The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy

The importance of gaining insight into the mechanisms underlying uterine quiescence and contractility is highlighted by the absence of an effective strategy to prevent or treat preterm labor, the greatest cause of perinatal mortality and morbidity worldwide. Although current evidence suggests that in myometrial smooth muscle cells (mSMCs) calcium homeostasis is modulated near term to promote uterine contractility, the efficacy of blocking voltage-operated calcium channels is limited by dose-related cardiovascular side effects. Thus, we considered whether uterine contractility might be modulated by calcium entry via transient receptor potential vanilloid 4 (TRPV4) channels. In mSMC, TRPV4 gene and protein expression increased with gestation, and TRPV4-mediated Ca2+ entry and contractility were increased in mSMC from pregnant compared to nonpregnant rats. Cell membrane TRPV4 expression was specifically increased, whereas the expression of β-arrestin-1 and β-arrestin-2, molecules that can sequester TRPV4 in the cytoplasm, decreased. Physical interaction of β-arrestin-2 and TRPV4 was apparent in nonpregnant, but absent in pregnant, mouse uterus. Moreover, direct pharmacologic activation of TRPV4 increased uterine contraction, but oxytocin-induced myometrial contraction was blocked by pharmacologic inhibition of TRPV4 and decreased in mice with global deletion of TRPV4. Finally, TRPV4 channel blockade prolonged pregnancy in two distinct in vivomurinemodels of preterm labor, whereas the absence of either β-arrestin-1 or β-arrestin-2 increased susceptibility to preterm labor. These data suggest that TRPV4 channel activity modulates uterine contractility and might represent a therapeutic target to address preterm labor

Obstetric comorbidity scores and disparities in severe maternal morbidity across marginalized groups.

BACKGROUND: A recently developed obstetrical comorbidity scoring system enables the comparison of severe maternal morbidity rates independent of health status at the time of birth hospitalization. However, the scoring system has not been evaluated in racial-ethnic and socioeconomic groups or used to assess disparities in severe maternal morbidity. OBJECTIVE: This study aimed to evaluate the performance of an obstetrical comorbidity scoring system when applied across racial-ethnic and socioeconomic groups and to determine the effect of comorbidity score risk adjustment on disparities in severe maternal morbidity. STUDY DESIGN: We analyzed a population-based cohort of live births that occurred in California during 2011 through 2017 with linked birth certificates and birth hospitalization discharge data (n=3,308,554). We updated a previously developed comorbidity scoring system to include the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modifications diagnosis codes and applied the scoring system to subpopulations (groups) defined by race-ethnicity, nativity, payment method, and educational attainment. We then calculated the risk-adjusted rates of severe maternal morbidity (including and excluding blood transfusion-only cases) for each group and estimated the disparities for these outcomes before and after adjustment for the comorbidity score using logistic regression. RESULTS: The obstetric comorbidity scores performed consistently across groups (C-statistics ranged from 0.68 to 0.76; calibration curves demonstrated overall excellent prediction of absolute risk). All non-White groups had significantly elevated rates of severe maternal morbidity before and after risk adjustment for comorbidities when compared with the White group (1.3% before, 1.3% after) (American Indian-Alaska Native: 2.1% before, 1.8% after; Asian: 1.5% before, 1.7% after; Black: 2.5% before, 2.0% after; Latinx: 1.6% before, 1.7% after; Pacific Islander: 2.2% before, 1.9% after; and multi-race groups: 1.7% before, 1.6% after). Risk adjustment also modestly increased disparities for the foreign-born group and government insurance groups. Higher educational attainment was associated with decreased severe maternal morbidity rates, which was largely unaffected by comorbidity risk adjustment. The pattern of results was the same whether or not transfusion-only cases were included as severe maternal morbidity. CONCLUSION: These results support the use of an updated comorbidity scoring system to assess disparities in severe maternal morbidity. Disparities in severe maternal morbidity decreased in magnitude for some racial-ethnic and socioeconomic groups and increased in magnitude for other groups after adjustment for the comorbidity score