Acyclovir and Transmission of HIV-1 From Persons Infected With HIV-1 and HSV-2

The following abstracts of articles from leading journals have been selected on the basis of their importance to the practice of obstetrics and gynecology. Effect of a Collector Bag for Measurement of Postpartum Blood Loss After Vaginal Delivery: Cluster Randomised Trial in 13 European Countries Objective: To evaluate the effectiveness of the systematic use of a transparent plastic collector bag to measure postpartum blood loss after vaginal delivery in reducing the incidence of severe postpartum haemorrhage. Design: Cluster randomised trial. Setting: 13 European countries. Participants: 78 maternity units and 25 381 women who had a vaginal delivery. Interventions: Maternity units were randomly assigned to systematic use of a collector bag (intervention group) or to continue to visually assess postpartum blood loss after vaginal delivery (control group). Main Outcome Measures: The primary outcome was the incidence of severe postpartum haemorrhage in vaginal deliveries, defined as a composite of one or more of blood transfusion, intravenous plasma expansion, arterial embolisation, surgical procedure, admission to an intensive care unit, treatment with recombinant factor VII, and death. Results: Severe postpartum haemorrhage occurred in 189 of 11 037 of vaginal deliveries (1.71%) in the intervention group compared with 295 of 14 344 in the control group (2.06%). The difference was not statistically significant either in individual level analysis (adjusted odds ratio 0.82, 95% confidence interval 0.26 to 2.53) or in cluster level analysis (difference in weighted mean rate adjusted for baseline rate 0.16%, 95% confidence interval 0.69% to 1.02%). Conclusion: Compared with visual estimation of postpartum blood loss the use of a collector bag after vaginal delivery did not reduce the rate of severe postpartum haemorrhage. Trial Registration: Current Controlled Trials ISRCTN66197422. Zhang WH, Deneux-Tharaux C, Brocklehurst P, Juszczak E, Joslin M, Alexander S; EUPHRATES Group. BMJ 2010;340:c293. doi: 10.1136/bmj.c293. (http://www.bmj.com) Acyclovir and Transmission of HIV-1 From Persons Infected With HIV-1 and HSV-2 Background: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. Methods: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, or 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. Results: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P 0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log (10) copies per milliliter (95% CI, 0.22 to 0.29; P 0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P 0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Conclusions: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log (10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.) 2010 Massachusetts Medical Society Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, Mujugira A, Baeten JM, Mullins JI, Hughes JP, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Stevens W, Campbell MS, Thomas KK, Coombs RW, Morrow R, Whittington WL, McElrath MJ, Barnes L, Ridzon R, Corey L; Partners in Prevention HSV/HIV Transmission Study Team. N Engl J Med 2010;362:427–39. Epub 2010 Jan 20. (http://content.nejm.org) Risk of Deep Vein Thrombosis Following a Single Negative Whole-Leg Compression Ultrasound: A Systematic Review and Meta-Analysis Context: In patients with suspected lower extremity deep vein thrombosis © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams


Acyclovir and Transmission of HIV-1 From Persons Infected With HIV-1 and HSV-2
Background: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. Methods: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, Ͼ or ϭ250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. Results: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; Pϭ0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log (10) copies per milliliter (95% CI, 0.22 to 0.29; PϽ0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; PϽ0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Conclusions: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log (10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.) (DVT), compression ultrasound (CUS) is typically the initial test to confirm or exclude DVT. Patients with an initial negative CUS result often require repeat CUS after 5 to 7 days. Whole-leg CUS may exclude proximal and distal DVT in a single evaluation. Objective: To determine the risk of venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT following a single negative whole-leg CUS result. Data Sources: MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases were searched for articles published from January 1970 through November 2009. Supplemental searches were performed of Internet resources, reference lists, and by contacting content experts. Study Selection: Included studies were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative wholeleg CUS result who did not receive anticoagulant therapy, and were followed up at least 90 days for venous thromboembolism events. Data Extraction: Two authors independently reviewed and extracted data regarding a single positive or negative whole-leg CUS result, occurrence of venous thromboembolism during follow-up, and study quality. Results: Seven studies were included totaling 4731 patients with negative whole-leg CUS examinations who did not receive anticoagulation. Of these, up to 647 patients (13.7%) had active cancer and up to 725 patients (15.3%) recently underwent a major surgery. Most participants were identified from an ambulatory setting. Venous thromboembolism or suspected venous thromboembolism-related death occurred in 34 patients (0.7%), including 11 patients with distal DVT (32.4%); 7 patients with proximal DVT (20.6%); 7 patients with nonfatal pulmonary emboli (20.6%); and 9 patients (26.5%) who died, possibly related to venous thromboembolism. Using a randomeffects model with inverse variance weighting, the combined venous thromboembolism event rate at 3 months was 0.57% (95% confidence interval, 0.25%-0.89%). Conclusion: Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up.

Method of Delivery and Pregnancy Outcomes in Asia: The WHO Global Survey on Maternal and Perinatal Health 2007-08
Background: There has been concern about rising rates of caesarean section worldwide. This Article reports the third phase of the WHO global survey, which aimed to estimate the rate of different methods of delivery and to examine the relation between method of delivery and maternal and perinatal outcomes in selected facilities in Africa and Latin America in 2004 -05, and in Asia in 2007-08. Methods: Nine countries participated in the Asia global survey: Cambodia, China, India, Japan, Nepal, Philippines, Sri Lanka, Thailand, and Vietnam. In each country, the capital city and two other regions or provinces were randomly selected. We studied all women admitted for delivery during 3 months in institutions with 6000 or fewer expected deliveries per year and during 2 months in those with more than 6000 deliveries. We gathered data for institutions to obtain a detailed description of the health facility and its resources for obstetric care. We obtained data from women's medical records to summarise obstetric and perinatal events. Findings: We obtained data for 109 101 of 112 152 deliveries reported in 122 recruited facilities (97% coverage), and analysed 107 950 deliveries. The overall rate of caesarean section was 27.3% (nϭ29 428) and of operative vaginal delivery was 3.2% (nϭ3465). Risk of maternal mortality and morbidity index (at least one of: maternal mortality, admission to intensive care unit [ICU], blood transfusion, hysterectomy, or internal iliac artery ligation) was increased for operative vaginal delivery (adjusted odds ratio 2.1, 95% CI 1.7-2.6) and all types of caesarean section (antepartum without indication 2.7, 1.4 -5.5; antepartum with indication 10.6, 9.3-12.0; intrapartum without indication 14. 2, 9.8 -20.7; intrapartum with indication 14.5, 13.2-16.0). For breech presentation, caesarean section, either antepartum (0.2, 0.1-0.3) or intrapartum (0.3, 0.2-0.4), was associated with improved perinatal outcomes, but also with increased risk of stay in neonatal ICU (2.0, 1.1-3.6; and 2.1, 1.2-3.7, respectively). Interpretation: To improve maternal and perinatal outcomes, caesarean section should be done only when there is a medical indication.

Trends in the Work Hours of Physicians in the United States
Context: Recent trends in hours worked by physicians may affect workforce needs but have not been thoroughly analyzed. Objectives: To estimate trends in hours worked by US physicians and assess for association with physician fees. Design, Setting, and Participants: A retrospective analysis of trends in hours worked among US physicians using nationally representative workforce information from the US Census Bureau Current Population Survey between 1976 and 2008 (Nϭ116,733). Trends were estimated among all US physicians and by residency status, sex, age, and work setting. Trends in hours were compared with national trends in physician fees, and estimated sepa-rately for physicians located in metropolitan areas with high and low fees in 2001. Main Outcome Measure: Self-reported hours worked in the week before the survey. Results: After remaining stable through the early 1990s, mean hours worked per week decreased by 7.2% between 1996 and 2008 among all physicians (from 54.9 hours per week in 1996 -1998 to 51.0 hours per week in 2006 -2008; 95% confidence interval [CI], 5.3%-9.0%; PϽ.001). Excluding resident physicians, whose hours decreased by 9.8% (95% CI, 5.8%-13.7%; PϽ.001) in the last decade due to duty hour limits imposed in 2003, nonresident physician hours decreased by 5.7% (95% CI, 3.8%-7.7%; PϽ.001). The decrease in hours was largest for nonresident physicians younger than 45 years (7.4%; 95% CI, 4.7%-10.2%; PϽ.001) and working outside of the hospital (6.4%; 95% CI, 4.1%-8.7%; PϽ.001), and the decrease was smallest for those aged 45 years or older (3.7%; 95% CI, 1.0%-6.5%; Pϭ.008) and working in the hospital (4.0%; 95% CI, 0.4%-7.6%; Pϭ.03). After adjusting for inflation, mean physician fees decreased nationwide by 25% between 1995 and 2006, coincident with the decrease in physician hours. In 2001, mean physician hours were less than 49 hours per week in metropolitan areas with the lowest physician fees, whereas physician hours remained more than 52 hours per week elsewhere (PϽ.001 for difference). Conclusion: A steady decrease in hours worked per week during the last decade was observed for all physicians, which was temporally and geographically associated with lower physician fees.

Risk Factors and Outcomes Associated With First-Trimester Fetal Growth Restriction
Context: Adverse environmental exposures lead to developmental adaptations in fetal life. The influences of maternal physical characteristics and lifestyle habits on first-trimester fetal adaptations and the postnatal consequences are not known. Objective: To determine the risk factors and outcomes associated with firsttrimester growth restriction. Design, Setting, and Participants: Prospective evaluation of the associations of maternal physical characteristics and lifestyle habits with first-trimester fetal crown to rump length in 1631 mothers with a known and reliable first day of their last menstrual period and a regular menstrual cycle. Subsequently, we assessed the associations of firsttrimester fetal growth restriction with the risks of adverse birth outcomes and postnatal growth acceleration until the age of 2 years. The study was based in Rotterdam, The Netherlands. Mothers were enrolled between 2001 and 2005. Main Outcome Measures: First-trimester fetal growth was measured as fetal crown to rump length by ultrasound between the gestational age of 10 weeks 0 days and 13 weeks 6 days. Main birth outcomes were preterm birth (gestational age Ͻ37 weeks), low birth weight (Ͻ2500 g), and small size for gestational age (lowest fifth birth centile). Postnatal growth was measured until the age of 2 years. Results: In the multivariate analysis, maternal age was positively associated with first-trimester fetal crown to rump length (difference per maternal year of age, 0.79 mm; 95% confidence interval [CI], 0.41 to 1.18 per standard deviation score increase). Higher diastolic blood pressure and higher hematocrit levels were associated with a shorter crown to rump length (differences, Ϫ0.40 mm; 95% CI, Ϫ0.74 to Ϫ0.06 and Ϫ0.52 mm; 95% CI, Ϫ0.90 to Ϫ0.14 per standard deviation increase, respectively). Compared with mothers who were nonsmokers and optimal users of folic acid supplements, those who both smoked and did not use folic acid supplements had shorter fetal crown to rump lengths (difference, Ϫ3.84 mm; 95% CI, Ϫ5.71 to Ϫ1.98). Compared with normal firsttrimester fetal growth, first-trimester growth restriction was associated with increased risks of preterm birth (4.0% vs 7.2%; adjusted odds ratio [OR], 2.12; 95% CI, 1.24 to 3.61), low birth weight (3.5% vs 7.5%; adjusted OR, 2.42; 95% CI, 1.41 to 4.16), and small size for gestational age at birth (4.0% vs 10.6%; adjusted OR, 2.64; 95% CI, 1.64 to 4.25). Each standard deviation decrease in first-trimester fetal crown to rump length was associated with a postnatal growth acceleration until the age of 2 years (standard deviation score increase, 0.139 per 2 years; 95% CI, 0.097 to 0.181). Conclusions: Maternal physical characteristics and lifestyle habits were independently associated with early fetal growth. First-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes and growth acceleration in early childhood.

Lasofoxifene in Postmenopausal Women With Osteoporosis
Background: The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. Methods: In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of Ϫ2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. Results: Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.

Conclusions:
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials. gov number, NCT00141323.)