Elagolix shows promising results in the treatment of heavy menstrual bleeding associated with uterine fibroids

Oral elagolix either alone or with add-back therapy significantly reduces menstrual blood loss in 90% of pre-menopausal women with uterine fibroids reports the results of a new clinical trial published in November issue of Journal Obstetrics & Gynecology.

Elagolix is an oral gonadotropin-releasing hormone receptor antagonist and recently won FDA approval as the first and only oral drug for the management of severe pain associated with endometriosis.

This interventional, double-blind, randomized Phase 2b Study was conducted across five countries to evaluate the safety and efficacy of elagolix. Over a period of nearly 2.5 years, researchers enrolled 571 premenopausal women suffering from heavy menstrual blood loss and an ultrasound documented uterine fibroids.

These women were randomized to cohorts 1 (259) and 2 (308) and received 300 mg twice daily and 600 mg daily elgolix respectively. Each cohort has four arms: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate.

The primary outcome measure was the percentage of women with a Menstrual Blood Loss (MBL) volume of < 80 mL at the last 28 days of the treatment cycle and a ≥ 50% Reduction in MBL volume from baseline to the final month.  The primary safety concern was the change in bone mineral density.

The average age of the participant was 43±5 years, and 70% were black.  Women in both cohorts demonstrated a significant reduction in menstrual blood loss and reached the primary endpoint in all three arms (all P<.001 vs. placebo). 

Elagolix arm showed a significant decrease in lumbar spine bone mineral density as compared to placebo, but add-on therapy with 1.0 mg estradiol/0.5 mg norethindrone acetate stopped the bone loss.

Dr. Bruce Carr, Professor of Obstetrics and Gynecology at UT Southwestern Medical Center and lead author on the study said the oral therapy offers new hope for patients suffering from menorrhagia with uterine fibroids for whom hysterectomy or myomectomy was the gold standard treatment. 

 “There are no orally approved drugs to decrease bleeding and prevent anemia in women with these tumors. Now, there is a medical option for this devastating disease that affects up to 75 percent of women,” he further added in a new release by UT Southwestern Medical Center.

A phase 3 ELARIS UF-EXTEND study of elagolix has also shown parallel results as the phase 2b trial and ELARIS UF-I and ELARIS UF-II phase 3 studies. AbbVie plans to include the ELARIS UF-EXTEND data as part of a submission for regulatory approval of elagolix for the treatment of uterine fibroids in 2019.

Abstract

UTSouthwestern Medical Center news release

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ACOG guidance on prevention of surgical-site infection in gynecologic surgery

Surgical site infection(SSI) after gynecological surgery is a significant cause of postoperative morbidity leading to repeated hospital visits.  These infections also incur heavy social and economic burden on patients and the healthcare system.

Two previous research papers have estimated that each SSI during a hysterectomy is going to add $5000 inpatient cost.

CDC defines SSI as an infection occurring at or near the surgical incision within 30 days of surgery and 12 months if a surgical implant was used.

A number of factors, both modifiable and not modifiable, contribute to the ultimate development of an SSI.

Steiner. Surgical-site infection in gynecologic surgery. Am J Obstet Gynecol 2017.

The recent ACOG practice bulletin is published in the June issue of Journal of Obstetrics and Gynecology and replaces Practice Bulletin Number 104, May 2009, and Committee Opinion Number 571, September 2013.

The practice bulletin includes guidelines about pre-operative and intraoperative prophylaxis, procedure-based antibiotic regimen, guidelines for patients with a history of Methicillin-resistant Staphylococcus aureus (MRSA) colonization, and penicillin allergy.

Preoperative prophylaxis:

Treat any remote infections before any elective gynecological procedure.

It is preferable not to shave the incision site unless it interferes with the procedure. When necessary, do not use a razor, clippers are preferred.

Screen women for diabetes before the procedure and if found hyperglycemic, aim at blood  glucose <200 mg/dL with or without diabetes.

Patients should have a full body shower or bath with Chlorhexidine instead of soap.

Pre-op abdominal skin preparation is preferably done with alcohol-based preparations, and chlorhexidine-alcohol was significantly more effective than a povidone-iodine scrub in preventing superficial and deep incisional infection.

Vaginal cleaning before surgery is done by 4% chlorhexidine gluconate or povidone-iodine, only povidone–iodine is FDA approved for vaginal preparation. Chlorhexidine gluconate with high alcohol concentration (70% isopropyl alcohol) is contraindicated for vaginal prep due to the risk of irritation.

Screen for bacterial vaginosis pre-operatively, if found positive initiate treatment with metronidazole or another CDC recommended regimen.

All members of the surgical team should maintain aseptic techniques and traffic in the OR should be limited

Intraoperative Prophylaxis:

Use excellent surgical techniques gentle tissue handling, good hemostasis, avoid hypothermia and short operative time < 100 minutes.

Use appropriate antimicrobial prophylaxis one hour before the surgery, in obese patients, the dose should be calculated accordingly.

In cases of long surgical procedures (> 4 hours) or blood loss > 1500 ml, repeat Cefazolin

Procedure based antibiotic regimens:

In all types of hysterectomy (abdominal, vaginal, laparoscopic, and robotic), Laparotomy, Vaginal sling, and Colporrhaphy: 2 g IV cefazolin (≤120 kg) and 3 g IV cefazolin (>120 kg)

In Uterine evacuation (suction D&C/D&E): 200 mg doxycycline orally or IV, Metronidazole is an effective second line of therapy.

No antibiotics are recommended: Colposcopy, Cervical tissue excision procedures (LEEP/biopsy/ECC), Endometrial biopsy, Cystoscopy, HSG, Hysteroscopy (operative/diagnostic), endometrial adhesions, IUD insertion, Oocyte retrieval and embryo transfer, D&C for nonpregnancy indications, and laparoscopic procedures.

History of MRSA Colonization or Infection:

It is recommended to follow the hospital protocol for MRSA antibiotic prophylaxis or a single preoperative intravenous dose of vancomycin (15 mg/kg) is included in the preoperative antibiotic prophylaxis regimen

Penicillin allergy:

In case of Immediate hypersensitivity reaction or Stevens-Johnson syndrome use Clindamycin 900 mg or metronidazole 500 mg PLUS Gentamicin 5mg/kg or aztreonam 2 g 

If there is no immediate hypersensitivity reaction (anaphylaxis, urticaria, bronchospasm) cephalosporins can be used. If there is a history of allergy to cephalosporins use Clindamycin 900 mg or metronidazole 500 mg PLUS Gentamicin 5mg/kg or aztreonam 2 g 

ACOG Practice Bulletin 195: Prevention of Infection After Gynecologic Procedures (login required)

JAMA Full Text: Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017

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Younger age at hysterectomy linked to increased risk of heart disease later in life

Ovarian conservation at hysterectomy does not reduce the risk of future cardiometabolic diseases reports the results of large prospective cohort study published in Menopause, the journal of The North American Menopause Society (NAMS).

This is one of the few studies that focuses on long term effect of hysterectomy with ovarian conservation. Earlier studies have documented strong evidence between increased incidence of cardiovascular diseases(CVD) and other chronic diseases after hysterectomy with bilateral oophorectomy.

The risk was especially increased if the hysterectomy was carried out before the age of 35.

Using Epidemiological project record, the researchers identified 2094 women who underwent hysterectomy with ovarian conservation between 1980 and 2002. Each woman was age matched with a control residing in the same county and who have neither undergone hysterectomy nor bilateral oophorectomy.

Cox proportional hazard models and Kaplan-Meier analysis was used to calculate hazards ratios and absolute risk after taking into consideration 20 risks factors and other potential confounders.

The two cohort were followed up for a period of 22 years, and women who have undergone hysterectomy were at increased risk of obesity, hyperlipidemia, hypertension, cardiac arrhythmias and coronary artery diseases.

Women who had hysterectomy under the age of 35 years were at nearly 5 times increased risk of congestive heart failure and 2.5 times increased risks of coronary artery disease.

Dr. JoAnn Pinkerton, NAMS executive director said in a NAMS press release, “These study results suggest that alternative uterine-preserving treatments may need to be considered more often in lieu of hysterectomies, especially in benign situations. For those women having hysterectomy, hormone therapy should be considered for added protection, because ovarian function appears to be impaired by the surgery.”

Abstract

NAMS press release

Media courtesy: Detroit Free Press

A simple, novel solution to identify and protect ureter during surgery

AllotropeMedical, a Houston based medical startup has devised StimSite, a novel, hand-held, single use device that precisely identifies ureter during surgery; thus, eliminating the need for ureteral stenting.

It is specifically useful in all gynecological, colorectal and oncosurgeries. Gynecological surgery accounts for 50% of all iatrogenic ureteric injuries.

It is estimated that around 3 million surgeries performed in US annually, require an identification of ureter. The rate of ureteric injuries is around 2% with disastrous consequences and the total healthcare burden of this complication is about $3.2B every year.

It is also estimated that about 30% surgical time is spent on identifying the ureter.

The surgeon can simply place the tip of the device in the vicinity of the ureter and with a push of a button, the ureter goes into contraction and the full length of ureter towards kidney and bladder can be identified.

There is no other smooth muscle structure in that anatomical region, so the device specifically identifies ureter only.

The device is single use, battery operated and avoids additional procedures like cystoscopy on the operation table.

Allotrope aims to initially market the device for two high volume procedures, Hyterectomy (750,000 in US) and colon resection (300,000 cases). The current alpha prototype is a hand held, stand alone device that can be used in both open and minimal invasive surgeries. The company plans to enter the Robotic market in future by designing device for their platforms.  

Currently, StemSite is at pre-FDA state, but plans to get FDA clearance through the 510(k) pathway, and entering the marketplace by first quarter of 2019.

Allotrope has recently won second place in MedTech Innovator’s 2017 competition, among 600 startups.

Here is a video by Allotrope showing the functioning of the device. 

An effective, minimal invasive but “vastly underutilized” treatment option for fibroids: Uterine Fibroid Embolization

Statistics by National Institute of Health (NIH) indicate that nearly 3 in 4 women will develop fibroid by the time they reach age 50, but more than half of these women have never heard of Uterine Fibroid Embolization and 11% think that hysterectomy is the only treatment option available to them says the results of a Nationwide survey conducted by Harris Poll between June 23 and 27, 2017.

The survey was conducted on behalf of the Society of Interventional Radiology (SIR) and results were presented at the Society of Interventional Radiology’s 2017 Annual Scientific Meeting.

The survey of almost 1,200 women found that about one third of women did not know what fibroids are, 37% did not know anybody else with the diagnosis of fibroid, and nearly 60% did not think that they are at risk of developing fibroid.

Courtesy: Linkedin.com 

One in 5 women thought fibroids are cancerous and surgery is the only treatment option they have.

A majority of women (62%)have never heard of Uterine Fibroid Embolization, and 73% of women who knew about UFE reported that they got the information elsewhere, other than their Ob/Gyn.

As per National Uterine Foundation, nearly 600,000 hysterectomies performed annually in the United States out of which ~170,000 - ~300,000 are due to uterine fibroids. A review of published studies has shown that nearly 1 in 5 hysterectomy is unindicated and 40% of patient who have hysterectomy do not receive full information about other medical or less invasive procedures available to them. It appears that it was presented to them as the best treatment option available, says the SIR report.

James Spies, MD, MPH, a professor of radiology at Georgetown University Medical Center, Washington, DC, and the president-elect of SIR said, "Misperceptions about uterine fibroids and the treatments available often lead women to undergo invasive and potentially unnecessary surgery for their fibroids, despite more than 20 years of clinical use supporting uterine fibroid embolization.”

"Unfortunately, still many health care professionals start and end with hysterectomy as the recommendation for patients," he further added.

An NIH study showed that 165,000 more hysterectomies were performed than UFEs (167,650 vs. 2,470) nationwide, a difference of whopping 67% between the two procedures.

The study also reported that nine out of 10 women who have uterine fibroid embolization have significant improvement. Many women report their symptoms disappear completely.

UFE also helps women in getting back to normal lives quickly after the procedure, with no residual effects of early menopause and sexual dysfunction, as often experienced after hysterectomies.

It is also minimally invasive with a hospital stay of one day or less, cost effective, low rate of complications and few women require follow up treatment. If the fibroids recur, they can be again be treated: A second UFE is not contraindicated, said Dr Spies.

It’s also a great option for women desiring future pregnancies.  A study published in Radiology Journal showed a 41.5 percent pregnancy rate after an average follow-up of almost six years.

The ACOG has included UAE in its FAQs on Uterine Fibroids. The procedure was included as one of the treatment option in its 2008 bulletin, reaffirmed again in 2016. The bulletin concludes, "Based on long- and short-term outcomes, uterine artery embolization is a safe and effective option for appropriately selected women who wish to retain their uteri." 

Courtesy: SIR

UFE is performed by an interventional radiologist who inserts a thin catheter into the artery at the groin or wrist. The doctor guides the catheter to the fibroid’s blood supply where small particles, about the size of grains of sand, are released to float downstream and block the small blood vessels and deprive the fibroid of nutrients. This results in the fibroid softening, bleeding less, and shrinking in size.

Does  the push to promote UFE by SIR means promoting self-interest? No, it only means that women diagnosed with fibroids deserve to know about all the options they have and the clinicians should be able to inform them about it. 

Executive summary of survey, Full PDF, SIR news release
RCOG recommendations for UAE for Fibroids

Value of hormonal treatment in endometrial hyperplasia debated— News from ACOG Annual Clinical and Scientific Meeting 2016.

The John I. Brewer Memorial Lecture on Day 2 of the Annual Clinical and Scientific meeting, ACOG  2016 considered the role of hormones in treatment of Endometrial Hyperplasia vs the common surgery of Hysterectomy.

Debaters were David E. Cohn, MD, professor in the Department of Obstetrics and Gynecology and director of the Division of Gynecologic Oncology at The Ohio State University College of Medicine, and Amanda Nickles Fader, MD, associate professor and director, The Kelly Gynecologic Oncology Service and Johns Hopkins Hospital in Baltimore. They all agreed that when treatment is tailored according to patient need both forms can be beneficial.

Dr. Cohn opined that in patients who are fit for surgery and have completed the family the most effective and definitive way of preventing the transition into endometrial cancer is hysterectomy. He cited the 2006 prospective cohort study in which out of 289 women with atypical endometrial hyperplasia on biopsy or curettage,42.6 percent had endometrial cancer at hysterectomy within 12 weeks of sampling. He also said that hormonal treatment has to be continued for an indefinite period of time vs hysterectomy which is a one-step procedure with much higher success rates.

He also referred to a meta-analysis of 34 observational studies in which progestins were used to treat atypical endometrial hyperplasia. The statistical analysis showed that while 86% of women saw regression, 3.6% of women had ovarian cancer and 1.9% had advanced endometrial cancer.

He further quoted “That’s sobering news about the potential for bad outcomes with progestins.”

He acknowledged the committee opinion from 2015 that says “Progestin treatment was an unproven but commonly used alternative to hysterectomy, but optimal doses and duration of treatment need to be defined and post-hormonal surveillance and frequency is yet to be determined. It is also not determined whether it should be continuous or cyclical. And also lacks the optimal clinical as well as histological measures of response.”

He concluded by seconding the ACOG committee opinion of lots of unanswered questions regarding the use of progestins therapy.

The second debater Dr. Fader argued in favor of progestins therapy and stressed that the surgical option is chosen more out of fear than by evidence, nonetheless ample evidence exists in support of hormonal treatment.

As times have changed in last 15 years and in contemporary times, a number of organ-sparing treatments have become a reality. She further said “Almost all endometrial hyperplasia is sensitive to hormonal treatment and most — including atypical hyperplasia — regresses or remains unchanged without therapy and doesn’t progress to cancer.”

She presented evidence in the form of results of 150 retrospective studies and 12 prospective, in which progestin treatment brings about atypical hyperplasia regression in 75 to 95 percent of cases. 

Additional review of 4 large studies also showed that progestins were associated with regression of hyperplasia due to unopposed estrogens in 90% of patients.

Dr. Fader also said that with 40% of endometrial hyperplasia patients are obese or want to retain fertility, making hormonal treatment a valid choice for them. Endometrial hyperplasia is a public health problem due to increasing demographics of obesity and endogenous estrogen production, with many of the women younger than 45 years of age, which increases the need of exploring life style modifications and treatment beyond surgery a viable option.

Both the debaters agreed upon the impact of obesity on endometrial hyperplasia and the Dr.Cohn pointed out that early data on  bariatric surgery is promising in converting abnormal endometrium into normal endometrium without surgery. 

References:

http://www.acog.org/-/media/Committee-Opinions/Committee-on-Gynecologic-Practice/co631.pdf?dmc=1&ts=20150426T1515499455

http://www.acogdailynews.com/role-of-hormones-in-endometrial-hyperplasia-debated/

Elective oophorectomy or ovarian conservation at the time of benign hysterectomy?

Hysterectomy is the second most common surgery performed in US after cesarean section.  According to CDC data approximately 600,000 hysterectomies are performed each year. A nationwide study further reported that unilateral or bilateral oophorectomy was performed in 68 percent of women at the time of abdominal hysterectomy, 60 percent at laparoscopic hysterectomy, and 26 percent at vaginal hysterectomy.

Women have an option of undergoing elective oophorectomy (EO) along with benign hysterectomy to reduce the risk of ovarian cancer, thereby reducing a chance of second surgery coupled with decreased perceived   anxiety of breast and ovarian cancer subsequently.But there are negative side effects of this surgical induced menopause such as death, total cancer mortality, osteoporosis, cognitive decline, decreased sexual drive and increased cardiac mishap support conservation of ovarian function.

There is considerable debated going on between EO and ovarian conservation, with strong statements are put forward in favor of each. Currently ACOG recommends “strong consideration should be made for retaining normal ovaries in premenopausal women who are not at increased genetic risk of ovarian cancer. [However,] given the risk of ovarian cancer in postmenopausal women, ovarian removal at the time of hysterectomy should be considered for these women.”

Arguments in favor of ovarian conservation:

• EO is detrimental for the overall health of women and decreases the life expectancy due to coronary artery disease. In a landmark study by Parker et al using Surveillance, Epidemiology, and End Results (SEER) database, the National center for Health Statistics, the Women’s Health Initiative, and the National Inpatient Sample it was seen that there is no clear cut benefit of EO at any age and women died early due to associate morbidity.
• The neuroprotective benefits of estrogen were seen in multiple studies and was further supported by declining cognitive functions specially in women undergoing EO under 50 yrs.
• EO leads to increase in hip fracture due to decrease in BMD as estrogen levels plummet. This was specifically seen in the light of mass discontinuation of hormone replacement therapy among postmenopausal women when results of Women’s Health Initiation trial published.
• A decrease in sexual desire and function, resulting in quality of life issues and conflict in interpersonal relationship, depression was seen after oophorectomy.

Arguments in favor of EO:

• Ovarian cancer is the fifth leading cause of death among women in US with estimated 22,280 new cases and  14,240 deaths in 2016. A woman’s lifetime risk of ovarian cancer is 1 in 70 or 1.4% with no known effective screening method that could diagnose it at very early stage. Researchers have estimated   that 1000 new cases of ovarian cancer could be avoided if EO is performed in women undergoing hysterectomy in women 40 years and older.
• In women at high risk for ovarian cancer (especially with familial history or genetic predisposition, BRCA1 or BRCA2 mutations) risk-reducing oophorectomy (RRO) reduced cancer specific mortality.
• In general population RRO is an ideal treatment for the prevention of ovarian cancer in women who have known risk factors like being white, never having been pregnant, late age of menopause, and a long estimate number of years of ovulation in absence of effective screening strategies.
• EO leads to avoiding the risk of second surgery after hysterectomy due to adnexal disease or masses.
• Effective replacement therapy available to prevent osteoporosis, cardiac and sexual dysfunctions is being put as a valid argument in support of EO, specifically after the beneficial results of hormone therapy from Women’s Health Initiative studies.
• A recent study by Trabuco et al published in the May issue of Obstetrics and Gynecology has concluded that even if ovaries are spared at the time of hysterectomy, it affects the ovarian reserve as evident by declining levels of Antimüllerian hormone. The study also reported that women undergoing hysterectomy became menopausal 1.9 years earlier than referent patient who has not undergone any surgery.

Despite all these arguments studies have recently documented that of all the hysterectomies performed for benign reason 36%-38% were deemed unnecessary and histologically normal.

So, the decision for EO should be made according to each woman’s individual genetic test results and her risk for developing ovarian malignancy. Age at the time of benign hysterectomy is an important decisive factor. In 2010, recommendations from the Society of Gynecologic Oncologists state “Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.”

A women’s risk of cardiovascular disease, dementia, osteoporosis, and family history must be taken into account before decisions for EO or ovarian conservation are made in woman considering hysterectomy.

References:

http://www.cdc.gov/reproductivehealth/data_stats/

http://journals.lww.com/greenjournal/Fulltext/2009/11000/Nationwide_Use_of_Laparoscopic_Hysterectomy.13.aspx

http://seer.cancer.gov/statfacts/html/ovary.html

http://www.ncbi.nlm.nih.gov/pubmed/1923173

http://journals.lww.com/greenjournal/Fulltext/2016/05000/Association_of_Ovary_Sparing_Hysterectomy_With.3.aspx

http://www.oncologypractice.com/home/article/high-rates-of-oophorectomy-documented-in-premenopausal-women/36d1b8f86358a40f14c648990ea87471.html?trendmd-shared=0

http://www.obgynnews.com/specialty-focus/gynecology/single-article-page/study-finds-inappropriate-oophorectomy-at-time-of-hysterectomy/afc916acf84845b47cce45ad136610e5.html

Acute Ovarian Insufficiency and Uterine Infarction Following Uterine Artery Embolization for Postpartum Hemorrhage-- A case report

Acute Ovarian Insufficiency and Uterine Infarction Following Uterine Artery Embolization for Postpartum Hemorrhage.

An interesting case reported by Elsarrag SZ et al in Clinical medical reviews and case reports. 2015;2(2):040.

This paper reports a case of acute ovarian insufficiency occurring within two weeks of UAE for PPH, most likely due to anomalous pelvic vasculature with large uterineovarian arteries anastomosis.

UAE is a life-saving procedure and complications are usually minimal.

There is, however, a possibility of uterine infarction and subsequent ovarian insufficiency in patients with significant ovarian to uterine artery anastomoses

A primparous patient underwent bilateral internal hypogastric artery embolization to control severe postpartum hemorrhage following primary cesarean section.

The bleeding continued, and a repeat aortogram demonstrated significant filling of the uterus from an anomalous proximal take off of the right uterine artery and from the left ovarian artery.

Further embolization was required to control the bleeding. The patient developed acute primary ovarian insufficiency within two weeks of the procedure and subsequently presented with uterine infarction necessitating hysterectomy.

 This case demonstrates the increased risk of acute ovarian insufficiency and uterine infarction following uterine artery embolization for postpartum hemorrhage in the settings of aberrant pelvic vasculature.

Uterine infarction has typically been reported with high injection of small-size polyvinyl alcohol particles (150-300μm), as these can migrate and block fine branches in the arterial tree, leading to ischemia

Avoiding uterine infarction may be facilitated by utilizing large size (>500μm) particles and particles with a shorter life span to allow sooner recanalization and collateral blood vessel formation.

Additionally, finer micro-catheterization techniques of select collateral vessels, where the catheter tip is meticulously placed as distal as possible and reflux of embolization material is minimized, is also warranted to prevent uterine infarction.

A total of seven cases of uterine infarction necessitating hysterectomy have also been described; two of these cases occurred following UAE for PPH, while five cases occurred following UAE for uterine fibroids.

Image courtesy-South Florida Fibroid Center

References: 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623578/

Elsarrag SZ, Forss AR, Richman S, Salih SM. Acute Ovarian Insufficiency and Uterine Infarction Following Uterine Artery Embolization for Postpartum Hemorrhage. Clinical medical reviews and case reports. 2015;2(2):040.

Vashisht A, Studd J, Carey A, Burn P. Fatal septicaemia after fibroid embolisation. Lancet. 1999;354:307–308. [PubMed]

Vedantham S, Goodwin SC, McLucas B, Mohr G. Uterine artery embolization: an underused method of controlling pelvic hemorrhage. Am J Obstet Gynecol. 1997;176:938–948. [PubMed]

Razavi MK, Wolanske KA, Hwang GL, Sze DY, Kee ST, et al. Angiographic classification of ovarian artery-to-uterine artery anastomoses: initial observations in uterine fibroid embolization. Radiology. 2002;224:707–712. [PubMed]