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Focus on Contraception: Continuous OC use to eliminate cyclic bleeding
Objective
To compare the bleeding profile of a traditional 28-day oral contraceptive (OC) cycle with continuous administration.
Methods and Results
Seventynine women were randomized to a 28-day regimen (21 active pills and a pill-free week) or continuous use of the same low-dose formulation (20 μg ethinyl estradiol/100 μg levonorgestrel) for 12 cycles. Women recorded the number of bleeding and spotting days, and a subset underwent pelvic ultrasound and endometrial biopsy in cycles 1 and 9.
During the first 3 cycles, 68% of continuous users experienced amenorrhea or infrequent bleeding; that rate increased to 88% during the last 3 cycles. Continuous users initially experienced a slight increase in spotting during cycle days 1 through 21, but it diminished over time and ultimately was less than that reported by cyclic users.
Who may be affected by these findings?
Women of reproductive age who wish to reduce monthly bleeding.
Expert commentary
The notion that menstruation must occur each month in healthy, nonpregnant women using contraception is increasingly being questioned. One of the main factors contributing to this perception has been the packaging and labeling of OCs to induce monthly withdrawal bleeding.
Endometrium does not ‘build up.’ Monthly menstruation is not critical to OCs’ mechanism of action. Nor does OC-induced amenorrhea lead to harmful “build-up” of the endometrium. Rather, extended OC use results in a thin, atrophic endometrium that is protective against hyperplasia and endometrial cancer.
Continuous use is well tolerated. This study showed continuous use to be well tolerated, with a low drop-out rate and little anxiety about pregnancy. Data also suggested a small improvement in compliance.
Comparable efficacy. Contraceptive efficacy with continuous OC use was comparable to a cyclic regimen. (In some cases, continuous use may even be superior, since follicular development can occur during the pill-free week.) As for safety, continuous users who underwent ultrasound and endometrial biopsy had no abnormal findings. Although long-term safety was not completely addressed in this study—as the authors acknowledge—the cumulative estrogen exposure with a daily 20-μg ethinyl estradiol OC over 1 year is less than that of a cyclic 30-μg formulation.
Other benefits. Many other health benefits occur with extended OC regimens. Besides its convenience, medically induced amenorrhea has been used successfully to treat dysmenorrhea, menorrhagia (particularly in women with anemia or bleeding diatheses), endometriosis-related pain, and menstruation-related headaches. In addition, some special populations, such as female athletes, find amenorrhea particularly beneficial.1
What do women want? A number of studies suggest they don’t necessarily want to menstruate monthly. For example, a Dutch survey found that 65% of women aged 25 to 34 preferred bleeding every 3 months or less and 31% favored no bleeding at all.2 Another trial allowed participants to choose their own OC regimen; the median duration of continuous OC use was 9 weeks (maximum 104 weeks), and the median pill-free interval was 5 days.3
Advising patients. In offering my patients the option of extended OC use, I previously recommended scheduled withdrawal bleeds at 3- to 6-month intervals to avoid spotting. With this new evidence, however, I can offer patients even longer periods of amenorrhea. Moreover, a new 91-day extended OC formulation (Seasonale; Barr Laboratories, Pomona, NY) is under development and should be approved later this year.4
Bottom line
Continuous use of a low-dose monophasic OC preparation for 1 year resulted in fewer bleeding days without a significant increase in overall spotting, compared with cyclic use of the same preparation. We can use this evidence to counsel patients about the benefits of continuous OC use and help them achieve menstrual “nirvana.”5
1. Bennell K, White S, Crossley K. The oral contraceptive pill: a revolution for sportswomen? Br J Sports Med. 1999;33:231-238.
2. den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement use. Contraception. 1999;59:357-362.
3. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
4. Anderson FD. The safety and efficacy of Seasonale, a novel 91-day extended oral contraceptive regimen. Obstet Gynecol. 2002;99(suppl):26S.-
5. Edelman A. Menstrual nirvana: amenorrhea through the use of continuous oral contraceptives. Curr Women’s Health Rep. 2002;2:434-438.
Objective
To compare the bleeding profile of a traditional 28-day oral contraceptive (OC) cycle with continuous administration.
Methods and Results
Seventynine women were randomized to a 28-day regimen (21 active pills and a pill-free week) or continuous use of the same low-dose formulation (20 μg ethinyl estradiol/100 μg levonorgestrel) for 12 cycles. Women recorded the number of bleeding and spotting days, and a subset underwent pelvic ultrasound and endometrial biopsy in cycles 1 and 9.
During the first 3 cycles, 68% of continuous users experienced amenorrhea or infrequent bleeding; that rate increased to 88% during the last 3 cycles. Continuous users initially experienced a slight increase in spotting during cycle days 1 through 21, but it diminished over time and ultimately was less than that reported by cyclic users.
Who may be affected by these findings?
Women of reproductive age who wish to reduce monthly bleeding.
Expert commentary
The notion that menstruation must occur each month in healthy, nonpregnant women using contraception is increasingly being questioned. One of the main factors contributing to this perception has been the packaging and labeling of OCs to induce monthly withdrawal bleeding.
Endometrium does not ‘build up.’ Monthly menstruation is not critical to OCs’ mechanism of action. Nor does OC-induced amenorrhea lead to harmful “build-up” of the endometrium. Rather, extended OC use results in a thin, atrophic endometrium that is protective against hyperplasia and endometrial cancer.
Continuous use is well tolerated. This study showed continuous use to be well tolerated, with a low drop-out rate and little anxiety about pregnancy. Data also suggested a small improvement in compliance.
Comparable efficacy. Contraceptive efficacy with continuous OC use was comparable to a cyclic regimen. (In some cases, continuous use may even be superior, since follicular development can occur during the pill-free week.) As for safety, continuous users who underwent ultrasound and endometrial biopsy had no abnormal findings. Although long-term safety was not completely addressed in this study—as the authors acknowledge—the cumulative estrogen exposure with a daily 20-μg ethinyl estradiol OC over 1 year is less than that of a cyclic 30-μg formulation.
Other benefits. Many other health benefits occur with extended OC regimens. Besides its convenience, medically induced amenorrhea has been used successfully to treat dysmenorrhea, menorrhagia (particularly in women with anemia or bleeding diatheses), endometriosis-related pain, and menstruation-related headaches. In addition, some special populations, such as female athletes, find amenorrhea particularly beneficial.1
What do women want? A number of studies suggest they don’t necessarily want to menstruate monthly. For example, a Dutch survey found that 65% of women aged 25 to 34 preferred bleeding every 3 months or less and 31% favored no bleeding at all.2 Another trial allowed participants to choose their own OC regimen; the median duration of continuous OC use was 9 weeks (maximum 104 weeks), and the median pill-free interval was 5 days.3
Advising patients. In offering my patients the option of extended OC use, I previously recommended scheduled withdrawal bleeds at 3- to 6-month intervals to avoid spotting. With this new evidence, however, I can offer patients even longer periods of amenorrhea. Moreover, a new 91-day extended OC formulation (Seasonale; Barr Laboratories, Pomona, NY) is under development and should be approved later this year.4
Bottom line
Continuous use of a low-dose monophasic OC preparation for 1 year resulted in fewer bleeding days without a significant increase in overall spotting, compared with cyclic use of the same preparation. We can use this evidence to counsel patients about the benefits of continuous OC use and help them achieve menstrual “nirvana.”5
Objective
To compare the bleeding profile of a traditional 28-day oral contraceptive (OC) cycle with continuous administration.
Methods and Results
Seventynine women were randomized to a 28-day regimen (21 active pills and a pill-free week) or continuous use of the same low-dose formulation (20 μg ethinyl estradiol/100 μg levonorgestrel) for 12 cycles. Women recorded the number of bleeding and spotting days, and a subset underwent pelvic ultrasound and endometrial biopsy in cycles 1 and 9.
During the first 3 cycles, 68% of continuous users experienced amenorrhea or infrequent bleeding; that rate increased to 88% during the last 3 cycles. Continuous users initially experienced a slight increase in spotting during cycle days 1 through 21, but it diminished over time and ultimately was less than that reported by cyclic users.
Who may be affected by these findings?
Women of reproductive age who wish to reduce monthly bleeding.
Expert commentary
The notion that menstruation must occur each month in healthy, nonpregnant women using contraception is increasingly being questioned. One of the main factors contributing to this perception has been the packaging and labeling of OCs to induce monthly withdrawal bleeding.
Endometrium does not ‘build up.’ Monthly menstruation is not critical to OCs’ mechanism of action. Nor does OC-induced amenorrhea lead to harmful “build-up” of the endometrium. Rather, extended OC use results in a thin, atrophic endometrium that is protective against hyperplasia and endometrial cancer.
Continuous use is well tolerated. This study showed continuous use to be well tolerated, with a low drop-out rate and little anxiety about pregnancy. Data also suggested a small improvement in compliance.
Comparable efficacy. Contraceptive efficacy with continuous OC use was comparable to a cyclic regimen. (In some cases, continuous use may even be superior, since follicular development can occur during the pill-free week.) As for safety, continuous users who underwent ultrasound and endometrial biopsy had no abnormal findings. Although long-term safety was not completely addressed in this study—as the authors acknowledge—the cumulative estrogen exposure with a daily 20-μg ethinyl estradiol OC over 1 year is less than that of a cyclic 30-μg formulation.
Other benefits. Many other health benefits occur with extended OC regimens. Besides its convenience, medically induced amenorrhea has been used successfully to treat dysmenorrhea, menorrhagia (particularly in women with anemia or bleeding diatheses), endometriosis-related pain, and menstruation-related headaches. In addition, some special populations, such as female athletes, find amenorrhea particularly beneficial.1
What do women want? A number of studies suggest they don’t necessarily want to menstruate monthly. For example, a Dutch survey found that 65% of women aged 25 to 34 preferred bleeding every 3 months or less and 31% favored no bleeding at all.2 Another trial allowed participants to choose their own OC regimen; the median duration of continuous OC use was 9 weeks (maximum 104 weeks), and the median pill-free interval was 5 days.3
Advising patients. In offering my patients the option of extended OC use, I previously recommended scheduled withdrawal bleeds at 3- to 6-month intervals to avoid spotting. With this new evidence, however, I can offer patients even longer periods of amenorrhea. Moreover, a new 91-day extended OC formulation (Seasonale; Barr Laboratories, Pomona, NY) is under development and should be approved later this year.4
Bottom line
Continuous use of a low-dose monophasic OC preparation for 1 year resulted in fewer bleeding days without a significant increase in overall spotting, compared with cyclic use of the same preparation. We can use this evidence to counsel patients about the benefits of continuous OC use and help them achieve menstrual “nirvana.”5
1. Bennell K, White S, Crossley K. The oral contraceptive pill: a revolution for sportswomen? Br J Sports Med. 1999;33:231-238.
2. den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement use. Contraception. 1999;59:357-362.
3. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
4. Anderson FD. The safety and efficacy of Seasonale, a novel 91-day extended oral contraceptive regimen. Obstet Gynecol. 2002;99(suppl):26S.-
5. Edelman A. Menstrual nirvana: amenorrhea through the use of continuous oral contraceptives. Curr Women’s Health Rep. 2002;2:434-438.
1. Bennell K, White S, Crossley K. The oral contraceptive pill: a revolution for sportswomen? Br J Sports Med. 1999;33:231-238.
2. den Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement use. Contraception. 1999;59:357-362.
3. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
4. Anderson FD. The safety and efficacy of Seasonale, a novel 91-day extended oral contraceptive regimen. Obstet Gynecol. 2002;99(suppl):26S.-
5. Edelman A. Menstrual nirvana: amenorrhea through the use of continuous oral contraceptives. Curr Women’s Health Rep. 2002;2:434-438.
New options in emergency contraception: A WHO study
Objective
Two 0.75-mg doses of levonorgestrel administered 12 hours apart and a single 10-mg dose of mifepristone are both effective emergency contraception (EC) options, prior research has shown. Researchers for this World Health Organization (WHO) study compared the efficacy and side-effects profile of these regimens, as well as a third, previously untested alternative: a single 1.5-mg dose of levonorgestrel.
Methods and results
The evidence presented here, from randomized blinded trials, shows that a single l.5-mg dose of levonorgestrel is as effective as 2 doses of 0.75 mg taken 12 hours apart. The findings of this study, and others like it, also indicate that efficacy continues for up to 5 days—not the 72 hours to which we have limited EC use in the past.2,3 The WHO group also found that the progesterone antagonist mifepristone (“RU 486”) is not a better EC than levonorgestrel.
Who may be affected by these findings?
Sexually active women.
Expert commentary
This study simplifies the postcoital contraceptive regimens established by Yuzpe decades ago and still in use today.1 We can now tell patients seeking EC, “Take these 2 tablets (of 0.75-mg levonorgestrel) together as soon as possible up to 5 days after unprotected intercourse.” This off-label instruction is firmly supported by evidence from the current study, as well as other trials.2,3 (Although the extended therapeutic opportunity demonstrated in this study applies specifically to EC with levonorgestrel, it presumably also holds true for older, less-effective forms of EC, like birth-control pills containing levonorgestrel and estrogen.)
Unfortunately, FDA approval may come slowly. If this simpler levonorgestrel regimen is accompanied by advance prescription and direct pharmacy access (as in the states of Alaska, Washington, and California), it could lead to a reduction in abortion rates beyond that already achieved with the expanded use of EC and other contraceptives.
Although mifepristone remains an effective EC option, it is more expensive than levonorgestrel and unlikely to be considered for over-the-counter use because of its additional abortifacient actions. Levonorgestrel, on the other hand, is inexpensive and has a long history of safety.
Bottom line
Levonorgestrel is an effective, economical alternative to mifepristone for EC, and a single 1.5-mg dose is a viable option.
1. WHO Task Force. Randomised controlled trial of the levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet. 1998;352:428-433.
2. Raine T, Harper C, Leon K, Darney P. Emergency contraception: advance provision in a young, high-risk clinic population. Obstet Gynecol. 2000;96:1-7.
3. Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med. 1998;352:428-433.
Objective
Two 0.75-mg doses of levonorgestrel administered 12 hours apart and a single 10-mg dose of mifepristone are both effective emergency contraception (EC) options, prior research has shown. Researchers for this World Health Organization (WHO) study compared the efficacy and side-effects profile of these regimens, as well as a third, previously untested alternative: a single 1.5-mg dose of levonorgestrel.
Methods and results
The evidence presented here, from randomized blinded trials, shows that a single l.5-mg dose of levonorgestrel is as effective as 2 doses of 0.75 mg taken 12 hours apart. The findings of this study, and others like it, also indicate that efficacy continues for up to 5 days—not the 72 hours to which we have limited EC use in the past.2,3 The WHO group also found that the progesterone antagonist mifepristone (“RU 486”) is not a better EC than levonorgestrel.
Who may be affected by these findings?
Sexually active women.
Expert commentary
This study simplifies the postcoital contraceptive regimens established by Yuzpe decades ago and still in use today.1 We can now tell patients seeking EC, “Take these 2 tablets (of 0.75-mg levonorgestrel) together as soon as possible up to 5 days after unprotected intercourse.” This off-label instruction is firmly supported by evidence from the current study, as well as other trials.2,3 (Although the extended therapeutic opportunity demonstrated in this study applies specifically to EC with levonorgestrel, it presumably also holds true for older, less-effective forms of EC, like birth-control pills containing levonorgestrel and estrogen.)
Unfortunately, FDA approval may come slowly. If this simpler levonorgestrel regimen is accompanied by advance prescription and direct pharmacy access (as in the states of Alaska, Washington, and California), it could lead to a reduction in abortion rates beyond that already achieved with the expanded use of EC and other contraceptives.
Although mifepristone remains an effective EC option, it is more expensive than levonorgestrel and unlikely to be considered for over-the-counter use because of its additional abortifacient actions. Levonorgestrel, on the other hand, is inexpensive and has a long history of safety.
Bottom line
Levonorgestrel is an effective, economical alternative to mifepristone for EC, and a single 1.5-mg dose is a viable option.
Objective
Two 0.75-mg doses of levonorgestrel administered 12 hours apart and a single 10-mg dose of mifepristone are both effective emergency contraception (EC) options, prior research has shown. Researchers for this World Health Organization (WHO) study compared the efficacy and side-effects profile of these regimens, as well as a third, previously untested alternative: a single 1.5-mg dose of levonorgestrel.
Methods and results
The evidence presented here, from randomized blinded trials, shows that a single l.5-mg dose of levonorgestrel is as effective as 2 doses of 0.75 mg taken 12 hours apart. The findings of this study, and others like it, also indicate that efficacy continues for up to 5 days—not the 72 hours to which we have limited EC use in the past.2,3 The WHO group also found that the progesterone antagonist mifepristone (“RU 486”) is not a better EC than levonorgestrel.
Who may be affected by these findings?
Sexually active women.
Expert commentary
This study simplifies the postcoital contraceptive regimens established by Yuzpe decades ago and still in use today.1 We can now tell patients seeking EC, “Take these 2 tablets (of 0.75-mg levonorgestrel) together as soon as possible up to 5 days after unprotected intercourse.” This off-label instruction is firmly supported by evidence from the current study, as well as other trials.2,3 (Although the extended therapeutic opportunity demonstrated in this study applies specifically to EC with levonorgestrel, it presumably also holds true for older, less-effective forms of EC, like birth-control pills containing levonorgestrel and estrogen.)
Unfortunately, FDA approval may come slowly. If this simpler levonorgestrel regimen is accompanied by advance prescription and direct pharmacy access (as in the states of Alaska, Washington, and California), it could lead to a reduction in abortion rates beyond that already achieved with the expanded use of EC and other contraceptives.
Although mifepristone remains an effective EC option, it is more expensive than levonorgestrel and unlikely to be considered for over-the-counter use because of its additional abortifacient actions. Levonorgestrel, on the other hand, is inexpensive and has a long history of safety.
Bottom line
Levonorgestrel is an effective, economical alternative to mifepristone for EC, and a single 1.5-mg dose is a viable option.
1. WHO Task Force. Randomised controlled trial of the levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet. 1998;352:428-433.
2. Raine T, Harper C, Leon K, Darney P. Emergency contraception: advance provision in a young, high-risk clinic population. Obstet Gynecol. 2000;96:1-7.
3. Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med. 1998;352:428-433.
1. WHO Task Force. Randomised controlled trial of the levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet. 1998;352:428-433.
2. Raine T, Harper C, Leon K, Darney P. Emergency contraception: advance provision in a young, high-risk clinic population. Obstet Gynecol. 2000;96:1-7.
3. Glasier A, Baird D. The effects of self-administering emergency contraception. N Engl J Med. 1998;352:428-433.
Does magnesium sulfate prevent neonatal brain injury?
Objective
Prior research has shown a reduced risk for cerebral palsy and other neurologic defects among premature infants exposed antenatally to magnesium sulfate.
Methods and results
Over 16 months, 149 gravidas between 24 and 34 weeks’ gestation in active labor were randomized to magnesium tocolysis, “other” tocolysis, “neuroprotective” magnesium, or placebo. In the tocolytic groups, 37 singletons and 9 pairs of twins were born to mothers administered magnesium via a 4-g bolus followed by an hourly infusion of 2 to 3 g, and 41 singletons and 5 pairs of twins were born to women receiving ritodrine, terbutaline, indomethacin, or nifedipine, at the discretion of the attending physician. In the preventive groups, 28 singletons and 1 pair of twins were randomized to a 4-g bolus of magnesium (without further infusion), and 27 singletons and 1 pair of twins were exposed to placebo.
Umbilical cord blood was collected at delivery to determine serum ionized magnesium levels, and neonatal cranial ultrasound scans were performed. Of 165 infants examined, 37 experienced neonatal intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, and/or death; those infants had higher umbilical cord magnesium levels.
The researchers concluded that the use of magnesium was associated with a higher risk of adverse perinatal outcome.
Who may be affected by these findings?
Infants exposed to magnesium.
Expert commentary
Mittendorf et al recommend “abandoning magnesium for use as routine tocolytic therapy,” but they fail to offer sufficient evidence to warrant such a conclusion.
For example, maternal and cord blood samples were obtained on only half of the population. And while placental cultures were obtained, the results were not reported.
Many potentially important differences between the groups were not explicated in this study. Instead, data are presented for the combined groups and divided into adverse versus no adverse outcomes. For instance, 101 of 142 patients for whom data are reported had preterm premature rupture of membranes, but we don’t know how many fell into either the tocolytic or preventive arms of the study.
The distribution of gestational ages in the 2 separate trials was not revealed—only that 42 of the 147 participants were at less than 28 weeks’ gestation. In addition, the use of betamethasone was roughly equivalent in both the adverse and no adverse outcome groups. Presumably, a higher proportion of women in the tocolytic arm were able to receive the full 24 hours of treatment than in the neuroprotective arm. Further, the rate of steroid use was available for only 135 of the 149 women. Since steroids have been shown to decrease the rate of intraventricular hemorrhage, this particular issue needs to be more clearly explored.
Finally, for both the tocolytic and preventive groups, results were reported as composite adverse outcomes. As such, an infant who died with an intraventricular hemorrhage had 2 adverse events. This method of counting may be misleading.
Bottom line
This study does not support the conclusion that tocolytic use of magnesium should be limited to controlled trials. Rather, we should await the results of 2 large, randomized magnesium trials before deciding to halt the use of magnesium. Until then, it is appropriate to continue judicious use of tocolytics to allow for steroid administration and effectiveness.
Objective
Prior research has shown a reduced risk for cerebral palsy and other neurologic defects among premature infants exposed antenatally to magnesium sulfate.
Methods and results
Over 16 months, 149 gravidas between 24 and 34 weeks’ gestation in active labor were randomized to magnesium tocolysis, “other” tocolysis, “neuroprotective” magnesium, or placebo. In the tocolytic groups, 37 singletons and 9 pairs of twins were born to mothers administered magnesium via a 4-g bolus followed by an hourly infusion of 2 to 3 g, and 41 singletons and 5 pairs of twins were born to women receiving ritodrine, terbutaline, indomethacin, or nifedipine, at the discretion of the attending physician. In the preventive groups, 28 singletons and 1 pair of twins were randomized to a 4-g bolus of magnesium (without further infusion), and 27 singletons and 1 pair of twins were exposed to placebo.
Umbilical cord blood was collected at delivery to determine serum ionized magnesium levels, and neonatal cranial ultrasound scans were performed. Of 165 infants examined, 37 experienced neonatal intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, and/or death; those infants had higher umbilical cord magnesium levels.
The researchers concluded that the use of magnesium was associated with a higher risk of adverse perinatal outcome.
Who may be affected by these findings?
Infants exposed to magnesium.
Expert commentary
Mittendorf et al recommend “abandoning magnesium for use as routine tocolytic therapy,” but they fail to offer sufficient evidence to warrant such a conclusion.
For example, maternal and cord blood samples were obtained on only half of the population. And while placental cultures were obtained, the results were not reported.
Many potentially important differences between the groups were not explicated in this study. Instead, data are presented for the combined groups and divided into adverse versus no adverse outcomes. For instance, 101 of 142 patients for whom data are reported had preterm premature rupture of membranes, but we don’t know how many fell into either the tocolytic or preventive arms of the study.
The distribution of gestational ages in the 2 separate trials was not revealed—only that 42 of the 147 participants were at less than 28 weeks’ gestation. In addition, the use of betamethasone was roughly equivalent in both the adverse and no adverse outcome groups. Presumably, a higher proportion of women in the tocolytic arm were able to receive the full 24 hours of treatment than in the neuroprotective arm. Further, the rate of steroid use was available for only 135 of the 149 women. Since steroids have been shown to decrease the rate of intraventricular hemorrhage, this particular issue needs to be more clearly explored.
Finally, for both the tocolytic and preventive groups, results were reported as composite adverse outcomes. As such, an infant who died with an intraventricular hemorrhage had 2 adverse events. This method of counting may be misleading.
Bottom line
This study does not support the conclusion that tocolytic use of magnesium should be limited to controlled trials. Rather, we should await the results of 2 large, randomized magnesium trials before deciding to halt the use of magnesium. Until then, it is appropriate to continue judicious use of tocolytics to allow for steroid administration and effectiveness.
Objective
Prior research has shown a reduced risk for cerebral palsy and other neurologic defects among premature infants exposed antenatally to magnesium sulfate.
Methods and results
Over 16 months, 149 gravidas between 24 and 34 weeks’ gestation in active labor were randomized to magnesium tocolysis, “other” tocolysis, “neuroprotective” magnesium, or placebo. In the tocolytic groups, 37 singletons and 9 pairs of twins were born to mothers administered magnesium via a 4-g bolus followed by an hourly infusion of 2 to 3 g, and 41 singletons and 5 pairs of twins were born to women receiving ritodrine, terbutaline, indomethacin, or nifedipine, at the discretion of the attending physician. In the preventive groups, 28 singletons and 1 pair of twins were randomized to a 4-g bolus of magnesium (without further infusion), and 27 singletons and 1 pair of twins were exposed to placebo.
Umbilical cord blood was collected at delivery to determine serum ionized magnesium levels, and neonatal cranial ultrasound scans were performed. Of 165 infants examined, 37 experienced neonatal intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy, and/or death; those infants had higher umbilical cord magnesium levels.
The researchers concluded that the use of magnesium was associated with a higher risk of adverse perinatal outcome.
Who may be affected by these findings?
Infants exposed to magnesium.
Expert commentary
Mittendorf et al recommend “abandoning magnesium for use as routine tocolytic therapy,” but they fail to offer sufficient evidence to warrant such a conclusion.
For example, maternal and cord blood samples were obtained on only half of the population. And while placental cultures were obtained, the results were not reported.
Many potentially important differences between the groups were not explicated in this study. Instead, data are presented for the combined groups and divided into adverse versus no adverse outcomes. For instance, 101 of 142 patients for whom data are reported had preterm premature rupture of membranes, but we don’t know how many fell into either the tocolytic or preventive arms of the study.
The distribution of gestational ages in the 2 separate trials was not revealed—only that 42 of the 147 participants were at less than 28 weeks’ gestation. In addition, the use of betamethasone was roughly equivalent in both the adverse and no adverse outcome groups. Presumably, a higher proportion of women in the tocolytic arm were able to receive the full 24 hours of treatment than in the neuroprotective arm. Further, the rate of steroid use was available for only 135 of the 149 women. Since steroids have been shown to decrease the rate of intraventricular hemorrhage, this particular issue needs to be more clearly explored.
Finally, for both the tocolytic and preventive groups, results were reported as composite adverse outcomes. As such, an infant who died with an intraventricular hemorrhage had 2 adverse events. This method of counting may be misleading.
Bottom line
This study does not support the conclusion that tocolytic use of magnesium should be limited to controlled trials. Rather, we should await the results of 2 large, randomized magnesium trials before deciding to halt the use of magnesium. Until then, it is appropriate to continue judicious use of tocolytics to allow for steroid administration and effectiveness.
Focus on Gynecologic Infections: Clindamycin treatment of bacterial vaginosis reduces preterm deliveries
Objective
To investigate whether treating abnormal genital tract flora with clindamycin vaginal cream in gravidas before 20 weeks’ gestation prevents preterm delivery.
Methods and results
This randomized, double-blind, placebo-controlled tricenter study included 409 women with abnormal genital tract flora presenting to antenatal care clinics at 13 to 20 weeks’ gestation. Infection or colonization consistent with bacterial vaginosis was defined as decreased lactobacilli and increased numbers of “other” bacterial morphotypes and was identified by Gram stain performed on secretions obtained from the upper portion of the vagina. Women who tested positive for infection or colonization were treated with a 3-day course of vaginal clindamycin cream (n = 208) or placebo (n = 201).
If infection or colonization persisted 3 weeks later, a second, 7-day course of the drug or placebo was given, in accordance with the original randomization.
Compared with controls, women treated with clindamycin had a statistically significant reduction in the incidence of preterm delivery (4% versus 10%, P = .03). Consequently, admission to the neonatal intensive care unit also was significantly reduced among babies born to women in the treatment group.
Expert commentary
Preterm delivery remains the bane of the obstetrician’s existence. Treatment of clinically evident preterm labor can delay delivery sufficiently to allow for administration of antenatal steroids, but only rarely is established labor abolished.
Given our limited effectiveness in combating premature labor, one alternative is identifying the woman at risk. Unfortunately, the majority of pregnancies complicated by preterm delivery have no obvious risk factors. The study by Lamont et al is important because it describes a means of identifying and successfully treating infection that might otherwise remain undiagnosed until preterm labor becomes established and essentially untreatable. Indeed, the essence of a good screening method is its ability to identify risk in those who exhibit no ostensible risk—that is, the population at large.
While this study is one of many to consider the role of bacterial vaginosis in preterm labor, the use of a Gram stain to identify the abnormal bacterial morphology is clever and deserves consideration. Once risk is identified, the next logical step is finding a means to facilitate its reduction—and the study succeeds here as well. If the risk of preterm delivery can be suitably diminished—as it was in the women given clindamycin—the potential to lower the preterm delivery rate is greater than with traditional interventions for clinically apparent preterm labor.
My practice is inner city, where preterm deliveries occur for a variety of reasons and the degree of prematurity is on the severe end of the scale. Thus, an approach that clearly lowers admissions to the neonatal intensive care unit would be valuable. In my opinion, this approach is worth a trial.
Bottom line
In the low-risk population studied here, identifying infection by Gram stain and treating it with intravaginal clindamycin cream had a marked impact on the goal of reducing preterm delivery. This is an elegant application of a simple, direct, and inexpensive means to a most valued end.
Objective
To investigate whether treating abnormal genital tract flora with clindamycin vaginal cream in gravidas before 20 weeks’ gestation prevents preterm delivery.
Methods and results
This randomized, double-blind, placebo-controlled tricenter study included 409 women with abnormal genital tract flora presenting to antenatal care clinics at 13 to 20 weeks’ gestation. Infection or colonization consistent with bacterial vaginosis was defined as decreased lactobacilli and increased numbers of “other” bacterial morphotypes and was identified by Gram stain performed on secretions obtained from the upper portion of the vagina. Women who tested positive for infection or colonization were treated with a 3-day course of vaginal clindamycin cream (n = 208) or placebo (n = 201).
If infection or colonization persisted 3 weeks later, a second, 7-day course of the drug or placebo was given, in accordance with the original randomization.
Compared with controls, women treated with clindamycin had a statistically significant reduction in the incidence of preterm delivery (4% versus 10%, P = .03). Consequently, admission to the neonatal intensive care unit also was significantly reduced among babies born to women in the treatment group.
Expert commentary
Preterm delivery remains the bane of the obstetrician’s existence. Treatment of clinically evident preterm labor can delay delivery sufficiently to allow for administration of antenatal steroids, but only rarely is established labor abolished.
Given our limited effectiveness in combating premature labor, one alternative is identifying the woman at risk. Unfortunately, the majority of pregnancies complicated by preterm delivery have no obvious risk factors. The study by Lamont et al is important because it describes a means of identifying and successfully treating infection that might otherwise remain undiagnosed until preterm labor becomes established and essentially untreatable. Indeed, the essence of a good screening method is its ability to identify risk in those who exhibit no ostensible risk—that is, the population at large.
While this study is one of many to consider the role of bacterial vaginosis in preterm labor, the use of a Gram stain to identify the abnormal bacterial morphology is clever and deserves consideration. Once risk is identified, the next logical step is finding a means to facilitate its reduction—and the study succeeds here as well. If the risk of preterm delivery can be suitably diminished—as it was in the women given clindamycin—the potential to lower the preterm delivery rate is greater than with traditional interventions for clinically apparent preterm labor.
My practice is inner city, where preterm deliveries occur for a variety of reasons and the degree of prematurity is on the severe end of the scale. Thus, an approach that clearly lowers admissions to the neonatal intensive care unit would be valuable. In my opinion, this approach is worth a trial.
Bottom line
In the low-risk population studied here, identifying infection by Gram stain and treating it with intravaginal clindamycin cream had a marked impact on the goal of reducing preterm delivery. This is an elegant application of a simple, direct, and inexpensive means to a most valued end.
Objective
To investigate whether treating abnormal genital tract flora with clindamycin vaginal cream in gravidas before 20 weeks’ gestation prevents preterm delivery.
Methods and results
This randomized, double-blind, placebo-controlled tricenter study included 409 women with abnormal genital tract flora presenting to antenatal care clinics at 13 to 20 weeks’ gestation. Infection or colonization consistent with bacterial vaginosis was defined as decreased lactobacilli and increased numbers of “other” bacterial morphotypes and was identified by Gram stain performed on secretions obtained from the upper portion of the vagina. Women who tested positive for infection or colonization were treated with a 3-day course of vaginal clindamycin cream (n = 208) or placebo (n = 201).
If infection or colonization persisted 3 weeks later, a second, 7-day course of the drug or placebo was given, in accordance with the original randomization.
Compared with controls, women treated with clindamycin had a statistically significant reduction in the incidence of preterm delivery (4% versus 10%, P = .03). Consequently, admission to the neonatal intensive care unit also was significantly reduced among babies born to women in the treatment group.
Expert commentary
Preterm delivery remains the bane of the obstetrician’s existence. Treatment of clinically evident preterm labor can delay delivery sufficiently to allow for administration of antenatal steroids, but only rarely is established labor abolished.
Given our limited effectiveness in combating premature labor, one alternative is identifying the woman at risk. Unfortunately, the majority of pregnancies complicated by preterm delivery have no obvious risk factors. The study by Lamont et al is important because it describes a means of identifying and successfully treating infection that might otherwise remain undiagnosed until preterm labor becomes established and essentially untreatable. Indeed, the essence of a good screening method is its ability to identify risk in those who exhibit no ostensible risk—that is, the population at large.
While this study is one of many to consider the role of bacterial vaginosis in preterm labor, the use of a Gram stain to identify the abnormal bacterial morphology is clever and deserves consideration. Once risk is identified, the next logical step is finding a means to facilitate its reduction—and the study succeeds here as well. If the risk of preterm delivery can be suitably diminished—as it was in the women given clindamycin—the potential to lower the preterm delivery rate is greater than with traditional interventions for clinically apparent preterm labor.
My practice is inner city, where preterm deliveries occur for a variety of reasons and the degree of prematurity is on the severe end of the scale. Thus, an approach that clearly lowers admissions to the neonatal intensive care unit would be valuable. In my opinion, this approach is worth a trial.
Bottom line
In the low-risk population studied here, identifying infection by Gram stain and treating it with intravaginal clindamycin cream had a marked impact on the goal of reducing preterm delivery. This is an elegant application of a simple, direct, and inexpensive means to a most valued end.
Focus on Gynecologic Infections: Chlamydia pneumoniae: Does previous infection increase preeclampsia risk?
Objective
Patients with immunoglobulin (Ig) G antibodies to Chlamydia pneumoniae tend to have a higher incidence of atherosclerosis. Since preeclampsia has many of the same pathophysiologic features and risk factors as coronary heart disease, the researchers investigated whether women with these antibodies also have a higher incidence of preeclampsia.
Methods and results
Investigators randomly collected serum samples from 74 nulliparous pregnant women—37 with preeclampsia and 37 with uncomplicated pregnancy—at the time of admission for labor and delivery. They then compared antibody titers for IgG, IgM, and IgA seroprevalence to Chlamydia pneumoniae, as well as IgG seroprevalence to Chlamydia trachomatis and Chlamydia psittaci, in the 2 groups.
IgG antibodies to C pneumoniae at a titer of at least 1:16 were more common in women with preeclampsia (25 of 37) than those without preeclampsia (15 of 37) (odds ratio 3.1; 95% confidence interval 1.2, 7.9).
There were no significant differences in the seroprevalence of IgA or IgM antibodies to C pneumoniae. Women with preeclampsia also were no more likely to have IgG antibodies to C trachomatis or C psittaci.
These data suggest a specific association between infection with C pneumoniae and preeclampsia.
Expert commentary
I began reviewing this article with 2 strong positive biases. First, Dr. Roberts is a respected colleague as well as a meticulous and honest investigator. Second, I believe that everything of importance in obstetrics and gynecology is somehow related to infection, bacteria, viruses, prions, and cytokines.
Those disclaimers aside, I was favorably impressed by this study.
The authors make a good point when they argue that past infection with C pneumoniae could be another risk factor for preeclampsia. However, since this study represents only the first step of investigation, it would be wise to avoid overenthusiasm.
Specifically, I don’t want to see a repeat of our current, very narrow strategy for preventing newborn group B streptococcal infections. The complete focus on extensive intrapartum antibiotic administration to mothers has resulted in an increase in newborn Gram-negative aerobic infections that, in 1 large study, matched the decrease in group B strep.1 The result: a zero-sum gain. Therefore, before we add macrolides to our prenatal vitamins, further investigation must be performed.
Although the statistical differences noted in this study are significant, the total patient population is small. Additional studies with larger numbers of patients are needed to verify these results. If confirmed, we would need careful prospective studies with selected therapeutic interventions to see if the progression to preeclampsia can be avoided.
Like all good studies, the results raise more questions than answers. I’m not an expert on preeclampsia, but I have been struck by how little attention—in the obstetrical literature—has been paid to the later life experiences of preeclamptic patients. I would assume that IgG C pneumoniae -positive preeclamptic women have a higher incidence of coronary artery disease in later years. Do we know the lifetime risks of preeclamptic patients? Perhaps it was C pneumoniae and not continuous medroxyprogesterone acetate that was the real culprit in the Women’s Health Initiative.
Bottom line
This well-conducted study presents preliminary evidence that past infection with C pneumoniae could be another risk factor for preeclampsia. Additional studies with larger patient populations are warranted to elucidate the clinical import of these findings.
REFERENCE
1. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very low birth weight infants. N Engl J Med. 2002;347:240-247.
Objective
Patients with immunoglobulin (Ig) G antibodies to Chlamydia pneumoniae tend to have a higher incidence of atherosclerosis. Since preeclampsia has many of the same pathophysiologic features and risk factors as coronary heart disease, the researchers investigated whether women with these antibodies also have a higher incidence of preeclampsia.
Methods and results
Investigators randomly collected serum samples from 74 nulliparous pregnant women—37 with preeclampsia and 37 with uncomplicated pregnancy—at the time of admission for labor and delivery. They then compared antibody titers for IgG, IgM, and IgA seroprevalence to Chlamydia pneumoniae, as well as IgG seroprevalence to Chlamydia trachomatis and Chlamydia psittaci, in the 2 groups.
IgG antibodies to C pneumoniae at a titer of at least 1:16 were more common in women with preeclampsia (25 of 37) than those without preeclampsia (15 of 37) (odds ratio 3.1; 95% confidence interval 1.2, 7.9).
There were no significant differences in the seroprevalence of IgA or IgM antibodies to C pneumoniae. Women with preeclampsia also were no more likely to have IgG antibodies to C trachomatis or C psittaci.
These data suggest a specific association between infection with C pneumoniae and preeclampsia.
Expert commentary
I began reviewing this article with 2 strong positive biases. First, Dr. Roberts is a respected colleague as well as a meticulous and honest investigator. Second, I believe that everything of importance in obstetrics and gynecology is somehow related to infection, bacteria, viruses, prions, and cytokines.
Those disclaimers aside, I was favorably impressed by this study.
The authors make a good point when they argue that past infection with C pneumoniae could be another risk factor for preeclampsia. However, since this study represents only the first step of investigation, it would be wise to avoid overenthusiasm.
Specifically, I don’t want to see a repeat of our current, very narrow strategy for preventing newborn group B streptococcal infections. The complete focus on extensive intrapartum antibiotic administration to mothers has resulted in an increase in newborn Gram-negative aerobic infections that, in 1 large study, matched the decrease in group B strep.1 The result: a zero-sum gain. Therefore, before we add macrolides to our prenatal vitamins, further investigation must be performed.
Although the statistical differences noted in this study are significant, the total patient population is small. Additional studies with larger numbers of patients are needed to verify these results. If confirmed, we would need careful prospective studies with selected therapeutic interventions to see if the progression to preeclampsia can be avoided.
Like all good studies, the results raise more questions than answers. I’m not an expert on preeclampsia, but I have been struck by how little attention—in the obstetrical literature—has been paid to the later life experiences of preeclamptic patients. I would assume that IgG C pneumoniae -positive preeclamptic women have a higher incidence of coronary artery disease in later years. Do we know the lifetime risks of preeclamptic patients? Perhaps it was C pneumoniae and not continuous medroxyprogesterone acetate that was the real culprit in the Women’s Health Initiative.
Bottom line
This well-conducted study presents preliminary evidence that past infection with C pneumoniae could be another risk factor for preeclampsia. Additional studies with larger patient populations are warranted to elucidate the clinical import of these findings.
Objective
Patients with immunoglobulin (Ig) G antibodies to Chlamydia pneumoniae tend to have a higher incidence of atherosclerosis. Since preeclampsia has many of the same pathophysiologic features and risk factors as coronary heart disease, the researchers investigated whether women with these antibodies also have a higher incidence of preeclampsia.
Methods and results
Investigators randomly collected serum samples from 74 nulliparous pregnant women—37 with preeclampsia and 37 with uncomplicated pregnancy—at the time of admission for labor and delivery. They then compared antibody titers for IgG, IgM, and IgA seroprevalence to Chlamydia pneumoniae, as well as IgG seroprevalence to Chlamydia trachomatis and Chlamydia psittaci, in the 2 groups.
IgG antibodies to C pneumoniae at a titer of at least 1:16 were more common in women with preeclampsia (25 of 37) than those without preeclampsia (15 of 37) (odds ratio 3.1; 95% confidence interval 1.2, 7.9).
There were no significant differences in the seroprevalence of IgA or IgM antibodies to C pneumoniae. Women with preeclampsia also were no more likely to have IgG antibodies to C trachomatis or C psittaci.
These data suggest a specific association between infection with C pneumoniae and preeclampsia.
Expert commentary
I began reviewing this article with 2 strong positive biases. First, Dr. Roberts is a respected colleague as well as a meticulous and honest investigator. Second, I believe that everything of importance in obstetrics and gynecology is somehow related to infection, bacteria, viruses, prions, and cytokines.
Those disclaimers aside, I was favorably impressed by this study.
The authors make a good point when they argue that past infection with C pneumoniae could be another risk factor for preeclampsia. However, since this study represents only the first step of investigation, it would be wise to avoid overenthusiasm.
Specifically, I don’t want to see a repeat of our current, very narrow strategy for preventing newborn group B streptococcal infections. The complete focus on extensive intrapartum antibiotic administration to mothers has resulted in an increase in newborn Gram-negative aerobic infections that, in 1 large study, matched the decrease in group B strep.1 The result: a zero-sum gain. Therefore, before we add macrolides to our prenatal vitamins, further investigation must be performed.
Although the statistical differences noted in this study are significant, the total patient population is small. Additional studies with larger numbers of patients are needed to verify these results. If confirmed, we would need careful prospective studies with selected therapeutic interventions to see if the progression to preeclampsia can be avoided.
Like all good studies, the results raise more questions than answers. I’m not an expert on preeclampsia, but I have been struck by how little attention—in the obstetrical literature—has been paid to the later life experiences of preeclamptic patients. I would assume that IgG C pneumoniae -positive preeclamptic women have a higher incidence of coronary artery disease in later years. Do we know the lifetime risks of preeclamptic patients? Perhaps it was C pneumoniae and not continuous medroxyprogesterone acetate that was the real culprit in the Women’s Health Initiative.
Bottom line
This well-conducted study presents preliminary evidence that past infection with C pneumoniae could be another risk factor for preeclampsia. Additional studies with larger patient populations are warranted to elucidate the clinical import of these findings.
REFERENCE
1. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very low birth weight infants. N Engl J Med. 2002;347:240-247.
REFERENCE
1. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very low birth weight infants. N Engl J Med. 2002;347:240-247.
Women’s Health Initiative: An inherently flawed design
Background
Since July 2002, the major news dominating headlines in medical publications dealing with women’s health has been the data from the WHI. Alarmingly, there is little consensus among both experts and practicing clinicians alike on how best to interpret the WHI results in this cohort of older women who were given estrogen-plus-progestin therapy. The general assumption of the lay press has been that randomized clinical trials are without study-design or interpretation flaws and therefore are the cornerstone of clinical practice. This unfortunate assumption fails to recognize the specific limitations of clinical trials–the very limitations that hinder this study.
As clinicians we are keenly aware of the WHI’s shortcomings. For instance, there have been concerns regarding the cohort studied. The WHI subjects were older than the typical menopausal patient, and generally without symptoms related to loss of estrogen. The cohort also represented a wide range of ages (from 50 to 70 years), and many patients with a markedly increased body mass index. Add to this some of the obvious idiosyncrasies of the data itself–for instance, the low rate of adverse events tracked in the placebo group for year-5 data–and the findings generate many questions for practicing clinicians and their patients.
Expert commentary
Questions about this newly released data focus on the same issues raised by the original article, as well as a few new ones. The most obvious concern is a practical one that usually stirs no debate: How can a clinical trial study the effects of pharmacologic interventions on quality of life in a group of women who were not recruited because of poor lifestyle or dissatisfaction with their everyday living? In fact, women were excluded from this study if they reported symptoms related to the menopause.
Studying asymptomatic menopausal women is akin to prescribing antifungal or placebo vaginal preparation in a blinded manner to subjects without a yeast vaginitis, and then collecting data to evaluate which group is most satisfied after intervention.
Prior studies using hormonal therapy in women with symptoms related to hypoestrogenism have shown improvement in vasomotor symptoms and quality of life.1,2 Women without symptoms related to estrogen loss cannot be expected to show an improvement in well-being with the use of hormone therapy.
My other concern is that these data may spur an increased use of unproven alternative therapies. For example, most nonhormonal interventions, such as herbal and dietary supplements, have either scant or nonexistent data supporting their role in improving patient well-being.
The question for clinicians is obvious: Is there a place for hormonal therapy in improving quality of life? To practice the bestquality medicine, we must use the data generated by randomized clinical trials, observational trials, retrospective reviews, and clinical judgement.
Each has a role in forming opinion: A randomized controlled trial recruits women willing to accept placebo intervention, randomization to different treatments, and a certain degree of the unknown.
Data from observational trials complement randomized controlled trial data because they more accurately reflect standards of medical care and either refute or support existing management protocols.
Retrospective reviews offer useful information about trends and prove helpful as pilot data to construct prospective trials.
Lastly, clinician acumen and the doctor-patient relationship take into account the individual needs of women. The best clinical practice does not rely on 1 set of data derived from a single data set.
Bottom line
The data from this article should be shared with women, but should not overshadow other data on hormone therapy or the individual needs of an informed patient. Rather, it should be a piece of the pie–i.e., the aggregation of all objective data on HRT–and assist the woman and her physician in deciding whether the benefits outweigh the risks for her specific situation.
1. Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: A double-blind placebo-placebo-controlled study. Am J Obstet Gynecol. 1993;168:824-830.
2. Bech P, Muck-Jensen N, Obel EB, Ulrich LG, Eiken P, Nielsen SP. Combined versus sequential hormonal replacement therapy: A double-blind, randomized, placebo-controlled study on quality of life-related outcome measures. Psychother Psychosom. 1998;67:259-265.
Background
Since July 2002, the major news dominating headlines in medical publications dealing with women’s health has been the data from the WHI. Alarmingly, there is little consensus among both experts and practicing clinicians alike on how best to interpret the WHI results in this cohort of older women who were given estrogen-plus-progestin therapy. The general assumption of the lay press has been that randomized clinical trials are without study-design or interpretation flaws and therefore are the cornerstone of clinical practice. This unfortunate assumption fails to recognize the specific limitations of clinical trials–the very limitations that hinder this study.
As clinicians we are keenly aware of the WHI’s shortcomings. For instance, there have been concerns regarding the cohort studied. The WHI subjects were older than the typical menopausal patient, and generally without symptoms related to loss of estrogen. The cohort also represented a wide range of ages (from 50 to 70 years), and many patients with a markedly increased body mass index. Add to this some of the obvious idiosyncrasies of the data itself–for instance, the low rate of adverse events tracked in the placebo group for year-5 data–and the findings generate many questions for practicing clinicians and their patients.
Expert commentary
Questions about this newly released data focus on the same issues raised by the original article, as well as a few new ones. The most obvious concern is a practical one that usually stirs no debate: How can a clinical trial study the effects of pharmacologic interventions on quality of life in a group of women who were not recruited because of poor lifestyle or dissatisfaction with their everyday living? In fact, women were excluded from this study if they reported symptoms related to the menopause.
Studying asymptomatic menopausal women is akin to prescribing antifungal or placebo vaginal preparation in a blinded manner to subjects without a yeast vaginitis, and then collecting data to evaluate which group is most satisfied after intervention.
Prior studies using hormonal therapy in women with symptoms related to hypoestrogenism have shown improvement in vasomotor symptoms and quality of life.1,2 Women without symptoms related to estrogen loss cannot be expected to show an improvement in well-being with the use of hormone therapy.
My other concern is that these data may spur an increased use of unproven alternative therapies. For example, most nonhormonal interventions, such as herbal and dietary supplements, have either scant or nonexistent data supporting their role in improving patient well-being.
The question for clinicians is obvious: Is there a place for hormonal therapy in improving quality of life? To practice the bestquality medicine, we must use the data generated by randomized clinical trials, observational trials, retrospective reviews, and clinical judgement.
Each has a role in forming opinion: A randomized controlled trial recruits women willing to accept placebo intervention, randomization to different treatments, and a certain degree of the unknown.
Data from observational trials complement randomized controlled trial data because they more accurately reflect standards of medical care and either refute or support existing management protocols.
Retrospective reviews offer useful information about trends and prove helpful as pilot data to construct prospective trials.
Lastly, clinician acumen and the doctor-patient relationship take into account the individual needs of women. The best clinical practice does not rely on 1 set of data derived from a single data set.
Bottom line
The data from this article should be shared with women, but should not overshadow other data on hormone therapy or the individual needs of an informed patient. Rather, it should be a piece of the pie–i.e., the aggregation of all objective data on HRT–and assist the woman and her physician in deciding whether the benefits outweigh the risks for her specific situation.
Background
Since July 2002, the major news dominating headlines in medical publications dealing with women’s health has been the data from the WHI. Alarmingly, there is little consensus among both experts and practicing clinicians alike on how best to interpret the WHI results in this cohort of older women who were given estrogen-plus-progestin therapy. The general assumption of the lay press has been that randomized clinical trials are without study-design or interpretation flaws and therefore are the cornerstone of clinical practice. This unfortunate assumption fails to recognize the specific limitations of clinical trials–the very limitations that hinder this study.
As clinicians we are keenly aware of the WHI’s shortcomings. For instance, there have been concerns regarding the cohort studied. The WHI subjects were older than the typical menopausal patient, and generally without symptoms related to loss of estrogen. The cohort also represented a wide range of ages (from 50 to 70 years), and many patients with a markedly increased body mass index. Add to this some of the obvious idiosyncrasies of the data itself–for instance, the low rate of adverse events tracked in the placebo group for year-5 data–and the findings generate many questions for practicing clinicians and their patients.
Expert commentary
Questions about this newly released data focus on the same issues raised by the original article, as well as a few new ones. The most obvious concern is a practical one that usually stirs no debate: How can a clinical trial study the effects of pharmacologic interventions on quality of life in a group of women who were not recruited because of poor lifestyle or dissatisfaction with their everyday living? In fact, women were excluded from this study if they reported symptoms related to the menopause.
Studying asymptomatic menopausal women is akin to prescribing antifungal or placebo vaginal preparation in a blinded manner to subjects without a yeast vaginitis, and then collecting data to evaluate which group is most satisfied after intervention.
Prior studies using hormonal therapy in women with symptoms related to hypoestrogenism have shown improvement in vasomotor symptoms and quality of life.1,2 Women without symptoms related to estrogen loss cannot be expected to show an improvement in well-being with the use of hormone therapy.
My other concern is that these data may spur an increased use of unproven alternative therapies. For example, most nonhormonal interventions, such as herbal and dietary supplements, have either scant or nonexistent data supporting their role in improving patient well-being.
The question for clinicians is obvious: Is there a place for hormonal therapy in improving quality of life? To practice the bestquality medicine, we must use the data generated by randomized clinical trials, observational trials, retrospective reviews, and clinical judgement.
Each has a role in forming opinion: A randomized controlled trial recruits women willing to accept placebo intervention, randomization to different treatments, and a certain degree of the unknown.
Data from observational trials complement randomized controlled trial data because they more accurately reflect standards of medical care and either refute or support existing management protocols.
Retrospective reviews offer useful information about trends and prove helpful as pilot data to construct prospective trials.
Lastly, clinician acumen and the doctor-patient relationship take into account the individual needs of women. The best clinical practice does not rely on 1 set of data derived from a single data set.
Bottom line
The data from this article should be shared with women, but should not overshadow other data on hormone therapy or the individual needs of an informed patient. Rather, it should be a piece of the pie–i.e., the aggregation of all objective data on HRT–and assist the woman and her physician in deciding whether the benefits outweigh the risks for her specific situation.
1. Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: A double-blind placebo-placebo-controlled study. Am J Obstet Gynecol. 1993;168:824-830.
2. Bech P, Muck-Jensen N, Obel EB, Ulrich LG, Eiken P, Nielsen SP. Combined versus sequential hormonal replacement therapy: A double-blind, randomized, placebo-controlled study on quality of life-related outcome measures. Psychother Psychosom. 1998;67:259-265.
1. Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: A double-blind placebo-placebo-controlled study. Am J Obstet Gynecol. 1993;168:824-830.
2. Bech P, Muck-Jensen N, Obel EB, Ulrich LG, Eiken P, Nielsen SP. Combined versus sequential hormonal replacement therapy: A double-blind, randomized, placebo-controlled study on quality of life-related outcome measures. Psychother Psychosom. 1998;67:259-265.
A study with 4 inescapable limitations
Expert commentary
Four key problems limit the effectiveness of this study.
1. Inappropriate population
Seventy percent of the women in this study were between the ages of 60 and 79 with a mean age of 63. This fact disqualified the WHI’s first report as a primary prevention study of cardiovascular disease, and it has a major nullifying impact on this study as well.
Only a small percentage of older postmenopausal women have vasomotor symptoms; in this study just 12% noted them as “moderate to severe.” Women with severe vasomotor symptoms were dissuaded from joining the study due to inability to take placebo. In her editorial, D. Grady comments that, “Among the 12% of women who did report moderate-to-severe vasomotor symptoms at baseline, the symptoms were unlikely to be very bothersome, since the women were willing to be randomly assigned to placebo.”1 Hence, this is not an appropriate population from which to draw conclusions about quality of life issues.
2. Discontinuation rate was 42%
This was an intent-to-treat study and almost half of those in the study group discontinued therapy. This is certainly not unexpected when women are arbitrarily placed on a single estrogen-progestin combination therapy without regard to individualizing treatment–especially when you consider that 88% were without vasomotor symptoms at baseline. The breast tenderness, bloating, bleeding, headaches, and mood changes from a 1-size-fits-all regimen would be enough to make most women discontinue treatment if their clinicians were unable to adjust their therapy.
Subjects who stopped therapy remained in the treatment arm for determination of quality of life results. The authors admit that “it is possible that differences were not significant at 3 years because of…poorer adherence to assigned therapy.”
3. The conjugated equine estrogen/medroxyprogesterone acetate combination in this study does not represent all HRT formulations
The definition of what constitutes HRT is vastly different today than it was a mere 20 years ago. Thus, it is impossible and misleading to extrapolate the WHI results to the many different options of estrogens, progestogens and delivery systems presently available in the US.
Numerous studies have shown estrogen-associated increases in quality of life. Progestogens, especially medroxyprogesterone acetate–the most potent synthetic progestin we have–can attenuate these estrogen benefits by down-regulation of the estrogen receptor. This is a process we seek in the endometrium, but want to avoid in brain, bone, vascular tree, genitalia, and skin. Better progestogen choices now available, such as micronized progesterone, norethindrone acetate, and norgestimate, are less potent and far better tolerated in combination with the many estrogen options.
4. Quality of evaluation tools
This study attempts to evaluate quality of life using various medical scales–each designed to assess a specific function, but none developed to actually measure quality of life. The most primitive scale, utilized to evaluate “sexual satisfaction,” consisted of just 1 question with 4 choices: very unsatisfied, a little unsatisfied, somewhat satisfied, or very satisfied. Other researchers have utilized vehicles with 40 questions on a 10-point scale in studies of sexuality, and the academic sexual societies are constantly trying to evolve more sophisticated tools to evaluate this complex concept. One question simply cannot assess sexual satisfaction.
Bottom line
Individualization of therapy has been, and should continue to be, the guiding principle in helping patients decide whether or not to begin HRT, and ultimately which combination best fits their needs. This unsatisfying study uses the wrong population, continuation, combination, and evaluation and fails to consider the variations in genetic complement of estrogen receptors. No single therapy is appropriate for all women.
REFERENCE
1. Grady D. Postmenopausal hormones–therapy for symptoms only. N Engl J Med. Posted March 17, 2003. Because of its potential therapeutic implications, this article was published early at: www.nejm.org. It appears in the May 8th issue.
Expert commentary
Four key problems limit the effectiveness of this study.
1. Inappropriate population
Seventy percent of the women in this study were between the ages of 60 and 79 with a mean age of 63. This fact disqualified the WHI’s first report as a primary prevention study of cardiovascular disease, and it has a major nullifying impact on this study as well.
Only a small percentage of older postmenopausal women have vasomotor symptoms; in this study just 12% noted them as “moderate to severe.” Women with severe vasomotor symptoms were dissuaded from joining the study due to inability to take placebo. In her editorial, D. Grady comments that, “Among the 12% of women who did report moderate-to-severe vasomotor symptoms at baseline, the symptoms were unlikely to be very bothersome, since the women were willing to be randomly assigned to placebo.”1 Hence, this is not an appropriate population from which to draw conclusions about quality of life issues.
2. Discontinuation rate was 42%
This was an intent-to-treat study and almost half of those in the study group discontinued therapy. This is certainly not unexpected when women are arbitrarily placed on a single estrogen-progestin combination therapy without regard to individualizing treatment–especially when you consider that 88% were without vasomotor symptoms at baseline. The breast tenderness, bloating, bleeding, headaches, and mood changes from a 1-size-fits-all regimen would be enough to make most women discontinue treatment if their clinicians were unable to adjust their therapy.
Subjects who stopped therapy remained in the treatment arm for determination of quality of life results. The authors admit that “it is possible that differences were not significant at 3 years because of…poorer adherence to assigned therapy.”
3. The conjugated equine estrogen/medroxyprogesterone acetate combination in this study does not represent all HRT formulations
The definition of what constitutes HRT is vastly different today than it was a mere 20 years ago. Thus, it is impossible and misleading to extrapolate the WHI results to the many different options of estrogens, progestogens and delivery systems presently available in the US.
Numerous studies have shown estrogen-associated increases in quality of life. Progestogens, especially medroxyprogesterone acetate–the most potent synthetic progestin we have–can attenuate these estrogen benefits by down-regulation of the estrogen receptor. This is a process we seek in the endometrium, but want to avoid in brain, bone, vascular tree, genitalia, and skin. Better progestogen choices now available, such as micronized progesterone, norethindrone acetate, and norgestimate, are less potent and far better tolerated in combination with the many estrogen options.
4. Quality of evaluation tools
This study attempts to evaluate quality of life using various medical scales–each designed to assess a specific function, but none developed to actually measure quality of life. The most primitive scale, utilized to evaluate “sexual satisfaction,” consisted of just 1 question with 4 choices: very unsatisfied, a little unsatisfied, somewhat satisfied, or very satisfied. Other researchers have utilized vehicles with 40 questions on a 10-point scale in studies of sexuality, and the academic sexual societies are constantly trying to evolve more sophisticated tools to evaluate this complex concept. One question simply cannot assess sexual satisfaction.
Bottom line
Individualization of therapy has been, and should continue to be, the guiding principle in helping patients decide whether or not to begin HRT, and ultimately which combination best fits their needs. This unsatisfying study uses the wrong population, continuation, combination, and evaluation and fails to consider the variations in genetic complement of estrogen receptors. No single therapy is appropriate for all women.
Expert commentary
Four key problems limit the effectiveness of this study.
1. Inappropriate population
Seventy percent of the women in this study were between the ages of 60 and 79 with a mean age of 63. This fact disqualified the WHI’s first report as a primary prevention study of cardiovascular disease, and it has a major nullifying impact on this study as well.
Only a small percentage of older postmenopausal women have vasomotor symptoms; in this study just 12% noted them as “moderate to severe.” Women with severe vasomotor symptoms were dissuaded from joining the study due to inability to take placebo. In her editorial, D. Grady comments that, “Among the 12% of women who did report moderate-to-severe vasomotor symptoms at baseline, the symptoms were unlikely to be very bothersome, since the women were willing to be randomly assigned to placebo.”1 Hence, this is not an appropriate population from which to draw conclusions about quality of life issues.
2. Discontinuation rate was 42%
This was an intent-to-treat study and almost half of those in the study group discontinued therapy. This is certainly not unexpected when women are arbitrarily placed on a single estrogen-progestin combination therapy without regard to individualizing treatment–especially when you consider that 88% were without vasomotor symptoms at baseline. The breast tenderness, bloating, bleeding, headaches, and mood changes from a 1-size-fits-all regimen would be enough to make most women discontinue treatment if their clinicians were unable to adjust their therapy.
Subjects who stopped therapy remained in the treatment arm for determination of quality of life results. The authors admit that “it is possible that differences were not significant at 3 years because of…poorer adherence to assigned therapy.”
3. The conjugated equine estrogen/medroxyprogesterone acetate combination in this study does not represent all HRT formulations
The definition of what constitutes HRT is vastly different today than it was a mere 20 years ago. Thus, it is impossible and misleading to extrapolate the WHI results to the many different options of estrogens, progestogens and delivery systems presently available in the US.
Numerous studies have shown estrogen-associated increases in quality of life. Progestogens, especially medroxyprogesterone acetate–the most potent synthetic progestin we have–can attenuate these estrogen benefits by down-regulation of the estrogen receptor. This is a process we seek in the endometrium, but want to avoid in brain, bone, vascular tree, genitalia, and skin. Better progestogen choices now available, such as micronized progesterone, norethindrone acetate, and norgestimate, are less potent and far better tolerated in combination with the many estrogen options.
4. Quality of evaluation tools
This study attempts to evaluate quality of life using various medical scales–each designed to assess a specific function, but none developed to actually measure quality of life. The most primitive scale, utilized to evaluate “sexual satisfaction,” consisted of just 1 question with 4 choices: very unsatisfied, a little unsatisfied, somewhat satisfied, or very satisfied. Other researchers have utilized vehicles with 40 questions on a 10-point scale in studies of sexuality, and the academic sexual societies are constantly trying to evolve more sophisticated tools to evaluate this complex concept. One question simply cannot assess sexual satisfaction.
Bottom line
Individualization of therapy has been, and should continue to be, the guiding principle in helping patients decide whether or not to begin HRT, and ultimately which combination best fits their needs. This unsatisfying study uses the wrong population, continuation, combination, and evaluation and fails to consider the variations in genetic complement of estrogen receptors. No single therapy is appropriate for all women.
REFERENCE
1. Grady D. Postmenopausal hormones–therapy for symptoms only. N Engl J Med. Posted March 17, 2003. Because of its potential therapeutic implications, this article was published early at: www.nejm.org. It appears in the May 8th issue.
REFERENCE
1. Grady D. Postmenopausal hormones–therapy for symptoms only. N Engl J Med. Posted March 17, 2003. Because of its potential therapeutic implications, this article was published early at: www.nejm.org. It appears in the May 8th issue.
Focus on Menopause: Hormone replacement and quality of life: 2 experts comment on the latest WHI findings
Objective
In this latest offering from the Women’s Health Initiative (WHI), researchers investigate whether estrogen plus progestin increases quality of life in postmenopausal women.
Methods and Results
This study consisted of 16,608 postmenopausal women ranging in age from 50 to 79 (mean, 63) with an intact uterus. Participants received either a combination of 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate (Prempro) or placebo. Quality-of-life measures were collected at baseline and 1 year, and again at 3 years in a subgroup of 1,511 women.
Estrogen and progestin resulted in no significant effects on general health, vitality, mental health, depressive symptoms or sexual satisfaction. After 1 year there was a statistically significant “but small and not clinically meaningful” benefit in terms of sleep disturbance, physical functioning, and bodily pain. At 3 years there were no significant benefits in terms of any quality-of-life outcomes.
Who may be affected by these findings?
Older, asymptomatic postmenopausal women on or considering hormone replacement therapy (HRT).
Objective
In this latest offering from the Women’s Health Initiative (WHI), researchers investigate whether estrogen plus progestin increases quality of life in postmenopausal women.
Methods and Results
This study consisted of 16,608 postmenopausal women ranging in age from 50 to 79 (mean, 63) with an intact uterus. Participants received either a combination of 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate (Prempro) or placebo. Quality-of-life measures were collected at baseline and 1 year, and again at 3 years in a subgroup of 1,511 women.
Estrogen and progestin resulted in no significant effects on general health, vitality, mental health, depressive symptoms or sexual satisfaction. After 1 year there was a statistically significant “but small and not clinically meaningful” benefit in terms of sleep disturbance, physical functioning, and bodily pain. At 3 years there were no significant benefits in terms of any quality-of-life outcomes.
Who may be affected by these findings?
Older, asymptomatic postmenopausal women on or considering hormone replacement therapy (HRT).
Objective
In this latest offering from the Women’s Health Initiative (WHI), researchers investigate whether estrogen plus progestin increases quality of life in postmenopausal women.
Methods and Results
This study consisted of 16,608 postmenopausal women ranging in age from 50 to 79 (mean, 63) with an intact uterus. Participants received either a combination of 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate (Prempro) or placebo. Quality-of-life measures were collected at baseline and 1 year, and again at 3 years in a subgroup of 1,511 women.
Estrogen and progestin resulted in no significant effects on general health, vitality, mental health, depressive symptoms or sexual satisfaction. After 1 year there was a statistically significant “but small and not clinically meaningful” benefit in terms of sleep disturbance, physical functioning, and bodily pain. At 3 years there were no significant benefits in terms of any quality-of-life outcomes.
Who may be affected by these findings?
Older, asymptomatic postmenopausal women on or considering hormone replacement therapy (HRT).
Another study links genital prolapse to incontinence
Objective
Researchers investigated the rate of anal incontinence in women who present with urinary incontinence and genital prolapse.
Method and results
In this study of almost 900 women, 20% of those with urinary incontinence and pelvic-organ prolapse also had anal incontinence. Subjects completed a bowel questionnaire and underwent a detailed exam. Researchers noted associations between anal incontinence and infant birth weights of 3,800 g or greater, rectocele greater than grade 2, urinary incontinence, hemorrhoidectomy, and irritable bowel syndrome.
Numerous studies report similar rates of anal incontinence associated with genital prolapse.1,2
Expert commentary
The social stigma of anal incontinence is not to be underestimated. Given the risk for anal incontinence from vaginal delivery and the inherent risks of elective cesarean section, which should we recommend for our patients? With the evidence before us, now is the time for a paradigm shift. While some academics and women’s rights groups dispute the utility and safety of elective cesarean delivery, investigations such as this one indicate that, in selected patients, it may be better.
Meschia and colleagues found a strong association between anal incontinence and urinary incontinence and genital prolapse, noting that this evidence is “consistent with the theory of a common pathogen mechanism for anal and genuine stress incontinence.” But do we really need more studies telling us that women who deliver large babies have more pelvic-floor dysfunction? As any pelvic reconstructive surgeon can attest, pelvic prolapse, urinary and fecal incontinence, and pelvic-floor dysfunction are epidemic. In a recent survey of obstetricians, many indicated that, given the choice, they would opt for elective cesarean section for themselves or family members.3
Many doctors resist when a patient asks for a specific mode of delivery. These physicians may feel such a request undermines their authority and somehow implies that a layperson knows best. When the evidence yields a clear message, however, it should be heeded: Cesarean delivery has a protective effect on the pelvis.
As O’Boyle outlines in an excellent opinion paper,4 we can set policy based on antiquated concepts, or we can conduct open, informed discussions with patients in the spirit of a true partnership and mutual decision-making.
Bottom line
Doctors don’t cause pelvic dysfunction during delivery, nature does. By communicating this concept we can help our patients make choices—and limit our already-catastrophic exposure to litigation.
1. McArthur C, Bick D, Keighley M. Faecal incontinence after childbirth. Br J Obstet Gynaecol. 1997;104:46-50.
2. Sultan AH, Kamn MA, Hudson CN, Thomas JM, Bartram CI. Anal-sphincter disruption during vaginal delivery. N Engl J Med. 1993;329:1905-1911.
3. Land R, Parry A, Rane A, Wilson D. Personal p of obstetricians towards childbirth. Aust N Z J Obstet Gynaecol. 2001;41:249-252.
4. O’Boyle AL, Davis GD, Calhoun BC. Informed consent and birth: Protecting the pelvic floor and ourselves. Am J Obstet Gynecol. 2002;187:981-983.
Objective
Researchers investigated the rate of anal incontinence in women who present with urinary incontinence and genital prolapse.
Method and results
In this study of almost 900 women, 20% of those with urinary incontinence and pelvic-organ prolapse also had anal incontinence. Subjects completed a bowel questionnaire and underwent a detailed exam. Researchers noted associations between anal incontinence and infant birth weights of 3,800 g or greater, rectocele greater than grade 2, urinary incontinence, hemorrhoidectomy, and irritable bowel syndrome.
Numerous studies report similar rates of anal incontinence associated with genital prolapse.1,2
Expert commentary
The social stigma of anal incontinence is not to be underestimated. Given the risk for anal incontinence from vaginal delivery and the inherent risks of elective cesarean section, which should we recommend for our patients? With the evidence before us, now is the time for a paradigm shift. While some academics and women’s rights groups dispute the utility and safety of elective cesarean delivery, investigations such as this one indicate that, in selected patients, it may be better.
Meschia and colleagues found a strong association between anal incontinence and urinary incontinence and genital prolapse, noting that this evidence is “consistent with the theory of a common pathogen mechanism for anal and genuine stress incontinence.” But do we really need more studies telling us that women who deliver large babies have more pelvic-floor dysfunction? As any pelvic reconstructive surgeon can attest, pelvic prolapse, urinary and fecal incontinence, and pelvic-floor dysfunction are epidemic. In a recent survey of obstetricians, many indicated that, given the choice, they would opt for elective cesarean section for themselves or family members.3
Many doctors resist when a patient asks for a specific mode of delivery. These physicians may feel such a request undermines their authority and somehow implies that a layperson knows best. When the evidence yields a clear message, however, it should be heeded: Cesarean delivery has a protective effect on the pelvis.
As O’Boyle outlines in an excellent opinion paper,4 we can set policy based on antiquated concepts, or we can conduct open, informed discussions with patients in the spirit of a true partnership and mutual decision-making.
Bottom line
Doctors don’t cause pelvic dysfunction during delivery, nature does. By communicating this concept we can help our patients make choices—and limit our already-catastrophic exposure to litigation.
Objective
Researchers investigated the rate of anal incontinence in women who present with urinary incontinence and genital prolapse.
Method and results
In this study of almost 900 women, 20% of those with urinary incontinence and pelvic-organ prolapse also had anal incontinence. Subjects completed a bowel questionnaire and underwent a detailed exam. Researchers noted associations between anal incontinence and infant birth weights of 3,800 g or greater, rectocele greater than grade 2, urinary incontinence, hemorrhoidectomy, and irritable bowel syndrome.
Numerous studies report similar rates of anal incontinence associated with genital prolapse.1,2
Expert commentary
The social stigma of anal incontinence is not to be underestimated. Given the risk for anal incontinence from vaginal delivery and the inherent risks of elective cesarean section, which should we recommend for our patients? With the evidence before us, now is the time for a paradigm shift. While some academics and women’s rights groups dispute the utility and safety of elective cesarean delivery, investigations such as this one indicate that, in selected patients, it may be better.
Meschia and colleagues found a strong association between anal incontinence and urinary incontinence and genital prolapse, noting that this evidence is “consistent with the theory of a common pathogen mechanism for anal and genuine stress incontinence.” But do we really need more studies telling us that women who deliver large babies have more pelvic-floor dysfunction? As any pelvic reconstructive surgeon can attest, pelvic prolapse, urinary and fecal incontinence, and pelvic-floor dysfunction are epidemic. In a recent survey of obstetricians, many indicated that, given the choice, they would opt for elective cesarean section for themselves or family members.3
Many doctors resist when a patient asks for a specific mode of delivery. These physicians may feel such a request undermines their authority and somehow implies that a layperson knows best. When the evidence yields a clear message, however, it should be heeded: Cesarean delivery has a protective effect on the pelvis.
As O’Boyle outlines in an excellent opinion paper,4 we can set policy based on antiquated concepts, or we can conduct open, informed discussions with patients in the spirit of a true partnership and mutual decision-making.
Bottom line
Doctors don’t cause pelvic dysfunction during delivery, nature does. By communicating this concept we can help our patients make choices—and limit our already-catastrophic exposure to litigation.
1. McArthur C, Bick D, Keighley M. Faecal incontinence after childbirth. Br J Obstet Gynaecol. 1997;104:46-50.
2. Sultan AH, Kamn MA, Hudson CN, Thomas JM, Bartram CI. Anal-sphincter disruption during vaginal delivery. N Engl J Med. 1993;329:1905-1911.
3. Land R, Parry A, Rane A, Wilson D. Personal p of obstetricians towards childbirth. Aust N Z J Obstet Gynaecol. 2001;41:249-252.
4. O’Boyle AL, Davis GD, Calhoun BC. Informed consent and birth: Protecting the pelvic floor and ourselves. Am J Obstet Gynecol. 2002;187:981-983.
1. McArthur C, Bick D, Keighley M. Faecal incontinence after childbirth. Br J Obstet Gynaecol. 1997;104:46-50.
2. Sultan AH, Kamn MA, Hudson CN, Thomas JM, Bartram CI. Anal-sphincter disruption during vaginal delivery. N Engl J Med. 1993;329:1905-1911.
3. Land R, Parry A, Rane A, Wilson D. Personal p of obstetricians towards childbirth. Aust N Z J Obstet Gynaecol. 2001;41:249-252.
4. O’Boyle AL, Davis GD, Calhoun BC. Informed consent and birth: Protecting the pelvic floor and ourselves. Am J Obstet Gynecol. 2002;187:981-983.
Is HPV DNA testing a reliable alternative to the Pap test?
Context
Screening women with limited access to health care is difficult—in both the United States and the third world. We now know that invasive cervical carcinoma is universally associated with persistent human Papillomavirus (HPV) infection, and that only a small subset of viral types place women at high risk for developing cervical intraepithelial neoplasia (CIN) 3 or carcinoma.
In an effort to increase the sensitivity of the initial encounter with the healthcare system among women with limited resources and access, several researchers and agencies are investigating the use of HPV DNA testing in conjunction with standard Papanicolaou (Pap) smears, thin-layer smears, or HPV testing alone as the primary screening method.
Method and Results
This well-designed prospective trial uses a large Planned Parenthood population to compare the sensitivity, specificity, and frequency of referral for colposcopy in patients undergoing thin-layer Pap smear, HPV testing by polymerase chain reaction (PCR), or HPV testing by liquid-based RNA-DNA hybridization capture with signal amplification.
Unfortunately, the demographics of the study population are not necessarily comparable to those of the average practicing Ob/Gyn. Therefore, it may not be appropriate to extrapolate the results universally. The mean age of participants was 25 years; more than 80% of the eligible women were under age 30. The prevalence of HPV DNA, cervical dysplasia, and carcinoma is significantly different in this age group, compared with women over 30 years of age.
Women in the trial were predominantly Caucasian, with an average of 5 sexual partners in the group under 25 years of age and 9 sexual partners in the over-30 group.
As the authors point out, another limitation of the study is the failure of some patients to return for colposcopy when recommended by the protocol. Only 72.7% of women with abnormal Pap test results and 67.9% of women with high-risk HPV DNA returned for colposcopic evaluation. This limited the reliability of the sensitivity and specificity calculations to some extent.
As expected, HPV DNA testing was more sensitive but less specific than cytology in identifying high-grade dysplasia or cervical carcinoma. HPV DNA by signal amplification identifies more intermediate- and low-risk HPV types than the PCR technique. Therefore, this method has a higher sensitivity but lower specificity for detecting high-grade lesions. All the screening strategies Human Papillomavirus were more sensitive for identifying CIN 3 or higher in women younger than 30 years of age. Specificity, however, was significantly greater for women older than 30 years of age.
Who May Be Affected?
All sexually active women.
Persistence of high-risk HPV DNA types—not the initial presence—is a risk factor for cervical carcinoma.
Expert Commentary
Universal cervical cytology screening of sexually active women has greatly decreased the incidence of invasive cervical carcinoma in developed countries. Recently, commercialization of molecular biology techniques and cytology processing improvements have led to new products for cervical carcinoma screening.
In counseling patients, it is important to remember that it is the persistence of high-risk HPV DNA types—not the initial presence—that is a risk factor for cervical carcinoma. Most HPV infections regress spontaneously, with only about 10% of women remaining infected at 5 years. Young, recently sexually active women are likely to test positive for multiple HPV types. If they can be educated to comply with routine screening recommendations, it will not be clinically useful to employ primary screening with HPV DNA testing.
The downside to universal HPV DNA primary screening is that large numbers of women with transient high-risk HPV infections have normal cytology findings and no “disease.” Labeling them as high risk would create a psychological burden on both the patient and the physician.
Until we have well-studied clinical protocols for managing these patients, we should avoid this dilemma by continuing current Pap screening in women who have good access to care and who are willing to participate in screening at appropriate intervals.
Primary HPV DNA screening is appropriate for women who are unwilling or unable to participate in routine screening.
Bottom Line
Screening strategies for cervical cancer are evolving. Techniques appropriate for young, sexually active women with somewhat limited access to care should not be extrapolated to a low-risk, stable, monogamous population.
If women understand the limitations of cytology screening and the need for repeated tests to capture the majority of true abnormal findings, and if they have financial and geographic access to routine care, it makes sense to use a specific but somewhat less sensitive testing strategy, i.e., cytology screening.
For women with minimal access to routine care, it is essential to use the simplest, most sensitive test to minimize false negatives. It is these women in whom primary screening with HPV DNA with or without cytology makes sense.
Suggested Reading
- Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348:489-901.
Context
Screening women with limited access to health care is difficult—in both the United States and the third world. We now know that invasive cervical carcinoma is universally associated with persistent human Papillomavirus (HPV) infection, and that only a small subset of viral types place women at high risk for developing cervical intraepithelial neoplasia (CIN) 3 or carcinoma.
In an effort to increase the sensitivity of the initial encounter with the healthcare system among women with limited resources and access, several researchers and agencies are investigating the use of HPV DNA testing in conjunction with standard Papanicolaou (Pap) smears, thin-layer smears, or HPV testing alone as the primary screening method.
Method and Results
This well-designed prospective trial uses a large Planned Parenthood population to compare the sensitivity, specificity, and frequency of referral for colposcopy in patients undergoing thin-layer Pap smear, HPV testing by polymerase chain reaction (PCR), or HPV testing by liquid-based RNA-DNA hybridization capture with signal amplification.
Unfortunately, the demographics of the study population are not necessarily comparable to those of the average practicing Ob/Gyn. Therefore, it may not be appropriate to extrapolate the results universally. The mean age of participants was 25 years; more than 80% of the eligible women were under age 30. The prevalence of HPV DNA, cervical dysplasia, and carcinoma is significantly different in this age group, compared with women over 30 years of age.
Women in the trial were predominantly Caucasian, with an average of 5 sexual partners in the group under 25 years of age and 9 sexual partners in the over-30 group.
As the authors point out, another limitation of the study is the failure of some patients to return for colposcopy when recommended by the protocol. Only 72.7% of women with abnormal Pap test results and 67.9% of women with high-risk HPV DNA returned for colposcopic evaluation. This limited the reliability of the sensitivity and specificity calculations to some extent.
As expected, HPV DNA testing was more sensitive but less specific than cytology in identifying high-grade dysplasia or cervical carcinoma. HPV DNA by signal amplification identifies more intermediate- and low-risk HPV types than the PCR technique. Therefore, this method has a higher sensitivity but lower specificity for detecting high-grade lesions. All the screening strategies Human Papillomavirus were more sensitive for identifying CIN 3 or higher in women younger than 30 years of age. Specificity, however, was significantly greater for women older than 30 years of age.
Who May Be Affected?
All sexually active women.
Persistence of high-risk HPV DNA types—not the initial presence—is a risk factor for cervical carcinoma.
Expert Commentary
Universal cervical cytology screening of sexually active women has greatly decreased the incidence of invasive cervical carcinoma in developed countries. Recently, commercialization of molecular biology techniques and cytology processing improvements have led to new products for cervical carcinoma screening.
In counseling patients, it is important to remember that it is the persistence of high-risk HPV DNA types—not the initial presence—that is a risk factor for cervical carcinoma. Most HPV infections regress spontaneously, with only about 10% of women remaining infected at 5 years. Young, recently sexually active women are likely to test positive for multiple HPV types. If they can be educated to comply with routine screening recommendations, it will not be clinically useful to employ primary screening with HPV DNA testing.
The downside to universal HPV DNA primary screening is that large numbers of women with transient high-risk HPV infections have normal cytology findings and no “disease.” Labeling them as high risk would create a psychological burden on both the patient and the physician.
Until we have well-studied clinical protocols for managing these patients, we should avoid this dilemma by continuing current Pap screening in women who have good access to care and who are willing to participate in screening at appropriate intervals.
Primary HPV DNA screening is appropriate for women who are unwilling or unable to participate in routine screening.
Bottom Line
Screening strategies for cervical cancer are evolving. Techniques appropriate for young, sexually active women with somewhat limited access to care should not be extrapolated to a low-risk, stable, monogamous population.
If women understand the limitations of cytology screening and the need for repeated tests to capture the majority of true abnormal findings, and if they have financial and geographic access to routine care, it makes sense to use a specific but somewhat less sensitive testing strategy, i.e., cytology screening.
For women with minimal access to routine care, it is essential to use the simplest, most sensitive test to minimize false negatives. It is these women in whom primary screening with HPV DNA with or without cytology makes sense.
Suggested Reading
- Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348:489-901.
Context
Screening women with limited access to health care is difficult—in both the United States and the third world. We now know that invasive cervical carcinoma is universally associated with persistent human Papillomavirus (HPV) infection, and that only a small subset of viral types place women at high risk for developing cervical intraepithelial neoplasia (CIN) 3 or carcinoma.
In an effort to increase the sensitivity of the initial encounter with the healthcare system among women with limited resources and access, several researchers and agencies are investigating the use of HPV DNA testing in conjunction with standard Papanicolaou (Pap) smears, thin-layer smears, or HPV testing alone as the primary screening method.
Method and Results
This well-designed prospective trial uses a large Planned Parenthood population to compare the sensitivity, specificity, and frequency of referral for colposcopy in patients undergoing thin-layer Pap smear, HPV testing by polymerase chain reaction (PCR), or HPV testing by liquid-based RNA-DNA hybridization capture with signal amplification.
Unfortunately, the demographics of the study population are not necessarily comparable to those of the average practicing Ob/Gyn. Therefore, it may not be appropriate to extrapolate the results universally. The mean age of participants was 25 years; more than 80% of the eligible women were under age 30. The prevalence of HPV DNA, cervical dysplasia, and carcinoma is significantly different in this age group, compared with women over 30 years of age.
Women in the trial were predominantly Caucasian, with an average of 5 sexual partners in the group under 25 years of age and 9 sexual partners in the over-30 group.
As the authors point out, another limitation of the study is the failure of some patients to return for colposcopy when recommended by the protocol. Only 72.7% of women with abnormal Pap test results and 67.9% of women with high-risk HPV DNA returned for colposcopic evaluation. This limited the reliability of the sensitivity and specificity calculations to some extent.
As expected, HPV DNA testing was more sensitive but less specific than cytology in identifying high-grade dysplasia or cervical carcinoma. HPV DNA by signal amplification identifies more intermediate- and low-risk HPV types than the PCR technique. Therefore, this method has a higher sensitivity but lower specificity for detecting high-grade lesions. All the screening strategies Human Papillomavirus were more sensitive for identifying CIN 3 or higher in women younger than 30 years of age. Specificity, however, was significantly greater for women older than 30 years of age.
Who May Be Affected?
All sexually active women.
Persistence of high-risk HPV DNA types—not the initial presence—is a risk factor for cervical carcinoma.
Expert Commentary
Universal cervical cytology screening of sexually active women has greatly decreased the incidence of invasive cervical carcinoma in developed countries. Recently, commercialization of molecular biology techniques and cytology processing improvements have led to new products for cervical carcinoma screening.
In counseling patients, it is important to remember that it is the persistence of high-risk HPV DNA types—not the initial presence—that is a risk factor for cervical carcinoma. Most HPV infections regress spontaneously, with only about 10% of women remaining infected at 5 years. Young, recently sexually active women are likely to test positive for multiple HPV types. If they can be educated to comply with routine screening recommendations, it will not be clinically useful to employ primary screening with HPV DNA testing.
The downside to universal HPV DNA primary screening is that large numbers of women with transient high-risk HPV infections have normal cytology findings and no “disease.” Labeling them as high risk would create a psychological burden on both the patient and the physician.
Until we have well-studied clinical protocols for managing these patients, we should avoid this dilemma by continuing current Pap screening in women who have good access to care and who are willing to participate in screening at appropriate intervals.
Primary HPV DNA screening is appropriate for women who are unwilling or unable to participate in routine screening.
Bottom Line
Screening strategies for cervical cancer are evolving. Techniques appropriate for young, sexually active women with somewhat limited access to care should not be extrapolated to a low-risk, stable, monogamous population.
If women understand the limitations of cytology screening and the need for repeated tests to capture the majority of true abnormal findings, and if they have financial and geographic access to routine care, it makes sense to use a specific but somewhat less sensitive testing strategy, i.e., cytology screening.
For women with minimal access to routine care, it is essential to use the simplest, most sensitive test to minimize false negatives. It is these women in whom primary screening with HPV DNA with or without cytology makes sense.
Suggested Reading
- Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348:489-901.