Browsing by Author "Patil, Avinash S."
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Item Alterations in endogenous progesterone metabolism associated with spontaneous very preterm delivery(Oxford University Press, 2020) Patil, Avinash S.; Gaikwad, Nilesh W.; Grotegut, Chad A.; Dowden, Shelley D.; Haas, David M.; Medicine, School of MedicineStudy question: Do maternal serum levels of progesterone metabolites early in pregnancy correspond to an increased risk for very preterm delivery prior to 32 weeks? Summary answer: Maternal serum levels of 11-deoxycorticosterone (DOC) measured during the late first trimester or early second trimester correlate with an increased risk for preterm delivery prior to 32 weeks, and the correlation becomes stronger when the ratio of DOC to 16-alpha-hydroxyprogesterone was measured. What is known already: Progesterone is a pro-gestational steroid hormone that has been shown to decrease the risk of preterm birth in some pregnant women. Progesterone is metabolized by the body into various metabolites including members of the mineralocorticoid and glucocorticoid families. Our group has previously demonstrated that some progesterone metabolites enhance myometrial contractility in an ex vivo system, while others result in myometrial relaxation. The current exploratory study was designed to determine if pre-specified metabolites of progesterone measured early in pregnancy were associated with a woman's risk for delivery prior to 32 weeks, which is referred to as a very preterm delivery. Study design size duration: The Building Blocks of Pregnancy Biobank (BBPB) is a biorepository at Indiana University (IU) that follows women prospectively through their pregnancy. A variety of biospecimens are collected at various time points during a woman's pregnancy. Women participating in the IU BBPB who were enrolled after 8 weeks' gestation with pregnancy outcome data were eligible for participation. Participants/materials setting methods: Women delivering prior to 37 weeks (preterm) and at or after 37 weeks (term) who had blood samples collected during the late first trimester/early second trimester and/or during the early third trimester were identified. These samples were then processed for mass spectroscopy, and the amount of progesterone and progesterone metabolites in the samples were measured. Mean values of each measured steroid metabolite were calculated and compared among women delivering at less than 32 weeks, less than 37 weeks and greater than or equal to 37 weeks. Receiver operating characteristic (ROC) curves were constructed and threshold levels determined for each compound to identify a level above or below which best predicted a woman's risk for delivery prior to 32 and prior to 37 weeks. Mann-Whitney U nonparametric testing with Holm-Bonferroni correction for multiple comparisons was utilized to identify steroid ratios that could differentiate women delivering spontaneously at less than 32 weeks from all other pregnancies. Main results and the role of chance: Steroid hormone levels and pregnancy outcome data were available for 93 women; 28 delivering prior to 32 weeks, 40 delivering between 32 0/7 and 36 6/7 weeks and 25 delivering at or greater than 37 weeks: the mean gestational age at delivery within the three groups was 27.0, 34.4 and 38.8 weeks, respectively. Among women delivering spontaneously at less than 37 weeks, maternal 11-deoxycorticosterone (DOC) levels drawn in the late first trimester/early second trimester were significantly associated with spontaneous preterm delivery prior to 32 weeks; a threshold level of 47.5 pg/ml had 78% sensitivity, 73% specificity and an AUC of 0.77 (P = 0.044). When DOC levels were analyzed as a ratio with other measured steroid hormones, the ratio of DOC to 16-alpha-hydroxyprogesterone among women delivering spontaneously prior to 37 weeks was able to significantly discriminate women delivering prior to 32 weeks from those delivering at or greater than 32 weeks, with a threshold value of 0.2 with 89% sensitivity, 91% specificity and an AUC of 0.92 (P = 0.002). When the entire study cohort population was considered, including women delivering at term and women having an iatrogenic preterm delivery, the ratio of DOC to 16-alpha-hydroxyprogesterone was able to discriminate women delivering spontaneously prior to 32 weeks from the rest of the population at a threshold of 0.18 and 89% sensitivity, 59% specificity and an AUC of 0.81 (P = 0.003). Limitations reasons for caution: This is a discovery study, and the findings have not been validated on an independent cohort. To mitigate issues with multiple comparisons, we limited our study to pre-specified metabolites that are most representative of the major metabolic pathways for progesterone, and adjustments for multiple comparisons were made. Wider implications of the findings: Spontaneous preterm birth is increasingly being recognized to represent a common end pathway for a number of different disease phenotypes that include infection, inflammation, premature rupture of the membranes, uterine over distension, cervical insufficiency, placental dysfunction and genetic predisposition. In addition to these phenotypes, longitudinal changes in the maternal-fetal hypothalamic-pituitary-adrenal (HPA) axis also likely contribute to a significant proportion of the disease burden of spontaneous preterm birth. Here, we demonstrate that differential production of steroid metabolites is associated with very early preterm birth. The identified biomarkers may hint at a pathophysiologic mechanism and changes in the maternal-fetal dyad that result in preterm delivery. The early identification of abnormal changes in HPA axis metabolites may allow for targeted interventions that reverse the aberrant steroid metabolic profile to a more favorable one, thereby decreasing the risk for early delivery. Further research is therefore required to validate and extend the results presented here. Study funding/competing interests: Funding for this study was provided from the Office of the Vice Chancellor for Research at IUPUI, 'Funding Opportunities for Research Commercialization and Economic Success (FORCES) grant'.Both A.S.P. and C.A.G. are affiliated with Nixxi, a biotech startup. The remaining authors report no conflict of interest.Item Is personalized medicine achievable in obstetrics?(Elsevier - WB Saunders, 2014-12) Quinney, Sara K.; Patil, Avinash S.; Flockhart, David A.; Department of Obstetrics and Gynecology, IU School of MedicinePersonalized medicine seeks to identify the right dose of the right drug for the right patient at the right time. Typically, individualization of therapy is based on the pharmacogenomic makeup of the individual and environmental factors that alter drug disposition and response. In addition to these factors, during pregnancy, a woman's body undergoes many changes that can impact the therapeutic efficacy of medications. Yet, there is minimal research regarding personalized medicine in obstetrics. Adoption of pharmacogenetic testing into the obstetrical care is dependent on evidence of analytical validity, clinical validity, and clinical utility. Here, we briefly present information regarding the potential utility of personalized medicine for treating the obstetric patient for pain with narcotics, hypertension, and preterm labor, and discuss the impediments of bringing personalized medicine to the obstetrical clinic.Item Prediction of neonatal morbidity and very preterm delivery using maternal steroid biomarkers in early gestation(PLOS, 2021-01-06) Patil, Avinash S.; Grotegut, Chad A.; Gaikwad, Nilesh W.; Dowden, Shelley D.; Haas, David M.; Obstetrics and Gynecology, School of MedicineBackground: Preterm delivery is a common pregnancy complication that can result in significant neonatal morbidity and mortality. Limited tools exist to predict preterm birth, and none to predict neonatal morbidity, from early in pregnancy. The objective of this study was to determine if the progesterone metabolites 11-deoxycorticosterone (DOC) and 16-alpha hydroxyprogesterone (16α-OHP), when combined with patient demographic and obstetric history known during the pregnancy, are predictive of preterm delivery-associated neonatal morbidity, neonatal length of stay, and risk for spontaneous preterm delivery prior to 32 weeks' gestation. Methods and findings: We conducted a cohort study of pregnant women with plasma samples collected as part of Building Blocks of Pregnancy Biobank at the Indiana University School of Medicine. The progesterone metabolites, DOC and 16α-OHP, were quantified by mass spectroscopy from the plasma of 58 pregnant women collected in the late first trimester/early second trimester. Steroid levels were combined with patient demographic and obstetric history data in multivariable logistic regression models. The primary outcome was composite neonatal morbidity as measured by the Hassan scale. Secondary outcomes included neonatal length of stay and spontaneous preterm delivery prior to 32 weeks' gestation. The final neonatal morbidity model, which incorporated antenatal corticosteroid exposure and fetal sex, was able to predict high morbidity (Hassan score ≥ 2) with an area under the ROC curve (AUROC) of 0.975 (95% CI 0.932, 1.00), while the model without corticosteroid and fetal sex predictors demonstrated an AUROC of 0.927 (95% CI 0.824, 1.00). The Hassan score was highly correlated with neonatal length of stay (p<0.001), allowing the neonatal morbidity model to also predict increased neonatal length of stay (53 [IQR 22, 76] days vs. 4.5 [2, 31] days, above and below the model cut point, respectively; p = 0.0017). Spontaneous preterm delivery prior to 32 weeks' gestation was also predicted with an AUROC of 0.94 (95% CI 0.869, 1.00). Conclusions: Plasma levels of DOC and 16α-OHP in early gestation can be combined with patient demographic and clinical data to predict significant neonatal morbidity, neonatal length of stay, and risk for very preterm delivery, though validation studies are needed to verify these findings. Early identification of pregnancies at risk for preterm delivery and neonatal morbidity allows for timely implementation of multidisciplinary care to improve perinatal outcomes.Item Progesterone Metabolites Inhibit the Human Ether-a-go-go-Related Gene and Predict QT Interval Length(Wiley, 2020) Shugg, Tyler; Egly, Christian; Stamatkin, Chris W.; Patil, Avinash S.; Tisdale, James E.; Overholser, Brian R.; Medicine, School of MedicineA decrease in the human ether-a-go-go-related gene (hERG/KCNH2)-related channel has been linked to intrauterine fetal death. The formation of cytochrome P450 (CYP) 3A-mediated progesterone metabolites, 6-beta-hydroxy-progesterone (6β-OHP) and 16α-hydroxy-progesterone (16α-OHP), is variable among adults and differs from fetal metabolism. The primary objective of this study was to assess the potential for progesterone metabolites to inhibit hERG-related current and predict QTc intervals. Whole-cell voltage-clamp electrophysiology was performed on human embryonic kidney 293 cells stably expressing hERG exposed to progesterone or metabolites. Both 6β-OHP and 16α-OHP positively shifted the voltage dependence of activation relative to vehicle from −4.0 ± 0.8 to −0.3 ± 0.8 mV, P < .01; and 1.0 ± 0.6 mV, P < .01, respectively. In addition, 6β-OHP decreased maximal outward tail currents from 49.4 ± 4.9 to 32.5 ± 4.1 pA/pF, P < 0.01, and reduced the expression of fully glycosylated hERG by 42%. Healthy female subjects were administered progesterone 400 mg orally for 7 days, ibutilide 0.003 mg/kg was infused, and serial electrocardiograms and blood samples collected. Relationships between rate-corrected QT intervals (QTcI) with circulating hormones and metabolites were assessed. The 6β-OHP and 16α-OHP metabolites were independent predictors of QTcI intervals prior to and following ibutilide administration. In conclusion, the progesterone metabolites formed via CYP3A cause inhibitory effects on hERG channels and predict QTcI intervals in healthy women pretreated with progesterone. Further study into maternal and fetal exposure to these metabolites and potential to prolong cardiac repolarization is warranted.Item Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model(Sage, 2015-12) Patil, Avinash S.; Swamy, Geeta K.; Murtha, Amy P.; Heine, R. Phillips; Zheng, Xiaomei; Grotegut, Chad A.; Department of Obstetrics and Gynecology, IU School of MedicineObjective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility.Item Pseudo-monoamniotic Pregnancy: Case Report and Review of Etiologic Considerations(Taylor and Francis, 2015) Patil, Avinash S.; Martin, Jessica; Tsukahara, Katharine; Skljarevski, Anja; Miller, Katherine; Towns, Rachel; Schubert, Frank P.; Department of Obstetrics and Gynecology, IU School of MedicinePseudomonoamniotic gestations are increasingly recognized through sonographic surveillance of monochorionic twins, though etiologic factors remain undefined. We present a case of spontaneous pseudomonoamniotic twins and propose umbilical cord insertion proximity as a sonographic marker. Systematic review of the literature was performed and additional cases with similar findings were noted. Approximately 75% of reported cases (28/37) were deemed spontaneous and several included short inter-cord distances. Shunting of blood away from the membranes in the region between the cord insertions may be responsible for membrane rupture. Further investigation is needed into short inter-cord distance as a marker for monochorionic twins at risk to become a pseudomonoamniotic gestation.Item Psychotropic Medications in Pregnancy and the Postpartum Period(Libertas Academia, 2015-07) Haas, David M.; McHugh, Katherine W.; Durst, Paula J.; Rose, Sarah M.; Patil, Avinash S.; Department of Obstetrics & Gynecology, IU School of MedicineMany pregnant women suffer from mental health conditions while pregnant. As providers and patients make decisions about risks of the conditions and treatments during pregnancy, information to populate those discussions is needed. Taking into account the physiologic changes in pregnancy, we may need to optimize medication therapy. This article reviews and summarizes some of the most common mental health conditions suffered in pregnancy: depression, bipolar disorder, anxiety, and psychosis. It further discusses the different medications used to treat them, as well as risks associated with these medications.Item Uterocervical angle measurement improves prediction of preterm birth in twin gestation(Thieme, 2017-01) Knight, Jordan C.; Tenbrink, Emily; Onslow, Mitchell; Patil, Avinash S.; Obstetrics and Gynecology, School of MedicineObjective An obtuse uterocervical angle (UCA) has been associated with increased risk of preterm birth in singleton gestations. Our objective was to compare the performance of UCA to cervical length (CL) as sonographic predictors of spontaneous preterm birth (sPTB) in patients with twin gestation. Study Design We conducted a retrospective cohort study of twin gestations at a single academic center from May 2008-2016 who received a transvaginal ultrasound for the evaluation of the cervix between 16 0/7 - 22 6/7 weeks. An investigator blinded to clinical outcomes reviewed images of cervical morphology and measured UCA and CL parameters. Data on obstetrical outcomes was extracted from the medical record. The primary outcome was prediction of preterm birth <28 weeks and <32 weeks by UCA and CL. Receiver operator characteristic (ROC) curves and binary logistic regression were used for statistical analysis. Statistical significance was defined as p <0.05. Results Among 259 women with twin gestation, the mean gestational age at birth was 34.83 +/- 3.48 weeks, and 44.7% (n=116) delivered prior to 36 weeks. ROC curves demonstrated optimal prediction of sPTB prior to 32 weeks at a UCA > 110o (80% sensitivity, 82% specificity) vs. CL < 25mm (27% sensitivity, 93% specificity; p<0.001) and similarly, prior to 28 weeks at a UCA>114o (80% sensitivity, 84% specificity) vs. CL< 25mm (35% sensitivity, 90% specificity; p<0.001, Figure). Binary logistic regression revealed UCA > 110o conferred an OR 15.7 (95% CI 7.2-34.4) for delivery prior to 32 weeks, and UCA > 114o an OR 24.3 (95% CI 6.7-88.5) for delivery prior to 28 weeks. In comparison, CL<25mm had an OR 5.2 (95% CI 2.2-12.2) and OR 6.0 (95% CI 2.0-18.1) prior to 32 and 28 weeks respectively. Conclusion Uterocervical angles >110o performed better than the traditional cervical length threshold (25mm) for the prediction of sPTB in a cohort of twin gestations. Measurement of the UCA during the mid-trimester may improve identification of twin gestations at risk for sPTB.