Advantages of large medical record database for outcomes research: Insights into post‐menopausal hormone therapy

Approximately 25 years ago, our team initiated studies to determine whether outcome results from a large medical record database would yield valid results. We utilized the data in the United Kingdom (UK) General Practice Research Database (GPRD) to replicate the randomized controlled trial (RCT) study result and compared them to confirm the database results. The initial studies compared favorably, but some subsequent studies did not. This prompted development of a new strategy to determine and correct for unrecognized confounding in the database. This strategy divided outcome rates prior to initiation of therapy in the database study (which should include both identified and unidentified confounders) into the outcome rates during the treatment interval. When they differed from Cox‐adjusted results, it reflected unrecognized confounding. We called this strategy Prior Event Rate Ratio (PERR)–adjusted outcome.One of our previously published observational studies replicated the Women’s Health Initiative (WHI) RCT study of hormone therapy in post‐menopausal women. Our study results replicated the WHI RCT results except it did not exhibit an increase in heart attack in contrast to the RCT. Furthermore, we could not evaluate death reliably since our analytic approach to overcome unrecognized confounding does not work for this outcome. In Volume 1, Issue 1 of the Learning Health Systems open access journal, we published a new study (titled “A new method to address unmeasured confounding of mortality in observational studies”) that reported a novel death method, based on our prior methodology, that could analyze unrecognized confounding of the death outcome. This new methodology, termed Post Treatment Event Rate Ratio (PTERR), permitted a reliable examination of mortality in post‐menopausal women undergoing hormone therapy. These results are reported in this manuscript. The study used the data from our previous observational study. It demonstrates that estrogen therapy markedly reduced death in post‐menopausal women.This work also illuminates principles of database construction and correspondingly demonstrates the use of novel methodologies for obtaining valid results, which can be applied to enable learning from such databases. Work to advance such methodologies is essential to advancing the scientific integrity Core Value underpinning learning health systems (LHSs). Indeed, in the absence of such efforts to develop and refine methodologies for learning trustworthy lessons from real‐world data, we risk inadvertently creating mis‐learning systems.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150513/1/lrh210193.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150513/2/lrh210193_am.pd

Evaluating the Association between Assisted Conception and the Severity of Preeclampsia

Objective. To investigate the association between assisted conceptions and preeclampsia (PEC), including assessment of severity of disease. Methods. In a prospective case control study, cases were selected from women with preeclampsia and controls from women without preeclampsia. Exposure was defined as assisted conception with intrauterine insemination or in vitro fertilization (IUI or IVF). We assessed the association between exposure and outcome, using Chi square or Fisher's exact tests. Stratified analyses and multivariable logistic regression were used to control for confounders. Results. Preeclampsia was associated with assisted conception after controlling for age and race (AOR 2.2, [1.03–4.72]). All women with preeclampsia who had assisted conceptions demonstrated severe disease and were more likely to have abnormal lab values: AST >45 (AOR = 6.01 [1.63–22.21] P = 0.007), creatinine ≥1 (AOR 2.92 [0.82–10.4], P = 0.09) or platelets <100 (AOR 5.74 [1.00–32.76] P = 0.049), after adjusting for race, age, and multiple gestations. Conclusion. Assisted conceptions are associated with a more severe preeclamptic phenotype

Effects of Long-Term Use of Nonoxynol-9 on Vaginal Flora

OBJECTIVE—Products containing nonoxynol-9 have been used as spermicidal contraceptives for many years, but limited data have been published describing the long-term effects of nonoxynol-9 use on the vaginal microbial ecosystem. This longitudinal study was conducted to examine the effects of nonoxynol-9 on the vaginal ecology. METHODS—Vaginal swabs were obtained from 235 women enrolled in a randomized clinical trial before initiation of use of 1 of 5 different formulations of nonoxynol-9 for contraception, and up to 3 more samples were gathered over 7 months of use. The swab samples were evaluated in a single laboratory. The prevalence of several constituents of the normal vaginal flora was evaluated. The associations between nonoxynol-9 dosage, formulation, average product use per week, and number of sex acts per week were calculated. RESULTS—The changes in prevalence of vaginal microbes after nonoxynol-9 use were minimal for each of the different nonoxynol-9 formulations. However, when both nonoxynol-9 concentration and number of product uses are taken into account, nonoxynol-9 did have dose-dependant effects on the increased prevalence of anaerobic gram-negative rods (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1–5.3), H2O2-negative lactobacilli (OR 2.0, 95% CI 1.0–4.1), and bacterial vaginosis (OR 2.3, 95% CI 1.1–4.7). CONCLUSION—This study demonstrated that most nonoxynol-9 users experienced minimal disruptions in their vaginal ecology. There were no differences between the different formulations evaluated with respect to changes in vaginal microflora. However, independent of the nonoxynol-9 formulation, there was a dose-dependent effect with increased exposure to nonoxynol-9 on the risk of bacterial vaginosis and its associated flora

Subtype Distribution of Human Papillomavirus in HIV-Infected Women With Cervical Intraepithelial Neoplasia Stages 2 and 3 in Botswana

Human papillomavirus (HPV) vaccines containing types 16 and 18 are likely to be effective in preventing cervical cancer associated with these HPV types. No information currently exists in Botswana concerning the HPV types causing precancerous or cancerous lesions. Our goal was to determine the prevalence of HPV types associated with precancerous cervical intraepithelial neoplasia (CIN) stages 2 and 3 in HIV-infected women in Gaborone, Botswana. HIV-infected women referred to our clinic with high-grade intraepithelial lesion on the Pap smear were enrolled in the study. HPV typing was only performed if the histopathology results showed CIN stage 2 or 3 disease using linear array genotyping (CE-IVD, Roche Diagnostics).One hundred HIV-infected women were identified with CIN stages 2 or 3 between August 11, 2009 and September 29, 2010. Eighty-two of 100 women enrolled had coinfection by multiple HPV subtypes (range, 2 to 12). Of the remaining 18 women, 14 were infected with a single high-risk subtype and 4 had no HPV detected. Overall, 92 (92%) women were infected with at least 1 high-risk HPV subtype, and 56 were coinfected with more than 1 high-risk HPV type (range, 2 to 5). Fifty-one (51%) women had HPV subtypes 16, 18, or both. HPV 16 and 18 are the most common types in HIV-infected women with CIN 2 or 3 in Gaborone, Botswana, suggesting that the implementation of HPV vaccination programs could have a significant impact on the reduction of cervical cancer incidence. However, given the relative lack of knowledge on the natural history of cervical cancer in HIV-infected women and the significant prevalence of infection and coinfection with other high-risk HPV types in our sample, the true impact and cost-effectiveness of such vaccination programs need to be evaluated

Mifepristone Pretreatment for the Medical Management of Early Pregnancy Loss

BACKGROUND Medical management of early pregnancy loss is an alternative to uterine aspira-tion, but standard medical treatment with misoprostol commonly results in treat-ment failure. We compared the efficacy and safety of pretreatment with mifepris-tone followed by treatment with misoprostol with the efficacy and safety of misoprostol use alone for the management of early pregnancy loss. METHODS We randomly assigned 300 women who had an anembryonic gestation or in whom embryonic or fetal death was confirmed to receive pretreatment with 200 mg of mifepristone, administered orally, followed by 800 µg of misoprostol, adminis-tered vaginally (mifepristone-pretreatment group), or 800 µg of misoprostol alone, administered vaginally (misoprostol-alone group). Participants returned 1 to 4 days after misoprostol use for evaluation, including ultrasound examination, by an in-vestigator who was unaware of the treatment-group assignments. Women in whom the gestational sac was not expelled were offered expectant management, a second dose of misoprostol, or uterine aspiration. We followed all participants for 30 days after randomization. Our primary outcome was gestational sac expulsion with one dose of misoprostol by the first follow-up visit and no additional intervention within 30 days after treatment. RESULTS Complete expulsion after one dose of misoprostol occurred in 124 of 148 women (83.8%; 95% confidence interval [CI], 76.8 to 89.3) in the mifepristone-pretreat-ment group and in 100 of 149 women (67.1%; 95% CI, 59.0 to 74.6) in the miso-prostol-alone group (relative risk, 1.25; 95% CI, 1.09 to 1.43). Uterine aspiration was performed less frequently in the mifepristone-pretreatment group than in the misoprostol-alone group (8.8% vs. 23.5%; relative risk, 0.37; 95% CI, 0.21 to 0.68). Bleeding that resulted in blood transfusion occurred in 2.0% of the women in the mifepristone-pretreatment group and in 0.7% of the women in the misoprostol-alone group (P = 0.31); pelvic infection was diagnosed in 1.3% of the women in each group. CONCLUSIONS Pretreatment with mifepristone followed by treatment with misoprostol resulted in a higher likelihood of successful management of first-trimester pregnancy loss than treatment with misoprostol alone. (Funded by the National Institute of Child Health and Human Development; PreFaiR ClinicalTrials.gov number, NCT02012491.

Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate.

ObjectiveTo evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200&nbsp;mcg/day and segesterone acetate (SA) 200&nbsp;mcg/day to identify a dose that avoids hypoestrogenism.Study designWe conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40&nbsp;pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information.ResultsSixty-five participants enrolled in E2 75 (n&nbsp;=&nbsp;22), 100 (n&nbsp;=&nbsp;21), and 200 (n&nbsp;=&nbsp;22)&nbsp;mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100&nbsp;mcg/day groups were &lt;40&nbsp;pg/mL. In the 200&nbsp;mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194&nbsp;pg/mL (range 114-312&nbsp;pg/mL) and remained &gt;40&nbsp;pg/mL throughout 30&nbsp;days; E2 concentrations were 37&nbsp;pg/mL (range 28-62&nbsp;pg/mL) on days 88-90 (n&nbsp;=&nbsp;11). Among the E2 200&nbsp;mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days.ConclusionsEstradiol concentrations with rings releasing E2 200&nbsp;mcg/day and SA 200&nbsp;mcg/day avoid hypoestrogenism over 30-day use.ImplicationsA 90-day contraceptive vaginal ring releasing estradiol 200&nbsp;mcg/day and segesterone acetate 200&nbsp;mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation

Participant characteristics associated with withdrawal from a large randomized trial of spermicide effectiveness

BACKGROUND: In most recent large efficacy trials of barrier contraceptive methods, a high proportion of participants withdrew before the intended end of follow-up. The objective of this analysis was to explore characteristics of participants who failed to complete seven months of planned participation in a trial of spermicide efficacy. METHODS: Trial participants were expected to use the assigned spermicide for contraception for 7 months or until pregnancy occurred. In bivariable and multivariable analyses, we assessed the associations between failure to complete the trial and 17 pre-specified baseline characteristics. In addition, among women who participated for at least 6 weeks, we evaluated the relationships between failure to complete, various features of their first 6 weeks of experience with the spermicide, and characteristics of the study centers and population. RESULTS: Of the 1514 participants in this analysis, 635 (42%) failed to complete the study for reasons other than pregnancy. Women were significantly less likely to complete if they were younger or unmarried, had intercourse at least 8 times per month, or were enrolled at a university center or at a center that enrolled fewer than 4 participants per month. Noncompliance with study procedures in the first 6 weeks was also associated with subsequent early withdrawal, but dissatisfaction with the spermicide was not. However, many participants without these risk factors withdrew early. CONCLUSIONS: Failure to complete is a major problem in barrier method trials that seriously compromises the interpretation of results. Targeting retention efforts at women at high risk for early withdrawal is not likely to address the problem sufficiently

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Full Text of Background... METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Full Text of Methods... RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P Full Text of Results... CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.