Gary Kelsberg, MD

Evidence summary

Breast stimulation works

A systematic review of 6 trials with a total of 719 participants compared unilateral breast stimulation with no intervention to induce labor in women at term.¹ In 2 trials, the 300 participants stimulated 1 breast for 1 hour a day for 3 days; in the other 4 trials, 419 women stimulated either breast alternately for 3 hours a day.

Breast stimulation significantly reduced the number of women who hadn’t gone into labor at 72 hours compared with nonintervention (62.7% vs 93.6%; relative risk [RR]=0.67; 95% confidence interval [CI], 0.60-0.74; number needed to treat [NNT]=3.2). This result remained significant when primiparous and multiparous women were analyzed separately, but not in the 1 trial (37 participants) that reported on women with an unfavorable cervix.¹ Breast stimulation also reduced postpartum hemorrhage (0.7% vs 6%; RR=0.16; 95% CI, 0.03-0.87; NNT=18.8).

None of the trials documented uterine hyperstimulation or meconium-stained fluid, and they didn’t find significant differences in the rates of cesarean section (9% vs 10%; RR=0.90; 95% CI, 0.38-2.12). One trial reported 4 perinatal deaths in a high-risk population—3 in the breast stimulation group and 1 in the control group—but this finding was not replicated in any other trials.¹

Acupuncture may also help

A Cochrane systematic review evaluating acupuncture for inducing labor identified 1 randomized trial with methodologic flaws (allowing no conclusion), 3 case series, and 2 nonrandomized trials. The first case series used electroacupuncture at 38 to 42 weeks to successfully induce labor in 21 of 31 women. The second series, using acupuncture with and without electrical stimulation, induced labor in 10 of 12 women at 19 to 43 weeks. The third study induced labor with electroacupuncture in 78% of 41 women—34 term and postterm patients and 7 with a fetal demise.

In the first nonrandomized trial, 20 of 27 women at term who received electroacupuncture gave birth between 39 weeks 3 days and 40 weeks, compared with 47 of 102 women in the control group. In the second study, 31 of 35 women who received electroacupuncture reported increased intensity of contractions compared with none of the 35 women in the control group.²

Sexual intercourse induces pregnancy, not labor

A Cochrane systematic review found 1 observational study of the effect of sexual intercourse on cervical ripening and induction of labor among 28 women at term. The study evaluated cervical Bishop scores after sexual intercourse with intravaginal semen deposition for 3 consecutive nights compared with no intercourse. The difference in Bishop score was not significant (1.0 with coitus vs 0.5 controls; P>.05) and no difference in the number of women who delivered within 3 days was noted in the 2 groups (RR=0.99; 95% CI, 0.45-2.20).³

Castor oil made women nauseous

A Cochrane systematic review included 1 study of women at term with intact membranes who received 1 dose of castor oil to induce labor (n=52) compared with no treatment (n=48). All women who received castor oil felt nauseous, but no other differences were noted between the castor oil group and controls in rates of cesarean section, meconium-stained fluid, or Apgar scores less than 7 at 5 minutes.⁴

Herbal preparations raise many questions—and some concerns

A prospective controlled trial that randomized 192 women to receive either red raspberry leaf tablets (1.2 g twice daily beginning at 32 weeks) or placebo found no significant differences in duration of the first stage of labor or birth outcomes. Symptom surveys of 108 women revealed no adverse effects.⁵

A retrospective cohort study compared pregnancy outcomes in 54 women who took evening primrose oil (500 mg 3 times a day beginning at 37 weeks) with a matched group of 54 women who did not take it. The study found no significant differences between the groups in maternal age, Apgar scores, or days of gestation. However, the women taking evening primrose oil tended to have protracted active phase of labor, prolonged rupture of membranes, arrest of descent, and oxytocin augmentation (none of which were statistically significant).⁶

A systematic review of the literature on black cohosh in pregnancy found no trials that evaluated its efficacy for inducing labor.⁷ A review of herbal preparations used by midwives reported a case of an infant with low Apgar scores after black cohosh use.⁸ Both articles described black cohosh as potentially unsafe because of the lack of trials demonstrating safety and possible deleterious estrogenic effects.

A systematic review of the literature on blue cohosh found only in vitro studies of efficacy (increased estradiol-induced transcription in estrogen-responsive cells and increased tone in excised guinea pig uteri) and 3 case reports of maternal adverse events after ingestion (perinatal stroke, congestive heart failure with shock, and multiorgan hypoxic injury).⁹ In vitro evidence presented in the review suggests that blue cohosh may have teratogenic, embryotoxic, and oxytocic effects.

Recommendations

We found no recommendations from professional organizations regarding folk methods to stimulate labor. The authors of a survey of herbal preparations used by midwives do not advocate their use in pregnancy because of unknown risks to the fetus, although “raspberry leaf tea does not seem to have any significant pharmacologic activity and is probably safe.”⁸

Evidence summary

Breast stimulation works

A systematic review of 6 trials with a total of 719 participants compared unilateral breast stimulation with no intervention to induce labor in women at term.¹ In 2 trials, the 300 participants stimulated 1 breast for 1 hour a day for 3 days; in the other 4 trials, 419 women stimulated either breast alternately for 3 hours a day.

Breast stimulation significantly reduced the number of women who hadn’t gone into labor at 72 hours compared with nonintervention (62.7% vs 93.6%; relative risk [RR]=0.67; 95% confidence interval [CI], 0.60-0.74; number needed to treat [NNT]=3.2). This result remained significant when primiparous and multiparous women were analyzed separately, but not in the 1 trial (37 participants) that reported on women with an unfavorable cervix.¹ Breast stimulation also reduced postpartum hemorrhage (0.7% vs 6%; RR=0.16; 95% CI, 0.03-0.87; NNT=18.8).

None of the trials documented uterine hyperstimulation or meconium-stained fluid, and they didn’t find significant differences in the rates of cesarean section (9% vs 10%; RR=0.90; 95% CI, 0.38-2.12). One trial reported 4 perinatal deaths in a high-risk population—3 in the breast stimulation group and 1 in the control group—but this finding was not replicated in any other trials.¹

Acupuncture may also help

A Cochrane systematic review evaluating acupuncture for inducing labor identified 1 randomized trial with methodologic flaws (allowing no conclusion), 3 case series, and 2 nonrandomized trials. The first case series used electroacupuncture at 38 to 42 weeks to successfully induce labor in 21 of 31 women. The second series, using acupuncture with and without electrical stimulation, induced labor in 10 of 12 women at 19 to 43 weeks. The third study induced labor with electroacupuncture in 78% of 41 women—34 term and postterm patients and 7 with a fetal demise.

In the first nonrandomized trial, 20 of 27 women at term who received electroacupuncture gave birth between 39 weeks 3 days and 40 weeks, compared with 47 of 102 women in the control group. In the second study, 31 of 35 women who received electroacupuncture reported increased intensity of contractions compared with none of the 35 women in the control group.²

Sexual intercourse induces pregnancy, not labor

A Cochrane systematic review found 1 observational study of the effect of sexual intercourse on cervical ripening and induction of labor among 28 women at term. The study evaluated cervical Bishop scores after sexual intercourse with intravaginal semen deposition for 3 consecutive nights compared with no intercourse. The difference in Bishop score was not significant (1.0 with coitus vs 0.5 controls; P>.05) and no difference in the number of women who delivered within 3 days was noted in the 2 groups (RR=0.99; 95% CI, 0.45-2.20).³

Castor oil made women nauseous

A Cochrane systematic review included 1 study of women at term with intact membranes who received 1 dose of castor oil to induce labor (n=52) compared with no treatment (n=48). All women who received castor oil felt nauseous, but no other differences were noted between the castor oil group and controls in rates of cesarean section, meconium-stained fluid, or Apgar scores less than 7 at 5 minutes.⁴

Herbal preparations raise many questions—and some concerns

A prospective controlled trial that randomized 192 women to receive either red raspberry leaf tablets (1.2 g twice daily beginning at 32 weeks) or placebo found no significant differences in duration of the first stage of labor or birth outcomes. Symptom surveys of 108 women revealed no adverse effects.⁵

A retrospective cohort study compared pregnancy outcomes in 54 women who took evening primrose oil (500 mg 3 times a day beginning at 37 weeks) with a matched group of 54 women who did not take it. The study found no significant differences between the groups in maternal age, Apgar scores, or days of gestation. However, the women taking evening primrose oil tended to have protracted active phase of labor, prolonged rupture of membranes, arrest of descent, and oxytocin augmentation (none of which were statistically significant).⁶

A systematic review of the literature on black cohosh in pregnancy found no trials that evaluated its efficacy for inducing labor.⁷ A review of herbal preparations used by midwives reported a case of an infant with low Apgar scores after black cohosh use.⁸ Both articles described black cohosh as potentially unsafe because of the lack of trials demonstrating safety and possible deleterious estrogenic effects.

A systematic review of the literature on blue cohosh found only in vitro studies of efficacy (increased estradiol-induced transcription in estrogen-responsive cells and increased tone in excised guinea pig uteri) and 3 case reports of maternal adverse events after ingestion (perinatal stroke, congestive heart failure with shock, and multiorgan hypoxic injury).⁹ In vitro evidence presented in the review suggests that blue cohosh may have teratogenic, embryotoxic, and oxytocic effects.

Recommendations

We found no recommendations from professional organizations regarding folk methods to stimulate labor. The authors of a survey of herbal preparations used by midwives do not advocate their use in pregnancy because of unknown risks to the fetus, although “raspberry leaf tea does not seem to have any significant pharmacologic activity and is probably safe.”⁸

Evidence summary

Breast stimulation works

A systematic review of 6 trials with a total of 719 participants compared unilateral breast stimulation with no intervention to induce labor in women at term.¹ In 2 trials, the 300 participants stimulated 1 breast for 1 hour a day for 3 days; in the other 4 trials, 419 women stimulated either breast alternately for 3 hours a day.

Breast stimulation significantly reduced the number of women who hadn’t gone into labor at 72 hours compared with nonintervention (62.7% vs 93.6%; relative risk [RR]=0.67; 95% confidence interval [CI], 0.60-0.74; number needed to treat [NNT]=3.2). This result remained significant when primiparous and multiparous women were analyzed separately, but not in the 1 trial (37 participants) that reported on women with an unfavorable cervix.¹ Breast stimulation also reduced postpartum hemorrhage (0.7% vs 6%; RR=0.16; 95% CI, 0.03-0.87; NNT=18.8).

None of the trials documented uterine hyperstimulation or meconium-stained fluid, and they didn’t find significant differences in the rates of cesarean section (9% vs 10%; RR=0.90; 95% CI, 0.38-2.12). One trial reported 4 perinatal deaths in a high-risk population—3 in the breast stimulation group and 1 in the control group—but this finding was not replicated in any other trials.¹

Acupuncture may also help

A Cochrane systematic review evaluating acupuncture for inducing labor identified 1 randomized trial with methodologic flaws (allowing no conclusion), 3 case series, and 2 nonrandomized trials. The first case series used electroacupuncture at 38 to 42 weeks to successfully induce labor in 21 of 31 women. The second series, using acupuncture with and without electrical stimulation, induced labor in 10 of 12 women at 19 to 43 weeks. The third study induced labor with electroacupuncture in 78% of 41 women—34 term and postterm patients and 7 with a fetal demise.

In the first nonrandomized trial, 20 of 27 women at term who received electroacupuncture gave birth between 39 weeks 3 days and 40 weeks, compared with 47 of 102 women in the control group. In the second study, 31 of 35 women who received electroacupuncture reported increased intensity of contractions compared with none of the 35 women in the control group.²

Sexual intercourse induces pregnancy, not labor

A Cochrane systematic review found 1 observational study of the effect of sexual intercourse on cervical ripening and induction of labor among 28 women at term. The study evaluated cervical Bishop scores after sexual intercourse with intravaginal semen deposition for 3 consecutive nights compared with no intercourse. The difference in Bishop score was not significant (1.0 with coitus vs 0.5 controls; P>.05) and no difference in the number of women who delivered within 3 days was noted in the 2 groups (RR=0.99; 95% CI, 0.45-2.20).³

Castor oil made women nauseous

A Cochrane systematic review included 1 study of women at term with intact membranes who received 1 dose of castor oil to induce labor (n=52) compared with no treatment (n=48). All women who received castor oil felt nauseous, but no other differences were noted between the castor oil group and controls in rates of cesarean section, meconium-stained fluid, or Apgar scores less than 7 at 5 minutes.⁴

Herbal preparations raise many questions—and some concerns

A prospective controlled trial that randomized 192 women to receive either red raspberry leaf tablets (1.2 g twice daily beginning at 32 weeks) or placebo found no significant differences in duration of the first stage of labor or birth outcomes. Symptom surveys of 108 women revealed no adverse effects.⁵

A retrospective cohort study compared pregnancy outcomes in 54 women who took evening primrose oil (500 mg 3 times a day beginning at 37 weeks) with a matched group of 54 women who did not take it. The study found no significant differences between the groups in maternal age, Apgar scores, or days of gestation. However, the women taking evening primrose oil tended to have protracted active phase of labor, prolonged rupture of membranes, arrest of descent, and oxytocin augmentation (none of which were statistically significant).⁶

A systematic review of the literature on black cohosh in pregnancy found no trials that evaluated its efficacy for inducing labor.⁷ A review of herbal preparations used by midwives reported a case of an infant with low Apgar scores after black cohosh use.⁸ Both articles described black cohosh as potentially unsafe because of the lack of trials demonstrating safety and possible deleterious estrogenic effects.

A systematic review of the literature on blue cohosh found only in vitro studies of efficacy (increased estradiol-induced transcription in estrogen-responsive cells and increased tone in excised guinea pig uteri) and 3 case reports of maternal adverse events after ingestion (perinatal stroke, congestive heart failure with shock, and multiorgan hypoxic injury).⁹ In vitro evidence presented in the review suggests that blue cohosh may have teratogenic, embryotoxic, and oxytocic effects.

Recommendations

We found no recommendations from professional organizations regarding folk methods to stimulate labor. The authors of a survey of herbal preparations used by midwives do not advocate their use in pregnancy because of unknown risks to the fetus, although “raspberry leaf tea does not seem to have any significant pharmacologic activity and is probably safe.”⁸

Evidence summary

Studies without risk stratification find little benefit from beta-blockers

A systematic review including 25 randomized controlled trials (RCTs) evaluated perioperative beta-blocker therapy for noncardiac surgery in a total of 2722 patients who were not stratified according to cardiac risk status.¹

Perioperative beta-blockers produced no significant effect on:

• all-cause mortality (odds ratio [OR]=0.78; 95% confidence interval [CI], 0.33–1.87),
• acute myocardial infarction (OR=0.59; 95% CI, 0.25–1.39),
• atrial fibrillation/flutter and other supraventricular arrhythmias (OR=0.43; 95% CI, 0.14–1.37), or
• length of hospital stay (weighted mean difference, –5.6 days; 95% CI, –12.2, 1.04).

However, in this review perioperative beta-blocker therapy reduced perioperative myocardial ischemia (OR=0.38; 95% CI, 0.21–0.69), and increased 2 adverse outcomes: hemodynamically significant bradycardia (OR=1.98; 95% CI, 1.08– 3.66) and hypotension requiring treatment (OR=2.52; 95% CI, 1.94–3.28).¹ This study was limited by the inconsistent definition and assessment of outcomes among the individual trials.

No effect on total mortality, but a benefit in a composite outcome. An earlier systematic review with 22 RCTs and 2437 total patients, that was also not stratified according to cardiac risk status, found no effect from perioperative beta-blockers on total mortality or cardiovascular mortality alone. However, it did demonstrate a composite outcome of reduced cardiovascular mortality, reduced nonfatal myocardial infarction, and reduced nonfatal cardiac arrest (relative risk [RR]=0.44; 95% CI, 0.20–0.97) 30 days after surgery.²

Beta-blockers benefit certain high-risk patients
A retrospective cohort study evaluated the effect of perioperative beta-blocker therapy on perioperative mortality, according to preoperative RCRI assessment.³ The study population included 663,635 adults (mean age, 62 years) undergoing major noncardiac surgery at 329 US hospitals. Researchers calculated individual RCRI scores (TABLE).⁴ Half the patients had an RCRI of 0, 38% had an RCRI of 1, 10% had an RCRI of 2, and only 2% had an RCRI of 3 or greater.

Be wary of beta-blockers in low-risk patients. In the 580,665 patients with low cardiac risk, perioperative beta-blocker therapy increased the risk of in-hospital death: for all patients with an RCRI of 0: OR=1.36 (95% CI, 1.27–1.45); number needed to harm (NNH)=208; for all patients with an RCRI of 1: OR=1.09 (95% CI, 1.01–1.19); NNH=504).

A different story for high-risk cardiac patients. Perioperative beta-blocker therapy reduced the risk of in-hospital death in patients with an RCRI of 2 (OR=0.88; 95% CI, 0.80–0.98; number needed to treat [NNT]=227), an RCRI of 3 (OR=0.71; 95% CI, 0.63–0.80; NNT=62), or an RCRI of 4 or more (OR=0.58; 95% CI, 0.50–0.67; NNT=33).

TABLE
Before surgery, calculate your patient’s cardiac risk

Long-acting beta-blockers=fewer MIs

A population-based, retrospective cohort analysis with 37,151 patients over 65 years of age compared perioperative beta-blocker therapy using atenolol (a long-acting beta-blocker) with metoprolol (a shorter-acting beta-blocker) for elective surgery.⁵ Investigators excluded patients with symptomatic coronary disease.

Patients taking atenolol had fewer MIs (1.6% vs 2.0%, P=.004) and fewer deaths (1.2% vs 1.6%, P=.007) when compared with metoprolol. Atenolol produced a 13% relative risk reduction over metoprolol for MI or death after adjusting for age, sex, type of surgery, and use of furosemide, calcium-channel blockers, angiotensin-converting enzyme inhibitors, and statins (comparative NNT=165).

Dose titration by heart rate

An observational cohort study with 272 patients undergoing elective major vascular surgery (mean age 67.4 years, 80% male) evaluated whether higher doses of beta-blockers and tight heart rate control reduced perioperative myocardial ischemia and troponin T release.⁶ Patients with higher beta-blocker doses, lower heart rates, and lower absolute change in heart rate during the perioperative period had significantly less perioperative myocardial ischemia and troponin T release (P<.0001).

The DECREASE-II trial, a prospective cohort study with 1476 patients undergoing elective open abdominal aortic or infrainguinal arterial reconstruction also found that patients with heart rates <65 beats per minute had a significantly lower risk of cardiac death or MI at 30 days postoperatively (1.3% vs 5.2%, OR=0.24; 95% CI, 0.09–0.66).⁷

Begin therapy 30 days before surgery

Authors of a systematic review including 5 RCTs (586 total patients) evaluating perioperative beta-blocker therapy in noncardiac surgery concluded that beta-blocker therapy should begin as long as 30 days prior to surgery to allow for titration of dose to the target heart rate and continue at least throughout hospitalization (longer if adequate medical follow-up can be arranged postoperatively).⁸

Recommendations from others

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines⁹ recommends:

• continuing beta-blockers for patients already receiving them to treat angina, symptomatic arrhythmias, and hypertension before their surgical risk evaluation.
• initiating perioperative beta-blocker therapy for patients undergoing vascular surgery if they are at high cardiac risk, as evidenced by ischemia on preoperative testing.
• considering perioperative beta-blocker therapy for patients undergoing intermediate-to high-risk procedures if preoperative risk assessment identifies them as having intermediate or higher cardiac risk, and for patients undergoing vascular surgery who are at low cardiac risk.

Evidence summary

Studies without risk stratification find little benefit from beta-blockers

A systematic review including 25 randomized controlled trials (RCTs) evaluated perioperative beta-blocker therapy for noncardiac surgery in a total of 2722 patients who were not stratified according to cardiac risk status.¹

Perioperative beta-blockers produced no significant effect on:

• all-cause mortality (odds ratio [OR]=0.78; 95% confidence interval [CI], 0.33–1.87),
• acute myocardial infarction (OR=0.59; 95% CI, 0.25–1.39),
• atrial fibrillation/flutter and other supraventricular arrhythmias (OR=0.43; 95% CI, 0.14–1.37), or
• length of hospital stay (weighted mean difference, –5.6 days; 95% CI, –12.2, 1.04).

However, in this review perioperative beta-blocker therapy reduced perioperative myocardial ischemia (OR=0.38; 95% CI, 0.21–0.69), and increased 2 adverse outcomes: hemodynamically significant bradycardia (OR=1.98; 95% CI, 1.08– 3.66) and hypotension requiring treatment (OR=2.52; 95% CI, 1.94–3.28).¹ This study was limited by the inconsistent definition and assessment of outcomes among the individual trials.

No effect on total mortality, but a benefit in a composite outcome. An earlier systematic review with 22 RCTs and 2437 total patients, that was also not stratified according to cardiac risk status, found no effect from perioperative beta-blockers on total mortality or cardiovascular mortality alone. However, it did demonstrate a composite outcome of reduced cardiovascular mortality, reduced nonfatal myocardial infarction, and reduced nonfatal cardiac arrest (relative risk [RR]=0.44; 95% CI, 0.20–0.97) 30 days after surgery.²

Beta-blockers benefit certain high-risk patients
A retrospective cohort study evaluated the effect of perioperative beta-blocker therapy on perioperative mortality, according to preoperative RCRI assessment.³ The study population included 663,635 adults (mean age, 62 years) undergoing major noncardiac surgery at 329 US hospitals. Researchers calculated individual RCRI scores (TABLE).⁴ Half the patients had an RCRI of 0, 38% had an RCRI of 1, 10% had an RCRI of 2, and only 2% had an RCRI of 3 or greater.

Be wary of beta-blockers in low-risk patients. In the 580,665 patients with low cardiac risk, perioperative beta-blocker therapy increased the risk of in-hospital death: for all patients with an RCRI of 0: OR=1.36 (95% CI, 1.27–1.45); number needed to harm (NNH)=208; for all patients with an RCRI of 1: OR=1.09 (95% CI, 1.01–1.19); NNH=504).

A different story for high-risk cardiac patients. Perioperative beta-blocker therapy reduced the risk of in-hospital death in patients with an RCRI of 2 (OR=0.88; 95% CI, 0.80–0.98; number needed to treat [NNT]=227), an RCRI of 3 (OR=0.71; 95% CI, 0.63–0.80; NNT=62), or an RCRI of 4 or more (OR=0.58; 95% CI, 0.50–0.67; NNT=33).

TABLE
Before surgery, calculate your patient’s cardiac risk

Long-acting beta-blockers=fewer MIs

A population-based, retrospective cohort analysis with 37,151 patients over 65 years of age compared perioperative beta-blocker therapy using atenolol (a long-acting beta-blocker) with metoprolol (a shorter-acting beta-blocker) for elective surgery.⁵ Investigators excluded patients with symptomatic coronary disease.

Patients taking atenolol had fewer MIs (1.6% vs 2.0%, P=.004) and fewer deaths (1.2% vs 1.6%, P=.007) when compared with metoprolol. Atenolol produced a 13% relative risk reduction over metoprolol for MI or death after adjusting for age, sex, type of surgery, and use of furosemide, calcium-channel blockers, angiotensin-converting enzyme inhibitors, and statins (comparative NNT=165).

Dose titration by heart rate

An observational cohort study with 272 patients undergoing elective major vascular surgery (mean age 67.4 years, 80% male) evaluated whether higher doses of beta-blockers and tight heart rate control reduced perioperative myocardial ischemia and troponin T release.⁶ Patients with higher beta-blocker doses, lower heart rates, and lower absolute change in heart rate during the perioperative period had significantly less perioperative myocardial ischemia and troponin T release (P<.0001).

The DECREASE-II trial, a prospective cohort study with 1476 patients undergoing elective open abdominal aortic or infrainguinal arterial reconstruction also found that patients with heart rates <65 beats per minute had a significantly lower risk of cardiac death or MI at 30 days postoperatively (1.3% vs 5.2%, OR=0.24; 95% CI, 0.09–0.66).⁷

Begin therapy 30 days before surgery

Authors of a systematic review including 5 RCTs (586 total patients) evaluating perioperative beta-blocker therapy in noncardiac surgery concluded that beta-blocker therapy should begin as long as 30 days prior to surgery to allow for titration of dose to the target heart rate and continue at least throughout hospitalization (longer if adequate medical follow-up can be arranged postoperatively).⁸

Recommendations from others

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines⁹ recommends:

• continuing beta-blockers for patients already receiving them to treat angina, symptomatic arrhythmias, and hypertension before their surgical risk evaluation.
• initiating perioperative beta-blocker therapy for patients undergoing vascular surgery if they are at high cardiac risk, as evidenced by ischemia on preoperative testing.
• considering perioperative beta-blocker therapy for patients undergoing intermediate-to high-risk procedures if preoperative risk assessment identifies them as having intermediate or higher cardiac risk, and for patients undergoing vascular surgery who are at low cardiac risk.

Evidence summary

Studies without risk stratification find little benefit from beta-blockers

A systematic review including 25 randomized controlled trials (RCTs) evaluated perioperative beta-blocker therapy for noncardiac surgery in a total of 2722 patients who were not stratified according to cardiac risk status.¹

Perioperative beta-blockers produced no significant effect on:

• all-cause mortality (odds ratio [OR]=0.78; 95% confidence interval [CI], 0.33–1.87),
• acute myocardial infarction (OR=0.59; 95% CI, 0.25–1.39),
• atrial fibrillation/flutter and other supraventricular arrhythmias (OR=0.43; 95% CI, 0.14–1.37), or
• length of hospital stay (weighted mean difference, –5.6 days; 95% CI, –12.2, 1.04).

However, in this review perioperative beta-blocker therapy reduced perioperative myocardial ischemia (OR=0.38; 95% CI, 0.21–0.69), and increased 2 adverse outcomes: hemodynamically significant bradycardia (OR=1.98; 95% CI, 1.08– 3.66) and hypotension requiring treatment (OR=2.52; 95% CI, 1.94–3.28).¹ This study was limited by the inconsistent definition and assessment of outcomes among the individual trials.

No effect on total mortality, but a benefit in a composite outcome. An earlier systematic review with 22 RCTs and 2437 total patients, that was also not stratified according to cardiac risk status, found no effect from perioperative beta-blockers on total mortality or cardiovascular mortality alone. However, it did demonstrate a composite outcome of reduced cardiovascular mortality, reduced nonfatal myocardial infarction, and reduced nonfatal cardiac arrest (relative risk [RR]=0.44; 95% CI, 0.20–0.97) 30 days after surgery.²

Beta-blockers benefit certain high-risk patients
A retrospective cohort study evaluated the effect of perioperative beta-blocker therapy on perioperative mortality, according to preoperative RCRI assessment.³ The study population included 663,635 adults (mean age, 62 years) undergoing major noncardiac surgery at 329 US hospitals. Researchers calculated individual RCRI scores (TABLE).⁴ Half the patients had an RCRI of 0, 38% had an RCRI of 1, 10% had an RCRI of 2, and only 2% had an RCRI of 3 or greater.

Be wary of beta-blockers in low-risk patients. In the 580,665 patients with low cardiac risk, perioperative beta-blocker therapy increased the risk of in-hospital death: for all patients with an RCRI of 0: OR=1.36 (95% CI, 1.27–1.45); number needed to harm (NNH)=208; for all patients with an RCRI of 1: OR=1.09 (95% CI, 1.01–1.19); NNH=504).

A different story for high-risk cardiac patients. Perioperative beta-blocker therapy reduced the risk of in-hospital death in patients with an RCRI of 2 (OR=0.88; 95% CI, 0.80–0.98; number needed to treat [NNT]=227), an RCRI of 3 (OR=0.71; 95% CI, 0.63–0.80; NNT=62), or an RCRI of 4 or more (OR=0.58; 95% CI, 0.50–0.67; NNT=33).

TABLE
Before surgery, calculate your patient’s cardiac risk

Long-acting beta-blockers=fewer MIs

A population-based, retrospective cohort analysis with 37,151 patients over 65 years of age compared perioperative beta-blocker therapy using atenolol (a long-acting beta-blocker) with metoprolol (a shorter-acting beta-blocker) for elective surgery.⁵ Investigators excluded patients with symptomatic coronary disease.

Patients taking atenolol had fewer MIs (1.6% vs 2.0%, P=.004) and fewer deaths (1.2% vs 1.6%, P=.007) when compared with metoprolol. Atenolol produced a 13% relative risk reduction over metoprolol for MI or death after adjusting for age, sex, type of surgery, and use of furosemide, calcium-channel blockers, angiotensin-converting enzyme inhibitors, and statins (comparative NNT=165).

Dose titration by heart rate

An observational cohort study with 272 patients undergoing elective major vascular surgery (mean age 67.4 years, 80% male) evaluated whether higher doses of beta-blockers and tight heart rate control reduced perioperative myocardial ischemia and troponin T release.⁶ Patients with higher beta-blocker doses, lower heart rates, and lower absolute change in heart rate during the perioperative period had significantly less perioperative myocardial ischemia and troponin T release (P<.0001).

The DECREASE-II trial, a prospective cohort study with 1476 patients undergoing elective open abdominal aortic or infrainguinal arterial reconstruction also found that patients with heart rates <65 beats per minute had a significantly lower risk of cardiac death or MI at 30 days postoperatively (1.3% vs 5.2%, OR=0.24; 95% CI, 0.09–0.66).⁷

Begin therapy 30 days before surgery

Authors of a systematic review including 5 RCTs (586 total patients) evaluating perioperative beta-blocker therapy in noncardiac surgery concluded that beta-blocker therapy should begin as long as 30 days prior to surgery to allow for titration of dose to the target heart rate and continue at least throughout hospitalization (longer if adequate medical follow-up can be arranged postoperatively).⁸

Recommendations from others

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines⁹ recommends:

• continuing beta-blockers for patients already receiving them to treat angina, symptomatic arrhythmias, and hypertension before their surgical risk evaluation.
• initiating perioperative beta-blocker therapy for patients undergoing vascular surgery if they are at high cardiac risk, as evidenced by ischemia on preoperative testing.
• considering perioperative beta-blocker therapy for patients undergoing intermediate-to high-risk procedures if preoperative risk assessment identifies them as having intermediate or higher cardiac risk, and for patients undergoing vascular surgery who are at low cardiac risk.

Evidence summary

A systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.¹ Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA_1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.

Three later RCTs of overweight patients with inadequate control on oral agents (HbA_1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA_1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).² The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).

In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA_1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).³ Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA_1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.⁴

An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).⁵ A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA_1c than those on insulin alone (treatment difference 0.39%, P=.007).

Overall, combination therapy and 2 oral medications reduced HbA_1c by the same amount, but combination therapy reduced HbA_1c more in a subpopulation of patients with HbA_1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.

An open-label RCT of 756 patients with inadequate glycemic control (HbA_1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.⁶ Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA_1c (mean HbA_1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰

Evidence summary

A systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.¹ Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA_1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.

Three later RCTs of overweight patients with inadequate control on oral agents (HbA_1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA_1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).² The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).

In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA_1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).³ Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA_1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.⁴

An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).⁵ A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA_1c than those on insulin alone (treatment difference 0.39%, P=.007).

Overall, combination therapy and 2 oral medications reduced HbA_1c by the same amount, but combination therapy reduced HbA_1c more in a subpopulation of patients with HbA_1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.

An open-label RCT of 756 patients with inadequate glycemic control (HbA_1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.⁶ Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA_1c (mean HbA_1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰

Evidence summary

A systematic review evaluated beginning combination therapy (adding insulin to oral medication) compared with switching to insulin alone in patients with type 2 diabetes mellitus with inadequate glycemic control on oral medication.¹ Twenty RCTs studied a total of 1811 patients; glycemic control was the primary outcome measure. Oral medication comprised either sulfonylureas (75%), metformin (4%), or both (21%). Individual studies used different insulin dosing schedules and statistical measures. However, overall, combination therapy provided glucose control comparable with insulin alone. In only 1 small, low-quality study did insulin plus metformin reduce HbA_1c more than other combination therapy regimens or insulin alone. Ten studies reported a trend toward less weight gain with combination therapy that included metformin. Fourteen studies found the same incidence of hypoglycemic episodes in combination therapy and insulin alone.

Three later RCTs of overweight patients with inadequate control on oral agents (HbA_1c >7% on a sulfonylurea, metformin, or both) also compared beginning combination therapy with switching to insulin alone (with 70/30 or NPH insulin twice daily). In one study with 64 patients followed for 12 months, HbA_1c fell by 0.14% less (nonsignificant) in the combination therapy group (bedtime NPH plus sulfonylurea and metformin) than in the insulin alone group (70/30 twice daily).² The combination therapy group gained significantly less weight than the insulin-alone group (1.3 kg vs 4.2 kg; P=.01).

In the second study of 261 patients, the combination therapy group (glimepiride [Amaryl] plus bedtime NPH) had a significantly higher HbA_1c after 9 months than 2 groups using insulin alone (twice daily 70/30, and twice daily NPH insulin) (8.9% vs 8.3% and 8.4%).³ Mean weight gain was similar in all 3 groups but only a minority of patients reached a target HbA_1c of 6.5%. In the final study of only 16 patients, HbA1c after 6 months improved significantly and equally in both groups (baseline: 8.3%, combination therapy final: 6.8%; insulin alone final: 7.0%). However, the combination therapy group gained significantly less weight.⁴

An open-label RCT with 341 patients who were inadequately controlled on metformin compared beginning combination therapy (biphasic insulin aspart 30/70 [Novolog Mix 70/30] and metformin) with switching to insulin alone (biphasic insulin aspart 30/70).⁵ A third group added a second oral medication (sulfonylurea and metformin). After 16 weeks, patients taking combination therapy had a significantly lower HbA_1c than those on insulin alone (treatment difference 0.39%, P=.007).

Overall, combination therapy and 2 oral medications reduced HbA_1c by the same amount, but combination therapy reduced HbA_1c more in a subpopulation of patients with HbA_1c >9.0% at baseline (treatment difference 0.46%, P=.027). The group on insulin alone weighed significantly more (4.6 kg, P<.001) at the end of the trial than the group taking 2 oral medications.

An open-label RCT of 756 patients with inadequate glycemic control (HbA_1c >7.5%, mean 8.6%) on either 1 or 2 oral agents (70% taking both metformin and a sulfonylurea) compared combination therapy using bedtime insulin glargine with combination therapy using morning NPH.⁶ Each group titrated insulin doses to achieve a target fasting glucose ≤100. By 24 weeks, both groups had equivalently reduced HbA_1c (mean HbA_1c=6.96% with glargine, and 6.97% with NPH; P=NS), but fewer patients experienced nocturnal hypoglycemia with glargine than with NPH (33.2% vs 26.7%, P<.05).

Another open-label RCT evaluated 281 patients with at least 3 months of inadequate glycemic control (HbA_1c=7.4%–14.7%) on a sulfonylurea.⁷ Patients were randomized to a) switching to a combination of biphasic insulin aspart 30/70 plus pioglitazone, b) adding pioglitazone to the sulfonylurea, or c) switching to insulin alone (biphasic insulin aspart 30/70). After 18 weeks, insulin plus pioglitazone reduced HbA_1c significantly more than either glyburide plus pioglitazone (P=.005) or insulin alone (P=.005). However, the insulin plus pioglitazone group had the most weight gain (mean 4 kg, similar to other pioglitazone trials). There were no major hypoglycemic events.

Another open-label RCT evaluated 217 patients inadequately controlled (HbA_1c=7.5%–11%) on a 2-drug oral regimen (metformin and a sulfonylurea, each drug dosed at ≥50% of the recommended maximum), randomized to add either insulin glargine or rosiglitazone (Avandia).⁸ Both groups reduced HbA_1c equivalently after 24 weeks (–1.7% for glargine vs –1.5% for rosiglitazone). However, in patients with a baseline HbA_1c >9.5%, adding insulin glargine reduced HbA_1c significantly more than rosiglitazone.

Recommendations from others

A comparative analysis of guidelines on diabetes from 13 different countries (including the US) found general agreement in the recommendation to add a second oral agent to maximum doses of an initial agent in patients with poor glycemic control.⁹ However, no consensus was reached on the value or indications of combination therapy with oral agents and insulin.

The European Diabetes Policy Group recommends adding a second oral agent when the maximum dose of a single agent is reached, and using triple therapy when targets are not reached on maximum tolerated doses of 2 agents. Continued therapy with oral agents is advised when initiating insulin.¹⁰

Evidence summary

No studies specifically examine the risk of adverse outcomes for women who have mild elevations in blood pressure as a result of taking OCs. However, for the general population cardiovascular risk increases 30% for each 10 mm Hg rise in systolic pressure.¹

A prospective cohort study found an increased incidence of new hypertension developing among women taking OCs. The study, conducted in the US, included 68,297 female nurses aged 25 to 42 years without a previous diagnosis of hypertension, diabetes, coronary heart disease, stroke, or cancer, who were followed for 4 years. Women were excluded from the study if they had not had a physical exam in the last 2 years or were taking antihypertensive medication at study inception. The nurses self-reported their blood pressure readings via questionnaire; medical records were sampled to validate the accuracy of self-reports. After adjusting for risk factors, current oral contraceptive use increased the risk of developing hypertension (relative risk [RR]=1.8; 95% confidence interval [CI], 1.5–2.3; corresponding to 41.5 new cases of hypertension per 10,000 person-years).²

A systematic review of 8 case control studies (with 4907 cases and 13,443 controls) found an increased risk of stroke and MI among hypertensive women taking combined type OCs vs those not taking OCs. Women with hypertension aged 20 to 24 years had an estimated CV event risk of 312 per million woman-years while taking OCs vs 134 per million woman-years not taking OCs. Among hypertensive women aged 40 to 44 years, the estimated risks were 1213 vs 529 per million woman-years, respectively. Primary endpoints varied across the studies and statistical significance was not given.³

Three studies showed that blood pressure elevations due to taking oral contraceptives returned to baseline with discontinuation of the medication. A prospective cohort study followed 13,358 women who were neither pregnant nor postpartum between the ages of 15 and 60. Women who either initiated or resumed using OCs experienced a statistically significant rise of about 4 mm Hg in the systolic pressure and 1 mm Hg in the diastolic pressure. Women who stopped using OCs experienced significant decreases in both systolic and diastolic components (about 5 mm Hg and 1.5 mm Hg, respectively).¹

Similarly, a survey study of 461 women attending family planning clinics found that mean blood pressures were significantly higher for those taking OCs than for those using nonhormonal contraception. Elevated blood pressures correlated with duration of current use of OCs but returned to normal soon after stopping OCs. The mean pressures of those who had stopped OCs more than a month were similar to those of women who had never taken an OC and significantly lower than those of women who were currently taking OCs.⁴

Finally, a prospective study which followed 32 women who had taken combined OCs for 1 to 3 years and then stopped found that blood pressures returned to pretreatment levels at 3 months. Systolic pressure fell by 9.7 mm Hg and diastolic by 2.9 mm Hg compared with measurements made 1 month before stopping. No cardiovascular complications were reported among women during this study.⁵

Recommendations from others

The American College of Obstetricians and Gynecologists says that women with well-controlled and monitored hypertension aged 35 years and younger are appropriate candidates for a trial of combination OCs, provided they are otherwise healthy, have no evidence of end-organ vascular disease, and do not smoke cigarettes.⁶ If blood pressure remains well controlled with careful monitoring several months after initiating OCs, use can be continued.

Evidence summary

No studies specifically examine the risk of adverse outcomes for women who have mild elevations in blood pressure as a result of taking OCs. However, for the general population cardiovascular risk increases 30% for each 10 mm Hg rise in systolic pressure.¹

A prospective cohort study found an increased incidence of new hypertension developing among women taking OCs. The study, conducted in the US, included 68,297 female nurses aged 25 to 42 years without a previous diagnosis of hypertension, diabetes, coronary heart disease, stroke, or cancer, who were followed for 4 years. Women were excluded from the study if they had not had a physical exam in the last 2 years or were taking antihypertensive medication at study inception. The nurses self-reported their blood pressure readings via questionnaire; medical records were sampled to validate the accuracy of self-reports. After adjusting for risk factors, current oral contraceptive use increased the risk of developing hypertension (relative risk [RR]=1.8; 95% confidence interval [CI], 1.5–2.3; corresponding to 41.5 new cases of hypertension per 10,000 person-years).²

A systematic review of 8 case control studies (with 4907 cases and 13,443 controls) found an increased risk of stroke and MI among hypertensive women taking combined type OCs vs those not taking OCs. Women with hypertension aged 20 to 24 years had an estimated CV event risk of 312 per million woman-years while taking OCs vs 134 per million woman-years not taking OCs. Among hypertensive women aged 40 to 44 years, the estimated risks were 1213 vs 529 per million woman-years, respectively. Primary endpoints varied across the studies and statistical significance was not given.³

Three studies showed that blood pressure elevations due to taking oral contraceptives returned to baseline with discontinuation of the medication. A prospective cohort study followed 13,358 women who were neither pregnant nor postpartum between the ages of 15 and 60. Women who either initiated or resumed using OCs experienced a statistically significant rise of about 4 mm Hg in the systolic pressure and 1 mm Hg in the diastolic pressure. Women who stopped using OCs experienced significant decreases in both systolic and diastolic components (about 5 mm Hg and 1.5 mm Hg, respectively).¹

Similarly, a survey study of 461 women attending family planning clinics found that mean blood pressures were significantly higher for those taking OCs than for those using nonhormonal contraception. Elevated blood pressures correlated with duration of current use of OCs but returned to normal soon after stopping OCs. The mean pressures of those who had stopped OCs more than a month were similar to those of women who had never taken an OC and significantly lower than those of women who were currently taking OCs.⁴

Finally, a prospective study which followed 32 women who had taken combined OCs for 1 to 3 years and then stopped found that blood pressures returned to pretreatment levels at 3 months. Systolic pressure fell by 9.7 mm Hg and diastolic by 2.9 mm Hg compared with measurements made 1 month before stopping. No cardiovascular complications were reported among women during this study.⁵

Recommendations from others

The American College of Obstetricians and Gynecologists says that women with well-controlled and monitored hypertension aged 35 years and younger are appropriate candidates for a trial of combination OCs, provided they are otherwise healthy, have no evidence of end-organ vascular disease, and do not smoke cigarettes.⁶ If blood pressure remains well controlled with careful monitoring several months after initiating OCs, use can be continued.

Evidence summary

No studies specifically examine the risk of adverse outcomes for women who have mild elevations in blood pressure as a result of taking OCs. However, for the general population cardiovascular risk increases 30% for each 10 mm Hg rise in systolic pressure.¹

A prospective cohort study found an increased incidence of new hypertension developing among women taking OCs. The study, conducted in the US, included 68,297 female nurses aged 25 to 42 years without a previous diagnosis of hypertension, diabetes, coronary heart disease, stroke, or cancer, who were followed for 4 years. Women were excluded from the study if they had not had a physical exam in the last 2 years or were taking antihypertensive medication at study inception. The nurses self-reported their blood pressure readings via questionnaire; medical records were sampled to validate the accuracy of self-reports. After adjusting for risk factors, current oral contraceptive use increased the risk of developing hypertension (relative risk [RR]=1.8; 95% confidence interval [CI], 1.5–2.3; corresponding to 41.5 new cases of hypertension per 10,000 person-years).²

A systematic review of 8 case control studies (with 4907 cases and 13,443 controls) found an increased risk of stroke and MI among hypertensive women taking combined type OCs vs those not taking OCs. Women with hypertension aged 20 to 24 years had an estimated CV event risk of 312 per million woman-years while taking OCs vs 134 per million woman-years not taking OCs. Among hypertensive women aged 40 to 44 years, the estimated risks were 1213 vs 529 per million woman-years, respectively. Primary endpoints varied across the studies and statistical significance was not given.³

Three studies showed that blood pressure elevations due to taking oral contraceptives returned to baseline with discontinuation of the medication. A prospective cohort study followed 13,358 women who were neither pregnant nor postpartum between the ages of 15 and 60. Women who either initiated or resumed using OCs experienced a statistically significant rise of about 4 mm Hg in the systolic pressure and 1 mm Hg in the diastolic pressure. Women who stopped using OCs experienced significant decreases in both systolic and diastolic components (about 5 mm Hg and 1.5 mm Hg, respectively).¹

Similarly, a survey study of 461 women attending family planning clinics found that mean blood pressures were significantly higher for those taking OCs than for those using nonhormonal contraception. Elevated blood pressures correlated with duration of current use of OCs but returned to normal soon after stopping OCs. The mean pressures of those who had stopped OCs more than a month were similar to those of women who had never taken an OC and significantly lower than those of women who were currently taking OCs.⁴

Finally, a prospective study which followed 32 women who had taken combined OCs for 1 to 3 years and then stopped found that blood pressures returned to pretreatment levels at 3 months. Systolic pressure fell by 9.7 mm Hg and diastolic by 2.9 mm Hg compared with measurements made 1 month before stopping. No cardiovascular complications were reported among women during this study.⁵

Recommendations from others

The American College of Obstetricians and Gynecologists says that women with well-controlled and monitored hypertension aged 35 years and younger are appropriate candidates for a trial of combination OCs, provided they are otherwise healthy, have no evidence of end-organ vascular disease, and do not smoke cigarettes.⁶ If blood pressure remains well controlled with careful monitoring several months after initiating OCs, use can be continued.

Evidence summary

No studies specifically evaluate effective treatments for ODD (distinguished by chronic argumentativeness and refusal to comply with adult requests) for adolescent patients. However, there are treatment studies of younger children with ODD and studies of adolescents with the more disruptive behavior problem of conduct disorder (distinguished by a persistent pattern of violating other’s rights, aggression, and illegal acts).

A Clinical Inquiry summarized 8 well-done systematic reviews of ODD treatments of preadolescent children and found improved behavior with parenting interventions and behavioral therapy.¹ Each of the systematic reviews assessed multiple randomized controlled trials (RCTs) using a variety of parenting and behavioral therapy interventions. The most rigorous systematic review (which included 16 RCTs), compared group-based parenting skills training with untreated wait-list controls and found decreased aggression, noncompliance, and temper tantrums by children aged 3 to 10 years (total number of subjects not given) by an average effect size of 0.6 to 2.9. (Effect size is the difference between the means of the experimental and control groups expressed in standard deviations. An effect size of 0.2 is considered small, 0.5 is medium, and 0.8 is moderate to large.) Behavioral therapy (cognitive-behavioral therapy, social problem-solving skills training, parent management training), comprising 12 to 25 sessions with either the child alone or with teachers or parents, decreased disruptive or aggressive behaviors by 20% to 30%.

A 2-year case-control study² of 158 self-referred families with young adolescents (11 to 14 years old) without a formal ODD diagnosis but with reported problem behaviors (defined as smoking, negative engagement in family problem solving, and parental ratings of unpleasant events) found significant improvements (P<.01) with parent-only, teen-only, and parent-teen behavioral interventions for negative engagement behaviors (average of 30% reduction in scores), and with parent and teen interventions for unpleasant events (average of 9% reduction in scores). Interventions comprised 12 weekly 90-minute sessions, with the parent-only group targeting family management practices and communication skills, the teen-only group targeting adolescent self-regulation and pro-social behavior, and the parent-teen group following a structured curriculum.

A meta-analysis³ of 8 RCTs (with a total of 749 children) of various behavioral treatments for conduct disorder and juvenile delinquency among children aged 10 to 17 years found significant reductions in rearrest rates (relative risk [RR]=0.66; 95% confidence interval [CI], 0.44–0.98; number needed to treat [NNT] to prevent 1 rearrest=3.7) and time spent in institutions (mean difference, 51 days) with family and parenting interventions (comprising 1 to 6 months of individual and group parenting training, short and long-term family therapy, and individual and group adolescent interventions).

ODD comorbid with other psychiatric conditions

Approximately half to two-thirds of adolescents with ODD also have ADHD.⁴ A meta-analysis⁵ evaluated 28 studies of stimulant medication (methylphenidate, amphetamine, or pemoline) for children with comorbid ADHD and ODD. A total of 683 patients aged 8 to 18 years were included. Stimulants reduced aggression-related behaviors in these children by an effect size of 0.84 for overt aggression and 0.69 for covert aggression. Stimulants typically reduce aggressive behaviors by similar effect sizes when prescribed for children with ADD alone. The study groups did not separate children with ADHD and ODD from those with ADHD and conduct disorder; they also grouped adolescents together with younger children.

An RCT⁶ of different doses of atomoxetine (Strattera) treatment vs placebo for children ages 8 to 18 (mean age=11) with ADHD alone (N=178) and children with both ADHD and ODD (N=115) found significant effect sizes for atomoxetine in both groups. Two dosages of atomoxetine (1.2 and 1.8 mg/kg/d) produced equivalent effect sizes in the ADHD-only group (0.55 and 0.56); however, the higher dosage had a greater effect size (0.49 vs 0.69) in the group with ODD comorbid with ADHD.

A double-blind crossover RCT⁷ evaluated divalproex (Depakote) vs placebo for 20 children (aged 10 to 18 years) with explosive temper and mood lability who also met DSM-IV criteria for either ODD or conduct disorder. Patients with significant medical problems, such as bipolar disorder, major depression, or mental retardation, were excluded. Divalproex significantly (P=.003) reduced aggressive behaviors and anger-hostility items by approximately 33% as reported by child, parent, school, and clinician on 2 standardized scales.

Experts say antidepressant medications may be helpful in treating children with conduct disorder and comorbid major depression.⁸

Recommendations by others

An international consensus statement on ADHD and disruptive behavior disorders (comprising ODD, conduct disorder, and disruptive behavior not otherwise specified) says that psychopharmacologic treatment would not be appropriate for cases of ODD in the absence of psychiatric comorbidity, unless severe aggression or destructive behavior persisted despite attempts at psychosocial interventions of established efficacy.⁴

Evidence summary

No studies specifically evaluate effective treatments for ODD (distinguished by chronic argumentativeness and refusal to comply with adult requests) for adolescent patients. However, there are treatment studies of younger children with ODD and studies of adolescents with the more disruptive behavior problem of conduct disorder (distinguished by a persistent pattern of violating other’s rights, aggression, and illegal acts).

A Clinical Inquiry summarized 8 well-done systematic reviews of ODD treatments of preadolescent children and found improved behavior with parenting interventions and behavioral therapy.¹ Each of the systematic reviews assessed multiple randomized controlled trials (RCTs) using a variety of parenting and behavioral therapy interventions. The most rigorous systematic review (which included 16 RCTs), compared group-based parenting skills training with untreated wait-list controls and found decreased aggression, noncompliance, and temper tantrums by children aged 3 to 10 years (total number of subjects not given) by an average effect size of 0.6 to 2.9. (Effect size is the difference between the means of the experimental and control groups expressed in standard deviations. An effect size of 0.2 is considered small, 0.5 is medium, and 0.8 is moderate to large.) Behavioral therapy (cognitive-behavioral therapy, social problem-solving skills training, parent management training), comprising 12 to 25 sessions with either the child alone or with teachers or parents, decreased disruptive or aggressive behaviors by 20% to 30%.

A 2-year case-control study² of 158 self-referred families with young adolescents (11 to 14 years old) without a formal ODD diagnosis but with reported problem behaviors (defined as smoking, negative engagement in family problem solving, and parental ratings of unpleasant events) found significant improvements (P<.01) with parent-only, teen-only, and parent-teen behavioral interventions for negative engagement behaviors (average of 30% reduction in scores), and with parent and teen interventions for unpleasant events (average of 9% reduction in scores). Interventions comprised 12 weekly 90-minute sessions, with the parent-only group targeting family management practices and communication skills, the teen-only group targeting adolescent self-regulation and pro-social behavior, and the parent-teen group following a structured curriculum.

A meta-analysis³ of 8 RCTs (with a total of 749 children) of various behavioral treatments for conduct disorder and juvenile delinquency among children aged 10 to 17 years found significant reductions in rearrest rates (relative risk [RR]=0.66; 95% confidence interval [CI], 0.44–0.98; number needed to treat [NNT] to prevent 1 rearrest=3.7) and time spent in institutions (mean difference, 51 days) with family and parenting interventions (comprising 1 to 6 months of individual and group parenting training, short and long-term family therapy, and individual and group adolescent interventions).

ODD comorbid with other psychiatric conditions

Approximately half to two-thirds of adolescents with ODD also have ADHD.⁴ A meta-analysis⁵ evaluated 28 studies of stimulant medication (methylphenidate, amphetamine, or pemoline) for children with comorbid ADHD and ODD. A total of 683 patients aged 8 to 18 years were included. Stimulants reduced aggression-related behaviors in these children by an effect size of 0.84 for overt aggression and 0.69 for covert aggression. Stimulants typically reduce aggressive behaviors by similar effect sizes when prescribed for children with ADD alone. The study groups did not separate children with ADHD and ODD from those with ADHD and conduct disorder; they also grouped adolescents together with younger children.

An RCT⁶ of different doses of atomoxetine (Strattera) treatment vs placebo for children ages 8 to 18 (mean age=11) with ADHD alone (N=178) and children with both ADHD and ODD (N=115) found significant effect sizes for atomoxetine in both groups. Two dosages of atomoxetine (1.2 and 1.8 mg/kg/d) produced equivalent effect sizes in the ADHD-only group (0.55 and 0.56); however, the higher dosage had a greater effect size (0.49 vs 0.69) in the group with ODD comorbid with ADHD.

A double-blind crossover RCT⁷ evaluated divalproex (Depakote) vs placebo for 20 children (aged 10 to 18 years) with explosive temper and mood lability who also met DSM-IV criteria for either ODD or conduct disorder. Patients with significant medical problems, such as bipolar disorder, major depression, or mental retardation, were excluded. Divalproex significantly (P=.003) reduced aggressive behaviors and anger-hostility items by approximately 33% as reported by child, parent, school, and clinician on 2 standardized scales.

Experts say antidepressant medications may be helpful in treating children with conduct disorder and comorbid major depression.⁸

Recommendations by others

An international consensus statement on ADHD and disruptive behavior disorders (comprising ODD, conduct disorder, and disruptive behavior not otherwise specified) says that psychopharmacologic treatment would not be appropriate for cases of ODD in the absence of psychiatric comorbidity, unless severe aggression or destructive behavior persisted despite attempts at psychosocial interventions of established efficacy.⁴

Evidence summary

No studies specifically evaluate effective treatments for ODD (distinguished by chronic argumentativeness and refusal to comply with adult requests) for adolescent patients. However, there are treatment studies of younger children with ODD and studies of adolescents with the more disruptive behavior problem of conduct disorder (distinguished by a persistent pattern of violating other’s rights, aggression, and illegal acts).

A Clinical Inquiry summarized 8 well-done systematic reviews of ODD treatments of preadolescent children and found improved behavior with parenting interventions and behavioral therapy.¹ Each of the systematic reviews assessed multiple randomized controlled trials (RCTs) using a variety of parenting and behavioral therapy interventions. The most rigorous systematic review (which included 16 RCTs), compared group-based parenting skills training with untreated wait-list controls and found decreased aggression, noncompliance, and temper tantrums by children aged 3 to 10 years (total number of subjects not given) by an average effect size of 0.6 to 2.9. (Effect size is the difference between the means of the experimental and control groups expressed in standard deviations. An effect size of 0.2 is considered small, 0.5 is medium, and 0.8 is moderate to large.) Behavioral therapy (cognitive-behavioral therapy, social problem-solving skills training, parent management training), comprising 12 to 25 sessions with either the child alone or with teachers or parents, decreased disruptive or aggressive behaviors by 20% to 30%.

A 2-year case-control study² of 158 self-referred families with young adolescents (11 to 14 years old) without a formal ODD diagnosis but with reported problem behaviors (defined as smoking, negative engagement in family problem solving, and parental ratings of unpleasant events) found significant improvements (P<.01) with parent-only, teen-only, and parent-teen behavioral interventions for negative engagement behaviors (average of 30% reduction in scores), and with parent and teen interventions for unpleasant events (average of 9% reduction in scores). Interventions comprised 12 weekly 90-minute sessions, with the parent-only group targeting family management practices and communication skills, the teen-only group targeting adolescent self-regulation and pro-social behavior, and the parent-teen group following a structured curriculum.

A meta-analysis³ of 8 RCTs (with a total of 749 children) of various behavioral treatments for conduct disorder and juvenile delinquency among children aged 10 to 17 years found significant reductions in rearrest rates (relative risk [RR]=0.66; 95% confidence interval [CI], 0.44–0.98; number needed to treat [NNT] to prevent 1 rearrest=3.7) and time spent in institutions (mean difference, 51 days) with family and parenting interventions (comprising 1 to 6 months of individual and group parenting training, short and long-term family therapy, and individual and group adolescent interventions).

ODD comorbid with other psychiatric conditions

Approximately half to two-thirds of adolescents with ODD also have ADHD.⁴ A meta-analysis⁵ evaluated 28 studies of stimulant medication (methylphenidate, amphetamine, or pemoline) for children with comorbid ADHD and ODD. A total of 683 patients aged 8 to 18 years were included. Stimulants reduced aggression-related behaviors in these children by an effect size of 0.84 for overt aggression and 0.69 for covert aggression. Stimulants typically reduce aggressive behaviors by similar effect sizes when prescribed for children with ADD alone. The study groups did not separate children with ADHD and ODD from those with ADHD and conduct disorder; they also grouped adolescents together with younger children.

An RCT⁶ of different doses of atomoxetine (Strattera) treatment vs placebo for children ages 8 to 18 (mean age=11) with ADHD alone (N=178) and children with both ADHD and ODD (N=115) found significant effect sizes for atomoxetine in both groups. Two dosages of atomoxetine (1.2 and 1.8 mg/kg/d) produced equivalent effect sizes in the ADHD-only group (0.55 and 0.56); however, the higher dosage had a greater effect size (0.49 vs 0.69) in the group with ODD comorbid with ADHD.

A double-blind crossover RCT⁷ evaluated divalproex (Depakote) vs placebo for 20 children (aged 10 to 18 years) with explosive temper and mood lability who also met DSM-IV criteria for either ODD or conduct disorder. Patients with significant medical problems, such as bipolar disorder, major depression, or mental retardation, were excluded. Divalproex significantly (P=.003) reduced aggressive behaviors and anger-hostility items by approximately 33% as reported by child, parent, school, and clinician on 2 standardized scales.

Experts say antidepressant medications may be helpful in treating children with conduct disorder and comorbid major depression.⁸

Recommendations by others

An international consensus statement on ADHD and disruptive behavior disorders (comprising ODD, conduct disorder, and disruptive behavior not otherwise specified) says that psychopharmacologic treatment would not be appropriate for cases of ODD in the absence of psychiatric comorbidity, unless severe aggression or destructive behavior persisted despite attempts at psychosocial interventions of established efficacy.⁴

Evidence summary

A prospective cohort study¹ evaluated dobutamine or dipyridamole pharmacologic stress echocardiography among 904 primary care patients with either typical or atypical chest pain. Patients were enrolled into the study if they had normal resting wall motion, sinus rhythm, and had no history of coronary artery disease, unstable angina, or PTCA. Patients (average age 61 years, 42% men) were followed for an average of 44 months for primary cardiovascular endpoints (fatal or nonfatal myocardial infarction [MI], unstable angina, PTCA, or cardiac death). A negative or positive stress echocardiography is defined as the absence or presence of abnormal cardiac wall motion on either exercise or pharmacologic stress echocardiography. Eighteen percent of patients had a positive pharmacologic stress echocardiography. Over the length of the study, 81 of 904 patients (9%) suffered a cardiovascular event. Patients with a negative pharmacologic stress echocardiography had a mean annual probability of a cardiovascular event of 0.8% vs 8.5% with a positive pharmacologic stress echocardiography (P<0001). The 4-year infarct-free negative predictive value (NPV) of pharmacologic stress echocardiography was 97%, and the positive predictive value (PPV) was 70%.

A similar prospective cohort study² evaluated 105 patients (50% men) with atypical chest pain in an emergency department setting with either exercise or dobutamine/atropine stress echocardiography. The average patient age was 55 years and follow-up was 2.8 years. Patients were clinically stable, had normal or nondiagnostic electrocardiogram (ECG), normal cardiac enzymes, normal left ventricular function, and no history of coronary artery disease or unstable angina. Cardiovascular endpoints included fatal or nonfatal MI, unstable angina, PTCA, or cardiac death. A total of 7 patients (7%) suffered a cardiovascular event during the follow-up period. Positive stress echocardiography results occurred for 9% of patients. The NPV was 99% and the PPV was 75%.

Three other cohort studies^3-5 evaluated exercise or dobutamine/atropine stress echocardiography for a total of 615 patients (48%–67% men, average age 56–58 years) presenting to an emergency department with classical cardiac or atypical chest pain. Patients had normal or nondiagnostic ECG, negative cardiac enzymes, and either no history of coronary artery disease^3,4 or known coronary artery disease of unknown significance.⁵ A positive stress echocardiography was obtained for 4.8% to 42% of patients in the cohorts. During 6 months of follow-up, cardiovascular events occurred in 4 of 145 patients (3%),³ 22 of 227 patients (6%),⁴ and in 11 of 80 patients (14%).⁵ At 6-month follow-up, exercise stress echocardiography had a NPV of 99.3% and a PPV of 43%.³ Dobutamine/atropine stress echocardiography had a NPV of 95% to 96% and a PPV of 25% to 31%.^4,5

One retrospective review⁶ evaluated exercise and dobutamine/atropine stress echocardiography and stress ECG for 661 low-risk outpatients (48% men, average age 58 years) with atypical chest pain. All patients had normal left ventricular function and no history of coronary artery disease and were followed for an average of 23 months. A positive stress echocardiography test occurred among 16% of the patient population.

During follow-up, 41 of 661 patients (6%) suffered a cardiovascular event. For either exercise or dobutamine/atropine stress echocardiography, the NPV was 99% at 12 months and 96% at 30 months. Patients with a positive stress echocardiography test and a negative stress ECG had a 66% event-free survival rate. Event-free survival rate for patients with a negative stress echocardiography and a positive or negative stress ECG was 97% and 96%, respectively.

Recommendations from others

The American College of Cardiology⁷ gives a Class I recommendation (tests for which there is evidence or general agreement that a given procedure or treatment is useful and effective) for standard echocardiogram for evaluation of chest pain for patients with suspected acute myocardial ischemia (when baseline ECG and other laboratory markers are nondiagnostic and when the study can be obtained during pain or within minutes after its abatement).

It gives a Class IIa recommendation (tests for which there is conflicting evidence or divergence of opinion, but favoring usefulness) to stress echocardiography for the detection of myocardial ischemia for women with an intermediate pretest likelihood of coronary artery disease. It also gives a Class IIa recommendation to stress echocardiography for determining the prognosis of myocardial ischemia among patients for whom ECG assessment is less reliable. This group comprises patients with the following ECG abnormalities: pre-excitation syndrome (such as Wolff-Parkinson-White), electronically paced ventricular rhythm, more than 1 mm of ST depression at rest, and complete left bundle branch block.

Evidence summary

A prospective cohort study¹ evaluated dobutamine or dipyridamole pharmacologic stress echocardiography among 904 primary care patients with either typical or atypical chest pain. Patients were enrolled into the study if they had normal resting wall motion, sinus rhythm, and had no history of coronary artery disease, unstable angina, or PTCA. Patients (average age 61 years, 42% men) were followed for an average of 44 months for primary cardiovascular endpoints (fatal or nonfatal myocardial infarction [MI], unstable angina, PTCA, or cardiac death). A negative or positive stress echocardiography is defined as the absence or presence of abnormal cardiac wall motion on either exercise or pharmacologic stress echocardiography. Eighteen percent of patients had a positive pharmacologic stress echocardiography. Over the length of the study, 81 of 904 patients (9%) suffered a cardiovascular event. Patients with a negative pharmacologic stress echocardiography had a mean annual probability of a cardiovascular event of 0.8% vs 8.5% with a positive pharmacologic stress echocardiography (P<0001). The 4-year infarct-free negative predictive value (NPV) of pharmacologic stress echocardiography was 97%, and the positive predictive value (PPV) was 70%.

A similar prospective cohort study² evaluated 105 patients (50% men) with atypical chest pain in an emergency department setting with either exercise or dobutamine/atropine stress echocardiography. The average patient age was 55 years and follow-up was 2.8 years. Patients were clinically stable, had normal or nondiagnostic electrocardiogram (ECG), normal cardiac enzymes, normal left ventricular function, and no history of coronary artery disease or unstable angina. Cardiovascular endpoints included fatal or nonfatal MI, unstable angina, PTCA, or cardiac death. A total of 7 patients (7%) suffered a cardiovascular event during the follow-up period. Positive stress echocardiography results occurred for 9% of patients. The NPV was 99% and the PPV was 75%.

Three other cohort studies^3-5 evaluated exercise or dobutamine/atropine stress echocardiography for a total of 615 patients (48%–67% men, average age 56–58 years) presenting to an emergency department with classical cardiac or atypical chest pain. Patients had normal or nondiagnostic ECG, negative cardiac enzymes, and either no history of coronary artery disease^3,4 or known coronary artery disease of unknown significance.⁵ A positive stress echocardiography was obtained for 4.8% to 42% of patients in the cohorts. During 6 months of follow-up, cardiovascular events occurred in 4 of 145 patients (3%),³ 22 of 227 patients (6%),⁴ and in 11 of 80 patients (14%).⁵ At 6-month follow-up, exercise stress echocardiography had a NPV of 99.3% and a PPV of 43%.³ Dobutamine/atropine stress echocardiography had a NPV of 95% to 96% and a PPV of 25% to 31%.^4,5

One retrospective review⁶ evaluated exercise and dobutamine/atropine stress echocardiography and stress ECG for 661 low-risk outpatients (48% men, average age 58 years) with atypical chest pain. All patients had normal left ventricular function and no history of coronary artery disease and were followed for an average of 23 months. A positive stress echocardiography test occurred among 16% of the patient population.

During follow-up, 41 of 661 patients (6%) suffered a cardiovascular event. For either exercise or dobutamine/atropine stress echocardiography, the NPV was 99% at 12 months and 96% at 30 months. Patients with a positive stress echocardiography test and a negative stress ECG had a 66% event-free survival rate. Event-free survival rate for patients with a negative stress echocardiography and a positive or negative stress ECG was 97% and 96%, respectively.

Recommendations from others

The American College of Cardiology⁷ gives a Class I recommendation (tests for which there is evidence or general agreement that a given procedure or treatment is useful and effective) for standard echocardiogram for evaluation of chest pain for patients with suspected acute myocardial ischemia (when baseline ECG and other laboratory markers are nondiagnostic and when the study can be obtained during pain or within minutes after its abatement).

It gives a Class IIa recommendation (tests for which there is conflicting evidence or divergence of opinion, but favoring usefulness) to stress echocardiography for the detection of myocardial ischemia for women with an intermediate pretest likelihood of coronary artery disease. It also gives a Class IIa recommendation to stress echocardiography for determining the prognosis of myocardial ischemia among patients for whom ECG assessment is less reliable. This group comprises patients with the following ECG abnormalities: pre-excitation syndrome (such as Wolff-Parkinson-White), electronically paced ventricular rhythm, more than 1 mm of ST depression at rest, and complete left bundle branch block.

Evidence summary

A prospective cohort study¹ evaluated dobutamine or dipyridamole pharmacologic stress echocardiography among 904 primary care patients with either typical or atypical chest pain. Patients were enrolled into the study if they had normal resting wall motion, sinus rhythm, and had no history of coronary artery disease, unstable angina, or PTCA. Patients (average age 61 years, 42% men) were followed for an average of 44 months for primary cardiovascular endpoints (fatal or nonfatal myocardial infarction [MI], unstable angina, PTCA, or cardiac death). A negative or positive stress echocardiography is defined as the absence or presence of abnormal cardiac wall motion on either exercise or pharmacologic stress echocardiography. Eighteen percent of patients had a positive pharmacologic stress echocardiography. Over the length of the study, 81 of 904 patients (9%) suffered a cardiovascular event. Patients with a negative pharmacologic stress echocardiography had a mean annual probability of a cardiovascular event of 0.8% vs 8.5% with a positive pharmacologic stress echocardiography (P<0001). The 4-year infarct-free negative predictive value (NPV) of pharmacologic stress echocardiography was 97%, and the positive predictive value (PPV) was 70%.

A similar prospective cohort study² evaluated 105 patients (50% men) with atypical chest pain in an emergency department setting with either exercise or dobutamine/atropine stress echocardiography. The average patient age was 55 years and follow-up was 2.8 years. Patients were clinically stable, had normal or nondiagnostic electrocardiogram (ECG), normal cardiac enzymes, normal left ventricular function, and no history of coronary artery disease or unstable angina. Cardiovascular endpoints included fatal or nonfatal MI, unstable angina, PTCA, or cardiac death. A total of 7 patients (7%) suffered a cardiovascular event during the follow-up period. Positive stress echocardiography results occurred for 9% of patients. The NPV was 99% and the PPV was 75%.

Three other cohort studies^3-5 evaluated exercise or dobutamine/atropine stress echocardiography for a total of 615 patients (48%–67% men, average age 56–58 years) presenting to an emergency department with classical cardiac or atypical chest pain. Patients had normal or nondiagnostic ECG, negative cardiac enzymes, and either no history of coronary artery disease^3,4 or known coronary artery disease of unknown significance.⁵ A positive stress echocardiography was obtained for 4.8% to 42% of patients in the cohorts. During 6 months of follow-up, cardiovascular events occurred in 4 of 145 patients (3%),³ 22 of 227 patients (6%),⁴ and in 11 of 80 patients (14%).⁵ At 6-month follow-up, exercise stress echocardiography had a NPV of 99.3% and a PPV of 43%.³ Dobutamine/atropine stress echocardiography had a NPV of 95% to 96% and a PPV of 25% to 31%.^4,5

One retrospective review⁶ evaluated exercise and dobutamine/atropine stress echocardiography and stress ECG for 661 low-risk outpatients (48% men, average age 58 years) with atypical chest pain. All patients had normal left ventricular function and no history of coronary artery disease and were followed for an average of 23 months. A positive stress echocardiography test occurred among 16% of the patient population.

During follow-up, 41 of 661 patients (6%) suffered a cardiovascular event. For either exercise or dobutamine/atropine stress echocardiography, the NPV was 99% at 12 months and 96% at 30 months. Patients with a positive stress echocardiography test and a negative stress ECG had a 66% event-free survival rate. Event-free survival rate for patients with a negative stress echocardiography and a positive or negative stress ECG was 97% and 96%, respectively.

Recommendations from others

The American College of Cardiology⁷ gives a Class I recommendation (tests for which there is evidence or general agreement that a given procedure or treatment is useful and effective) for standard echocardiogram for evaluation of chest pain for patients with suspected acute myocardial ischemia (when baseline ECG and other laboratory markers are nondiagnostic and when the study can be obtained during pain or within minutes after its abatement).

It gives a Class IIa recommendation (tests for which there is conflicting evidence or divergence of opinion, but favoring usefulness) to stress echocardiography for the detection of myocardial ischemia for women with an intermediate pretest likelihood of coronary artery disease. It also gives a Class IIa recommendation to stress echocardiography for determining the prognosis of myocardial ischemia among patients for whom ECG assessment is less reliable. This group comprises patients with the following ECG abnormalities: pre-excitation syndrome (such as Wolff-Parkinson-White), electronically paced ventricular rhythm, more than 1 mm of ST depression at rest, and complete left bundle branch block.

Evidence summary

Three large cohort studies determined that cryptorchidism (FIGURE) is present at birth in approximately 3% of term infants (higher in preterm infants), with spontaneous descent occurring in two thirds of cases by age 3 to 6 months. One study¹ of 10,730 consecutive male term infants found cryptorchidism at birth in 2.7%, dropping to 1.22% by 6 months of age, but without further change at 1 year. A similar study² followed 6935 infant boys, finding cryptorchidism at birth in 3.7%, which decreased to 1% at 3 months and remained unchanged at 1 year. A third study³ found cryptorchidism at birth in 90 of 6414 (2.7%) infant boys. At follow-up, 45 of 90 had testicular descent at 1 month, 60 of 90 at 3 months, 67 of 90 at 9 months and at 1 year.

The 2 main indications for orchiopexy are potential avoidance of infertility and early detection and treatment of testicular cancer. A literature review⁴ of fertility after orchiopexy for undescended testis found inconclusive results. While epidemiological and pathological data (testicular biopsy, hormonal analysis, and sperm counts performed after orchiopexy) predict diminished fertility potential for men with unilaterally undescended testes, studies evaluating paternity find no difference from normal men. Biopsy studies of undescended testes at the time of orchiopexy show increased incidence of germ cell aplasia with older age at surgery (0.5%, 2%, 20%, and 45% at 6, 12, 24, and 48 months, respectively).⁴ A retrospective cohort study⁵ found 87% successful paternity after orchiopexy for 24 patients with unilateral undescended testis and 33% success for 9 with bilateral undescended testes but there was no normal control group. The boys were aged 1 to 14 years (mean, 7 years) at surgery, and there was no relationship between timing of orchiopexy and paternity success.⁵

The benefits of orchiopexy for testicular cancer are also unclear; expert opinion suggests that orchiopexy may allow earlier detection of testicular tumors.⁶ A cohort study⁷ of boys with cryptorchidism showed an increased risk of testicular cancer (relative risk=5.2). However, risk did not decrease after orchiopexy in early childhood. A retrospective cohort study⁸ of 137 men with cryptorchidism who developed testicular cancer found no difference in 5-year survival between those who had orchiopexy (at ages 2 to 42) and those who had not (61% vs 63%, respectively).

FIGURE
Cryptorchidism

Recommendations from others

The American Academy of Pediatrics policy section on urology says that spontaneous descent after 6 months is unlikely and recommends orchiopexy by 1 year of age.⁹

Evidence summary

Three large cohort studies determined that cryptorchidism (FIGURE) is present at birth in approximately 3% of term infants (higher in preterm infants), with spontaneous descent occurring in two thirds of cases by age 3 to 6 months. One study¹ of 10,730 consecutive male term infants found cryptorchidism at birth in 2.7%, dropping to 1.22% by 6 months of age, but without further change at 1 year. A similar study² followed 6935 infant boys, finding cryptorchidism at birth in 3.7%, which decreased to 1% at 3 months and remained unchanged at 1 year. A third study³ found cryptorchidism at birth in 90 of 6414 (2.7%) infant boys. At follow-up, 45 of 90 had testicular descent at 1 month, 60 of 90 at 3 months, 67 of 90 at 9 months and at 1 year.

The 2 main indications for orchiopexy are potential avoidance of infertility and early detection and treatment of testicular cancer. A literature review⁴ of fertility after orchiopexy for undescended testis found inconclusive results. While epidemiological and pathological data (testicular biopsy, hormonal analysis, and sperm counts performed after orchiopexy) predict diminished fertility potential for men with unilaterally undescended testes, studies evaluating paternity find no difference from normal men. Biopsy studies of undescended testes at the time of orchiopexy show increased incidence of germ cell aplasia with older age at surgery (0.5%, 2%, 20%, and 45% at 6, 12, 24, and 48 months, respectively).⁴ A retrospective cohort study⁵ found 87% successful paternity after orchiopexy for 24 patients with unilateral undescended testis and 33% success for 9 with bilateral undescended testes but there was no normal control group. The boys were aged 1 to 14 years (mean, 7 years) at surgery, and there was no relationship between timing of orchiopexy and paternity success.⁵

The benefits of orchiopexy for testicular cancer are also unclear; expert opinion suggests that orchiopexy may allow earlier detection of testicular tumors.⁶ A cohort study⁷ of boys with cryptorchidism showed an increased risk of testicular cancer (relative risk=5.2). However, risk did not decrease after orchiopexy in early childhood. A retrospective cohort study⁸ of 137 men with cryptorchidism who developed testicular cancer found no difference in 5-year survival between those who had orchiopexy (at ages 2 to 42) and those who had not (61% vs 63%, respectively).

FIGURE
Cryptorchidism

Recommendations from others

The American Academy of Pediatrics policy section on urology says that spontaneous descent after 6 months is unlikely and recommends orchiopexy by 1 year of age.⁹

Evidence summary

Three large cohort studies determined that cryptorchidism (FIGURE) is present at birth in approximately 3% of term infants (higher in preterm infants), with spontaneous descent occurring in two thirds of cases by age 3 to 6 months. One study¹ of 10,730 consecutive male term infants found cryptorchidism at birth in 2.7%, dropping to 1.22% by 6 months of age, but without further change at 1 year. A similar study² followed 6935 infant boys, finding cryptorchidism at birth in 3.7%, which decreased to 1% at 3 months and remained unchanged at 1 year. A third study³ found cryptorchidism at birth in 90 of 6414 (2.7%) infant boys. At follow-up, 45 of 90 had testicular descent at 1 month, 60 of 90 at 3 months, 67 of 90 at 9 months and at 1 year.

The 2 main indications for orchiopexy are potential avoidance of infertility and early detection and treatment of testicular cancer. A literature review⁴ of fertility after orchiopexy for undescended testis found inconclusive results. While epidemiological and pathological data (testicular biopsy, hormonal analysis, and sperm counts performed after orchiopexy) predict diminished fertility potential for men with unilaterally undescended testes, studies evaluating paternity find no difference from normal men. Biopsy studies of undescended testes at the time of orchiopexy show increased incidence of germ cell aplasia with older age at surgery (0.5%, 2%, 20%, and 45% at 6, 12, 24, and 48 months, respectively).⁴ A retrospective cohort study⁵ found 87% successful paternity after orchiopexy for 24 patients with unilateral undescended testis and 33% success for 9 with bilateral undescended testes but there was no normal control group. The boys were aged 1 to 14 years (mean, 7 years) at surgery, and there was no relationship between timing of orchiopexy and paternity success.⁵

The benefits of orchiopexy for testicular cancer are also unclear; expert opinion suggests that orchiopexy may allow earlier detection of testicular tumors.⁶ A cohort study⁷ of boys with cryptorchidism showed an increased risk of testicular cancer (relative risk=5.2). However, risk did not decrease after orchiopexy in early childhood. A retrospective cohort study⁸ of 137 men with cryptorchidism who developed testicular cancer found no difference in 5-year survival between those who had orchiopexy (at ages 2 to 42) and those who had not (61% vs 63%, respectively).

FIGURE
Cryptorchidism

Recommendations from others

The American Academy of Pediatrics policy section on urology says that spontaneous descent after 6 months is unlikely and recommends orchiopexy by 1 year of age.⁹

Evidence summary

Progesterone. A Cochrane meta-analysis on the use of progesterone to prevent pregnancy loss looked at a subset of 3 small RCTs that evaluated women with 3 or more pregnancy losses. Patients with primary recurrent spontaneous abortion (RSA) (no prior live births), were not differentiated from those with secondary RSA (previous live birth with subsequent miscarriages).

Progesterone administration resulted in a significant reduction in miscarriage compared with placebo (odds ratio [OR]=0.37; 95% confidence interval [CI], 0.17–0.91), independent of administration routes (oral, vaginal, or intramuscular). This benefit was lost in the larger meta-analysis when studies containing women with fewer than 3 pregnancy losses were included.¹

Human choriogonadotropin. A meta-analysis reviewed 4 trials (n=180 total) of varying methodological quality, which were constructed to determine if women, with at least 2 consecutive miscarriages of unknown cause, derive any protective effect when they receive HCG during the first trimester. Although the overall outcome favored the use of HCG (OR=0.26 compared with placebo; 95% CI, 0.14–0.52), the trials contained major methodological weaknesses (poor description of methods, no power calculations, selection and unclear randomization techniques).²

Immunotherapy. A systematic review of 22 RCTs evaluating 4 different types of immunotherapy for recurrent miscarriage found no significant improvement in live birth rates. All studies were of high quality with a low level of bias. Only one lacked double-blinding.

Immunotherapy types included: paternal leukocyte immunization (PLI) (11 trials, 596 women) (OR=1.05; 95% CI, 0.75–1.47); intravenous immune globulin (IVIG) (OR=0.98; 95% CI, 0.61–1.58); third-party donor cell immunization (3 trials, 156 women) (OR=1.39; 95% CI, 0.68–2.82); and trophoblast membrane infusion (1 trial, 37 women) (OR=0.40; 95% CI, 0.11–1.45).³

A subsequent RCT comparing PLI with placebo among 79 women with primary RSA of unknown cause again found no significant difference in live birth rates (89% vs 71%, respectively).⁴ However, an additional RCT evaluating PLI (32 patients) vs placebo (19 patients) among women with unexplained primary RSA did find significantly higher birth rates with PLI (84% vs 25%; P=.001). This small study used different techniques than previous PLI studies.⁵

A later meta-analysis of 5 RCTs including a total of 246 patients also found that IVIG did not improve the subsequent live birth rate for women with a history of primary or secondary RSA (OR=0.98; 95% CI, 0.45–2.13).⁶

Aspirin. An RCT involving 54 pregnant women (mean age 32.7 years) with a history of primary RSA of unknown cause (negative standard workup) evaluated 50 mg of aspirin daily (n=27) vs placebo (n=27).⁷ The method of blinding was not reported.

The live birth rate was identical for the 2 groups (88%). A second (unblinded) trial randomized 805 women from a large referral center (mean age 34 years) with a history of first-trimester RSA (not differentiated between primary and secondary RSA) of unknown cause to either 75 mg of aspirin daily or no treatment.⁸ There was no significant difference in the live birth rate between those who took aspirin (251/367; 68.4%) and those who did not (278/438; 63.5%; OR=1.24; 95% CI, 0.93–1.67).

Recommendations from others

The American College of Obstetricians and Gynecologists (ACOG) states that “it has not been shown conclusively that progesterone treatment or corpus luteum support (HCG) influences pregnancy outcome for women with recurrent spontaneous abortion.”⁹ ACOG does not recommend immunotherapy, citing a lack of demonstrated efficacy (IVIG and PLI), a lack of standards for cell storage and administration, and a risk profile similar to that of blood transfusion (PLI). They recommend “couples with otherwise unexplained recurrent pregnancy loss should be counseled regarding the potential for successful pregnancy without treatment.”

Evidence summary

Progesterone. A Cochrane meta-analysis on the use of progesterone to prevent pregnancy loss looked at a subset of 3 small RCTs that evaluated women with 3 or more pregnancy losses. Patients with primary recurrent spontaneous abortion (RSA) (no prior live births), were not differentiated from those with secondary RSA (previous live birth with subsequent miscarriages).

Progesterone administration resulted in a significant reduction in miscarriage compared with placebo (odds ratio [OR]=0.37; 95% confidence interval [CI], 0.17–0.91), independent of administration routes (oral, vaginal, or intramuscular). This benefit was lost in the larger meta-analysis when studies containing women with fewer than 3 pregnancy losses were included.¹

Human choriogonadotropin. A meta-analysis reviewed 4 trials (n=180 total) of varying methodological quality, which were constructed to determine if women, with at least 2 consecutive miscarriages of unknown cause, derive any protective effect when they receive HCG during the first trimester. Although the overall outcome favored the use of HCG (OR=0.26 compared with placebo; 95% CI, 0.14–0.52), the trials contained major methodological weaknesses (poor description of methods, no power calculations, selection and unclear randomization techniques).²

Immunotherapy. A systematic review of 22 RCTs evaluating 4 different types of immunotherapy for recurrent miscarriage found no significant improvement in live birth rates. All studies were of high quality with a low level of bias. Only one lacked double-blinding.

Immunotherapy types included: paternal leukocyte immunization (PLI) (11 trials, 596 women) (OR=1.05; 95% CI, 0.75–1.47); intravenous immune globulin (IVIG) (OR=0.98; 95% CI, 0.61–1.58); third-party donor cell immunization (3 trials, 156 women) (OR=1.39; 95% CI, 0.68–2.82); and trophoblast membrane infusion (1 trial, 37 women) (OR=0.40; 95% CI, 0.11–1.45).³

A subsequent RCT comparing PLI with placebo among 79 women with primary RSA of unknown cause again found no significant difference in live birth rates (89% vs 71%, respectively).⁴ However, an additional RCT evaluating PLI (32 patients) vs placebo (19 patients) among women with unexplained primary RSA did find significantly higher birth rates with PLI (84% vs 25%; P=.001). This small study used different techniques than previous PLI studies.⁵

A later meta-analysis of 5 RCTs including a total of 246 patients also found that IVIG did not improve the subsequent live birth rate for women with a history of primary or secondary RSA (OR=0.98; 95% CI, 0.45–2.13).⁶

Aspirin. An RCT involving 54 pregnant women (mean age 32.7 years) with a history of primary RSA of unknown cause (negative standard workup) evaluated 50 mg of aspirin daily (n=27) vs placebo (n=27).⁷ The method of blinding was not reported.

The live birth rate was identical for the 2 groups (88%). A second (unblinded) trial randomized 805 women from a large referral center (mean age 34 years) with a history of first-trimester RSA (not differentiated between primary and secondary RSA) of unknown cause to either 75 mg of aspirin daily or no treatment.⁸ There was no significant difference in the live birth rate between those who took aspirin (251/367; 68.4%) and those who did not (278/438; 63.5%; OR=1.24; 95% CI, 0.93–1.67).

Recommendations from others

The American College of Obstetricians and Gynecologists (ACOG) states that “it has not been shown conclusively that progesterone treatment or corpus luteum support (HCG) influences pregnancy outcome for women with recurrent spontaneous abortion.”⁹ ACOG does not recommend immunotherapy, citing a lack of demonstrated efficacy (IVIG and PLI), a lack of standards for cell storage and administration, and a risk profile similar to that of blood transfusion (PLI). They recommend “couples with otherwise unexplained recurrent pregnancy loss should be counseled regarding the potential for successful pregnancy without treatment.”

Evidence summary

Progesterone. A Cochrane meta-analysis on the use of progesterone to prevent pregnancy loss looked at a subset of 3 small RCTs that evaluated women with 3 or more pregnancy losses. Patients with primary recurrent spontaneous abortion (RSA) (no prior live births), were not differentiated from those with secondary RSA (previous live birth with subsequent miscarriages).

Progesterone administration resulted in a significant reduction in miscarriage compared with placebo (odds ratio [OR]=0.37; 95% confidence interval [CI], 0.17–0.91), independent of administration routes (oral, vaginal, or intramuscular). This benefit was lost in the larger meta-analysis when studies containing women with fewer than 3 pregnancy losses were included.¹

Human choriogonadotropin. A meta-analysis reviewed 4 trials (n=180 total) of varying methodological quality, which were constructed to determine if women, with at least 2 consecutive miscarriages of unknown cause, derive any protective effect when they receive HCG during the first trimester. Although the overall outcome favored the use of HCG (OR=0.26 compared with placebo; 95% CI, 0.14–0.52), the trials contained major methodological weaknesses (poor description of methods, no power calculations, selection and unclear randomization techniques).²

Immunotherapy. A systematic review of 22 RCTs evaluating 4 different types of immunotherapy for recurrent miscarriage found no significant improvement in live birth rates. All studies were of high quality with a low level of bias. Only one lacked double-blinding.

Immunotherapy types included: paternal leukocyte immunization (PLI) (11 trials, 596 women) (OR=1.05; 95% CI, 0.75–1.47); intravenous immune globulin (IVIG) (OR=0.98; 95% CI, 0.61–1.58); third-party donor cell immunization (3 trials, 156 women) (OR=1.39; 95% CI, 0.68–2.82); and trophoblast membrane infusion (1 trial, 37 women) (OR=0.40; 95% CI, 0.11–1.45).³

A subsequent RCT comparing PLI with placebo among 79 women with primary RSA of unknown cause again found no significant difference in live birth rates (89% vs 71%, respectively).⁴ However, an additional RCT evaluating PLI (32 patients) vs placebo (19 patients) among women with unexplained primary RSA did find significantly higher birth rates with PLI (84% vs 25%; P=.001). This small study used different techniques than previous PLI studies.⁵

A later meta-analysis of 5 RCTs including a total of 246 patients also found that IVIG did not improve the subsequent live birth rate for women with a history of primary or secondary RSA (OR=0.98; 95% CI, 0.45–2.13).⁶

Aspirin. An RCT involving 54 pregnant women (mean age 32.7 years) with a history of primary RSA of unknown cause (negative standard workup) evaluated 50 mg of aspirin daily (n=27) vs placebo (n=27).⁷ The method of blinding was not reported.

The live birth rate was identical for the 2 groups (88%). A second (unblinded) trial randomized 805 women from a large referral center (mean age 34 years) with a history of first-trimester RSA (not differentiated between primary and secondary RSA) of unknown cause to either 75 mg of aspirin daily or no treatment.⁸ There was no significant difference in the live birth rate between those who took aspirin (251/367; 68.4%) and those who did not (278/438; 63.5%; OR=1.24; 95% CI, 0.93–1.67).

Recommendations from others

The American College of Obstetricians and Gynecologists (ACOG) states that “it has not been shown conclusively that progesterone treatment or corpus luteum support (HCG) influences pregnancy outcome for women with recurrent spontaneous abortion.”⁹ ACOG does not recommend immunotherapy, citing a lack of demonstrated efficacy (IVIG and PLI), a lack of standards for cell storage and administration, and a risk profile similar to that of blood transfusion (PLI). They recommend “couples with otherwise unexplained recurrent pregnancy loss should be counseled regarding the potential for successful pregnancy without treatment.”

Evidence summary

A systematic review of 18 studies, including 3 RCTs, compared outcomes for expectant management (545 women) vs surgical evacuation (1408 women) for first-trimester spontaneous abortion.¹ A successful first-trimester spontaneous abortion was defined as vaginal bleeding for 3 weeks or less, fully expelled products of conception by 14 days, and no complications (infection, transfusion, uterine perforation, hospitalization, or death). Expectant management was successful in 93% overall, and 80% using only the data from RCTs.

An observational study evaluated 1096 consecutive patients with suspected first-trimester abortion, classified by ultrasound as complete, incomplete, missed, or anembryonic.² In the latter 3 categories, patients chose expectant management (478) or immediate surgical evacuation (208). Those choosing expectant management were monitored weekly and offered surgical evacuation if their abortion was incomplete after 1 month (TABLE). Complications arose in 6 of 451 patients (1%) managed expectantly for up to 46 days, and in 5 of 208 patients (2%) managed surgically (not statistically significant). One patient in the expectant group had emergency surgery and blood transfusion.²

A smaller observational study evaluated 108 women with first-trimester missed abortions or anembryonic pregnancies who chose either expectant (85 women) or surgical management. They were followed with weekly ultrasound (including color Doppler imaging) and serum β-hCG for up to 1 month. Fifty-three (62%) completed a spontaneous abortion at 14 days and 71 (84%) at 28 days. There were no significant differences in the rate of complications.³

A prospective trial compared psychological morbidity for 86 women with ultrasound-confirmed first-trimester missed abortions, randomized to expectant or surgical management. At 2 weeks, a self-administered questionnaire about the experience of pregnancy loss found no significant difference in psychological reactions. No increase was seen in anxiety or depression symptoms between women who had miscarried and healthy nonpregnant working women aged 19 to 39 years.⁴

Expert opinion recommends that women with spontaneous abortion beyond 13 weeks, a temperature >100.4° F, unstable blood pressure, uncontrolled vaginal bleeding, or evidence of endometritis or pelvic inflammatory disease should have surgical evacuation.²

TABLE
Completed abortions with expectant management by type²

Recommendations from others

UpToDate recommends expectant management for stable women who do not want any medical or surgical intervention, and are willing to wait for expulsion to occur. Surgical evacuation is recommended for women who are not stable because of bleeding or infection or for those who want immediate, definitive treatment of the nonviable pregnancy.⁵

Evidence summary

A systematic review of 18 studies, including 3 RCTs, compared outcomes for expectant management (545 women) vs surgical evacuation (1408 women) for first-trimester spontaneous abortion.¹ A successful first-trimester spontaneous abortion was defined as vaginal bleeding for 3 weeks or less, fully expelled products of conception by 14 days, and no complications (infection, transfusion, uterine perforation, hospitalization, or death). Expectant management was successful in 93% overall, and 80% using only the data from RCTs.

An observational study evaluated 1096 consecutive patients with suspected first-trimester abortion, classified by ultrasound as complete, incomplete, missed, or anembryonic.² In the latter 3 categories, patients chose expectant management (478) or immediate surgical evacuation (208). Those choosing expectant management were monitored weekly and offered surgical evacuation if their abortion was incomplete after 1 month (TABLE). Complications arose in 6 of 451 patients (1%) managed expectantly for up to 46 days, and in 5 of 208 patients (2%) managed surgically (not statistically significant). One patient in the expectant group had emergency surgery and blood transfusion.²

A smaller observational study evaluated 108 women with first-trimester missed abortions or anembryonic pregnancies who chose either expectant (85 women) or surgical management. They were followed with weekly ultrasound (including color Doppler imaging) and serum β-hCG for up to 1 month. Fifty-three (62%) completed a spontaneous abortion at 14 days and 71 (84%) at 28 days. There were no significant differences in the rate of complications.³

A prospective trial compared psychological morbidity for 86 women with ultrasound-confirmed first-trimester missed abortions, randomized to expectant or surgical management. At 2 weeks, a self-administered questionnaire about the experience of pregnancy loss found no significant difference in psychological reactions. No increase was seen in anxiety or depression symptoms between women who had miscarried and healthy nonpregnant working women aged 19 to 39 years.⁴

Expert opinion recommends that women with spontaneous abortion beyond 13 weeks, a temperature >100.4° F, unstable blood pressure, uncontrolled vaginal bleeding, or evidence of endometritis or pelvic inflammatory disease should have surgical evacuation.²

TABLE
Completed abortions with expectant management by type²

Recommendations from others

UpToDate recommends expectant management for stable women who do not want any medical or surgical intervention, and are willing to wait for expulsion to occur. Surgical evacuation is recommended for women who are not stable because of bleeding or infection or for those who want immediate, definitive treatment of the nonviable pregnancy.⁵

Evidence summary

A systematic review of 18 studies, including 3 RCTs, compared outcomes for expectant management (545 women) vs surgical evacuation (1408 women) for first-trimester spontaneous abortion.¹ A successful first-trimester spontaneous abortion was defined as vaginal bleeding for 3 weeks or less, fully expelled products of conception by 14 days, and no complications (infection, transfusion, uterine perforation, hospitalization, or death). Expectant management was successful in 93% overall, and 80% using only the data from RCTs.

An observational study evaluated 1096 consecutive patients with suspected first-trimester abortion, classified by ultrasound as complete, incomplete, missed, or anembryonic.² In the latter 3 categories, patients chose expectant management (478) or immediate surgical evacuation (208). Those choosing expectant management were monitored weekly and offered surgical evacuation if their abortion was incomplete after 1 month (TABLE). Complications arose in 6 of 451 patients (1%) managed expectantly for up to 46 days, and in 5 of 208 patients (2%) managed surgically (not statistically significant). One patient in the expectant group had emergency surgery and blood transfusion.²

A smaller observational study evaluated 108 women with first-trimester missed abortions or anembryonic pregnancies who chose either expectant (85 women) or surgical management. They were followed with weekly ultrasound (including color Doppler imaging) and serum β-hCG for up to 1 month. Fifty-three (62%) completed a spontaneous abortion at 14 days and 71 (84%) at 28 days. There were no significant differences in the rate of complications.³

A prospective trial compared psychological morbidity for 86 women with ultrasound-confirmed first-trimester missed abortions, randomized to expectant or surgical management. At 2 weeks, a self-administered questionnaire about the experience of pregnancy loss found no significant difference in psychological reactions. No increase was seen in anxiety or depression symptoms between women who had miscarried and healthy nonpregnant working women aged 19 to 39 years.⁴

Expert opinion recommends that women with spontaneous abortion beyond 13 weeks, a temperature >100.4° F, unstable blood pressure, uncontrolled vaginal bleeding, or evidence of endometritis or pelvic inflammatory disease should have surgical evacuation.²

TABLE
Completed abortions with expectant management by type²

Recommendations from others

UpToDate recommends expectant management for stable women who do not want any medical or surgical intervention, and are willing to wait for expulsion to occur. Surgical evacuation is recommended for women who are not stable because of bleeding or infection or for those who want immediate, definitive treatment of the nonviable pregnancy.⁵

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

There are currently no large outcome studies evaluating the initial work-up of hypertension; however, 4 international expert panels have published recommendations.^2-5 These panels advise 3 initial objectives: 1) assess lifestyle and identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment; 2) search for treatable causes of high blood pressure; and 3) assess for the presence of target organ damage that would change the management of the patient (such as chronic kidney disease or heart disease).

In addition to a thorough history and physical, the following studies are recommended for patients with newly diagnosed hypertension:

Serum potassium and creatinine. All 4 panels recommend measuring serum potassium and creatinine in order to: 1) monitor the effects of diuretics and angiotensin-converting enzyme (ACE) inhibitors used in hypertension therapy, 2) screen for unexplained hypokalemia that may indicate a low-renin form of hypertension, 3) calculate baseline creatinine clearance, and 4) screen for chronic kidney disease.

Fasting blood glucose. All 4 panels recommend measuring a fasting glucose level to screen for diabetes. An abnormal glucose level may also reveal glucose intolerance, one of the diagnostic criteria of metabolic syndrome. Up to 60% of patients with diabetes also have hypertension.⁶

Fasting lipid panel. All 4 expert panels recommend screening for dyslipidemia with a fasting lipid panel to assess cardiovascular risk. A cohort study evaluating 356,222 men aged 35 to 57 years found a continuous, positive, graded correlation between plasma cholesterol levels and coronary risk.⁷

Hematocrit. All 4 panels recommend a hematocrit to screen for anemia, which may be due to chronic kidney disease.

Urinalysis. All 4 panels recommend a urinalysis to screen for renal disease.

Electrocardiogram (ECG). All 4 panels recommend an ECG to screen for findings associated with hypertension, including left ventricular hypertrophy (LVH), myocardial infarction, and rhythm abnormalities. A cohort study followed 2363 patients for 14 years who had untreated hypertension and were without pre-existing cardiovascular disease. After controlling for age, sex, diabetes, and mean blood pressure, LVH by ECG conferred a significant increased risk for cerebrovascular events (relative risk=1.79; 95% confidence interval [CI], 1.17–2.76).⁸ However, in a cohort of 4684 subjects from the Framingham Heart Study, ECG had a sensitivity of only 6.9% for the detection of LVH (specificity 98.8%; positive likelihood ratio=5.3; negative likelihood ratio=0.94).⁸

Echocardiography. Two panels^3,4 and an online text¹⁰ recommend echocardiography, preferably limited echo, as an optional study. A systematic review of studies comparing the sensitivities and specificities of ECG and echo found that each was highly specific for the detection of LVH (77%–97%), but the sensitivity of echocardiography (88%–93%) exceeded that of ECG (21%–54%). However, LVH detected by ECG is a better predictor of cardiovascular complications.¹¹ Because echocardiography may help assess disease duration and guide management, both panels recommend it for patients with severe or refractory hypertension but without other target organ damage.

Microalbuminuria. All panels listed microalbuminuria testing as an optional study for patients without diabetes because of its association with an increased incidence of cerebrovascular disease.¹² It is unclear whether microalbuminuria results from the increased intraglomerular pressure in hypertension or if it represents glomerular damage.¹³

Sodium, calcium, uric acid. There is no consensus on the routine inclusion of several studies: serum sodium (recommended by 2 panels and an online text^4,5,10 ), serum calcium (recommended by 1 panel and the text^2,10), and uric acid (1 panel³ recommends it while the text¹⁰ lists it as optional).

Recommendations from others

Recommendations from major organizations are included in Evidence Summary, above.

Acknowledgments

The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.