Susan D. Reed

Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women: A Randomized Controlled Trial

CONTEXT Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes. OBJECTIVE To determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes. DESIGN, SETTING, AND PATIENTS A multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010. INTERVENTION Women received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks. MAIN OUTCOME MEASURES Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency ≥50% decrease from baseline). RESULTS Mean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P < .001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P = .009) at the 8-week follow-up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to -0.17 for placebo; P < .001). Race did not significantly modify the treatment effect (P = .62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P = .02) more hot flashes per day than women in the placebo group. CONCLUSION Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00894543.

Factors Associated With Peripartum Hysterectomy

OBJECTIVE: To identify factors associated with peripartum hysterectomy performed within 30 days postpartum. METHODS: This was a population-based case–control study using Washington State birth certificate registry (1987–2006) linked to the Comprehensive Hospital Abstract Reporting System. Cases underwent hysterectomy within 30 days postpartum. Controls were frequency matched 4:1. Exposures included factors related to hemorrhage, delivery method, multiple gestations, and infection. Incidence rates of peripartum hysterectomy and maternal and neonatal morbidity and mortality were assessed. Adjusted odds ratios (aORs) by maternal age, parity, gestational age, year of birth, and mode of delivery and 95% confidence intervals (CIs) were computed. RESULTS: There were 896 hysterectomies. Incidence rates ranged from 0.25 in 1987 to 0.82 per 1,000 deliveries in 2006 (&khgr;2 for trend, P<.001). Factors related to hemorrhage were strongly related to peripartum hysterectomy. Placenta previa (192 cases compared with 23 controls; aOR 7.9, 95% CI 4.1–15.0), abruptio placenta (71 compared with 55; aOR 3.2, 95% CI 1.8–5.8), and retained placenta (214 compared with 28; aOR 43.0, 95% CI 19.0–97.7) increased the risk of hysterectomy, as did uterine atony, uterine rupture, and thrombocytopenia. Having multiple gestations did not. As compared with vaginal delivery, vaginal delivery after cesarean (27 cases compared with 105 controls; aOR 1.9, 95% CI 1.2–3.0), primary cesarean (270 compared with 504; aOR 4.6, 95% CI 3.5–6.0), and repeat cesarean (296 compared with 231; aOR 7.9, 95% CI 5.8–10.7) increased the risk of peripartum hysterectomy. Among the 111 women who had hysterectomy on readmission (12.8% of cases), hemorrhage- and infection-related factors were still strongly associated with peripartum hysterectomy. CONCLUSION: Incidence rates of peripartum hysterectomy are increasing over time. The most important risk factor for peripartum hysterectomy is hemorrhage, most notably caused by uterine rupture, retained placenta, and atony of uterus. LEVEL OF EVIDENCE: II

Pregnancy Outcomes in Women with Rheumatoid Arthritis in Washington State

Objective: To determine whether rheumatoid arthritis (RA) is associated with increased adverse obstetric or neonatal outcomes. Study design and setting: Washington State birth records and hospital discharge data between 1987 and 2001 identified a cohort of women with rheumatoid arthritis and a comparison group of women without rheumatoid arthritis. Pregnancy and neonatal outcomes were compared using general linear models for common outcomes, calculating approximate relative risks and 95% confidence intervals. Results: There were 243 women with rheumatoid arthritis and 2559 controls. Infants of women with rheumatoid arthritis had increased risk of cesarean delivery (adjusted approximate relative risk, aRR=1.66, 95% CI (1.22, 2.26)), prematurity (aRR=1.78, 95% CI (1.21, 2.60)), and longer birth hospitalization (aRR=1.86, 95% CI (1.32, 2.60)) compared to those born to women without rheumatoid arthritis. Conclusions: We speculate that the increased risks for cesarean delivery, prematurity, and longer hospitalization at birth among infants born to women with rheumatoid arthritis may be due to the pathophysiologic changes associated with rheumatoid arthritis or medications used to treat the disease.

Efficacy of exercise for menopausal symptoms: A randomized controlled trial

ObjectiveThis study aims to determine the efficacy of exercise training for alleviating vasomotor and other menopausal symptoms. MethodsLate perimenopausal and postmenopausal sedentary women with frequent vasomotor symptoms (VMS) participated in a randomized controlled trial conducted in three sites: 106 women randomized to exercise and 142 women randomized to usual activity. The exercise intervention consisted of individual facility-based aerobic exercise training three times per week for 12 weeks. VMS frequency and bother were recorded on daily diaries at baseline and on weeks 6 and 12. Intent-to-treat analyses compared between-group differences in changes in VMS frequency and bother, sleep symptoms (Insomnia Severity Index and Pittsburgh Sleep Quality Index), and mood (Patient Health Questionnaire-8 and Generalized Anxiety Disorder-7 questionnaire). ResultsAt the end of week 12, changes in VMS frequency in the exercise group (mean change, −2.4 VMS/d; 95% CI, −3.0 to −1.7) and VMS bother (mean change on a four-point scale, −0.5; 95% CI, −0.6 to −0.4) were not significantly different from those in the control group (−2.6 VMS/d; 95% CI, −3.2 to −2.0; P = 0.43; −0.5 points; 95% CI, −0.6 to −0.4; P = 0.75). The exercise group reported greater improvement in insomnia symptoms (P = 0.03), subjective sleep quality (P = 0.01), and depressive symptoms (P = 0.04), but differences were small and not statistically significant when P values were adjusted for multiple comparisons. Results were similar when considering treatment-adherent women only. ConclusionsThese findings provide strong evidence that 12 weeks of moderate-intensity aerobic exercise do not alleviate VMS but may result in small improvements in sleep quality, insomnia, and depression in midlife sedentary women.

Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study.

Objective: To evaluate vaginal, endometrial, and reproductive hormone effects of three herbal regimens compared with placebo and hormone therapy (HT). Design: This was a 1-year, randomized, double-blind, placebo-controlled trial of 351 women, ages 45 to 55, with two or more vasomotor symptoms per day. Women were randomly assigned to (1) black cohosh, (2) a multibotanical containing black cohosh, (3) the same multibotanical plus dietary soy counseling, (4) HT, or (5) placebo. Women were ineligible if they had used HT in the previous 3 months or menopausal herbal therapies in the previous month. Data on vaginal cytology and dryness were collected (at baseline and 3 and 12 mo). Daily menstrual diaries were maintained by 313 women with a uterus, and abnormal bleeding was evaluated. Serum estradiol, follicle-stimulating hormone, luteinizing hormone, and steroid hormone-binding globulin were assessed (baseline and 12 mo) among 133 postmenopausal women. Gynecologic outcomes of the five groups were compared. Results: The five groups did not vary in baseline vaginal cytology profiles, vaginal dryness, menstrual cyclicity, or hormone profiles. The HT group had a lower percentage of parabasal cells and vaginal dryness than the placebo group at 3 and 12 months (P < 0.05). Abnormal bleeding occurred in 53 of 313 (16.9%) women. There were no differences in frequency of abnormal bleeding between any of the herbal and placebo groups, whereas women in the HT group had a greater risk than those in the placebo group (P < 0.001). Among postmenopausal women, HT significantly decreased follicle-stimulating hormone and increased estradiol; none of the herbal interventions showed significant effects on any outcomes at any time point. Conclusion: Black cohosh, used alone or as part of a multibotanical product with or without soy dietary changes, had no effects on vaginal epithelium, endometrium, or reproductive hormones.

Low-Dose Estradiol and the Serotonin-Norepinephrine Reuptake Inhibitor Venlafaxine for Vasomotor Symptoms: A Randomized Clinical Trial

IMPORTANCE Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date. OBJECTIVE To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS). DESIGN, SETTING, AND PARTICIPANTS In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012. INTERVENTIONS Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments. RESULTS Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated. CONCLUSIONS AND RELEVANCE Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01418209.

INCIDENCE OF ENDOMETRIAL HYPERPLASIA

OBJECTIVE The objective of the study was to estimate the age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma. STUDY DESIGN Women aged 18-90 years with endometrial pathology specimens (1985-2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus. RESULTS Endometrial hyperplasia peak incidence was: simple, 142 per 100,000 woman-years, complex, 213 per 100,000 woman-years, both in the early 50s; and atypical, 56 per 100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia. CONCLUSION Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence.

Antibiotic treatment of tuboovarian abscess: Comparison of broad-spectrum β-lactam agents versus clindamycin-containing regimens

One hundred nineteen patients with tuboovarian abscess were evaluated for response to antibiotics. Results were stratified into three groups by antimicrobial regimen. Group 1 consisted of 37 patients treated with a single-agent broad-spectrum intravenous antibiotic and oral doxycycline. Initial clinical response (defined as decreased pain, diminished white blood cell count, or defervescence) in group 1 was 31/37 (84%). Group 2 consisted of 64 patients treated with clindamycin in combination with an aminoglycoside with or without a penicillin. There was an initial clinical response in 45 of 64 (70%). Group 3 consisted of 18 patients from group 1 who were changed to a clindamycin-containing regimen after 2 to 3 days of initial treatment with a single-agent broad-spectrum antibiotic. The decision to switch antibiotics was not based on treatment failure but occurred when delayed ultrasonography confirmed the diagnosis of tuboovarian abscess. The switch reflected physician preference for clindamycin-containing regimens in the treatment of tuboovarian abscesses. The response rate in this subset of patients was 14 of 18 (78%). Overall initial clinical response rate was 90 of 119 (75%). There were no statistically significant demographic or clinical differences among the three groups. There was no statistical difference in the rate of early and late antibiotic failure rates among the groups. Our study demonstrates that extended-spectrum antibiotic coverage, including single-agent broad-spectrum antibiotics such as cefoxitin, in conjunction with doxycycline has efficacy that is equivalent to that of clindamycin-containing regimens. An overall medical treatment success rate of 75% suggests that conservative treatment of tuboovarian abscesses is warranted.

Risk of Complex and Atypical Endometrial Hyperplasia in Relation to Anthropometric Measures and Reproductive History

The authors sought to test the hypothesis that characteristics and exposures which influence the balance of estrogen and progesterone bear on the incidence of endometrial hyperplasia (EH), a noninvasive proliferation of the lining of the uterus. Cases included all female members of Group Health (Washington State) who were diagnosed with complex EH or EH with atypia during the period 1985-2003 and whose diagnoses were confirmed in a pathology review (n = 446). Controls were selected randomly from Group Health membership files and were matched to the cases by age and enrollment status at the reference date. An increased risk of EH was associated with increasing body mass index and nulliparity. There was a suggestion of a decreased risk of EH with atypia among current smokers. No association with diabetes or hypertension was found. The risk factors observed to be associated with EH in this study are similar to those associated with endometrial cancer. Whether these risk factors predispose women to cancer simply by increasing EH incidence or continue to augment cancer risk even after EH is present is currently unknown.

The sex ratio of pregnancies complicated by hospitalisation for hyperemesis gravidarum

Objective  To evaluate the sex ratio among pregnancies complicated by first trimester hyperemesis gravidarum and extend previous findings to include a measure of severity.