ABSTRACTS
antihypertensives for severe hypertension in pregnancy. Inde-
The following abstracts of articles from leading
journals have been selected on the basis of their
importance to the practice of obstetrics and
gynecology.
Metformin in polycystic ovary syndrome:
systematic review and meta-analysis
OBJECTIVE: To assess the effectiveness of metformin in improv-
ing clinical and biochemical features of polycystic ovary syn-
drome.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Randomized controlled trials that investigated
the effect of metformin compared with either placebo or no
treatment, or compared with an ovulation induction agent.
SELECTION OF STUDIES: 13 trials were included for analysis,
including 543 women with polycystic ovary syndrome that
was defined by using biochemical or ultrasound evidence.
MAIN OUTCOME MEASURE: Pregnancy and ovulation rates.
Secondary outcomes of clinical and biochemical features of
polycystic ovary syndrome.
RESULTS: Meta-analysis showed that metformin is effective in
achieving ovulation in women with polycystic ovary syndrome,
with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for
metformin compared with placebo and 4.41 (2.37 to 8.22) for
metformin and clomifene compared with clomifene alone. An
analysis of pregnancy rates shows a significant treatment effect for
metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Met-
formin has an effect in reducing fasting insulin concentrations,
blood pressure, and low density lipoprotein cholesterol. We
found no evidence of any effect on body mass index or waist:hip
ratio. Metformin was associated with a higher incidence of nausea,
vomiting, and other gastrointestinal disturbance.
CONCLUSIONS: Metformin is an effective treatment for anovula-
tion in women with polycystic ovary syndrome. Its choice as a first
line agent seems justified, and there is some evidence of benefit on
variables of the metabolic syndrome. No data are available regard-
ing the safety of metformin in long-term use in young women and
only limited data on its safety in early pregnancy. It should be used
as an adjuvant to general lifestyle improvements and not as a
replacement for increased exercise and improved diet.
Lord JM, Flight IH, Norman RJ. BMJ 2003;327:951–3.
(http://bmj.com)
Hydralazine for treatment of severe hypertension
in pregnancy: meta-analysis
OBJECTIVE: To review outcomes in randomized controlled
trials comparing hydralazine against other antihypertensives
for severe hypertension in pregnancy.
STUDY DESIGN: Meta-analysis of randomized controlled trials
(published between 1966 and September 2002) of short acting
VOL. 103, NO. 2, FEBRUARY 2004
© 2004 by The American College of Obstetricians and Gynecologists.
Published by Lippincott Williams & Wilkins.
pendent data abstraction by two reviewers. Data were entered
into RevMan software for analysis (fixed effects model, relative
risk and 95% confidence interval); in a secondary analysis, risk
difference was also calculated.
RESULTS: Of 21 trials (893 women), eight compared hydral-
azine with nifedipine and five with labetalol. Hydralazine was
associated with a trend toward less persistent severe hyperten-
sion than labetalol (RR 0.29 [95% CI 0.08 to 1.04]); two trials),
but more severe hypertension than nifedipine or isradipine
(1.41 [0.95 to 2.09]; four trials); there was significant heteroge-
neity in outcome between trials and differences in methodolog-
ical quality. Hydralazine was associated with more maternal
hypotension (3.29 [1.50 to 7.23]; 13 trials); more caesarean
sections (1.30 [1.08 to 1.59]; 14 trials); more placental abrup-
tion (4.17 [1.19 to 14.28]; five trials); more maternal oliguria
(4.00 [1.22 to 12.50]; three trials); more adverse effects on fetal
heart rate (2.04 [1.32 to 3.16]; 12 trials); and more low Apgar
scores at one minute (2.70 [1.27 to 5.88]; three trials). For all
but Apgar scores, analysis by risk difference showed heteroge-
neity between trials. Hydralazine was associated with more
maternal side effects (1.50 [1.16 to 1.94]; 12 trials) and with less
neonatal bradycardia than labetalol (risk difference ⫺0.24
[⫺0.42 to ⫺0.06]); three trials).
CONCLUSIONS: The results are not robust enough to guide
clinical practice, but they do not support use of hydralazine as
first line for treatment of severe hypertension in pregnancy.
Adequately powered clinical trials are needed, with a compar-
ison of labetalol and nifedipine showing the most promise.
Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P.
BMJ 2003;327:955– 60.
(http://bmj.com)
The effects of parathyroid hormone and
alendronate alone or in combination in
postmenopausal osteoporosis*
BACKGROUND: Parathyroid hormone (PH) stimulates bone
formation. In contrast, the bisphosphonates reduce bone resorp-
tion. In an effort to determine if the use of both agents would
increase bone density more than the use of either one alone, the
authors performed a randomized, double-blind clinical study.
METHODS: A total of 238 postmenopausal women with low
bone density (mean T score at femoral neck ⫺2.2 ⫾ 0.7) who
were not using bisphosphonates were randomly assigned to a
treatment arm. One group (N ⫽ 119) received 100 ␮g parathy-
roid hormone daily; one group (N ⫽ 60) received 10 milligram
alendronate daily; and one group (N ⫽ 59) received both
therapies. This paper reports the results of the first 12 months
of the study. Bone mineral density (BMD) tests were con-
ducted at both the spine and hip using both DEXA and
ⴱModified abstract.
0029-7844/04/$30.00 397
doi:10.1097/01.AOG.0000112920.95451.5a
quantitative computerized tomography. Markers of bone turn-
over were measured in fasting blood samples.
RESULTS: BMD at the spine increased in all treatment groups.
There was no significant difference in the increase between the
PH group and the combination treatment group. The volumet-
ric density of the trabecular bone at the spine increased in all
groups, but the increase in the PH group was about twice that
found in either of the other groups. Bone formation increased
in the PH group but not in the combination group. Bone
resorption decreased in the combination group and the alendr-
onate-alone group.
CONCLUSIONS: This study found no evidence of synergy be-
tween PH and alendronate. That is, there was little evidence
that combination therapy is better than either drug, used alone.
Changes in the volumetric density of trabecular bone, the
cortical volume at the hip, and levels of markers of bone
turnover suggest that the concurrent use of alendronate may
reduce the anabolic effects of PH. Longer studies are needed to
determine if there is a reduction in the occurrence of fractures
with combination therapy.
Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA,
Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ;
PaTH Study Investigators. N Engl J Med 2003;349:1207–15.
(http://nejm.org)
Effects of different blood-pressure-lowering
regimens on major cardiovascular events: results
of prospectively-designed overviews of
randomized trials
BACKGROUND: The benefits of reducing blood pressure on the
risks of major cardiovascular disease are well established, but
uncertainty remains about the comparative effects of different
blood-pressure-lowering regimens. We aimed to estimate effects
of strategies based on different drug classes (angiotensin-convert-
ing-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-
receptor blockers [ARBs], and diuretics or ␤-blockers) or those
targeting different blood pressure goals, on the risks of major
cardiovascular events and death.
METHODS: We did seven sets of prospectively-designed over-
views with data from 29 randomized trials (n ⫽ 162341). The trial
eligibility criteria, primary outcomes, and main hypotheses were
specified before the result of any contributing trial was known.
FINDINGS: In placebo-controlled trials the relative risks of total
major cardiovascular events were reduced by regimens based
on ACE inhibitors (22%; 95% confidence interval 17, 27) or
calcium antagonists (18%; 5, 29). Greater risk reductions were
produced by regimens that targeted lower blood pressure goals
(15%; 5, 24). ARB-based regimens reduced the risks of total
major cardiovascular events (10%; 4, 17) compared with con-
trol regimens. There were no significant differences in total
major cardiovascular events between regimens based on ACE
inhibitors, calcium antagonists, or diuretics or ␤ blockers,
although ACE-inhibitor-based regimens reduced blood pres-
sure less. There was evidence of some differences between
active regimens in their effects on cause-specific outcomes. For
398 Abstracts
every outcome other than heart failure, the difference between
randomized groups in achieved blood pressure reduction was
directly related to the observed difference in risk.
INTERPRETATION: Treatment with any commonly-used regimen
reduces the risk of total major cardiovascular events, and larger
reductions in blood pressure produce larger reductions in risk.
Turnbull F, Blood Pressure Lowering Treatment Trialists’
Collaboration. Lancet 2003;362:1527–35.
(http://www.thelancet.com)
Influence of controllable lifestyle on recent trends
in specialty choice by US medical students
CONTEXT: Recent specialty choices of graduating US medical
students suggest that lifestyle may be an increasingly important
factor in their career decision making.
OBJECTIVE: To determine whether and to what degree control-
lable lifestyle and other specialty-related characteristics are
associated with recent (1996 –2002) changes in the specialty
preferences of US senior medical students.
DESIGN AND SETTING: Specialty preference was based on anal-
ysis of results from the National Resident Matching Program, the
San Francisco Matching Program, and the American Urological
Association Matching Program from 1996 to 2002. Specialty
lifestyle (controllable vs uncontrollable) was classified using earlier
research. Log-linear models were developed that examined spe-
cialty preference and the specialty’s controllability, income, work
hours, and years of graduate medical education required.
MAIN OUTCOME MEASURE: Proportion of variability in specialty
preference from 1996 to 2002 explained by controllable lifestyle.
RESULTS: The specialty preferences of US senior medical
students, as determined by the distribution of applicants across
selected specialties, changed significantly from 1996 to 2002
(P ⬍ .001). In the log-linear model, controllable lifestyle ex-
plained 55% of the variability in specialty preference from 1996
to 2002 after controlling for income, work hours, and years of
graduate medical education required (P ⬍ .001).
CONCLUSION: Perception of controllable lifestyle accounts for
most of the variability in recent changing patterns in the
specialty choices of graduating US medical students.
Dorsey ER, Jarjoura D, Rutecki GW. JAMA 2003;290:1173– 8.
(http://jama.ama-assn.org)
Ability of exercise testing to predict
cardiovascular and all-cause death in
asymptomatic women: a 20-year follow-up of the
lipid research clinics prevalence study
CONTEXT: The value of exercise testing in women has been
questioned.
OBJECTIVE: To determine the prognostic value of exercise
testing in a population-based cohort of asymptomatic women
followed up for 20 years.
OBSTETRICS & GYNECOLOGY
DESIGN AND SETTING: Near-maximal Bruce-protocol treadmill
test data from the Lipid Research Clinics Prevalence Study
(1972–1976) with follow-up through 1995.
PARTICIPANTS: A total of 2,994 asymptomatic North Ameri-
can women, aged 30 to 80 years, without known cardiovascu-
lar disease.
MAIN OUTCOME MEASURES: Cardiovascular and all-cause
mortality.
RESULTS: There were 427 (14%) deaths during 20 years of
follow-up, of which 147 were due to cardiovascular causes.
Low exercise capacity, low heart rate recovery (HRR), and not
achieving target heart rate were independently associated with
increased all-cause and cardiovascular mortality. There was no
increased cardiovascular death risk for exercise-induced ST-
segment depression (age-adjusted hazard ratio, 1.02; 95% con-
fidence interval [CI] 0.57, 1.80; P ⫽ .96). The age-adjusted
hazard ratio for cardiovascular death for every metabolic
equivalent (MET) decrement in exercise capacity was 1.20
(95% CI 1.18, 1.30; P ⬍ .001); for every 10 beats per minute
(bpm) decrement in HRR, the hazard ratio was 1.36 (95% CI
1.19, 1.55; P ⬍ .001). After adjusting for multiple other risk
factors, women who were below the median for both exercise
capacity and HRR had a 3.5-fold increased risk of cardiovas-
cular death (95% CI 1.57, 7.86; P ⫽ .002) compared with those
above the median for both variables. Among women with low
risk Framingham scores, those with below median levels of
both exercise capacity and HRR had significantly increased
risk compared with women who had above median levels of
these 2 exercise variables, 44.5 and 3.5 cardiovascular deaths
per 10,000 person-years, respectively (hazard ratio for cardio-
vascular death, 12.93; 95% CI 5.62, 29.73; P ⬍ .001).
CONCLUSION: The prognostic value of exercise testing in
asymptomatic women derives not from electrocardiographic
ischemia but from fitness-related variables.
Mora S, Redberg RF, Cui Y, Whiteman MK, Flaws JA, Sharrett
AR, Blumenthal RS. JAMA 2003;290:1600 –7.
(http://jama.ama-assn.org)
A randomized trial of letrozole in
postmenopausal women after five years of
tamoxifen therapy for early-stage breast cancer*
BACKGROUND: Up to five years of tamoxifen therapy (but not
longer) prolongs disease-free and overall survival in women
with hormone-dependent breast cancer. Letrozole is an aro-
matase inhibitor that might improve survival after tamoxifen
therapy by suppressing estrogen production.
METHODS: Postmenopausal women with breast cancer who
had completed five years of tamoxifen therapy were recruited
for this study. Each study participant was randomly assigned to
receive five years of letrozole therapy or placebo. The primary
endpoint was disease-free survival.
RESULTS: A total of 5,187 women were enrolled in the study.
At the time of the first interim analysis, the independent data and
VOL. 103, NO. 2, FEBRUARY 2004
safety monitoring committee recommended termination of the
trial because of the difference in outcome between the treated and
placebo groups. There were 75 local or metastatic recurrences or
cancer in the contralateral breast in the letrozole group, and 132 in
the placebo group (P ⬍ .001 for disease-free survival). Although
more women in the placebo group died (N ⫽ 42) than in the
treatment group (N ⫽ 31) the difference was not statistically
significant. Hot flushes, arthritis, arthalgia, and myalgia were
more common in the letrozole group. Vaginal bleeding was more
common in the placebo group. Osteoporosis was newly diag-
nosed in 5.8% of the treated group and 4.5% of the placebo group
(P ⫽ .07). The rates of fracture were similar.
CONCLUSIONS: After the completion of standard tamoxifen
therapy in women with breast cancer, letrozole improves dis-
ease-free survival when compared to placebo.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ,
Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB,
Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P,
Palmer MJ, Pater JL. N Engl J Med 2003;349:1793– 802.
(http://www.nejm.org)
A randomized study of prophylactic catheter
ablation in asymptomatic patients with the Wolff-
Parkinson-White syndrome*
BACKGROUND: Young age and inducibility of atrioventricular
recoprocating tachycardia or atrial fibrillation during invasive
electrophysiological testing identify asymptomatic patients
with a Wolff-Parkinson-White (WPW) pattern on an electro-
cardiogram as high risk for arrhythmic events. We tested the
hypothesis that prophylactic catheter ablation of accessory
pathways would benefit such patients.
METHODS: Between 1997 and 2002, eligible, asymptomatic
patients with the WPW syndrome at high risk for arrhythmias
were randomly assigned to radio frequency ablation of acces-
sory pathways (N ⫽ 37) or no treatment (N ⫽ 35). The primary
end point was the occurrence of arrhythmic events over a five
year follow-up period.
RESULTS: Two patients in the ablation group (5%) and 21
(60%) in the control group had arrhythmic events. One con-
trol patient had ventricular fibrillation as the presenting ar-
rhythmia. The risk reduction with ablation was 92% (relative
risk 0.08; 95% confidence interval 0.02, 0.33, P ⬍ .001).
CONCLUSIONS: Prophylactic ablation of accessory pathways
reduces the frequency of arrhythmic events in young asymp-
tomatic patients with the WPW syndrome who are at high risk
for such events.
Pappone C, Santinelli V, Manguso F, Augello G, Santinelli O,
Vicedomini G, Gulletta S, Mazzone P, Tortoriello V, Pappone A,
Dicandia C, Rosanio S. N Engl J Med 2003;349:1803–11.
(http://www.nejm.org)
ⴱModified abstract.
Abstracts 399