The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

Association between cigarette smoking and ovarian reserve among women seeking fertility care.

INTRODUCTION: This study examined the association of smoking with ovarian reserve in a cross-sectional study of 207 women enrolled in the Louisville Tobacco Smoke Exposure, Genetic Susceptibility, and Infertility (LOUSSI) Study and assessed effect modification by NAT2 acetylator phenotype. METHODS: Information on current smoking status was collected using a structured questionnaire and confirmed by cotinine assay. Serum anti-Müllerian hormone (AMH) levels were used to assess ovarian reserve. Diminished ovarian reserve (DOR) was defined as AMH <1ng/mL. Single nucleotide polymorphisms in the NAT2 gene, which metabolizes toxins found in cigarette smoke, were analyzed to determine NAT2 acetylator status. Linear and logistic regression were used to determine the effects of smoking on ovarian reserve and evaluate effect modification by NAT2. Regression analyses were stratified by polycystic ovary syndrome (PCOS) status and adjusted for age. RESULTS: Current smoking status, either passive or active as measured by urinary cotinine assay, was not significantly associated with DOR. For dose-response assessed using self-report, the odds of DOR increased significantly for every additional cigarette currently smoked (Odds ratio, OR:1.08; 95% confidence interval, 95%CI:1.01-1.15); additionally, every 1 pack-year increase in lifetime exposure was associated with an increased odds of DOR among women without PCOS (OR: 1.08 95%CI: 0.99-1.18). These trends appear to be driven by the heavy or long-term smokers. Effect modification by NAT2 genotype was not established. CONCLUSION: A history of heavy smoking may indicate increased risk of diminished ovarian reserve.

Pharmacokinetics of vaginal versus buccal misoprostol for labor induction at term.

The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 µg followed by 50 µg doses every 4 h. Misoprostol acid concentrations were determined using liquid chromatography-tandem mass spectrometry for the first 8 h in a subgroup of participants. A population pharmacokinetic model was developed using NONMEM. Plasma concentrations (n = 469) from 47 women were fit to a one-compartment nonlinear clearance model. The absorption rate constant (ka ) was dependent on both route and dose of administration: buccal 25 µg 0.724 (95% confidence interval, 0.54-0.92) h-1 ; 50 µg 0.531 (0.37-0.63) h-1 ; vaginal 25 µg 0.507 (0. 2-1. 4) h-1 ; and 50 µg 0.246 (0.103-0.453) h-1 . Relative bioavailability for vaginal compared to buccal route was 2.4 (1.63-4.77). There was no effect of body mass index or age on apparent clearance 705 (431-1099) L/h or apparent volume of distribution 632 (343-1008) L. The area under the concentration-time curve to 4 h following the first 25 µg dose of misoprostol was 16.5 (15.4-17.5) pg h/ml for buccal and 34.3 (32.5-36.1) pg h/ml for vaginal administration. The rate of buccal absorption was two times faster than that of vaginal, whereas bioavailability of vaginal administration was 2.4 times higher than that of buccal. Decreased time to delivery observed with vaginal dosing may be due to higher exposure to misoprostol acid compared to buccal.

Current Practices and Preferences of Fellows and Program Directors on Taking the Certifying Examination During Subspecialty Fellowships.

OBJECTIVE: Fellows in obstetrics and gynecology subspecialties often take their oral specialty certifying examination (referred to here as generalist certifying examination [GCE]) during fellowship. We sought to compare the opinions of current fellows and program directors (PDs) regarding their program's handling of GCE during fellowship. METHODS: In this online, survey-based study, fellows and PDs currently affiliated with an accredited fellowship in maternal-fetal medicine, reproductive endocrinology and infertility, female pelvic medicine and reconstructive surgery, or gynecologic oncology (GO) received the link to an unvalidated survey. This survey was open for 8 weeks, between April and June 2020; eligible participants were contacted through their programs, society Listserv, and social media and received 3 reminder e-mails. RESULTS: Final analysis included 408 (408/834; response rate, 49%) fellows and 163 (163/223; response rate, 73%) PDs across the 4 subspecialties. There were significant differences in whether fellows responded that they were required or encouraged to take the GCE (52% maternal-fetal medicine, 65% reproductive endocrinology and infertility, 39% female pelvic medicine and reconstructive surgery, 8% GO; P < 0.01) during fellowship. Fewer GO fellows noted that they were permitted to use educational funds for GCE when compared with the other subspecialties (P < 0.01). Most fellows responded that the inability to take GCE during fellowship would decrease their satisfaction with fellowship, and this was significantly higher than PD estimates (78% vs 39%, P < 0.01). CONCLUSIONS: There are significant differences in reported ability to take GCE during fellowship across different obstetrics and gynecology subspecialty fellowships. Program directors significantly underestimate fellow dissatisfaction with inability to take GCE during fellowship.

Utility of Endocervical Sampling at Time of Colposcopy when Referral Cytology Is Low Grade or Better.

The utility of endocervical sampling at the time of colposcopic examination after less than high-grade screening Papanicolaou smear is unknown. To address this question, we performed a retrospective review using a colposcopy patient care database maintained at our urban academic medical center. We examined the prevalence of high-grade dysplasia in endocervical samples, the prevalence of high-grade dysplasia in directed cervical biopsies, and the correlations between high-grade endocervical dysplasia and patient factors of age and time to colposcopy. A total of 3026 patient records met inclusion criteria. Mean age at the time of colposcopy was 30 ± 9 years with a range of 21-75 years. The mean time to colposcopy was 96 ± 90 days with a range of 4-1207 days. There was no difference in mean age or days to colposcopy in women who had grade 2 or greater cervical intraepithelial neoplasia on endocervical sampling compared to those who did not. The overall prevalence of high-grade dysplasia in endocervical samples in women with less than high-grade screening Pap results was 5.3%. For all entries, 4.2% (126/3026) had grade 2 or greater cervical intraepithelial neoplasia on endocervical sampling that would not otherwise have been identified. This study demonstrates that endocervical sampling has diagnostic utility in the setting of less than high-grade referral Pap smears. No benefit was demonstrated in patients with normal cytology and high-risk strains of human papillomavirus identified on referral Pap.

A comparison of vaginal versus buccal misoprostol for cervical ripening in women for labor induction at term (the IMPROVE trial): a triple-masked randomized controlled trial.

BACKGROUND: Cervical ripening is commonly needed for labor induction. Finding an optimal route of misoprostol dosing for efficacy, safety, and patient satisfaction is important and not well studied for the buccal route. OBJECTIVE: To compare the efficacy and safety of vaginal and buccal misoprostol for women undergoing labor induction at term. STUDY DESIGN: The IMPROVE trial was an institutional review board-approved, triple-masked, placebo-controlled randomized noninferiority trial for women undergoing labor induction at term with a Bishop score ≤6. Enrolled women received 25 mcg (first dose), then 50 mcg (subsequent doses) of misoprostol by assigned route (vaginal or buccal) and a matching placebo tablet by the opposite route. The primary outcomes were time to delivery and the rate of cesarean delivery performed urgently for fetal nonreassurance. A sample size of 300 was planned to test the noninferiority hypothesis. RESULTS: The trial enrolled 319 women, with 300 available for analysis, 152 in the vaginal misoprostol group and 148 in the buccal. Groups had similar baseline characteristics. We were unable to demonstrate noninferiority. The time to vaginal delivery was lower for the vaginal misoprostol group (median [95% confidence interval] in hours: vaginal: 20.1 [18.2, 22.8] vs buccal: 28.1 [24.1, 31.4], log-rank test P = .006, Pnoninferiority = .663). The rate of cesarean deliveries for nonreassuring fetal status was 3.3% for the vaginal misoprostol group and 9.5% for the buccal misoprostol group (P = .033). The rate of vaginal delivery in <24 hours was higher in the vaginal group (58.6% vs 39.2%, P = .001). CONCLUSION: We were unable to demonstrate noninferiority. In leading to a higher rate of vaginal deliveries, more rapid vaginal delivery, and fewer cesareans for fetal issues, vaginal misoprostol may be superior to buccal misoprostol for cervical ripening at term.

Buccal versus Vaginal Misoprostol for Term Induction of Labor: A Retrospective Cohort Study.

OBJECTIVE: To compare the efficacy of similar buccal and vaginal misoprostol doses for induction of labor. STUDY DESIGN: Retrospective chart review of 207 consecutive women undergoing term induction of labor with misoprostol. Misoprostol route and dosing were collected. Time to delivery and other labor outcomes (e.g., vaginal delivery less than 24 hours) were compared between women receiving buccal and vaginal misoprostol. RESULTS: There was no significant difference in time to delivery for women receiving buccal (median 18.2 hour, 95% confidence interval [CI] = [14.9, 21.5]) versus vaginal (median 18.3 hour, 95% CI = [15.0, 20.4]) misoprostol (p = 0.428); even after adjusting for covariates (p = 0.381). Women who presented with premature rupture of membranes were more likely to receive buccal misoprostol (92.7% received buccal vs. 7.3% received vaginal, p < 0.001). A similar number of women delivered vaginally in the buccal group (88.2%) and vaginal misoprostol group (86.8%, p = 0.835). The proportion of women who experienced uterine tachysystole or chorioamnionitis did not significantly differ by route of administration. CONCLUSION: We found no significant differences in time to delivery or other labor outcomes between buccal or vaginal dosing of misoprostol in women undergoing labor induction at term.

A review of post-caesarean infectious morbidity: how to prevent and treat.

Post-caesarean infectious complications result in significant maternal morbidity and mortality as well as increased readmissions and increased health care cost worldwide. This review provides a discussion of several risk factors that have been identified which predispose women to post-surgical infection. We also provide an overview of strategies for infection prevention including antibiotics, surgical techniques and negative pressure wound therapy. Criteria for diagnosis of wound infection are provided, as well as appropriate treatment regimens. Given the impact of maternal post caesarean infection, it is important for women's health care providers to understand how to prevent these infections, as well as recognise and treat them.

Survey of Provider Preferences Regarding the Route of Misoprostol for Induction of Labor at Term.

Objective To survey obstetrical provider preferences regarding use of misoprostol for induction of labor (IOL). Methods An anonymous 25-question survey was distributed at an American College of Obstetricians and Gynecologists (ACOG) joint District V and VII Meeting in 2014 to obstetrics providers. The same survey was sent electronically to local providers. A separate survey was emailed to the labor and delivery nurses at two of the teaching hospitals in Indianapolis. The surveys queried provider demographics, dosing practice for misoprostol, opinions regarding different dosing strategies, and instructions on buccal administration. Results A total of 113 (46.5%) providers responded. Of these, 92.9% used misoprostol for IOL, 73% preferred the vaginal route, 20% preferred buccal administration, and 7% oral administration. Only resident physician and midwife providers endorsed buccal route preference. Being a midwife independently predicted a preference for using buccal misoprostol (odds ratio [OR]: 125.8, 95% confidence interval [CI]: 7.9-1992.3). Additionally, 44 nurses completed the survey regarding administration techniques of buccal misoprostol. Also, 54.5% of nurses correctly instructed their patients on buccal administration techniques. Conclusion Although not extensively studied, one-fifth of providers, particularly nurse midwives, prefer buccal administration of misoprostol for IOL. The majority of nurses correctly administered buccal misoprostol. There may be a need for further study and education about buccal administration of misoprostol for IOL.

Clinical and educational impact of pharmacogenomics testing: a case series from the INGENIOUS trial.

Pharmacogenomic testing has become increasingly widespread. However, there remains a need to bridge the gap between test results and providers lacking the expertise required to interpret these results. The Indiana Genomics Implementation trial is underway at our institution to examine total healthcare cost and patient outcomes after genotyping in a safety-net healthcare system. As part of the study, trial investigators and clinical pharmacology fellows interpret genotype results, review patient histories and medication lists and evaluate potential drug-drug interactions. We present a case series of patients in whom pharmacogenomic consultations aided providers in appropriately applying pharmacogenomic results within the clinical context. Formal consultations not only provide valuable patient care information but educational opportunities for the fellows to cement pharmacogenomic concepts.

Fundamentals of Clinical Pharmacology With Application for Pregnant Women.

Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off-label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications-preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity-is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy.

Increasing Influenza Vaccination Rates in a Busy Urban Clinic.

Influenza infection is the cause of thousands of hospitalizations and deaths each year; infection during pregnancy results in increased morbidity and mortality. Underserved women are particularly susceptible to not receiving recommended vaccinations. This project explored the effect of a simple paper based prompt on the influenza vaccination rate in a resident continuity clinic for the underserved. Using this reminder to providers to discuss the influenza vaccination with their patients, we were able to increase vaccination rates in our clinic from 2.2% to 14.2%. This implementation of a simple, low cost, low tech prompt to providers increased the rate of influenza vaccination in our clinic and we present this approach as an easy to implement method of improving vaccination rates. We also suggest this method as an alternative to an alert in the electronic medical record in situations where the electronic medical record may not be accessed during every patient encounter.

A retrospective comparison of antibiotic regimens for preterm premature rupture of membranes.

OBJECTIVE: To evaluate whether the use of ampicillin and azithromycin leads to a similar latency period in preterm premature rupture of membranes as ampicillin and erythromycin and whether the substitution of azithromycin for erythromycin effects rates of other outcomes. METHODS: We performed a retrospective cohort study of women with preterm premature rupture of membranes between 24 and 34 completed weeks of gestation and compared two groups: those who received ampicillin and erythromycin and those who received ampicillin and azithromycin. Primary outcome was length of latency (defined as time from first antibiotic dose to delivery) and secondary outcomes were rates of chorioamnionitis, cesarean delivery, Apgar scores, birth weight, neonatal death, neonatal sepsis, and neonatal respiratory distress syndrome. RESULTS: Of 168 women who met inclusion criteria, 75 received ampicillin and erythromycin and 93 received ampicillin and azithromycin. There was no difference in latency between groups: 9.6±13.2 days (erythromycin) compared with 9.4±10.0 (azithromycin) days (P=.40). Secondary outcomes did not differ between groups. We had 80% power to detect a difference of 5 days. CONCLUSION: Among women with preterm premature rupture of membranes between 24 and 34 completed weeks of gestation, substitution of azithromycin for erythromycin in the recommended antibiotic regimen did not affect latency or any other measured maternal or fetal outcomes. LEVEL OF EVIDENCE: III.

Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons.

Changes in gonadal steroid hormone levels during the menstrual cycle affect seizure frequency in women with catamenial epilepsy. Since GABA(A) receptors (GABARs) contribute to the prevention and termination of seizures by reducing neuronal excitability, we hypothesized that fluctuating gonadal steroid levels might affect GABAR subunit expression, which could alter inhibitory tone leading to increased seizure activity. To address this question in a simplified environment in vitro, we examined the effects of gonadal steroids on NT2-N neuronal cells. We have previously shown that NT2-N cells express functional GABARs, and that the expression pattern of GABAR subunits is regulated by chronic benzodiazepine exposure and hypoxia. NT2-N neurons were exposed to progesterone (0.1 microM), beta-estradiol (3 nM), or vehicle (DMSO) for 2 days or 7 days prior to RNA harvesting. GABAR subunit mRNA levels were assessed by semiquantitative RT-PCR normalized to actin levels. Progesterone exposure for 7 days increased alpha2 and gamma3 and decreased alpha5 subunit mRNAs, while beta-estradiol caused significant increases in alpha3, beta3 and epsilon expression. Further analysis revealed differential regulation of alpha4, alpha5, epsilon and pi subunit expression. Plots of relative PCR density in progesterone-treated cells for alpha2 vs. alpha5, alpha5 vs. gamma3 and alpha2 vs. gamma3 showed correlation between samples, suggesting coordinate regulation. Both progesterone and estrogen nuclear receptor mRNAs were detected by RT-PCR, and 2 days but not 7 days estrogen exposure upregulated progesterone receptor mRNA. Gonadal steroid fluctuations regulate GABA(A) receptor subunit expression in NT2-N cells. Such changes, if observed in vivo, could affect seizure frequency.