Clinical Review

The authors report no financial relationships relevant to this article.

We’ve heard that troubling statistic: Approximately 50% of pregnancies in the United States are unintended. But did you know that one half of those unintended pregnancies occur in women who were using some form of birth control at the time of conception?¹ Such pregnancies are due to discontinuation of the method, incorrect use, or method failure.² The focus of this article is contraceptive counseling, with special attention to:

• which methods of combination hormonal contraception women prefer
• the controversy surrounding the contraceptive patch in regard to thromboembolic disease
• long-acting reversible contraception (LARC), such as the intrauterine device (IUD) and the contraceptive implant, with an emphasis on how LARC is of benefit to both the patient and society.

The ultimate goal of good contraceptive counseling? To help women choose the easiest and most effective method with the fewest side effects.

In head-to-head comparison, women preferred the ring to the patch

Creinin MD, Meyn LA, Borgatta L, et al. Multicenter comparison of the contraceptive ring and patch. Obstet Gynecol. 2008;111:267–277.

The ethinyl estradiol/etonogestril vaginal ring (NuvaRing) and the ethinyl estradiol/norelgestromin patch (OrthoEvra)—both approved by the Food and Drug Administration (FDA) in 2001—are the only nonoral forms of combined hormonal contraception on the market. These methods are said to increase patient compliance and, potentially, efficacy, because they are nondaily forms of contraception.

Until recently, these methods had been compared only with the combination oral contraceptive (OC), but a recent trial compared them directly to each other. At the conclusion of the study, 71% of ring users and 26.5% of patch users planned to continue using the assigned method (P<.001).

This information should aid clinicians in counseling women about which combination hormonal method to choose.

Participants started out using the OC

The multicenter, randomized, controlled clinical trial comparing the patch and ring included 479 women who were using, and happy with, the combination OC. After rating their satisfaction with the OC, women were randomized to the patch or ring and given 3 months’ worth of product. Follow-up involved only two telephone calls and one visit at the end of the third cycle, because this degree of monitoring was thought to mimic clinical practice.

The percentages of women who completed three cycles of their assigned product were 94.6% and 88.2% in the ring and patch groups, respectively (P=.03). The most common reasons for early discontinuation in the ring group were discomfort and adverse effects. In the patch group, the most common reasons were adverse effects, skin irritation, and adherence problems.

Even after adjusting for age, education, and whether an OC was actively being used at the time the study began, patch users were twice as likely to discontinue the patch at the end of three cycles and seven times more likely to state that they did not want to continue the patch.

Adverse effects were greater than with the pill

Women switching from pill to patch were significantly more likely to report breast pain, nausea, skin rash, longer menstrual bleeding, and menstrual pain than women who switched from the pill to the ring (P<.001).

Women who switched from the pill to the ring were more likely to experience vaginal discharge (P=.003) and a larger amount of vaginal discharge than patch users (P<.001).

These findings are similar to those of previous studies that compared the patch with the pill, noting that breast discomfort, application-site reaction, and dysmenorrhea were more common in patch than pill users.³ Earlier studies also found the ring to be associated with complaints of vaginal discharge.^4,5

Findings may not be generalizable

The most important finding from this direct comparison is the difference in patient satisfaction between groups. Visual analog scales showed that women using the ring were happier with the ring than with the pill, whereas women using the patch were happier with the pill than with the patch (P<.001). Questionnaires revealed that women were more satisfied with the ring than they were with the patch, and were more likely to recommend the ring than the patch to a friend (P<.001).

Based on continuation rates, patient satisfaction, and adverse-effect profiles, women in this study clearly preferred the ring to the pill, and the pill to the patch. When using this information to counsel patients, however, it is important to recall that this population was specific. The women had been using an OC, with which they were happy. This study cannot necessarily be generalized to women who are just initiating combination hormonal contraception, but it can be helpful in counseling a patient who may want to switch from an OC to a method that involves nondaily dosing.

Does the contraceptive patch raise the risk of thromboembolism?

Jick SS, Kaye JA, Russman S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73:223–228.

Jick S, Kaye JA, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2007;76:4–7.

Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive users. Obstet Gynecol. 2007;109(2 Pt 1):339–346.

Both the media and regulatory agencies have raised concerns about whether the contraceptive patch heightens the risk of thromboembolism and is less effective in women above a certain body weight.

The controversy surrounding thromboembolic disease stems from a pharmacokinetics study by van den Heuvel and colleagues that compared serum ethinyl estradiol levels in users of the patch, vaginal ring, and a combination OC containing 30 μg of ethinyl estradiol and 150 μg of levonorgestrel.⁶ Women randomized to the patch had serum ethinyl estradiol levels 1.6 times higher than women randomized to an OC, and 3.4 times higher than women randomized to the ring.

These findings led the FDA to update package labeling of the patch to warn health-care providers and patients that the patch exposes women to 60% more estrogen and may increase the risk of thromboembolic events. Oddly, the FDA did not require any labeling change to combination OCs to indicate that they contain up to twice as much estrogen as the contraceptive ring.

A set of studies finds no elevated risk

Although the study by van den Heuvel and associates raised the possibility of increased blood clots in patch users, no association between the two had been corroborated at the time it was published.⁶ Since then, three epidemiological studies have explored the potential link between thromboembolic events and use of the patch.

In the first of these studies, Jick and colleagues used the PharMetrics database to extract data on users of the patch and norg-estimate-containing OCs. This database contains drug prescription information, patient demographic data, and ICD-9 billing codes submitted by managed care health plans. A nested case-control study design was used to compare patch and pill users and control for confounding variables.

The base population was women 15 to 44 years old who were new users of the patch or a norgestimate-containing OC. A thromboembolic event was diagnosed if the patient’s record included a diagnosis code for pulmonary embolus, deep vein thrombosis, or an emergency room visit or diagnostic testing indicating venous thromboembolism (VTE). These diagnosis codes, combined with the prescription of long-term anticoagulation therapy, strengthened the identification of cases. As many as four controls were selected for each case.

The 215,769 women included in this study contributed 147,323 woman-years of exposure to the drugs. There were 31 and 37 cases of VTE identified in the patch and pill groups, respectively, with an incidence of 52.8 for every 100,000 woman-years in the patch group and 41.8 for every 100,000 woman-years in the pill group and an unadjusted, matched odds ratio of VTE in patch versus pill users of 0.9. When the data were adjusted for duration of drug exposure, the odds ratio did not change.

A follow-up study by Jick and associates, published in 2007, had the same study design and included 17 additional months of data. Another 56 cases of VTE were diagnosed. The odds ratio for patch users, compared with pill users, was 1.1. When data from the two studies were combined, 73 and 51 total cases of VTE had occurred in the pill and patch groups, respectively. The overall odds ratio was 1.0.

A third study finds significantly heightened risk

Cole and associates studied insurance claims data from UnitedHealthcare, a database containing medical and prescription claim information as well as patient demographics. Because researchers used pharmacy dispensing records, they were able to include women 15 to 44 years old who had received at least one prescription for the contraceptive patch or a norgestimate-containing OC with 35 μg of ethinyl estradiol.

Unlike the studies by Jick and colleagues, the study by Cole and associates considered all women eligible, even if they had used OCs in the past. Cases of VTE, stroke, and acute myocardial infarction (AMI) were abstracted from this group, identified from insurance claim information, and confirmed by chart review. Review of medical records is an important strength of this study; no such review was done in the studies by Jick and colleagues. Four controls were matched to each case, by age and duration of contraceptive use.

(This study was commissioned in conjunction with both the FDA and Johnson & Johnson, makers of the contraceptive patch, but researchers had full control over the data and results and were not required to consult with Johnson & Johnson when reporting findings.)

There were 49,048 woman-years of exposure to the patch and 202,344 woman-years of exposure to the pill, with an incidence of VTE of 40.8 and 18.3 for every 100,000 woman-years in patch and pill users, respectively. The incidence of AMI was 6.1 and 3.5 for every 100,000 woman-years in patch and pill users, respectively. No ischemic strokes were noted in patch users.

The adjusted incidence ratio for VTE in patch users compared with pill users was 2.2, and for AMI it was 1.8. Following publication of this study, the FDA issued a statement in January of this year that women using the patch face an increased risk of VTE, compared with women using the pill. Package labeling was changed to reflect this heightened risk.

Reasons for different findings

The studies by Jick and colleagues and Cole and associates present very different findings. The studies by Jick and colleagues give the impression that there is no increased risk of VTE in patch users compared with pill users, but the studies have significant flaws. First, Jick and colleagues do not confirm the diagnosis of VTE in the medical record. This is particularly problematic because the reported number of pulmonary emboli (PE) is very high, compared with the number of deep vein thromboses. The 2006 study found 42 cases of PE and only 26 cases of deep vein thrombosis. Because the latter is more common than PE, this could indicate that deep vein thrombosis was underdiagnosed.

Another shortcoming is that Jick and colleagues included only nonfatal thromboembolic events, which may mean that they missed many cases of fatal VTE because they were not looking for this information. The inclusion of new initiators only also may have skewed the data. This would mean that former users of an OC may have been included in the patch group but were ineligible for inclusion in the pill group. This may bias the data toward experienced hormonal contraceptive users in the patch group, thereby falsely lowering the VTE rate.

The study by Cole and associates also has limitations. It included long-term users of hormonal contraceptives in both the patch and the OC groups, which may bias the data toward lower rates of VTE, AMI, and stroke for the same reasons cited above. One would assume that this bias was corrected, because prior use was allowed in both groups, making the bias equally distributed, but there is no way to confirm this with any degree of certainty.

All three studies have some flaws in common

All three studies used prescription information to determine exposure, but there is no guarantee that the women who filled the prescriptions actually used the agents. Patients given drug samples by their clinicians were overlooked because these samples are not tracked through pharmacy data.

Because the data were collected from insurance claims information of privately insured patients, it is impossible to generalize these findings to the general population. We cannot use the findings to determine whether the same results would be seen in uninsured women or women insured through nonprivate programs such as Medicaid or the Veterans Administration.

So what’s the bottom line?

Health-care providers should be cautious about citing these studies as “evidence” when advising patients about the risk of VTE while using the patch. The twofold increased risk of VTE observed in patch users and the almost twofold increased risk of AMI observed by Cole and associates cannot be completely ignored, however, particularly because this study was better designed than those by Jick and colleagues.

It is more important to remember that the incidence of VTE in patch users is extremely low. If a patient has been using the patch, is happy with the method, and has had no adverse effects, there is no reason, based on these findings, to discontinue it. When counseling new initiators, the best that can be done is to explain the potential risks and side effects associated with the method and allow the patient to make an informed choice using the information that is available.

If the increased risk of VTE is accurate, it would still be equal to or lower than the risk during pregnancy. A recent review found the overall incidence of VTE in pregnancy or the postpartum period to be 200 for every 100,000 woman-years.⁷

Why don’t American women choose long-acting reversible contraception?

Do American women not want to use long-acting reversible contraception (LARC), or are we, as providers, failing to properly educate them about its benefits?

The ParaGard copper IUD, the Mirena levonorgestrel intrauterine system (LNGIUS), and the Implanon etonorgestrel contraceptive implant are all highly effective, convenient, long-duration, and reversible (FIGURE). Despite substantial evidence indicating that these methods are well tolerated and highly effective, only about 2% of American women are choosing them to prevent pregnancy.¹ This rate lags far behind other countries in IUD utilization. In contrast, more than 50% of contraceptive users in China and Egypt are using intrauterine contraception.⁸

FIGURE

Copper IUD is effective for 12 years or longer

The copper IUD is FDA-approved for 10 years of use, although studies continue to support its continued efficacy for 12 years or longer.⁹ The 1-year perfect-use failure rate is 0.6%, and the typical use failure rate is 0.5% to 0.8%.¹⁰ The total failure rate over 12 years is 2.2%.⁹

Benefits. The copper IUD does not increase the risk of intrauterine infection and is safe to place in nulliparous patients.¹¹ It is an excellent choice for women who clearly prefer to have monthly menses and for women who have personal or medical contraindications to hormonal birth control. Women using this method of birth control can expect excellent efficacy, rapid reversibility, and minimal side effects.

Adverse effects. The most common adverse events in copper IUD users are heavier menses and dysmenorrhea. Approximately 4.5% of women discontinue the copper IUD in the first year of use because of these particular side effects.¹²

LNG-IUS: Highly effective, with important noncontraceptive benefits

This method of birth control is comparable to the copper IUD in terms of efficacy and tolerability. It is FDA-approved for 5 years of use, with a cumulative 5-year failure rate of 0.7 for every 100 women.¹³ One small study demonstrated that this method is potentially effective up to 7 years, with a 1.1% pregnancy rate.¹¹ With perfect use, the first-year pregnancy rate is 0.1% to 0.2%.¹⁴

Benefits. The progestin component provides noncontraceptive benefits, including a reduction in menstrual bleeding and dysmenorrhea,¹⁵ treatment of endometrial hyperplasia¹⁶ and endometrial cancer,¹⁷ endometrial protection in women using tamoxifen,¹⁸ treatment of endometriosis,¹⁹ and protection from pelvic inflammatory disease.²⁰

Adverse effects. The primary disadvantage of this device is a change in bleeding pattern in some women, who may experience irregular spotting, primarily in the first 3 to 6 months.²¹ About 20% of users will become amenorrheic by 12 months of use, a feature that is highly desirable for many, but troubling to some.

Implant is essentially 100% effective

The newest LARC device is the etonorgestrel implant, which was approved by the FDA in July 2006. The single-rod implant is typically placed in the subcuticular tissue of the non-dominant arm, although placement in the dominant arm is fine if the patient prefers.

Benefits. In a 3-year study involving 635 subjects, no pregnancies were reported.²² The reported Pearl index of 0.38 pregnancies for every 100,000 woman-years of use relates to pregnancies that occurred shortly after discontinuation rather than during actual use. These studies included only women below 130% of their ideal body weight who were not using liver enzyme-inducing medications. The pregnancy rate in women who use such medications, or weigh above 130% of their ideal body weight, is unknown. Postmarketing surveillance has reported some pregnancies, as would be expected. The device is easily inserted and easily removed as long as 3 years later.

Adverse effects. The primary adverse effect of this implant is bleeding disturbances; discontinuation was usually due to this side effect.²² The cumulative discontinuation rate was 10% at 6 months, 20% at 12 months, 31% at 2 years, and 32.2% at 3 years.²²

Training required. FDA approval included a stipulation that practitioners complete company-sponsored training (www.implanonusa.com) to insert and remove the device.

Overall benefits include minimal side effects, low cost

All LARC methods provide excellent protection against pregnancy (equal to or better than sterilization), have minimal side effects, and are rapidly reversible. They are also appropriate for women in whom combination hormonal contraception is contraindicated, such as smokers older than 35 years and women who have had VTE.

A final and important advantage: These methods are more cost-effective than other contraceptive methods, including combination OCs. They may require a higher initial investment, but the LNG-IUS and copper IUD are the least costly methods of contraception over 5 years of use.²³

As providers continue to educate themselves and help women gain a better understanding of which methods are truly highly effective, they will likely begin to recommend LARC more often. Use of these devices has the potential to significantly decrease the high rate of unintended pregnancy.

Authors’ note: The figure at right depicts how the efficacy and convenience of contraceptive options rise (and side effects fall) along a continuum. LARC methods are “high up the ladder”—an observation that serves as food for thought as we counsel patients about what methods of birth control are best for them.

The authors report no financial relationships relevant to this article.

We’ve heard that troubling statistic: Approximately 50% of pregnancies in the United States are unintended. But did you know that one half of those unintended pregnancies occur in women who were using some form of birth control at the time of conception?¹ Such pregnancies are due to discontinuation of the method, incorrect use, or method failure.² The focus of this article is contraceptive counseling, with special attention to:

• which methods of combination hormonal contraception women prefer
• the controversy surrounding the contraceptive patch in regard to thromboembolic disease
• long-acting reversible contraception (LARC), such as the intrauterine device (IUD) and the contraceptive implant, with an emphasis on how LARC is of benefit to both the patient and society.

The ultimate goal of good contraceptive counseling? To help women choose the easiest and most effective method with the fewest side effects.

In head-to-head comparison, women preferred the ring to the patch

Creinin MD, Meyn LA, Borgatta L, et al. Multicenter comparison of the contraceptive ring and patch. Obstet Gynecol. 2008;111:267–277.

The ethinyl estradiol/etonogestril vaginal ring (NuvaRing) and the ethinyl estradiol/norelgestromin patch (OrthoEvra)—both approved by the Food and Drug Administration (FDA) in 2001—are the only nonoral forms of combined hormonal contraception on the market. These methods are said to increase patient compliance and, potentially, efficacy, because they are nondaily forms of contraception.

Until recently, these methods had been compared only with the combination oral contraceptive (OC), but a recent trial compared them directly to each other. At the conclusion of the study, 71% of ring users and 26.5% of patch users planned to continue using the assigned method (P<.001).

This information should aid clinicians in counseling women about which combination hormonal method to choose.

Participants started out using the OC

The multicenter, randomized, controlled clinical trial comparing the patch and ring included 479 women who were using, and happy with, the combination OC. After rating their satisfaction with the OC, women were randomized to the patch or ring and given 3 months’ worth of product. Follow-up involved only two telephone calls and one visit at the end of the third cycle, because this degree of monitoring was thought to mimic clinical practice.

The percentages of women who completed three cycles of their assigned product were 94.6% and 88.2% in the ring and patch groups, respectively (P=.03). The most common reasons for early discontinuation in the ring group were discomfort and adverse effects. In the patch group, the most common reasons were adverse effects, skin irritation, and adherence problems.

Even after adjusting for age, education, and whether an OC was actively being used at the time the study began, patch users were twice as likely to discontinue the patch at the end of three cycles and seven times more likely to state that they did not want to continue the patch.

Adverse effects were greater than with the pill

Women switching from pill to patch were significantly more likely to report breast pain, nausea, skin rash, longer menstrual bleeding, and menstrual pain than women who switched from the pill to the ring (P<.001).

Women who switched from the pill to the ring were more likely to experience vaginal discharge (P=.003) and a larger amount of vaginal discharge than patch users (P<.001).

These findings are similar to those of previous studies that compared the patch with the pill, noting that breast discomfort, application-site reaction, and dysmenorrhea were more common in patch than pill users.³ Earlier studies also found the ring to be associated with complaints of vaginal discharge.^4,5

Findings may not be generalizable

The most important finding from this direct comparison is the difference in patient satisfaction between groups. Visual analog scales showed that women using the ring were happier with the ring than with the pill, whereas women using the patch were happier with the pill than with the patch (P<.001). Questionnaires revealed that women were more satisfied with the ring than they were with the patch, and were more likely to recommend the ring than the patch to a friend (P<.001).

Based on continuation rates, patient satisfaction, and adverse-effect profiles, women in this study clearly preferred the ring to the pill, and the pill to the patch. When using this information to counsel patients, however, it is important to recall that this population was specific. The women had been using an OC, with which they were happy. This study cannot necessarily be generalized to women who are just initiating combination hormonal contraception, but it can be helpful in counseling a patient who may want to switch from an OC to a method that involves nondaily dosing.

Does the contraceptive patch raise the risk of thromboembolism?

Jick SS, Kaye JA, Russman S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73:223–228.

Jick S, Kaye JA, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2007;76:4–7.

Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive users. Obstet Gynecol. 2007;109(2 Pt 1):339–346.

Both the media and regulatory agencies have raised concerns about whether the contraceptive patch heightens the risk of thromboembolism and is less effective in women above a certain body weight.

The controversy surrounding thromboembolic disease stems from a pharmacokinetics study by van den Heuvel and colleagues that compared serum ethinyl estradiol levels in users of the patch, vaginal ring, and a combination OC containing 30 μg of ethinyl estradiol and 150 μg of levonorgestrel.⁶ Women randomized to the patch had serum ethinyl estradiol levels 1.6 times higher than women randomized to an OC, and 3.4 times higher than women randomized to the ring.

These findings led the FDA to update package labeling of the patch to warn health-care providers and patients that the patch exposes women to 60% more estrogen and may increase the risk of thromboembolic events. Oddly, the FDA did not require any labeling change to combination OCs to indicate that they contain up to twice as much estrogen as the contraceptive ring.

A set of studies finds no elevated risk

Although the study by van den Heuvel and associates raised the possibility of increased blood clots in patch users, no association between the two had been corroborated at the time it was published.⁶ Since then, three epidemiological studies have explored the potential link between thromboembolic events and use of the patch.

In the first of these studies, Jick and colleagues used the PharMetrics database to extract data on users of the patch and norg-estimate-containing OCs. This database contains drug prescription information, patient demographic data, and ICD-9 billing codes submitted by managed care health plans. A nested case-control study design was used to compare patch and pill users and control for confounding variables.

The base population was women 15 to 44 years old who were new users of the patch or a norgestimate-containing OC. A thromboembolic event was diagnosed if the patient’s record included a diagnosis code for pulmonary embolus, deep vein thrombosis, or an emergency room visit or diagnostic testing indicating venous thromboembolism (VTE). These diagnosis codes, combined with the prescription of long-term anticoagulation therapy, strengthened the identification of cases. As many as four controls were selected for each case.

The 215,769 women included in this study contributed 147,323 woman-years of exposure to the drugs. There were 31 and 37 cases of VTE identified in the patch and pill groups, respectively, with an incidence of 52.8 for every 100,000 woman-years in the patch group and 41.8 for every 100,000 woman-years in the pill group and an unadjusted, matched odds ratio of VTE in patch versus pill users of 0.9. When the data were adjusted for duration of drug exposure, the odds ratio did not change.

A follow-up study by Jick and associates, published in 2007, had the same study design and included 17 additional months of data. Another 56 cases of VTE were diagnosed. The odds ratio for patch users, compared with pill users, was 1.1. When data from the two studies were combined, 73 and 51 total cases of VTE had occurred in the pill and patch groups, respectively. The overall odds ratio was 1.0.

A third study finds significantly heightened risk

Cole and associates studied insurance claims data from UnitedHealthcare, a database containing medical and prescription claim information as well as patient demographics. Because researchers used pharmacy dispensing records, they were able to include women 15 to 44 years old who had received at least one prescription for the contraceptive patch or a norgestimate-containing OC with 35 μg of ethinyl estradiol.

Unlike the studies by Jick and colleagues, the study by Cole and associates considered all women eligible, even if they had used OCs in the past. Cases of VTE, stroke, and acute myocardial infarction (AMI) were abstracted from this group, identified from insurance claim information, and confirmed by chart review. Review of medical records is an important strength of this study; no such review was done in the studies by Jick and colleagues. Four controls were matched to each case, by age and duration of contraceptive use.

(This study was commissioned in conjunction with both the FDA and Johnson & Johnson, makers of the contraceptive patch, but researchers had full control over the data and results and were not required to consult with Johnson & Johnson when reporting findings.)

There were 49,048 woman-years of exposure to the patch and 202,344 woman-years of exposure to the pill, with an incidence of VTE of 40.8 and 18.3 for every 100,000 woman-years in patch and pill users, respectively. The incidence of AMI was 6.1 and 3.5 for every 100,000 woman-years in patch and pill users, respectively. No ischemic strokes were noted in patch users.

The adjusted incidence ratio for VTE in patch users compared with pill users was 2.2, and for AMI it was 1.8. Following publication of this study, the FDA issued a statement in January of this year that women using the patch face an increased risk of VTE, compared with women using the pill. Package labeling was changed to reflect this heightened risk.

Reasons for different findings

The studies by Jick and colleagues and Cole and associates present very different findings. The studies by Jick and colleagues give the impression that there is no increased risk of VTE in patch users compared with pill users, but the studies have significant flaws. First, Jick and colleagues do not confirm the diagnosis of VTE in the medical record. This is particularly problematic because the reported number of pulmonary emboli (PE) is very high, compared with the number of deep vein thromboses. The 2006 study found 42 cases of PE and only 26 cases of deep vein thrombosis. Because the latter is more common than PE, this could indicate that deep vein thrombosis was underdiagnosed.

Another shortcoming is that Jick and colleagues included only nonfatal thromboembolic events, which may mean that they missed many cases of fatal VTE because they were not looking for this information. The inclusion of new initiators only also may have skewed the data. This would mean that former users of an OC may have been included in the patch group but were ineligible for inclusion in the pill group. This may bias the data toward experienced hormonal contraceptive users in the patch group, thereby falsely lowering the VTE rate.

The study by Cole and associates also has limitations. It included long-term users of hormonal contraceptives in both the patch and the OC groups, which may bias the data toward lower rates of VTE, AMI, and stroke for the same reasons cited above. One would assume that this bias was corrected, because prior use was allowed in both groups, making the bias equally distributed, but there is no way to confirm this with any degree of certainty.

All three studies have some flaws in common

All three studies used prescription information to determine exposure, but there is no guarantee that the women who filled the prescriptions actually used the agents. Patients given drug samples by their clinicians were overlooked because these samples are not tracked through pharmacy data.

Because the data were collected from insurance claims information of privately insured patients, it is impossible to generalize these findings to the general population. We cannot use the findings to determine whether the same results would be seen in uninsured women or women insured through nonprivate programs such as Medicaid or the Veterans Administration.

So what’s the bottom line?

Health-care providers should be cautious about citing these studies as “evidence” when advising patients about the risk of VTE while using the patch. The twofold increased risk of VTE observed in patch users and the almost twofold increased risk of AMI observed by Cole and associates cannot be completely ignored, however, particularly because this study was better designed than those by Jick and colleagues.

It is more important to remember that the incidence of VTE in patch users is extremely low. If a patient has been using the patch, is happy with the method, and has had no adverse effects, there is no reason, based on these findings, to discontinue it. When counseling new initiators, the best that can be done is to explain the potential risks and side effects associated with the method and allow the patient to make an informed choice using the information that is available.

If the increased risk of VTE is accurate, it would still be equal to or lower than the risk during pregnancy. A recent review found the overall incidence of VTE in pregnancy or the postpartum period to be 200 for every 100,000 woman-years.⁷

Why don’t American women choose long-acting reversible contraception?

Do American women not want to use long-acting reversible contraception (LARC), or are we, as providers, failing to properly educate them about its benefits?

The ParaGard copper IUD, the Mirena levonorgestrel intrauterine system (LNGIUS), and the Implanon etonorgestrel contraceptive implant are all highly effective, convenient, long-duration, and reversible (FIGURE). Despite substantial evidence indicating that these methods are well tolerated and highly effective, only about 2% of American women are choosing them to prevent pregnancy.¹ This rate lags far behind other countries in IUD utilization. In contrast, more than 50% of contraceptive users in China and Egypt are using intrauterine contraception.⁸

FIGURE

Copper IUD is effective for 12 years or longer

The copper IUD is FDA-approved for 10 years of use, although studies continue to support its continued efficacy for 12 years or longer.⁹ The 1-year perfect-use failure rate is 0.6%, and the typical use failure rate is 0.5% to 0.8%.¹⁰ The total failure rate over 12 years is 2.2%.⁹

Benefits. The copper IUD does not increase the risk of intrauterine infection and is safe to place in nulliparous patients.¹¹ It is an excellent choice for women who clearly prefer to have monthly menses and for women who have personal or medical contraindications to hormonal birth control. Women using this method of birth control can expect excellent efficacy, rapid reversibility, and minimal side effects.

Adverse effects. The most common adverse events in copper IUD users are heavier menses and dysmenorrhea. Approximately 4.5% of women discontinue the copper IUD in the first year of use because of these particular side effects.¹²

LNG-IUS: Highly effective, with important noncontraceptive benefits

This method of birth control is comparable to the copper IUD in terms of efficacy and tolerability. It is FDA-approved for 5 years of use, with a cumulative 5-year failure rate of 0.7 for every 100 women.¹³ One small study demonstrated that this method is potentially effective up to 7 years, with a 1.1% pregnancy rate.¹¹ With perfect use, the first-year pregnancy rate is 0.1% to 0.2%.¹⁴

Benefits. The progestin component provides noncontraceptive benefits, including a reduction in menstrual bleeding and dysmenorrhea,¹⁵ treatment of endometrial hyperplasia¹⁶ and endometrial cancer,¹⁷ endometrial protection in women using tamoxifen,¹⁸ treatment of endometriosis,¹⁹ and protection from pelvic inflammatory disease.²⁰

Adverse effects. The primary disadvantage of this device is a change in bleeding pattern in some women, who may experience irregular spotting, primarily in the first 3 to 6 months.²¹ About 20% of users will become amenorrheic by 12 months of use, a feature that is highly desirable for many, but troubling to some.

Implant is essentially 100% effective

The newest LARC device is the etonorgestrel implant, which was approved by the FDA in July 2006. The single-rod implant is typically placed in the subcuticular tissue of the non-dominant arm, although placement in the dominant arm is fine if the patient prefers.

Benefits. In a 3-year study involving 635 subjects, no pregnancies were reported.²² The reported Pearl index of 0.38 pregnancies for every 100,000 woman-years of use relates to pregnancies that occurred shortly after discontinuation rather than during actual use. These studies included only women below 130% of their ideal body weight who were not using liver enzyme-inducing medications. The pregnancy rate in women who use such medications, or weigh above 130% of their ideal body weight, is unknown. Postmarketing surveillance has reported some pregnancies, as would be expected. The device is easily inserted and easily removed as long as 3 years later.

Adverse effects. The primary adverse effect of this implant is bleeding disturbances; discontinuation was usually due to this side effect.²² The cumulative discontinuation rate was 10% at 6 months, 20% at 12 months, 31% at 2 years, and 32.2% at 3 years.²²

Training required. FDA approval included a stipulation that practitioners complete company-sponsored training (www.implanonusa.com) to insert and remove the device.

Overall benefits include minimal side effects, low cost

All LARC methods provide excellent protection against pregnancy (equal to or better than sterilization), have minimal side effects, and are rapidly reversible. They are also appropriate for women in whom combination hormonal contraception is contraindicated, such as smokers older than 35 years and women who have had VTE.

A final and important advantage: These methods are more cost-effective than other contraceptive methods, including combination OCs. They may require a higher initial investment, but the LNG-IUS and copper IUD are the least costly methods of contraception over 5 years of use.²³

As providers continue to educate themselves and help women gain a better understanding of which methods are truly highly effective, they will likely begin to recommend LARC more often. Use of these devices has the potential to significantly decrease the high rate of unintended pregnancy.

Authors’ note: The figure at right depicts how the efficacy and convenience of contraceptive options rise (and side effects fall) along a continuum. LARC methods are “high up the ladder”—an observation that serves as food for thought as we counsel patients about what methods of birth control are best for them.

The authors report no financial relationships relevant to this article.

We’ve heard that troubling statistic: Approximately 50% of pregnancies in the United States are unintended. But did you know that one half of those unintended pregnancies occur in women who were using some form of birth control at the time of conception?¹ Such pregnancies are due to discontinuation of the method, incorrect use, or method failure.² The focus of this article is contraceptive counseling, with special attention to:

• which methods of combination hormonal contraception women prefer
• the controversy surrounding the contraceptive patch in regard to thromboembolic disease
• long-acting reversible contraception (LARC), such as the intrauterine device (IUD) and the contraceptive implant, with an emphasis on how LARC is of benefit to both the patient and society.

The ultimate goal of good contraceptive counseling? To help women choose the easiest and most effective method with the fewest side effects.

In head-to-head comparison, women preferred the ring to the patch

Creinin MD, Meyn LA, Borgatta L, et al. Multicenter comparison of the contraceptive ring and patch. Obstet Gynecol. 2008;111:267–277.

The ethinyl estradiol/etonogestril vaginal ring (NuvaRing) and the ethinyl estradiol/norelgestromin patch (OrthoEvra)—both approved by the Food and Drug Administration (FDA) in 2001—are the only nonoral forms of combined hormonal contraception on the market. These methods are said to increase patient compliance and, potentially, efficacy, because they are nondaily forms of contraception.

Until recently, these methods had been compared only with the combination oral contraceptive (OC), but a recent trial compared them directly to each other. At the conclusion of the study, 71% of ring users and 26.5% of patch users planned to continue using the assigned method (P<.001).

This information should aid clinicians in counseling women about which combination hormonal method to choose.

Participants started out using the OC

The multicenter, randomized, controlled clinical trial comparing the patch and ring included 479 women who were using, and happy with, the combination OC. After rating their satisfaction with the OC, women were randomized to the patch or ring and given 3 months’ worth of product. Follow-up involved only two telephone calls and one visit at the end of the third cycle, because this degree of monitoring was thought to mimic clinical practice.

The percentages of women who completed three cycles of their assigned product were 94.6% and 88.2% in the ring and patch groups, respectively (P=.03). The most common reasons for early discontinuation in the ring group were discomfort and adverse effects. In the patch group, the most common reasons were adverse effects, skin irritation, and adherence problems.

Even after adjusting for age, education, and whether an OC was actively being used at the time the study began, patch users were twice as likely to discontinue the patch at the end of three cycles and seven times more likely to state that they did not want to continue the patch.

Adverse effects were greater than with the pill

Women switching from pill to patch were significantly more likely to report breast pain, nausea, skin rash, longer menstrual bleeding, and menstrual pain than women who switched from the pill to the ring (P<.001).

Women who switched from the pill to the ring were more likely to experience vaginal discharge (P=.003) and a larger amount of vaginal discharge than patch users (P<.001).

These findings are similar to those of previous studies that compared the patch with the pill, noting that breast discomfort, application-site reaction, and dysmenorrhea were more common in patch than pill users.³ Earlier studies also found the ring to be associated with complaints of vaginal discharge.^4,5

Findings may not be generalizable

The most important finding from this direct comparison is the difference in patient satisfaction between groups. Visual analog scales showed that women using the ring were happier with the ring than with the pill, whereas women using the patch were happier with the pill than with the patch (P<.001). Questionnaires revealed that women were more satisfied with the ring than they were with the patch, and were more likely to recommend the ring than the patch to a friend (P<.001).

Based on continuation rates, patient satisfaction, and adverse-effect profiles, women in this study clearly preferred the ring to the pill, and the pill to the patch. When using this information to counsel patients, however, it is important to recall that this population was specific. The women had been using an OC, with which they were happy. This study cannot necessarily be generalized to women who are just initiating combination hormonal contraception, but it can be helpful in counseling a patient who may want to switch from an OC to a method that involves nondaily dosing.

Does the contraceptive patch raise the risk of thromboembolism?

Jick SS, Kaye JA, Russman S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73:223–228.

Jick S, Kaye JA, Li L, Jick H. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2007;76:4–7.

Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive users. Obstet Gynecol. 2007;109(2 Pt 1):339–346.

Both the media and regulatory agencies have raised concerns about whether the contraceptive patch heightens the risk of thromboembolism and is less effective in women above a certain body weight.

The controversy surrounding thromboembolic disease stems from a pharmacokinetics study by van den Heuvel and colleagues that compared serum ethinyl estradiol levels in users of the patch, vaginal ring, and a combination OC containing 30 μg of ethinyl estradiol and 150 μg of levonorgestrel.⁶ Women randomized to the patch had serum ethinyl estradiol levels 1.6 times higher than women randomized to an OC, and 3.4 times higher than women randomized to the ring.

These findings led the FDA to update package labeling of the patch to warn health-care providers and patients that the patch exposes women to 60% more estrogen and may increase the risk of thromboembolic events. Oddly, the FDA did not require any labeling change to combination OCs to indicate that they contain up to twice as much estrogen as the contraceptive ring.

A set of studies finds no elevated risk

Although the study by van den Heuvel and associates raised the possibility of increased blood clots in patch users, no association between the two had been corroborated at the time it was published.⁶ Since then, three epidemiological studies have explored the potential link between thromboembolic events and use of the patch.

In the first of these studies, Jick and colleagues used the PharMetrics database to extract data on users of the patch and norg-estimate-containing OCs. This database contains drug prescription information, patient demographic data, and ICD-9 billing codes submitted by managed care health plans. A nested case-control study design was used to compare patch and pill users and control for confounding variables.

The base population was women 15 to 44 years old who were new users of the patch or a norgestimate-containing OC. A thromboembolic event was diagnosed if the patient’s record included a diagnosis code for pulmonary embolus, deep vein thrombosis, or an emergency room visit or diagnostic testing indicating venous thromboembolism (VTE). These diagnosis codes, combined with the prescription of long-term anticoagulation therapy, strengthened the identification of cases. As many as four controls were selected for each case.

The 215,769 women included in this study contributed 147,323 woman-years of exposure to the drugs. There were 31 and 37 cases of VTE identified in the patch and pill groups, respectively, with an incidence of 52.8 for every 100,000 woman-years in the patch group and 41.8 for every 100,000 woman-years in the pill group and an unadjusted, matched odds ratio of VTE in patch versus pill users of 0.9. When the data were adjusted for duration of drug exposure, the odds ratio did not change.

A follow-up study by Jick and associates, published in 2007, had the same study design and included 17 additional months of data. Another 56 cases of VTE were diagnosed. The odds ratio for patch users, compared with pill users, was 1.1. When data from the two studies were combined, 73 and 51 total cases of VTE had occurred in the pill and patch groups, respectively. The overall odds ratio was 1.0.

A third study finds significantly heightened risk

Cole and associates studied insurance claims data from UnitedHealthcare, a database containing medical and prescription claim information as well as patient demographics. Because researchers used pharmacy dispensing records, they were able to include women 15 to 44 years old who had received at least one prescription for the contraceptive patch or a norgestimate-containing OC with 35 μg of ethinyl estradiol.

Unlike the studies by Jick and colleagues, the study by Cole and associates considered all women eligible, even if they had used OCs in the past. Cases of VTE, stroke, and acute myocardial infarction (AMI) were abstracted from this group, identified from insurance claim information, and confirmed by chart review. Review of medical records is an important strength of this study; no such review was done in the studies by Jick and colleagues. Four controls were matched to each case, by age and duration of contraceptive use.

(This study was commissioned in conjunction with both the FDA and Johnson & Johnson, makers of the contraceptive patch, but researchers had full control over the data and results and were not required to consult with Johnson & Johnson when reporting findings.)

There were 49,048 woman-years of exposure to the patch and 202,344 woman-years of exposure to the pill, with an incidence of VTE of 40.8 and 18.3 for every 100,000 woman-years in patch and pill users, respectively. The incidence of AMI was 6.1 and 3.5 for every 100,000 woman-years in patch and pill users, respectively. No ischemic strokes were noted in patch users.

The adjusted incidence ratio for VTE in patch users compared with pill users was 2.2, and for AMI it was 1.8. Following publication of this study, the FDA issued a statement in January of this year that women using the patch face an increased risk of VTE, compared with women using the pill. Package labeling was changed to reflect this heightened risk.

Reasons for different findings

The studies by Jick and colleagues and Cole and associates present very different findings. The studies by Jick and colleagues give the impression that there is no increased risk of VTE in patch users compared with pill users, but the studies have significant flaws. First, Jick and colleagues do not confirm the diagnosis of VTE in the medical record. This is particularly problematic because the reported number of pulmonary emboli (PE) is very high, compared with the number of deep vein thromboses. The 2006 study found 42 cases of PE and only 26 cases of deep vein thrombosis. Because the latter is more common than PE, this could indicate that deep vein thrombosis was underdiagnosed.

Another shortcoming is that Jick and colleagues included only nonfatal thromboembolic events, which may mean that they missed many cases of fatal VTE because they were not looking for this information. The inclusion of new initiators only also may have skewed the data. This would mean that former users of an OC may have been included in the patch group but were ineligible for inclusion in the pill group. This may bias the data toward experienced hormonal contraceptive users in the patch group, thereby falsely lowering the VTE rate.

The study by Cole and associates also has limitations. It included long-term users of hormonal contraceptives in both the patch and the OC groups, which may bias the data toward lower rates of VTE, AMI, and stroke for the same reasons cited above. One would assume that this bias was corrected, because prior use was allowed in both groups, making the bias equally distributed, but there is no way to confirm this with any degree of certainty.

All three studies have some flaws in common

All three studies used prescription information to determine exposure, but there is no guarantee that the women who filled the prescriptions actually used the agents. Patients given drug samples by their clinicians were overlooked because these samples are not tracked through pharmacy data.

Because the data were collected from insurance claims information of privately insured patients, it is impossible to generalize these findings to the general population. We cannot use the findings to determine whether the same results would be seen in uninsured women or women insured through nonprivate programs such as Medicaid or the Veterans Administration.

So what’s the bottom line?

Health-care providers should be cautious about citing these studies as “evidence” when advising patients about the risk of VTE while using the patch. The twofold increased risk of VTE observed in patch users and the almost twofold increased risk of AMI observed by Cole and associates cannot be completely ignored, however, particularly because this study was better designed than those by Jick and colleagues.

It is more important to remember that the incidence of VTE in patch users is extremely low. If a patient has been using the patch, is happy with the method, and has had no adverse effects, there is no reason, based on these findings, to discontinue it. When counseling new initiators, the best that can be done is to explain the potential risks and side effects associated with the method and allow the patient to make an informed choice using the information that is available.

If the increased risk of VTE is accurate, it would still be equal to or lower than the risk during pregnancy. A recent review found the overall incidence of VTE in pregnancy or the postpartum period to be 200 for every 100,000 woman-years.⁷

Why don’t American women choose long-acting reversible contraception?

Do American women not want to use long-acting reversible contraception (LARC), or are we, as providers, failing to properly educate them about its benefits?

The ParaGard copper IUD, the Mirena levonorgestrel intrauterine system (LNGIUS), and the Implanon etonorgestrel contraceptive implant are all highly effective, convenient, long-duration, and reversible (FIGURE). Despite substantial evidence indicating that these methods are well tolerated and highly effective, only about 2% of American women are choosing them to prevent pregnancy.¹ This rate lags far behind other countries in IUD utilization. In contrast, more than 50% of contraceptive users in China and Egypt are using intrauterine contraception.⁸

FIGURE

Copper IUD is effective for 12 years or longer

The copper IUD is FDA-approved for 10 years of use, although studies continue to support its continued efficacy for 12 years or longer.⁹ The 1-year perfect-use failure rate is 0.6%, and the typical use failure rate is 0.5% to 0.8%.¹⁰ The total failure rate over 12 years is 2.2%.⁹

Benefits. The copper IUD does not increase the risk of intrauterine infection and is safe to place in nulliparous patients.¹¹ It is an excellent choice for women who clearly prefer to have monthly menses and for women who have personal or medical contraindications to hormonal birth control. Women using this method of birth control can expect excellent efficacy, rapid reversibility, and minimal side effects.

Adverse effects. The most common adverse events in copper IUD users are heavier menses and dysmenorrhea. Approximately 4.5% of women discontinue the copper IUD in the first year of use because of these particular side effects.¹²

LNG-IUS: Highly effective, with important noncontraceptive benefits

This method of birth control is comparable to the copper IUD in terms of efficacy and tolerability. It is FDA-approved for 5 years of use, with a cumulative 5-year failure rate of 0.7 for every 100 women.¹³ One small study demonstrated that this method is potentially effective up to 7 years, with a 1.1% pregnancy rate.¹¹ With perfect use, the first-year pregnancy rate is 0.1% to 0.2%.¹⁴

Benefits. The progestin component provides noncontraceptive benefits, including a reduction in menstrual bleeding and dysmenorrhea,¹⁵ treatment of endometrial hyperplasia¹⁶ and endometrial cancer,¹⁷ endometrial protection in women using tamoxifen,¹⁸ treatment of endometriosis,¹⁹ and protection from pelvic inflammatory disease.²⁰

Adverse effects. The primary disadvantage of this device is a change in bleeding pattern in some women, who may experience irregular spotting, primarily in the first 3 to 6 months.²¹ About 20% of users will become amenorrheic by 12 months of use, a feature that is highly desirable for many, but troubling to some.

Implant is essentially 100% effective

The newest LARC device is the etonorgestrel implant, which was approved by the FDA in July 2006. The single-rod implant is typically placed in the subcuticular tissue of the non-dominant arm, although placement in the dominant arm is fine if the patient prefers.

Benefits. In a 3-year study involving 635 subjects, no pregnancies were reported.²² The reported Pearl index of 0.38 pregnancies for every 100,000 woman-years of use relates to pregnancies that occurred shortly after discontinuation rather than during actual use. These studies included only women below 130% of their ideal body weight who were not using liver enzyme-inducing medications. The pregnancy rate in women who use such medications, or weigh above 130% of their ideal body weight, is unknown. Postmarketing surveillance has reported some pregnancies, as would be expected. The device is easily inserted and easily removed as long as 3 years later.

Adverse effects. The primary adverse effect of this implant is bleeding disturbances; discontinuation was usually due to this side effect.²² The cumulative discontinuation rate was 10% at 6 months, 20% at 12 months, 31% at 2 years, and 32.2% at 3 years.²²

Training required. FDA approval included a stipulation that practitioners complete company-sponsored training (www.implanonusa.com) to insert and remove the device.

Overall benefits include minimal side effects, low cost

All LARC methods provide excellent protection against pregnancy (equal to or better than sterilization), have minimal side effects, and are rapidly reversible. They are also appropriate for women in whom combination hormonal contraception is contraindicated, such as smokers older than 35 years and women who have had VTE.

A final and important advantage: These methods are more cost-effective than other contraceptive methods, including combination OCs. They may require a higher initial investment, but the LNG-IUS and copper IUD are the least costly methods of contraception over 5 years of use.²³

As providers continue to educate themselves and help women gain a better understanding of which methods are truly highly effective, they will likely begin to recommend LARC more often. Use of these devices has the potential to significantly decrease the high rate of unintended pregnancy.

Authors’ note: The figure at right depicts how the efficacy and convenience of contraceptive options rise (and side effects fall) along a continuum. LARC methods are “high up the ladder”—an observation that serves as food for thought as we counsel patients about what methods of birth control are best for them.

As increasing numbers of people work in windowless environments and as computer time, gaming consoles, and TV viewing keep more of them indoors during their leisure hours, many are losing access to their natural source of vitamin D: sunshine. In response to the justifiably publicized risk of skin cancers, people avoid sunlight or take great care to cover the skin with sunscreen—minimizing the risk of sun-related skin cancer, but greatly increasing the risk of vitamin D deficiency.

The importance of vitamin D was first recognized in the prevention of rickets and its role in absorption of calcium and phosphate in the diet.¹ In recent decades, however, the growing understanding of vitamin D's influence on leukocytes, vascular smooth muscle cells, and other tissues² has led to an increased awareness of this nutrient's contribution to numerous processes and functions.

Considering vitamin D's subtle but substantial impact on mental, cardiovascular, musculoskeletal, and autoimmune health (not to mention bone disorders and calcium deficiency), vitamin D deficiency is overlooked and undertreated with surprising frequency in the clinical setting, where clinicians are more likely to screen for and treat other disorders.

The Facts
Exposure of the skin to sunlight or ultraviolet (UV) light is the human body's natural way to synthesize vitamin D3.^1,3 This nutrient can also be ingested in fish and fish liver oils; in the form of vitamin D2, which has been used since the 1930s in efforts to reduce rickets and other bone disorders by fortifying milk, cereals, and a variety of food products^4,5; and in dietary supplements.

Unfortunately, the intake of vitamin D–fortified foods and/or supplements is often insufficient for the average person to maintain an adequate level of this essential substance.³ Fatty fish, including sardines, mackerel, tuna, and salmon,⁶ are among the few foods that represent a valuable source of vitamin D, but these are not commonly considered a staple in today's American diet. Additionally, it has been questioned whether the current recommended daily allowance guidelines for vitamin D intake are adequate for most of the population.⁷

Widespread Effects
The impact of vitamin D deficiency or insufficiency affects patients of both genders across the life span. Exclusive breastfeeding without adequate vitamin D supplementation can result in rickets in infants, children, and adolescents.^3,4,8 Research indicates that even healthy-appearing adolescents may be deficient in this nutrient.⁹ Inadequate intake or supplementation of vitamin D during pregnancy has been shown to increase women's risk of preeclampsia, with potential impact on their infants' well-being.¹⁰

Adults with inadequate levels of vitamin D are at risk for periodontal disease and other dental concerns,^11,12 hypertension and cardiovascular disease,^2,13-16 musculoskeletal disorders, depression,¹⁷ and malignancies of the breast,¹⁸ colon,^1,19,20 and prostate.¹³ Older persons with insufficient levels of this essential substance are at increased risk of falls and fractures,^12,21 osteoporosis,^21,22 hyperparathyroidism,²³ impaired cognitive function, and depression.²⁴

Vitamin D Synthesis
Vitamin D is synthesized in the skin by UV light between wavelengths of 290 and 315 nm,^4,13 converting 7-dehydrocholesterol to previtamin D3, then by thermal isomerization to vitamin D3.^1,3 Both vitamin D3 and vitamin D2 are incorporated into chylomicrons and absorbed by the lymph system, then put into systemic circulation by vitamin D–binding protein.^4,13

Two additional steps—one that occurs in the liver, the other in the kidneys—are needed to complete the conversion from an inert form to usable vitamin D. In the liver, the molecule is hydroxylated by enzymes called the vitamin D-25-hydroxylases to form 25-hydroxyvitamin D. Then in the kidneys, the cytochrome P-450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase continues the hydroxylation process, converting the molecule to vitamin D's biologically active form, 1,25-dihydroxyvitamin D.^4,13,25 It is next bound to the vitamin D receptors and in an additional step is transcribed in RNA and replicated.

The known actions of vitamin D include increasing calcium and phosphorus absorption from the small bowel, enhancement of renal tubule resorption of phosphate, and maturation of osteoclasts to resorb calcium from the bones. Vitamin D also improves measurable bone mineral density.¹

Who Is at Risk?
Many individuals may not recognize their risk for vitamin D deficiency or insufficiency. Clinicians must be aware of the conditions and factors that increase the risk. Many of these are identified in Table 1.^{3,5,6,8,10,24,26-31}

Assessment
Clinicians in any number of specialties may encounter patients with vitamin D deficiency or insufficiency. Thus, it is important during the interview and review of systems to ask routinely about the patient's occupation, sun exposure, and use of sunscreen. Clinicians should also ask about dietary habits and dietary supplements, including multivitamins and supplemental vitamin D (eg, calcium with vitamin D).

The examining clinician should also key in on fatigue, bone pain, and muscle pain or weakness. While reviewing the patient's medical history and the current problem list, the clinician should maintain an awareness of disease processes that may mimic vitamin D insufficiency. These include fibromyalgia, chronic fatigue syndrome, myositis, hyperparathyroidism, and depression.^13,17,23 Comorbidities that often coexist with vitamin D deficiency include hypertension and cardiovascular disease,¹⁶ obesity, type 1 diabetes mellitus,¹³ multiple sclerosis,⁵ secondary hyperparathyroidism,¹³ and prostate, breast, or colorectal cancer.^1,2,9,13

Assessment of the patient's constitution, of course, includes vital signs and general appearance. As mentioned earlier, hypertension may coexist with vitamin D deficiency.^2,13-16 Obesity, it is also important to note, has been associated with reduced vitamin D bioavailability.²⁸ The type and coverage of the patient's clothing can provide an important clue to a potential lack of sunlight exposure and its impact on his or her vitamin D status.²⁹ As for inspection of the integument, it should be noted that darker skin pigmentation is included among the risk factors for vitamin D insufficiency, as melanin in darker skin reduces vitamin D synthesis.^9,31

Testing for Vitamin D
The most accurate means of meassuring the patient's vitamin D status is 25-hydroxyvitamin D, also known as serum 25(OH)D.^4,25 With a relative half-life of two weeks,⁴ this marker reliably indicates the body's stores of vitamin D. Some laboratories report three aspects—total serum 25(OH)D, 25[OH]D3, and 25[OH]D2—while others report only total serum 25(OH)D. Interpretation of the latter is shown in Table 2.^4,25

Additional research suggests that higher levels of serum 25(OH)D (ie, 36 to 48 ng/mL) may be desirable for the prevention of cancer.¹²

Treatment
Vitamin D insufficiency and deficiency are relatively easy and inexpensive to treat. With a target treatment goal of serum 25(OH)D greater than 30 ng/mL, the patient can be advised to increase his or her sunlight or UV exposure in moderate amounts, such as exposure of the hands and face to bright sunlight for 15 minutes daily. During winter or at northern latitudes with reduced sunlight, moderate exposure in a tanning bed (ie, one emitting 2% to 6% UVB radiation) can be helpful.^6,32 For recommended supplementation to correct vitamin D deficiency or insufficiency, see Table 3.^6,32

Oral supplementation for adults is an inexpensive, well-tolerated solution. A conscious effort to increase dietary intake of fortified dairy products and cereals or fatty fish may be adequate. OTC oral vitamin D3 supplements are available in 200, 400, and 1,000 IU for a few cents per dose. Prescription vitamin D2 ergocalciferol is also available.⁶

Infants who are exclusively breastfed or who consume less than 500 mL/d of vitamin D–fortified formula can be given a combination multivitamin containing 400 IU/mL for adequate supplementation^3,6; Hollis and Wagner⁸ recommend that breastfeeding women have 4,000 IU/d of vitamin D intake to protect both themselves and their infants. Single-source or concentrated vitamin D is not recommended for infants.³ Gartner and Greer³ recommend a vitamin D intake of 200 IU/d from childhood through adolescence.

Research indicates that higher levels of vitamin D supplementation than previously recommended are needed for most people and are safe.^7,12 Additionally, higher doses of vitamin D are not as toxic as were previously believed, as excess amounts are stored.³³ Daily doses of no less than 1,000 IU (with or without sunlight exposure and/or dietary intake) may improve the serum 25(OH)D levels in the majority of the population.¹² Results from one study suggest that a total of 3,600 to 4,200 IU/d from all sources is desirable and safe.³³

Reevaluation
The serum 25(OH)D test should be repeated after six to eight weeks to ensure adequate vitamin D absorption, targeting a level of at least 30 ng/mL. If serum 25(OH)D falls persistently below that level, the clinician should consider vitamin D in an injectable form and reassess the patient for malabsorption or other interference issues.³⁴

Conclusion
The health benefits of vitamin D are frequently overlooked in everyday practice. Screening and treatment are simple, cost-effective, and beneficial for patients' wellness.

As increasing numbers of people work in windowless environments and as computer time, gaming consoles, and TV viewing keep more of them indoors during their leisure hours, many are losing access to their natural source of vitamin D: sunshine. In response to the justifiably publicized risk of skin cancers, people avoid sunlight or take great care to cover the skin with sunscreen—minimizing the risk of sun-related skin cancer, but greatly increasing the risk of vitamin D deficiency.

The importance of vitamin D was first recognized in the prevention of rickets and its role in absorption of calcium and phosphate in the diet.¹ In recent decades, however, the growing understanding of vitamin D's influence on leukocytes, vascular smooth muscle cells, and other tissues² has led to an increased awareness of this nutrient's contribution to numerous processes and functions.

Considering vitamin D's subtle but substantial impact on mental, cardiovascular, musculoskeletal, and autoimmune health (not to mention bone disorders and calcium deficiency), vitamin D deficiency is overlooked and undertreated with surprising frequency in the clinical setting, where clinicians are more likely to screen for and treat other disorders.

The Facts
Exposure of the skin to sunlight or ultraviolet (UV) light is the human body's natural way to synthesize vitamin D3.^1,3 This nutrient can also be ingested in fish and fish liver oils; in the form of vitamin D2, which has been used since the 1930s in efforts to reduce rickets and other bone disorders by fortifying milk, cereals, and a variety of food products^4,5; and in dietary supplements.

Unfortunately, the intake of vitamin D–fortified foods and/or supplements is often insufficient for the average person to maintain an adequate level of this essential substance.³ Fatty fish, including sardines, mackerel, tuna, and salmon,⁶ are among the few foods that represent a valuable source of vitamin D, but these are not commonly considered a staple in today's American diet. Additionally, it has been questioned whether the current recommended daily allowance guidelines for vitamin D intake are adequate for most of the population.⁷

Widespread Effects
The impact of vitamin D deficiency or insufficiency affects patients of both genders across the life span. Exclusive breastfeeding without adequate vitamin D supplementation can result in rickets in infants, children, and adolescents.^3,4,8 Research indicates that even healthy-appearing adolescents may be deficient in this nutrient.⁹ Inadequate intake or supplementation of vitamin D during pregnancy has been shown to increase women's risk of preeclampsia, with potential impact on their infants' well-being.¹⁰

Adults with inadequate levels of vitamin D are at risk for periodontal disease and other dental concerns,^11,12 hypertension and cardiovascular disease,^2,13-16 musculoskeletal disorders, depression,¹⁷ and malignancies of the breast,¹⁸ colon,^1,19,20 and prostate.¹³ Older persons with insufficient levels of this essential substance are at increased risk of falls and fractures,^12,21 osteoporosis,^21,22 hyperparathyroidism,²³ impaired cognitive function, and depression.²⁴

Vitamin D Synthesis
Vitamin D is synthesized in the skin by UV light between wavelengths of 290 and 315 nm,^4,13 converting 7-dehydrocholesterol to previtamin D3, then by thermal isomerization to vitamin D3.^1,3 Both vitamin D3 and vitamin D2 are incorporated into chylomicrons and absorbed by the lymph system, then put into systemic circulation by vitamin D–binding protein.^4,13

Two additional steps—one that occurs in the liver, the other in the kidneys—are needed to complete the conversion from an inert form to usable vitamin D. In the liver, the molecule is hydroxylated by enzymes called the vitamin D-25-hydroxylases to form 25-hydroxyvitamin D. Then in the kidneys, the cytochrome P-450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase continues the hydroxylation process, converting the molecule to vitamin D's biologically active form, 1,25-dihydroxyvitamin D.^4,13,25 It is next bound to the vitamin D receptors and in an additional step is transcribed in RNA and replicated.

The known actions of vitamin D include increasing calcium and phosphorus absorption from the small bowel, enhancement of renal tubule resorption of phosphate, and maturation of osteoclasts to resorb calcium from the bones. Vitamin D also improves measurable bone mineral density.¹

Who Is at Risk?
Many individuals may not recognize their risk for vitamin D deficiency or insufficiency. Clinicians must be aware of the conditions and factors that increase the risk. Many of these are identified in Table 1.^{3,5,6,8,10,24,26-31}

Assessment
Clinicians in any number of specialties may encounter patients with vitamin D deficiency or insufficiency. Thus, it is important during the interview and review of systems to ask routinely about the patient's occupation, sun exposure, and use of sunscreen. Clinicians should also ask about dietary habits and dietary supplements, including multivitamins and supplemental vitamin D (eg, calcium with vitamin D).

The examining clinician should also key in on fatigue, bone pain, and muscle pain or weakness. While reviewing the patient's medical history and the current problem list, the clinician should maintain an awareness of disease processes that may mimic vitamin D insufficiency. These include fibromyalgia, chronic fatigue syndrome, myositis, hyperparathyroidism, and depression.^13,17,23 Comorbidities that often coexist with vitamin D deficiency include hypertension and cardiovascular disease,¹⁶ obesity, type 1 diabetes mellitus,¹³ multiple sclerosis,⁵ secondary hyperparathyroidism,¹³ and prostate, breast, or colorectal cancer.^1,2,9,13

Assessment of the patient's constitution, of course, includes vital signs and general appearance. As mentioned earlier, hypertension may coexist with vitamin D deficiency.^2,13-16 Obesity, it is also important to note, has been associated with reduced vitamin D bioavailability.²⁸ The type and coverage of the patient's clothing can provide an important clue to a potential lack of sunlight exposure and its impact on his or her vitamin D status.²⁹ As for inspection of the integument, it should be noted that darker skin pigmentation is included among the risk factors for vitamin D insufficiency, as melanin in darker skin reduces vitamin D synthesis.^9,31

Testing for Vitamin D
The most accurate means of meassuring the patient's vitamin D status is 25-hydroxyvitamin D, also known as serum 25(OH)D.^4,25 With a relative half-life of two weeks,⁴ this marker reliably indicates the body's stores of vitamin D. Some laboratories report three aspects—total serum 25(OH)D, 25[OH]D3, and 25[OH]D2—while others report only total serum 25(OH)D. Interpretation of the latter is shown in Table 2.^4,25

Additional research suggests that higher levels of serum 25(OH)D (ie, 36 to 48 ng/mL) may be desirable for the prevention of cancer.¹²

Treatment
Vitamin D insufficiency and deficiency are relatively easy and inexpensive to treat. With a target treatment goal of serum 25(OH)D greater than 30 ng/mL, the patient can be advised to increase his or her sunlight or UV exposure in moderate amounts, such as exposure of the hands and face to bright sunlight for 15 minutes daily. During winter or at northern latitudes with reduced sunlight, moderate exposure in a tanning bed (ie, one emitting 2% to 6% UVB radiation) can be helpful.^6,32 For recommended supplementation to correct vitamin D deficiency or insufficiency, see Table 3.^6,32

Oral supplementation for adults is an inexpensive, well-tolerated solution. A conscious effort to increase dietary intake of fortified dairy products and cereals or fatty fish may be adequate. OTC oral vitamin D3 supplements are available in 200, 400, and 1,000 IU for a few cents per dose. Prescription vitamin D2 ergocalciferol is also available.⁶

Infants who are exclusively breastfed or who consume less than 500 mL/d of vitamin D–fortified formula can be given a combination multivitamin containing 400 IU/mL for adequate supplementation^3,6; Hollis and Wagner⁸ recommend that breastfeeding women have 4,000 IU/d of vitamin D intake to protect both themselves and their infants. Single-source or concentrated vitamin D is not recommended for infants.³ Gartner and Greer³ recommend a vitamin D intake of 200 IU/d from childhood through adolescence.

Research indicates that higher levels of vitamin D supplementation than previously recommended are needed for most people and are safe.^7,12 Additionally, higher doses of vitamin D are not as toxic as were previously believed, as excess amounts are stored.³³ Daily doses of no less than 1,000 IU (with or without sunlight exposure and/or dietary intake) may improve the serum 25(OH)D levels in the majority of the population.¹² Results from one study suggest that a total of 3,600 to 4,200 IU/d from all sources is desirable and safe.³³

Reevaluation
The serum 25(OH)D test should be repeated after six to eight weeks to ensure adequate vitamin D absorption, targeting a level of at least 30 ng/mL. If serum 25(OH)D falls persistently below that level, the clinician should consider vitamin D in an injectable form and reassess the patient for malabsorption or other interference issues.³⁴

Conclusion
The health benefits of vitamin D are frequently overlooked in everyday practice. Screening and treatment are simple, cost-effective, and beneficial for patients' wellness.

As increasing numbers of people work in windowless environments and as computer time, gaming consoles, and TV viewing keep more of them indoors during their leisure hours, many are losing access to their natural source of vitamin D: sunshine. In response to the justifiably publicized risk of skin cancers, people avoid sunlight or take great care to cover the skin with sunscreen—minimizing the risk of sun-related skin cancer, but greatly increasing the risk of vitamin D deficiency.

The importance of vitamin D was first recognized in the prevention of rickets and its role in absorption of calcium and phosphate in the diet.¹ In recent decades, however, the growing understanding of vitamin D's influence on leukocytes, vascular smooth muscle cells, and other tissues² has led to an increased awareness of this nutrient's contribution to numerous processes and functions.

Considering vitamin D's subtle but substantial impact on mental, cardiovascular, musculoskeletal, and autoimmune health (not to mention bone disorders and calcium deficiency), vitamin D deficiency is overlooked and undertreated with surprising frequency in the clinical setting, where clinicians are more likely to screen for and treat other disorders.

The Facts
Exposure of the skin to sunlight or ultraviolet (UV) light is the human body's natural way to synthesize vitamin D3.^1,3 This nutrient can also be ingested in fish and fish liver oils; in the form of vitamin D2, which has been used since the 1930s in efforts to reduce rickets and other bone disorders by fortifying milk, cereals, and a variety of food products^4,5; and in dietary supplements.

Unfortunately, the intake of vitamin D–fortified foods and/or supplements is often insufficient for the average person to maintain an adequate level of this essential substance.³ Fatty fish, including sardines, mackerel, tuna, and salmon,⁶ are among the few foods that represent a valuable source of vitamin D, but these are not commonly considered a staple in today's American diet. Additionally, it has been questioned whether the current recommended daily allowance guidelines for vitamin D intake are adequate for most of the population.⁷

Widespread Effects
The impact of vitamin D deficiency or insufficiency affects patients of both genders across the life span. Exclusive breastfeeding without adequate vitamin D supplementation can result in rickets in infants, children, and adolescents.^3,4,8 Research indicates that even healthy-appearing adolescents may be deficient in this nutrient.⁹ Inadequate intake or supplementation of vitamin D during pregnancy has been shown to increase women's risk of preeclampsia, with potential impact on their infants' well-being.¹⁰

Adults with inadequate levels of vitamin D are at risk for periodontal disease and other dental concerns,^11,12 hypertension and cardiovascular disease,^2,13-16 musculoskeletal disorders, depression,¹⁷ and malignancies of the breast,¹⁸ colon,^1,19,20 and prostate.¹³ Older persons with insufficient levels of this essential substance are at increased risk of falls and fractures,^12,21 osteoporosis,^21,22 hyperparathyroidism,²³ impaired cognitive function, and depression.²⁴

Vitamin D Synthesis
Vitamin D is synthesized in the skin by UV light between wavelengths of 290 and 315 nm,^4,13 converting 7-dehydrocholesterol to previtamin D3, then by thermal isomerization to vitamin D3.^1,3 Both vitamin D3 and vitamin D2 are incorporated into chylomicrons and absorbed by the lymph system, then put into systemic circulation by vitamin D–binding protein.^4,13

Two additional steps—one that occurs in the liver, the other in the kidneys—are needed to complete the conversion from an inert form to usable vitamin D. In the liver, the molecule is hydroxylated by enzymes called the vitamin D-25-hydroxylases to form 25-hydroxyvitamin D. Then in the kidneys, the cytochrome P-450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase continues the hydroxylation process, converting the molecule to vitamin D's biologically active form, 1,25-dihydroxyvitamin D.^4,13,25 It is next bound to the vitamin D receptors and in an additional step is transcribed in RNA and replicated.

The known actions of vitamin D include increasing calcium and phosphorus absorption from the small bowel, enhancement of renal tubule resorption of phosphate, and maturation of osteoclasts to resorb calcium from the bones. Vitamin D also improves measurable bone mineral density.¹

Who Is at Risk?
Many individuals may not recognize their risk for vitamin D deficiency or insufficiency. Clinicians must be aware of the conditions and factors that increase the risk. Many of these are identified in Table 1.^{3,5,6,8,10,24,26-31}

Assessment
Clinicians in any number of specialties may encounter patients with vitamin D deficiency or insufficiency. Thus, it is important during the interview and review of systems to ask routinely about the patient's occupation, sun exposure, and use of sunscreen. Clinicians should also ask about dietary habits and dietary supplements, including multivitamins and supplemental vitamin D (eg, calcium with vitamin D).

The examining clinician should also key in on fatigue, bone pain, and muscle pain or weakness. While reviewing the patient's medical history and the current problem list, the clinician should maintain an awareness of disease processes that may mimic vitamin D insufficiency. These include fibromyalgia, chronic fatigue syndrome, myositis, hyperparathyroidism, and depression.^13,17,23 Comorbidities that often coexist with vitamin D deficiency include hypertension and cardiovascular disease,¹⁶ obesity, type 1 diabetes mellitus,¹³ multiple sclerosis,⁵ secondary hyperparathyroidism,¹³ and prostate, breast, or colorectal cancer.^1,2,9,13

Assessment of the patient's constitution, of course, includes vital signs and general appearance. As mentioned earlier, hypertension may coexist with vitamin D deficiency.^2,13-16 Obesity, it is also important to note, has been associated with reduced vitamin D bioavailability.²⁸ The type and coverage of the patient's clothing can provide an important clue to a potential lack of sunlight exposure and its impact on his or her vitamin D status.²⁹ As for inspection of the integument, it should be noted that darker skin pigmentation is included among the risk factors for vitamin D insufficiency, as melanin in darker skin reduces vitamin D synthesis.^9,31

Testing for Vitamin D
The most accurate means of meassuring the patient's vitamin D status is 25-hydroxyvitamin D, also known as serum 25(OH)D.^4,25 With a relative half-life of two weeks,⁴ this marker reliably indicates the body's stores of vitamin D. Some laboratories report three aspects—total serum 25(OH)D, 25[OH]D3, and 25[OH]D2—while others report only total serum 25(OH)D. Interpretation of the latter is shown in Table 2.^4,25

Additional research suggests that higher levels of serum 25(OH)D (ie, 36 to 48 ng/mL) may be desirable for the prevention of cancer.¹²

Treatment
Vitamin D insufficiency and deficiency are relatively easy and inexpensive to treat. With a target treatment goal of serum 25(OH)D greater than 30 ng/mL, the patient can be advised to increase his or her sunlight or UV exposure in moderate amounts, such as exposure of the hands and face to bright sunlight for 15 minutes daily. During winter or at northern latitudes with reduced sunlight, moderate exposure in a tanning bed (ie, one emitting 2% to 6% UVB radiation) can be helpful.^6,32 For recommended supplementation to correct vitamin D deficiency or insufficiency, see Table 3.^6,32

Oral supplementation for adults is an inexpensive, well-tolerated solution. A conscious effort to increase dietary intake of fortified dairy products and cereals or fatty fish may be adequate. OTC oral vitamin D3 supplements are available in 200, 400, and 1,000 IU for a few cents per dose. Prescription vitamin D2 ergocalciferol is also available.⁶

Infants who are exclusively breastfed or who consume less than 500 mL/d of vitamin D–fortified formula can be given a combination multivitamin containing 400 IU/mL for adequate supplementation^3,6; Hollis and Wagner⁸ recommend that breastfeeding women have 4,000 IU/d of vitamin D intake to protect both themselves and their infants. Single-source or concentrated vitamin D is not recommended for infants.³ Gartner and Greer³ recommend a vitamin D intake of 200 IU/d from childhood through adolescence.

Research indicates that higher levels of vitamin D supplementation than previously recommended are needed for most people and are safe.^7,12 Additionally, higher doses of vitamin D are not as toxic as were previously believed, as excess amounts are stored.³³ Daily doses of no less than 1,000 IU (with or without sunlight exposure and/or dietary intake) may improve the serum 25(OH)D levels in the majority of the population.¹² Results from one study suggest that a total of 3,600 to 4,200 IU/d from all sources is desirable and safe.³³

Reevaluation
The serum 25(OH)D test should be repeated after six to eight weeks to ensure adequate vitamin D absorption, targeting a level of at least 30 ng/mL. If serum 25(OH)D falls persistently below that level, the clinician should consider vitamin D in an injectable form and reassess the patient for malabsorption or other interference issues.³⁴

Conclusion
The health benefits of vitamin D are frequently overlooked in everyday practice. Screening and treatment are simple, cost-effective, and beneficial for patients' wellness.

The authors report no financial relationships relevant to this article.

CASE: Postcesarean hemorrhage fails to respond to early maneuvers.

A 25-year-old G1P0 undergoes cesarean section at our hospital for fetal distress. She has no history of coagulopathy, and no intraoperative complications are noted during the procedure. Upon her arrival in the postanesthesia care unit, however, vaginal bleeding is observed. She is given 40 U of oxytocin in 1 L of lactated Ringer solution, two intramuscular doses of 0.2 mg of methylergonovine maleate, and 1,000 μg of misoprostol to treat the postpartum bleeding. Nevertheless, she loses almost 1 L of additional blood from her vagina and is returned to the operating room for exploration and resuscitation for hypotensive shock. What are the next steps?

Management of obstetrical hemorrhage often begins with conservative measures, circumstances permitting. It is common practice to give 20–40 U of oxytocin in 1 L of lactated Ringer solution after delivery of the placenta and to perform uterine massage as part of initial management of uterine atony, along with careful evaluation and repair of any laceration or hematoma. In addition, ultrasonography (US) can help detect any retained uterine products.

Medical management usually involves the use of various uterotonics, such as methylergonovine maleate, 15-methylprostaglandin F2α, dinoprostone, and misoprostol. If uterotonics fail, techniques of tamponade include uterine packing with gauze material or use of the Foley intrauterine catheter, Sengstaken–Blakemore tube, and Bakri balloon.^1-3

Surgical management is often the last resort, and is limited by the clinician’s experience. Some surgical methods include uterine or hypogastric artery ligation, or both. Newer techniques include a variation of uterine compression sutures such as the B-Lynch suture or multiple-square suturing. The B-Lynch provides continuous compression of the uterus, thereby decreasing blood loss.⁴ Multiple-square suturing joins the anterior and posterior walls of the uterus, also compressing the uterus.

Hysterectomy should be a last resort, with the knowledge that bleeding may continue after the procedure, in which case pelvic packing becomes an alternative. Unfortunately, pelvic packing of the intraperitoneal cavity often has little effect on endometrial hemorrhage or retroperitoneal bleeding.^2-5

CASE CONTINUED

Resuscitation calls for blood products. Our resuscitation regimen includes recent clinical recommendations from military medical units in Iraq and Afghanistan and from domestic trauma centers. These guidelines propose that 1 U of fresh frozen plasma be administered with every 1 or 2 U of packed red blood cells (RBCs) until the clinical situation stabilizes or coagulopathy is excluded. Because of massive blood loss in this case, however, fluid replacement continues throughout the procedure—totaling 6 U of packed RBCs, 6 U of fresh frozen plasma, and 5 U of cryoprecipitate with additional crystalloid.^6-8

A decision is made to undertake surgical exploration. We open a Pfannenstiel incision and enter the peritoneal cavity, encountering scant dark red blood without gross intraperitoneal bleeding. The uterus is intact with apparent endometrial hemorrhage. Uterine vessels are not easily visualized because they are obscured by retroperitoneal blood and an engorged uterus. The uterus has increased in size severalfold during hemorrhage and occupies the entire pelvic cavity, making dissection difficult for emergent hysterectomy.

As the uterus is exteriorized, Péan clamps are placed on the cornua for retraction, and the round ligaments are transected and ligated bilaterally. Ecchymoses along the peritoneum suggest that retroperitoneal bleeding is occurring in addition to the endometrial blood loss.

What can be done about the retroperitoneal bleeding?

Although laparotomy and hysterectomy are last resorts in postpartum hemorrhage, the use of retroperitoneal packing during these procedures may hasten life-saving hemostasis. In pelvic trauma, a technique of retroperitoneal packing has significantly reduced mortality.⁹ The same technique of retroperitoneal packing is ideally suited for such devastating circumstances as life-threatening postpartum hemorrhage.

Retroperitoneal packing is a lesson gleaned from trauma surgery and has profound application in cases of severe postpartum hemorrhage.

CASE CONTINUED

Hemorrhage is stanched. Blood loss continues, and the patient remains in hypotensive shock. Vital signs are critical:

• systolic blood pressure, 40 mm Hg
• heart rate, 160 bpm
• minimal urine output
• hemoglobin level, 4 g/dL.

Hemorrhage is obvious from the appearance of the pelvis, and continuing blood loss suggests disseminated coagulopathy. Total abdominal hysterectomy cannot be safely or quickly performed.

To quickly prevent further blood loss, we pack the retroperitoneum using a technique adapted from trauma surgery and first described by Smith and colleagues.⁹ We make a 5-cm incision into the space of Retzius just cephalad to the pubic symphysis (FIGURES 1 and 2). This incision is separate and inferior to the earlier laparotomy incision.

Four laparotomy sponges are packed along the retroperitoneal space to provide tamponade (FIGURE 3). Within seconds, the patient stabilizes, with systolic blood pressure rising to 90 mm Hg and the heart rate declining toward 100 bpm. Bleeding ceases immediately, and the hysterectomy is completed under stable conditions without further blood loss.

FIGURE 1 Packing begins with a 5-cm incision

Make a 5-cm incision just cephalad to the symphysis pubis, deep to the fascia, and into the space of Retzius.

FIGURE 2 Preparing to place sponges

Use blunt dissection in the space of Retzius before placing packing material.

FIGURE 3 Insert packing into retroperitoneal space

Packing is usually sufficient when two or three laparotomy sponges are placed at each side of the retroperitoneal pelvis.

How retroperitoneal packing saves lives

Most of the pelvic packing that has been described in the literature has consistently involved intraperitoneal packing. However, packing of the peritoneal cavity is often insufficient tamponade for bleeding associated with retroperitoneal and endometrial bleeding. Direct compression in the retroperitoneal space stanches bleeding from the iliac vessels and branches. In trauma, this technique is used to provide quick relief of pelvic hemorrhage in any setting, including the emergency and operating rooms.^9-11

Technique

Retroperitoneal packing consists of a few basic steps and can be easily reproduced and applied in life-threatening circumstances. First, a 5-cm incision is made just cephalad to the symphysis pubis deep to the fascia and into the space of Retzius (FIGURE 1). The buildup of blood often causes autodissection of this plane (FIGURE 4). It is often useful to keep this fascial incision separate from the laparotomy fascial incision to assist with tamponade. Next, blunt dissection is performed in the continuous space of Retzius and retroperitoneum to the level of the presacral space (FIGURE 2).

FIGURE 4 Expect autodissection

Blood loss frequently causes autodissection of the surgical plane. Tamponade is then achieved by placing laparotomy sponges into the retroperitoneal space (FIGURE 3). Packing with two or three laparotomy sponges at each side of the retroperitoneal pelvis is usually sufficient. In emergent situations, this entire procedure can be completed in an emergency room or postanesthesia care unit, with a drain left in place along with the packs (FIGURE 5). In trauma, this technique allows immediate stabilization of the patient until the underlying injury can be thoroughly addressed. Careful examination of the ureters and bladder should be completed to address any injury promptly.

FIGURE 5 A drain may be required

Packing can be left in place until bleeding is stanched, with a drain added for optimal recovery. The success of this technique is clear from the trauma literature, but the data have yet to be widely applied in nontraumatic applications.⁹ It is especially advantageous to have a space separate from the intraperitoneal cavity to provide tamponade because the uterus itself may obstruct visualization. It is possible that, in some cases, this technique may control bleeding without the need for postpartum hysterectomy.

CASE RESOLVED

When the retroperitoneal packs are removed after the hysterectomy, no further bleeding occurs. However, moderate hydronephrosis is apparent along the patient’s left ureter.

The wound is closed, and the patient is transferred to intensive care. She subsequently undergoes placement of a ureteral stent for the hydronephrosis and is discharged 5 days later. The stent is removed on an outpatient basis without further morbidity or the need for additional procedures.

The authors report no financial relationships relevant to this article.

CASE: Postcesarean hemorrhage fails to respond to early maneuvers.

A 25-year-old G1P0 undergoes cesarean section at our hospital for fetal distress. She has no history of coagulopathy, and no intraoperative complications are noted during the procedure. Upon her arrival in the postanesthesia care unit, however, vaginal bleeding is observed. She is given 40 U of oxytocin in 1 L of lactated Ringer solution, two intramuscular doses of 0.2 mg of methylergonovine maleate, and 1,000 μg of misoprostol to treat the postpartum bleeding. Nevertheless, she loses almost 1 L of additional blood from her vagina and is returned to the operating room for exploration and resuscitation for hypotensive shock. What are the next steps?

Management of obstetrical hemorrhage often begins with conservative measures, circumstances permitting. It is common practice to give 20–40 U of oxytocin in 1 L of lactated Ringer solution after delivery of the placenta and to perform uterine massage as part of initial management of uterine atony, along with careful evaluation and repair of any laceration or hematoma. In addition, ultrasonography (US) can help detect any retained uterine products.

Medical management usually involves the use of various uterotonics, such as methylergonovine maleate, 15-methylprostaglandin F2α, dinoprostone, and misoprostol. If uterotonics fail, techniques of tamponade include uterine packing with gauze material or use of the Foley intrauterine catheter, Sengstaken–Blakemore tube, and Bakri balloon.^1-3

Surgical management is often the last resort, and is limited by the clinician’s experience. Some surgical methods include uterine or hypogastric artery ligation, or both. Newer techniques include a variation of uterine compression sutures such as the B-Lynch suture or multiple-square suturing. The B-Lynch provides continuous compression of the uterus, thereby decreasing blood loss.⁴ Multiple-square suturing joins the anterior and posterior walls of the uterus, also compressing the uterus.

Hysterectomy should be a last resort, with the knowledge that bleeding may continue after the procedure, in which case pelvic packing becomes an alternative. Unfortunately, pelvic packing of the intraperitoneal cavity often has little effect on endometrial hemorrhage or retroperitoneal bleeding.^2-5

CASE CONTINUED

Resuscitation calls for blood products. Our resuscitation regimen includes recent clinical recommendations from military medical units in Iraq and Afghanistan and from domestic trauma centers. These guidelines propose that 1 U of fresh frozen plasma be administered with every 1 or 2 U of packed red blood cells (RBCs) until the clinical situation stabilizes or coagulopathy is excluded. Because of massive blood loss in this case, however, fluid replacement continues throughout the procedure—totaling 6 U of packed RBCs, 6 U of fresh frozen plasma, and 5 U of cryoprecipitate with additional crystalloid.^6-8

A decision is made to undertake surgical exploration. We open a Pfannenstiel incision and enter the peritoneal cavity, encountering scant dark red blood without gross intraperitoneal bleeding. The uterus is intact with apparent endometrial hemorrhage. Uterine vessels are not easily visualized because they are obscured by retroperitoneal blood and an engorged uterus. The uterus has increased in size severalfold during hemorrhage and occupies the entire pelvic cavity, making dissection difficult for emergent hysterectomy.

As the uterus is exteriorized, Péan clamps are placed on the cornua for retraction, and the round ligaments are transected and ligated bilaterally. Ecchymoses along the peritoneum suggest that retroperitoneal bleeding is occurring in addition to the endometrial blood loss.

What can be done about the retroperitoneal bleeding?

Although laparotomy and hysterectomy are last resorts in postpartum hemorrhage, the use of retroperitoneal packing during these procedures may hasten life-saving hemostasis. In pelvic trauma, a technique of retroperitoneal packing has significantly reduced mortality.⁹ The same technique of retroperitoneal packing is ideally suited for such devastating circumstances as life-threatening postpartum hemorrhage.

Retroperitoneal packing is a lesson gleaned from trauma surgery and has profound application in cases of severe postpartum hemorrhage.

CASE CONTINUED

Hemorrhage is stanched. Blood loss continues, and the patient remains in hypotensive shock. Vital signs are critical:

• systolic blood pressure, 40 mm Hg
• heart rate, 160 bpm
• minimal urine output
• hemoglobin level, 4 g/dL.

Hemorrhage is obvious from the appearance of the pelvis, and continuing blood loss suggests disseminated coagulopathy. Total abdominal hysterectomy cannot be safely or quickly performed.

To quickly prevent further blood loss, we pack the retroperitoneum using a technique adapted from trauma surgery and first described by Smith and colleagues.⁹ We make a 5-cm incision into the space of Retzius just cephalad to the pubic symphysis (FIGURES 1 and 2). This incision is separate and inferior to the earlier laparotomy incision.

Four laparotomy sponges are packed along the retroperitoneal space to provide tamponade (FIGURE 3). Within seconds, the patient stabilizes, with systolic blood pressure rising to 90 mm Hg and the heart rate declining toward 100 bpm. Bleeding ceases immediately, and the hysterectomy is completed under stable conditions without further blood loss.

FIGURE 1 Packing begins with a 5-cm incision

Make a 5-cm incision just cephalad to the symphysis pubis, deep to the fascia, and into the space of Retzius.

FIGURE 2 Preparing to place sponges

Use blunt dissection in the space of Retzius before placing packing material.

FIGURE 3 Insert packing into retroperitoneal space

Packing is usually sufficient when two or three laparotomy sponges are placed at each side of the retroperitoneal pelvis.

How retroperitoneal packing saves lives

Most of the pelvic packing that has been described in the literature has consistently involved intraperitoneal packing. However, packing of the peritoneal cavity is often insufficient tamponade for bleeding associated with retroperitoneal and endometrial bleeding. Direct compression in the retroperitoneal space stanches bleeding from the iliac vessels and branches. In trauma, this technique is used to provide quick relief of pelvic hemorrhage in any setting, including the emergency and operating rooms.^9-11

Technique

Retroperitoneal packing consists of a few basic steps and can be easily reproduced and applied in life-threatening circumstances. First, a 5-cm incision is made just cephalad to the symphysis pubis deep to the fascia and into the space of Retzius (FIGURE 1). The buildup of blood often causes autodissection of this plane (FIGURE 4). It is often useful to keep this fascial incision separate from the laparotomy fascial incision to assist with tamponade. Next, blunt dissection is performed in the continuous space of Retzius and retroperitoneum to the level of the presacral space (FIGURE 2).

FIGURE 4 Expect autodissection

Blood loss frequently causes autodissection of the surgical plane. Tamponade is then achieved by placing laparotomy sponges into the retroperitoneal space (FIGURE 3). Packing with two or three laparotomy sponges at each side of the retroperitoneal pelvis is usually sufficient. In emergent situations, this entire procedure can be completed in an emergency room or postanesthesia care unit, with a drain left in place along with the packs (FIGURE 5). In trauma, this technique allows immediate stabilization of the patient until the underlying injury can be thoroughly addressed. Careful examination of the ureters and bladder should be completed to address any injury promptly.

FIGURE 5 A drain may be required

Packing can be left in place until bleeding is stanched, with a drain added for optimal recovery. The success of this technique is clear from the trauma literature, but the data have yet to be widely applied in nontraumatic applications.⁹ It is especially advantageous to have a space separate from the intraperitoneal cavity to provide tamponade because the uterus itself may obstruct visualization. It is possible that, in some cases, this technique may control bleeding without the need for postpartum hysterectomy.

CASE RESOLVED

When the retroperitoneal packs are removed after the hysterectomy, no further bleeding occurs. However, moderate hydronephrosis is apparent along the patient’s left ureter.

The wound is closed, and the patient is transferred to intensive care. She subsequently undergoes placement of a ureteral stent for the hydronephrosis and is discharged 5 days later. The stent is removed on an outpatient basis without further morbidity or the need for additional procedures.

The authors report no financial relationships relevant to this article.

CASE: Postcesarean hemorrhage fails to respond to early maneuvers.

A 25-year-old G1P0 undergoes cesarean section at our hospital for fetal distress. She has no history of coagulopathy, and no intraoperative complications are noted during the procedure. Upon her arrival in the postanesthesia care unit, however, vaginal bleeding is observed. She is given 40 U of oxytocin in 1 L of lactated Ringer solution, two intramuscular doses of 0.2 mg of methylergonovine maleate, and 1,000 μg of misoprostol to treat the postpartum bleeding. Nevertheless, she loses almost 1 L of additional blood from her vagina and is returned to the operating room for exploration and resuscitation for hypotensive shock. What are the next steps?

Management of obstetrical hemorrhage often begins with conservative measures, circumstances permitting. It is common practice to give 20–40 U of oxytocin in 1 L of lactated Ringer solution after delivery of the placenta and to perform uterine massage as part of initial management of uterine atony, along with careful evaluation and repair of any laceration or hematoma. In addition, ultrasonography (US) can help detect any retained uterine products.

Medical management usually involves the use of various uterotonics, such as methylergonovine maleate, 15-methylprostaglandin F2α, dinoprostone, and misoprostol. If uterotonics fail, techniques of tamponade include uterine packing with gauze material or use of the Foley intrauterine catheter, Sengstaken–Blakemore tube, and Bakri balloon.^1-3

Surgical management is often the last resort, and is limited by the clinician’s experience. Some surgical methods include uterine or hypogastric artery ligation, or both. Newer techniques include a variation of uterine compression sutures such as the B-Lynch suture or multiple-square suturing. The B-Lynch provides continuous compression of the uterus, thereby decreasing blood loss.⁴ Multiple-square suturing joins the anterior and posterior walls of the uterus, also compressing the uterus.

Hysterectomy should be a last resort, with the knowledge that bleeding may continue after the procedure, in which case pelvic packing becomes an alternative. Unfortunately, pelvic packing of the intraperitoneal cavity often has little effect on endometrial hemorrhage or retroperitoneal bleeding.^2-5

CASE CONTINUED

Resuscitation calls for blood products. Our resuscitation regimen includes recent clinical recommendations from military medical units in Iraq and Afghanistan and from domestic trauma centers. These guidelines propose that 1 U of fresh frozen plasma be administered with every 1 or 2 U of packed red blood cells (RBCs) until the clinical situation stabilizes or coagulopathy is excluded. Because of massive blood loss in this case, however, fluid replacement continues throughout the procedure—totaling 6 U of packed RBCs, 6 U of fresh frozen plasma, and 5 U of cryoprecipitate with additional crystalloid.^6-8

A decision is made to undertake surgical exploration. We open a Pfannenstiel incision and enter the peritoneal cavity, encountering scant dark red blood without gross intraperitoneal bleeding. The uterus is intact with apparent endometrial hemorrhage. Uterine vessels are not easily visualized because they are obscured by retroperitoneal blood and an engorged uterus. The uterus has increased in size severalfold during hemorrhage and occupies the entire pelvic cavity, making dissection difficult for emergent hysterectomy.

As the uterus is exteriorized, Péan clamps are placed on the cornua for retraction, and the round ligaments are transected and ligated bilaterally. Ecchymoses along the peritoneum suggest that retroperitoneal bleeding is occurring in addition to the endometrial blood loss.

What can be done about the retroperitoneal bleeding?

Although laparotomy and hysterectomy are last resorts in postpartum hemorrhage, the use of retroperitoneal packing during these procedures may hasten life-saving hemostasis. In pelvic trauma, a technique of retroperitoneal packing has significantly reduced mortality.⁹ The same technique of retroperitoneal packing is ideally suited for such devastating circumstances as life-threatening postpartum hemorrhage.

Retroperitoneal packing is a lesson gleaned from trauma surgery and has profound application in cases of severe postpartum hemorrhage.

CASE CONTINUED

Hemorrhage is stanched. Blood loss continues, and the patient remains in hypotensive shock. Vital signs are critical:

• systolic blood pressure, 40 mm Hg
• heart rate, 160 bpm
• minimal urine output
• hemoglobin level, 4 g/dL.

Hemorrhage is obvious from the appearance of the pelvis, and continuing blood loss suggests disseminated coagulopathy. Total abdominal hysterectomy cannot be safely or quickly performed.

To quickly prevent further blood loss, we pack the retroperitoneum using a technique adapted from trauma surgery and first described by Smith and colleagues.⁹ We make a 5-cm incision into the space of Retzius just cephalad to the pubic symphysis (FIGURES 1 and 2). This incision is separate and inferior to the earlier laparotomy incision.

Four laparotomy sponges are packed along the retroperitoneal space to provide tamponade (FIGURE 3). Within seconds, the patient stabilizes, with systolic blood pressure rising to 90 mm Hg and the heart rate declining toward 100 bpm. Bleeding ceases immediately, and the hysterectomy is completed under stable conditions without further blood loss.

FIGURE 1 Packing begins with a 5-cm incision

Make a 5-cm incision just cephalad to the symphysis pubis, deep to the fascia, and into the space of Retzius.

FIGURE 2 Preparing to place sponges

Use blunt dissection in the space of Retzius before placing packing material.

FIGURE 3 Insert packing into retroperitoneal space

Packing is usually sufficient when two or three laparotomy sponges are placed at each side of the retroperitoneal pelvis.

How retroperitoneal packing saves lives

Most of the pelvic packing that has been described in the literature has consistently involved intraperitoneal packing. However, packing of the peritoneal cavity is often insufficient tamponade for bleeding associated with retroperitoneal and endometrial bleeding. Direct compression in the retroperitoneal space stanches bleeding from the iliac vessels and branches. In trauma, this technique is used to provide quick relief of pelvic hemorrhage in any setting, including the emergency and operating rooms.^9-11

Technique

Retroperitoneal packing consists of a few basic steps and can be easily reproduced and applied in life-threatening circumstances. First, a 5-cm incision is made just cephalad to the symphysis pubis deep to the fascia and into the space of Retzius (FIGURE 1). The buildup of blood often causes autodissection of this plane (FIGURE 4). It is often useful to keep this fascial incision separate from the laparotomy fascial incision to assist with tamponade. Next, blunt dissection is performed in the continuous space of Retzius and retroperitoneum to the level of the presacral space (FIGURE 2).

FIGURE 4 Expect autodissection

Blood loss frequently causes autodissection of the surgical plane. Tamponade is then achieved by placing laparotomy sponges into the retroperitoneal space (FIGURE 3). Packing with two or three laparotomy sponges at each side of the retroperitoneal pelvis is usually sufficient. In emergent situations, this entire procedure can be completed in an emergency room or postanesthesia care unit, with a drain left in place along with the packs (FIGURE 5). In trauma, this technique allows immediate stabilization of the patient until the underlying injury can be thoroughly addressed. Careful examination of the ureters and bladder should be completed to address any injury promptly.

FIGURE 5 A drain may be required

Packing can be left in place until bleeding is stanched, with a drain added for optimal recovery. The success of this technique is clear from the trauma literature, but the data have yet to be widely applied in nontraumatic applications.⁹ It is especially advantageous to have a space separate from the intraperitoneal cavity to provide tamponade because the uterus itself may obstruct visualization. It is possible that, in some cases, this technique may control bleeding without the need for postpartum hysterectomy.

CASE RESOLVED

When the retroperitoneal packs are removed after the hysterectomy, no further bleeding occurs. However, moderate hydronephrosis is apparent along the patient’s left ureter.

The wound is closed, and the patient is transferred to intensive care. She subsequently undergoes placement of a ureteral stent for the hydronephrosis and is discharged 5 days later. The stent is removed on an outpatient basis without further morbidity or the need for additional procedures.

The authors report no financial relationships relevant to this article.

Postmenopausal bleeding is a symptom evaluated often by general gynecologists. It necessitates assessment of the endometrium, most often by tissue sampling. When endometrial cancer is confirmed by biopsy, management becomes complex. Should the patient be referred to a gynecologic oncologist? What kind of surgery does she need? What kind of adjuvant treatment will be offered? Could the diagnosis be part of a genetic cancer syndrome?

Recent studies have yielded new information:

• Preoperative, intraoperative, and postoperative care by a gynecologic oncologist significantly lowers the cost of health care
• Lymphadenectomy for endometrial cancer remains controversial, and may be unnecessary in low-risk patients
• Chemotherapy plays an expanding role in the treatment of endometrial cancer. Adjuvant therapy with doxorubicin, cisplatin, and paclitaxel is the treatment of choice for patients who have advanced-stage disease
• Nine percent of women who are given a diagnosis of endometrial cancer before 50 years of age have a germ-line Lynch syndrome-associated mutation, which demonstrates that heredity is an important aspect of endometrial cancer and should be considered at all times.

It’s good economics to refer patients to gyn oncology sooner, not later

Hoekstra A, Singh DK, Garb M, Arekapudi S, Rademaker A, Lurain JR. Participation of the general gynecologist in the surgical staging of endometrial cancer: analysis of cost and perioperative outcomes. Gynecol Oncol. 2006;103:897–901.

Early-stage endometrial cancer is often curable with surgery alone because a full 88% of endometrial cancers present as clinical stage I.¹ The role of the general gynecologist in surgical management of these cases is controversial; at some institutions, the practice is to call in the gynecologic oncologist for lymph-node sampling or when gross disease is identified; at others, the standard is to refer the patient to gynecologic oncology as soon as malignancy is diagnosed by endometrial biopsy. Hoekstra and colleagues have attempted to shed light on this issue with a retrospective chart review of 121 patients who were treated at one institution from 1998 to 2000.

Costs of early treatment by a gynecologic oncologist were lower than without referral

The authors performed a retrospective analysis of a group of women with clinical stage-I endometrial cancer who were treated surgically at Prentice Women’s Hospital in Chicago.

The cohort was divided in two:

• Group 1 comprised patients who underwent surgery with a general gynecologist, who consulted a gynecologic oncologist intraoperatively
• Group 2 comprised patients who were referred to a gynecologic oncologist before surgery and underwent the procedure with a gynecologic oncologist.

Overall, subjects in both groups were similar in age, distribution of surgical stage, need for lymphadenectomy, and length of follow-up.

Group 2 had a significantly shorter operative time overall, and shorter total time in the operating room. Cost per procedure was also significantly lower in this group, in terms of cost to the payer and the physician’s charge. Perioperative costs were also lower in Group 2.

No difference was observed in postoperative outcome. Total hospital costs and lengths of stay were also similar.

Recommendation for practice

With health-care costs rising, be aware of referral strategies that promote cost containment. Women who have endometrial cancer may benefit from the early involvement of a gynecologic oncologist.

Is lymphadenectomy necessary when risk of metastasis is low?

Mariani A, Dowdy S, Cliby W, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11–18.

The need for surgical staging of endometrial cancer has been recognized since surgical staging criteria were adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988. Staging includes hysterectomy, bilateral salpingo-oophorectomy, and biopsy of any gross disease. Clear guidelines on the assessment of lymphatic dissemination and the anatomic extent of this assessment are, however, still lacking.

Proponents of systematic pelvic and para-aortic lymph-node dissection for patients with endometrial cancer cite:

• the 15% risk of lymph-node metastasis in women who have tumors 2 cm or larger in diameter²
• poor correlation between frozen-section grade and myometrial invasion with final pathology³
• the potential therapeutic benefit of the procedure.⁴

Opponents of such lymph-node dissection argue that women who have grade-1, stage-I disease will be overtreated if standardized lymphadenectomy is adopted.

Several retrospective studies have explored this question, with varying results. A large, prospective, randomized trial evaluating lymphadenectomy in clinical stage-I patients (ASTEC trial) has been completed, but is yet to be published.

When lymphadenectomy may (or may not) be necessary

After prospectively studying more than 300 endometrial cancer patients treated at the Mayo Clinic between 1984 and 1996,⁵ Mariani and colleagues launched a new study to assess a novel pattern of surgical management that aims to reduce the number of low-risk patients receiving lymphadenectomy. According to this pattern, the following types of women were able to bypass lymphadenectomy:

• those who had type-I, grades-1 and -2 tumors
• those with myometrial invasion ≤50%
• those with a primary tumor ≤2 cm in diameter.

Women who had endometrial cancer that did not meet these criteria underwent complete lymphadenectomy to the level of the renal vessels. Histologic assessment of the uterus to determine grade, depth of invasion, and primary tumor diameter was performed by frozen-section analysis in all cases.

The study included 422 women from January 2004 to December 2006. According to the guidelines of the study, 112 patients did not require lymphadenectomy. However, 22 (20%) women in this group did undergo the procedure because of palpable lymphadenopathy, initiation of dissection before the frozen-section report was received, or physician preference. All nodes were negative in these patients.

Of the women who met criteria for lymphadenectomy, 29 (9%) did not undergo dissection; among the reasons were disseminated disease, comorbid conditions, and advanced age. Of the women defined as at-risk who did undergo lymphadenectomy, 22% had lymph-node metastases.

Most positive para-aortic nodes lay above the inferior mesenteric artery

Information regarding the anatomic location of para-aortic nodal metastases was available for a small subset of women in the study. Seventy-seven percent of these women had para-aortic nodal metastasis above the inferior mesenteric artery. In addition, 71% of these patients had ipsilateral pelvic nodes that were free of disease. However, these patients had a poorer prognosis, and many would have received adjuvant therapy based on their hysterectomy specimen alone.

Recommendation for practice

This study suggests that there is a subset of patients who have endometrial cancer that is very low in risk and, because of this, they may forego lymph-node dissection without harm. In addition, a significant number of periaortic nodal metastases occur above the inferior mesenteric artery and in the absence of pelvic node involvement.

One of the limitations of this study is the need for intraoperative uterine assessment by frozen section by an expert pathologist—a service that is not widely available.

Taken together, these data suggest that, if the uterus can be assessed by frozen section at the time of surgery, a subset of clinical stage-I patients can be spared lymphadenectomy and its attendant risks.

Patients undergoing lymphatic assessment should undergo full systematic lymphnode dissection, not sampling. The dissection should include the region above the inferior mesenteric artery.

Removal of lymph nodes in endometrial cancer remains complex and controversial, a fact that strengthens the argument that an experienced gynecologic oncologist should be involved in the care of patients who have this disease.

Chemotherapy is warranted in advanced or recurrent disease

Homesley H, Filiaci V, Gibbons S, et al. Randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Abstract presented at the Society of Gynecologic Oncologists, March 2008.

Adjuvant therapy for advanced-stage endometrial cancer has varied considerably over the years, and treatment of these patients remains somewhat controversial. Clinical trials comparing chemotherapy with radiation, and chemotherapy regimens with each other, have led to an era in which chemotherapy is used to treat more women than ever before.

In 2006, the Gynecologic Oncology Group (GOG) published the results of a prospective randomized study (GOG 122) that compared whole-abdomen radiation to doxorubicin and cisplatin in stage-III or -IV endometrial cancer. The investigators determined that chemotherapy was superior to whole-abdomen radiation in this trial.⁶

This finding was quickly followed by another trial (GOG 177) in which doxorubicin plus cisplatin was compared with a regimen of doxorubicin, cisplatin, and paclitaxel. Women in this trial had stage-III or -IV or recurrent disease. A history of radiation treatment did not disqualify patients from the study, and the treatment groups were well balanced in randomization. The doxorubicin–cisplatin–paclitaxel arm improved progression-free and overall survival, making this combination the preferred treatment.⁷

After volume-directed radiation, paclitaxel does not add benefit

Several retrospective analyses of radiation versus chemotherapy have shown improvement with radiation or combination therapy.⁸ Most recently, the GOG released data from a trial comparing chemotherapy regimens after radiation treatment. GOG 184 evaluated surgically debulked, stage-III or -IV patients who had received volume-directed radiation; subjects were randomized into either of two chemotherapy regimens:

• doxorubicin plus cisplatin
• doxorubicin, cisplatin, and paclitaxel.

In these patients, there was no improvement in survival when paclitaxel was added to the chemotherapeutic regimen, compared with doxorubicin plus cisplatin. Morbidity increased, however, with the addition of paclitaxel.

Patients in this trial underwent surgical resection of all gross disease, with no residual tumor larger than 2 cm. The role of optimal cytoreduction in endometrial cancer has been debated, however. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter (FIGURE).^9-11 GOG 184 inclusion criteria required surgical resection of gross disease to ≤2 cm in diameter. It is possible that the therapeutic benefit of surgical debulking may have improved outcome in these patients—to the extent that the addition of paclitaxel did not provide appreciable benefit.

FIGURE Debulk gross disease?

The role of optimal cytoreduction in endometrial cancer has been debated. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter.

Recommendation for practice

Data on adjuvant therapy for endometrial cancer remains conflicting. Women who have advanced-stage or recurrent endometrial cancer should receive chemotherapy—either with doxorubicin, cisplatin, and paclitaxel, or a platinum taxane regimen. The addition of paclitaxel in surgically debulked patients who have undergone radiation treatment does not appear to improve survival.

There is, however, a clear recommendation for paclitaxel in radiation-naïve patients and those who have gross residual disease. Further studies are needed to elucidate the role of radiation therapy in an era of volume-directed radiation.

Look for Lynch syndrome in young women with endometrial cancer

Lu K, Schorge J, Rodabaugh K, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158–5164.

Endometrial cancer is part of the spectrum of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). Patients with this autosomal-dominant hereditary cancer susceptibility syndrome may present with colorectal cancer, endometrial cancer, or, more rarely, ovarian cancer. Lynch syndrome derives from germline mutations in DNA mismatch repair genes, most often MLH1, MSH2, and MSH6.¹² Genetic testing for all three genes is available for clinical use.

In the past, screening for Lynch syndrome focused on colorectal cancer, but it is now clear that women who have this disorder have a lifetime risk of developing endometrial cancer that exceeds 40%.¹³

In Lynch syndrome, gynecologic cancer often precedes colon cancer

Women with Lynch syndrome-associated endometrial cancer typically present at a younger age than their syndrome-free counterparts (48 compared with 60 years).¹⁴ Previous retrospective studies demonstrated that 50% of women with Lynch syndrome-associated colon and gynecologic cancers had gynecologic cancer preceding the colon cancer. The average was 11 years earlier for endometrial cancer, which suggests that, if these women could be identified at the time they are given their diagnosis of endometrial cancer, more intensive screening for colon cancer could then be initiated.¹⁵

9% of women who develop endometrial cancer before age 50 have Lynch syndrome

One of the screening criteria for Lynch syndrome-associated colon cancer is age <50 years. In this recent prospective, multicenter study involving 100 women who were diagnosed with endometrial cancer at less than 50 years of age, germline Lynch syndrome mutations were identified in 9% of patients. (In this study, germline mutation testing was performed for MLH1, MSH2, and MSH6 genes by full sequencing, and immunohistochemistry was performed for all three genes. Microsatellite analysis was performed on 95 patients, with five women having insufficient tumor for DNA extraction.)

All women who had a germline mutation had a first-degree relative with Lynch syndrome-associated cancer. The combination of a negative family history for Lynch syndrome and a body mass index greater than 30 was highly predictive of having no Lynch syndrome mutation, with a negative predictive value of 96%.

Recommendation for practice

Patients who have an hereditary cancer syndrome such as Lynch syndrome can begin cancer-prevention screening—and be engaged in that screening—when the syndrome is recognized early. Because women who have endometrial cancer that was diagnosed before they were 50 years old are at significant risk of a germline mutation, they should be offered genetic counseling and testing.

The authors report no financial relationships relevant to this article.

Postmenopausal bleeding is a symptom evaluated often by general gynecologists. It necessitates assessment of the endometrium, most often by tissue sampling. When endometrial cancer is confirmed by biopsy, management becomes complex. Should the patient be referred to a gynecologic oncologist? What kind of surgery does she need? What kind of adjuvant treatment will be offered? Could the diagnosis be part of a genetic cancer syndrome?

Recent studies have yielded new information:

• Preoperative, intraoperative, and postoperative care by a gynecologic oncologist significantly lowers the cost of health care
• Lymphadenectomy for endometrial cancer remains controversial, and may be unnecessary in low-risk patients
• Chemotherapy plays an expanding role in the treatment of endometrial cancer. Adjuvant therapy with doxorubicin, cisplatin, and paclitaxel is the treatment of choice for patients who have advanced-stage disease
• Nine percent of women who are given a diagnosis of endometrial cancer before 50 years of age have a germ-line Lynch syndrome-associated mutation, which demonstrates that heredity is an important aspect of endometrial cancer and should be considered at all times.

It’s good economics to refer patients to gyn oncology sooner, not later

Hoekstra A, Singh DK, Garb M, Arekapudi S, Rademaker A, Lurain JR. Participation of the general gynecologist in the surgical staging of endometrial cancer: analysis of cost and perioperative outcomes. Gynecol Oncol. 2006;103:897–901.

Early-stage endometrial cancer is often curable with surgery alone because a full 88% of endometrial cancers present as clinical stage I.¹ The role of the general gynecologist in surgical management of these cases is controversial; at some institutions, the practice is to call in the gynecologic oncologist for lymph-node sampling or when gross disease is identified; at others, the standard is to refer the patient to gynecologic oncology as soon as malignancy is diagnosed by endometrial biopsy. Hoekstra and colleagues have attempted to shed light on this issue with a retrospective chart review of 121 patients who were treated at one institution from 1998 to 2000.

Costs of early treatment by a gynecologic oncologist were lower than without referral

The authors performed a retrospective analysis of a group of women with clinical stage-I endometrial cancer who were treated surgically at Prentice Women’s Hospital in Chicago.

The cohort was divided in two:

• Group 1 comprised patients who underwent surgery with a general gynecologist, who consulted a gynecologic oncologist intraoperatively
• Group 2 comprised patients who were referred to a gynecologic oncologist before surgery and underwent the procedure with a gynecologic oncologist.

Overall, subjects in both groups were similar in age, distribution of surgical stage, need for lymphadenectomy, and length of follow-up.

Group 2 had a significantly shorter operative time overall, and shorter total time in the operating room. Cost per procedure was also significantly lower in this group, in terms of cost to the payer and the physician’s charge. Perioperative costs were also lower in Group 2.

No difference was observed in postoperative outcome. Total hospital costs and lengths of stay were also similar.

Recommendation for practice

With health-care costs rising, be aware of referral strategies that promote cost containment. Women who have endometrial cancer may benefit from the early involvement of a gynecologic oncologist.

Is lymphadenectomy necessary when risk of metastasis is low?

Mariani A, Dowdy S, Cliby W, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11–18.

The need for surgical staging of endometrial cancer has been recognized since surgical staging criteria were adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988. Staging includes hysterectomy, bilateral salpingo-oophorectomy, and biopsy of any gross disease. Clear guidelines on the assessment of lymphatic dissemination and the anatomic extent of this assessment are, however, still lacking.

Proponents of systematic pelvic and para-aortic lymph-node dissection for patients with endometrial cancer cite:

• the 15% risk of lymph-node metastasis in women who have tumors 2 cm or larger in diameter²
• poor correlation between frozen-section grade and myometrial invasion with final pathology³
• the potential therapeutic benefit of the procedure.⁴

Opponents of such lymph-node dissection argue that women who have grade-1, stage-I disease will be overtreated if standardized lymphadenectomy is adopted.

Several retrospective studies have explored this question, with varying results. A large, prospective, randomized trial evaluating lymphadenectomy in clinical stage-I patients (ASTEC trial) has been completed, but is yet to be published.

When lymphadenectomy may (or may not) be necessary

After prospectively studying more than 300 endometrial cancer patients treated at the Mayo Clinic between 1984 and 1996,⁵ Mariani and colleagues launched a new study to assess a novel pattern of surgical management that aims to reduce the number of low-risk patients receiving lymphadenectomy. According to this pattern, the following types of women were able to bypass lymphadenectomy:

• those who had type-I, grades-1 and -2 tumors
• those with myometrial invasion ≤50%
• those with a primary tumor ≤2 cm in diameter.

Women who had endometrial cancer that did not meet these criteria underwent complete lymphadenectomy to the level of the renal vessels. Histologic assessment of the uterus to determine grade, depth of invasion, and primary tumor diameter was performed by frozen-section analysis in all cases.

The study included 422 women from January 2004 to December 2006. According to the guidelines of the study, 112 patients did not require lymphadenectomy. However, 22 (20%) women in this group did undergo the procedure because of palpable lymphadenopathy, initiation of dissection before the frozen-section report was received, or physician preference. All nodes were negative in these patients.

Of the women who met criteria for lymphadenectomy, 29 (9%) did not undergo dissection; among the reasons were disseminated disease, comorbid conditions, and advanced age. Of the women defined as at-risk who did undergo lymphadenectomy, 22% had lymph-node metastases.

Most positive para-aortic nodes lay above the inferior mesenteric artery

Information regarding the anatomic location of para-aortic nodal metastases was available for a small subset of women in the study. Seventy-seven percent of these women had para-aortic nodal metastasis above the inferior mesenteric artery. In addition, 71% of these patients had ipsilateral pelvic nodes that were free of disease. However, these patients had a poorer prognosis, and many would have received adjuvant therapy based on their hysterectomy specimen alone.

Recommendation for practice

This study suggests that there is a subset of patients who have endometrial cancer that is very low in risk and, because of this, they may forego lymph-node dissection without harm. In addition, a significant number of periaortic nodal metastases occur above the inferior mesenteric artery and in the absence of pelvic node involvement.

One of the limitations of this study is the need for intraoperative uterine assessment by frozen section by an expert pathologist—a service that is not widely available.

Taken together, these data suggest that, if the uterus can be assessed by frozen section at the time of surgery, a subset of clinical stage-I patients can be spared lymphadenectomy and its attendant risks.

Patients undergoing lymphatic assessment should undergo full systematic lymphnode dissection, not sampling. The dissection should include the region above the inferior mesenteric artery.

Removal of lymph nodes in endometrial cancer remains complex and controversial, a fact that strengthens the argument that an experienced gynecologic oncologist should be involved in the care of patients who have this disease.

Chemotherapy is warranted in advanced or recurrent disease

Homesley H, Filiaci V, Gibbons S, et al. Randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Abstract presented at the Society of Gynecologic Oncologists, March 2008.

Adjuvant therapy for advanced-stage endometrial cancer has varied considerably over the years, and treatment of these patients remains somewhat controversial. Clinical trials comparing chemotherapy with radiation, and chemotherapy regimens with each other, have led to an era in which chemotherapy is used to treat more women than ever before.

In 2006, the Gynecologic Oncology Group (GOG) published the results of a prospective randomized study (GOG 122) that compared whole-abdomen radiation to doxorubicin and cisplatin in stage-III or -IV endometrial cancer. The investigators determined that chemotherapy was superior to whole-abdomen radiation in this trial.⁶

This finding was quickly followed by another trial (GOG 177) in which doxorubicin plus cisplatin was compared with a regimen of doxorubicin, cisplatin, and paclitaxel. Women in this trial had stage-III or -IV or recurrent disease. A history of radiation treatment did not disqualify patients from the study, and the treatment groups were well balanced in randomization. The doxorubicin–cisplatin–paclitaxel arm improved progression-free and overall survival, making this combination the preferred treatment.⁷

After volume-directed radiation, paclitaxel does not add benefit

Several retrospective analyses of radiation versus chemotherapy have shown improvement with radiation or combination therapy.⁸ Most recently, the GOG released data from a trial comparing chemotherapy regimens after radiation treatment. GOG 184 evaluated surgically debulked, stage-III or -IV patients who had received volume-directed radiation; subjects were randomized into either of two chemotherapy regimens:

• doxorubicin plus cisplatin
• doxorubicin, cisplatin, and paclitaxel.

In these patients, there was no improvement in survival when paclitaxel was added to the chemotherapeutic regimen, compared with doxorubicin plus cisplatin. Morbidity increased, however, with the addition of paclitaxel.

Patients in this trial underwent surgical resection of all gross disease, with no residual tumor larger than 2 cm. The role of optimal cytoreduction in endometrial cancer has been debated, however. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter (FIGURE).^9-11 GOG 184 inclusion criteria required surgical resection of gross disease to ≤2 cm in diameter. It is possible that the therapeutic benefit of surgical debulking may have improved outcome in these patients—to the extent that the addition of paclitaxel did not provide appreciable benefit.

FIGURE Debulk gross disease?

The role of optimal cytoreduction in endometrial cancer has been debated. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter.

Recommendation for practice

Data on adjuvant therapy for endometrial cancer remains conflicting. Women who have advanced-stage or recurrent endometrial cancer should receive chemotherapy—either with doxorubicin, cisplatin, and paclitaxel, or a platinum taxane regimen. The addition of paclitaxel in surgically debulked patients who have undergone radiation treatment does not appear to improve survival.

There is, however, a clear recommendation for paclitaxel in radiation-naïve patients and those who have gross residual disease. Further studies are needed to elucidate the role of radiation therapy in an era of volume-directed radiation.

Look for Lynch syndrome in young women with endometrial cancer

Lu K, Schorge J, Rodabaugh K, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158–5164.

Endometrial cancer is part of the spectrum of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). Patients with this autosomal-dominant hereditary cancer susceptibility syndrome may present with colorectal cancer, endometrial cancer, or, more rarely, ovarian cancer. Lynch syndrome derives from germline mutations in DNA mismatch repair genes, most often MLH1, MSH2, and MSH6.¹² Genetic testing for all three genes is available for clinical use.

In the past, screening for Lynch syndrome focused on colorectal cancer, but it is now clear that women who have this disorder have a lifetime risk of developing endometrial cancer that exceeds 40%.¹³

In Lynch syndrome, gynecologic cancer often precedes colon cancer

Women with Lynch syndrome-associated endometrial cancer typically present at a younger age than their syndrome-free counterparts (48 compared with 60 years).¹⁴ Previous retrospective studies demonstrated that 50% of women with Lynch syndrome-associated colon and gynecologic cancers had gynecologic cancer preceding the colon cancer. The average was 11 years earlier for endometrial cancer, which suggests that, if these women could be identified at the time they are given their diagnosis of endometrial cancer, more intensive screening for colon cancer could then be initiated.¹⁵

9% of women who develop endometrial cancer before age 50 have Lynch syndrome

One of the screening criteria for Lynch syndrome-associated colon cancer is age <50 years. In this recent prospective, multicenter study involving 100 women who were diagnosed with endometrial cancer at less than 50 years of age, germline Lynch syndrome mutations were identified in 9% of patients. (In this study, germline mutation testing was performed for MLH1, MSH2, and MSH6 genes by full sequencing, and immunohistochemistry was performed for all three genes. Microsatellite analysis was performed on 95 patients, with five women having insufficient tumor for DNA extraction.)

All women who had a germline mutation had a first-degree relative with Lynch syndrome-associated cancer. The combination of a negative family history for Lynch syndrome and a body mass index greater than 30 was highly predictive of having no Lynch syndrome mutation, with a negative predictive value of 96%.

Recommendation for practice

Patients who have an hereditary cancer syndrome such as Lynch syndrome can begin cancer-prevention screening—and be engaged in that screening—when the syndrome is recognized early. Because women who have endometrial cancer that was diagnosed before they were 50 years old are at significant risk of a germline mutation, they should be offered genetic counseling and testing.

The authors report no financial relationships relevant to this article.

Postmenopausal bleeding is a symptom evaluated often by general gynecologists. It necessitates assessment of the endometrium, most often by tissue sampling. When endometrial cancer is confirmed by biopsy, management becomes complex. Should the patient be referred to a gynecologic oncologist? What kind of surgery does she need? What kind of adjuvant treatment will be offered? Could the diagnosis be part of a genetic cancer syndrome?

Recent studies have yielded new information:

• Preoperative, intraoperative, and postoperative care by a gynecologic oncologist significantly lowers the cost of health care
• Lymphadenectomy for endometrial cancer remains controversial, and may be unnecessary in low-risk patients
• Chemotherapy plays an expanding role in the treatment of endometrial cancer. Adjuvant therapy with doxorubicin, cisplatin, and paclitaxel is the treatment of choice for patients who have advanced-stage disease
• Nine percent of women who are given a diagnosis of endometrial cancer before 50 years of age have a germ-line Lynch syndrome-associated mutation, which demonstrates that heredity is an important aspect of endometrial cancer and should be considered at all times.

It’s good economics to refer patients to gyn oncology sooner, not later

Hoekstra A, Singh DK, Garb M, Arekapudi S, Rademaker A, Lurain JR. Participation of the general gynecologist in the surgical staging of endometrial cancer: analysis of cost and perioperative outcomes. Gynecol Oncol. 2006;103:897–901.

Early-stage endometrial cancer is often curable with surgery alone because a full 88% of endometrial cancers present as clinical stage I.¹ The role of the general gynecologist in surgical management of these cases is controversial; at some institutions, the practice is to call in the gynecologic oncologist for lymph-node sampling or when gross disease is identified; at others, the standard is to refer the patient to gynecologic oncology as soon as malignancy is diagnosed by endometrial biopsy. Hoekstra and colleagues have attempted to shed light on this issue with a retrospective chart review of 121 patients who were treated at one institution from 1998 to 2000.

Costs of early treatment by a gynecologic oncologist were lower than without referral

The authors performed a retrospective analysis of a group of women with clinical stage-I endometrial cancer who were treated surgically at Prentice Women’s Hospital in Chicago.

The cohort was divided in two:

• Group 1 comprised patients who underwent surgery with a general gynecologist, who consulted a gynecologic oncologist intraoperatively
• Group 2 comprised patients who were referred to a gynecologic oncologist before surgery and underwent the procedure with a gynecologic oncologist.

Overall, subjects in both groups were similar in age, distribution of surgical stage, need for lymphadenectomy, and length of follow-up.

Group 2 had a significantly shorter operative time overall, and shorter total time in the operating room. Cost per procedure was also significantly lower in this group, in terms of cost to the payer and the physician’s charge. Perioperative costs were also lower in Group 2.

No difference was observed in postoperative outcome. Total hospital costs and lengths of stay were also similar.

Recommendation for practice

With health-care costs rising, be aware of referral strategies that promote cost containment. Women who have endometrial cancer may benefit from the early involvement of a gynecologic oncologist.

Is lymphadenectomy necessary when risk of metastasis is low?

Mariani A, Dowdy S, Cliby W, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11–18.

The need for surgical staging of endometrial cancer has been recognized since surgical staging criteria were adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988. Staging includes hysterectomy, bilateral salpingo-oophorectomy, and biopsy of any gross disease. Clear guidelines on the assessment of lymphatic dissemination and the anatomic extent of this assessment are, however, still lacking.

Proponents of systematic pelvic and para-aortic lymph-node dissection for patients with endometrial cancer cite:

• the 15% risk of lymph-node metastasis in women who have tumors 2 cm or larger in diameter²
• poor correlation between frozen-section grade and myometrial invasion with final pathology³
• the potential therapeutic benefit of the procedure.⁴

Opponents of such lymph-node dissection argue that women who have grade-1, stage-I disease will be overtreated if standardized lymphadenectomy is adopted.

Several retrospective studies have explored this question, with varying results. A large, prospective, randomized trial evaluating lymphadenectomy in clinical stage-I patients (ASTEC trial) has been completed, but is yet to be published.

When lymphadenectomy may (or may not) be necessary

After prospectively studying more than 300 endometrial cancer patients treated at the Mayo Clinic between 1984 and 1996,⁵ Mariani and colleagues launched a new study to assess a novel pattern of surgical management that aims to reduce the number of low-risk patients receiving lymphadenectomy. According to this pattern, the following types of women were able to bypass lymphadenectomy:

• those who had type-I, grades-1 and -2 tumors
• those with myometrial invasion ≤50%
• those with a primary tumor ≤2 cm in diameter.

Women who had endometrial cancer that did not meet these criteria underwent complete lymphadenectomy to the level of the renal vessels. Histologic assessment of the uterus to determine grade, depth of invasion, and primary tumor diameter was performed by frozen-section analysis in all cases.

The study included 422 women from January 2004 to December 2006. According to the guidelines of the study, 112 patients did not require lymphadenectomy. However, 22 (20%) women in this group did undergo the procedure because of palpable lymphadenopathy, initiation of dissection before the frozen-section report was received, or physician preference. All nodes were negative in these patients.

Of the women who met criteria for lymphadenectomy, 29 (9%) did not undergo dissection; among the reasons were disseminated disease, comorbid conditions, and advanced age. Of the women defined as at-risk who did undergo lymphadenectomy, 22% had lymph-node metastases.

Most positive para-aortic nodes lay above the inferior mesenteric artery

Information regarding the anatomic location of para-aortic nodal metastases was available for a small subset of women in the study. Seventy-seven percent of these women had para-aortic nodal metastasis above the inferior mesenteric artery. In addition, 71% of these patients had ipsilateral pelvic nodes that were free of disease. However, these patients had a poorer prognosis, and many would have received adjuvant therapy based on their hysterectomy specimen alone.

Recommendation for practice

This study suggests that there is a subset of patients who have endometrial cancer that is very low in risk and, because of this, they may forego lymph-node dissection without harm. In addition, a significant number of periaortic nodal metastases occur above the inferior mesenteric artery and in the absence of pelvic node involvement.

One of the limitations of this study is the need for intraoperative uterine assessment by frozen section by an expert pathologist—a service that is not widely available.

Taken together, these data suggest that, if the uterus can be assessed by frozen section at the time of surgery, a subset of clinical stage-I patients can be spared lymphadenectomy and its attendant risks.

Patients undergoing lymphatic assessment should undergo full systematic lymphnode dissection, not sampling. The dissection should include the region above the inferior mesenteric artery.

Removal of lymph nodes in endometrial cancer remains complex and controversial, a fact that strengthens the argument that an experienced gynecologic oncologist should be involved in the care of patients who have this disease.

Chemotherapy is warranted in advanced or recurrent disease

Homesley H, Filiaci V, Gibbons S, et al. Randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Abstract presented at the Society of Gynecologic Oncologists, March 2008.

Adjuvant therapy for advanced-stage endometrial cancer has varied considerably over the years, and treatment of these patients remains somewhat controversial. Clinical trials comparing chemotherapy with radiation, and chemotherapy regimens with each other, have led to an era in which chemotherapy is used to treat more women than ever before.

In 2006, the Gynecologic Oncology Group (GOG) published the results of a prospective randomized study (GOG 122) that compared whole-abdomen radiation to doxorubicin and cisplatin in stage-III or -IV endometrial cancer. The investigators determined that chemotherapy was superior to whole-abdomen radiation in this trial.⁶

This finding was quickly followed by another trial (GOG 177) in which doxorubicin plus cisplatin was compared with a regimen of doxorubicin, cisplatin, and paclitaxel. Women in this trial had stage-III or -IV or recurrent disease. A history of radiation treatment did not disqualify patients from the study, and the treatment groups were well balanced in randomization. The doxorubicin–cisplatin–paclitaxel arm improved progression-free and overall survival, making this combination the preferred treatment.⁷

After volume-directed radiation, paclitaxel does not add benefit

Several retrospective analyses of radiation versus chemotherapy have shown improvement with radiation or combination therapy.⁸ Most recently, the GOG released data from a trial comparing chemotherapy regimens after radiation treatment. GOG 184 evaluated surgically debulked, stage-III or -IV patients who had received volume-directed radiation; subjects were randomized into either of two chemotherapy regimens:

• doxorubicin plus cisplatin
• doxorubicin, cisplatin, and paclitaxel.

In these patients, there was no improvement in survival when paclitaxel was added to the chemotherapeutic regimen, compared with doxorubicin plus cisplatin. Morbidity increased, however, with the addition of paclitaxel.

Patients in this trial underwent surgical resection of all gross disease, with no residual tumor larger than 2 cm. The role of optimal cytoreduction in endometrial cancer has been debated, however. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter (FIGURE).^9-11 GOG 184 inclusion criteria required surgical resection of gross disease to ≤2 cm in diameter. It is possible that the therapeutic benefit of surgical debulking may have improved outcome in these patients—to the extent that the addition of paclitaxel did not provide appreciable benefit.

FIGURE Debulk gross disease?

The role of optimal cytoreduction in endometrial cancer has been debated. Several studies have pointed to improved survival in women after removal of visible disease to less than 1 to 2 cm in diameter.

Recommendation for practice

Data on adjuvant therapy for endometrial cancer remains conflicting. Women who have advanced-stage or recurrent endometrial cancer should receive chemotherapy—either with doxorubicin, cisplatin, and paclitaxel, or a platinum taxane regimen. The addition of paclitaxel in surgically debulked patients who have undergone radiation treatment does not appear to improve survival.

There is, however, a clear recommendation for paclitaxel in radiation-naïve patients and those who have gross residual disease. Further studies are needed to elucidate the role of radiation therapy in an era of volume-directed radiation.

Look for Lynch syndrome in young women with endometrial cancer

Lu K, Schorge J, Rodabaugh K, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158–5164.

Endometrial cancer is part of the spectrum of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). Patients with this autosomal-dominant hereditary cancer susceptibility syndrome may present with colorectal cancer, endometrial cancer, or, more rarely, ovarian cancer. Lynch syndrome derives from germline mutations in DNA mismatch repair genes, most often MLH1, MSH2, and MSH6.¹² Genetic testing for all three genes is available for clinical use.

In the past, screening for Lynch syndrome focused on colorectal cancer, but it is now clear that women who have this disorder have a lifetime risk of developing endometrial cancer that exceeds 40%.¹³

In Lynch syndrome, gynecologic cancer often precedes colon cancer

Women with Lynch syndrome-associated endometrial cancer typically present at a younger age than their syndrome-free counterparts (48 compared with 60 years).¹⁴ Previous retrospective studies demonstrated that 50% of women with Lynch syndrome-associated colon and gynecologic cancers had gynecologic cancer preceding the colon cancer. The average was 11 years earlier for endometrial cancer, which suggests that, if these women could be identified at the time they are given their diagnosis of endometrial cancer, more intensive screening for colon cancer could then be initiated.¹⁵

9% of women who develop endometrial cancer before age 50 have Lynch syndrome

One of the screening criteria for Lynch syndrome-associated colon cancer is age <50 years. In this recent prospective, multicenter study involving 100 women who were diagnosed with endometrial cancer at less than 50 years of age, germline Lynch syndrome mutations were identified in 9% of patients. (In this study, germline mutation testing was performed for MLH1, MSH2, and MSH6 genes by full sequencing, and immunohistochemistry was performed for all three genes. Microsatellite analysis was performed on 95 patients, with five women having insufficient tumor for DNA extraction.)

All women who had a germline mutation had a first-degree relative with Lynch syndrome-associated cancer. The combination of a negative family history for Lynch syndrome and a body mass index greater than 30 was highly predictive of having no Lynch syndrome mutation, with a negative predictive value of 96%.

Recommendation for practice

Patients who have an hereditary cancer syndrome such as Lynch syndrome can begin cancer-prevention screening—and be engaged in that screening—when the syndrome is recognized early. Because women who have endometrial cancer that was diagnosed before they were 50 years old are at significant risk of a germline mutation, they should be offered genetic counseling and testing.