Richard Guido

Misoprostol for medical evacuation of early pregnancy failure

Objective To determine whether misoprostol (a prostaglandin El analogue) 400 μg orally (group 1) or 800 μg vaginally (group 2) will cause complete uterine evacuation in women with early pregnancy failure. Methods Twenty subjects were recruited for a prospective, non-blinded, randomized clinical trial. Early pregnancy failure was diagnosed by transvaginal ultrasound examination; only women with a closed cervical os and minimal vaginal bleeding were enrolled. Subjects returned 24 hours after misoprostol administration for a transvaginal ultrasound examination. If the gestational sac was still present, the misoprostol dose was repeated and the subject returned again 24 hours later. Subjects who failed to expel the pregnancy were offered a suction curettage. Results Twelve and eight women were randomized to groups 1 and 2, respectively. Complete uterine evacuation occurred in three of 12 [25%, 95% confidence interval (CI) 1%, 50%] and seven of eight (88%, 95% CI 65%, 100%, P = .010) subjects in groups 1 and 2, respectively. Vomiting occurred in 30% and 13%, respectively, and diarrhea in 50% and 38%, respectively. Conclusion Vaginal misoprostol 800 μg is more effective than oral misoprostol 400 μg for uterine evacuation of early pregnancy failure and may be an effective alternative to dilation and curettage.

Smoking Is a Risk Factor for Cervical Intraepithelial Neoplasia Grade 3 among Oncogenic Human Papillomavirus DNA–Positive Women with Equivocal or Mildly Abnormal Cytology

Background: Smoking is a potential risk factor for cervical cancer and its immediate precursor, cervical intraepithelial neoplasia grade 3 (CIN3), but few studies have adequately taken into account the possible confounding effect of oncogenic human papillomavirus (HPV) infection. Methods: Women (n = 5,060) with minimally abnormal Papanicolaou smears were enrolled in the ASCUS and LSIL Triage Study, a clinical trial to evaluate management strategies, and were seen every 6 months for the 2-year duration of the study. Cervical specimens were tested for HPV DNA using both Hybrid Capture 2 and PGMY09/11 L1 consensus primer PCR with reverse line blot hybridization for genotyping. Multivariate logistics regression models were used to assess associations [odds ratio (OR) with 95% confidence intervals (95% CI)] between smoking behaviors and rigorously reviewed cases of cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3) identified throughout the study (n = 506) in women with oncogenic HPV (n = 3,133). Results: Current smoking was only weakly associated with increased HPV infection. Among infected women, current smokers (OR, 1.7; 95% CI, 1.4-2.1) and past smokers (OR, 1.7; 95% CI, 1.2-2.4) were more likely to be diagnosed with ≥CIN3 than nonsmokers. Greater smoking intensity (PTrend < 0.0005) and duration (PTrend < 0.0005) increased the strength of the association, with smoking ≥2 packs/d (OR, 3.3; 95% CI, 1.5-7.5) and smoking for ≥11 years (OR, 2.1; 95% CI, 1.5-2.9) most strongly associated with ≥CIN3 as compared to non-smokers. The effects of intensity and duration seemed additive. Conclusions: Women with oncogenic HPV and minimally abnormal Papanicolaou smears who smoke were up to three times more likely to be diagnosed with ≥CIN3 than nonsmokers. Smoking cessation trials targeting this population might be warranted.

The accuracy of colposcopic grading for detection of high-grade cervical intraepithelial neoplasia

Objective. To relate aspects of online colposcopic image assessment to the diagnosis of grades 2 and 3 cervical intraepithelial neoplasia (CIN 2+). Methods: To simulate colposcopic assessment, we obtained digitized cervical images at enrollment after acetic acid application from 919 women referred for equivocal or minor cytologic abnormalities into the ASCUS-LSIL Triage Study. For each, 2 randomly assigned evaluators from a pool of 20 colposcopists assessed images using a standardized tool online. We calculated the accuracy of these assessments for predicting histologic CIN 2+ over the 2 years of study. For validation, a subset of online results was compared with same-day enrollment colposcopic assessments. Results. Identifying any acetowhite lesion in images yielded high sensitivity: 93% of women with CIN 2+ had at least 1 acetowhite lesion. However, 74% of women without CIN 2+ also had acetowhitening, regardless of human papillomavirus status. The sensitivity for CIN 2+ of an online colpophotographic assessment of high-grade disease was 39%. The sensitivity for CIN 2+ of a high-grade diagnosis by Reid Index scoring was 30%, and individual Reid Index component scores had similar levels of sensitivity and specificity. The performance of online assessment was not meaningfully different from that of same-day enrollment colposcopy, suggesting that these approaches have similar utility. Conclusions. Finding acetowhite lesions identifies women with CIN 2+, but using subtler colposcopic characteristics to grade lesions is insensitive. All acetowhite lesions should be assessed with biopsy to maximize sensitivity of colposcopic diagnosis with good specificity.

Human Papillomavirus Testing Following Loop Electrosurgical Excision Procedure Identifies Women at Risk for Posttreatment Cervical Intraepithelial Neoplasia Grade 2 or 3 Disease

Background: Loop electrosurgical excision procedure (LEEP) is the predominant treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN2+) in the United States, yet following treatment ∼10% of women are diagnosed again with CIN2+, necessitating close follow-up of such patients. Methods: Surveillance strategies using cytology and/or human papillomavirus (HPV) testing were compared among women who underwent LEEP (n = 610) in the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. Cervical specimens, collected at 6-month visits for 2 years, were used for cytology, Hybrid Capture 2 (HC2) detection of carcinogenic HPVs, and PCR for genotyping of carcinogenic and noncarcinogenic HPV types. At exit, women had colposcopy for safety and disease ascertainment. Results: At the visit post-LEEP (median time: 4.5 months after LEEP), 36.9% [95% confidence interval (95% CI), 32.7-41.1%] of women were positive for carcinogenic HPV by PCR and 33.7% (95% CI, 29.7-37.9) had ASCUS or more severe (ASCUS+) cytology. The overall 2-year cumulative incidence of histologically confirmed posttreatment CIN2+ was 7.0%; this could be further stratified by the HPV risk category detected at the 6-month visit after LEEP. The 2-year risk associated with HPV16 positivity was 37.0%, significantly higher than for other carcinogenic HPV types (10.8%, P < 0.001), noncarcinogenic types (1.5%, P < 0.001), or testing HPV negative (0%). Post-LEEP cytology (using a positive threshold of ASCUS+) was 78.1% (95% CI, 60.0-90.7%) sensitive for detection of posttreatment CIN2+. By comparison, PCR for carcinogenic HPV and combination testing (using a positive result from carcinogenic HPV testing or cytology as the test threshold with HPV-negative ASCUS not referred) were significantly more sensitive (96.9% for each, P = 0.03); HC2 alone was nonsignificantly more sensitive (90.6%, P = 0.3). Specificity was similar for ASCUS+ cytology (69.1%, 95% CI, 64.6-73.3%) and PCR for carcinogenic HPV (67.1%, P = 0.5), yet was lower for HC2 (63.8%, P = 0.048) and combination testing (62.9%, P = 0.02). Conclusion: Women who tested positive after LEEP for carcinogenic HPV types, especially HPV16, had high risk of subsequent CIN2+. HPV-based detection methods, alone or in combination with cytology, may be useful to incorporate in post-LEEP management strategies. (Cancer Epidemiol Biomarkers Prev 2006;15(5):908–14)

Vaginal cuff dehiscence after different modes of hysterectomy.

OBJECTIVE: To update the incidence of vaginal cuff dehiscence after different modes of hysterectomy and to describe surgical and patient characteristics of dehiscence complications. METHODS: This was an observational cohort study at a large academic hospital. All women who underwent hysterectomy and dehiscence repair between January 2006 and December 2009 were identified. Data from this study period were analyzed separately and in combination with our preliminary study (January 2000 to December 2005) for a 10-year analysis (January 2000 to December 2009). The primary outcome was incidence of vaginal cuff dehiscence after total laparoscopic hysterectomy compared with abdominal, vaginal, and laparoscopically assisted vaginal hysterectomy (LAVH). RESULTS: Between 2006 and 2009, the overall incidence of dehiscence was 0.39% (95% confidence interval [CI] 0.21–0.56). The incidence after total laparoscopic hysterectomy was 0.75% (95% CI 0.09–1.4), which was the highest among all modes of hysterectomy (LAVH was 0.46% [95% CI 0.0–1.10]; total abdominal hysterectomy was 0.38% [95% CI 0.16–0.61]; and total vaginal hysterectomy was 0.11%, [95% CI 0.0–0.32]). This incidence was appreciably lower than previously reported (4.93% in 2007 publication, 2.76% readjusted calculation). The 10-year cumulative incidence of dehiscence after all modes of hysterectomy was 0.24% (95% CI 0.15–0.33) and 1.35% (95% CI 0.72–2.3) among total laparoscopic hysterectomies. During the 10-year study period, total laparoscopic hysterectomy-related dehiscence was significantly increased compared with other modes of hysterectomy, with a risk ratio of dehiscence after total laparoscopic hysterectomy of 9.1 (95% CI 4.1–20.3) compared with total abdominal hysterectomy, risk ratio of 17.2 (95% CI 3.9–75.9) compared with total vaginal hysterectomy, and risk ratio of 4.9 (95% CI 1.1–21.5) compared with LAVH. CONCLUSION: Our updated 1.35% incidence of dehiscence after total laparoscopic hysterectomy is much lower than previously reported. LEVEL OF EVIDENCE: II

Reproductive Function and Outcome of Pregnancy After Liver Transplantation in Women

OBJECTIVE To discuss menstrual function before and after liver transplantation, immunosuppression during pregnancy, outcome and management of pregnancy, and use of contraception in women after liver transplantation. MATERIAL AND METHODS We review the relevant medical literature and describe our clinical experience in the management of gynecologic and obstetric issues in recipients of liver transplants. RESULTS Menstrual abnormalities, such as amenorrhea, oligomenorrhea, irregular bleeding, and metrorrhagia, are common in women with liver disease and may often be the first clinical indication of liver dysfunction. Normal menstrual function is frequently restored after transplantation. Successful pregnancies have occurred in recipients of liver transplants, but such pregnancies are often complicated by preterm delivery, preeclampsia, and infection. Use of immunosuppressive medications should be maintained during pregnancy, and drug concentrations should be carefully monitored; none has been found to be teratogenic. Pregnancy does not seem to accelerate graft rejection. Barrier contraception or sterilization, if appropriate, seems to be the safest option for these patients. CONCLUSION Because liver transplantation leads to restoration of normal menstruation, female patients of reproductive age must be counseled about the possibility of pregnancy and the use of contraception. Pregnancy should be avoided for at least the first 6 months after transplantation. With specialized care and attention, pregnancies are generally associated with good outcomes.

Early pregnancy failure--current management concepts.

Approximately one in four women will experience a miscarriage during her lifetime. For more than 50 years, the standard management of early pregnancy failure has been a dilatation and curettage (D & C). Typically, the procedure is performed in an operating room, which significantly increases cost. There is little objective information in the modern literature to prove that a D & C for all patients will lower morbidity or improve emotional well being. Treatment options include expectant management, D & C in an outpatient setting, and medical management with misoprostol (not approved by the U.S. Food and Drug Administration for treatment of early pregnancy failure). The medical literature supports that expectant management may result in more complications, including the need for “emergent” curettage, if clinicians do not understand the true normal course of expectant management. In general, women prefer some form of active management. Dilatation and curettage can be performed safely in the office or other outpatient setting using manual vacuum aspiration. Vaginal misoprostol will cause expulsion in 80% to 90% of women up to 13 weeks’ uterine size or gestation, including patients who have a gestational sac present. However, these data come from only three trials involving a total of 42 subjects treated with vaginal misoprostol, and another study of 42 women who received vaginal misoprostol for “missed abortion” before a scheduled D & C. There is a significant lack of information from large-scale studies about when treatment is necessary and the relative efficacy, rates of side effects, and acceptability of these various treatment options for early pregnancy failure. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to summarize the current literature on the management of early pregnancy failures, describe the various management options for patients with early pregnancy failures, and contrast the efficacy and complications of each management option.

Outcomes from leiomyoma therapies: comparison with normal controls.

OBJECTIVE: To assess the severity of symptoms caused by uterine leiomyomas, their effect on health-related quality of life, and the change after treatment compared with a normal control group. METHODS: A multicenter nonrandomized prospective study was completed assessing 12-month outcomes from three leiomyoma treatments. Outcome measures included the Uterine Fibroid Symptom and Quality of Life and the Short Form 36 questionnaires. Women scheduled for hysterectomy, myomectomy, or uterine artery embolization were recruited, as well as normal control group members. Questionnaires were completed at baseline and at 6 and 12 months posttreatment. Baseline characteristics were summarized using descriptive statistics. General linear models were used to examine differences among the patient groups. RESULTS: A total of 375 patients completed baseline enrollment: 101 normal, 107 embolization, 61 myomectomy, and 106 hysterectomy. At baseline, the mean Uterine Fibroid Symptom and Quality of Life Symptom Severity score for women in the normal control group was 15.3 (±14.5) and 64.8 (±20) for the leiomyoma patients (P<.001). At 6 and 12 months, the mean Symptom score for women in the normal control group was unchanged, while the leiomyoma treatment group score reduced to a mean of 17.8 (±17.5) at 12 months. Similar magnitude changes occurred among the Uterine Fibroid Symptom and Quality of Life health-related quality of life subscale scores for the normal control group members and leiomyoma patients. At 12 months, the hysterectomy group reported significantly lower symptoms and better health-related quality of life than the other two therapies (P<.001). CONCLUSION: At 12 months after treatment, all three leiomyoma therapies resulted in substantial symptom relief, to near normal levels, with the greatest improvement after hysterectomy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00390494. LEVEL OF EVIDENCE: II

Endometrial thickness after misoprostol use for early pregnancy failure

Objectives: To assess if there was any potential relationship between endometrial thickness and final treatment outcome in women successfully treated with misoprostol for a first trimester anembryonic gestation, embryonic demise or fetal demise. Methods: Eighty women were treated with up to two doses of misoprostol 800 μg vaginally for early pregnancy failure. Subjects were scheduled to return 2 (range 1–4), 7 (range 5–9) and 14 (range 12–17) days after treatment. Transvaginal ultrasonography was performed at each follow‐up visit. Results: The median endometrial thickness at each of the follow‐up visits for women who had expelled the gestational sac was 14 mm, 10 mm, and 7 mm, respectively. The endometrial thickness at the first follow‐up visit exceeded 15 mm in 20 subjects (36%) and 30 mm in four subjects (7%). Only three women had a suction aspiration for bleeding after documented expulsion. The endometrial thickness for these women was 11, 13, and 14 mm at the first follow‐up visit. Conclusions: There is no obvious relationship between increasing endometrial thickness and the need for surgical intervention in women treated with misoprostol for early pregnancy failure.

Disease-Stage Variance in Functional CD4 T-Cell Responses Against Novel Pan-Human Leukocyte Antigen-D Region Presented Human Papillomavirus-16 E7 Epitopes

Given the anticipated clinical importance of helper and regulatory CD4+ T cells reactive against human papillomavirus-16 E7 in the cervical carcinoma setting, we performed this study to identify novel E7-derived T helper (Th) epitopes and to characterize functional anti-E7 Th responses in normal donors and patients with cervical intraepithelial neoplasia I-III or cervical cancer. Candidate pan-HLA-DR (D region) binding peptides were identified and synthesized based on results obtained using a predictive computer algorithm, then applied in short-term in vitro T-cell sensitization assays. Using IFN-γ/IL-5 (interleukin 5) enzyme-linked immunospot assays as readouts for Th1-type and Th2-type CD4+ T-cell responses, respectively, we identified three E7-derived T helper epitopes (E71–12, E748–62, and E762–75), two of which are novel. Normal donor CD4+ T cells failed to react against these E7 peptides, whereas patients with premalignant cervical intraepithelial neoplasia I-III lesions displayed preferential Th1-type responses against all three E7 epitopes. Th1-type responses were still observed to the E748–62 but not to the E71–12 and E762–75 peptides in cancer patients, where these latter two epitopes evoked Th2-type responses. Notably all responders to the E71–12 and E762–75 peptides expressed the HLA-DR4 or -DR15 alleles, whereas all responders to the E748–62 peptide failed to express the HLA-DR4 allele. Our results are consistent with a model in which cervical cancer progression is linked to an undesirable Th1- to Th2-type shift in functional CD4+ T cell responses to two novel E7-derived epitopes. These peptides may prove important in vaccines to promote and maintain protective Th1-type antihuman papillomavirus immunity and in the immune monitoring of treated patients harboring HPV-16+ malignancies.