Clinical Review

The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

• landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
• data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
• data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.¹

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

• When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
• In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

Transdermal estrogen is as effective as oral therapy

Like oral estrogen therapy, transdermal therapy effectively treats vasomotor symptoms, prevents loss of bone density, and treats genital atrophy.

Because transdermal menopausal estrogen therapy does not increase hepatic production of procoagulant factors, as does oral estrogen, it is biologically plausible that transdermal therapy is safer than oral therapy in terms of the risk of VTE.⁶

Combined with other evidence, the findings of this important French study suggest that ObGyns should consider transdermal therapy when helping menopausal women select a HT regimen.

Micronized progesterone might not raise the risk of breast cancer

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111.

In contrast to estrogen-only therapy, long-term use of combination estrogen– progestin HT is associated with a modestly elevated risk of breast cancer.^7-10

In France, micronized progesterone is the progestin most commonly used in HT. In 2008, results from a large French case-control study suggested that—in contrast to combination HT that contains MPA or norethindrone acetate—use of combination HT formulated with micronized progesterone was not associated with an elevated risk of breast cancer.

In women taking menopausal estrogen, the appropriate dosage of micronized progesterone to prevent endometrial hyperplasia is 100 mg nightly or 200 mg for 12 or more nights each month.

Avoid micronized progesterone in patients with peanut allergy

Because micronized progesterone contains peanut oil, patients with a history of peanut allergy should not use it.

Estrogen’s effects on cognition depend on, again, age at use

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008;70:200–209.

One intriguing possibility entertained in recent years is that HT prevents dementia, although data so far have been conflicting. A large, high-quality observational study performed in Utah and published in 2002 provided evidence that HT use by young menopausal women prevents cognitive decline later in life, particularly when HT is used over the long term.¹¹

In contrast, the WHI Memory Study found that HT increases the risk of mild cognitive impairment and dementia.¹² However, that study enrolled an older subgroup of WHI participants (65 to 79 years old at randomization).

Very young estrogen-deprived women stand to benefit from HT

Over the past year, Rocca and colleagues at the Mayo Clinic in Minnesota published two reports assessing the risk of neurologic disease among several thousand Midwestern women who had undergone oophorectomy (unilateral or bilateral) before reaching menopause. A history of oophorectomy, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was prescribed until at least 50 years of age following bilateral oophorectomy, no increased risk of cognitive impairment was found.

Using similar methods, the same research group at Mayo found that oophorectomy before menopause was associated with a significantly increased risk of parkinsonism (symptoms that did not meet the formal criteria for Parkinson’s disease) as well as an increased risk, which did not attain statistica significance, of Parkinson’s disease itself.

Taken in totality, the evidence suggests that when HT is initiated in young menopausal women, protection against dementia and other neurologic disease may result. These findings parallel the evidence on the risk of CAD during HT use presented at the beginning of this article.

The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

• landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
• data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
• data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.¹

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

• When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
• In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

Transdermal estrogen is as effective as oral therapy

Like oral estrogen therapy, transdermal therapy effectively treats vasomotor symptoms, prevents loss of bone density, and treats genital atrophy.

Because transdermal menopausal estrogen therapy does not increase hepatic production of procoagulant factors, as does oral estrogen, it is biologically plausible that transdermal therapy is safer than oral therapy in terms of the risk of VTE.⁶

Combined with other evidence, the findings of this important French study suggest that ObGyns should consider transdermal therapy when helping menopausal women select a HT regimen.

Micronized progesterone might not raise the risk of breast cancer

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111.

In contrast to estrogen-only therapy, long-term use of combination estrogen– progestin HT is associated with a modestly elevated risk of breast cancer.^7-10

In France, micronized progesterone is the progestin most commonly used in HT. In 2008, results from a large French case-control study suggested that—in contrast to combination HT that contains MPA or norethindrone acetate—use of combination HT formulated with micronized progesterone was not associated with an elevated risk of breast cancer.

In women taking menopausal estrogen, the appropriate dosage of micronized progesterone to prevent endometrial hyperplasia is 100 mg nightly or 200 mg for 12 or more nights each month.

Avoid micronized progesterone in patients with peanut allergy

Because micronized progesterone contains peanut oil, patients with a history of peanut allergy should not use it.

Estrogen’s effects on cognition depend on, again, age at use

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008;70:200–209.

One intriguing possibility entertained in recent years is that HT prevents dementia, although data so far have been conflicting. A large, high-quality observational study performed in Utah and published in 2002 provided evidence that HT use by young menopausal women prevents cognitive decline later in life, particularly when HT is used over the long term.¹¹

In contrast, the WHI Memory Study found that HT increases the risk of mild cognitive impairment and dementia.¹² However, that study enrolled an older subgroup of WHI participants (65 to 79 years old at randomization).

Very young estrogen-deprived women stand to benefit from HT

Over the past year, Rocca and colleagues at the Mayo Clinic in Minnesota published two reports assessing the risk of neurologic disease among several thousand Midwestern women who had undergone oophorectomy (unilateral or bilateral) before reaching menopause. A history of oophorectomy, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was prescribed until at least 50 years of age following bilateral oophorectomy, no increased risk of cognitive impairment was found.

Using similar methods, the same research group at Mayo found that oophorectomy before menopause was associated with a significantly increased risk of parkinsonism (symptoms that did not meet the formal criteria for Parkinson’s disease) as well as an increased risk, which did not attain statistica significance, of Parkinson’s disease itself.

Taken in totality, the evidence suggests that when HT is initiated in young menopausal women, protection against dementia and other neurologic disease may result. These findings parallel the evidence on the risk of CAD during HT use presented at the beginning of this article.

The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

• landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
• data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
• data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.¹

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

• When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
• In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

Transdermal estrogen is as effective as oral therapy

Like oral estrogen therapy, transdermal therapy effectively treats vasomotor symptoms, prevents loss of bone density, and treats genital atrophy.

Because transdermal menopausal estrogen therapy does not increase hepatic production of procoagulant factors, as does oral estrogen, it is biologically plausible that transdermal therapy is safer than oral therapy in terms of the risk of VTE.⁶

Combined with other evidence, the findings of this important French study suggest that ObGyns should consider transdermal therapy when helping menopausal women select a HT regimen.

Micronized progesterone might not raise the risk of breast cancer

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111.

In contrast to estrogen-only therapy, long-term use of combination estrogen– progestin HT is associated with a modestly elevated risk of breast cancer.^7-10

In France, micronized progesterone is the progestin most commonly used in HT. In 2008, results from a large French case-control study suggested that—in contrast to combination HT that contains MPA or norethindrone acetate—use of combination HT formulated with micronized progesterone was not associated with an elevated risk of breast cancer.

In women taking menopausal estrogen, the appropriate dosage of micronized progesterone to prevent endometrial hyperplasia is 100 mg nightly or 200 mg for 12 or more nights each month.

Avoid micronized progesterone in patients with peanut allergy

Because micronized progesterone contains peanut oil, patients with a history of peanut allergy should not use it.

Estrogen’s effects on cognition depend on, again, age at use

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008;70:200–209.

One intriguing possibility entertained in recent years is that HT prevents dementia, although data so far have been conflicting. A large, high-quality observational study performed in Utah and published in 2002 provided evidence that HT use by young menopausal women prevents cognitive decline later in life, particularly when HT is used over the long term.¹¹

In contrast, the WHI Memory Study found that HT increases the risk of mild cognitive impairment and dementia.¹² However, that study enrolled an older subgroup of WHI participants (65 to 79 years old at randomization).

Very young estrogen-deprived women stand to benefit from HT

Over the past year, Rocca and colleagues at the Mayo Clinic in Minnesota published two reports assessing the risk of neurologic disease among several thousand Midwestern women who had undergone oophorectomy (unilateral or bilateral) before reaching menopause. A history of oophorectomy, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was prescribed until at least 50 years of age following bilateral oophorectomy, no increased risk of cognitive impairment was found.

Using similar methods, the same research group at Mayo found that oophorectomy before menopause was associated with a significantly increased risk of parkinsonism (symptoms that did not meet the formal criteria for Parkinson’s disease) as well as an increased risk, which did not attain statistica significance, of Parkinson’s disease itself.

Taken in totality, the evidence suggests that when HT is initiated in young menopausal women, protection against dementia and other neurologic disease may result. These findings parallel the evidence on the risk of CAD during HT use presented at the beginning of this article.

The author reports no financial relationships relevant to this article.

CASE 1 Rapid growth=cancer?

Mrs. G., 47 years old, has had uterine fibroids the size of a 12-week pregnancy for about 6 years. At today’s examination, however, her uterus feels about the size of a 16-week pregnancy.

She is aware that her abdomen is bigger, and she complains of some abdominal pressure and urinary frequency. She reports no abnormal bleeding and no abdominal pain.

Mrs. G. is upset because another physician told her she might have cancer and needs a hysterectomy immediately. She tells you that she does not want a hysterectomy unless “it’s absolutely necessary.”

Ultrasonography at this visit reveals that two of the three fibroids noted on a previous sonogram have grown—one from 6 cm to 9 cm in diameter; the other from 5 cm to 8 cm.

What do you tell Mrs. G.?

Understanding myomas

Uterine fibroids, also called myomas, are benign, monoclonal tumors of the myometrium that contain collagen, fibronectin, and proteoglycan. The collagen fibrils are abnormally formed and in disarray; they look like the collagen found in keloids.¹ Although the precise causes of fibroids are unknown, hormonal, genetic, and growth factors appear to be involved in their development and growth.^2,3

About 40% of fibroids are chromosomally abnormal; the remaining 60% may have undetected mutations. More than 100 genes have been found to be up-regulated or down-regulated in fibroid cells. Many of these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis.

Differentiating benign myoma from uterine sarcoma

Myomas have chromosomal rearrangements similar to other benign lesions, whereas leiomyosarcomas are undifferentiated and have complex chromosomal rearrangements not seen in myomas.⁴ Genetic differences between myomas and leiomyosarcomas indicate they most likely have distinct origins, and that leiomyosarcomas do not result from malignant degeneration of myomas.²

In premenopausal women, rapid uterine growth almost never indicates uterine sarcoma: One study found only one sarcoma among 371 (0.26%) women operated on for rapid growth of a presumed myoma, and no sarcomas were found in the 198 women who had a 6-week-pregnancy-equivalent increase in uterine size over 1 year.⁵

Clinical indications. The clinical signs that would lead to suspicion of pelvic malignancy are:

• older age
• abdominal pain
• irregular vaginal bleeding.⁶

The average age of 2,098 women with uterine sarcoma reported in the SEER (Surveillance Epidemiology and End Results) cancer database from 1989 to 1999 was 63 years, whereas a review of the literature found a mean age of 36 years in women subjected to myomectomy who did not have sarcoma.^3,7

Diagnostic tests. The distinction between benign myoma and leiomyosarcoma need not be based on clinical signs alone. Preoperative diagnosis of leiomyosarcoma may be possible, using laboratory values of total serum lactate dehydrogenase (LDH) and LDH isoenzyme 3 plus gadolinium-enhanced magnetic resonance imaging (MRI) scan (Gd-DTPA), with initial images taken 40 to 60 seconds after injection of gadolinium. A study of 87 women with fibroids, 10 women with leiomyosarcoma, and 130 women with degenerating fibroids reported 100% specificity, 100% positive predictive value, 100% negative predictive value, and 100% diagnostic accuracy for leiomyosarcoma with this combination diagnostic procedure.⁸

CASE 1 RESOLVED What advice for Mrs. G.?

You order a gadolinium-enhanced, dynamic MRI scan and have blood drawn for total LDH and LDH isoenzymes. Total LDH and isoenzyme 3 are normal. MRI shows no increased enhancement of the fibroids on images taken 40 to 60 seconds after injection of gadolinium. You advise the patient that there is no evidence of cancer (sarcoma) and no urgent need for hysterectomy. You also tell her that, because she is symptomatic, myomectomy is an option that will preserve her uterus.

CASE 2 Fibroids, and contemplating childbearing

Mrs. H., a 35-year-old nulligravida, comes to the office for her first visit with you. She has no complaints, but your pelvic examination reveals a 10 week-size enlarged uterus. A sonogram shows a 6-cm subserosal fibroid and a 3-cm intramural fibroid near the endometrial cavity (see FIGURE). This patient was recently married and wants to become pregnant within the coming year.

When you tell Mrs. H. that she has fibroids, she grows concerned. She asks: “Will this affect my fertility, or a pregnancy?” and “Do I need surgery?”

You explain that the larger, subserosal fibroid is not a concern. The smaller, intramural fibroid could, however, have an impact on fertility and pregnancy if it distorts the uterine cavity.

To find out if that is the case, you order a saline infusion sonogram, which demonstrates, clearly, a normal cavity without distortion by the fibroid.

What is your advice to this woman?

Fibroids and fertility

Submucous fibroids that distort the uterine cavity decrease fertility; removal increases fertility. Otherwise, neither intramural nor subserosal fibroids appear to affect the fertility rate; removal has not been shown to increase fertility. Meta-analysis of 11 studies found that submucous myomas that distort the uterine cavity appear to decrease the pregnancy rate by 70% (relative risk [RR], 0.32; confidence interval [CI], 0.13–0.70).⁹

Assessing the uterine cavity. Evaluating a woman with fibroids for fertility requires reliable assessment of the uterine cavity. Hysteroscopy and saline infusion sonography have been shown to be far superior to transvaginal sonography or hysterosalpingography for detecting submucosal fibroids.¹⁰

The best modality for determining the extent of submucosal penetration of a myoma into the myometrium is MRI. It is also an excellent modality for evaluating the size, position, and number of multiple fibroids.¹¹ The drawback to using MRI? It is more costly than other modalities.

Note: Classification of submucosal fibroids is based on the fraction of the mass within the cavity:

• Class 0 myomas are entirely intracavitary
• Class I myomas have 50% or more of the fibroid within the cavity
• Class II myomas have less than 50% within the cavity.¹²

Resection and fertility. Submucous fibroids can often be removed hysteroscopically. Systematic review of the evidence found that resection-restored fertility is equal to that of infertile controls undergoing in vitro fertilization who do not have fibroids (RR, 1.72; CI, 1.13–2.58).⁹ In that review, the presence of neither intramural nor subserosal fibroids decreased fertility (intramural: RR, 0.94, and CI, 0.73–1.20; subserosal: RR, 1.1, and CI, 0.06–1.72). Furthermore, removal of intramural and subserosal myomas by abdominal or laparoscopic myomectomy did not improve fertility. An updated unpublished meta-analysis, including studies published after 2001, came to the same conclusion (Pritts E, personal communication, 2008).

CASE 2: Subserosal, intramural myomas cause concern

In a woman contemplating childbearing, does a subserosal (left) or intramural (right) myoma present a problem because of potential to distort the uterine cavity?

Fibroids and pregnancy

The incidence of sonographically detected fibroids during pregnancy is low.¹³ Among 12,600 women at a prenatal clinic, routine second-trimester sonography identified myomas in 183 (mean age, 33 years)—an incidence of 1.5%.

Pregnancy has a variable and unpredictable effect on myoma growth, likely dependent on individual differences in genetics, circulating growth factors, and myoma-localized receptors. Most myomas do not, however, grow during pregnancy. A prospective study of pregnant women who had a single myoma found that 69% had no increase in volume throughout their pregnancy. In women who were noted to have an increase in the volume of their myoma, the greatest growth occurred before 10 weeks’ gestation. No relationship was found between initial myoma volume and myoma growth during the gestational period. ¹⁴

Do myomas complicate pregnancy?

Very rarely. Two studies reported on outcomes in large populations of pregnant women who were examined with routine second-trimester ultrasonography, with follow-up and delivery at the same institution.

In one of those studies, 12,600 pregnant women were evaluated, and the outcome in 167 women who were given a diagnosis of myoma was compared with the outcome in women who did not have a myoma.¹⁵ Despite similar clinical management between the two groups, no significant differences were seen in regard to the incidence of:

• preterm delivery
• premature rupture of membranes
• fetal growth restriction
• placenta previa
• placental abruption
• postpartum hemorrhage
• retained placenta.

Only cesarean section was more common among women with fibroids (23% vs 12%).

The second study reviewed 15,104 pregnancies and compared 401 women found to have myomas and the remaining women who did not.¹⁶ Although the presence of myoma did not increase the risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis, or endomyometritis, there was some increased risk of pre-term delivery (19.2% vs 12.7%), placenta previa (3.5% vs 1.8%), and post-partum hemorrhage (8.3% vs 2.9%). Cesarean section was, again, more common (49.1% vs 21.4%).

Do myomas injure the fetus?

Fetal injury as a consequence of fibroids has been reported very infrequently. A review of the literature from 1980 to 2005 revealed only four cases—one each of:

• fetal head anomalies with fetal growth restriction
• postural deformity
• limb reduction
• fetal head deformation with torticollis.^17-19

CASE 2 RESOLVED Should Mrs. H. have a myomectomy?

Probably not. Abdominal and laparoscopic myomectomy involve substantial operative and anesthetic risks, including infection, postoperative adhesions, a very small risk of uterine rupture during pregnancy, and increased likelihood of cesarean section. Costs are also substantial, involving not only the expense of surgery, but also patient discomfort and time for recovery. Therefore, until it is proved that intramural myomas decrease fertility and myomectomy increases fertility, surgery should be undertaken with caution. As far as the effects of myoma on pregnancy are concerned, no data are available by which to compare pregnancy outcomes following myomectomy with pregnancy outcomes in women whose myomas are untreated. Randomized studies are needed to clarify these important issues.

CASES 3 & 4 The effects of oral contraceptives and hormone replacement therapy

Mrs. J. is a 32-year-old G0P0 woman who has a 5-cm fundal myoma. She is sexually active and wants to use an oral contraceptive (OC). She has heard from friends, however, that taking an OC makes fibroids grow, and she asks for your advice.

The same day, you see Mrs. K., a 54-year-old, recently menopausal woman. She complains of severe hot flashes and night sweats that disturb her sleep. She has had asymptomatic uterine fibroids for about 10 years and, although she would like to take menopausal hormone therapy, she is worried that the medication will make the fibroids larger.

How do you advise these two women?

What research shows

OCs. OCs do not appear to influence the growth of fibroids. One study found a slightly increased risk of fibroids, another study found no increased risk, and a third found a decreased risk.^18,19 These studies are retrospective, however, and may be marked by selection bias.

Postmenopausal hormone replacement therapy. Postmenopausal hormone therapy does not ordinarily cause fibroid growth. After 3 years, only three of 34 (8%) post-menopausal women who had fibroids and were treated with 0.625 mg of conjugated equine estrogen (CEE) and 5 mg of medroxyprogesterone acetate (MPA) a day had any increase in the size of fibroids.²⁰ If any increase in the size of the uterus is noted, it is likely related to progestins.

A study found that 23% of women taking oral estrogen plus 2.5 mg of MPA a day for 1 year had a slight increase in the size of fibroids, whereas 50% of women taking 5 mg of MPA had an increase in size (mean increase in diameter, 3.2 cm).²¹ Transdermal estrogen plus oral MPA was shown, after 1 year, to cause, on average, a 0.5-cm increase in the diameter of fibroids; oral estrogen and MPA caused no increase in size.²²

CASES RESOLVED Rx: Reassurance

Advise Mrs. J. that taking an OC is unlikely to make her fibroids grow larger.

Mrs. K., who is older, can seek relief from postmenopausal symptoms by taking hormone therapy without fear of her fibroids being stimulated to grow.

The author reports no financial relationships relevant to this article.

CASE 1 Rapid growth=cancer?

Mrs. G., 47 years old, has had uterine fibroids the size of a 12-week pregnancy for about 6 years. At today’s examination, however, her uterus feels about the size of a 16-week pregnancy.

She is aware that her abdomen is bigger, and she complains of some abdominal pressure and urinary frequency. She reports no abnormal bleeding and no abdominal pain.

Mrs. G. is upset because another physician told her she might have cancer and needs a hysterectomy immediately. She tells you that she does not want a hysterectomy unless “it’s absolutely necessary.”

Ultrasonography at this visit reveals that two of the three fibroids noted on a previous sonogram have grown—one from 6 cm to 9 cm in diameter; the other from 5 cm to 8 cm.

What do you tell Mrs. G.?

Understanding myomas

Uterine fibroids, also called myomas, are benign, monoclonal tumors of the myometrium that contain collagen, fibronectin, and proteoglycan. The collagen fibrils are abnormally formed and in disarray; they look like the collagen found in keloids.¹ Although the precise causes of fibroids are unknown, hormonal, genetic, and growth factors appear to be involved in their development and growth.^2,3

About 40% of fibroids are chromosomally abnormal; the remaining 60% may have undetected mutations. More than 100 genes have been found to be up-regulated or down-regulated in fibroid cells. Many of these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis.

Differentiating benign myoma from uterine sarcoma

Myomas have chromosomal rearrangements similar to other benign lesions, whereas leiomyosarcomas are undifferentiated and have complex chromosomal rearrangements not seen in myomas.⁴ Genetic differences between myomas and leiomyosarcomas indicate they most likely have distinct origins, and that leiomyosarcomas do not result from malignant degeneration of myomas.²

In premenopausal women, rapid uterine growth almost never indicates uterine sarcoma: One study found only one sarcoma among 371 (0.26%) women operated on for rapid growth of a presumed myoma, and no sarcomas were found in the 198 women who had a 6-week-pregnancy-equivalent increase in uterine size over 1 year.⁵

Clinical indications. The clinical signs that would lead to suspicion of pelvic malignancy are:

• older age
• abdominal pain
• irregular vaginal bleeding.⁶

The average age of 2,098 women with uterine sarcoma reported in the SEER (Surveillance Epidemiology and End Results) cancer database from 1989 to 1999 was 63 years, whereas a review of the literature found a mean age of 36 years in women subjected to myomectomy who did not have sarcoma.^3,7

Diagnostic tests. The distinction between benign myoma and leiomyosarcoma need not be based on clinical signs alone. Preoperative diagnosis of leiomyosarcoma may be possible, using laboratory values of total serum lactate dehydrogenase (LDH) and LDH isoenzyme 3 plus gadolinium-enhanced magnetic resonance imaging (MRI) scan (Gd-DTPA), with initial images taken 40 to 60 seconds after injection of gadolinium. A study of 87 women with fibroids, 10 women with leiomyosarcoma, and 130 women with degenerating fibroids reported 100% specificity, 100% positive predictive value, 100% negative predictive value, and 100% diagnostic accuracy for leiomyosarcoma with this combination diagnostic procedure.⁸

CASE 1 RESOLVED What advice for Mrs. G.?

You order a gadolinium-enhanced, dynamic MRI scan and have blood drawn for total LDH and LDH isoenzymes. Total LDH and isoenzyme 3 are normal. MRI shows no increased enhancement of the fibroids on images taken 40 to 60 seconds after injection of gadolinium. You advise the patient that there is no evidence of cancer (sarcoma) and no urgent need for hysterectomy. You also tell her that, because she is symptomatic, myomectomy is an option that will preserve her uterus.

CASE 2 Fibroids, and contemplating childbearing

Mrs. H., a 35-year-old nulligravida, comes to the office for her first visit with you. She has no complaints, but your pelvic examination reveals a 10 week-size enlarged uterus. A sonogram shows a 6-cm subserosal fibroid and a 3-cm intramural fibroid near the endometrial cavity (see FIGURE). This patient was recently married and wants to become pregnant within the coming year.

When you tell Mrs. H. that she has fibroids, she grows concerned. She asks: “Will this affect my fertility, or a pregnancy?” and “Do I need surgery?”

You explain that the larger, subserosal fibroid is not a concern. The smaller, intramural fibroid could, however, have an impact on fertility and pregnancy if it distorts the uterine cavity.

To find out if that is the case, you order a saline infusion sonogram, which demonstrates, clearly, a normal cavity without distortion by the fibroid.

What is your advice to this woman?

Fibroids and fertility

Submucous fibroids that distort the uterine cavity decrease fertility; removal increases fertility. Otherwise, neither intramural nor subserosal fibroids appear to affect the fertility rate; removal has not been shown to increase fertility. Meta-analysis of 11 studies found that submucous myomas that distort the uterine cavity appear to decrease the pregnancy rate by 70% (relative risk [RR], 0.32; confidence interval [CI], 0.13–0.70).⁹

Assessing the uterine cavity. Evaluating a woman with fibroids for fertility requires reliable assessment of the uterine cavity. Hysteroscopy and saline infusion sonography have been shown to be far superior to transvaginal sonography or hysterosalpingography for detecting submucosal fibroids.¹⁰

The best modality for determining the extent of submucosal penetration of a myoma into the myometrium is MRI. It is also an excellent modality for evaluating the size, position, and number of multiple fibroids.¹¹ The drawback to using MRI? It is more costly than other modalities.

Note: Classification of submucosal fibroids is based on the fraction of the mass within the cavity:

• Class 0 myomas are entirely intracavitary
• Class I myomas have 50% or more of the fibroid within the cavity
• Class II myomas have less than 50% within the cavity.¹²

Resection and fertility. Submucous fibroids can often be removed hysteroscopically. Systematic review of the evidence found that resection-restored fertility is equal to that of infertile controls undergoing in vitro fertilization who do not have fibroids (RR, 1.72; CI, 1.13–2.58).⁹ In that review, the presence of neither intramural nor subserosal fibroids decreased fertility (intramural: RR, 0.94, and CI, 0.73–1.20; subserosal: RR, 1.1, and CI, 0.06–1.72). Furthermore, removal of intramural and subserosal myomas by abdominal or laparoscopic myomectomy did not improve fertility. An updated unpublished meta-analysis, including studies published after 2001, came to the same conclusion (Pritts E, personal communication, 2008).

CASE 2: Subserosal, intramural myomas cause concern

In a woman contemplating childbearing, does a subserosal (left) or intramural (right) myoma present a problem because of potential to distort the uterine cavity?

Fibroids and pregnancy

The incidence of sonographically detected fibroids during pregnancy is low.¹³ Among 12,600 women at a prenatal clinic, routine second-trimester sonography identified myomas in 183 (mean age, 33 years)—an incidence of 1.5%.

Pregnancy has a variable and unpredictable effect on myoma growth, likely dependent on individual differences in genetics, circulating growth factors, and myoma-localized receptors. Most myomas do not, however, grow during pregnancy. A prospective study of pregnant women who had a single myoma found that 69% had no increase in volume throughout their pregnancy. In women who were noted to have an increase in the volume of their myoma, the greatest growth occurred before 10 weeks’ gestation. No relationship was found between initial myoma volume and myoma growth during the gestational period. ¹⁴

Do myomas complicate pregnancy?

Very rarely. Two studies reported on outcomes in large populations of pregnant women who were examined with routine second-trimester ultrasonography, with follow-up and delivery at the same institution.

In one of those studies, 12,600 pregnant women were evaluated, and the outcome in 167 women who were given a diagnosis of myoma was compared with the outcome in women who did not have a myoma.¹⁵ Despite similar clinical management between the two groups, no significant differences were seen in regard to the incidence of:

• preterm delivery
• premature rupture of membranes
• fetal growth restriction
• placenta previa
• placental abruption
• postpartum hemorrhage
• retained placenta.

Only cesarean section was more common among women with fibroids (23% vs 12%).

The second study reviewed 15,104 pregnancies and compared 401 women found to have myomas and the remaining women who did not.¹⁶ Although the presence of myoma did not increase the risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis, or endomyometritis, there was some increased risk of pre-term delivery (19.2% vs 12.7%), placenta previa (3.5% vs 1.8%), and post-partum hemorrhage (8.3% vs 2.9%). Cesarean section was, again, more common (49.1% vs 21.4%).

Do myomas injure the fetus?

Fetal injury as a consequence of fibroids has been reported very infrequently. A review of the literature from 1980 to 2005 revealed only four cases—one each of:

• fetal head anomalies with fetal growth restriction
• postural deformity
• limb reduction
• fetal head deformation with torticollis.^17-19

CASE 2 RESOLVED Should Mrs. H. have a myomectomy?

Probably not. Abdominal and laparoscopic myomectomy involve substantial operative and anesthetic risks, including infection, postoperative adhesions, a very small risk of uterine rupture during pregnancy, and increased likelihood of cesarean section. Costs are also substantial, involving not only the expense of surgery, but also patient discomfort and time for recovery. Therefore, until it is proved that intramural myomas decrease fertility and myomectomy increases fertility, surgery should be undertaken with caution. As far as the effects of myoma on pregnancy are concerned, no data are available by which to compare pregnancy outcomes following myomectomy with pregnancy outcomes in women whose myomas are untreated. Randomized studies are needed to clarify these important issues.

CASES 3 & 4 The effects of oral contraceptives and hormone replacement therapy

Mrs. J. is a 32-year-old G0P0 woman who has a 5-cm fundal myoma. She is sexually active and wants to use an oral contraceptive (OC). She has heard from friends, however, that taking an OC makes fibroids grow, and she asks for your advice.

The same day, you see Mrs. K., a 54-year-old, recently menopausal woman. She complains of severe hot flashes and night sweats that disturb her sleep. She has had asymptomatic uterine fibroids for about 10 years and, although she would like to take menopausal hormone therapy, she is worried that the medication will make the fibroids larger.

How do you advise these two women?

What research shows

OCs. OCs do not appear to influence the growth of fibroids. One study found a slightly increased risk of fibroids, another study found no increased risk, and a third found a decreased risk.^18,19 These studies are retrospective, however, and may be marked by selection bias.

Postmenopausal hormone replacement therapy. Postmenopausal hormone therapy does not ordinarily cause fibroid growth. After 3 years, only three of 34 (8%) post-menopausal women who had fibroids and were treated with 0.625 mg of conjugated equine estrogen (CEE) and 5 mg of medroxyprogesterone acetate (MPA) a day had any increase in the size of fibroids.²⁰ If any increase in the size of the uterus is noted, it is likely related to progestins.

A study found that 23% of women taking oral estrogen plus 2.5 mg of MPA a day for 1 year had a slight increase in the size of fibroids, whereas 50% of women taking 5 mg of MPA had an increase in size (mean increase in diameter, 3.2 cm).²¹ Transdermal estrogen plus oral MPA was shown, after 1 year, to cause, on average, a 0.5-cm increase in the diameter of fibroids; oral estrogen and MPA caused no increase in size.²²

CASES RESOLVED Rx: Reassurance

Advise Mrs. J. that taking an OC is unlikely to make her fibroids grow larger.

Mrs. K., who is older, can seek relief from postmenopausal symptoms by taking hormone therapy without fear of her fibroids being stimulated to grow.

The author reports no financial relationships relevant to this article.

CASE 1 Rapid growth=cancer?

Mrs. G., 47 years old, has had uterine fibroids the size of a 12-week pregnancy for about 6 years. At today’s examination, however, her uterus feels about the size of a 16-week pregnancy.

She is aware that her abdomen is bigger, and she complains of some abdominal pressure and urinary frequency. She reports no abnormal bleeding and no abdominal pain.

Mrs. G. is upset because another physician told her she might have cancer and needs a hysterectomy immediately. She tells you that she does not want a hysterectomy unless “it’s absolutely necessary.”

Ultrasonography at this visit reveals that two of the three fibroids noted on a previous sonogram have grown—one from 6 cm to 9 cm in diameter; the other from 5 cm to 8 cm.

What do you tell Mrs. G.?

Understanding myomas

Uterine fibroids, also called myomas, are benign, monoclonal tumors of the myometrium that contain collagen, fibronectin, and proteoglycan. The collagen fibrils are abnormally formed and in disarray; they look like the collagen found in keloids.¹ Although the precise causes of fibroids are unknown, hormonal, genetic, and growth factors appear to be involved in their development and growth.^2,3

About 40% of fibroids are chromosomally abnormal; the remaining 60% may have undetected mutations. More than 100 genes have been found to be up-regulated or down-regulated in fibroid cells. Many of these genes appear to regulate cell growth, differentiation, proliferation, and mitogenesis.

Differentiating benign myoma from uterine sarcoma

Myomas have chromosomal rearrangements similar to other benign lesions, whereas leiomyosarcomas are undifferentiated and have complex chromosomal rearrangements not seen in myomas.⁴ Genetic differences between myomas and leiomyosarcomas indicate they most likely have distinct origins, and that leiomyosarcomas do not result from malignant degeneration of myomas.²

In premenopausal women, rapid uterine growth almost never indicates uterine sarcoma: One study found only one sarcoma among 371 (0.26%) women operated on for rapid growth of a presumed myoma, and no sarcomas were found in the 198 women who had a 6-week-pregnancy-equivalent increase in uterine size over 1 year.⁵

Clinical indications. The clinical signs that would lead to suspicion of pelvic malignancy are:

• older age
• abdominal pain
• irregular vaginal bleeding.⁶

The average age of 2,098 women with uterine sarcoma reported in the SEER (Surveillance Epidemiology and End Results) cancer database from 1989 to 1999 was 63 years, whereas a review of the literature found a mean age of 36 years in women subjected to myomectomy who did not have sarcoma.^3,7

Diagnostic tests. The distinction between benign myoma and leiomyosarcoma need not be based on clinical signs alone. Preoperative diagnosis of leiomyosarcoma may be possible, using laboratory values of total serum lactate dehydrogenase (LDH) and LDH isoenzyme 3 plus gadolinium-enhanced magnetic resonance imaging (MRI) scan (Gd-DTPA), with initial images taken 40 to 60 seconds after injection of gadolinium. A study of 87 women with fibroids, 10 women with leiomyosarcoma, and 130 women with degenerating fibroids reported 100% specificity, 100% positive predictive value, 100% negative predictive value, and 100% diagnostic accuracy for leiomyosarcoma with this combination diagnostic procedure.⁸

CASE 1 RESOLVED What advice for Mrs. G.?

You order a gadolinium-enhanced, dynamic MRI scan and have blood drawn for total LDH and LDH isoenzymes. Total LDH and isoenzyme 3 are normal. MRI shows no increased enhancement of the fibroids on images taken 40 to 60 seconds after injection of gadolinium. You advise the patient that there is no evidence of cancer (sarcoma) and no urgent need for hysterectomy. You also tell her that, because she is symptomatic, myomectomy is an option that will preserve her uterus.

CASE 2 Fibroids, and contemplating childbearing

Mrs. H., a 35-year-old nulligravida, comes to the office for her first visit with you. She has no complaints, but your pelvic examination reveals a 10 week-size enlarged uterus. A sonogram shows a 6-cm subserosal fibroid and a 3-cm intramural fibroid near the endometrial cavity (see FIGURE). This patient was recently married and wants to become pregnant within the coming year.

When you tell Mrs. H. that she has fibroids, she grows concerned. She asks: “Will this affect my fertility, or a pregnancy?” and “Do I need surgery?”

You explain that the larger, subserosal fibroid is not a concern. The smaller, intramural fibroid could, however, have an impact on fertility and pregnancy if it distorts the uterine cavity.

To find out if that is the case, you order a saline infusion sonogram, which demonstrates, clearly, a normal cavity without distortion by the fibroid.

What is your advice to this woman?

Fibroids and fertility

Submucous fibroids that distort the uterine cavity decrease fertility; removal increases fertility. Otherwise, neither intramural nor subserosal fibroids appear to affect the fertility rate; removal has not been shown to increase fertility. Meta-analysis of 11 studies found that submucous myomas that distort the uterine cavity appear to decrease the pregnancy rate by 70% (relative risk [RR], 0.32; confidence interval [CI], 0.13–0.70).⁹

Assessing the uterine cavity. Evaluating a woman with fibroids for fertility requires reliable assessment of the uterine cavity. Hysteroscopy and saline infusion sonography have been shown to be far superior to transvaginal sonography or hysterosalpingography for detecting submucosal fibroids.¹⁰

The best modality for determining the extent of submucosal penetration of a myoma into the myometrium is MRI. It is also an excellent modality for evaluating the size, position, and number of multiple fibroids.¹¹ The drawback to using MRI? It is more costly than other modalities.

Note: Classification of submucosal fibroids is based on the fraction of the mass within the cavity:

• Class 0 myomas are entirely intracavitary
• Class I myomas have 50% or more of the fibroid within the cavity
• Class II myomas have less than 50% within the cavity.¹²

Resection and fertility. Submucous fibroids can often be removed hysteroscopically. Systematic review of the evidence found that resection-restored fertility is equal to that of infertile controls undergoing in vitro fertilization who do not have fibroids (RR, 1.72; CI, 1.13–2.58).⁹ In that review, the presence of neither intramural nor subserosal fibroids decreased fertility (intramural: RR, 0.94, and CI, 0.73–1.20; subserosal: RR, 1.1, and CI, 0.06–1.72). Furthermore, removal of intramural and subserosal myomas by abdominal or laparoscopic myomectomy did not improve fertility. An updated unpublished meta-analysis, including studies published after 2001, came to the same conclusion (Pritts E, personal communication, 2008).

CASE 2: Subserosal, intramural myomas cause concern

In a woman contemplating childbearing, does a subserosal (left) or intramural (right) myoma present a problem because of potential to distort the uterine cavity?

Fibroids and pregnancy

The incidence of sonographically detected fibroids during pregnancy is low.¹³ Among 12,600 women at a prenatal clinic, routine second-trimester sonography identified myomas in 183 (mean age, 33 years)—an incidence of 1.5%.

Pregnancy has a variable and unpredictable effect on myoma growth, likely dependent on individual differences in genetics, circulating growth factors, and myoma-localized receptors. Most myomas do not, however, grow during pregnancy. A prospective study of pregnant women who had a single myoma found that 69% had no increase in volume throughout their pregnancy. In women who were noted to have an increase in the volume of their myoma, the greatest growth occurred before 10 weeks’ gestation. No relationship was found between initial myoma volume and myoma growth during the gestational period. ¹⁴

Do myomas complicate pregnancy?

Very rarely. Two studies reported on outcomes in large populations of pregnant women who were examined with routine second-trimester ultrasonography, with follow-up and delivery at the same institution.

In one of those studies, 12,600 pregnant women were evaluated, and the outcome in 167 women who were given a diagnosis of myoma was compared with the outcome in women who did not have a myoma.¹⁵ Despite similar clinical management between the two groups, no significant differences were seen in regard to the incidence of:

• preterm delivery
• premature rupture of membranes
• fetal growth restriction
• placenta previa
• placental abruption
• postpartum hemorrhage
• retained placenta.

Only cesarean section was more common among women with fibroids (23% vs 12%).

The second study reviewed 15,104 pregnancies and compared 401 women found to have myomas and the remaining women who did not.¹⁶ Although the presence of myoma did not increase the risk of premature rupture of membranes, operative vaginal delivery, chorioamnionitis, or endomyometritis, there was some increased risk of pre-term delivery (19.2% vs 12.7%), placenta previa (3.5% vs 1.8%), and post-partum hemorrhage (8.3% vs 2.9%). Cesarean section was, again, more common (49.1% vs 21.4%).

Do myomas injure the fetus?

Fetal injury as a consequence of fibroids has been reported very infrequently. A review of the literature from 1980 to 2005 revealed only four cases—one each of:

• fetal head anomalies with fetal growth restriction
• postural deformity
• limb reduction
• fetal head deformation with torticollis.^17-19

CASE 2 RESOLVED Should Mrs. H. have a myomectomy?

Probably not. Abdominal and laparoscopic myomectomy involve substantial operative and anesthetic risks, including infection, postoperative adhesions, a very small risk of uterine rupture during pregnancy, and increased likelihood of cesarean section. Costs are also substantial, involving not only the expense of surgery, but also patient discomfort and time for recovery. Therefore, until it is proved that intramural myomas decrease fertility and myomectomy increases fertility, surgery should be undertaken with caution. As far as the effects of myoma on pregnancy are concerned, no data are available by which to compare pregnancy outcomes following myomectomy with pregnancy outcomes in women whose myomas are untreated. Randomized studies are needed to clarify these important issues.

CASES 3 & 4 The effects of oral contraceptives and hormone replacement therapy

Mrs. J. is a 32-year-old G0P0 woman who has a 5-cm fundal myoma. She is sexually active and wants to use an oral contraceptive (OC). She has heard from friends, however, that taking an OC makes fibroids grow, and she asks for your advice.

The same day, you see Mrs. K., a 54-year-old, recently menopausal woman. She complains of severe hot flashes and night sweats that disturb her sleep. She has had asymptomatic uterine fibroids for about 10 years and, although she would like to take menopausal hormone therapy, she is worried that the medication will make the fibroids larger.

How do you advise these two women?

What research shows

OCs. OCs do not appear to influence the growth of fibroids. One study found a slightly increased risk of fibroids, another study found no increased risk, and a third found a decreased risk.^18,19 These studies are retrospective, however, and may be marked by selection bias.

Postmenopausal hormone replacement therapy. Postmenopausal hormone therapy does not ordinarily cause fibroid growth. After 3 years, only three of 34 (8%) post-menopausal women who had fibroids and were treated with 0.625 mg of conjugated equine estrogen (CEE) and 5 mg of medroxyprogesterone acetate (MPA) a day had any increase in the size of fibroids.²⁰ If any increase in the size of the uterus is noted, it is likely related to progestins.

A study found that 23% of women taking oral estrogen plus 2.5 mg of MPA a day for 1 year had a slight increase in the size of fibroids, whereas 50% of women taking 5 mg of MPA had an increase in size (mean increase in diameter, 3.2 cm).²¹ Transdermal estrogen plus oral MPA was shown, after 1 year, to cause, on average, a 0.5-cm increase in the diameter of fibroids; oral estrogen and MPA caused no increase in size.²²

CASES RESOLVED Rx: Reassurance

Advise Mrs. J. that taking an OC is unlikely to make her fibroids grow larger.

Mrs. K., who is older, can seek relief from postmenopausal symptoms by taking hormone therapy without fear of her fibroids being stimulated to grow.

In general, when a patient inquires about elective primary C-section, it is best to consider the “6 C’s of elective cesarean” in a careful discussion with her. That approach entails consideration of the following:

• Clarification of her request
  
• Comorbidities in maternal health or surgical history
  
• number of Children planned overall
  
• clear Consent for the procedure
  
• Correct determination of gestational age at the time of planned delivery
  
• Confirmation of coverage by her insurance carrier.
  

One trend is clear: Maternal requests for primary cesarean delivery are on the rise in the United States, although we lack precise data on exactly how fast the rate is rising. Many experts estimate it to be 4% to 18%.¹ In Brazil, the rate of elective C-section for women in private hospitals is thought to be as high as 80% to 90%.²

As more celebrities and other prominent figures undergo elective C-section, more American women are beginning to ask for the same “privilege.” In this article, I lay out an evidence-based and ethically sensitive approach to counseling patients who request C-section on an elective basis.

The points raised in the list that begins this article are all discussed here.

The difficulty of calculating the rate of primary C-section

We are limited by terminology and data-collection practices, as well as a multitude of confounding obstetric factors. Practicing providers recognize the inherent difference between a planned C-section at term without the onset of labor and an unplanned C-section at term after the onset of labor—as well as every scenario in between.

Unplanned C-section can be performed to address fetal compromise or an unsuccessful attempt at vaginal delivery—each scenario replete with its own risks and potential complications. The urgency of C-section also confounds subsequent maternal and fetal complications. Underlying maternal factors such as obesity and medical and surgical history further complicate the scenario.

For these reasons, the discussion of elective C-section is best managed by limiting the parameters considered to the requested, scheduled, elective C-section at term without maternal or fetal indications. Most patients have this paradigm in mind when they make their request, even though physicians and midwives understand that this is the ideal and not generally the reality.

Medicolegal and ethical considerations

The ethical principles surrounding cesarean delivery upon maternal request balance on the tension between beneficence and patient autonomy. The former requires the promotion of the patient’s overall health and well-being, along with attention to the closely related dictum, primum non nocere, or “first do no harm.”

Patient autonomy requires respectful consideration of the patient and her world view when making a medical decision. The ethical principle of patient autonomy is usually understood as a right to decline medical intervention—not necessarily to demand dangerous or unproven intervention.¹

This raises the question: Is a scheduled C-section in the absence of obstetric indications dangerous? Harmful? Imprudent? The medical community has accepted these inherent tensions in the field of aesthetic plastic surgery, but societies in obstetrics and gynecology continue to struggle with the ethical principles involved in maternal-choice cesarean.

FIGO: C-section for nonmedical reasons is not justified

The International Federation of Gynecology and Obstetrics (FIGO) Committee for the Ethical Aspects of Human Reproduction and Women’s Health bases its guidelines on the use of cesarean delivery for nonmedical reasons on the principles of beneficence and social justice. It concludes: “Cesarean section is a surgical intervention with potential hazards for both mother and child. It also uses more health-care resources than normal vaginal delivery…performing cesarean section for nonmedical reasons is ethically not justified.”³

ACOG: Individualize the decision consistent with ethical principles

The American College of Obstetricians and Gynecologists (ACOG), in a recent Committee Opinion, acknowledged the paucity of research data directly comparing cesarean delivery on maternal request with planned vaginal delivery. The document reviews the National Institutes of Health (NIH) State-of-the-Science Conference on Cesarean Delivery on Maternal Request (see below), which was convened in 2006, and notes the panel’s conclusion that the available body of evidence does not allow for a conclusive recommendation of one mode of delivery over another.⁴ The ACOG Committee Opinion states: “Any decision to perform a cesarean delivery on maternal request should be carefully individualized and consistent with ethical principles.”⁵

Different world views likely account for different conclusions

The difference in the FIGO and ACOG positions may arise from differences in cultural contexts between a general world health view and a highly patient-centered Western perspective. The former view bases the decision on universal good and the utilization of scarce health-care resources; the latter view recognizes the individual within an ethical context.

Both views acknowledge the limited data available to inform the decision. So what do the data say, and how can we help our patients understand it?

NIH State-of-the-Science Conference

In March of 2006, an independent panel of experts from a range of medical fields reviewed the scientific literature regarding cesarean delivery on maternal request at the NIH in Bethesda, Maryland. Although the panel found no Level I, or strong, evidence within the literature, it was able to characterize the risks and benefits of maternal-request C-section based on Level II (moderate), Level III (weak), and Level IV (absent) evidence.

Moderate evidence was scarce

From a maternal perspective, the panel found that “the frequency of postpartum hemorrhage associated with planned cesarean delivery is lower than that reported with the combination of planned vaginal delivery and unplanned cesarean delivery,”⁵ although hospital stay is longer than with vaginal delivery.

From a neonatal perspective, moderate evidence favors vaginal delivery because of a decreased incidence of respiratory morbidity, such as transient tachypnea of the newborn and respiratory distress syndrome. Respiratory morbidity is directly related to gestational age, and there is a risk of iatrogenic prematurity with scheduled C-section. The possibility of incorrect obstetric dating would seem to favor awaiting the spontaneous onset of labor at term and an attempt at vaginal delivery to reduce the risk of respiratory complications due to iatrogenic prematurity.

Weak evidence goes both ways

Weakly supported evidence favored both cesarean section and vaginal delivery for either the mother or fetus. Weak evidence favoring vaginal delivery for maternal interests included:

• decreased maternal infectious morbidity and anesthetic complications, compared with C-section
  
• greater ease establishing breastfeeding, due to logistical challenges surrounding mother–infant bonding after C-section
  
• greater freedom in planning family size because increasing numbers of repeat C-sections with subsequent pregnancies increase risk of uterine rupture, cesarean hysterectomy, and abnormal placentation.
  

• lower rate of postpartum stress urinary incontinence, compared with women undergoing vaginal delivery, in the short term
  
• lower risk of surgical morbidity and traumatic obstetric lacerations with elective C-section, compared with the injuries that can occur at the time of unscheduled C-section or vaginal delivery.
  

Weak evidence of neonatal benefit

From the neonatal perspective, the NIH Consensus Committee found weak evidence favoring C-section. A scheduled C-section protects the neonate from stillbirth arising from postdates intrauterine fetal demise, because, with elective cesarean, a pregnancy is not usually allowed to continue post-term.

The Committee also documented protection from intracranial hemorrhage, neonatal asphyxia, encephalopathy, birth injury, and neonatal infection with C-section, compared with vaginal delivery.⁵

The socioeconomic picture matters

From a socioeconomic standpoint, women who request C-section may have financial concerns such as the amount of time off from work that may be necessary for both themselves and their partners. The availability of family support may be relevant and improved if a specific time frame for delivery is anticipated.

In many cultures, “lucky days” exist, and women may have preferences or aspirations for their child to be born on one of them.

Last, although it may be more cost-effective for a patient to undergo vaginal delivery, we, as health-care providers, cannot predict who will be successful in that regard. A complicated labor that necessitates unscheduled, urgent, or emergent C-section costs more in health-care dollars than does a C-section without labor.

Canadian researchers in 2005 examined the hospital care costs over 18 years in 27,614 pregnancies associated with varying types of delivery and found that the cost of delivery was highest for a C-section performed after the onset of labor ($2,137). The lowest cost was for spontaneous vaginal delivery ($1,340), followed by C-section without labor ($1,532).⁶ Therefore, some could argue that the overall cost to the patient and system is lower with a scheduled cesarean delivery because it avoids the other possible comorbidities and utilization of resources.

TABLE

Risks and benefits of planned cesarean delivery

When a patient raises the subject

Your first responsibility is to clarify her request. Key to this discussion is the patient’s reason for requesting a scheduled C-section. Many women—especially primiparous women—have a fear of labor itself, not to mention concerns about their safety and the safety of their baby.⁷ Another major concern to many women is the risk of injury to their perineum and pelvic floor.¹ These fears and concerns may motivate their request.

Educating patients about labor and discussing options for pain relief during labor can help soothe the patients’ fears. Clarifying long-term risks and benefits in regard to pelvic floor dysfunction also is important. Patients may have an unrealistic understanding of C-section and its potential complications. Often, education about the birth process and mode of delivery can alleviate a patient’s fears and change her hopes for delivery.

Explore any comorbidities

Because C-section is a major abdominal surgical procedure, maternal factors such as weight, age, surgical history, and medical comorbidities are relevant considerations when discussing the risks and benefits of cesarean in the absence of obstetric indications. Even in the absence of such comorbidities, certain risks of surgery should be clarified, including the risk of hemorrhage, infection, wound complication, thromboembolism, need for future surgery, and postoperative recovery.

The risks and benefits of vaginal delivery also should be discussed, including the factors that may lead up to an un-scheduled cesarean delivery despite the desire for a vaginal delivery.

How many children are planned?

Given the reluctance of health-care providers to manage attempted vaginal birth after C-section, women who opt for elective C-section for their first delivery may be committing themselves to C-section with subsequent pregnancies, too.⁸ Data suggest that an increasing number of C-sections place women at increasing risk of placenta accreta or previa, hysterectomy, blood transfusion, cystotomy, endometritis, prolonged operative time, and longer hospital stays. That said, overall maternal mortality from C-section remains low.⁹

Therefore, if a patient plans to have more than one or two children, she needs to understand the ramifications of repeat C-section at the time of her next delivery as well as in any additional pregnancies. Although a successful vaginal delivery cannot be guaranteed for any parturient, an attempt at vaginal delivery might be preferable for a woman hoping for a larger family.

Ensure clear consent

Chervenak and McCullough have provided an algorithm for offering C-section that balances the ethical concepts of autonomy and beneficence; that model is described above.¹⁰

If the patient requests C-section, but the clinician is uncomfortable performing one under the circumstances, referral is reasonable.

A patient’s thoughtful request can be considered out of respect for autonomy and supported by thorough counseling.

Ensuring a correct gestational age

Once the decision to proceed with scheduled C-section is made, accurate determination of gestational age is crucial to avoid iatrogenic prematurity.

ACOG Educational Bulletin No. 230 (November 1996) lists a number of criteria by which to infer gestational age and, therefore, fetal lung maturity. The criteria include:

• documented fetal heart tone for 30 weeks by Doppler ultrasound
  
• 36 weeks having passed since reliable documentation of a positive urine or serum human chorionic gonadotropin pregnancy test
  
• crown–rump measurement by ultrasonography (US) at 6 to 11 weeks of gestation that supports the current gestational age of 39 weeks or more
  
• US measurement at 12 to 20 weeks’ gestation that supports the clinically determined estimated gestational age above 39 weeks.
  

Insurance concerns are vital to the decision

The Newborns’ and Mothers’ Health Protection Act (NMHPA) was passed in 1996. The law delineates a minimum requirement of coverage by insurers for hospital stays of 48 hours after vaginal delivery or 96 hours after C-section, thereby preventing health insurance plans from restricting hospital stays after delivery.¹¹ The law was passed as a response to political concerns about “drive-thru deliveries.”

The NMHPA also allows for provider discretion regarding the length of stay required after childbirth, meaning that, if an attending-level provider deems discharge feasible in less than 48 or 96 hours, the insurer is not mandated to continue coverage beyond discharge.

The law, however, does not mandate coverage by health insurance plans for prenatal care, delivery, and postpartum care. Confounding the actions of health insurance companies are state laws governing the care of newborns and mothers, as these laws superceded the NMHPA. So, although most states have mandated benefit laws regarding a variety of services, as of 2002, only 18 states had laws mandating specific maternity services.¹² Some states specifically mention elective C-sections as nonmandated services, meaning that a patient who elects a scheduled C-section at term without obstetric indications may be required to pay for her obstetric care.

In general, when a patient inquires about elective primary C-section, it is best to consider the “6 C’s of elective cesarean” in a careful discussion with her. That approach entails consideration of the following:

• Clarification of her request
  
• Comorbidities in maternal health or surgical history
  
• number of Children planned overall
  
• clear Consent for the procedure
  
• Correct determination of gestational age at the time of planned delivery
  
• Confirmation of coverage by her insurance carrier.
  

One trend is clear: Maternal requests for primary cesarean delivery are on the rise in the United States, although we lack precise data on exactly how fast the rate is rising. Many experts estimate it to be 4% to 18%.¹ In Brazil, the rate of elective C-section for women in private hospitals is thought to be as high as 80% to 90%.²

As more celebrities and other prominent figures undergo elective C-section, more American women are beginning to ask for the same “privilege.” In this article, I lay out an evidence-based and ethically sensitive approach to counseling patients who request C-section on an elective basis.

The points raised in the list that begins this article are all discussed here.

The difficulty of calculating the rate of primary C-section

We are limited by terminology and data-collection practices, as well as a multitude of confounding obstetric factors. Practicing providers recognize the inherent difference between a planned C-section at term without the onset of labor and an unplanned C-section at term after the onset of labor—as well as every scenario in between.

Unplanned C-section can be performed to address fetal compromise or an unsuccessful attempt at vaginal delivery—each scenario replete with its own risks and potential complications. The urgency of C-section also confounds subsequent maternal and fetal complications. Underlying maternal factors such as obesity and medical and surgical history further complicate the scenario.

For these reasons, the discussion of elective C-section is best managed by limiting the parameters considered to the requested, scheduled, elective C-section at term without maternal or fetal indications. Most patients have this paradigm in mind when they make their request, even though physicians and midwives understand that this is the ideal and not generally the reality.

Medicolegal and ethical considerations

The ethical principles surrounding cesarean delivery upon maternal request balance on the tension between beneficence and patient autonomy. The former requires the promotion of the patient’s overall health and well-being, along with attention to the closely related dictum, primum non nocere, or “first do no harm.”

Patient autonomy requires respectful consideration of the patient and her world view when making a medical decision. The ethical principle of patient autonomy is usually understood as a right to decline medical intervention—not necessarily to demand dangerous or unproven intervention.¹

This raises the question: Is a scheduled C-section in the absence of obstetric indications dangerous? Harmful? Imprudent? The medical community has accepted these inherent tensions in the field of aesthetic plastic surgery, but societies in obstetrics and gynecology continue to struggle with the ethical principles involved in maternal-choice cesarean.

FIGO: C-section for nonmedical reasons is not justified

The International Federation of Gynecology and Obstetrics (FIGO) Committee for the Ethical Aspects of Human Reproduction and Women’s Health bases its guidelines on the use of cesarean delivery for nonmedical reasons on the principles of beneficence and social justice. It concludes: “Cesarean section is a surgical intervention with potential hazards for both mother and child. It also uses more health-care resources than normal vaginal delivery…performing cesarean section for nonmedical reasons is ethically not justified.”³

ACOG: Individualize the decision consistent with ethical principles

The American College of Obstetricians and Gynecologists (ACOG), in a recent Committee Opinion, acknowledged the paucity of research data directly comparing cesarean delivery on maternal request with planned vaginal delivery. The document reviews the National Institutes of Health (NIH) State-of-the-Science Conference on Cesarean Delivery on Maternal Request (see below), which was convened in 2006, and notes the panel’s conclusion that the available body of evidence does not allow for a conclusive recommendation of one mode of delivery over another.⁴ The ACOG Committee Opinion states: “Any decision to perform a cesarean delivery on maternal request should be carefully individualized and consistent with ethical principles.”⁵

Different world views likely account for different conclusions

The difference in the FIGO and ACOG positions may arise from differences in cultural contexts between a general world health view and a highly patient-centered Western perspective. The former view bases the decision on universal good and the utilization of scarce health-care resources; the latter view recognizes the individual within an ethical context.

Both views acknowledge the limited data available to inform the decision. So what do the data say, and how can we help our patients understand it?

NIH State-of-the-Science Conference

In March of 2006, an independent panel of experts from a range of medical fields reviewed the scientific literature regarding cesarean delivery on maternal request at the NIH in Bethesda, Maryland. Although the panel found no Level I, or strong, evidence within the literature, it was able to characterize the risks and benefits of maternal-request C-section based on Level II (moderate), Level III (weak), and Level IV (absent) evidence.

Moderate evidence was scarce

From a maternal perspective, the panel found that “the frequency of postpartum hemorrhage associated with planned cesarean delivery is lower than that reported with the combination of planned vaginal delivery and unplanned cesarean delivery,”⁵ although hospital stay is longer than with vaginal delivery.

From a neonatal perspective, moderate evidence favors vaginal delivery because of a decreased incidence of respiratory morbidity, such as transient tachypnea of the newborn and respiratory distress syndrome. Respiratory morbidity is directly related to gestational age, and there is a risk of iatrogenic prematurity with scheduled C-section. The possibility of incorrect obstetric dating would seem to favor awaiting the spontaneous onset of labor at term and an attempt at vaginal delivery to reduce the risk of respiratory complications due to iatrogenic prematurity.

Weak evidence goes both ways

Weakly supported evidence favored both cesarean section and vaginal delivery for either the mother or fetus. Weak evidence favoring vaginal delivery for maternal interests included:

• decreased maternal infectious morbidity and anesthetic complications, compared with C-section
  
• greater ease establishing breastfeeding, due to logistical challenges surrounding mother–infant bonding after C-section
  
• greater freedom in planning family size because increasing numbers of repeat C-sections with subsequent pregnancies increase risk of uterine rupture, cesarean hysterectomy, and abnormal placentation.
  

• lower rate of postpartum stress urinary incontinence, compared with women undergoing vaginal delivery, in the short term
  
• lower risk of surgical morbidity and traumatic obstetric lacerations with elective C-section, compared with the injuries that can occur at the time of unscheduled C-section or vaginal delivery.
  

Weak evidence of neonatal benefit

From the neonatal perspective, the NIH Consensus Committee found weak evidence favoring C-section. A scheduled C-section protects the neonate from stillbirth arising from postdates intrauterine fetal demise, because, with elective cesarean, a pregnancy is not usually allowed to continue post-term.

The Committee also documented protection from intracranial hemorrhage, neonatal asphyxia, encephalopathy, birth injury, and neonatal infection with C-section, compared with vaginal delivery.⁵

The socioeconomic picture matters

From a socioeconomic standpoint, women who request C-section may have financial concerns such as the amount of time off from work that may be necessary for both themselves and their partners. The availability of family support may be relevant and improved if a specific time frame for delivery is anticipated.

In many cultures, “lucky days” exist, and women may have preferences or aspirations for their child to be born on one of them.

Last, although it may be more cost-effective for a patient to undergo vaginal delivery, we, as health-care providers, cannot predict who will be successful in that regard. A complicated labor that necessitates unscheduled, urgent, or emergent C-section costs more in health-care dollars than does a C-section without labor.

Canadian researchers in 2005 examined the hospital care costs over 18 years in 27,614 pregnancies associated with varying types of delivery and found that the cost of delivery was highest for a C-section performed after the onset of labor ($2,137). The lowest cost was for spontaneous vaginal delivery ($1,340), followed by C-section without labor ($1,532).⁶ Therefore, some could argue that the overall cost to the patient and system is lower with a scheduled cesarean delivery because it avoids the other possible comorbidities and utilization of resources.

TABLE

Risks and benefits of planned cesarean delivery

When a patient raises the subject

Your first responsibility is to clarify her request. Key to this discussion is the patient’s reason for requesting a scheduled C-section. Many women—especially primiparous women—have a fear of labor itself, not to mention concerns about their safety and the safety of their baby.⁷ Another major concern to many women is the risk of injury to their perineum and pelvic floor.¹ These fears and concerns may motivate their request.

Educating patients about labor and discussing options for pain relief during labor can help soothe the patients’ fears. Clarifying long-term risks and benefits in regard to pelvic floor dysfunction also is important. Patients may have an unrealistic understanding of C-section and its potential complications. Often, education about the birth process and mode of delivery can alleviate a patient’s fears and change her hopes for delivery.

Explore any comorbidities

Because C-section is a major abdominal surgical procedure, maternal factors such as weight, age, surgical history, and medical comorbidities are relevant considerations when discussing the risks and benefits of cesarean in the absence of obstetric indications. Even in the absence of such comorbidities, certain risks of surgery should be clarified, including the risk of hemorrhage, infection, wound complication, thromboembolism, need for future surgery, and postoperative recovery.

The risks and benefits of vaginal delivery also should be discussed, including the factors that may lead up to an un-scheduled cesarean delivery despite the desire for a vaginal delivery.

How many children are planned?

Given the reluctance of health-care providers to manage attempted vaginal birth after C-section, women who opt for elective C-section for their first delivery may be committing themselves to C-section with subsequent pregnancies, too.⁸ Data suggest that an increasing number of C-sections place women at increasing risk of placenta accreta or previa, hysterectomy, blood transfusion, cystotomy, endometritis, prolonged operative time, and longer hospital stays. That said, overall maternal mortality from C-section remains low.⁹

Therefore, if a patient plans to have more than one or two children, she needs to understand the ramifications of repeat C-section at the time of her next delivery as well as in any additional pregnancies. Although a successful vaginal delivery cannot be guaranteed for any parturient, an attempt at vaginal delivery might be preferable for a woman hoping for a larger family.

Ensure clear consent

Chervenak and McCullough have provided an algorithm for offering C-section that balances the ethical concepts of autonomy and beneficence; that model is described above.¹⁰

If the patient requests C-section, but the clinician is uncomfortable performing one under the circumstances, referral is reasonable.

A patient’s thoughtful request can be considered out of respect for autonomy and supported by thorough counseling.

Ensuring a correct gestational age

Once the decision to proceed with scheduled C-section is made, accurate determination of gestational age is crucial to avoid iatrogenic prematurity.

ACOG Educational Bulletin No. 230 (November 1996) lists a number of criteria by which to infer gestational age and, therefore, fetal lung maturity. The criteria include:

• documented fetal heart tone for 30 weeks by Doppler ultrasound
  
• 36 weeks having passed since reliable documentation of a positive urine or serum human chorionic gonadotropin pregnancy test
  
• crown–rump measurement by ultrasonography (US) at 6 to 11 weeks of gestation that supports the current gestational age of 39 weeks or more
  
• US measurement at 12 to 20 weeks’ gestation that supports the clinically determined estimated gestational age above 39 weeks.
  

Insurance concerns are vital to the decision

The Newborns’ and Mothers’ Health Protection Act (NMHPA) was passed in 1996. The law delineates a minimum requirement of coverage by insurers for hospital stays of 48 hours after vaginal delivery or 96 hours after C-section, thereby preventing health insurance plans from restricting hospital stays after delivery.¹¹ The law was passed as a response to political concerns about “drive-thru deliveries.”

The NMHPA also allows for provider discretion regarding the length of stay required after childbirth, meaning that, if an attending-level provider deems discharge feasible in less than 48 or 96 hours, the insurer is not mandated to continue coverage beyond discharge.

The law, however, does not mandate coverage by health insurance plans for prenatal care, delivery, and postpartum care. Confounding the actions of health insurance companies are state laws governing the care of newborns and mothers, as these laws superceded the NMHPA. So, although most states have mandated benefit laws regarding a variety of services, as of 2002, only 18 states had laws mandating specific maternity services.¹² Some states specifically mention elective C-sections as nonmandated services, meaning that a patient who elects a scheduled C-section at term without obstetric indications may be required to pay for her obstetric care.

In general, when a patient inquires about elective primary C-section, it is best to consider the “6 C’s of elective cesarean” in a careful discussion with her. That approach entails consideration of the following:

• Clarification of her request
  
• Comorbidities in maternal health or surgical history
  
• number of Children planned overall
  
• clear Consent for the procedure
  
• Correct determination of gestational age at the time of planned delivery
  
• Confirmation of coverage by her insurance carrier.
  

One trend is clear: Maternal requests for primary cesarean delivery are on the rise in the United States, although we lack precise data on exactly how fast the rate is rising. Many experts estimate it to be 4% to 18%.¹ In Brazil, the rate of elective C-section for women in private hospitals is thought to be as high as 80% to 90%.²

As more celebrities and other prominent figures undergo elective C-section, more American women are beginning to ask for the same “privilege.” In this article, I lay out an evidence-based and ethically sensitive approach to counseling patients who request C-section on an elective basis.

The points raised in the list that begins this article are all discussed here.

The difficulty of calculating the rate of primary C-section

We are limited by terminology and data-collection practices, as well as a multitude of confounding obstetric factors. Practicing providers recognize the inherent difference between a planned C-section at term without the onset of labor and an unplanned C-section at term after the onset of labor—as well as every scenario in between.

Unplanned C-section can be performed to address fetal compromise or an unsuccessful attempt at vaginal delivery—each scenario replete with its own risks and potential complications. The urgency of C-section also confounds subsequent maternal and fetal complications. Underlying maternal factors such as obesity and medical and surgical history further complicate the scenario.

For these reasons, the discussion of elective C-section is best managed by limiting the parameters considered to the requested, scheduled, elective C-section at term without maternal or fetal indications. Most patients have this paradigm in mind when they make their request, even though physicians and midwives understand that this is the ideal and not generally the reality.

Medicolegal and ethical considerations

The ethical principles surrounding cesarean delivery upon maternal request balance on the tension between beneficence and patient autonomy. The former requires the promotion of the patient’s overall health and well-being, along with attention to the closely related dictum, primum non nocere, or “first do no harm.”

Patient autonomy requires respectful consideration of the patient and her world view when making a medical decision. The ethical principle of patient autonomy is usually understood as a right to decline medical intervention—not necessarily to demand dangerous or unproven intervention.¹

This raises the question: Is a scheduled C-section in the absence of obstetric indications dangerous? Harmful? Imprudent? The medical community has accepted these inherent tensions in the field of aesthetic plastic surgery, but societies in obstetrics and gynecology continue to struggle with the ethical principles involved in maternal-choice cesarean.

FIGO: C-section for nonmedical reasons is not justified

The International Federation of Gynecology and Obstetrics (FIGO) Committee for the Ethical Aspects of Human Reproduction and Women’s Health bases its guidelines on the use of cesarean delivery for nonmedical reasons on the principles of beneficence and social justice. It concludes: “Cesarean section is a surgical intervention with potential hazards for both mother and child. It also uses more health-care resources than normal vaginal delivery…performing cesarean section for nonmedical reasons is ethically not justified.”³

ACOG: Individualize the decision consistent with ethical principles

The American College of Obstetricians and Gynecologists (ACOG), in a recent Committee Opinion, acknowledged the paucity of research data directly comparing cesarean delivery on maternal request with planned vaginal delivery. The document reviews the National Institutes of Health (NIH) State-of-the-Science Conference on Cesarean Delivery on Maternal Request (see below), which was convened in 2006, and notes the panel’s conclusion that the available body of evidence does not allow for a conclusive recommendation of one mode of delivery over another.⁴ The ACOG Committee Opinion states: “Any decision to perform a cesarean delivery on maternal request should be carefully individualized and consistent with ethical principles.”⁵

Different world views likely account for different conclusions

The difference in the FIGO and ACOG positions may arise from differences in cultural contexts between a general world health view and a highly patient-centered Western perspective. The former view bases the decision on universal good and the utilization of scarce health-care resources; the latter view recognizes the individual within an ethical context.

Both views acknowledge the limited data available to inform the decision. So what do the data say, and how can we help our patients understand it?

NIH State-of-the-Science Conference

In March of 2006, an independent panel of experts from a range of medical fields reviewed the scientific literature regarding cesarean delivery on maternal request at the NIH in Bethesda, Maryland. Although the panel found no Level I, or strong, evidence within the literature, it was able to characterize the risks and benefits of maternal-request C-section based on Level II (moderate), Level III (weak), and Level IV (absent) evidence.

Moderate evidence was scarce

From a maternal perspective, the panel found that “the frequency of postpartum hemorrhage associated with planned cesarean delivery is lower than that reported with the combination of planned vaginal delivery and unplanned cesarean delivery,”⁵ although hospital stay is longer than with vaginal delivery.

From a neonatal perspective, moderate evidence favors vaginal delivery because of a decreased incidence of respiratory morbidity, such as transient tachypnea of the newborn and respiratory distress syndrome. Respiratory morbidity is directly related to gestational age, and there is a risk of iatrogenic prematurity with scheduled C-section. The possibility of incorrect obstetric dating would seem to favor awaiting the spontaneous onset of labor at term and an attempt at vaginal delivery to reduce the risk of respiratory complications due to iatrogenic prematurity.

Weak evidence goes both ways

Weakly supported evidence favored both cesarean section and vaginal delivery for either the mother or fetus. Weak evidence favoring vaginal delivery for maternal interests included:

• decreased maternal infectious morbidity and anesthetic complications, compared with C-section
  
• greater ease establishing breastfeeding, due to logistical challenges surrounding mother–infant bonding after C-section
  
• greater freedom in planning family size because increasing numbers of repeat C-sections with subsequent pregnancies increase risk of uterine rupture, cesarean hysterectomy, and abnormal placentation.
  

• lower rate of postpartum stress urinary incontinence, compared with women undergoing vaginal delivery, in the short term
  
• lower risk of surgical morbidity and traumatic obstetric lacerations with elective C-section, compared with the injuries that can occur at the time of unscheduled C-section or vaginal delivery.
  

Weak evidence of neonatal benefit

From the neonatal perspective, the NIH Consensus Committee found weak evidence favoring C-section. A scheduled C-section protects the neonate from stillbirth arising from postdates intrauterine fetal demise, because, with elective cesarean, a pregnancy is not usually allowed to continue post-term.

The Committee also documented protection from intracranial hemorrhage, neonatal asphyxia, encephalopathy, birth injury, and neonatal infection with C-section, compared with vaginal delivery.⁵

The socioeconomic picture matters

From a socioeconomic standpoint, women who request C-section may have financial concerns such as the amount of time off from work that may be necessary for both themselves and their partners. The availability of family support may be relevant and improved if a specific time frame for delivery is anticipated.

In many cultures, “lucky days” exist, and women may have preferences or aspirations for their child to be born on one of them.

Last, although it may be more cost-effective for a patient to undergo vaginal delivery, we, as health-care providers, cannot predict who will be successful in that regard. A complicated labor that necessitates unscheduled, urgent, or emergent C-section costs more in health-care dollars than does a C-section without labor.

Canadian researchers in 2005 examined the hospital care costs over 18 years in 27,614 pregnancies associated with varying types of delivery and found that the cost of delivery was highest for a C-section performed after the onset of labor ($2,137). The lowest cost was for spontaneous vaginal delivery ($1,340), followed by C-section without labor ($1,532).⁶ Therefore, some could argue that the overall cost to the patient and system is lower with a scheduled cesarean delivery because it avoids the other possible comorbidities and utilization of resources.

TABLE

Risks and benefits of planned cesarean delivery

When a patient raises the subject

Your first responsibility is to clarify her request. Key to this discussion is the patient’s reason for requesting a scheduled C-section. Many women—especially primiparous women—have a fear of labor itself, not to mention concerns about their safety and the safety of their baby.⁷ Another major concern to many women is the risk of injury to their perineum and pelvic floor.¹ These fears and concerns may motivate their request.

Educating patients about labor and discussing options for pain relief during labor can help soothe the patients’ fears. Clarifying long-term risks and benefits in regard to pelvic floor dysfunction also is important. Patients may have an unrealistic understanding of C-section and its potential complications. Often, education about the birth process and mode of delivery can alleviate a patient’s fears and change her hopes for delivery.

Explore any comorbidities

Because C-section is a major abdominal surgical procedure, maternal factors such as weight, age, surgical history, and medical comorbidities are relevant considerations when discussing the risks and benefits of cesarean in the absence of obstetric indications. Even in the absence of such comorbidities, certain risks of surgery should be clarified, including the risk of hemorrhage, infection, wound complication, thromboembolism, need for future surgery, and postoperative recovery.

The risks and benefits of vaginal delivery also should be discussed, including the factors that may lead up to an un-scheduled cesarean delivery despite the desire for a vaginal delivery.

How many children are planned?

Given the reluctance of health-care providers to manage attempted vaginal birth after C-section, women who opt for elective C-section for their first delivery may be committing themselves to C-section with subsequent pregnancies, too.⁸ Data suggest that an increasing number of C-sections place women at increasing risk of placenta accreta or previa, hysterectomy, blood transfusion, cystotomy, endometritis, prolonged operative time, and longer hospital stays. That said, overall maternal mortality from C-section remains low.⁹

Therefore, if a patient plans to have more than one or two children, she needs to understand the ramifications of repeat C-section at the time of her next delivery as well as in any additional pregnancies. Although a successful vaginal delivery cannot be guaranteed for any parturient, an attempt at vaginal delivery might be preferable for a woman hoping for a larger family.

Ensure clear consent

Chervenak and McCullough have provided an algorithm for offering C-section that balances the ethical concepts of autonomy and beneficence; that model is described above.¹⁰

If the patient requests C-section, but the clinician is uncomfortable performing one under the circumstances, referral is reasonable.

A patient’s thoughtful request can be considered out of respect for autonomy and supported by thorough counseling.

Ensuring a correct gestational age

Once the decision to proceed with scheduled C-section is made, accurate determination of gestational age is crucial to avoid iatrogenic prematurity.

ACOG Educational Bulletin No. 230 (November 1996) lists a number of criteria by which to infer gestational age and, therefore, fetal lung maturity. The criteria include:

• documented fetal heart tone for 30 weeks by Doppler ultrasound
  
• 36 weeks having passed since reliable documentation of a positive urine or serum human chorionic gonadotropin pregnancy test
  
• crown–rump measurement by ultrasonography (US) at 6 to 11 weeks of gestation that supports the current gestational age of 39 weeks or more
  
• US measurement at 12 to 20 weeks’ gestation that supports the clinically determined estimated gestational age above 39 weeks.
  

Insurance concerns are vital to the decision

The Newborns’ and Mothers’ Health Protection Act (NMHPA) was passed in 1996. The law delineates a minimum requirement of coverage by insurers for hospital stays of 48 hours after vaginal delivery or 96 hours after C-section, thereby preventing health insurance plans from restricting hospital stays after delivery.¹¹ The law was passed as a response to political concerns about “drive-thru deliveries.”

The NMHPA also allows for provider discretion regarding the length of stay required after childbirth, meaning that, if an attending-level provider deems discharge feasible in less than 48 or 96 hours, the insurer is not mandated to continue coverage beyond discharge.

The law, however, does not mandate coverage by health insurance plans for prenatal care, delivery, and postpartum care. Confounding the actions of health insurance companies are state laws governing the care of newborns and mothers, as these laws superceded the NMHPA. So, although most states have mandated benefit laws regarding a variety of services, as of 2002, only 18 states had laws mandating specific maternity services.¹² Some states specifically mention elective C-sections as nonmandated services, meaning that a patient who elects a scheduled C-section at term without obstetric indications may be required to pay for her obstetric care.

The author reports no financial relationships relevant to this article.

A common thread ties together the studies and developments highlighted here: the notion that maladaptive changes in the neurologic supply to pelvic organs may contribute to chronic pain to a greater extent than do stimuli from damaged tissue. This understanding is consistent with the general lack of any obvious relationship between the degree (i.e., volume) of tissue change in disease (e.g., endometriosis) and the intensity of associated pain. It may also open new avenues to the prevention and treatment of chronic pain.

In the future, treatments for painful conditions seen in gynecology are likely to expand beyond nonsteroidal analgesics and narcotics to include

• neuromodulatory drugs
• local anesthetics applied in novel ways
• nerve-stimulation procedures that are less invasive than methods used so far.

Furthermore, the art of treatment will involve an understanding of the most effective ways to mix and sequence these methods.

Preoperative preemptive analgesia may reduce long-term incisional pain

Mathiesen O, Moiniche S, Dahl JB. Gabapentin and post-operative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007;7:6.

Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141.

The study of preemptive analgesia over the past 20 or more years has focused almost exclusively on one goal: reducing immediate postoperative pain, usually with narcotic consumption as the primary outcome measure. Results have been mixed, with few studies showing clear and clinically meaningful benefit.

More recently, several studies have focused on what may be a more important longer-term clinical outcome measure: incisional pain long after surgery. Multiple studies document an incidence of 10% to 25% of patients reporting incisional pain long after their surgery.¹ Thoracotomy, reconstructive breast procedures, and abdominal incisions have all been associated with this problem. The study by Fassoulaki and associates shows that one dose of gabapentin before abdominal hysterectomy was associated with less incisional pain a full month after surgery.

Implications for patients in chronic pain

Patients who suffer chronic pain and who undergo surgery require a higher dosage of narcotic analgesics during postoperative care than other patients might. This need is usually attributed to accelerated metabolism of the drugs, brought about by longstanding use before surgery. An alternative hypothesis that would unite these observations is that pain pathways in the central nervous system are activated when surgical trauma is inflicted and that they affect the intensity of pain after surgery. For example, if the spinal cord segments associated with the pelvic reproductive organs have been involved in conducting nociceptive (pain) signals for the months or years leading to surgery, superimposed stimulus of surgery may be less well tolerated.

This hypothesis gives rise to several tantalizing questions:

• Would preoperative medication with drugs used to treat neuropathic pain reduce both visceral and somatic components of postoperative pain?
• Would these medications, given early in the clinical course, help prevent the chronic pain associated with pelvic infection and endometriosis?
• Would this approach be an avenue to reduce long-term postoperative pain in women with chronic pain before surgery?

Observations from research into preemptive analgesia are providing the impetus for what promises to be a productive and exciting area of clinical research in the treatment of pain in a variety of clinical situations in gynecology.

In chronic pain, changes in innervation may extend to peripheral organs

Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol. 2005;193:1650–1655.

One widely accepted hypothesis is that chronic pain states are accompanied by changes in spinal cord neurophysiology at both neurochemical and neuroanatomic levels. Indeed, in animal models of chronic pain, neuronal connections are altered in the spinal cord such that touch and pressure excite true central pain fibers. New evidence suggests that changes in innervation associated with chronic pain may also affect peripheral organs (FIGURE).

For example, in the study by Atwal and associates, the uterus of women undergoing hysterectomy was stained for unmyelinated nerve fibers of the type commonly involved in visceral pain signals. Women undergoing surgery for painless conditions had a low density of pain fibers in the lower uterine segment compared with women who had chronic pain before surgery, who had a higher density of pain fibers. This was true for women who had otherwise normal pelvic anatomy, as well as for those who had endometriosis. These findings may explain the puzzling observation that hysterectomy relieves central pelvic pain in 78% of women undergoing the procedure (and improves pain in 22% of women with persistent pain) even when the uterus is histologically normal on routine pathologic examination.²

Perhaps even more intriguing is the notion that pelvic pain may ultimately be elucidated through the study of changes in neurologic systems rather than changes in gynecologic end organs themselves. If pain, initially triggered by alterations in end organs, becomes chronic and intractable by virtue of neurologic changes, this perspective may lead to entirely new approaches to preventing chronic pain.

Chronic pain may alter spinal cord neurophysiology

Under physiologic conditions, the nerves of the central nervous system guide the uterus and other organs through their respective functions. In some women, however, spinal cord neuronal circuitry becomes distorted, eliciting a pain response even when no trigger is present.

Less invasive nerve-stimulation method holds promise for pelvic pain

Nerve stimulation in a wide variety of forms has long been used to block nociceptive signals. Examples include sacral nerve root stimulators, spinal cord implants, and transcutaneous electrical nerve stimulation (TENS) units. Their efficacy varies across pain syndromes, and the duration of impact (even in successfully treated women) is uncertain. The invasive nature of the implanted devices adds to the risk and often relegates them to the bottom of the list of treatment options.

Another method of peripheral nerve stimulation—posterior tibial nerve stimulation—was recently approved by the Food and Drug Administration for treatment of bladder irritability, and may also improve urge incontinence and pelvic pain.^3,4 It involves application of electrical stimuli to a very fine (acupuncture-like) needle placed next to the posterior tibial nerve, just posterior to the medial maleolus. The nerve is generally stimulated for 30 minutes a week for a series of 12 treatments. Other protocols are bound to emerge as this method is applied more broadly.

In the case of irritability, bladder pain is also often relieved. The treatment is now being tried in women with interstitial cystitis. Even though the nerve supplies of the various pelvic and vulvar organs do not all arise from the same spinal cord segments, communications within the cord may explain the broader impact of techniques like posterior tibial nerve stimulation.

The author reports no financial relationships relevant to this article.

A common thread ties together the studies and developments highlighted here: the notion that maladaptive changes in the neurologic supply to pelvic organs may contribute to chronic pain to a greater extent than do stimuli from damaged tissue. This understanding is consistent with the general lack of any obvious relationship between the degree (i.e., volume) of tissue change in disease (e.g., endometriosis) and the intensity of associated pain. It may also open new avenues to the prevention and treatment of chronic pain.

In the future, treatments for painful conditions seen in gynecology are likely to expand beyond nonsteroidal analgesics and narcotics to include

• neuromodulatory drugs
• local anesthetics applied in novel ways
• nerve-stimulation procedures that are less invasive than methods used so far.

Furthermore, the art of treatment will involve an understanding of the most effective ways to mix and sequence these methods.

Preoperative preemptive analgesia may reduce long-term incisional pain

Mathiesen O, Moiniche S, Dahl JB. Gabapentin and post-operative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007;7:6.

Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141.

The study of preemptive analgesia over the past 20 or more years has focused almost exclusively on one goal: reducing immediate postoperative pain, usually with narcotic consumption as the primary outcome measure. Results have been mixed, with few studies showing clear and clinically meaningful benefit.

More recently, several studies have focused on what may be a more important longer-term clinical outcome measure: incisional pain long after surgery. Multiple studies document an incidence of 10% to 25% of patients reporting incisional pain long after their surgery.¹ Thoracotomy, reconstructive breast procedures, and abdominal incisions have all been associated with this problem. The study by Fassoulaki and associates shows that one dose of gabapentin before abdominal hysterectomy was associated with less incisional pain a full month after surgery.

Implications for patients in chronic pain

Patients who suffer chronic pain and who undergo surgery require a higher dosage of narcotic analgesics during postoperative care than other patients might. This need is usually attributed to accelerated metabolism of the drugs, brought about by longstanding use before surgery. An alternative hypothesis that would unite these observations is that pain pathways in the central nervous system are activated when surgical trauma is inflicted and that they affect the intensity of pain after surgery. For example, if the spinal cord segments associated with the pelvic reproductive organs have been involved in conducting nociceptive (pain) signals for the months or years leading to surgery, superimposed stimulus of surgery may be less well tolerated.

This hypothesis gives rise to several tantalizing questions:

• Would preoperative medication with drugs used to treat neuropathic pain reduce both visceral and somatic components of postoperative pain?
• Would these medications, given early in the clinical course, help prevent the chronic pain associated with pelvic infection and endometriosis?
• Would this approach be an avenue to reduce long-term postoperative pain in women with chronic pain before surgery?

Observations from research into preemptive analgesia are providing the impetus for what promises to be a productive and exciting area of clinical research in the treatment of pain in a variety of clinical situations in gynecology.

In chronic pain, changes in innervation may extend to peripheral organs

Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol. 2005;193:1650–1655.

One widely accepted hypothesis is that chronic pain states are accompanied by changes in spinal cord neurophysiology at both neurochemical and neuroanatomic levels. Indeed, in animal models of chronic pain, neuronal connections are altered in the spinal cord such that touch and pressure excite true central pain fibers. New evidence suggests that changes in innervation associated with chronic pain may also affect peripheral organs (FIGURE).

For example, in the study by Atwal and associates, the uterus of women undergoing hysterectomy was stained for unmyelinated nerve fibers of the type commonly involved in visceral pain signals. Women undergoing surgery for painless conditions had a low density of pain fibers in the lower uterine segment compared with women who had chronic pain before surgery, who had a higher density of pain fibers. This was true for women who had otherwise normal pelvic anatomy, as well as for those who had endometriosis. These findings may explain the puzzling observation that hysterectomy relieves central pelvic pain in 78% of women undergoing the procedure (and improves pain in 22% of women with persistent pain) even when the uterus is histologically normal on routine pathologic examination.²

Perhaps even more intriguing is the notion that pelvic pain may ultimately be elucidated through the study of changes in neurologic systems rather than changes in gynecologic end organs themselves. If pain, initially triggered by alterations in end organs, becomes chronic and intractable by virtue of neurologic changes, this perspective may lead to entirely new approaches to preventing chronic pain.

Chronic pain may alter spinal cord neurophysiology

Under physiologic conditions, the nerves of the central nervous system guide the uterus and other organs through their respective functions. In some women, however, spinal cord neuronal circuitry becomes distorted, eliciting a pain response even when no trigger is present.

Less invasive nerve-stimulation method holds promise for pelvic pain

Nerve stimulation in a wide variety of forms has long been used to block nociceptive signals. Examples include sacral nerve root stimulators, spinal cord implants, and transcutaneous electrical nerve stimulation (TENS) units. Their efficacy varies across pain syndromes, and the duration of impact (even in successfully treated women) is uncertain. The invasive nature of the implanted devices adds to the risk and often relegates them to the bottom of the list of treatment options.

Another method of peripheral nerve stimulation—posterior tibial nerve stimulation—was recently approved by the Food and Drug Administration for treatment of bladder irritability, and may also improve urge incontinence and pelvic pain.^3,4 It involves application of electrical stimuli to a very fine (acupuncture-like) needle placed next to the posterior tibial nerve, just posterior to the medial maleolus. The nerve is generally stimulated for 30 minutes a week for a series of 12 treatments. Other protocols are bound to emerge as this method is applied more broadly.

In the case of irritability, bladder pain is also often relieved. The treatment is now being tried in women with interstitial cystitis. Even though the nerve supplies of the various pelvic and vulvar organs do not all arise from the same spinal cord segments, communications within the cord may explain the broader impact of techniques like posterior tibial nerve stimulation.

The author reports no financial relationships relevant to this article.

A common thread ties together the studies and developments highlighted here: the notion that maladaptive changes in the neurologic supply to pelvic organs may contribute to chronic pain to a greater extent than do stimuli from damaged tissue. This understanding is consistent with the general lack of any obvious relationship between the degree (i.e., volume) of tissue change in disease (e.g., endometriosis) and the intensity of associated pain. It may also open new avenues to the prevention and treatment of chronic pain.

In the future, treatments for painful conditions seen in gynecology are likely to expand beyond nonsteroidal analgesics and narcotics to include

• neuromodulatory drugs
• local anesthetics applied in novel ways
• nerve-stimulation procedures that are less invasive than methods used so far.

Furthermore, the art of treatment will involve an understanding of the most effective ways to mix and sequence these methods.

Preoperative preemptive analgesia may reduce long-term incisional pain

Mathiesen O, Moiniche S, Dahl JB. Gabapentin and post-operative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007;7:6.

Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol. 2006;23:136–141.

The study of preemptive analgesia over the past 20 or more years has focused almost exclusively on one goal: reducing immediate postoperative pain, usually with narcotic consumption as the primary outcome measure. Results have been mixed, with few studies showing clear and clinically meaningful benefit.

More recently, several studies have focused on what may be a more important longer-term clinical outcome measure: incisional pain long after surgery. Multiple studies document an incidence of 10% to 25% of patients reporting incisional pain long after their surgery.¹ Thoracotomy, reconstructive breast procedures, and abdominal incisions have all been associated with this problem. The study by Fassoulaki and associates shows that one dose of gabapentin before abdominal hysterectomy was associated with less incisional pain a full month after surgery.

Implications for patients in chronic pain

Patients who suffer chronic pain and who undergo surgery require a higher dosage of narcotic analgesics during postoperative care than other patients might. This need is usually attributed to accelerated metabolism of the drugs, brought about by longstanding use before surgery. An alternative hypothesis that would unite these observations is that pain pathways in the central nervous system are activated when surgical trauma is inflicted and that they affect the intensity of pain after surgery. For example, if the spinal cord segments associated with the pelvic reproductive organs have been involved in conducting nociceptive (pain) signals for the months or years leading to surgery, superimposed stimulus of surgery may be less well tolerated.

This hypothesis gives rise to several tantalizing questions:

• Would preoperative medication with drugs used to treat neuropathic pain reduce both visceral and somatic components of postoperative pain?
• Would these medications, given early in the clinical course, help prevent the chronic pain associated with pelvic infection and endometriosis?
• Would this approach be an avenue to reduce long-term postoperative pain in women with chronic pain before surgery?

Observations from research into preemptive analgesia are providing the impetus for what promises to be a productive and exciting area of clinical research in the treatment of pain in a variety of clinical situations in gynecology.

In chronic pain, changes in innervation may extend to peripheral organs

Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol. 2005;193:1650–1655.

One widely accepted hypothesis is that chronic pain states are accompanied by changes in spinal cord neurophysiology at both neurochemical and neuroanatomic levels. Indeed, in animal models of chronic pain, neuronal connections are altered in the spinal cord such that touch and pressure excite true central pain fibers. New evidence suggests that changes in innervation associated with chronic pain may also affect peripheral organs (FIGURE).

For example, in the study by Atwal and associates, the uterus of women undergoing hysterectomy was stained for unmyelinated nerve fibers of the type commonly involved in visceral pain signals. Women undergoing surgery for painless conditions had a low density of pain fibers in the lower uterine segment compared with women who had chronic pain before surgery, who had a higher density of pain fibers. This was true for women who had otherwise normal pelvic anatomy, as well as for those who had endometriosis. These findings may explain the puzzling observation that hysterectomy relieves central pelvic pain in 78% of women undergoing the procedure (and improves pain in 22% of women with persistent pain) even when the uterus is histologically normal on routine pathologic examination.²

Perhaps even more intriguing is the notion that pelvic pain may ultimately be elucidated through the study of changes in neurologic systems rather than changes in gynecologic end organs themselves. If pain, initially triggered by alterations in end organs, becomes chronic and intractable by virtue of neurologic changes, this perspective may lead to entirely new approaches to preventing chronic pain.

Chronic pain may alter spinal cord neurophysiology

Under physiologic conditions, the nerves of the central nervous system guide the uterus and other organs through their respective functions. In some women, however, spinal cord neuronal circuitry becomes distorted, eliciting a pain response even when no trigger is present.

Less invasive nerve-stimulation method holds promise for pelvic pain

Nerve stimulation in a wide variety of forms has long been used to block nociceptive signals. Examples include sacral nerve root stimulators, spinal cord implants, and transcutaneous electrical nerve stimulation (TENS) units. Their efficacy varies across pain syndromes, and the duration of impact (even in successfully treated women) is uncertain. The invasive nature of the implanted devices adds to the risk and often relegates them to the bottom of the list of treatment options.

Another method of peripheral nerve stimulation—posterior tibial nerve stimulation—was recently approved by the Food and Drug Administration for treatment of bladder irritability, and may also improve urge incontinence and pelvic pain.^3,4 It involves application of electrical stimuli to a very fine (acupuncture-like) needle placed next to the posterior tibial nerve, just posterior to the medial maleolus. The nerve is generally stimulated for 30 minutes a week for a series of 12 treatments. Other protocols are bound to emerge as this method is applied more broadly.

In the case of irritability, bladder pain is also often relieved. The treatment is now being tried in women with interstitial cystitis. Even though the nerve supplies of the various pelvic and vulvar organs do not all arise from the same spinal cord segments, communications within the cord may explain the broader impact of techniques like posterior tibial nerve stimulation.