-variant normal breast epithelial cells exhibit a mesenchymal phenotype, which appears to be due to numerous molecular changes, including miRNA dysregulation and autocrine pathway alterations, including elevated TGF-ß, resulting in ZEB and SNAIL upregulation. Our findings support the hypothesis that the KRAS-variant has a fundamental biological impact on normal cellular biology, that is conserved in these patients when they develop cancer.