Intramural Leiomyomas and Fertility: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate fertility outcomes based on size and number of intramural leiomyomas and outcomes after removal. DATA SOURCES: Online searches: MEDLINE, ClinicalTrials.gov, PubMed, Cochrane Library, and PROSPERO Library from 1994 to 2023. METHODS OF STUDY SELECTION: A total of 5,143 studies were identified, with inclusion of 13 study groups. TABULATION, INTEGRATION AND RESULTS: Outcomes for size and number of leiomyomas were reported with clinical pregnancy rates and ongoing pregnancy or live-birth rates. In data sets with maximum leiomyoma diameters of less than 6 cm for study inclusion, women with leiomyomas smaller than 3 cm had lower clinical pregnancy rates than women without leiomyomas, with an odds ratio (OR) of 0.53 (95% CI, 0.38-0.76) and, for ongoing pregnancy or live-birth rates, an OR of 0.59 (95% CI, 0.41-0.86). The ORs for clinical pregnancy rates in women with intermediately-sized leiomyomas (those between 3 cm and 6 cm) were lower than in women without leiomyomas, with an OR at 0.43 (95% CI, 0.29-0.63) and, for ongoing pregnancy or live-birth rates, an OR at 0.38 (95% CI, 0.24-0.59). In data sets without exclusion for women with larger-sized leiomyomas, clinical pregnancy rates were lower for those with leiomyomas smaller than 5 cm compared with those without leiomyomas, with an OR of 0.75 (95% CI, 0.58-0.96). Women with leiomyomas larger than 5 cm showed no differences in clinical pregnancy rate compared with women without leiomyomas, with an OR of 0.71 (95% CI, 0.32-1.58). Although women with a single leiomyoma in any location had no differences in outcomes, those with more than one leiomyoma had lower clinical pregnancy rates and ongoing pregnancy or live-birth rates, with an OR of 0.62 (95% CI, 0.44-0.86) and 0.57 (95% CI, 0.36-0.88), respectively. The clinical pregnancy rate for women undergoing myomectomy for intramural leiomyomas was no different than those with intramural leiomyomas in situ, with an OR of 1.10 (95% CI, 0.77-1.59). CONCLUSION: Even small intramural leiomyomas are associated with lower fertility; removal does not confer benefit. Women with more than one leiomyoma in any location have reduced fertility.

The prevalence of occult leiomyosarcoma in women undergoing presumed fibroid surgery and outcomes after morcellation.

PURPOSE OF REVIEW: To review the data-derived prevalence rates for occult leiomyosarcoma (LMS), and outcomes for women who have these tumors inadvertently morcellated. RECENT FINDINGS: In 2014, the Food and Drug Administration presented data showing the prevalence rates of occult LMS at 2.02/1000 surgeries for presumed benign fibroids. They also attributed poorer outcomes for women undergoing power morcellation of these tumors. Two more recent meta-analyses have shown much lower rates, as low as one in 8300 surgeries when including only prospective studies, and one in 1428 surgeries when including both prospective and retrospective studies. When looking at outcomes, both studies show no difference in outcomes when comparing power or any other type of morcellation. The most recent data suggest that even intact removal has no advantage when looking at mortality rates. SUMMARY: Prevalence of occult LMS remains quite rare, but outcomes after intact removal or any type of morcellation appear to be no different.

U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women?

The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.

What is the Future of Open Intraperitoneal Power-Morcellation of Fibroids?

In November 2014, the Food and Drug Administration (FDA) calculated that for every 498 women having surgery for presumed fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). The FDA issued a safety communication warning against the use of laparoscopic morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids. This communication was prompted by concern that if a patient had an occult LMS, the morcellator might spread tumor cells within the peritoneal cavity. We submit that the FDA directive was based on a flawed and misleading analysis. More rigorous evidence estimates the prevalence of LMS among women operated upon for presumed uterine fibroids at approximately one in 2000 women, significantly lower than the FDA's estimate. In addition, there is no reliable evidence that morcellation influences survival or that power-morcellation is inferior to vaginal or mini-lap morcellation with a scalpel. Recent publication shows that open surgery carries more risk for women when compared with minimally invasive surgery. Although the possibility of occult LMS should be considered by women and their gynecologists, we suggest that current morcellation techniques be continued for women who wish to benefit from minimally invasive surgery. Investigation into new and, hopefully, better morcellating devices may make the procedure safer for women.

The prevalence of occult leiomyosarcoma at surgery for presumed uterine fibroids: a meta-analysis.

There is a concern regarding the risk of occult leiomyosarcomas found at surgery for presumed benign fibroids. We sought to produce a comprehensive review of published data addressing this issue and provide high-quality prevalence estimates for clinical practice and future research. A comprehensive literature search using the PubMed/MEDLINE database and the Cochrane Library was performed. Inclusion criteria were human studies, peer-reviewed, with original data, involving cases for surgery in which fibroid-related indications were the primary reason for surgery, and histopathology was provided. Candidate studies (4864) were found; 3844 were excluded after review of the abstract. The remaining 1020 manuscripts were reviewed in their entirety, and 133 were included in the Bayesian binomial random effect meta-analysis. The estimated rate of leiomyosarcoma was 0.51 per 1000 procedures (95 % credible interval (CrI) 0.16-0.98) or approximately 1 in 2000. Restricting the meta-analysis to the 64 prospective studies resulted in a substantially lower estimate of 0.12 leiomyosarcomas per 1000 procedures (95 % CrI <0.01-0.75) or approximately 1 leiomyosarcoma per 8300 surgeries. Results suggest that the prevalence of occult leiomyosarcomas at surgery for presumed uterine fibroids is much less frequent than previously estimated. This rate should be incorporated into both clinical practice and future research.

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review.

There is concern that morcellation of occult leiomyosarcomas during surgery to treat presumed myomas may substantially worsen patient outcome. We reviewed the existing medical literature to better understand whether such a risk was demonstrable and, if so, what the magnitude of that risk might be. We identified 4864 articles initially, of which 60 were evaluated in full. Seventeen were found to have outcomes information and are included in this review. Six studies addressed the question of whether morcellation of occult leiomyosarcomas resulted in inferior outcomes as compared with en bloc uterine and tumor removal. In these 6 studies, results suggested that en bloc removal may result in improved survival and less recurrence; however, the data are highly biased and of poor quality. There is no reliable evidence that morcellation, power or otherwise, substantially results in tumor upstaging. There is no evidence from these 17 studies that power morcellation differs in any way from other types of morcellation or even simple myomectomy insofar as patient outcome. Whether electromechanical morcellation poses a unique danger to the patient with occult leiomyosarcoma is an unanswered question and one clearly in need of more extensive investigation before conclusions are drawn and policies created.

The use of high dose letrozole in ovulation induction and controlled ovarian hyperstimulation.

Letrozole, an aromatase inhibitor, has been demonstrated to be effective as an ovulation induction and controlled ovarian hyperstimulation agent. However, dose administration has generally been limited to 5 days at 2.5 to 7.5 mg daily. We undertook a retrospective review of over 900 treatment cycles using letrozole in doses as high as 12.5 mg per day. Results indicate that such doses do indeed offer benefit to patients; in that there is increased follicular growth and a higher number of predicted ovulations with higher doses of the drug. However, increasing doses does not produce a detrimental effect upon endometrial thickness. High-dose letrozole may be of value in women who fail to respond adequately to lower doses. Furthermore, randomized trials are needed to determine whether high-dose letrozole might actually be optimal as a starting dose for certain treatment groups.

Letrozole for ovulation induction and controlled ovarian hyperstimulation.

PURPOSE OF REVIEW: Letrozole, an aromatase inhibitor, is the newest addition to our armamentarium in the treatment of infertility. It is utilized in much the same way as clomiphene citrate, but with some additional benefits. In this review, the latest studies will be summarized with emphasis on dose, duration of use, safety, number of mature follicles, and pregnancy outcomes. RECENT FINDINGS: Letrozole has fewer side effects, and a shorter half-life than clomiphene citrate, and no demonstrable effect upon the receptivity of the endometrium. It is efficacious in treating women with chronic anovulation, unexplained infertility and diminished ovarian reserve. Its safety is superior to clomiphene citrate. Utilizing bio-equivalent doses, letrozole pregnancy rates are equal or superior to clomiphene citrate. Several studies suggest situations where it is more efficacious than gonadotropin treatment. SUMMARY: With further study, this drug could replace clomiphene citrate as the primary medication for chronic anovulation and/or unexplained infertility. It could augment or even obviate the use of gonadotropins in the treatment of women who have been unsuccessful in achieving pregnancy with clomiphene citrate. It may also be an adjunct for women with diminished ovarian reserve. Further studies are needed to determine optimal dosing and long term safety for women treated with the drug.

Fibroids and reproduction.

Uterine fibroids are commonly seen in women with reproductive disorders such as infertility, spontaneous abortion (SAB), and obstetric complications. Although it is certain that these tumors can occasionally cause such pathophysiology, it is critical to understand the rate of such occurrences, the degree of causality of the fibroids, and our ability to ameliorate the problems via surgical treatment. Evaluation of the available data is hampered by poor quality studies, heterogeneity of the disease, and confounding factors affecting outcomes. Nevertheless, the best available evidence suggests the following: (1) Submucous myomas decrease fertility and increase SAB rates; myomectomy is likely to be of value; (2) intramural myomas may decrease fertility, but the issue is less clear; they do seem to increase rates of miscarriage; there is no solid evidence that myomectomy restores the patient to normal; (3) subserosal myomas do not impair fertility but may enhance the rate of SAB; and (4) fibroids increase the risk of several obstetric complications, including cesarean delivery, malpresentation, postpartum hemorrhage, retained placenta, intrauterine growth retardation, preterm labor, placenta previa, and abruption. Higher quality studies are desperately needed to add confidence to these tenuous conclusions.

Fibroids and infertility: an updated systematic review of the evidence.

OBJECTIVE: To investigate the effect of fibroids on fertility and of myomectomy in improving outcomes. DESIGN: Systematic literature review and meta-analysis of existing controlled studies. SETTING: Private center for Reproductive endocrinology and infertility. PATIENT(S): Women with fibroids and infertility. INTERVENTION(S): A systematic literature review, raw data extraction and data analysis. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, spontaneous abortion rate, ongoing pregnancy/live birth rate, implantation rate, and preterm delivery rate in women with and without fibroids, and in women who underwent myomectomy. RESULT(S): Women with subserosal fibroids had no differences in their fertility outcomes compared with infertile controls with no myomas, and myomectomy did not change these outcomes compared with women with fibroids in situ. Women with intramural fibroids appear to have decreased fertility and increased pregnancy loss compared with women without such tumors, but study quality is poor. Myomectomy does not significantly increase the clinical pregnancy and live birth rates, but the data are scarce. Fibroids with a submucosal component led to decreased clinical pregnancy and implantation rates compared with infertile control subjects. Removal of submucous myomas appears likely to improve fertility. CONCLUSION(S): Fertility outcomes are decreased in women with submucosal fibroids, and removal seems to confer benefit. Subserosal fibroids do not affect fertility outcomes, and removal does not confer benefit. Intramural fibroids appear to decrease fertility, but the results of therapy are unclear. More high-quality studies need to be directed toward the value of myomectomy for intramural fibroids, focusing on issues such as size, number, and proximity to the endometrium.

MR hysterosalpingography with an angiographic time-resolved 3D pulse sequence: assessment of tubal patency.

OBJECTIVE: The purpose of our study was to determine if tubal patency can be assessed by MR hysterosalpingography (HSG) using a clinically available MR angiographic sequence (3D time-resolved imaging of contrast kinetics [TRICKS]). This capability would enhance the value of MRI in women with infertility. CONCLUSION: MR HSG effectively shows tubal patency and can be considered when both conventional HSG and standard MRI are necessary for the evaluation of women with infertility, such as in women with suspected uterine anomalies or extrauterine disease.

Venous thromboembolism prevention in gynecologic cancer surgery: a systematic review.

OBJECTIVES: Advanced age, pelvic surgery, and the presence of malignancy place gynecologic oncology patients at high risk for venous thromboembolism (VTE). This study was designed to systematically analyze the world's literature on VTE in these patients and determine the optimal prophylaxis regimen. METHODS: Computerized searches of Pubmed, Ovid, DARE, ACP Journal Club, Cochrane Database of Systematic Reviews, and Cochrane Controlled Trials Registry 1966-2005 were performed, as well as EMBASE 1980-2005. Major conferences and target references were hand-searched. Inclusion criteria were randomized controlled trials (RCTs) evaluating VTE prophylaxis with heparin, low-molecular-weight heparin (LMWH), and sequential compression devices (SCD). The search yielded 278 articles; 11 met inclusion criteria. Data were abstracted by one author and analyzed with the Mantel-Haenszel method. RESULTS: The analysis of heparin-versus-control revealed a significant decrease in DVT in patients receiving heparin (RR=0.58, 95% CI 0.35-0.95). There were no significant differences in EBL or transfusions between the two groups. In the 320 patients in the heparin vs. LMWH studies, there was no significant difference in DVT (RR 0.91, 95% CI 0.38-2.17), although power analysis demonstrated insufficient numbers to show a difference. No patient in either group required re-exploration for bleeding. CONCLUSIONS: All gynecologic cancer patients should receive VTE prophylaxis. Although heparin, LMWH, and SCD have been shown to be safe and effective, due to the paucity of data in the gynecologic oncology literature, no one prevention modality can be considered superior at this time. Adequately powered RCTs are urgently needed to determine the optimal regimen in these high-risk patients.

Estimating infertility: the devil is in the details.

Self-reported data have serious limitations, particularly when the outcome is constructed from indirect questions. Policy decisions require clearly defined issues, validated tools, careful and comprehensive analysis, and cautious interpretation.