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American College of Obstetricians and Gynecologists 2018
The American College of Obstetricians and Gynecologists (ACOG) annual meeting was held in Austin, Texas, from April 27 to 30. We review below key sessions on endometriosis, hypoactive sexual desire disorder, neonatal abstinence syndrome, minimally invasive hysterectomy, and postpartum hemorrhage.
Long-Term Safety and Efficacy of Elagolix Treatment in Women With Endometriosis-Associated Pain
In women with endometriosis-associated pain, long-term elagolix (investigational, AbbVie) treatment was associated with improved dysmenorrhea and reduced nonmenstrual pelvic pain and lower dyspareunia scores in results of six-month extensions of six-month phase 3 double-blind studies.1
The extension studies focused on efficacy and safety in women treated for 12 or more continuous months with either elagolix 150 mg once daily or elagolix 200 mg twice daily. The two studies (EM-III [150 mg, n = 116; 200 mg, n = 110] and EM-IV [150 mg, n = 120; 200 mg, n = 112]) did not have a placebo arm.
“There have been no drugs approved for endometriosis in over 15 years. It’s a field that’s desperate for new therapies,” Dr. Surrey commented in an interview. Elagolix, an oral gonadotropin-releasing hormone receptor antagonist (GnRH), is a short-acting molecule that blocks endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. The studies’ coprimary endpoints were the percentage of dysmenorrhea and nonmenstrual pelvic pain responders at month 6 of the extension. Changes of “much” and “very much improved” represented a clinically meaningful response threshold (measured by Patient Global Impression of Change) on the four-point scales with stable or decreased rescue analgesic use (naproxen and/or a single opioid). Daily pill counts were recorded in an electronic diary.
For each elagolix dose, the responder rates were maintained or increased over 12 or more continuous months of treatment. In EM-III, compared with the six-month findings in the double-blind study, dysmenorrhea responder rates rose from 40% to 52% at 150 mg daily and were maintained at 200 mg twice daily (80% and 78%, respectively). In EM-IV, dysmenorrhea responder rates rose from 50% to 68% (150 mg daily) and were maintained at 200 mg twice daily (76% for both). Nonmenstrual pelvic pain responder rates rose from 50% to 68% for 150 mg daily in EM-III and were maintained at 71% versus 69% at 200 mg twice daily. In EM-IV, rates for nonmenstrual pelvic pain rose from 58% to 66% for 150 mg daily and rose from 64% to 67% for 200 mg twice daily. The average number of analgesic pills taken per day (average over monthly intervals) decreased 46% to 77% from baseline across doses during the extension studies, Dr. Surrey said.
Across the two studies, mean score improvements from baseline in dysmenorrhea scores after 12 months ranged from 49% to 53% at 150 mg daily and 82% at 200 mg twice daily. For nonmenstrual pelvic pain, mean scores improved from 49% to 54% at 150 mg daily and 56% to 57% at 200 mg twice daily across studies. Dyspareunia mean scores improved 31% to 51% at 150 mg daily and 42% to 50% at 200 mg twice daily.
Safety findings long-term were consistent with elagolix’s mechanism of action, Dr. Surrey said. Discontinuation rates ranged from 11% to 24% across studies and dose groups. No women discontinued treatment in the extension studies for new incidence of hot flushes, which in the majority of women were mild/moderate (greater than 50%).
“If approved, I believe it will replace or partially supplant the GnRH agonists. What patient wouldn’t prefer to take an oral agent over injections or implants?” Dr. Surrey said.
Decreased Rescue Analgesic Use With Elagolix Treatment in Women With Endometriosis-Associated Pain
“It looks like elagolix will be able to reduce the amount of pain medication that women with endometriosis pain need in order to conduct their lives,” Dr. Diamond said at his poster presentation of results from two phase 3 trials of elagolix (investigational, AbbVie). Elagolix is an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist.
Elagolix was evaluated in two studies (Elaris EM-I, N = 871; and Elaris EM-II, N = 815) of six months of elagolix treatment at either 150 mg once daily or 200 mg twice daily compared with placebo in women with endometriosis-associated pain. In both studies, elagolix treatment was associated with improved dysmenorrhea and nonmenstrual pelvic pain. Women could use either naproxen and/or a single opioid as rescue analgesia. Daily pill counts were recorded in an electronic diary.
At baseline in both studies, patients (734 women receiving placebo and 952 receiving elagolix) receiving the 200-mg dose twice daily used a mean of 0.4 nonsteroidal anti-inflammatory drugs (NSAIDs) daily, and relative to placebo, there was a statistically significant decrease from baseline in months 2–6 (0.4 and 0.3). In addition, the mean change from baseline in days per month with opioid use decreased significantly in the elagolix 200-mg twice-daily group. The reduction in NSAID use in the 150-mg daily group was not significant, although in months 3 and 4 the days per month with NSAID use was lower.
Dr. Diamond reported that mean changes from baseline in the percentage of days with use of an NSAID and/or opioid for the 200-mg twice-daily dose were highly significant (P < 0.001). Investigators also evaluated women in both trials who used opioids as rescue analgesia at baseline with or without NSAIDs (placebo group, n = 433; elagolix 150 mg, n = 272; elagolix 200 mg, n = 284) and again at month 6 or at time of discontinuation. They found that opioid use was stable, stopped, or decreased in 78% of placebo, 84% of elagolix 150 mg, and 92% of elagolix 200 mg patients.
Adverse events were consistent with elagolix’s mechanism of action, with hypoestrogenic effects of hot flushes and decreased bone mineral density.
“Given the risks of opioid use, including abuse and dependence, it is important to evaluate changes in opioid use associated with new treatments for chronic pain conditions, such as endometriosis.” The 200-mg twice-daily dose showed significant reductions in rescue analgesic use, both by daily pill count or percentage of days per month with pills taken. “Also,” Dr. Diamond said, “women are likely to prefer the oral dosing to having to disrupt their activities to run to the doctor’s office for an injection.”
Impact of Long-Acting Reversible Contraception Counseling on Postpartum Contraceptive Choice
In an obstetric office treating women at high risk for comorbid disease and unplanned pregnancies, a prenatal contraceptive education program influenced long-acting reversible contraceptive (LARC) choice and will likely reduce unplanned pregnancies, according to a prospective cohort study of 55 pregnant women. Ms. Torre described the study’s findings in a poster presentation.
Approximately half of pregnancies occurring in the United States annually are unintended. While LARCs could help reduce unintended pregnancy, they are used by less than 3% of women in the U.S. In addition, women with unintended pregnancies tend to have a less optimal age distribution, present later for prenatal care, partake in risky behaviors, or have more chronic medical problems with higher rates of pregnancy complications. The study objective was to determine if prenatal contraceptive counseling for high-risk pregnant women would impact their postpartum LARC choice.
Participants in the study, which was conducted at the Perinatal Center of Women and Children’s Hospital of Buffalo in Buffalo, New York, were between 18 and 45 years of age and were within 34 weeks of gestation. All women had comorbid conditions, including chronic hypertension, diabetes, and venous thromboembolism. LARCs have proven to be safe in high-risk pregnant women with chronic conditions, such as diabetes (types 1 and 2), congenital heart disease, human immunodeficiency virus infection, and rheumatic disease.
Investigators conducted two prenatal counseling sessions and postpartum follow-up within eight weeks of delivery. The prenatal counseling sessions were based on a standardized, easy-to-follow script. Before baseline, only 18% of the participants had LARC histories, and only 27% expressed interest in LARC use pre-counseling (with 20% intending to use LARC). The rest intended to use non-LARC methods (69%) or undergo bilateral tubal ligation (4%).
Analysis showed that differences in religious affiliation, marital status, and contraceptive history were not reflected in postpartum LARC choice. Women interested in LARC before the intervention, however, were more likely to choose a LARC postpartum (P = 0.011). “That lets us know that increased societal awareness of LARCs could be helpful in inducing women to adopt one of these methods,” Ms. Torre said in an interview. Overall, after counseling, LARC intent rose to 42% compared with 20% in the historical cohort. LARC intended use also increased significantly in women planning to become pregnant again after counseling (P = 0.013).
Ms. Torre noted that future studies will look at postpartum LARC insertion rates and postpartum LARC continuation rates. She concluded, “Our study suggests that instituting a prenatal contraceptive education program can improve LARC rates in high-risk pregnant women.”
Commenting on the findings, Althea M. O’Shaughnessy, MD, of Conceptions Reproductive Associates of Colorado in Littleton and Presbyterian St. Luke’s Medical Center in Denver, Colorado, concurred that educating women about LARCs is important; this is because LARCs have a low failure rate (less than 1% for hormone-infused intrauterine devices [IUDs]), compared with 9% to 18% for non-LARC methods. She also noted the value of education about emergency contraceptives based on the same type of progesterone (levonorgestrel) that is used in infused IUDs. About half of women may need emergency contraception in their lifetimes, but only about one in 10 make use of it. If used within 72 hours of unprotected intercourse, they are effective in seven out of eight women, Dr. O’Shaughnessy explained. She underscored, “Levonorgestrel prevents ovulation and has no effect on ongoing pregnancies, which is important.”
Efficacy of Bremelanotide for HSDD in Women: RECONNECT Open-Label Extension Study Results
Subcutaneous injections of bremelanotide (investigational, Palatin Technologies, Inc.) led to continued safety and treatment benefits in women with hypoactive sexual desire disorder (HSDD) in an open-label extension of the RECONNECT study, Dr. Clayton reported.
Bremelanotide is a novel cyclic seven amino acid melanocortin-4-receptor agonist which had, in analysis of the core phase of RECONNECT, shown statistically significant increases in Female Sexual Functioning Index–Desire (FSFI–D) scores and decreases in Female Sexual Distress Scale–Desire Arousal Orgasm (FSDS–DAO) scores for women randomized to active treatment. The double-blind, placebo-controlled core phase of RECONNECT (Study 301 and Study 302) enrolled 1,267 premenopausal women (mean age, approximately 39 years; more than 84% Caucasian) with HSDD. They received 52 weeks of self-administered bremelanotide 1.75 mg via autoinjector pen or placebo after a screening month and a placebo self-dosing month (to determine baseline sexual desire). Analysis of the coprimary endpoints, FSFI–D and FSDS-DAO resulting from low desire, revealed statistically significant increases in desire and decreases in distress among women randomized to active treatment.
The objective of this analysis was to evaluate sustained maintenance of bremelanotide’s effect on HSDD during an open-label extension phase of the RECONNECT study. The Study 301 extension included 124 patients from the bremelanotide arm and 239 patients from the placebo arm. At week 4, women who had received bremelanotide or placebo in the core phase then demonstrated respective mean changes from group baseline of 1.11 and 0.80 in FSFI–D, and –1.20 and –0.60 in FSDS–DAO Item 13. The Study 302 open-label extension had similar results. For all women, improvements were consistently maintained until week 52. Treatment onset was rapid; benefits continued to increase and sexual stress decreased over the study period and extension.
Adverse events were treatment limiting in 12.1% and 6.2% of patients in the bremelanotide/bremelanotide group and 25.5% and 23.6% in the placebo/bremelanotide group, respectively. The most common adverse events with bremelanotide use were nausea, flushing, sunburn, and headache. Dr. Clayton noted that there were no clinically significant effects on electrocardiography, weight, depression, suicidal ideation, or alcohol consumption.
“There’s an increase in the level of desire and a decrease in the level of distress about desire,” Dr. Clayton said. “Also, because this treatment is given on an as-desired basis, there’s less concern about adverse effects from daily dosing.” She concluded, “The findings support extended use of bremelanotide in premenopausal women with hypoactive sexual desire disorder.”
Therapeutic Substitution: A Cogent Response to the Opioid-Induced Neonatal Abstinence Syndrome Crisis
Outpatient therapeutic substitution with oral buprenorphine to obtain abstinence in carefully selected pregnant women reduces neonatal abstinence syndrome (NAS), according to results of a prospective, observational study conducted at a tertiary care center resident service obstetric addictions clinic. It also reduces costs, Dr. Patel said.
The overall incidence of NAS among West Virginia residents in 2017 was 50.6 per 1,000 live births (5.06%). Dr. Patel pointed out that, already in 2013, the West Virginia figure was 500% that of the national average. His study investigated an innovative strategy of oral buprenorphine taper toward abstinence to combat opioid dependence and its associated neonatal comorbidities among 582 new obstetrical patients over one year (July 2016 to June 2017).
Urine drug screening found 69 of these patients (11.9%) positive for opiates. Among them, 34 (49.3%) enrolled in the program. Patients had group and individual counseling, weekly and random drug screens, and follow-up with obstetricians and an addictions nurse. The study outcomes were NAS and mean days hospitalized among neonates for mothers achieving or not achieving abstinence prior to delivery. Cost savings were also calculated using NAS incidence and length of stay.
Among the 34 women, 19 remained in the program, with eight (42.1%) of those reaching abstinence before delivery. Only one (12.5%) of the newborns had NAS, with a nine-day length of stay. Among the remaining 11 women who did not achieve abstinence, six neonates had NAS (54.4%). Mean days hospitalized for the seven total neonates with NAS was 18.4. For the neonates of women not achieving abstinence, mean length of stay was 20 days. Data were available for nine of the 63 women not entering the program. Among these, seven delivered newborns with NAS (77.8%).
No adverse outcomes occurred among patients or neonates entering or completing the program. Hospital cost-savings for the 12 neonates born free of NAS were estimated at more than $400,000, Dr. Patel said.
While confirmatory data are still needed from future research, Dr. Patel concluded: “Outpatient therapeutic substitution with oral buprenorphine to obtain abstinence is possible in pregnant patients and results in significant cost-savings.”
Enhanced Recovery Pathway for Minimally Invasive Hysterectomy: Outcomes of a Quality Improvement Initiative
Postoperative recovery outcomes were better and postoperative narcotic use was reduced among women undergoing minimally invasive hysterectomy with an enhanced recovery after surgery (ERAS) pathway quality improvement initiative. In general, Dr. Bozzuto said, postoperative pain was reduced and hospital stays shortened with ERAS pathways, which have been studied mostly in colorectal surgery and open abdominal surgery, and in gynecological oncology.
Dr. Bozzuto’s quality improvement project was conducted at a tertiary care academic medical center among 47 consecutively treated patients over three months. The ERAS pathway was implemented from August 2016 to October 2016 among patients undergoing minimally invasive hysterectomy (vaginal, laparoscopic, or robotic) for benign indications. Results in 2016 from 47 procedures performed by 18 surgeons under the ERAS protocol were compared with outcomes during the same months in 2015 in 41 procedures performed by 15 surgeons.
The ERAS protocol included patient education, reduced perioperative fasting, judicious use of intravenous fluids, aggressive multimodal analgesia, and early ambulation and feeding.
After ERAS implementation, the percentage of patients discharged by noon increased from 14.6% to 36.2% (P = 0.022), indicating a significant reduction in length of stay (P = 0.029). Use of patient-controlled analgesia (PCA) dropped from 51.2% to 10.6% (P < 0.001), and postoperative narcotic use decreased significantly with a reduction in intravenous oral morphine equivalents from a median of 5 mg (SD, 0–25 mg) to 0 mg (SD, 0–4 mg) (P < 0.001) and in median total oral morphine equivalents from 45 mg (SD, 25–128.5 mg) to 24 mg (SD, 5–48 mg) (P < 0.001). Postoperative complications and readmission rates were similar for both groups.
“To address the needs of the patient in the perioperative period, having a standardized approach is helpful to physicians, nurses, and patients,” Dr. Bozzuto noted in an interview. She added, “By scheduling non-narcotic medications, along with early ambulation, decreased fluids, and early feeding, we were able to more quickly discharge patients and increase the number of patients discharged by noon, as well as decrease their overall narcotic use in the hospital.”
Use of Tranexamic Acid to Prevent Postpartum Hemorrhage in Women Undergoing Vaginal Delivery: A Meta-Analysis
Postpartum hemorrhage and need for additional medical intervention were reduced with prophylactic administration of tranexamic acid after vaginal delivery, according to Dr. Boyd. The finding emerged from a meta-analysis of three randomized, controlled trials enrolling a total of 659 women.
Tranexamic acid is a lysine analogue that binds to lysine receptors on plasminogen and plasmin, inhibiting plasmin-mediated fibrin degradation. It has been found to significantly decrease the risk of death in bleeding trauma patients, as well as to decrease blood loss in elective surgery. Postpartum hemorrhage (estimated blood loss greater than 1,000 cc) remains a leading cause of maternal morbidity and mortality worldwide, Dr. Boyd said. While randomized clinical trials (RCTs) have evaluated the use of tranexamic acid for treatment and prevention of postpartum hemorrhage, there is currently insufficient evidence to support prophylactic use, she said. Her objective was to conduct a systematic review and meta-analysis using available data from RCTs that evaluated the efficacy of prophylactic utilization of tranexamic acid at the time of vaginal delivery.
Her review demonstrated that in all three studies (Gungorduk et al.,2 Mirghafourvand et al.,3 and Roy et al.4), prophylactic administration of tranexamic acid led to significantly reduced mean blood loss (odds ratios [ORs] of 0.563, 0.495, 0.470, respectively; P = 0.001, P = 0.036, P = 0.039, respectively). In Gungorduk et al. and Mirghafourvand et al., it reduced blood loss by more than 500 cc (ORs, 0.26, 0.63; P = 0.02, P = 0.20, respectively), and in all three studies, prophylactic administration of tranexamic acid reduced the need for additional medical intervention (ORs, 0.30, 0.40. 0.07; P = 0.01, P = 0.20, P = 0.01, respectively). In two of the three studies, tranexamic acid reduced blood loss by more than 1,000 cc.
The need for transfusions was not reduced with prophylactic use of tranexamic acid. Importantly, prophylactic administration of tranexamic acid did not increase risk of venous thromboembolism.
Dr. Boyd said in an interview that the lack of reductions in need for transfusions was likely attributable to the higher baseline levels of hemoglobin in most women evaluated, who were generally not anemic and who had uncomplicated deliveries.
She concluded, “Prophylactic administration of tranexamic acid following vaginal delivery decreases major blood loss by approximately 125 cc, decreases the incidence of postpartum hemorrhage, and reduces the need for additional medical interventions without raising postpartum venous thromboembolism risk.” She commented, “Although tranexamic acid prophylaxis significantly reduces blood loss following vaginal delivery, the clinical significance and utility in uncomplicated vaginal delivery is likely minimal. But in women who are at high risk, who start with a hemoglobin of 8, for example, a blood loss of 500 mL can be significant and lead to a transfusion. So, if we can decrease their blood loss, this would be a good option.”
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med 2017;377(1):28–40.
- Gungorduk K, Asıcıog˘lu O, Yıldırım G, et al. Can intravenous injection of tranexamic acid be used in routine practice with active management of the third stage of labor in vaginal delivery? A randomized controlled study. Am J Perinatol 2013;30(5):407–413.
- Mirghafourvand M, Mohammad-Alizadeh S, Abbasalizadeh F, Shirdel M. The effect of prophylactic intravenous tranexamic acid on blood loss after vaginal delivery in women at low risk of postpartum haemorrhage: a double-blind randomised controlled trial. Aust N Z J Obstet Gynaecol 2015;55(1):53–58.
- Roy P, Sujatha MS, Bhandiwad A, Biswas B. Role of tranexamic acid in reducing blood loss in vaginal delivery. J Obstet Gynaecol India 2016;66(suppl 1):S246–S250.