Development and validation of a model for individualized prediction of hospitalization risk in 4,536 patients with COVID-19.

BACKGROUND: Coronavirus Disease 2019 is a pandemic that is straining healthcare resources, mainly hospital beds. Multiple risk factors of disease progression requiring hospitalization have been identified, but medical decision-making remains complex. OBJECTIVE: To characterize a large cohort of patients hospitalized with COVID-19, their outcomes, develop and validate a statistical model that allows individualized prediction of future hospitalization risk for a patient newly diagnosed with COVID-19. DESIGN: Retrospective cohort study of patients with COVID-19 applying a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm to retain the most predictive features for hospitalization risk, followed by validation in a temporally distinct patient cohort. The final model was displayed as a nomogram and programmed into an online risk calculator. SETTING: One healthcare system in Ohio and Florida. PARTICIPANTS: All patients infected with SARS-CoV-2 between March 8, 2020 and June 5, 2020. Those tested before May 1 were included in the development cohort, while those tested May 1 and later comprised the validation cohort. MEASUREMENTS: Demographic, clinical, social influencers of health, exposure risk, medical co-morbidities, vaccination history, presenting symptoms, medications, and laboratory values were collected on all patients, and considered in our model development. RESULTS: 4,536 patients tested positive for SARS-CoV-2 during the study period. Of those, 958 (21.1%) required hospitalization. By day 3 of hospitalization, 24% of patients were transferred to the intensive care unit, and around half of the remaining patients were discharged home. Ten patients died. Hospitalization risk was increased with older age, black race, male sex, former smoking history, diabetes, hypertension, chronic lung disease, poor socioeconomic status, shortness of breath, diarrhea, and certain medications (NSAIDs, immunosuppressive treatment). Hospitalization risk was reduced with prior flu vaccination. Model discrimination was excellent with an area under the curve of 0.900 (95% confidence interval of 0.886-0.914) in the development cohort, and 0.813 (0.786, 0.839) in the validation cohort. The scaled Brier score was 42.6% (95% CI 37.8%, 47.4%) in the development cohort and 25.6% (19.9%, 31.3%) in the validation cohort. Calibration was very good. The online risk calculator is freely available and found at https://riskcalc.org/COVID19Hospitalization/. LIMITATION: Retrospective cohort design. CONCLUSION: Our study crystallizes published risk factors of COVID-19 progression, but also provides new data on the role of social influencers of health, race, and influenza vaccination. In a context of a pandemic and limited healthcare resources, individualized outcome prediction through this nomogram or online risk calculator can facilitate complex medical decision-making.

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium.

Estrogens are thought to promote labor by increasing the expression of pro-contraction genes in myometrial cells. The specific estrogen receptors ((ERs: ERα and ERß (also known as ESR1 and ESR2)) and G protein-coupled receptor 30 (GPR30; also known as G protein-coupled estrogen receptor 1)) and signaling pathways that mediate these actions are not clearly understood. In this study, we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol (E(2)) modulates expression of the gene encoding the oxytocin receptor (OXTR), a major pro-contraction protein. Using quantitative RT-PCR, we found that ERα and GPR30 mRNAs were expressed in the human pregnant myometrium while ERß mRNA was virtually undetectable. While mRNA encoding ERα was the predominant ER transcript in the pregnant myometrium, ERα protein was largely undetectable in myometrial tissue by immunoblotting. Pharmacological inhibition of 26S proteasome activity increased ERα protein abundance to detectable levels in term myometrial explants, however, indicating rapid turnover of ERα protein by proteasomal processing in the pregnant myometrium. E(2) stimulated rapid extranuclear signaling in myometrial explants, as evidenced by increased extracellularly regulated kinase (ERK1/2) phosphorylation within 10 min. This effect was inhibited by pre-treatment with an ER antagonist, ICI 182 780, indicating the involvement of ERα. Inhibition of ERK signaling abrogated the ability of E(2) to stimulate OXTR gene expression in myometrial explants. We conclude that estrogenic actions in the human myometrium during pregnancy, including the stimulation of contraction-associated gene expression, can be mediated by extranuclear signaling through ERα via activation of the ERK/mitogen-activated protein kinase pathway.

Magnesium sulfate for preterm labor and preterm birth.

Approximately half of the more than 500,000 preterm births each year result from preterm labor. Tocolytic therapy continues to be the focus of treatment of these women. Although a variety of tocolytics are used in clinical practice, magnesium sulfate remains one of the most commonly used agents. Magnesium sulfate has also been the focus of recent research for its potential neuroprotective effects for neonates born preterm. Evaluation of 19 randomized clinical trials reveals that magnesium sulfate tocolysis does not reduce the frequencies of delivery within 48 hours, 7 days, or early/late preterm birth, and is not associated with improvements in newborn morbidities or mortality. No other tocolytic class resulted in improved newborn outcomes when compared with magnesium sulfate tocolysis. We conclude that it is appropriate to withhold tocolysis with magnesium sulfate or other agents from women presenting in preterm labor as newborn benefit has not been demonstrated with such treatment. If initiated to achieve time for antenatal corticosteroid administration, or for other acute reasons, treatment can be discontinued once these goals have been achieved or if labor subsides before then. Because brief pregnancy prolongation is unlikely to improve newborn outcomes after corticosteroid administration has been completed, it is appropriate to withhold magnesium sulfate tocolysis from women with recurrent preterm labor thereafter. If magnesium sulfate is given for neuroprotection, a protocol from one of the three major trials that have demonstrated benefits should be used.

Nuclear progesterone receptor expression in the human fetal membranes and decidua at term before and after labor.

To explore how progesterone affects human pregnancy, we identified the progesterone target cells within the fetal membranes (amnion, chorion, and decidua) at term by assessing the extent of expression and localization of the nuclear progesterone receptors, progesterone receptor-A and progesterone receptor-B. Fetal membranes (separated into amnion and chorion-decidua) were obtained after term cesarean deliveries performed before (n = 7) and after (n = 7) labor onset. Nuclear progesterone receptor expression was determined by the abundance of nuclear progesterone receptor mRNAs (by quantitative reverse transcriptase-polymerase chain reaction) and proteins (by western blotting). Localization of nPRs was determined by immunohistochemistry. Progesterone receptor-A and progesterone receptor-B mRNA and protein levels were highest in the chorion-decidua and did not change in association with labor. Nuclear progesterone receptor mRNAs and proteins were barely detectable in amnion. Nuclear progesterone receptor immunostaining was detected only in the nucleus of decidual cells. These findings suggest that the decidua, and not the amnion and chorion, is a direct target for nuclear progesterone receptor-mediated progesterone actions during human pregnancy.

Small fetal size before 20 weeks' gestation: associations with maternal tobacco use, early preterm birth, and low birthweight.

OBJECTIVE: The objective of the study was to determine whether small fetal size before 20 weeks' gestation is associated with preterm birth (PTB), low birthweight (LBW), and poor fetal growth. STUDY DESIGN: A total of 4405 singleton pregnancies at 10-19 weeks' gestation (GA) based on a known last menstrual period (LMP) were evaluated. Ultrasound-estimated GA (US-GA) was calculated based on crown-rump length at 10-13 weeks and by femur, head, and abdominal measurements from 14 to 19 weeks. The outcomes were compared between small (1-10 days smaller than LMP-GA) and large (0-10 days larger than LMP-GA) fetuses. RESULTS: At 10-19 weeks, small fetuses measured 2.7 days younger and were more likely to have mothers who smoked (P = .004). Small fetuses had no more PTB (11.4 vs 12.1%, P = .47) but did have more early PTB before 34 (5.4 vs 4.3%, P = .07) and before 32 weeks (4.1 vs 2.7%, P = .009). Small fetuses had lower birthweights (BWT), more frequent BWT below 2500 g (13.0 vs 8.6%), below 1500 g (4.0 vs 2.4%), and below 1000 g (2.9 vs 1.4%) as well as BWT below 2500 g at term (4.9 vs 2.3%) and BWT less than the 10th percentile (8.8 vs 3.7%), P < or = .003 for each. Small fetuses at 10-19 weeks also had less frequent macrosomia and were less frequently large for gestational age at birth (P < .0001 for each). These findings largely persisted in multivariable analyses. CONCLUSION: Small fetal size at 10-19 weeks is associated with tobacco use in pregnancy, early PTB, LBW, and poor fetal growth.

Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A.

CONTEXT: We examined whether human parturition involves functional progesterone withdrawal mediated by changes in myometrial expression of progesterone receptors (PRs)-A and -B. OBJECTIVE: Our objectives were to: 1) measure PR-A and PR-B protein levels in human pregnancy myometrium and determine whether the PR-A to PR-B ratio changes with advancing gestation and labor onset; and 2) determine how changes in the PR-A to PR-B ratio affect myometrial cell progesterone responsiveness. DESIGN: PR protein levels and cellular localization were measured by Western blotting and immunohistochemistry, respectively, in lower uterine segment uterine wall tissue from preterm (<37 wk; not laboring; n = 5) and term (37-40 wk; not in labor: n = 6; in labor: n = 5) cesarean delivery. The capacity for PR-A and PR-B, alone and in combination, to mediate genomic progesterone responsiveness measured by the activity of a progesterone-responsive reporter plasmid was examined by artificially modulating their levels in the PHM1-31 myometrial cell line. RESULTS: PR-A and PR-B immunostaining was detected only in the nucleus of myometrial cells. The PR-A to PR-B protein ratio was 0.49 +/- 0.082 (mean +/- sem) in preterm tissue; increased to 1.03 +/- 0.071 (P < 0.001) in nonlaboring term tissue; and increased further to 2.65 +/- 0.344 (P < 0.001) in laboring term tissue. Only PR-B mediated progesterone-induced transcriptional activity. PR-A had no effect alone but markedly decreased PR-B-mediated progesterone responsiveness. CONCLUSIONS: Functional progesterone withdrawal in human parturition may be mediated by an increase in the myometrial PR-A to PR-B ratio due to increased PR-A expression.

Impact of weight loss between pregnancies on recurrent preterm birth.

OBJECTIVE: Low maternal pre-pregnancy body-mass index (BMI) has been associated with preterm birth (PTB). Women delivering preterm are at increased for recurrent PTB. Our goal was to determine whether change in BMI between pregnancies alters the risk of PTB. STUDY DESIGN: From our electronic perinatal database, we identified women who delivered consecutive pregnancies at our institution. Women were grouped by prepregnancy BMI category (underweight: <18.5, normal: 18.5-24.9, overweight: 25-29.9, obese: >30 kg/m2). They were then grouped based on change in actual BMI ("increase": >5 kg/m2, "stable": within 5 kg/m2, "decrease": >5 kg/m2) and change in BMI category between pregnancies. The risk of PTB was correlated to change in BMI. P < .05 was considered significant. RESULTS: One thousand two hundred forty-one women met inclusion criteria. Women with a PTB in their first pregnancy had more PTB in their second than those with a term birth in their first pregnancy (33.6% vs 8.0%, P < .001). Women whose BMI decreased more than 5 kg/m2 had more frequent PTB in the second pregnancy than those who did not (21.1% vs 9.3%, P = .01). For those with a term birth in the first pregnancy, PTB in the second did not increase with declining BMI. However, for women with a PTB in the first pregnancy, PTB was more frequent in the second if their BMI decreased a BMI category (53.8% vs 27.6%, P = .05) or if BMI decreased more than 5 kg/m2 (80.0% vs 28.2%, P = .01). CONCLUSION: Women whose BMI declines between pregnancies are at increased risk for PTB, particularly if they delivered a prior preterm gestation.