Assessment of Knowledge, Attitude, and Practice of Obstetricians and Gynecologists Toward Off-Label Medicine Use in Female Reproductive Health Issues.

Background: Off-label medication usage (OLMU) is prevalent in the treatment of various diseases, including female reproductive health issues (FRHIs). However, there is a paucity of literature on the perspective of health professionals on this subject. The purpose of the current study was to assess gynecologists/obstetricians' knowledge, attitude and practice toward OLMU in the treatment of FRHIs. Methods: The current cross-sectional study was conducted in September and October 2021, at five tertiary care hospitals (two public and three private sector), different clinics and maternity homes in a metropolitan city of Karachi, Pakistan. The target population was gynecologists, obstetricians and physicians/residents working in the ob/gyn department in various hospitals and clinical settings of Karachi. Results: The overall response rate was 77.1%. The mean age of the study respondents was 36.1 ± 7.7 years; n = 85 (55.9%) respondents were working in primary patient care. The majorly reported OLMU by the respondents were clomiphene citrate in unexplained infertility (n = 66; 43.4%), metformin to improve cycle regularity in females with polycystic ovary syndrome (PCOS) (n = 59; 38.8%) and letrozole to induce ovulation (n = 31; 20.4%). The majorly stated categories of OLMU were at a different dose (n = 95; 62.5%) and at different indications than approved to treat (n = 89; 58.5%). It was reported by the majority of the respondents (n = 95; 62.5%) that they do not follow any guidelines or regulations for OLMU in their work setting; however, the response was statistically varied with the working organization (CI 2.14-2.93; p = 0.037) and practice area (CI 2.85-4.32; p = 0.0001) of respondents. Conclusions: The present study revealed that the respondents were well-familiar with the practice of OLMU in the treatment of FRHIs. They expressed their concerns about decreasing such practices by being involved in collective decision-making procedures, and they were inclined to accept initiatives aimed at ensuring drug safety in patients.

A biochemometric approach for the assessment of Phyllanthus emblica female fertility effects as determined via UPLC-ESI-qTOF-MS and GC-MS.

Phyllanthus emblica L. fruits have long been used in Ayurvedic medicine for their many health benefits. In this study, we present P. emblica fruit crude extract and fractions' effects on the female reproductive system by assessing its estrogenic and gonadotropic activities. Results revealed that the non-polar petroleum ether and chloroform fractions exhibited the strongest estrogenic and follicle-stimulating hormone-like [FSH] activity, while the n-butanol fraction exhibited a significant luteinizing hormone-like [LH] activity. The ethyl acetate fraction showed neither estrogenic nor gonadotropic activities and in contrast it may impair female fertility suggesting that different metabolite classes contribute to the plant's overall effect on female fertility. To pinpoint active agents in these fractions, UPLC/ESI-qTOF-MS- was employed for secondary metabolite profiling with 100 metabolites annotated including ellagitannins, gallic acid derivatives, terpeneoids, sterols, phthalates and fatty acids. Correlation between extracts/fraction bioassays and UPLC/MS data was attempted using orthogonal partial least squares-discriminant analysis (OPLS-DA) revealing that guaiane-type sesquiterpenes, phthalates, diterpenes and oxygenated fatty acids showed positive correlation with estrogenic and gonadotropic activities. In contrast, mucic acid gallates, gallic acid derivatives and ellagitannins correlated negatively. GC/MS analysis of the non-polar bioactive fractions viz. petroleum ether and chloroform was also attempted which revealed its enrichment in fatty acids/fatty acyl esters (34%) and phenolic compounds (19.6%). This study provides the first report on the estrogenic and gonadotropic activities of P. emblica fruits in relation to their metabolite fingerprint.

Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

INTRODUCTION: We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers. The development process involved an extensive Australian-led international and multidisciplinary collaboration of health professionals and consumers over 2 years. The guideline is approved by the National Health and Medical Research Council and aims to support both health professionals and women with PCOS in improving care, health outcomes and quality of life. A robust evaluation process will enable practice benchmarking and feedback to further inform evidence-based practice. We propose that this methodology could be used in developing and implementing guidelines for other women's health conditions and beyond. Main recommendations: The recommendations cover the following broad areas: diagnosis, screening and risk assessment depending on life stage; emotional wellbeing; healthy lifestyle; pharmacological treatment for non-fertility indications; and assessment and treatment of infertility. Changes in management as a result of this guideline: •Diagnosis:▪when the combination of hyperandrogenism and ovulatory dysfunction is present, ultrasound examination of the ovaries is not necessary for diagnosis of PCOS in adult women;▪requires the combination of hyperandrogenism and ovulatory dysfunction in young women within 8 years of menarche, with ultrasound examination of the ovaries not recommended, owing to the overlap with normal ovarian physiology; and▪adolescents with some clinical features of PCOS, but without a clear diagnosis, should be regarded as "at risk" and receive follow-up assessment.•Screening for metabolic complications has been refined and incorporates both PCOS status and additional metabolic risk factors.•Treatment of infertility: letrozole is now first line treatment for infertility as it improves live birth rates while reducing multiple pregnancies compared with clomiphene citrate.

Bemfola® fixed dose pens potentially reduce drug wastage and associated costs of infertility treatment.

Bemfola® is a recombinant follicle-stimulating hormone (FSH) used during infertility treatment. One main differentiator between FSH products is their delivery device; consisting of multi-dose pens (Gonal-f®), vials or multi-dose preparations (Menopur®), or adjustable daily disposable dose pens (Bemfola®). To determine the potential impact of delivery device on drug wastage during infertility treatment this study retrospectively analysed Gonal-f® and Menopur® prescription and usage data from five UK clinics. Incurred drug wastage was then compared to potential Bemfola® drug wastage. Data collected included: (i) number of treatment cycles; (ii) daily FSH dose; (iii) length of treatment; (iv) dose adjustment following ultrasound scan; (v) FSH formulation(s) prescribed and (vi) agonist/antagonist protocol used. Treatment with Gonal-f® (4078 cycles) and Menopur® (646 cycles) resulted in an average drug wastage of 160 and 294 IU per treatment cycle. Use of Bemfola® instead of Gonal-f® and Menopur® may reduce the wastage to 104 and 61 IU per cycle, respectively. The use of Bemfola®, across all 4724 cycles, could result in a drug wastage reduction of up to 376,800 IUs with an associated cost saving of £100,011. Bemfola® is a viable alternative to Gonal-f® and Menopur® with its drug delivery system potentially reducing drug wastage and associated costs during infertility treatment.

Contribution of Hormonal Cytology in Girls and Adolescents to Reproductive Health: A Traditional Technique Monitoring Recent Problems.

OBJECTIVE: To study the contribution of hormonal cytology in contemporary disturbances of fertility. DESIGN: Over a 10-year period (2006-2015), 6,688 vaginal fornix cytologies of 2,350 patients were investigated. For a more detailed analysis, a 3-year period from 2013 to 2015 was chosen. Four hundred and fifty-two patients were investigated, many of them several times and for a period longer than the 3 years analyzed. RESULTS: The main disorders examined and treated via a gentle hormonal medication support and life style corrections by a pediatric gynecologist were: pubertas praecox - thelarche praecox and early menarche; dysfunctional juvenile metrorrhagia; central and peripheral endocrine disorders; eating disorders - anorexia mentalis and bulimia; obesity; excessive sport activities; autoimmune disorders, and others. Normalization of the menstrual cycle was achieved while monitoring progress with a series of hormonal cytologies in a majority of patients. CONCLUSIONS: Hormonal cytology is a non-invasive and economical method, illustrating the direct effect of steroid on target cells. It contributes to reproductive health support by: (a) indicating the possible need and type of steroid therapy; (b) monitoring the normalization of cycle disturbances; (c) ruling out or indicating the need for more detailed steroid metabolism investigation. Thus, it represents a basic but valuable means of examination in child and adolescent gynecology.

Gonadotropin Therapy versus Laparoscopic Ovarian Drilling in Clomiphene Citrate-Resistant Polycystic Ovary Syndrome Patients: A Retrospective Cost-Effectiveness Analysis.

BACKGROUND: Gonadotropin therapy and laparoscopic ovarian drilling (LOD) are treatment options for ovulation induction (OI) in clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients. The current evidence of the cost-effectiveness of both treatments is scarce, conflicting and performed from different health-economic perspectives. METHODS: A retrospective health-economic evaluation was performed from a societal perspective in which human menopausal gonadotropin (hMG) therapy (n = 43) was compared with LOD (n = 35), followed by OI with CC and/or hMG if spontaneous ovulation did not occur within 2 months. Data were collected until the patients were pregnant, with a time limit of 6 months after the onset of treatment. Outcomes were expressed as ongoing pregnancy rate and number of live-born children. RESULTS: The ongoing pregnancy rate was 21/35 (60%) after LOD and 30/43 (69.8%) after hMG treatment (relative risk 0.85, 95% CI 0.61-1.19). The societal cost per patient, up to an ongoing pregnancy, was significantly higher after LOD versus hMG treatment (adjusted mean difference EUR 1,073, 95% CI 180-1,967). CONCLUSION: This economic evaluation based on real-life data shows that the societal cost up to an ongoing pregnancy is less after hMG treatment when compared with LOD surgery in CC-resistant PCOS patients.

Biological risk versus socio-economic advantage: low birth-weight, multiple births and income variations among Irish infants born following fertility treatments.

The Growing Up in Ireland Infant Cohort dataset (n = 11,134) includes information on fertility treatments for over 400 infants. IVF (28.1 %) and IVF-related treatments (17.8 %) were the most frequent, but there was also a high percentage following clomiphene citrate alone (31.5 %). Infants born following fertility treatment were much more likely to be in higher income families, and this relationship was not accounted for by older mothers in wealthier families. Analysis of fertility-treatment pregnancies among Irish infants, controlling for income and maternal age, shows a greater risk of multiple birth and low birth-weight, although the latter appears to be largely related to the former especially for IVF-type treatments.

Maternal hormonal interventions as a risk factor for Autism Spectrum Disorder: an epidemiological assessment from India.

Globalization and women empowerment have led to stressful life among Indian women. This stress impairs women's hormonal makeup and menstrual cycle, leading to infertility. National Family Health Survey-3 (NFHS-3) reports a decline in fertility status in India, indicating a rise in various infertility treatments involving hormonal interventions. No studies are available from India on the risk association link between maternal hormonal treatments and ASD. Hence, this study explores the association of maternal hormonal interventions with risk for ASD. Parents of 942 children (471 ASD and 471 controls) across 9 cities in India participated in the questionnaire-based study. The questionnaire was pilot tested and validated for its content and reliability as a psychometric instrument. Data collection was done at 70 centres through direct interaction with parents and with the help of trained staff. Statistical analysis of data was carried out using SAS 9.1.3. Out of the 471 ASD cases analysed, 58 mothers had undergone hormonal interventions (12.3 percent) while there were only 22 mothers among controls who underwent hormonal interventions (4.6 percent). According to logistic regression analysis maternal hormonal intervention (OR=2.24) was a significant risk factor for ASD.

An assessment of current clinical attitudes toward letrozole use in reproductive endocrinology practices.

OBJECTIVE: To assess the clinical use and practice attitudes among Society for Assisted Reproductive Technology (SART) members regarding the use of letrozole for ovulation induction and infertility treatment. DESIGN: The SART clinic physicians were mailed a cover letter and consent form, a two-page survey, and return envelope. The surveys were returned and analyzed using descriptive statistics. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): A 13-question survey. MAIN OUTCOME MEASURE(S): Reproductive endocrinology and infertility physicians use patterns and attitudes regarding letrozole. RESULT(S): A total of 77.9% of physician prescribe letrozole. Of those who do not, 32.4% cited concern about the US Food and Drug Administration warning, 35.1% cited satisfaction with current medications, 25.7% cited both reasons, and 6.8% cited no experience with letrozole. Physicians (11.5%) were unaware of the US Food and Drug Administration warning. Physicians (99.7%) were aware that ovulation induction is an off-label use of letrozole. The most common use was for ovulation induction in patients with polycystic ovary syndrome (PCOS). Physicians (14.9%) prescribe letrozole as first-line ovulation therapy prior to clomid, 47.9% use for clomid failures, and 25.7% reported use in both situations. CONCLUSION(S): Most physicians surveyed use letrozole for ovulation induction despite the current US Food and Drug Administration warning. Even when accounting for nonrespondents, more than 25% of physicians indicated success with letrozole use. Questions regarding doses and clinical concerns about letrozole revealed no standardized manner of letrozole administration despite wide interest, therefore additional research is warranted.

Sequential clomiphene citrate/hMG versus hMG for ovulation induction in clomiphene citrate-resistant women.

OBJECTIVE: This study was designed to compare sequential clomiphene citrate/hMG regimen to hMG regimen for ovulation induction in clomiphene citrate-resistant women. STUDY DESIGN: A comparative prospective study. PATIENTS AND METHODS: Ninety infertile women were randomized to receive either sequential CC/hMG regimen (45 women) or low-dose step-up protocol of hMG (45 women). All participants had received at least six consecutive cycles of clomiphene citrate for ovulation induction within the last year before inclusion in this study, but they did not conceive. The CC/hMG regimen group received clomiphene citrate 100 mg/day for 5 days, followed by hMG 75 IU for 4 days. The hMG group received low-dose step-up protocol for 10-14 days. To detect the number and size of the follicles, TVS was done on cycle day 8 and repeated daily or every other day according to follicular development. When one to three follicles reached a diameter ≥18 mm, hCG injection was scheduled. Before hCG injection, the E2 level and endometrial thickness were evaluated. ß-hCG levels were measured on cycle day 22. RESULTS: There was no significant difference between the two studied groups regarding the demographic data, sperm parameters, and day 3 FSH, LH and estradiol. Also, there was no significant difference between the two studied groups regarding endometrial thickness, number of mature follicles, peak of E2 before hCG injection and number of cases that developed ovarian cyst or OHSS. The dose of gonadotropins used was significantly low in the CC/hMG group compared to the hMG group (295.2 ± 75.5 vs. 625.3 ± 65.0, respectively), and the pregnancy rate was significantly high in the CC/hMG group compared to the hMG group [12 (26.7 %) vs. 3 (6.7 %), respectively, p < 0.05]. CONCLUSION: The sequential CC/hMG regimen is as effective as hMG regimen for ovulation induction, produces satisfactory pregnancy results and reduces the treatment cost.

Long-term follow-up of laparoscopic electrocautery of the ovaries versus ovulation induction with recombinant FSH in clomiphene citrate-resistant women with polycystic ovary syndrome: an economic evaluation.

BACKGROUND: Laparoscopic electrocautery of the ovaries and ovulation induction with gonadotrophins are both second line treatments for women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Long-term follow-up after electrocautery versus ovulation induction with gonadotrophins has demonstrated at least comparable chances for a first live born child with a reduced need for ovulation induction or assisted reproduction treatment and increased chances for a second live born child. In this study, we report on the long-term economic consequences of both treatment modalities. METHODS: Between February 1998 and October 2001, we performed a multi-centre randomized controlled trial (RCT) comparing a strategy of laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and gonadotrophins when anovulation persisted, and a strategy of ovulation induction with gonadotrophins in women with clomiphene citrate-resistant PCOS. Eight to twelve years after randomization we performed a follow-up study on reproductive outcome in these women and the fertility treatments they had needed including data on direct medical costs of pregnancy and delivery. Clinical data included number of treatment cycles, live births, miscarriages, ectopic pregnancies and multiple pregnancies. We calculated mean costs per woman after randomization until the first live birth. Confidence intervals (CIs) were estimated by bootstrapping. RESULTS: We obtained data for an economic analysis on 159 of the 168 randomized women (95%). In total, 71 of 83 women (86%) allocated to the electrocautery strategy and 69 of 85 women (81%) allocated to the gonadotrophin strategy had at least one live birth. Given the equivalence between the two treatment strategies in terms of a first live birth-the primary outcome measure-our analysis focused on the cost difference between the two strategies within a mean follow-up time of 8-12 years. The mean costs per first live birth after randomization were €11 176 (95% CI: €9689-€12 549) for the electrocautery group and €14 423 (95% CI: €12 239-€16 606) for the recombinant FSH group, resulting in significantly lower costs (P < 0.05) per first live birth for women allocated to the electrocautery group (mean difference €3247; 95% CI: €650-€5814). CONCLUSION: In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries results in significantly lower costs per live birth than ovulation induction with gonadotrophins for an at least equal effectiveness.

The epidemiology and management of gynatresia in Lagos, southwest Nigeria.

OBJECTIVE: To document data from patients presenting with gynatresia at 2 tertiary health centers in Lagos, southwest Nigeria. METHODS: In a prospective, descriptive study, clinical history and physical examination data were collected for women who presented with gynatresia between January 2004 and January 2011. Ultrasonography results and abnormality at surgery were also documented. Where possible, the severity of stenosis and surgical outcome were assessed by published scales. RESULTS: Forty-seven patients were included in the study. Eight patients (17.0%) presented with congenital gynatresia, the commonest cause of which was Mayer-Rokitansky-Küster-Hauser syndrome (4 patients, 50%). Thirty-nine patients (83.0%) presented with acquired gynatresia, the main cause of which was herbal pessaries (30 patients, 76.9%). Herbal pessaries were used to treat fibroids (23 patients, 76.7%), uterovaginal prolapse (3, 10.0%), and infertility (2, 6.7%); and to procure abortion (2, 6.7%). The ages of the patients who used herbal pessary ranged from 18 to 50 years (mean 36.10 ± 1.24 years). Other causes of acquired gynatresia were birth injuries (6 patients, 15.4%), and female genital mutilation (2, 5.1%). CONCLUSION: Acquired gynatresia was more common in Lagos than congenital gynatresia. The causes of acquired gynatresia are preventable and could be eliminated by health education.

Willingness to pay and conjoint analysis to determine women's preferences for ovarian stimulating hormones in the treatment of infertility in Spain.

BACKGROUND: Despite many advances in assisted reproductive techniques (ART), little is known about preferences for technological developments of women undergoing fertility treatments. The aims of this study were to investigate the preferences of infertile women undergoing ART for controlled ovarian stimulation (COS) treatments; to determine the utility values ascribed to different attributes of COS treatments; and to estimate women's willingness to pay (WTP) for COS. METHODS: A representative sample of ambulatory patients ready to receive, or receiving, COS therapies for infertility were recruited from seven specialized private centres in six autonomous communities in Spain. Descriptive, inferential and conjoint analyses (CA) were used to elicit preferences and WTP. Attributes and levels of COS treatments were identified by literature review and two focus groups with experts and patients. WTP valuations were derived by a combination of double-bounded (closed-ended) and open questions and contingent ranking methods. RESULTS: In total, 160 patients [mean (standard deviation; SD) age: 35.8 (4.2) years] were interviewed. Over half of the participants (55.0%) had a high level of education (university degree), most (78.8%) were married and half (50.0%) had an estimated net income of >€1502 per month and had paid a mean (SD) €1194.17 (€778.29) for their most recent hormonal treatment. The most frequent causes of infertility were related to sperm abnormalities (50.3%). In 30.6% of cases, there were two causes of infertility. The maximum WTP for COS treatment was €800 (median) per cycle; 35.5% were willing to pay an additional €101-€300 for a 1-2% effectiveness gain in the treatment. Utility values (CA) showed that effectiveness was the most valued attribute (39.82), followed by costs (18.74), safety (17.75) and information sharing with physicians (14.93). CONCLUSIONS: WTP for COS therapies exceeds current cost. Additional WTP exists for 1-2% effectiveness improvement. Effectiveness and costs were the most important determinants of preferences, followed by safety and information sharing with physicians.

Ovarian drilling for surgical treatment of polycystic ovarian syndrome: a comprehensive review.

This systematic literature review is intended to clarify and evaluate the results obtained by ovarian drilling as surgical treatment for polycystic ovarian syndrome (PCOS). Four databases were consulted (Medline at the National Library of Medicine, USA; Cochrane Library, UK; National Guideline Clearinghouse, USA; and the Health Technology Assessment Database, Sweden) and searched for 'polycystic ovary syndrome' plus 'drilling' in the title or abstract. The assessment criteria used to define the efficacy of the procedure were the rates of ovulation, clinical pregnancy and early miscarriage. Alternatives to surgical ovarian drilling were evaluated. This search produced 147 references, 81 of which met the selection criteria. This review of infertility management in women with PCOS indicates that ovarian drilling is a second-line treatment when treatment with clomiphene citrate fails to lead to conception. The benefits of ovarian drilling are that it does not induce either hyperstimulation syndrome or multiple pregnancies. It is concluded that ovarian drilling is an option in the management of female infertility associated with PCOS, especially as a second-line treatment after the failure of clomiphene citrate treatment.

Ovulation induction in polycystic ovary syndrome: No. 242, May 2010.

OBJECTIVE: To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS). OPTIONS: This guideline reviews the evidence for the various options for ovulation induction in PCOS. OUTCOMES: Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. EVIDENCE: Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies. VALIDATION: These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC.

Decision trees for identifying predictors of treatment effectiveness in clinical trials and its application to ovulation in a study of women with polycystic ovary syndrome.

BACKGROUND: Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables. METHODS: The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses. RESULTS: Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (≥ 19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin. CONCLUSIONS: Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation.

Drug use evaluation of tamoxifen focusing on off-label use in a managed care population in Israel.

BACKGROUND: Policy development to manage new off-label uses of medications is an issue relevant to health policy stakeholders internationally. Retrospective drug utilization analyses may be useful to identify practice trends in the use of drugs for unapproved (off-label) uses. Since drug use evaluations (DUE) are generally performed for expensive medications or when safety concerns warrant increased scrutiny, patterns of off-label use of inexpensive drugs will probably be undetected. Tamoxifen citrate, an estrogen receptor antagonist, is indicated in Israel exclusively for palliative [sic: meaning adjuvant] treatment of breast cancer. This DUE was motivated by observations that tamoxifen may be used off-label for indications without evidence of safety or efficacy. OBJECTIVES: To assess the extent of off-label prescribing of tamoxifen and ascertain what evidence is available supporting the use of the drug for the off-label indications observed. METHODS: A retrospective DUE of tamoxifen was performed for the 12 months of calendar year 2008 in a 650,000-member HMO in Israel for patients who received at least 1 prescription for tamoxifen. All patients for whom tamoxifen was dispensed in 2008 were identified from pharmacy claims data. The HMO's electronic patient record (EPR) was subsequently queried to identify the diagnoses of patients who received tamoxifen and exclude those patients who had a diagnosis code (ICD-9-CM 174.x or 175.x) for breast cancer. An EPR chart review was also performed to identify and exclude patients who had a diagnosis or treatment of breast cancer that was recorded in free text. For the patients who did not have a diagnosis code or free-text description of breast cancer, the recorded off-label diagnoses and ICD-9-CM codes in the EPR during the visit when tamoxifen was first prescribed were tabulated. A literature search was conducted to collect information supporting the use of tamoxifen for the observed off-label indications. We defined the use as "supported" if studies were found in PubMed, Cochrane database, or Micromedex that supported the clinical decision to use the drug for the off-label indication. RESULTS: 877 patients were treated with tamoxifen in 2008 of whom 826 (94.2%) had a diagnosis of breast cancer, and 51 patients (5.8%) received the drug from 41 physicians in 7 medical specialty categories for 25 different off-label diagnoses. Of these 25 diagnoses, 33 patients (64.7% of 51 patients with off-label use) received tamoxifen for 8 diagnoses that were associated with some evidence to support their off-label use. Malignant neoplasm of ovary (n = 13) and female infertility (n = 13) were the most commonly recorded indications with some evidence to support off-label use. Of the 13 women treated for infertility, 9 (69.2%) had been treated with clomiphene citrate prior to being treated with tamoxifen, suggesting that some physicians may be experimenting with tamoxifen as second-line treatment. CONCLUSIONS: Tamoxifen was found to be used off-label in only 5.8% of the patients who received the drug in 2008 in this HMO, and only 18 patients (2.1%) received tamoxifen for a diagnosis that did not have some supporting evidence of efficacy. Since off-label prescribing of tamoxifen was found to be relatively rare, this HMO did not impose a prior authorization requirement for this drug and instead added an edit in the EPR to block off-label prescribing by requiring the physician to register a diagnosis of breast cancer.

Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents.

OBJECTIVE: To compare different oral ovulation induction agents in treating infertile women with polycystic ovary syndrome (PCOS). DESIGN: Decision-analytic model comparing three treatment strategies using probability estimates derived from literature review and sensitivity analyses performed on the baseline assumptions. SETTING: Outpatient reproductive medicine and gynecology practices. PATIENT(S): Infertile women with PCOS. INTERVENTION(S): Metformin, clomiphene citrate, or metformin with clomiphene citrate. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Within the baseline assumptions, combination therapy with metformin and clomiphene citrate was the preferred therapy for achieving live birth in women with PCOS. Sensitivity analysis revealed the model to be robust over a wide range of probabilities. CONCLUSION(S): Combination therapy with metformin and clomiphene citrate should be considered as first-line treatment for infertile women with PCOS.

Comparison of diagnostic approaches, and a cost-benefit analysis of different diagnostic approaches and treatments of anoestrous dairy cows.

AIM: To compare diagnostic techniques, and to assess the economic effects of diagnosing and treating dairy cows not detected in oestrus before the planned start of mating (PSM). METHODS: Cows from 12 herds were defined as anoestrus at Day -9 (where Day 0=PSM) based on presence of tail paint that had been applied at Day -35. The presence of a corpus luteum (CL) was diagnosed by palpation or ultrasonography on Day -9, or by determining the concentration of progesterone (P4) in milk at Days -16 and -9. Cows with concentrations of P4 in milk >1 ng/ml at one or both times were defined as CL+. Cows were randomly assigned to be treated with (a) nothing (Control; n=558); (b) gonadotrophin-releasing hormone (GnRH) on Day -9, prostaglandin F(2alpha) (PGF(2alpha)) on Day -2, and GnRH on Day 0, with set-time artificial insemination (AI) 16-20 h after the second GnRH treatment (Ovsynch; n=553); or (c) as for (b) but with placement of an intravaginal P4-releasing device on Day -9, and removal on Day -2 (Ovsynch+P4; n=551). Cows detected in oestrus between Day -2 and the second GnRH treatment did not receive the second GnRH treatment. Pregnancy diagnosis took place on three occasions, and the date of conception estimated, from which the PSM-to-conception interval was calculated. Agreement between the three diagnostic techniques for CL status was evaluated using Kappa analyses, and sensitivities and specificities were calculated using a Bayesian Monte Carlo approach that does not assume a gold standard. Partial budgets and decision trees were constructed to assess the cost effectiveness of diagnosis and treatment. RESULTS: The level of agreement was higher between ultrasonography and concentration of P4 in milk (0.64) than for palpation and ultrasonography or concentration of P4 in milk (0.50 and 0.49, respectively). The Ovsynch+P4 treatment had a higher net benefit than Ovsynch relative to no treatment (NZ$80.40 and NZ$47.50/cow treated, respectively) in the absence of diagnosis of CL status. Following diagnosis, the Ovsynch+P4 treatment remained the most cost-effective option for both CL+ and CL- cows. It was concluded that the Ovsynch+P4 treatment without any diagnostic procedure was the most cost-effective option. CLINICAL RELEVANCE: Treatment of anoestrous cows was more cost-effective than no treatment, with Ovsynch+P4 more cost-effective than Ovsynch in cows with or without a CL. Differentiation of anoestrous cows into CL+ and CL- groups for treatment was not cost-effective.