A.E. Karmon

Reproductive outcomes in oocyte donation cycles are associated with donor BMI

STUDY QUESTION When adjusting for recipient BMI, is donor body mass index (BMI) associated with IVF outcomes in donor oocyte IVF cycles? SUMMARY ANSWER Increasing oocyte donor BMI is associated with a reduction in clinical pregnancy and live birth rates. WHAT IS KNOWN ALREADY Increased BMI has been associated with suboptimal reproductive outcomes, particularly in assisted reproductive technology (ART) cycles. However, it remains unclear if this association implies an effect of BMI on oocyte quality and/or endometrial receptivity. STUDY DESIGN, SIZE, DURATION A retrospective cohort study of two hundred and thirty five consecutive fresh donor oocyte IVF cycles from 1 January 2007 through 31 December 2013 at the Massachusetts General Hospital (MGH) Fertility Center. PARTICIPANTS/MATERIALS, SETTING, METHODS Analyses included a total of 202 oocyte donors and 235 total cycles. Following adjustments for recipient BMI, the relationship between donor BMI (categorized into quartiles) and IVF outcomes was assessed. MAIN RESULTS AND THE ROLE OF CHANCE In the entire (anonymous and known) donor population, a reduced odds of clinical pregnancy (P-trend = 0.046) and live birth (P-trend = 0.06) was observed with increasing BMI quartile. Compared with quartile 1 (BMI 17.8-21.1), odds ratio (OR) (95% CI) of clinical pregnancy was 0.9 (0.4-2.0), 0.5 (0.2-1.1) and 0.5 (0.2-1.1), and OR of live birth was 1.1 (0.5-2.6), 0.6 (0.3-1.2) and 0.6 (0.3-1.2) for quartiles 2 through 4 respectively. In anonymous donors only, the odds of clinical pregnancy (P-trend = 0.02) and live birth (P-trend = 0.03) also declined as BMI quartile increased. Compared with quartile 1 (BMI 17.8-21.1), odds ratio (OR) (95% CI) of clinical pregnancy was 0.7 (0.3-1.7), 0.5 (0.2-1.1) and 0.4 (0.1-0.9), and OR of live birth was 0.9 (0.4-2.2), 0.5 (0.3-1.2) and 0.4 (0.2-1.1) for quartiles 2 through 4 respectively. LIMITATIONS, REASONS FOR CAUTION Limitations include the retrospective design, sample size and data from a single institution. Clinical application may not be limited to oocyte donors, though caution should be used prior to applying these principles to the general population. Data should not be interpreted to mean that all oocyte donors should be restricted to a BMI of less than 21.2 kg/m(2). WIDER IMPLICATIONS OF THE FINDINGS Following adjustments for the respective BMI of the oocyte donor and recipient, this study demonstrates an association of preconception BMI with subsequent IVF outcomes. The observations of this study are consistent with prior animal studies, suggest a possible effect of BMI at the oocyte level prior to fertilization and implantation, and warrant further investigation. STUDY FUNDING/COMPETING INTERESTS None.

Preconceptional thyroid-stimulating hormone levels and outcomes of intrauterine insemination among euthyroid infertile women.

OBJECTIVE To evaluate differences in intrauterine insemination (IUI) outcomes among euthyroid women with preconceptional thyroid-stimulating hormone (TSH) values in the normal (0.4-2.4 mIU/L) and high-normal (2.5-4.9 mIU/L) ranges. DESIGN Cohort study. SETTING A single fertility center. PATIENT(S) A total of 1,477 women who underwent 4,064 IUI cycles between the years 2004 and 2012. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Live birth, clinical pregnancy, spontaneous abortion (SAB), and IUI cycle parameters. RESULT(S) Cycles were categorized into 4 groups based on preconceptional TSH values: 0.40-1.36 mIU/L; 1.37-1.86 mIU/L; 1.87-2.49 mIU/L; and 2.50-4.99 mIU/L. No statistically significant differences were found in IUI cycle parameters, clinical pregnancy rates, or live births per initiated cycle among the 4 TSH groups. However, preconceptional TSH was inversely related to SAB and positively related to live birth among women who achieved a clinical pregnancy. In this group of women, cycles with TSH values between 2.5 and 4.9 mIU/L were related to lower odds of SAB (odds ratio: 0.32; 95% confidence interval: 0.16-0.65) and higher odds of live birth (odds ratio: 2.80; 95% confidence interval: 1.43-5.48) compared with cycles among women in the lowest TSH group. CONCLUSION(S) Among euthyroid patients, preconceptional TSH values in the high-normal range (between 2.5 and 4.9 mIU/L) are not associated with adverse IUI outcomes.

MicroRNAs in the development and pathobiology of uterine leiomyomata: does evidence support future strategies for clinical intervention?

BACKGROUND Human leiomyomata (fibroids) are benign tumors of the uterus, represent the most common neoplasms of reproductive-aged women and have a prevalence of ∼70% in the general population. This disorder conveys a significant degree of morbidity and remains the leading indication for hysterectomy in the USA. Prior investigations of aberrant microRNA (miRNA) expression in various malignancies have provided invaluable insight into the role of this class of small non-coding RNAs in tumor growth. Evidence of irregular miRNA expression in uterine fibroids has garnered recent interest for diagnostic and therapeutic applications. Since miRNA gene targets modulate several processes implicated in the genesis of uterine fibroids, more focused investigation has the potential to elucidate the functional significance of miRNA in the genesis and pathology of the disease. METHODS Comprehensive electronic searches of peer reviewed published literature in PubMed (US National Library of Medicine, National Institute of Health; http://www.ncbi.nlm.nih.gov/pubmed/) were performed for content related to the biologic functions of miRNA, the roles of miRNA in human disease and studies investigating miRNA in the context of uterine leiomyomata. Herein, this article will review the current evidence supporting the use of miRNA expression profiling as an investigative tool to assess the pathobiology of uterine fibroids and will discuss potential future applications of miRNAs as biomarkers and therapeutic targets. RESULTS Mounting evidence supports a functional role for miRNA as either indirect or direct regulators of gene expression which impacts the pathobiology of uterine fibroids. Specifically, miRNAs let-7, 200a, 200c, 93, 106b and 21 have been implicated in cellular proliferation, apoptosis, extracellular matrix turnover, angiogenesis and inflammation. Preliminary data provide evidence to suggest that respective in vitro miRNA expression in leiomyomata and myometrium is regulated by sex steroids. CONCLUSIONS Collectively, the identification of aberrantly expressed miRNAs in uterine leiomyomata and accumulating data derived from mining of gene target prediction models and recent functional studies support the concept that miRNAs might impact the genesis and progression of disease. However, the specific biologic functions of differential miRNA expression have yet to be confirmed in vivo. Further functional studies and developing miRNA technology may provide the basis for future applications of miRNAs in clinical medicine as biomarkers and therapeutic targets.

Male caffeine and alcohol intake in relation to semen parameters and in vitro fertilization outcomes among fertility patients

Much of the literature on the impact of male caffeine and alcohol intake on reproductive outcomes has utilized semen quality as a proxy for male fertility, although semen parameters have a limited predictive value for spontaneous pregnancy. The objective of this study was to investigate whether male caffeine and alcohol intakes are associated with semen parameters and assisted reproductive technology outcome. The Environment and Reproductive Health Study, an ongoing prospective cohort study, enrolls subfertile couples presenting for treatment at an academic fertility center (2007–2012). A total of 171 men with 338 semen analyses and 205 assisted reproductive technology cycles were included in this analysis. Diet was assessed using a 131‐item food frequency questionnaire. Mixed models adjusting for potential confounders were used to evaluate the relationships of male caffeine and alcohol intakes with semen parameters and assisted reproductive technology outcomes. There was no association between male caffeine and alcohol intake and semen quality. Male caffeine intake was negatively related to live birth after assisted reproductive technologies (p‐trend < 0.01), and male alcohol intake was positively related to live birth after assisted reproductive technologies (p‐trend = 0.04). Adjusted live birth rate among couples with a male partner in the highest quartile of caffeine intake (≥272 mg/day) compared to couples with a male partner in the lowest quartile of intake (<99 mg/day) was 19% vs. 55%, respectively, p < 0.01. In terms of alcohol intake, adjusted live birth rate among couples with a male partner in the highest quartile of alcohol intake (≥22 g/day) compared to couples with a male partner in the lowest quartile of intake (<3 g/day) was 61% vs. 28%, respectively, p = 0.05. In conclusion, male pre‐treatment caffeine and alcohol intakes were associated with live birth after assisted reproductive technologies, but not with semen parameters, among fertility patients.

Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction

STUDY QUESTION Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (ω3-PUFA) and omega-6 (ω6-PUFA), related to ART outcomes? SUMMARY ANSWER Serum levels of long-chain ω3-PUFA were positively associated with probability of live birth among women undergoing ART. WHAT IS KNOWN ALREADY Intake of ω3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating ω3-PUFA levels and pregnancy rates after ART. STUDY DESIGN SIZE, AND DURATION This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. PARTICIPANTS/MATERIALS, SETTING, METHODS Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. MAIN RESULTS AND ROLE OF CHANCE The median [25th, 75th percentile] serum level of ω3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain ω3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain ω3-PUFA levels. Intake of long-chain ω3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain ω3-PUFA for 1% energy of saturated fatty acids. Serum ω6-PUFA, ratios of ω6 and ω3-PUFA, and total PUFA were not associated with ART outcomes. LIMITATIONS REASONS FOR CAUTION The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. WIDER IMPLICATIONS OF THE FINDINGS Serum ω3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain ω3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. STUDY FUNDING/COMPETING INTERESTS NIH grants R01-ES009718 from the National Institute of Environmental Health Sciences, P30-DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare.

Clinical Characteristics Associated with Antibiotic Treatment Failure for Tuboovarian Abscesses

Objective. Although parenteral antibiotic treatment is a standard approach for tuboovarian abscesses, a significant proportion of patients fail therapy and require interventional radiology (IR) guided drainage. The objective of this study is to assess if specific clinical factors are associated with antibiotic treatment failure. Study Design. Retrospective medical record review of patients hospitalized for tuboovarian abscesses from 2001 through 2012 was performed. Clinical characteristics were compared for patients who underwent successful parenteral antibiotic treatment, failed antibiotic treatment necessitating subsequent IR drainage, initial drainage with concurrent antibiotics, and surgery. Results. One hundred thirteen patients admitted for inpatient treatment were identified. Sixty-one (54%) patients were treated with antibiotics alone. Within this group, 24.6% failed antibiotic treatment and required drainage. Mean white blood cell count (K/μL) (18.7 ± 5.94 versus 13.9 ± 5.12) (p = 0.003), mean maximum diameter of tuboovarian abscess (cm) (6.8 ± 2.9 versus 5.2 ± 2.0) (p = 0.03), and length of stay (days) (9.47 ± 7.43 versus 4.59 ± 2.4) (p = 0.002) were significantly greater for patients who failed antibiotic treatment. Conclusions. Admission white blood cell count greater than 16 K/μL and abscess size greater than 5.18 cm are associated with antibiotic treatment failure. These factors may provide guidance for initial selection of IR guided drainage.

MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma

BackgroundMicroRNAs (MiR) may promote fibroid development via altered expression of genes involved in cell proliferation and ECM formation, and evidence supports aberrant expression of MicroRNA (MiR) 21a-5p in fibroids. The purpose of this study was to investigate the functional significance of MiR 21a-5p overexpression in the pathobiology of leiomyomata (fibroids).MethodsA basic science experimental design using immortalized fibroid and myometrial cell lines derived from patient-matched specimens was used. Stable overexpression of MiR-21a-5p in an immortalized fibroid and patient matched myometrial cell line was achieved through lentiviral vector infection. Main outcome measures were MiR-21-5p overexpression, target gene and protein expression, collagen (COL1A1) production, cell proliferation, cell migration, and cell cycle stages of fibroid and myometrial immortalized cell lines.ResultsMiR-21a-5p was overexpressed to similar levels in fibroid and myometrial cell lines after lentiviral infection. Increased expression of miR-21 resulted in increased gene and protein expression of TGF-β3 in both fibroid and myometrial cells. Changes in expression of the ECM genes Fibronectin, Collagen 1A1, CTGF, Versican and DPT were seen in both fibroid and myometrial cells. Changes were also seen in Matrix Metalloproteinase (MMP) related genes including MMP 2, MMP 9, MMP 11 and Serpine 1 in both fibroid and myometrial cells. MiR-21 upregulation resulted in increased proliferation and migration in fibroid cells compared to myometrial cells.ConclusionsMiR-21a-5p overexpression results in changes in the expression of ECM mediators in both fibroid and myometrial cells, and increased cell proliferation in fibroid cells. These finding suggest a potential functional role of MiR-21a-5p in the development of uterine fibroids and warrant further investigation.

Clomid Compared With Follicle-Stimulating Hormone Treatment: Similar Follicle Number Means Different Success Rates [178]

INTRODUCTION: Clomiphene citrate and gonadotropins are used during intrauterine insemination cycles to help recruit one or more follicles. The objective of this study is to evaluate whether one treatment confers a higher pregnancy rate over the other, even when number of preovulatory follicles are held constant. METHODS: Data from 1,463 women who underwent 3,960 clomiphene or gonadotropin intrauterine insemination cycles were reviewed. Cycles occurred at Massachusetts General Hospital between 2004 and 2012. Regression models using generalized estimating equations were fit to investigate the relationship between cycle type and clinical pregnancy. Results were adjusted for age, body mass index, infertility diagnosis, day 3 follicle-stimulating hormone, and number of follicles greater than 14 mm. A final model was fit adjusting for endometrial thickness in addition to other covariates. RESULTS: Mean endometrial thickness was 7.0 mm and 8.5 mm among women who underwent clomiphene and gonadotropin cycles, respectively (P<.01). Crude clinical pregnancy rate per intrauterine insemination was 11% and 13% among clomiphene and gonadotropin cycles, respectively. After adjusting for potential confounders including number of follicles, odds of clinical pregnancy was higher among gonadotropin cycles as compared with clomiphene cycles (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1–1.7). When endometrial thickness was also controlled for, odds of clinical pregnancy remained higher among gonadotropin cycles although the strength of the relationship decreased (OR 1.3, 95% CI 1.0–1.6). CONCLUSION: Even when number of follicles is held constant, gonadotropin cycles are more likely to result in clinical pregnancy compared with clomiphene cycles. Differential effects on the endometrium may play a role.