Clinical Review

The author is a consultant to Merck & Co., Inc., GlaxoSmithKline, and Roche Molecular Diagnostics.

New data enhance our knowledge in two critical areas previously covered in this update: the human papillomavirus (HPV) vaccine and HPV DNA testing for cervical cancer screening.

Among findings published in 2007:

• results of phase-3 trials of the quadrivalent and bivalent HPV vaccines, which confirm the remarkable efficacy seen in phase-2 trials among women not previously exposed to the vaccine-targeted HPV types
• three large randomized cervical cancer screening trials from Canada, Sweden, and the Netherlands, which confirm the superiority of cervical cancer screening programs that add HPV DNA testing to cytology in women 30 years and older
• the much-anticipated update of consensus guidelines on the management of women with abnormal cervical cancer screening tests.

Efficacy of HPV vaccine approaches 100% in targeted population

Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915–1927.

Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356:1928–1943.

These trials, referred to as FUTURE I and II, were multicenter, multicountry, double-blinded, placebo-controlled trials of the quadrivalent vaccine (Gardasil) that enrolled women 15 to 26 years of age (TABLE).¹ Participants were followed for an average of 3 years after receiving the first of the series of three vaccinations. The efficacy of the vaccine at preventing high-grade neoplasia associated with vaccine-targeted HPV types (HPV 6, 11, 16, and 18) was 98% and 100% in the two trials among the “per-protocol,” susceptible population. That population was defined as women who had no evidence of exposure to the targeted HPV types, according to serologic or HPV DNA testing during the first 7 months of the trials, and who received all three vaccinations. This population is a good indicator of how the vaccine will work in adolescents who are not yet sexually active (TABLE).

Efficacy is high in key phase-3 trials of the HPV vaccine

The vaccine was less effective in the “intention-to-treat” population that included all women enrolled in the study regardless of HPV status. At 3 years, the vaccine reduced high-grade neoplasia associated with vaccine-targeted HPV types in this population by only 29% and 50% in the two trials.

When these results were published, some experts expressed concern and questioned the benefit of the vaccines.² There is no reason for concern, however, because lower short-term efficacy in the intention-to-treat population was expected. Because the current generation of HPV vaccines does not have a measurable therapeutic effect, vaccination will not prevent cervical intraepithelial neoplasia (CIN) in women who are already infected with vaccine-targeted HPV types; nor will it cause regression of CIN lesions that are already present when the woman is vaccinated.

There were a number of women already infected with vaccine-targeted HPV types at enrollment in the “intention-to-treat” population. Some of these women developed CIN 2,3 associated with vaccine-targeted HPV strains during the first 18 months of the trial (FIGURE 1). However, with longer follow-up, the cumulative number of cases of CIN 2,3 plateaued in vaccinated women, whereas it continued to rise in the placebo arm. Thus, with longer follow-up, vaccine efficacy will improve. Therefore, both the American College of Obstetricians and Gynecologists and the Advisory Committee on Immunization Practices recommend that all sexually active adolescents and young women be vaccinated through 26 years of age.

Figure 1 Cases of CIN 2,3 eventually plateau in vaccinated women

The graph charts the efficacy of the quadrivalent HPV vaccine in preventing CIN 2,3 in the intention-to-treat population of a phase-3 efficacy trial.
SOURCE: Garland et al. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Bivalent vaccine was 90.4% effective against CIN 2,3

Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369:2161–2170.

This interim analysis of a phase-3 double-blind, placebo-controlled trial of the bivalent HPV vaccine (Cervarix), which targets HPV types 16 and 18, also was published last year. It enrolled more than 18,000 women 15 to 25 years old who had a mean length of follow-up of 15 months. The vaccine was 90.4% effective against CIN 2,3 associated with the targeted strains (types 16 and 18), the primary endpoint of the trial (TABLE). There was no significant difference in safety outcome between vaccine and placebo recipients.

This trial is ongoing, with final results expected in approximately 2 years. Based on interim findings, the vaccine has been approved for use in a number of countries, including all 27 European Union nations, and the manufacturer of the vaccine has filed an application for approval with the US Food and Drug Administration (FDA).

Screening is more effective when HPV testing is included—or used alone

Bulkmans NW, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007;370:1764–1772.

Naucler P, Ryd W, Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357:1589–1597.

Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357:1579–1588.

These major studies compared cytology alone with HPV DNA testing for high-risk strains (16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 68) and found HPV testing—with or without cytology—to be superior to cytology alone.

In a trial from the Netherlands, Bulkmans and colleagues randomly assigned more than 17,000 women 29 years and older to cytologic screening only or a combination of cytology and HPV DNA testing. After 5 years of follow-up, all women were rescreened using both tests. The baseline screen including a combination of cytology and HPV DNA testing identified 70% more CIN 3 lesions and cancers than did cytology alone. More important, during the subsequent round of screening, CIN 3 lesions and cancers decreased by 55% in the group initially screened with both tests.

Naucler and associates had similar results in a prospective Swedish trial that randomized women to screening by cytology alone or a combination of cytology and HPV DNA testing. During the initial round of screening, 31% more CIN 3 lesions and cancers were detected in the group screened with both tests (FIGURE 2). In subsequent rounds of screening, 47% fewer CIN 3 lesions or cancers were identified in this group.

Figure 2 Screening protocol that includes HPV DNA testing is superior, large trial confirmsTaken together, these two prospective studies clearly demonstrate that the addition of HPV DNA testing to cytology increases detection of high-grade lesions and reduces the incidence of high-grade neoplasia and cancers detected subsequently.

HPV testing is more sensitive, only slightly less specific, than cytology

In a cross-sectional study from Canada, Mayrand and colleagues compared HPV DNA testing and cytology during a single round of screening in more than 10,000 women. The findings were consistent with those of previous studies showing HPV DNA testing to be significantly more sensitive but somewhat less specific than cytology.³

The sensitivity of HPV testing for CIN 2,3 was 95% (95% confidence interval [CI], 84–100), compared with 55% (95% CI, 34–77) for cytology. Specificity of HPV DNA testing and cytology was 94% and 97%, respectively. When the two tests were used together, sensitivity was 100% and specificity was 93%.

New consensus guidelines clarify screening in special populations

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197:346–355.

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol. 2007;197:340–345.

The 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests clarify management of special populations such as adolescents, postmenopausal women, and patients with cervical adenocarcinoma in situ. Although the 2001 guidelines were widely adopted in the United States as the standard for managing women with abnormal screening tests—more than 500,000 copies were downloaded from Web site of the American Society for Colposcopy and Cervical Pathology (ASCCP)⁴—it became apparent after their implementation in a variety of clinical settings that some clarification of the guidelines was needed.

In adolescents, treat abnormalities conservatively

A major theme of the 2006 guidelines is a more conservative approach to adolescent patients (ages 13 to 20 years). Although this population has a very low risk of developing invasive cervical cancer, women 15 to 19 years of age are very likely to be diagnosed with minor cytologic abnormalities such as atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL), owing to the very high prevalence of anogenital HPV infection in this age group.

Because most anogenital HPV infections will spontaneously clear, minor cytologic abnormalities are usually of little consequence in adolescents.

Therefore, the 2006 consensus guidelines discourage the use of colposcopy in adolescents who have ASC-US and LSIL. Instead, these patients should be followed with annual repeat cytology and referred to colposcopy only when a high-grade cytologic abnormality is identified or when a low-grade cytologic abnormality persists for 24 months.

HPV testing most informative in older women

The new guidelines expand the clinical indications for HPV DNA testing and provide recommendations for managing different combinations of cytology and HPV test results when screening women 30 years and older. For example, they emphasize the use of HPV DNA testing in postmenopausal women because recent studies clearly demonstrate that the prevalence of high-risk HPV DNA positivity is lower in postmenopausal women with ASC-US or LSIL than in younger women.

Use only FDA-approved HPV tests

With the expanded indications for HPV DNA testing, the new guidelines take pains to point out that HPV test methods that have not been approved by the FDA may not produce findings consistent with approved methods. This is a very important point because many laboratories have started using unapproved testing methods. Although these methods have been validated internally by the laboratories, they have not been through the rigorous evaluation required for FDA approval. The new guidelines therefore state: “Appropriate use of these guidelines requires that laboratories utilize only HPV tests that have been analytically and clinically validated with proven acceptable reproducibility, clinical sensitivity, specificity, and positive and negative predictive values for cervical cancer and verified precancer (CIN 2,3), as documented by FDA approval and/or publication in peer-reviewed scientific literature.”

The guidelines are accessible online at the ASCCP Web site at www.asccp.org/consensus/cytological.shtml.

The author is a consultant to Merck & Co., Inc., GlaxoSmithKline, and Roche Molecular Diagnostics.

New data enhance our knowledge in two critical areas previously covered in this update: the human papillomavirus (HPV) vaccine and HPV DNA testing for cervical cancer screening.

Among findings published in 2007:

• results of phase-3 trials of the quadrivalent and bivalent HPV vaccines, which confirm the remarkable efficacy seen in phase-2 trials among women not previously exposed to the vaccine-targeted HPV types
• three large randomized cervical cancer screening trials from Canada, Sweden, and the Netherlands, which confirm the superiority of cervical cancer screening programs that add HPV DNA testing to cytology in women 30 years and older
• the much-anticipated update of consensus guidelines on the management of women with abnormal cervical cancer screening tests.

Efficacy of HPV vaccine approaches 100% in targeted population

Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915–1927.

Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356:1928–1943.

These trials, referred to as FUTURE I and II, were multicenter, multicountry, double-blinded, placebo-controlled trials of the quadrivalent vaccine (Gardasil) that enrolled women 15 to 26 years of age (TABLE).¹ Participants were followed for an average of 3 years after receiving the first of the series of three vaccinations. The efficacy of the vaccine at preventing high-grade neoplasia associated with vaccine-targeted HPV types (HPV 6, 11, 16, and 18) was 98% and 100% in the two trials among the “per-protocol,” susceptible population. That population was defined as women who had no evidence of exposure to the targeted HPV types, according to serologic or HPV DNA testing during the first 7 months of the trials, and who received all three vaccinations. This population is a good indicator of how the vaccine will work in adolescents who are not yet sexually active (TABLE).

Efficacy is high in key phase-3 trials of the HPV vaccine

The vaccine was less effective in the “intention-to-treat” population that included all women enrolled in the study regardless of HPV status. At 3 years, the vaccine reduced high-grade neoplasia associated with vaccine-targeted HPV types in this population by only 29% and 50% in the two trials.

When these results were published, some experts expressed concern and questioned the benefit of the vaccines.² There is no reason for concern, however, because lower short-term efficacy in the intention-to-treat population was expected. Because the current generation of HPV vaccines does not have a measurable therapeutic effect, vaccination will not prevent cervical intraepithelial neoplasia (CIN) in women who are already infected with vaccine-targeted HPV types; nor will it cause regression of CIN lesions that are already present when the woman is vaccinated.

There were a number of women already infected with vaccine-targeted HPV types at enrollment in the “intention-to-treat” population. Some of these women developed CIN 2,3 associated with vaccine-targeted HPV strains during the first 18 months of the trial (FIGURE 1). However, with longer follow-up, the cumulative number of cases of CIN 2,3 plateaued in vaccinated women, whereas it continued to rise in the placebo arm. Thus, with longer follow-up, vaccine efficacy will improve. Therefore, both the American College of Obstetricians and Gynecologists and the Advisory Committee on Immunization Practices recommend that all sexually active adolescents and young women be vaccinated through 26 years of age.

Figure 1 Cases of CIN 2,3 eventually plateau in vaccinated women

The graph charts the efficacy of the quadrivalent HPV vaccine in preventing CIN 2,3 in the intention-to-treat population of a phase-3 efficacy trial.
SOURCE: Garland et al. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Bivalent vaccine was 90.4% effective against CIN 2,3

Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369:2161–2170.

This interim analysis of a phase-3 double-blind, placebo-controlled trial of the bivalent HPV vaccine (Cervarix), which targets HPV types 16 and 18, also was published last year. It enrolled more than 18,000 women 15 to 25 years old who had a mean length of follow-up of 15 months. The vaccine was 90.4% effective against CIN 2,3 associated with the targeted strains (types 16 and 18), the primary endpoint of the trial (TABLE). There was no significant difference in safety outcome between vaccine and placebo recipients.

This trial is ongoing, with final results expected in approximately 2 years. Based on interim findings, the vaccine has been approved for use in a number of countries, including all 27 European Union nations, and the manufacturer of the vaccine has filed an application for approval with the US Food and Drug Administration (FDA).

Screening is more effective when HPV testing is included—or used alone

Bulkmans NW, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007;370:1764–1772.

Naucler P, Ryd W, Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357:1589–1597.

Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357:1579–1588.

These major studies compared cytology alone with HPV DNA testing for high-risk strains (16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 68) and found HPV testing—with or without cytology—to be superior to cytology alone.

In a trial from the Netherlands, Bulkmans and colleagues randomly assigned more than 17,000 women 29 years and older to cytologic screening only or a combination of cytology and HPV DNA testing. After 5 years of follow-up, all women were rescreened using both tests. The baseline screen including a combination of cytology and HPV DNA testing identified 70% more CIN 3 lesions and cancers than did cytology alone. More important, during the subsequent round of screening, CIN 3 lesions and cancers decreased by 55% in the group initially screened with both tests.

Naucler and associates had similar results in a prospective Swedish trial that randomized women to screening by cytology alone or a combination of cytology and HPV DNA testing. During the initial round of screening, 31% more CIN 3 lesions and cancers were detected in the group screened with both tests (FIGURE 2). In subsequent rounds of screening, 47% fewer CIN 3 lesions or cancers were identified in this group.

Figure 2 Screening protocol that includes HPV DNA testing is superior, large trial confirmsTaken together, these two prospective studies clearly demonstrate that the addition of HPV DNA testing to cytology increases detection of high-grade lesions and reduces the incidence of high-grade neoplasia and cancers detected subsequently.

HPV testing is more sensitive, only slightly less specific, than cytology

In a cross-sectional study from Canada, Mayrand and colleagues compared HPV DNA testing and cytology during a single round of screening in more than 10,000 women. The findings were consistent with those of previous studies showing HPV DNA testing to be significantly more sensitive but somewhat less specific than cytology.³

The sensitivity of HPV testing for CIN 2,3 was 95% (95% confidence interval [CI], 84–100), compared with 55% (95% CI, 34–77) for cytology. Specificity of HPV DNA testing and cytology was 94% and 97%, respectively. When the two tests were used together, sensitivity was 100% and specificity was 93%.

New consensus guidelines clarify screening in special populations

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197:346–355.

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol. 2007;197:340–345.

The 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests clarify management of special populations such as adolescents, postmenopausal women, and patients with cervical adenocarcinoma in situ. Although the 2001 guidelines were widely adopted in the United States as the standard for managing women with abnormal screening tests—more than 500,000 copies were downloaded from Web site of the American Society for Colposcopy and Cervical Pathology (ASCCP)⁴—it became apparent after their implementation in a variety of clinical settings that some clarification of the guidelines was needed.

In adolescents, treat abnormalities conservatively

A major theme of the 2006 guidelines is a more conservative approach to adolescent patients (ages 13 to 20 years). Although this population has a very low risk of developing invasive cervical cancer, women 15 to 19 years of age are very likely to be diagnosed with minor cytologic abnormalities such as atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL), owing to the very high prevalence of anogenital HPV infection in this age group.

Because most anogenital HPV infections will spontaneously clear, minor cytologic abnormalities are usually of little consequence in adolescents.

Therefore, the 2006 consensus guidelines discourage the use of colposcopy in adolescents who have ASC-US and LSIL. Instead, these patients should be followed with annual repeat cytology and referred to colposcopy only when a high-grade cytologic abnormality is identified or when a low-grade cytologic abnormality persists for 24 months.

HPV testing most informative in older women

The new guidelines expand the clinical indications for HPV DNA testing and provide recommendations for managing different combinations of cytology and HPV test results when screening women 30 years and older. For example, they emphasize the use of HPV DNA testing in postmenopausal women because recent studies clearly demonstrate that the prevalence of high-risk HPV DNA positivity is lower in postmenopausal women with ASC-US or LSIL than in younger women.

Use only FDA-approved HPV tests

With the expanded indications for HPV DNA testing, the new guidelines take pains to point out that HPV test methods that have not been approved by the FDA may not produce findings consistent with approved methods. This is a very important point because many laboratories have started using unapproved testing methods. Although these methods have been validated internally by the laboratories, they have not been through the rigorous evaluation required for FDA approval. The new guidelines therefore state: “Appropriate use of these guidelines requires that laboratories utilize only HPV tests that have been analytically and clinically validated with proven acceptable reproducibility, clinical sensitivity, specificity, and positive and negative predictive values for cervical cancer and verified precancer (CIN 2,3), as documented by FDA approval and/or publication in peer-reviewed scientific literature.”

The guidelines are accessible online at the ASCCP Web site at www.asccp.org/consensus/cytological.shtml.

The author is a consultant to Merck & Co., Inc., GlaxoSmithKline, and Roche Molecular Diagnostics.

New data enhance our knowledge in two critical areas previously covered in this update: the human papillomavirus (HPV) vaccine and HPV DNA testing for cervical cancer screening.

Among findings published in 2007:

• results of phase-3 trials of the quadrivalent and bivalent HPV vaccines, which confirm the remarkable efficacy seen in phase-2 trials among women not previously exposed to the vaccine-targeted HPV types
• three large randomized cervical cancer screening trials from Canada, Sweden, and the Netherlands, which confirm the superiority of cervical cancer screening programs that add HPV DNA testing to cytology in women 30 years and older
• the much-anticipated update of consensus guidelines on the management of women with abnormal cervical cancer screening tests.

Efficacy of HPV vaccine approaches 100% in targeted population

Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915–1927.

Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356:1928–1943.

These trials, referred to as FUTURE I and II, were multicenter, multicountry, double-blinded, placebo-controlled trials of the quadrivalent vaccine (Gardasil) that enrolled women 15 to 26 years of age (TABLE).¹ Participants were followed for an average of 3 years after receiving the first of the series of three vaccinations. The efficacy of the vaccine at preventing high-grade neoplasia associated with vaccine-targeted HPV types (HPV 6, 11, 16, and 18) was 98% and 100% in the two trials among the “per-protocol,” susceptible population. That population was defined as women who had no evidence of exposure to the targeted HPV types, according to serologic or HPV DNA testing during the first 7 months of the trials, and who received all three vaccinations. This population is a good indicator of how the vaccine will work in adolescents who are not yet sexually active (TABLE).

Efficacy is high in key phase-3 trials of the HPV vaccine

The vaccine was less effective in the “intention-to-treat” population that included all women enrolled in the study regardless of HPV status. At 3 years, the vaccine reduced high-grade neoplasia associated with vaccine-targeted HPV types in this population by only 29% and 50% in the two trials.

When these results were published, some experts expressed concern and questioned the benefit of the vaccines.² There is no reason for concern, however, because lower short-term efficacy in the intention-to-treat population was expected. Because the current generation of HPV vaccines does not have a measurable therapeutic effect, vaccination will not prevent cervical intraepithelial neoplasia (CIN) in women who are already infected with vaccine-targeted HPV types; nor will it cause regression of CIN lesions that are already present when the woman is vaccinated.

There were a number of women already infected with vaccine-targeted HPV types at enrollment in the “intention-to-treat” population. Some of these women developed CIN 2,3 associated with vaccine-targeted HPV strains during the first 18 months of the trial (FIGURE 1). However, with longer follow-up, the cumulative number of cases of CIN 2,3 plateaued in vaccinated women, whereas it continued to rise in the placebo arm. Thus, with longer follow-up, vaccine efficacy will improve. Therefore, both the American College of Obstetricians and Gynecologists and the Advisory Committee on Immunization Practices recommend that all sexually active adolescents and young women be vaccinated through 26 years of age.

Figure 1 Cases of CIN 2,3 eventually plateau in vaccinated women

The graph charts the efficacy of the quadrivalent HPV vaccine in preventing CIN 2,3 in the intention-to-treat population of a phase-3 efficacy trial.
SOURCE: Garland et al. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Bivalent vaccine was 90.4% effective against CIN 2,3

Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369:2161–2170.

This interim analysis of a phase-3 double-blind, placebo-controlled trial of the bivalent HPV vaccine (Cervarix), which targets HPV types 16 and 18, also was published last year. It enrolled more than 18,000 women 15 to 25 years old who had a mean length of follow-up of 15 months. The vaccine was 90.4% effective against CIN 2,3 associated with the targeted strains (types 16 and 18), the primary endpoint of the trial (TABLE). There was no significant difference in safety outcome between vaccine and placebo recipients.

This trial is ongoing, with final results expected in approximately 2 years. Based on interim findings, the vaccine has been approved for use in a number of countries, including all 27 European Union nations, and the manufacturer of the vaccine has filed an application for approval with the US Food and Drug Administration (FDA).

Screening is more effective when HPV testing is included—or used alone

Bulkmans NW, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007;370:1764–1772.

Naucler P, Ryd W, Törnberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med. 2007;357:1589–1597.

Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357:1579–1588.

These major studies compared cytology alone with HPV DNA testing for high-risk strains (16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 68) and found HPV testing—with or without cytology—to be superior to cytology alone.

In a trial from the Netherlands, Bulkmans and colleagues randomly assigned more than 17,000 women 29 years and older to cytologic screening only or a combination of cytology and HPV DNA testing. After 5 years of follow-up, all women were rescreened using both tests. The baseline screen including a combination of cytology and HPV DNA testing identified 70% more CIN 3 lesions and cancers than did cytology alone. More important, during the subsequent round of screening, CIN 3 lesions and cancers decreased by 55% in the group initially screened with both tests.

Naucler and associates had similar results in a prospective Swedish trial that randomized women to screening by cytology alone or a combination of cytology and HPV DNA testing. During the initial round of screening, 31% more CIN 3 lesions and cancers were detected in the group screened with both tests (FIGURE 2). In subsequent rounds of screening, 47% fewer CIN 3 lesions or cancers were identified in this group.

Figure 2 Screening protocol that includes HPV DNA testing is superior, large trial confirmsTaken together, these two prospective studies clearly demonstrate that the addition of HPV DNA testing to cytology increases detection of high-grade lesions and reduces the incidence of high-grade neoplasia and cancers detected subsequently.

HPV testing is more sensitive, only slightly less specific, than cytology

In a cross-sectional study from Canada, Mayrand and colleagues compared HPV DNA testing and cytology during a single round of screening in more than 10,000 women. The findings were consistent with those of previous studies showing HPV DNA testing to be significantly more sensitive but somewhat less specific than cytology.³

The sensitivity of HPV testing for CIN 2,3 was 95% (95% confidence interval [CI], 84–100), compared with 55% (95% CI, 34–77) for cytology. Specificity of HPV DNA testing and cytology was 94% and 97%, respectively. When the two tests were used together, sensitivity was 100% and specificity was 93%.

New consensus guidelines clarify screening in special populations

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197:346–355.

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol. 2007;197:340–345.

The 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests clarify management of special populations such as adolescents, postmenopausal women, and patients with cervical adenocarcinoma in situ. Although the 2001 guidelines were widely adopted in the United States as the standard for managing women with abnormal screening tests—more than 500,000 copies were downloaded from Web site of the American Society for Colposcopy and Cervical Pathology (ASCCP)⁴—it became apparent after their implementation in a variety of clinical settings that some clarification of the guidelines was needed.

In adolescents, treat abnormalities conservatively

A major theme of the 2006 guidelines is a more conservative approach to adolescent patients (ages 13 to 20 years). Although this population has a very low risk of developing invasive cervical cancer, women 15 to 19 years of age are very likely to be diagnosed with minor cytologic abnormalities such as atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL), owing to the very high prevalence of anogenital HPV infection in this age group.

Because most anogenital HPV infections will spontaneously clear, minor cytologic abnormalities are usually of little consequence in adolescents.

Therefore, the 2006 consensus guidelines discourage the use of colposcopy in adolescents who have ASC-US and LSIL. Instead, these patients should be followed with annual repeat cytology and referred to colposcopy only when a high-grade cytologic abnormality is identified or when a low-grade cytologic abnormality persists for 24 months.

HPV testing most informative in older women

The new guidelines expand the clinical indications for HPV DNA testing and provide recommendations for managing different combinations of cytology and HPV test results when screening women 30 years and older. For example, they emphasize the use of HPV DNA testing in postmenopausal women because recent studies clearly demonstrate that the prevalence of high-risk HPV DNA positivity is lower in postmenopausal women with ASC-US or LSIL than in younger women.

Use only FDA-approved HPV tests

With the expanded indications for HPV DNA testing, the new guidelines take pains to point out that HPV test methods that have not been approved by the FDA may not produce findings consistent with approved methods. This is a very important point because many laboratories have started using unapproved testing methods. Although these methods have been validated internally by the laboratories, they have not been through the rigorous evaluation required for FDA approval. The new guidelines therefore state: “Appropriate use of these guidelines requires that laboratories utilize only HPV tests that have been analytically and clinically validated with proven acceptable reproducibility, clinical sensitivity, specificity, and positive and negative predictive values for cervical cancer and verified precancer (CIN 2,3), as documented by FDA approval and/or publication in peer-reviewed scientific literature.”

The guidelines are accessible online at the ASCCP Web site at www.asccp.org/consensus/cytological.shtml.

CASE Smoker who uses OCs

Ann G. is a 34-year-old mother of two who has been coming to the office for her annual Pap smear for several years. Her medical history is significant only for her vaginal deliveries and mild gastroesophageal reflux. She takes oral contraceptives (OCs) and uses over-the-counter ranitidine hydrochloride (Zantac) as needed. On Ann’s most recent annual visit, the medical assistant, Tammy, takes her vital signs. The chart has a section about smoking status, and Tammy notes that Ann is a smoker.

During the office visit, the ObGyn explains to Ann that her smoking is a serious health risk and advises her to quit. She also informs Ann that she needs to find a new form of birth control next year, as smoking increases the risks of using OCs, especially after age 35. Ann nervously laughs off the warning.

When she returns the following year, Ann confesses to Tammy that she is still a smoker. When Tammy asks about quitting, Ann remains adamant: “No way—I can’t do it.” Nonetheless, during the office visit, the ObGyn raises the subject again, and Ann admits that she is afraid that quitting smoking will cause her to gain weight. The physician attempts to address Ann’s fears, talks about other birth control options, and gives her a 3-month prescription for OCs. Before ending the visit, the ObGyn tells Ann that they will discuss what to do about birth control when she returns in 3 months.

Ann faces an uphill battle. The amount of nicotine in cigarettes is increasing,¹ making it harder to quit. The good news is that the treatment of tobacco addiction is constantly improving, and the number of tools in our arsenal is growing. In fact, there are many resources that we can try before turning to the prescription pad. However, when needed, pharmacotherapy is an important adjunct in a patient’s struggle to achieve abstinence.

“5-A” strategy sets stage for success

Treating Tobacco Use and Dependence, a useful publication from the Agency for Healthcare Research and Quality (AHRQ), offers guidelines on many aspects of tobacco cessation, from counseling to pharmacotherapy to reimbursement.^2,3 The guidelines break the smoking cessation process into five A’s:

1. Ask each patient about her smoking status.
   
2. Advise each patient who smokes that she needs to stop smoking.
   
3. Assess your patient’s willingness to make a quit attempt in the next 30 days.
   
4. Assist your patient in making this quit attempt or encourage her to consider a quit attempt later.
   
5. Arrange close follow-up of any quit attempts to help prevent relapse.
   

Take advantage of every opportunity you have to discuss the issue with patients; short conversations can make a difference. A Cochrane review of 39 trials including 31,000 smokers revealed that even brief advice—simply encouraging patients to quit—was statistically significant in helping the smoker quit (odds ratio [OR]=1.74; 95% confidence interval [CI], 1.48–2.05).⁵ The pooled data generated a quit rate difference of 2.5%: for every 40 people who were told to quit, one more smoker would.

Empower the office staff

Enlisting the help of the office staff can have a significant impact on the health of patients. Fiore and colleagues evaluated a proactive approach in which medical assistants, while assessing smoking status, invited all smokers to participate in a cessation study.⁶ (The assistants received periodic thank-you gifts for their efforts.)

Participants were randomized to self-selected treatment or nicotine replacement therapy (NRT) patches, with or without a support program. Some who received the patches and support program also received individual counseling. The result: Most smokers were open to encouragement to quit smoking. The 13% point-prevalence abstinence rate 1 year out was comparable to the rate observed (14%) in smokers volunteering for NRT studies in the Cochrane review of 39 trials noted earlier.⁵

Likewise, in a randomized controlled trial (RCT) involving community-based primary care clinics, Katz and associates demonstrated that intake clinicians can also play an important role in smoking cessation.⁷ In the study, researchers trained intake clinicians (including registered nurses, licensed practical nurses, and medical assistants) to identify smokers, provide brief counseling, and assist in their preparation to quit. Patients were offered vouchers for patches and a counselor’s business card. Intake clinicians received periodic feedback on their performance based on exit interviews of the patients. These interventions had a statistically significant effect in moderate-to-heavy smokers in quit attempts, quit rates, and continuous abstinence.

CASE…continued A change of heart

At the 3-month follow-up, Tammy learns that Ann is still smoking—but she now wants to quit. Ann says that she found a pack of cigarettes in her 14-year-old daughter’s backpack, and feels that the only way to prevent her from getting hooked is to set a good example.

Tammy gives her the state’s quitline number, suggests some online quitting programs, and works with Ann to choose her target quit date and to pick the Web-based program she is going to use. Ann likes the fact that she can go online whenever she needs support. She also likes being able to put her quit date into the system so that the program will give her timely reminders of all her reasons to quit when she logs on.

The ObGyn writes prescriptions for varenicline (Chantix) and OCs and tells Ann to come back in 4 weeks. For her part, Tammy adds Ann to the list of patients she calls and will get in touch the day after Ann’s quit date. Tammy makes this her practice with patients because she knows that one well-timed phone call can be the key to a successful quit attempt.

Outside support improves abstinence rates

Improving your patients’ chances of long-term abstinence hinges, in part, on making the most of outside support. In many cases, your patients can take advantage of it without leaving their homes.

Quitlines increase quit rates, reduce relapse

Telephone counseling is an effective support system.⁸ Smokers who call to a single number (800-QUITNOW)—a service provided by the National Cancer Institute (NCI)—are directed to the quitline for their state. Smokers can also call the NCI directly at its quitline (877-44U-QUIT). Calling a quitline provides smokers with real-time counseling and information about how to quit smoking. Quitlines can be appealing to patients who are uncomfortable discussing their smoking in a group—and they are free to the patient.

Evidence supports the use of such help lines. In their study of the California Smokers’ Helpline, Zhu and colleagues tested a proactive protocol where smokers were funneled into a research trial when the help line was overwhelmed.⁹

The smokers in the treatment arm of this RCT were assigned a counselor who called the smokers as many as six times, following a relapse-sensitive schedule. The 12-month abstinence rate increased from 4.1% to 7.5% (P<.001 in the group that had close telephone contact. this improved quit rate reflects both an increase percentage of smokers who and more importantly a decrease quitters relapsed.>

Another prospective RCT enrolled patients from Veterans Affairs (VA) medical centers and involved the same proactive telephone protocol that Zhu and associates used.¹⁰ The treatment group was offered telephone counseling as well as pharmacotherapy; the control group had access to the regular smoking-cessation program of the VA system. Quit rates were similar in both groups if the participant utilized both counseling and pharmacotherapy: 12.7% in the control group and 11.9% in the treatment group. However, only 18% of patients in the control group used both services. Among patients in the treatment group, 88% utilized both counseling and medication. This led to 6-month abstinence rates of 13% in the treatment group versus 4.1% in the control group (OR=3.5; 95% CI, 1.99–6.15). Patients who were directed to and enrolled in treatment programs were therefore more likely to attempt to quit and remain abstinent for up to 6 months.

Web-based programs offer reminders

Like quitlines, Web-based programs offer smokers immediate feedback to help them quit. Many of the programs include links to quitting resources, stories from former smokers and cancer patients, live advice from counselors, and message boards (TABLE 1). Web-based programs have been shown to help improve quit rates.

One study compared two Web programs involving 11,969 smokers.¹¹ This RCT looked at an interactive program based, in part, on the AHRQ treatment guidelines. This program generates personalized letters for the participants along with monthly e-mail reminders. A modified program, developed by a maker of NRT products, served as the control; it contained more information about nicotine than about tobacco dependence and cessation. This program was also shorter than the interactive program, which was designed to assist smoking cessation.

Both programs improved quit rates: 10.9% for the interactive program and 8% for the modified/control program, compared with 3.3% for no treatment at all. Although this study was based on participant reports of abstinence over the previous 7 days, and had low followup rates (which Internet studies tend to have), the interactive program produced one more quitter for every 26 participants than the modified (control) program did, according to an intent-to-treat analysis (14.6% vs 10.7%, P<.001 or="1.43;" ci>

Another RCT looked at the use of a more extensive Web site, combining video, audio, and text.¹² This program was fully automated and delivered entirely by computer. Again, using the AHRQ guidelines and other sources, researchers designed a series of five modules to simulate work with a live counselor. There were 13 different versions to match the demographics of the participant. The modules ended with a “quit calendar” for use by the participant to pick a date within the next 30 days. The program included 20 hours of video, although no participant saw every section. The intent-to-treat analysis showed a significant difference between groups: 12.3% in the treatment group versus 5% in the control group (OR=2.66; 95% CI, 1.18–5.99).

TABLE 1

Web-based support helps smokers quit

Text messages work

A short but interesting study used text messaging to target younger smokers in New Zealand.¹³ This RCT involved 1,705 smokers who had cell phones with text messaging. Researchers sent participants up to five messages daily around their quit date, drawing from over 100 messages that could be personalized with individual names/nicknames. The quit rate doubled 6 weeks out (28% vs 13%; relative risk=2.2; 95% CI, 1.79–2.70).

CASE…continued Support in place

Ann leaves the office with her prescription for varenicline and OCs, the state’s quitline number, and the URL for an online support program. She is eager to try varenicline: A coworker of hers is using it and doing well. Ann has tried the nicotine patch in the past, but says that it gave her nightmares. (She kept smoking while wearing it.) This time, she hopes she’ll finally be able to quit for good.

Weighing the drug treatment options

The AHRQ guidelines recommend several types of pharmacotherapy. First-line therapies include different forms of NRT and sustained-release bupropion (Zyban).^2,3

Nicotine replacement therapy doubles the chance of quitting

With NRT, the nicotine in cigarettes is replaced with nicotine from another source to reduce withdrawal symptoms so that the patient is less likely to relapse. Nicotine replacement is available in several forms: gum, transdermal patches, intra-nasal spray, inhaler, and lozenges.

A Cochrane meta-analysis of NRT analyzed 123 studies that followed patients for at least 6 months after their quit date.¹⁴ The authors concluded that NRT could almost double a patient’s chance of quitting smoking. The data from various types of NRT revealed the types to be similarly effective (TABLE 2). In the treated groups, 17% were abstinent, compared with only 10% in the control groups at the various endpoints of the trials. Smokers who had higher levels of nicotine dependence, as indicated by smoking 10 or more cigarettes daily, had higher quit rates using replacement nicotine. Generally, treatment for 8 weeks was as effective as a longer course.

The Cochrane meta-analysis also revealed that:

• Duration of therapy ranges from 3 weeks to 12 months with the various forms of NRT.
  
• There was no benefit to tapering off the NRT, compared with abrupt withdrawal.
  
• Patients are much more likely to relapse after NRT in the first 3 months.
  
• Combining several forms of NRT may aid a relapsed smoker in another quit attempt. However, the reattempt should be delayed by a few months, as back-to-back courses are unlikely to improve quit rates.
  

Nicotine replacement therapy: Methods are similarly effective¹¹

Sustained-release bupropion: Similar results to NRT

The other first-line therapy suggested by the AHRQ guidelines is sustained-release bupropion (Wellbutrin).^2,3 A separate Cochrane Review analyzed the data from 36 studies using antidepressants and revealed that two thirds of the studies used bupropion.¹⁵ The odds of quitting smoking essentially doubled in the placebo-controlled studies when the patient used bupropion. This effect is similar to that of NRT. Neither the AHRQ guidelines nor the Cochrane Review recommend bupropion over NRT, or vice versa.

According to the Cochrane Review, there was no benefit to increasing the dosage of bupropion from 150 mg to 300 mg daily.¹⁵ Although the initial multidose study of bupropion showed a difference between dosages, it was not clinically significant by the end of the study.¹⁶ A larger, open-label randomized trial of 1,524 smokers followed for 1 year had similar results.¹⁷ At the 3-month evaluation, the higher dosage had superior efficacy, but that effect was not statistically significant by the end of the study.

Lastly, there is no benefit to continuing the bupropion beyond 7 weeks after the target quit date.

With other antidepressants, results vary

The Cochrane Review also looked at other antidepressants. There were four RCTs of nortriptyline (Aventyl/Pamelor) without NRT, totaling 777 smokers followed for at least 6 months.^18-21 The pooled data essentially showed a doubling of the odds of quitting from 7% among controls to 17.2% in the treated groups (OR=2.79; 95% CI, 1.70–4.59). Adding nortriptyline to NRT did increase the quit rate, but not significantly. The dosage used in these studies (75–150 mg) is much lower than that used for depression, where significant side effects often interfere with treatment. Generally, the starting dosage for smoking cessation is 25 mg at bedtime. After 1 week, the dosage is increased to 50 mg, and the following week it is increased again to 75 mg. After a week at 75 mg, the dose is titrated upward only if necessary. The titration continues at an additional 25 mg weekly.

One of the four placebo-controlled studies included both nortriptyline and bupropion arms.²⁰ The abstinence rates, as indicated by no smoking during the final week of treatment, were comparable for the two groups that received active medication. Treatment with bupropion or nortriptyline was significantly more effective than placebo. However, the effect was lost at the 1-year continuous-abstinence mark; the two drugs did not differ from each other or placebo (TABLE 3).

Other antidepressants were evaluated in the Cochrane study.¹⁵ Long-term studies of the tricyclic antidepressants doxepin and imipramine (Tofranil) were lacking. Nor were there statistically significant differences in smaller trials. Of the selective serotonin reuptake inhibitors, only fluoxetine (Prozac) had been studied in long-term trials, and none noted statistically significant differences. Likewise, venlafaxine (Effexor) was studied in only one trial in which the confidence interval allowed for a potentially useful clinical effect, but there was no statistically significant increase in 12-month quit rates.

TABLE 3

Varenicline, nortriptyline, bupropion—strong allies in patients’ efforts to quit

Clonidine is an option, but side effects are an issue

Another Cochrane Review looked at the effectiveness of clonidine (Catapres) on smoking cessation.²² Most of the studies assessed withdrawal symptoms rather than abstinence. Of those that did assess quit rates, the pooled OR for clonidine compares favorably at 1.89 (95% CI, 1.30–2.74). Unfortunately, clonidine has significant side effects: sedation and postural hypotension. The starting dosage is 0.1 mg twice daily, and it may be titrated to a maximum dose of 0.4 mg daily. It should be used for 3 to 4 weeks only to decrease withdrawal symptoms. The smoker is then weaned off the drug.

The anxiolytics were the subject of another Cochrane Review.²³ This review, however, did not recommend any anxiolytics, including diazepam and buspirone, for smoking cessation.

A new category of therapy: Nicotinic receptor agonists

With US Food and Drug Administration (FDA) approval of varenicline in May 2006, a new class of drugs became available for tobacco dependence. This α4β2 nicotinic acetylcholine receptor partial agonist was designed as a smoking cessation drug. By releasing dopamine in the brain like nicotine, it prevents craving. However, it also blocks nicotine from binding, thereby preventing the reinforcing effect of continued smoking.

Two RCTs have assessed varenicline against both bupropion and placebo (TABLE 3). Jorenby and colleagues showed that varenicline-treated participants were significantly more likely to be continuously abstinent at 52 weeks than the placebo- or bupropion-treated groups (23% vs 10.3% placebo [OR= 2.66; 95% CI, 1.72–4.11; P<.001 and bupropion ci>P=.004]).²⁴ Gonzales and associates also showed that varenicline-treated smokers were more likely to be continuously abstinent at 52 weeks than the placebo group (21.9% vs 8.4% [OR=3.09; 95% CI, 1.95–4.91; P<.001>25

However, when compared with varenicline, bupropion’s effects were no longer statically significant at 52 weeks (21.9% vs 16.1% [OR=1.46; 95% CI, 0.99– 2.17; P=.057]).

The patient initiating varenicline begins by taking 0.5 mg nightly for 3 nights, then increases to 0.5 mg twice a day for 4 days. The second week, the patient begins the 1-mg twice-daily dosage that is continued through treatment.

Vaccines hold promise

Several promising ideas for the treatment of tobacco dependence are in development, including several vaccines.²⁶ When the immune system produces antibodies to nicotine in response to the vaccine, and when these antibodies bind to the nicotine, the resultant compound is too large to cross the blood–brain barrier. This prevents the reinforcing effect of nicotine. Initial studies of vaccines show that smokers decrease the amount they smoke and find abstinence easier to maintain. However, the vaccine requires frequent boosters to maintain effective antibody titers.

NicVAX from Nabi Biopharmaceuticals was placed on a fast track for approval by the FDA, which is still at least 1 year away. The other two nicotine vaccines are unlikely to be approved for several years.²⁷

Researchers are also studying other compounds that block the euphoria associated with smoking.²⁸ The initial studies of rimonabant (Acomplia), a cannabinoid blocker, have shown that it is no better than other treatments already available. With its indication in some European countries for weight loss, it offered promise as an important option for patients who are concerned about the weight gain associated with smoking cessation. However, the FDA did not approve rimonabant for tobacco cessation when it issued its initial approval letter for weight loss in 2006. Because of safety concerns, the manufacturer subsequently withdrew the new drug application for rimonabant in 2007.

CASE…resolved She kicks the habit

Ann begins taking varenicline the day she leaves the office, and reaches her quit date a week later.

At her 1-month follow-up, she reports that it was easy for her to stay off the cigarettes. With the varenicline, she lost the desire to smoke. The ObGyn reminds her to work on the triggers for her smoking, urging her not to light up when she makes her morning coffee or gets in the car. The physician also suggests that Ann put $4 each morning into a jar on her dresser, so she can see how much she saves now that she isn’t buying cigarettes.

At Ann’s next annual exam, she is marked in the computer as a reformed smoker. She is very proud of that label. When she is asked what she is doing with all that extra cash, she laughs: “My daughter spends it all! But not on cigarettes!”

CASE Smoker who uses OCs

Ann G. is a 34-year-old mother of two who has been coming to the office for her annual Pap smear for several years. Her medical history is significant only for her vaginal deliveries and mild gastroesophageal reflux. She takes oral contraceptives (OCs) and uses over-the-counter ranitidine hydrochloride (Zantac) as needed. On Ann’s most recent annual visit, the medical assistant, Tammy, takes her vital signs. The chart has a section about smoking status, and Tammy notes that Ann is a smoker.

During the office visit, the ObGyn explains to Ann that her smoking is a serious health risk and advises her to quit. She also informs Ann that she needs to find a new form of birth control next year, as smoking increases the risks of using OCs, especially after age 35. Ann nervously laughs off the warning.

When she returns the following year, Ann confesses to Tammy that she is still a smoker. When Tammy asks about quitting, Ann remains adamant: “No way—I can’t do it.” Nonetheless, during the office visit, the ObGyn raises the subject again, and Ann admits that she is afraid that quitting smoking will cause her to gain weight. The physician attempts to address Ann’s fears, talks about other birth control options, and gives her a 3-month prescription for OCs. Before ending the visit, the ObGyn tells Ann that they will discuss what to do about birth control when she returns in 3 months.

Ann faces an uphill battle. The amount of nicotine in cigarettes is increasing,¹ making it harder to quit. The good news is that the treatment of tobacco addiction is constantly improving, and the number of tools in our arsenal is growing. In fact, there are many resources that we can try before turning to the prescription pad. However, when needed, pharmacotherapy is an important adjunct in a patient’s struggle to achieve abstinence.

“5-A” strategy sets stage for success

Treating Tobacco Use and Dependence, a useful publication from the Agency for Healthcare Research and Quality (AHRQ), offers guidelines on many aspects of tobacco cessation, from counseling to pharmacotherapy to reimbursement.^2,3 The guidelines break the smoking cessation process into five A’s:

1. Ask each patient about her smoking status.
   
2. Advise each patient who smokes that she needs to stop smoking.
   
3. Assess your patient’s willingness to make a quit attempt in the next 30 days.
   
4. Assist your patient in making this quit attempt or encourage her to consider a quit attempt later.
   
5. Arrange close follow-up of any quit attempts to help prevent relapse.
   

Take advantage of every opportunity you have to discuss the issue with patients; short conversations can make a difference. A Cochrane review of 39 trials including 31,000 smokers revealed that even brief advice—simply encouraging patients to quit—was statistically significant in helping the smoker quit (odds ratio [OR]=1.74; 95% confidence interval [CI], 1.48–2.05).⁵ The pooled data generated a quit rate difference of 2.5%: for every 40 people who were told to quit, one more smoker would.

Empower the office staff

Enlisting the help of the office staff can have a significant impact on the health of patients. Fiore and colleagues evaluated a proactive approach in which medical assistants, while assessing smoking status, invited all smokers to participate in a cessation study.⁶ (The assistants received periodic thank-you gifts for their efforts.)

Participants were randomized to self-selected treatment or nicotine replacement therapy (NRT) patches, with or without a support program. Some who received the patches and support program also received individual counseling. The result: Most smokers were open to encouragement to quit smoking. The 13% point-prevalence abstinence rate 1 year out was comparable to the rate observed (14%) in smokers volunteering for NRT studies in the Cochrane review of 39 trials noted earlier.⁵

Likewise, in a randomized controlled trial (RCT) involving community-based primary care clinics, Katz and associates demonstrated that intake clinicians can also play an important role in smoking cessation.⁷ In the study, researchers trained intake clinicians (including registered nurses, licensed practical nurses, and medical assistants) to identify smokers, provide brief counseling, and assist in their preparation to quit. Patients were offered vouchers for patches and a counselor’s business card. Intake clinicians received periodic feedback on their performance based on exit interviews of the patients. These interventions had a statistically significant effect in moderate-to-heavy smokers in quit attempts, quit rates, and continuous abstinence.

CASE…continued A change of heart

At the 3-month follow-up, Tammy learns that Ann is still smoking—but she now wants to quit. Ann says that she found a pack of cigarettes in her 14-year-old daughter’s backpack, and feels that the only way to prevent her from getting hooked is to set a good example.

Tammy gives her the state’s quitline number, suggests some online quitting programs, and works with Ann to choose her target quit date and to pick the Web-based program she is going to use. Ann likes the fact that she can go online whenever she needs support. She also likes being able to put her quit date into the system so that the program will give her timely reminders of all her reasons to quit when she logs on.

The ObGyn writes prescriptions for varenicline (Chantix) and OCs and tells Ann to come back in 4 weeks. For her part, Tammy adds Ann to the list of patients she calls and will get in touch the day after Ann’s quit date. Tammy makes this her practice with patients because she knows that one well-timed phone call can be the key to a successful quit attempt.

Outside support improves abstinence rates

Improving your patients’ chances of long-term abstinence hinges, in part, on making the most of outside support. In many cases, your patients can take advantage of it without leaving their homes.

Quitlines increase quit rates, reduce relapse

Telephone counseling is an effective support system.⁸ Smokers who call to a single number (800-QUITNOW)—a service provided by the National Cancer Institute (NCI)—are directed to the quitline for their state. Smokers can also call the NCI directly at its quitline (877-44U-QUIT). Calling a quitline provides smokers with real-time counseling and information about how to quit smoking. Quitlines can be appealing to patients who are uncomfortable discussing their smoking in a group—and they are free to the patient.

Evidence supports the use of such help lines. In their study of the California Smokers’ Helpline, Zhu and colleagues tested a proactive protocol where smokers were funneled into a research trial when the help line was overwhelmed.⁹

The smokers in the treatment arm of this RCT were assigned a counselor who called the smokers as many as six times, following a relapse-sensitive schedule. The 12-month abstinence rate increased from 4.1% to 7.5% (P<.001 in the group that had close telephone contact. this improved quit rate reflects both an increase percentage of smokers who and more importantly a decrease quitters relapsed.>

Another prospective RCT enrolled patients from Veterans Affairs (VA) medical centers and involved the same proactive telephone protocol that Zhu and associates used.¹⁰ The treatment group was offered telephone counseling as well as pharmacotherapy; the control group had access to the regular smoking-cessation program of the VA system. Quit rates were similar in both groups if the participant utilized both counseling and pharmacotherapy: 12.7% in the control group and 11.9% in the treatment group. However, only 18% of patients in the control group used both services. Among patients in the treatment group, 88% utilized both counseling and medication. This led to 6-month abstinence rates of 13% in the treatment group versus 4.1% in the control group (OR=3.5; 95% CI, 1.99–6.15). Patients who were directed to and enrolled in treatment programs were therefore more likely to attempt to quit and remain abstinent for up to 6 months.

Web-based programs offer reminders

Like quitlines, Web-based programs offer smokers immediate feedback to help them quit. Many of the programs include links to quitting resources, stories from former smokers and cancer patients, live advice from counselors, and message boards (TABLE 1). Web-based programs have been shown to help improve quit rates.

One study compared two Web programs involving 11,969 smokers.¹¹ This RCT looked at an interactive program based, in part, on the AHRQ treatment guidelines. This program generates personalized letters for the participants along with monthly e-mail reminders. A modified program, developed by a maker of NRT products, served as the control; it contained more information about nicotine than about tobacco dependence and cessation. This program was also shorter than the interactive program, which was designed to assist smoking cessation.

Both programs improved quit rates: 10.9% for the interactive program and 8% for the modified/control program, compared with 3.3% for no treatment at all. Although this study was based on participant reports of abstinence over the previous 7 days, and had low followup rates (which Internet studies tend to have), the interactive program produced one more quitter for every 26 participants than the modified (control) program did, according to an intent-to-treat analysis (14.6% vs 10.7%, P<.001 or="1.43;" ci>

Another RCT looked at the use of a more extensive Web site, combining video, audio, and text.¹² This program was fully automated and delivered entirely by computer. Again, using the AHRQ guidelines and other sources, researchers designed a series of five modules to simulate work with a live counselor. There were 13 different versions to match the demographics of the participant. The modules ended with a “quit calendar” for use by the participant to pick a date within the next 30 days. The program included 20 hours of video, although no participant saw every section. The intent-to-treat analysis showed a significant difference between groups: 12.3% in the treatment group versus 5% in the control group (OR=2.66; 95% CI, 1.18–5.99).

TABLE 1

Web-based support helps smokers quit

Text messages work

A short but interesting study used text messaging to target younger smokers in New Zealand.¹³ This RCT involved 1,705 smokers who had cell phones with text messaging. Researchers sent participants up to five messages daily around their quit date, drawing from over 100 messages that could be personalized with individual names/nicknames. The quit rate doubled 6 weeks out (28% vs 13%; relative risk=2.2; 95% CI, 1.79–2.70).

CASE…continued Support in place

Ann leaves the office with her prescription for varenicline and OCs, the state’s quitline number, and the URL for an online support program. She is eager to try varenicline: A coworker of hers is using it and doing well. Ann has tried the nicotine patch in the past, but says that it gave her nightmares. (She kept smoking while wearing it.) This time, she hopes she’ll finally be able to quit for good.

Weighing the drug treatment options

The AHRQ guidelines recommend several types of pharmacotherapy. First-line therapies include different forms of NRT and sustained-release bupropion (Zyban).^2,3

Nicotine replacement therapy doubles the chance of quitting

With NRT, the nicotine in cigarettes is replaced with nicotine from another source to reduce withdrawal symptoms so that the patient is less likely to relapse. Nicotine replacement is available in several forms: gum, transdermal patches, intra-nasal spray, inhaler, and lozenges.

A Cochrane meta-analysis of NRT analyzed 123 studies that followed patients for at least 6 months after their quit date.¹⁴ The authors concluded that NRT could almost double a patient’s chance of quitting smoking. The data from various types of NRT revealed the types to be similarly effective (TABLE 2). In the treated groups, 17% were abstinent, compared with only 10% in the control groups at the various endpoints of the trials. Smokers who had higher levels of nicotine dependence, as indicated by smoking 10 or more cigarettes daily, had higher quit rates using replacement nicotine. Generally, treatment for 8 weeks was as effective as a longer course.

The Cochrane meta-analysis also revealed that:

• Duration of therapy ranges from 3 weeks to 12 months with the various forms of NRT.
  
• There was no benefit to tapering off the NRT, compared with abrupt withdrawal.
  
• Patients are much more likely to relapse after NRT in the first 3 months.
  
• Combining several forms of NRT may aid a relapsed smoker in another quit attempt. However, the reattempt should be delayed by a few months, as back-to-back courses are unlikely to improve quit rates.
  

Nicotine replacement therapy: Methods are similarly effective¹¹

Sustained-release bupropion: Similar results to NRT

The other first-line therapy suggested by the AHRQ guidelines is sustained-release bupropion (Wellbutrin).^2,3 A separate Cochrane Review analyzed the data from 36 studies using antidepressants and revealed that two thirds of the studies used bupropion.¹⁵ The odds of quitting smoking essentially doubled in the placebo-controlled studies when the patient used bupropion. This effect is similar to that of NRT. Neither the AHRQ guidelines nor the Cochrane Review recommend bupropion over NRT, or vice versa.

According to the Cochrane Review, there was no benefit to increasing the dosage of bupropion from 150 mg to 300 mg daily.¹⁵ Although the initial multidose study of bupropion showed a difference between dosages, it was not clinically significant by the end of the study.¹⁶ A larger, open-label randomized trial of 1,524 smokers followed for 1 year had similar results.¹⁷ At the 3-month evaluation, the higher dosage had superior efficacy, but that effect was not statistically significant by the end of the study.

Lastly, there is no benefit to continuing the bupropion beyond 7 weeks after the target quit date.

With other antidepressants, results vary

The Cochrane Review also looked at other antidepressants. There were four RCTs of nortriptyline (Aventyl/Pamelor) without NRT, totaling 777 smokers followed for at least 6 months.^18-21 The pooled data essentially showed a doubling of the odds of quitting from 7% among controls to 17.2% in the treated groups (OR=2.79; 95% CI, 1.70–4.59). Adding nortriptyline to NRT did increase the quit rate, but not significantly. The dosage used in these studies (75–150 mg) is much lower than that used for depression, where significant side effects often interfere with treatment. Generally, the starting dosage for smoking cessation is 25 mg at bedtime. After 1 week, the dosage is increased to 50 mg, and the following week it is increased again to 75 mg. After a week at 75 mg, the dose is titrated upward only if necessary. The titration continues at an additional 25 mg weekly.

One of the four placebo-controlled studies included both nortriptyline and bupropion arms.²⁰ The abstinence rates, as indicated by no smoking during the final week of treatment, were comparable for the two groups that received active medication. Treatment with bupropion or nortriptyline was significantly more effective than placebo. However, the effect was lost at the 1-year continuous-abstinence mark; the two drugs did not differ from each other or placebo (TABLE 3).

Other antidepressants were evaluated in the Cochrane study.¹⁵ Long-term studies of the tricyclic antidepressants doxepin and imipramine (Tofranil) were lacking. Nor were there statistically significant differences in smaller trials. Of the selective serotonin reuptake inhibitors, only fluoxetine (Prozac) had been studied in long-term trials, and none noted statistically significant differences. Likewise, venlafaxine (Effexor) was studied in only one trial in which the confidence interval allowed for a potentially useful clinical effect, but there was no statistically significant increase in 12-month quit rates.

TABLE 3

Varenicline, nortriptyline, bupropion—strong allies in patients’ efforts to quit

Clonidine is an option, but side effects are an issue

Another Cochrane Review looked at the effectiveness of clonidine (Catapres) on smoking cessation.²² Most of the studies assessed withdrawal symptoms rather than abstinence. Of those that did assess quit rates, the pooled OR for clonidine compares favorably at 1.89 (95% CI, 1.30–2.74). Unfortunately, clonidine has significant side effects: sedation and postural hypotension. The starting dosage is 0.1 mg twice daily, and it may be titrated to a maximum dose of 0.4 mg daily. It should be used for 3 to 4 weeks only to decrease withdrawal symptoms. The smoker is then weaned off the drug.

The anxiolytics were the subject of another Cochrane Review.²³ This review, however, did not recommend any anxiolytics, including diazepam and buspirone, for smoking cessation.

A new category of therapy: Nicotinic receptor agonists

With US Food and Drug Administration (FDA) approval of varenicline in May 2006, a new class of drugs became available for tobacco dependence. This α4β2 nicotinic acetylcholine receptor partial agonist was designed as a smoking cessation drug. By releasing dopamine in the brain like nicotine, it prevents craving. However, it also blocks nicotine from binding, thereby preventing the reinforcing effect of continued smoking.

Two RCTs have assessed varenicline against both bupropion and placebo (TABLE 3). Jorenby and colleagues showed that varenicline-treated participants were significantly more likely to be continuously abstinent at 52 weeks than the placebo- or bupropion-treated groups (23% vs 10.3% placebo [OR= 2.66; 95% CI, 1.72–4.11; P<.001 and bupropion ci>P=.004]).²⁴ Gonzales and associates also showed that varenicline-treated smokers were more likely to be continuously abstinent at 52 weeks than the placebo group (21.9% vs 8.4% [OR=3.09; 95% CI, 1.95–4.91; P<.001>25

However, when compared with varenicline, bupropion’s effects were no longer statically significant at 52 weeks (21.9% vs 16.1% [OR=1.46; 95% CI, 0.99– 2.17; P=.057]).

The patient initiating varenicline begins by taking 0.5 mg nightly for 3 nights, then increases to 0.5 mg twice a day for 4 days. The second week, the patient begins the 1-mg twice-daily dosage that is continued through treatment.

Vaccines hold promise

Several promising ideas for the treatment of tobacco dependence are in development, including several vaccines.²⁶ When the immune system produces antibodies to nicotine in response to the vaccine, and when these antibodies bind to the nicotine, the resultant compound is too large to cross the blood–brain barrier. This prevents the reinforcing effect of nicotine. Initial studies of vaccines show that smokers decrease the amount they smoke and find abstinence easier to maintain. However, the vaccine requires frequent boosters to maintain effective antibody titers.

NicVAX from Nabi Biopharmaceuticals was placed on a fast track for approval by the FDA, which is still at least 1 year away. The other two nicotine vaccines are unlikely to be approved for several years.²⁷

Researchers are also studying other compounds that block the euphoria associated with smoking.²⁸ The initial studies of rimonabant (Acomplia), a cannabinoid blocker, have shown that it is no better than other treatments already available. With its indication in some European countries for weight loss, it offered promise as an important option for patients who are concerned about the weight gain associated with smoking cessation. However, the FDA did not approve rimonabant for tobacco cessation when it issued its initial approval letter for weight loss in 2006. Because of safety concerns, the manufacturer subsequently withdrew the new drug application for rimonabant in 2007.

CASE…resolved She kicks the habit

Ann begins taking varenicline the day she leaves the office, and reaches her quit date a week later.

At her 1-month follow-up, she reports that it was easy for her to stay off the cigarettes. With the varenicline, she lost the desire to smoke. The ObGyn reminds her to work on the triggers for her smoking, urging her not to light up when she makes her morning coffee or gets in the car. The physician also suggests that Ann put $4 each morning into a jar on her dresser, so she can see how much she saves now that she isn’t buying cigarettes.

At Ann’s next annual exam, she is marked in the computer as a reformed smoker. She is very proud of that label. When she is asked what she is doing with all that extra cash, she laughs: “My daughter spends it all! But not on cigarettes!”

CASE Smoker who uses OCs

Ann G. is a 34-year-old mother of two who has been coming to the office for her annual Pap smear for several years. Her medical history is significant only for her vaginal deliveries and mild gastroesophageal reflux. She takes oral contraceptives (OCs) and uses over-the-counter ranitidine hydrochloride (Zantac) as needed. On Ann’s most recent annual visit, the medical assistant, Tammy, takes her vital signs. The chart has a section about smoking status, and Tammy notes that Ann is a smoker.

During the office visit, the ObGyn explains to Ann that her smoking is a serious health risk and advises her to quit. She also informs Ann that she needs to find a new form of birth control next year, as smoking increases the risks of using OCs, especially after age 35. Ann nervously laughs off the warning.

When she returns the following year, Ann confesses to Tammy that she is still a smoker. When Tammy asks about quitting, Ann remains adamant: “No way—I can’t do it.” Nonetheless, during the office visit, the ObGyn raises the subject again, and Ann admits that she is afraid that quitting smoking will cause her to gain weight. The physician attempts to address Ann’s fears, talks about other birth control options, and gives her a 3-month prescription for OCs. Before ending the visit, the ObGyn tells Ann that they will discuss what to do about birth control when she returns in 3 months.

Ann faces an uphill battle. The amount of nicotine in cigarettes is increasing,¹ making it harder to quit. The good news is that the treatment of tobacco addiction is constantly improving, and the number of tools in our arsenal is growing. In fact, there are many resources that we can try before turning to the prescription pad. However, when needed, pharmacotherapy is an important adjunct in a patient’s struggle to achieve abstinence.

“5-A” strategy sets stage for success

Treating Tobacco Use and Dependence, a useful publication from the Agency for Healthcare Research and Quality (AHRQ), offers guidelines on many aspects of tobacco cessation, from counseling to pharmacotherapy to reimbursement.^2,3 The guidelines break the smoking cessation process into five A’s:

1. Ask each patient about her smoking status.
   
2. Advise each patient who smokes that she needs to stop smoking.
   
3. Assess your patient’s willingness to make a quit attempt in the next 30 days.
   
4. Assist your patient in making this quit attempt or encourage her to consider a quit attempt later.
   
5. Arrange close follow-up of any quit attempts to help prevent relapse.
   

Take advantage of every opportunity you have to discuss the issue with patients; short conversations can make a difference. A Cochrane review of 39 trials including 31,000 smokers revealed that even brief advice—simply encouraging patients to quit—was statistically significant in helping the smoker quit (odds ratio [OR]=1.74; 95% confidence interval [CI], 1.48–2.05).⁵ The pooled data generated a quit rate difference of 2.5%: for every 40 people who were told to quit, one more smoker would.

Empower the office staff

Enlisting the help of the office staff can have a significant impact on the health of patients. Fiore and colleagues evaluated a proactive approach in which medical assistants, while assessing smoking status, invited all smokers to participate in a cessation study.⁶ (The assistants received periodic thank-you gifts for their efforts.)

Participants were randomized to self-selected treatment or nicotine replacement therapy (NRT) patches, with or without a support program. Some who received the patches and support program also received individual counseling. The result: Most smokers were open to encouragement to quit smoking. The 13% point-prevalence abstinence rate 1 year out was comparable to the rate observed (14%) in smokers volunteering for NRT studies in the Cochrane review of 39 trials noted earlier.⁵

Likewise, in a randomized controlled trial (RCT) involving community-based primary care clinics, Katz and associates demonstrated that intake clinicians can also play an important role in smoking cessation.⁷ In the study, researchers trained intake clinicians (including registered nurses, licensed practical nurses, and medical assistants) to identify smokers, provide brief counseling, and assist in their preparation to quit. Patients were offered vouchers for patches and a counselor’s business card. Intake clinicians received periodic feedback on their performance based on exit interviews of the patients. These interventions had a statistically significant effect in moderate-to-heavy smokers in quit attempts, quit rates, and continuous abstinence.

CASE…continued A change of heart

At the 3-month follow-up, Tammy learns that Ann is still smoking—but she now wants to quit. Ann says that she found a pack of cigarettes in her 14-year-old daughter’s backpack, and feels that the only way to prevent her from getting hooked is to set a good example.

Tammy gives her the state’s quitline number, suggests some online quitting programs, and works with Ann to choose her target quit date and to pick the Web-based program she is going to use. Ann likes the fact that she can go online whenever she needs support. She also likes being able to put her quit date into the system so that the program will give her timely reminders of all her reasons to quit when she logs on.

The ObGyn writes prescriptions for varenicline (Chantix) and OCs and tells Ann to come back in 4 weeks. For her part, Tammy adds Ann to the list of patients she calls and will get in touch the day after Ann’s quit date. Tammy makes this her practice with patients because she knows that one well-timed phone call can be the key to a successful quit attempt.

Outside support improves abstinence rates

Improving your patients’ chances of long-term abstinence hinges, in part, on making the most of outside support. In many cases, your patients can take advantage of it without leaving their homes.

Quitlines increase quit rates, reduce relapse

Telephone counseling is an effective support system.⁸ Smokers who call to a single number (800-QUITNOW)—a service provided by the National Cancer Institute (NCI)—are directed to the quitline for their state. Smokers can also call the NCI directly at its quitline (877-44U-QUIT). Calling a quitline provides smokers with real-time counseling and information about how to quit smoking. Quitlines can be appealing to patients who are uncomfortable discussing their smoking in a group—and they are free to the patient.

Evidence supports the use of such help lines. In their study of the California Smokers’ Helpline, Zhu and colleagues tested a proactive protocol where smokers were funneled into a research trial when the help line was overwhelmed.⁹

The smokers in the treatment arm of this RCT were assigned a counselor who called the smokers as many as six times, following a relapse-sensitive schedule. The 12-month abstinence rate increased from 4.1% to 7.5% (P<.001 in the group that had close telephone contact. this improved quit rate reflects both an increase percentage of smokers who and more importantly a decrease quitters relapsed.>

Another prospective RCT enrolled patients from Veterans Affairs (VA) medical centers and involved the same proactive telephone protocol that Zhu and associates used.¹⁰ The treatment group was offered telephone counseling as well as pharmacotherapy; the control group had access to the regular smoking-cessation program of the VA system. Quit rates were similar in both groups if the participant utilized both counseling and pharmacotherapy: 12.7% in the control group and 11.9% in the treatment group. However, only 18% of patients in the control group used both services. Among patients in the treatment group, 88% utilized both counseling and medication. This led to 6-month abstinence rates of 13% in the treatment group versus 4.1% in the control group (OR=3.5; 95% CI, 1.99–6.15). Patients who were directed to and enrolled in treatment programs were therefore more likely to attempt to quit and remain abstinent for up to 6 months.

Web-based programs offer reminders

Like quitlines, Web-based programs offer smokers immediate feedback to help them quit. Many of the programs include links to quitting resources, stories from former smokers and cancer patients, live advice from counselors, and message boards (TABLE 1). Web-based programs have been shown to help improve quit rates.

One study compared two Web programs involving 11,969 smokers.¹¹ This RCT looked at an interactive program based, in part, on the AHRQ treatment guidelines. This program generates personalized letters for the participants along with monthly e-mail reminders. A modified program, developed by a maker of NRT products, served as the control; it contained more information about nicotine than about tobacco dependence and cessation. This program was also shorter than the interactive program, which was designed to assist smoking cessation.

Both programs improved quit rates: 10.9% for the interactive program and 8% for the modified/control program, compared with 3.3% for no treatment at all. Although this study was based on participant reports of abstinence over the previous 7 days, and had low followup rates (which Internet studies tend to have), the interactive program produced one more quitter for every 26 participants than the modified (control) program did, according to an intent-to-treat analysis (14.6% vs 10.7%, P<.001 or="1.43;" ci>

Another RCT looked at the use of a more extensive Web site, combining video, audio, and text.¹² This program was fully automated and delivered entirely by computer. Again, using the AHRQ guidelines and other sources, researchers designed a series of five modules to simulate work with a live counselor. There were 13 different versions to match the demographics of the participant. The modules ended with a “quit calendar” for use by the participant to pick a date within the next 30 days. The program included 20 hours of video, although no participant saw every section. The intent-to-treat analysis showed a significant difference between groups: 12.3% in the treatment group versus 5% in the control group (OR=2.66; 95% CI, 1.18–5.99).

TABLE 1

Web-based support helps smokers quit

Text messages work

A short but interesting study used text messaging to target younger smokers in New Zealand.¹³ This RCT involved 1,705 smokers who had cell phones with text messaging. Researchers sent participants up to five messages daily around their quit date, drawing from over 100 messages that could be personalized with individual names/nicknames. The quit rate doubled 6 weeks out (28% vs 13%; relative risk=2.2; 95% CI, 1.79–2.70).

CASE…continued Support in place

Ann leaves the office with her prescription for varenicline and OCs, the state’s quitline number, and the URL for an online support program. She is eager to try varenicline: A coworker of hers is using it and doing well. Ann has tried the nicotine patch in the past, but says that it gave her nightmares. (She kept smoking while wearing it.) This time, she hopes she’ll finally be able to quit for good.

Weighing the drug treatment options

The AHRQ guidelines recommend several types of pharmacotherapy. First-line therapies include different forms of NRT and sustained-release bupropion (Zyban).^2,3

Nicotine replacement therapy doubles the chance of quitting

With NRT, the nicotine in cigarettes is replaced with nicotine from another source to reduce withdrawal symptoms so that the patient is less likely to relapse. Nicotine replacement is available in several forms: gum, transdermal patches, intra-nasal spray, inhaler, and lozenges.

A Cochrane meta-analysis of NRT analyzed 123 studies that followed patients for at least 6 months after their quit date.¹⁴ The authors concluded that NRT could almost double a patient’s chance of quitting smoking. The data from various types of NRT revealed the types to be similarly effective (TABLE 2). In the treated groups, 17% were abstinent, compared with only 10% in the control groups at the various endpoints of the trials. Smokers who had higher levels of nicotine dependence, as indicated by smoking 10 or more cigarettes daily, had higher quit rates using replacement nicotine. Generally, treatment for 8 weeks was as effective as a longer course.

The Cochrane meta-analysis also revealed that:

• Duration of therapy ranges from 3 weeks to 12 months with the various forms of NRT.
  
• There was no benefit to tapering off the NRT, compared with abrupt withdrawal.
  
• Patients are much more likely to relapse after NRT in the first 3 months.
  
• Combining several forms of NRT may aid a relapsed smoker in another quit attempt. However, the reattempt should be delayed by a few months, as back-to-back courses are unlikely to improve quit rates.
  

Nicotine replacement therapy: Methods are similarly effective¹¹

Sustained-release bupropion: Similar results to NRT

The other first-line therapy suggested by the AHRQ guidelines is sustained-release bupropion (Wellbutrin).^2,3 A separate Cochrane Review analyzed the data from 36 studies using antidepressants and revealed that two thirds of the studies used bupropion.¹⁵ The odds of quitting smoking essentially doubled in the placebo-controlled studies when the patient used bupropion. This effect is similar to that of NRT. Neither the AHRQ guidelines nor the Cochrane Review recommend bupropion over NRT, or vice versa.

According to the Cochrane Review, there was no benefit to increasing the dosage of bupropion from 150 mg to 300 mg daily.¹⁵ Although the initial multidose study of bupropion showed a difference between dosages, it was not clinically significant by the end of the study.¹⁶ A larger, open-label randomized trial of 1,524 smokers followed for 1 year had similar results.¹⁷ At the 3-month evaluation, the higher dosage had superior efficacy, but that effect was not statistically significant by the end of the study.

Lastly, there is no benefit to continuing the bupropion beyond 7 weeks after the target quit date.

With other antidepressants, results vary

The Cochrane Review also looked at other antidepressants. There were four RCTs of nortriptyline (Aventyl/Pamelor) without NRT, totaling 777 smokers followed for at least 6 months.^18-21 The pooled data essentially showed a doubling of the odds of quitting from 7% among controls to 17.2% in the treated groups (OR=2.79; 95% CI, 1.70–4.59). Adding nortriptyline to NRT did increase the quit rate, but not significantly. The dosage used in these studies (75–150 mg) is much lower than that used for depression, where significant side effects often interfere with treatment. Generally, the starting dosage for smoking cessation is 25 mg at bedtime. After 1 week, the dosage is increased to 50 mg, and the following week it is increased again to 75 mg. After a week at 75 mg, the dose is titrated upward only if necessary. The titration continues at an additional 25 mg weekly.

One of the four placebo-controlled studies included both nortriptyline and bupropion arms.²⁰ The abstinence rates, as indicated by no smoking during the final week of treatment, were comparable for the two groups that received active medication. Treatment with bupropion or nortriptyline was significantly more effective than placebo. However, the effect was lost at the 1-year continuous-abstinence mark; the two drugs did not differ from each other or placebo (TABLE 3).

Other antidepressants were evaluated in the Cochrane study.¹⁵ Long-term studies of the tricyclic antidepressants doxepin and imipramine (Tofranil) were lacking. Nor were there statistically significant differences in smaller trials. Of the selective serotonin reuptake inhibitors, only fluoxetine (Prozac) had been studied in long-term trials, and none noted statistically significant differences. Likewise, venlafaxine (Effexor) was studied in only one trial in which the confidence interval allowed for a potentially useful clinical effect, but there was no statistically significant increase in 12-month quit rates.

TABLE 3

Varenicline, nortriptyline, bupropion—strong allies in patients’ efforts to quit

Clonidine is an option, but side effects are an issue

Another Cochrane Review looked at the effectiveness of clonidine (Catapres) on smoking cessation.²² Most of the studies assessed withdrawal symptoms rather than abstinence. Of those that did assess quit rates, the pooled OR for clonidine compares favorably at 1.89 (95% CI, 1.30–2.74). Unfortunately, clonidine has significant side effects: sedation and postural hypotension. The starting dosage is 0.1 mg twice daily, and it may be titrated to a maximum dose of 0.4 mg daily. It should be used for 3 to 4 weeks only to decrease withdrawal symptoms. The smoker is then weaned off the drug.

The anxiolytics were the subject of another Cochrane Review.²³ This review, however, did not recommend any anxiolytics, including diazepam and buspirone, for smoking cessation.

A new category of therapy: Nicotinic receptor agonists

With US Food and Drug Administration (FDA) approval of varenicline in May 2006, a new class of drugs became available for tobacco dependence. This α4β2 nicotinic acetylcholine receptor partial agonist was designed as a smoking cessation drug. By releasing dopamine in the brain like nicotine, it prevents craving. However, it also blocks nicotine from binding, thereby preventing the reinforcing effect of continued smoking.

Two RCTs have assessed varenicline against both bupropion and placebo (TABLE 3). Jorenby and colleagues showed that varenicline-treated participants were significantly more likely to be continuously abstinent at 52 weeks than the placebo- or bupropion-treated groups (23% vs 10.3% placebo [OR= 2.66; 95% CI, 1.72–4.11; P<.001 and bupropion ci>P=.004]).²⁴ Gonzales and associates also showed that varenicline-treated smokers were more likely to be continuously abstinent at 52 weeks than the placebo group (21.9% vs 8.4% [OR=3.09; 95% CI, 1.95–4.91; P<.001>25

However, when compared with varenicline, bupropion’s effects were no longer statically significant at 52 weeks (21.9% vs 16.1% [OR=1.46; 95% CI, 0.99– 2.17; P=.057]).

The patient initiating varenicline begins by taking 0.5 mg nightly for 3 nights, then increases to 0.5 mg twice a day for 4 days. The second week, the patient begins the 1-mg twice-daily dosage that is continued through treatment.

Vaccines hold promise

Several promising ideas for the treatment of tobacco dependence are in development, including several vaccines.²⁶ When the immune system produces antibodies to nicotine in response to the vaccine, and when these antibodies bind to the nicotine, the resultant compound is too large to cross the blood–brain barrier. This prevents the reinforcing effect of nicotine. Initial studies of vaccines show that smokers decrease the amount they smoke and find abstinence easier to maintain. However, the vaccine requires frequent boosters to maintain effective antibody titers.

NicVAX from Nabi Biopharmaceuticals was placed on a fast track for approval by the FDA, which is still at least 1 year away. The other two nicotine vaccines are unlikely to be approved for several years.²⁷

Researchers are also studying other compounds that block the euphoria associated with smoking.²⁸ The initial studies of rimonabant (Acomplia), a cannabinoid blocker, have shown that it is no better than other treatments already available. With its indication in some European countries for weight loss, it offered promise as an important option for patients who are concerned about the weight gain associated with smoking cessation. However, the FDA did not approve rimonabant for tobacco cessation when it issued its initial approval letter for weight loss in 2006. Because of safety concerns, the manufacturer subsequently withdrew the new drug application for rimonabant in 2007.

CASE…resolved She kicks the habit

Ann begins taking varenicline the day she leaves the office, and reaches her quit date a week later.

At her 1-month follow-up, she reports that it was easy for her to stay off the cigarettes. With the varenicline, she lost the desire to smoke. The ObGyn reminds her to work on the triggers for her smoking, urging her not to light up when she makes her morning coffee or gets in the car. The physician also suggests that Ann put $4 each morning into a jar on her dresser, so she can see how much she saves now that she isn’t buying cigarettes.

At Ann’s next annual exam, she is marked in the computer as a reformed smoker. She is very proud of that label. When she is asked what she is doing with all that extra cash, she laughs: “My daughter spends it all! But not on cigarettes!”

The field of reproductive endocrinology and infertility is anything but stagnant. New technologies continue to enter the market at a brisk pace, and a greater emphasis on evidence has produced better-designed randomized controlled trials, meta-analyses, and practice guidelines. This means greater availability of standardized protocols that reflect best practice and can be tailored to a patient’s condition and needs.

Highlighted here are notable studies and guidelines from the past year, including advice on:

• preventing peritoneal adhesions
  
• expediting in vitro fertilization (IVF) for unexplained infertility
  
• counseling the patient about the real limitations of preimplantation genetic screening for aneuploidy
  
• informing patients that oocyte cryopreservation is unlikely to lead to live birth.
  

Guideline urges good surgical technique in battle against adhesions

Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society of Re-productive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery. Fertil Steril. 2007;88:21–26.

This newly released practice guideline from the American Society of Reproductive Medicine (ASRM) focuses on adhesions and their impact on fertility. The guideline reiterates that peritoneal adhesions are a common and serious complication of gynecologic surgery and emphasizes key principles to reduce their likelihood and extent. These principles include the need to:

• Perform surgery only when the benefits of doing so clearly outweigh the risks
  
• Handle tissue gently (this is the most important preventive technique)
  
• Don’t assume laparoscopy is superior to laparotomy—it will be only if less tissue injury occurs
  
• Be especially careful when operating on or near ovaries, which form adhesions easily.
  

Ovarian surgery often necessitates additional operations

Studies have demonstrated that approximately 33% of patients who undergo open abdominal or pelvic surgery are readmitted, on average, two times over the subsequent 10 years for conditions directly or possibly related to adhesions or for further surgery that could be complicated by adhesions. The highest readmission rate directly related to adhesions—7.5 for every 100 initial operations—was associated with ovarian surgery performed via laparotomy.

Adhesion-related complications of gynecologic surgery include small-bowel obstruction, which occurs in approximately 1.5% of women who have undergone abdominal hysterectomy.

The relationship between adhesions and pelvic pain is unclear, although severe bowel adhesions can cause visceral pain. The ASRM guideline notes that “the impact that lysis of bowel or adnexal adhesions may have on abdominal and pelvic pain cannot be predicted confidently.” Postoperative adhesions increase subsequent operating times and risk of bowel injury.

How adhesions affect fertility

Adhesions may impair fertility by distorting adnexal anatomy and interfering with gamete and embryo transport. Among infertile women who have adnexal adhesions, adhesiolysis is associated with pregnancy rates of 32% at 12 months and 45% at 24 months, compared with 11% and 16%, respectively, for untreated women.¹ Pregnancy rates are inversely correlated with adhesion scores on the ASRM classification system for adnexal adhesions.²

Some, but not all, adhesion-reducing measures work

According to the ASRM guideline, adhesions may be prevented, at least theoretically, by:

• minimizing peritoneal injury during surgery
  
• avoiding the introduction of reactive foreign bodies
  
• reducing the local inflammatory response
  
• inhibiting the coagulation cascade and promoting fibrinolysis
  
• placing barriers between damaged tissues.
  

Pharmacotherapeutic and fluid agents. ASRM found no evidence of improved pregnancy outcomes for pharmacologic and fluid agents used as an adjunct during pelvic surgery. For example, anti-inflammatory agents that have been evaluated, both locally and systemically, including dexamethasone and promethazine, have not reduced postoperative adhesions. Antibiotic solutions, 32% Dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids have been used to separate adjacent peritoneal surfaces via “hydroflotation,” but none have reduced adhesion formation.

Surgical barriers may help decrease postoperative adhesion formation but cannot compensate for poor surgical technique. I rarely use adhesion barriers because I feel that careful tissue handling, excellent hemostasis, avoiding trauma to healthy tissue, and removal of all diseased tissue are the key ways to obtain good postsurgical results and reduce adhesions.

Hyaluronic acid agents may decrease the prevalence of adhesions and prevent the deterioration of preexisting adhesions, but because of the limited number of studies available, these data should be interpreted with caution.³ However, ASRM found no substantial evidence that they improve fertility, decrease pain, or reduce the incidence of postoperative bowel obstruction.

Averting adhesions: Surgical techniques and tools

By Togas Tulandi, MD, MHCM, and Mohammed Al-Sunaidi, MD It’s available in our archive at www.obgmanagement.com

A move from clomiphene directly to IVF may cut time to pregnancy

Reindollar RH, Regan MM, Neumann PJ, Thornton KL, Alper MM, Goldman MB. A randomized controlled trial of 503 couples assigned to conventional infertility treatment or an accelerated track to IVF: Preliminary results of the fast track and standard treatment (FASTT) trial. Fertil Steril. 2007;88(Suppl 1):S41.

This very important abstract, presented at the annual meeting of ASRM, has the potential to dramatically change fertility treatment. The multicenter randomized controlled clinical trial measured the efficacy and time to pregnancy of an accelerated treatment strategy for women 21 to 39 years old who had unexplained infertility. A similar percentage of patients—approximately 75%—became pregnant in each arm (traditional versus accelerated), with a shorter time to pregnancy in the accelerated arm.

The new paradigm for management of unexplained infertility includes:

• comprehensive fertility history and physical examination
  
• targeted laboratory testing and other investigation, as needed
  
• counseling and psychological support for the patient once the diagnosis is made
  
• empiric treatment with clomiphene citrate plus intrauterine insemination (IUI) for as many as three cycles
  
• immediate IVF for as many as six cycles.
  

Details of the trial

Women in the trial had attempted to conceive for 12 months and had normal ovarian reserve (and semen analysis) and no pelvic pathology. Couples already treated for infertility were excluded.

Participants were randomized to:

• a conventional treatment regimen of three cycles of clomiphene citrate with IUI, three cycles of folliclestimulating hormone (FSH) and IUI, and as many as six cycles of IVF or
  
• three cycles of clomiphene citrate with IUI and then as many as six cycles of IVF.
  

Regimen likely reduces cost, stress

Major issues affecting the eventual success rate for infertile couples are cost and psychological stress, which can cause even patients who have a good prognosis to drop out of treatment. The major complication of fertility treatment is multiple pregnancy. By avoiding the use of gonadotropins in couples with unexplained infertility and accelerating the transition to IVF, physicians can lower the cost and psychological stress of treatment. They can also reduce the likelihood of multiple pregnancy because it is easier to control the number of embryos transferred in IVF than the number of follicles that develop with gonadotropins.

In women younger than 35 years on the first IVF cycle who have a good prognosis, ASRM now recommends that only one or two day-3 embryos be transferred, and not more than one day-5 blastocyst.⁴ The multiple-birth rate has declined in recent years, as more and more IVF clinics place fewer embryos; the rate should continue to fall with wider application of elective single-embryo transfer.^5,6

Because this accelerated protocol produces a similar number of births over a shorter period and has the potential to lower cost, psychological stress, and the multiple-birth rate, it deserves implementation for many patients and warrants further evaluation for potential benefits in other populations.

It’s no help, after all: Preimplantation genetic screening for aneuploidy

Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: A Practice Committee report. Fertil Steril. 2007;88:1497–1504.

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Preimplantation genetic diagnosis of known single-gene defects, structural chromosomal rearrangements, X-linked disorders, and human leukocyte antigen typing is a major benefit to couples known to be at risk of passing on a heritable and debilitating genetic disease. Aneuploidy is the most common cause of early pregnancy loss, and its prevalence increases with maternal age and may increase in chromosomally normal couples who experience recurrent early pregnancy loss or repeated failure of IVF cycles. Preimplantation genetic screening (PGS) has been advocated to identify and transfer only euploid embryos and increase the chance of successful pregnancy.

New data from Mastenbroek and colleagues indicate that PGS for aneuploidy does not increase the rate of pregnancy or live birth. After several years of increasing utilization and studies suggesting that PGS has benefit, the first multicenter, randomized, doubleblind, controlled study that compared three cycles of IVF with and without PGS in women 35 to 41 years old concluded that PGS does not increase but, in fact, significantly reduces the rate of pregnancy and live birth in this group.

Findings sparked controversy

This trial generated controversy within the genetics and reproductive endocrinology specialties because it challenged the intuitive view that screening of embryos before transfer into the uterus should be beneficial—or, at least, harmless. Some now argue that the benefits of PGS, if any, cannot be intuitively assumed and assert that the burden of proof of those benefits rests with proponents of PGS.

The practice committees of the Society for Assisted Reproductive Technology (SART) and ASRM found insufficient evidence to support the use of PGS to improve the live birth rate in women of advanced age or in those who have had implantation failure or recurrent pregnancy loss (TABLE). Many physicians believe, however, that technologies under development will soon bring verifiable benefits of PGS to patients.

SART and ASRM weigh in on use of preimplantation genetic testing

Advise your patients that oocyte cryopreservation is “a long shot”

Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Essential elements of informed consent for elective oocyte cryopreservation: a practice committee opinion. Fertil Steril. 2007;88:1495–1496.

Oocyte cryopreservation is an experimental procedure that should not be offered or marketed as a means to defer reproductive aging, primarily because data on clinical outcomes are limited. That is the conclusion of this guideline from SART and ASRM. Consequently, women who may be considering the procedure should be fully informed about the process and likely outcomes and counseled by a qualified mental health professional.

Counseling is crucial

According to the SART and ASRM guideline, pretreatment counseling should include comprehensive information on a range of topics (see the box below). In addition, women considering oocyte cryopreservation should be counseled thoroughly about reproductive aging and life planning.^7,8

Few alternatives for some women

Women who have cancer should receive the same counseling. Unlike healthy women, however, they may have no other options, and cryopreservation may be more appropriate for them despite experimental status.

The field of reproductive endocrinology and infertility is anything but stagnant. New technologies continue to enter the market at a brisk pace, and a greater emphasis on evidence has produced better-designed randomized controlled trials, meta-analyses, and practice guidelines. This means greater availability of standardized protocols that reflect best practice and can be tailored to a patient’s condition and needs.

Highlighted here are notable studies and guidelines from the past year, including advice on:

• preventing peritoneal adhesions
  
• expediting in vitro fertilization (IVF) for unexplained infertility
  
• counseling the patient about the real limitations of preimplantation genetic screening for aneuploidy
  
• informing patients that oocyte cryopreservation is unlikely to lead to live birth.
  

Guideline urges good surgical technique in battle against adhesions

Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society of Re-productive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery. Fertil Steril. 2007;88:21–26.

This newly released practice guideline from the American Society of Reproductive Medicine (ASRM) focuses on adhesions and their impact on fertility. The guideline reiterates that peritoneal adhesions are a common and serious complication of gynecologic surgery and emphasizes key principles to reduce their likelihood and extent. These principles include the need to:

• Perform surgery only when the benefits of doing so clearly outweigh the risks
  
• Handle tissue gently (this is the most important preventive technique)
  
• Don’t assume laparoscopy is superior to laparotomy—it will be only if less tissue injury occurs
  
• Be especially careful when operating on or near ovaries, which form adhesions easily.
  

Ovarian surgery often necessitates additional operations

Studies have demonstrated that approximately 33% of patients who undergo open abdominal or pelvic surgery are readmitted, on average, two times over the subsequent 10 years for conditions directly or possibly related to adhesions or for further surgery that could be complicated by adhesions. The highest readmission rate directly related to adhesions—7.5 for every 100 initial operations—was associated with ovarian surgery performed via laparotomy.

Adhesion-related complications of gynecologic surgery include small-bowel obstruction, which occurs in approximately 1.5% of women who have undergone abdominal hysterectomy.

The relationship between adhesions and pelvic pain is unclear, although severe bowel adhesions can cause visceral pain. The ASRM guideline notes that “the impact that lysis of bowel or adnexal adhesions may have on abdominal and pelvic pain cannot be predicted confidently.” Postoperative adhesions increase subsequent operating times and risk of bowel injury.

How adhesions affect fertility

Adhesions may impair fertility by distorting adnexal anatomy and interfering with gamete and embryo transport. Among infertile women who have adnexal adhesions, adhesiolysis is associated with pregnancy rates of 32% at 12 months and 45% at 24 months, compared with 11% and 16%, respectively, for untreated women.¹ Pregnancy rates are inversely correlated with adhesion scores on the ASRM classification system for adnexal adhesions.²

Some, but not all, adhesion-reducing measures work

According to the ASRM guideline, adhesions may be prevented, at least theoretically, by:

• minimizing peritoneal injury during surgery
  
• avoiding the introduction of reactive foreign bodies
  
• reducing the local inflammatory response
  
• inhibiting the coagulation cascade and promoting fibrinolysis
  
• placing barriers between damaged tissues.
  

Pharmacotherapeutic and fluid agents. ASRM found no evidence of improved pregnancy outcomes for pharmacologic and fluid agents used as an adjunct during pelvic surgery. For example, anti-inflammatory agents that have been evaluated, both locally and systemically, including dexamethasone and promethazine, have not reduced postoperative adhesions. Antibiotic solutions, 32% Dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids have been used to separate adjacent peritoneal surfaces via “hydroflotation,” but none have reduced adhesion formation.

Surgical barriers may help decrease postoperative adhesion formation but cannot compensate for poor surgical technique. I rarely use adhesion barriers because I feel that careful tissue handling, excellent hemostasis, avoiding trauma to healthy tissue, and removal of all diseased tissue are the key ways to obtain good postsurgical results and reduce adhesions.

Hyaluronic acid agents may decrease the prevalence of adhesions and prevent the deterioration of preexisting adhesions, but because of the limited number of studies available, these data should be interpreted with caution.³ However, ASRM found no substantial evidence that they improve fertility, decrease pain, or reduce the incidence of postoperative bowel obstruction.

Averting adhesions: Surgical techniques and tools

By Togas Tulandi, MD, MHCM, and Mohammed Al-Sunaidi, MD It’s available in our archive at www.obgmanagement.com

A move from clomiphene directly to IVF may cut time to pregnancy

Reindollar RH, Regan MM, Neumann PJ, Thornton KL, Alper MM, Goldman MB. A randomized controlled trial of 503 couples assigned to conventional infertility treatment or an accelerated track to IVF: Preliminary results of the fast track and standard treatment (FASTT) trial. Fertil Steril. 2007;88(Suppl 1):S41.

This very important abstract, presented at the annual meeting of ASRM, has the potential to dramatically change fertility treatment. The multicenter randomized controlled clinical trial measured the efficacy and time to pregnancy of an accelerated treatment strategy for women 21 to 39 years old who had unexplained infertility. A similar percentage of patients—approximately 75%—became pregnant in each arm (traditional versus accelerated), with a shorter time to pregnancy in the accelerated arm.

The new paradigm for management of unexplained infertility includes:

• comprehensive fertility history and physical examination
  
• targeted laboratory testing and other investigation, as needed
  
• counseling and psychological support for the patient once the diagnosis is made
  
• empiric treatment with clomiphene citrate plus intrauterine insemination (IUI) for as many as three cycles
  
• immediate IVF for as many as six cycles.
  

Details of the trial

Women in the trial had attempted to conceive for 12 months and had normal ovarian reserve (and semen analysis) and no pelvic pathology. Couples already treated for infertility were excluded.

Participants were randomized to:

• a conventional treatment regimen of three cycles of clomiphene citrate with IUI, three cycles of folliclestimulating hormone (FSH) and IUI, and as many as six cycles of IVF or
  
• three cycles of clomiphene citrate with IUI and then as many as six cycles of IVF.
  

Regimen likely reduces cost, stress

Major issues affecting the eventual success rate for infertile couples are cost and psychological stress, which can cause even patients who have a good prognosis to drop out of treatment. The major complication of fertility treatment is multiple pregnancy. By avoiding the use of gonadotropins in couples with unexplained infertility and accelerating the transition to IVF, physicians can lower the cost and psychological stress of treatment. They can also reduce the likelihood of multiple pregnancy because it is easier to control the number of embryos transferred in IVF than the number of follicles that develop with gonadotropins.

In women younger than 35 years on the first IVF cycle who have a good prognosis, ASRM now recommends that only one or two day-3 embryos be transferred, and not more than one day-5 blastocyst.⁴ The multiple-birth rate has declined in recent years, as more and more IVF clinics place fewer embryos; the rate should continue to fall with wider application of elective single-embryo transfer.^5,6

Because this accelerated protocol produces a similar number of births over a shorter period and has the potential to lower cost, psychological stress, and the multiple-birth rate, it deserves implementation for many patients and warrants further evaluation for potential benefits in other populations.

It’s no help, after all: Preimplantation genetic screening for aneuploidy

Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: A Practice Committee report. Fertil Steril. 2007;88:1497–1504.

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Preimplantation genetic diagnosis of known single-gene defects, structural chromosomal rearrangements, X-linked disorders, and human leukocyte antigen typing is a major benefit to couples known to be at risk of passing on a heritable and debilitating genetic disease. Aneuploidy is the most common cause of early pregnancy loss, and its prevalence increases with maternal age and may increase in chromosomally normal couples who experience recurrent early pregnancy loss or repeated failure of IVF cycles. Preimplantation genetic screening (PGS) has been advocated to identify and transfer only euploid embryos and increase the chance of successful pregnancy.

New data from Mastenbroek and colleagues indicate that PGS for aneuploidy does not increase the rate of pregnancy or live birth. After several years of increasing utilization and studies suggesting that PGS has benefit, the first multicenter, randomized, doubleblind, controlled study that compared three cycles of IVF with and without PGS in women 35 to 41 years old concluded that PGS does not increase but, in fact, significantly reduces the rate of pregnancy and live birth in this group.

Findings sparked controversy

This trial generated controversy within the genetics and reproductive endocrinology specialties because it challenged the intuitive view that screening of embryos before transfer into the uterus should be beneficial—or, at least, harmless. Some now argue that the benefits of PGS, if any, cannot be intuitively assumed and assert that the burden of proof of those benefits rests with proponents of PGS.

The practice committees of the Society for Assisted Reproductive Technology (SART) and ASRM found insufficient evidence to support the use of PGS to improve the live birth rate in women of advanced age or in those who have had implantation failure or recurrent pregnancy loss (TABLE). Many physicians believe, however, that technologies under development will soon bring verifiable benefits of PGS to patients.

SART and ASRM weigh in on use of preimplantation genetic testing

Advise your patients that oocyte cryopreservation is “a long shot”

Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Essential elements of informed consent for elective oocyte cryopreservation: a practice committee opinion. Fertil Steril. 2007;88:1495–1496.

Oocyte cryopreservation is an experimental procedure that should not be offered or marketed as a means to defer reproductive aging, primarily because data on clinical outcomes are limited. That is the conclusion of this guideline from SART and ASRM. Consequently, women who may be considering the procedure should be fully informed about the process and likely outcomes and counseled by a qualified mental health professional.

Counseling is crucial

According to the SART and ASRM guideline, pretreatment counseling should include comprehensive information on a range of topics (see the box below). In addition, women considering oocyte cryopreservation should be counseled thoroughly about reproductive aging and life planning.^7,8

Few alternatives for some women

Women who have cancer should receive the same counseling. Unlike healthy women, however, they may have no other options, and cryopreservation may be more appropriate for them despite experimental status.

The field of reproductive endocrinology and infertility is anything but stagnant. New technologies continue to enter the market at a brisk pace, and a greater emphasis on evidence has produced better-designed randomized controlled trials, meta-analyses, and practice guidelines. This means greater availability of standardized protocols that reflect best practice and can be tailored to a patient’s condition and needs.

Highlighted here are notable studies and guidelines from the past year, including advice on:

• preventing peritoneal adhesions
  
• expediting in vitro fertilization (IVF) for unexplained infertility
  
• counseling the patient about the real limitations of preimplantation genetic screening for aneuploidy
  
• informing patients that oocyte cryopreservation is unlikely to lead to live birth.
  

Guideline urges good surgical technique in battle against adhesions

Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society of Re-productive Surgeons. Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery. Fertil Steril. 2007;88:21–26.

This newly released practice guideline from the American Society of Reproductive Medicine (ASRM) focuses on adhesions and their impact on fertility. The guideline reiterates that peritoneal adhesions are a common and serious complication of gynecologic surgery and emphasizes key principles to reduce their likelihood and extent. These principles include the need to:

• Perform surgery only when the benefits of doing so clearly outweigh the risks
  
• Handle tissue gently (this is the most important preventive technique)
  
• Don’t assume laparoscopy is superior to laparotomy—it will be only if less tissue injury occurs
  
• Be especially careful when operating on or near ovaries, which form adhesions easily.
  

Ovarian surgery often necessitates additional operations

Studies have demonstrated that approximately 33% of patients who undergo open abdominal or pelvic surgery are readmitted, on average, two times over the subsequent 10 years for conditions directly or possibly related to adhesions or for further surgery that could be complicated by adhesions. The highest readmission rate directly related to adhesions—7.5 for every 100 initial operations—was associated with ovarian surgery performed via laparotomy.

Adhesion-related complications of gynecologic surgery include small-bowel obstruction, which occurs in approximately 1.5% of women who have undergone abdominal hysterectomy.

The relationship between adhesions and pelvic pain is unclear, although severe bowel adhesions can cause visceral pain. The ASRM guideline notes that “the impact that lysis of bowel or adnexal adhesions may have on abdominal and pelvic pain cannot be predicted confidently.” Postoperative adhesions increase subsequent operating times and risk of bowel injury.

How adhesions affect fertility

Adhesions may impair fertility by distorting adnexal anatomy and interfering with gamete and embryo transport. Among infertile women who have adnexal adhesions, adhesiolysis is associated with pregnancy rates of 32% at 12 months and 45% at 24 months, compared with 11% and 16%, respectively, for untreated women.¹ Pregnancy rates are inversely correlated with adhesion scores on the ASRM classification system for adnexal adhesions.²

Some, but not all, adhesion-reducing measures work

According to the ASRM guideline, adhesions may be prevented, at least theoretically, by:

• minimizing peritoneal injury during surgery
  
• avoiding the introduction of reactive foreign bodies
  
• reducing the local inflammatory response
  
• inhibiting the coagulation cascade and promoting fibrinolysis
  
• placing barriers between damaged tissues.
  

Pharmacotherapeutic and fluid agents. ASRM found no evidence of improved pregnancy outcomes for pharmacologic and fluid agents used as an adjunct during pelvic surgery. For example, anti-inflammatory agents that have been evaluated, both locally and systemically, including dexamethasone and promethazine, have not reduced postoperative adhesions. Antibiotic solutions, 32% Dextran 70, and crystalloid solutions such as normal saline and Ringer’s lactate with or without heparin or corticosteroids have been used to separate adjacent peritoneal surfaces via “hydroflotation,” but none have reduced adhesion formation.

Surgical barriers may help decrease postoperative adhesion formation but cannot compensate for poor surgical technique. I rarely use adhesion barriers because I feel that careful tissue handling, excellent hemostasis, avoiding trauma to healthy tissue, and removal of all diseased tissue are the key ways to obtain good postsurgical results and reduce adhesions.

Hyaluronic acid agents may decrease the prevalence of adhesions and prevent the deterioration of preexisting adhesions, but because of the limited number of studies available, these data should be interpreted with caution.³ However, ASRM found no substantial evidence that they improve fertility, decrease pain, or reduce the incidence of postoperative bowel obstruction.

Averting adhesions: Surgical techniques and tools

By Togas Tulandi, MD, MHCM, and Mohammed Al-Sunaidi, MD It’s available in our archive at www.obgmanagement.com

A move from clomiphene directly to IVF may cut time to pregnancy

Reindollar RH, Regan MM, Neumann PJ, Thornton KL, Alper MM, Goldman MB. A randomized controlled trial of 503 couples assigned to conventional infertility treatment or an accelerated track to IVF: Preliminary results of the fast track and standard treatment (FASTT) trial. Fertil Steril. 2007;88(Suppl 1):S41.

This very important abstract, presented at the annual meeting of ASRM, has the potential to dramatically change fertility treatment. The multicenter randomized controlled clinical trial measured the efficacy and time to pregnancy of an accelerated treatment strategy for women 21 to 39 years old who had unexplained infertility. A similar percentage of patients—approximately 75%—became pregnant in each arm (traditional versus accelerated), with a shorter time to pregnancy in the accelerated arm.

The new paradigm for management of unexplained infertility includes:

• comprehensive fertility history and physical examination
  
• targeted laboratory testing and other investigation, as needed
  
• counseling and psychological support for the patient once the diagnosis is made
  
• empiric treatment with clomiphene citrate plus intrauterine insemination (IUI) for as many as three cycles
  
• immediate IVF for as many as six cycles.
  

Details of the trial

Women in the trial had attempted to conceive for 12 months and had normal ovarian reserve (and semen analysis) and no pelvic pathology. Couples already treated for infertility were excluded.

Participants were randomized to:

• a conventional treatment regimen of three cycles of clomiphene citrate with IUI, three cycles of folliclestimulating hormone (FSH) and IUI, and as many as six cycles of IVF or
  
• three cycles of clomiphene citrate with IUI and then as many as six cycles of IVF.
  

Regimen likely reduces cost, stress

Major issues affecting the eventual success rate for infertile couples are cost and psychological stress, which can cause even patients who have a good prognosis to drop out of treatment. The major complication of fertility treatment is multiple pregnancy. By avoiding the use of gonadotropins in couples with unexplained infertility and accelerating the transition to IVF, physicians can lower the cost and psychological stress of treatment. They can also reduce the likelihood of multiple pregnancy because it is easier to control the number of embryos transferred in IVF than the number of follicles that develop with gonadotropins.

In women younger than 35 years on the first IVF cycle who have a good prognosis, ASRM now recommends that only one or two day-3 embryos be transferred, and not more than one day-5 blastocyst.⁴ The multiple-birth rate has declined in recent years, as more and more IVF clinics place fewer embryos; the rate should continue to fall with wider application of elective single-embryo transfer.^5,6

Because this accelerated protocol produces a similar number of births over a shorter period and has the potential to lower cost, psychological stress, and the multiple-birth rate, it deserves implementation for many patients and warrants further evaluation for potential benefits in other populations.

It’s no help, after all: Preimplantation genetic screening for aneuploidy

Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: A Practice Committee report. Fertil Steril. 2007;88:1497–1504.

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Preimplantation genetic diagnosis of known single-gene defects, structural chromosomal rearrangements, X-linked disorders, and human leukocyte antigen typing is a major benefit to couples known to be at risk of passing on a heritable and debilitating genetic disease. Aneuploidy is the most common cause of early pregnancy loss, and its prevalence increases with maternal age and may increase in chromosomally normal couples who experience recurrent early pregnancy loss or repeated failure of IVF cycles. Preimplantation genetic screening (PGS) has been advocated to identify and transfer only euploid embryos and increase the chance of successful pregnancy.

New data from Mastenbroek and colleagues indicate that PGS for aneuploidy does not increase the rate of pregnancy or live birth. After several years of increasing utilization and studies suggesting that PGS has benefit, the first multicenter, randomized, doubleblind, controlled study that compared three cycles of IVF with and without PGS in women 35 to 41 years old concluded that PGS does not increase but, in fact, significantly reduces the rate of pregnancy and live birth in this group.

Findings sparked controversy

This trial generated controversy within the genetics and reproductive endocrinology specialties because it challenged the intuitive view that screening of embryos before transfer into the uterus should be beneficial—or, at least, harmless. Some now argue that the benefits of PGS, if any, cannot be intuitively assumed and assert that the burden of proof of those benefits rests with proponents of PGS.

The practice committees of the Society for Assisted Reproductive Technology (SART) and ASRM found insufficient evidence to support the use of PGS to improve the live birth rate in women of advanced age or in those who have had implantation failure or recurrent pregnancy loss (TABLE). Many physicians believe, however, that technologies under development will soon bring verifiable benefits of PGS to patients.

SART and ASRM weigh in on use of preimplantation genetic testing

Advise your patients that oocyte cryopreservation is “a long shot”

Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Essential elements of informed consent for elective oocyte cryopreservation: a practice committee opinion. Fertil Steril. 2007;88:1495–1496.

Oocyte cryopreservation is an experimental procedure that should not be offered or marketed as a means to defer reproductive aging, primarily because data on clinical outcomes are limited. That is the conclusion of this guideline from SART and ASRM. Consequently, women who may be considering the procedure should be fully informed about the process and likely outcomes and counseled by a qualified mental health professional.

Counseling is crucial

According to the SART and ASRM guideline, pretreatment counseling should include comprehensive information on a range of topics (see the box below). In addition, women considering oocyte cryopreservation should be counseled thoroughly about reproductive aging and life planning.^7,8

Few alternatives for some women

Women who have cancer should receive the same counseling. Unlike healthy women, however, they may have no other options, and cryopreservation may be more appropriate for them despite experimental status.

The authors report no financial relationships relevant to this article.

CASE Life on the line

A 32-year-old woman in the 24th week of her fourth pregnancy arrives at the emergency department complaining of cough and congestion, shortness of breath, and swelling in her face, hands, and feet. The swelling has become worse over the past 2 weeks, and she had several episodes of bloody vomiting the day before her visit. The patient says she has not experienced any leakage of fluid, vaginal bleeding, or contractions. She reports good fetal movement.

The patient’s medical history is unremarkable, but a review of systems reveals a 15-lb weight loss over the past 2 weeks, racing heart, worsening edema and shortness of breath, and diarrhea.

Physical findings include exophthalmia and an enlarged thyroid with a nodule on the right side, as well as bilateral rales, tachycardia, tremor, and increased deep tendon reflexes. There is no evidence of fetal cardiac failure or goiter.

A computed tomography (CT) scan of the mother shows bilateral pleural effusions indicative of high-output cardiac failure. Thyroid ultrasonography (US) reveals a diffusely enlarged thyroid gland with a right-sided mass.

The thyroid-stimulating hormone (TSH) level is undetectable. Fetal heart rate is in the 160s, with normal variability and occasional variable deceleration. Fetal US is consistent with the estimated gestational age and shows adequate amniotic fluid and no gross fetal anomalies.

What is the likely diagnosis?

This is a classic example of undiagnosed hyperthyroidism in pregnancy manifesting as thyroid storm.

As the case illustrates, uncontrolled hyperthyroidism in pregnancy poses a significant challenge for the obstetrician. The condition can cause miscarriage, preterm delivery, intrauterine growth restriction, preeclampsia, and—at its most dangerous—thyroid storm.¹ Thyroid storm is a life-threatening emergency, and treatment must be initiated even before hyperthyroidism is confirmed by thyroid function testing.² The good news is that these complications can be successfully avoided with adequate control of thyroid function.

Overt hyperthyroidism, seen in 0.2% of pregnancies, requires active intervention to avert adverse pregnancy outcome and neurologic damage to the fetus. Subclinical disease, seen in 1.7% of pregnancies, can also create serious obstetrical problems.¹

The effects of hyperthyroidism in pregnancy vary in severity, ranging from the fairly innocuous, transient, and self-limited state called gestational transient thyrotoxicosis to the life-threatening emergency of thyroid storm. This review will update you on how to manage this disorder for optimal pregnancy outcome.

To screen or not to screen

Routine screening for thyroid dysfunction has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of the disorder. Some authors recommend screening all pregnant women, but routine screening is not endorsed by the American College of Obstetricians and Gynecologists.^2,3

Thyroid testing in pregnancy is recommended in women who:

• have a family history of autoimmune thyroid disease
• are on thyroid therapy
• have a goiter or
• have insulin-dependent diabetes mellitus.

Pregnant women who have a history of high-dose neck radiation, thyroid therapy, postpartum thyroiditis, or an infant born with thyroid disease should also be tested at the first prenatal visit.⁴

Telltale signs and laboratory tests

The signs and symptoms of hyperthyroidism can include nervousness, heat intolerance, tachycardia, palpitations, goiter, weight loss, thyromegaly, exophthalmia, increased appetite, nausea and vomiting, sweating, and tremor.¹ The difficulty here? Many of these symptoms are also seen in pregnant women who have normal thyroid function, so that symptoms alone are not a reliable guide.

Instead, the diagnosis of overt hyperthyroidism is made on the basis of laboratory tests indicating suppressed TSH and elevated levels of free thyroxine (FT₄) and free triiodothyronine (FT₃). Subclinical hyperthyroidism is defined as a suppressed TSH level with normal FT₄ and FT₃ levels.²

The effects of hyperthyroidism on laboratory values are shown in TABLE 1. A form of hyperthyroidism called the T₃– toxicosis syndrome is diagnosed by suppressed TSH, normal FT₄, and elevated FT₃ levels.⁴

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

What are the causes?

The most common cause of hyperthyroidism in pregnancy—accounting for some 95% of cases—is Graves’ disease.² This autoimmune disorder is characterized by autoantibodies that activate the TSH receptor. These autoantibodies cross the placenta and can cause fetal and neonatal thyroid dysfunction even when the mother herself is in a euthyroid condition.⁴

Far less often, hyperthyroidism in pregnancy has a cause other than Graves’ disease; TABLE 2 summarizes the possibilities.¹ Other causes of hyperthyroidism in early pregnancy include choriocarcinoma and gestational trophoblastic disease (partial and complete moles) (TABLE 3).

TABLE 2

Causes of hyperthyroidism in pregnancy

TABLE 3

What causes severe hyperthyroidism before 20 weeks’ gestation?

Signs and symptoms of Graves’ disease

Women who have Graves’ disease usually have thyroid nodules and may have exophthalmia, pretibial myxedema, and tachycardia. They also display other classic signs and symptoms of hyperthyroidism, such as muscle weakness, tremor, and warm and moist skin.

During pregnancy, Graves’ disease usually becomes worse during the first trimester and postpartum period; symptoms resolve during the second and third trimesters.¹

Thyrotoxin receptor and antithyroid antibodies

Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a response to thyroid antigens. The two most common antithyroid antibodies are thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO antibodies are associated with postpartum thyroiditis and fetal and neonatal hyperthyroidism. TSH-receptor antibodies include thyroid-stimulating immunoglobulin (TSI) and TSH-receptor antibody. TSI is associated with Graves’ disease. TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism, and chronic thyroiditis without goiter.⁴

Who do you test for antibodies? Test for maternal thyroid antibodies in patients who:

• had Graves’ disease with fetal or neonatal hyperthyroidism in a previous pregnancy
• have active Graves’ disease being treated with antithyroid drugs
• are euthyroid or have undergone ablative therapy and have fetal tachycardia or intrauterine growth restriction
• have chronic thyroiditis without goiter
• have fetal goiter on ultrasound.

Newborns who have congenital hypothyroidism should also be screened for thyroid antibodies.⁴

What are the consequences?

Hyperthyroidism can have multiple effects on the pregnant patient and her fetus, ranging in severity from the minimal to the catastrophic.

Gestational transient thyrotoxicosis

This condition is presumably related to high levels of human chorionic gonadotropin, a substance known to stimulate TSH receptors. Unhappily for your patient, the condition is usually heralded by severe bouts of nausea and vomiting starting at 4 to 8 weeks’ gestation. Laboratory tests show significantly elevated levels of FT₄ and FT₃ and suppressed TSH. Despite this significant derangement, patients generally have no evidence of a hypermetabolic state.

This condition resolves by 14 to 20 weeks of gestation, is not associated with poor pregnancy outcomes, and does not require treatment with antithyroid medication.¹

Adverse pregnancy outcomes

Pregnant women who have uncontrolled hyperthyroidism are at increased risk of spontaneous miscarriage, congestive heart failure, preterm delivery, intrauterine growth restriction, and preeclampsia.¹ Studies that evaluated pregnancy outcomes in 239 women with overt hyperthyroidism showed increased risk of adverse pregnancy outcomes, compared with treated, euthyroid women (FIGURE 1).^5-7

FIGURE 1 Consequences of uncontrolled hyperthyroidism

Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.^5-7

PTD=preterm delivery; FGR=fetal growth restrictions.

Fetal and neonatal hyperthyroidism

Hyperthyroidism in the fetus or newborn is caused by placental transfer of maternal immunoglobulin antibodies (TSI) to the fetus and is associated with maternal Graves’ disease. The incidence of neonatal hyperthyroidism is less than 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are three to five times higher than they were at the beginning of pregnancy.⁴

Fetal hyperthyroidism develops at about 22 to 24 weeks’ gestation in mothers with a history of Graves’ disease who have been treated surgically or with ablative therapy prior to pregnancy. Even when these therapies achieve a euthyroid state in the mother, TSI levels may remain elevated and lead to fetal hyperthyroidism.

Characteristics of hyperthyroidism in the fetus include tachycardia, intrauterine growth restriction, congestive heart failure, oligohydramnios, and goiter. Treating the mother with antithyroid medications will ameliorate symptoms in the fetus.⁴

Thyroid storm

This is the worst-case scenario—a rare but potentially lethal complication of uncontrolled hyperthyroidism. Thyroid storm is a hypermetabolic state characterized by fever, nausea, vomiting, diarrhea, tachycardia, altered mental status, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It occurs in 1% to 2% of patients receiving thioamide therapy.⁸

In most instances, thyroid storm is a complication of uncontrolled hyperthyroidism, but it can also be precipitated by infection, surgery, thromboembolism, preeclampsia, labor, and delivery.

Thyroid storm is a medical emergency

This manifestation of uncontrolled hyperthyroidism is so urgent that treatment should be initiated before the results of TSH, FT₄, and FT₃ tests are available.^2,8 Delivery should be avoided, if possible, until the mother’s condition can be stabilized but, if the status of the fetus is compromised, delivery is indicated.

Treatment of thyroid storm begins with stabilization of the patient, followed by initiation of a stepwise management approach (FIGURE 2).

FIGURE 2 Management of thyroid storm

Aggressive management of thyroid storm is indicated, following a stepwise approach. Each medication used to treat thyroid storm plays a specific role in suppressing thyroid function. Propylthiouracil (PTU) blocks additional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T₄) to triiodothyronine (T₃). Methimazole blocks additional synthesis of thyroid hormones. Saturated solution of potassium iodide (SSKI), Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used to decrease thyroid hormone release and peripheral conversion of T₄ to T₃. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of excessive thyroid hormones. Finally, phenobarbital is used to treat maternal agitation and restlessness caused by the increased catabolism of thyroid hormones.

SOURCE: Adapted from ACOG.²

Treatment of hyperthyroidism in pregnancy

Two medications are available to treat hyperthyroidism in pregnancy: propylthiouracil (PTU) and methimazole. These medications are known as thioamides.^1,2

PTU blocks the oxidation of iodine in the thyroid gland, thereby preventing the synthesis of T₄ and T₃. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 mg/day in three divided doses every 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved with 100 to 150 mg/day in divided doses every 8 to 12 hours.⁹

Methimazole works by blocking the organification of iodide, which decreases thyroid hormone production. The usual dosing, given in three divided doses every 8 hours, is 15 mg/day for mild hyperthyroidism, 30 to 40 mg/day for moderately severe hyperthyroidism, and 60 mg/day for severe hyperthyroidism. Maintenance therapy with methimazole is usually given at a dosage of 5 to 15 mg/day.⁹

In the past, PTU was considered the drug of choice for treatment of hyperthyroidism in pregnancy because clinicians believed it crossed the placenta to a lesser degree than did methimazole, and because methimazole was associated with fetal esophageal and choanal atresia and fetal cutis aplasia (congenital skin defect of the scalp).^1,2 Available evidence does not, however, support these conclusions.^8,10 Whatever medication regimen you choose, thyroid function should be monitored 1) every 4 weeks until TSH and FT₄ levels are within normal limits and 2) every trimester thereafter. FIGURE 3 presents an algorithm for managing hyperthyroidism in pregnancy.

FIGURE 3 Management of hyperthyroidism in pregnancy

CASE Resolved

The patient in thyroid storm described at the beginning of this article requires aggressive management, as outlined in the algorithm in FIGURE 2. As her symptoms diminish, fetal tachycardia resolves. The patient’s FT₄ level begins to decline, consistent with appropriate treatment, and she is discharged home and instructed to continue PTU and labetalol and to follow up at the endocrinology and high-risk obstetrics clinics as soon as possible.

The patient does not follow this advice. Consequently, she presents at 33 5/7 weeks in a hypertensive crisis, with symptoms similar to those she first exhibited plus acute pulmonary edema. Fetal heart rate is initially in the 130s, with good variability and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean section is performed.

A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and 9 at 5 minutes. A 25% placental abruption is noted at the time of delivery.

Mother and fetus are stabilized and discharged.

FIGURE 4 Weakening fetal status in a mother who is in thyroid storm

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.

The authors report no financial relationships relevant to this article.

CASE Life on the line

A 32-year-old woman in the 24th week of her fourth pregnancy arrives at the emergency department complaining of cough and congestion, shortness of breath, and swelling in her face, hands, and feet. The swelling has become worse over the past 2 weeks, and she had several episodes of bloody vomiting the day before her visit. The patient says she has not experienced any leakage of fluid, vaginal bleeding, or contractions. She reports good fetal movement.

The patient’s medical history is unremarkable, but a review of systems reveals a 15-lb weight loss over the past 2 weeks, racing heart, worsening edema and shortness of breath, and diarrhea.

Physical findings include exophthalmia and an enlarged thyroid with a nodule on the right side, as well as bilateral rales, tachycardia, tremor, and increased deep tendon reflexes. There is no evidence of fetal cardiac failure or goiter.

A computed tomography (CT) scan of the mother shows bilateral pleural effusions indicative of high-output cardiac failure. Thyroid ultrasonography (US) reveals a diffusely enlarged thyroid gland with a right-sided mass.

The thyroid-stimulating hormone (TSH) level is undetectable. Fetal heart rate is in the 160s, with normal variability and occasional variable deceleration. Fetal US is consistent with the estimated gestational age and shows adequate amniotic fluid and no gross fetal anomalies.

What is the likely diagnosis?

This is a classic example of undiagnosed hyperthyroidism in pregnancy manifesting as thyroid storm.

As the case illustrates, uncontrolled hyperthyroidism in pregnancy poses a significant challenge for the obstetrician. The condition can cause miscarriage, preterm delivery, intrauterine growth restriction, preeclampsia, and—at its most dangerous—thyroid storm.¹ Thyroid storm is a life-threatening emergency, and treatment must be initiated even before hyperthyroidism is confirmed by thyroid function testing.² The good news is that these complications can be successfully avoided with adequate control of thyroid function.

Overt hyperthyroidism, seen in 0.2% of pregnancies, requires active intervention to avert adverse pregnancy outcome and neurologic damage to the fetus. Subclinical disease, seen in 1.7% of pregnancies, can also create serious obstetrical problems.¹

The effects of hyperthyroidism in pregnancy vary in severity, ranging from the fairly innocuous, transient, and self-limited state called gestational transient thyrotoxicosis to the life-threatening emergency of thyroid storm. This review will update you on how to manage this disorder for optimal pregnancy outcome.

To screen or not to screen

Routine screening for thyroid dysfunction has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of the disorder. Some authors recommend screening all pregnant women, but routine screening is not endorsed by the American College of Obstetricians and Gynecologists.^2,3

Thyroid testing in pregnancy is recommended in women who:

• have a family history of autoimmune thyroid disease
• are on thyroid therapy
• have a goiter or
• have insulin-dependent diabetes mellitus.

Pregnant women who have a history of high-dose neck radiation, thyroid therapy, postpartum thyroiditis, or an infant born with thyroid disease should also be tested at the first prenatal visit.⁴

Telltale signs and laboratory tests

The signs and symptoms of hyperthyroidism can include nervousness, heat intolerance, tachycardia, palpitations, goiter, weight loss, thyromegaly, exophthalmia, increased appetite, nausea and vomiting, sweating, and tremor.¹ The difficulty here? Many of these symptoms are also seen in pregnant women who have normal thyroid function, so that symptoms alone are not a reliable guide.

Instead, the diagnosis of overt hyperthyroidism is made on the basis of laboratory tests indicating suppressed TSH and elevated levels of free thyroxine (FT₄) and free triiodothyronine (FT₃). Subclinical hyperthyroidism is defined as a suppressed TSH level with normal FT₄ and FT₃ levels.²

The effects of hyperthyroidism on laboratory values are shown in TABLE 1. A form of hyperthyroidism called the T₃– toxicosis syndrome is diagnosed by suppressed TSH, normal FT₄, and elevated FT₃ levels.⁴

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

What are the causes?

The most common cause of hyperthyroidism in pregnancy—accounting for some 95% of cases—is Graves’ disease.² This autoimmune disorder is characterized by autoantibodies that activate the TSH receptor. These autoantibodies cross the placenta and can cause fetal and neonatal thyroid dysfunction even when the mother herself is in a euthyroid condition.⁴

Far less often, hyperthyroidism in pregnancy has a cause other than Graves’ disease; TABLE 2 summarizes the possibilities.¹ Other causes of hyperthyroidism in early pregnancy include choriocarcinoma and gestational trophoblastic disease (partial and complete moles) (TABLE 3).

TABLE 2

Causes of hyperthyroidism in pregnancy

TABLE 3

What causes severe hyperthyroidism before 20 weeks’ gestation?

Signs and symptoms of Graves’ disease

Women who have Graves’ disease usually have thyroid nodules and may have exophthalmia, pretibial myxedema, and tachycardia. They also display other classic signs and symptoms of hyperthyroidism, such as muscle weakness, tremor, and warm and moist skin.

During pregnancy, Graves’ disease usually becomes worse during the first trimester and postpartum period; symptoms resolve during the second and third trimesters.¹

Thyrotoxin receptor and antithyroid antibodies

Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a response to thyroid antigens. The two most common antithyroid antibodies are thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO antibodies are associated with postpartum thyroiditis and fetal and neonatal hyperthyroidism. TSH-receptor antibodies include thyroid-stimulating immunoglobulin (TSI) and TSH-receptor antibody. TSI is associated with Graves’ disease. TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism, and chronic thyroiditis without goiter.⁴

Who do you test for antibodies? Test for maternal thyroid antibodies in patients who:

• had Graves’ disease with fetal or neonatal hyperthyroidism in a previous pregnancy
• have active Graves’ disease being treated with antithyroid drugs
• are euthyroid or have undergone ablative therapy and have fetal tachycardia or intrauterine growth restriction
• have chronic thyroiditis without goiter
• have fetal goiter on ultrasound.

Newborns who have congenital hypothyroidism should also be screened for thyroid antibodies.⁴

What are the consequences?

Hyperthyroidism can have multiple effects on the pregnant patient and her fetus, ranging in severity from the minimal to the catastrophic.

Gestational transient thyrotoxicosis

This condition is presumably related to high levels of human chorionic gonadotropin, a substance known to stimulate TSH receptors. Unhappily for your patient, the condition is usually heralded by severe bouts of nausea and vomiting starting at 4 to 8 weeks’ gestation. Laboratory tests show significantly elevated levels of FT₄ and FT₃ and suppressed TSH. Despite this significant derangement, patients generally have no evidence of a hypermetabolic state.

This condition resolves by 14 to 20 weeks of gestation, is not associated with poor pregnancy outcomes, and does not require treatment with antithyroid medication.¹

Adverse pregnancy outcomes

Pregnant women who have uncontrolled hyperthyroidism are at increased risk of spontaneous miscarriage, congestive heart failure, preterm delivery, intrauterine growth restriction, and preeclampsia.¹ Studies that evaluated pregnancy outcomes in 239 women with overt hyperthyroidism showed increased risk of adverse pregnancy outcomes, compared with treated, euthyroid women (FIGURE 1).^5-7

FIGURE 1 Consequences of uncontrolled hyperthyroidism

Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.^5-7

PTD=preterm delivery; FGR=fetal growth restrictions.

Fetal and neonatal hyperthyroidism

Hyperthyroidism in the fetus or newborn is caused by placental transfer of maternal immunoglobulin antibodies (TSI) to the fetus and is associated with maternal Graves’ disease. The incidence of neonatal hyperthyroidism is less than 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are three to five times higher than they were at the beginning of pregnancy.⁴

Fetal hyperthyroidism develops at about 22 to 24 weeks’ gestation in mothers with a history of Graves’ disease who have been treated surgically or with ablative therapy prior to pregnancy. Even when these therapies achieve a euthyroid state in the mother, TSI levels may remain elevated and lead to fetal hyperthyroidism.

Characteristics of hyperthyroidism in the fetus include tachycardia, intrauterine growth restriction, congestive heart failure, oligohydramnios, and goiter. Treating the mother with antithyroid medications will ameliorate symptoms in the fetus.⁴

Thyroid storm

This is the worst-case scenario—a rare but potentially lethal complication of uncontrolled hyperthyroidism. Thyroid storm is a hypermetabolic state characterized by fever, nausea, vomiting, diarrhea, tachycardia, altered mental status, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It occurs in 1% to 2% of patients receiving thioamide therapy.⁸

In most instances, thyroid storm is a complication of uncontrolled hyperthyroidism, but it can also be precipitated by infection, surgery, thromboembolism, preeclampsia, labor, and delivery.

Thyroid storm is a medical emergency

This manifestation of uncontrolled hyperthyroidism is so urgent that treatment should be initiated before the results of TSH, FT₄, and FT₃ tests are available.^2,8 Delivery should be avoided, if possible, until the mother’s condition can be stabilized but, if the status of the fetus is compromised, delivery is indicated.

Treatment of thyroid storm begins with stabilization of the patient, followed by initiation of a stepwise management approach (FIGURE 2).

FIGURE 2 Management of thyroid storm

Aggressive management of thyroid storm is indicated, following a stepwise approach. Each medication used to treat thyroid storm plays a specific role in suppressing thyroid function. Propylthiouracil (PTU) blocks additional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T₄) to triiodothyronine (T₃). Methimazole blocks additional synthesis of thyroid hormones. Saturated solution of potassium iodide (SSKI), Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used to decrease thyroid hormone release and peripheral conversion of T₄ to T₃. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of excessive thyroid hormones. Finally, phenobarbital is used to treat maternal agitation and restlessness caused by the increased catabolism of thyroid hormones.

SOURCE: Adapted from ACOG.²

Treatment of hyperthyroidism in pregnancy

Two medications are available to treat hyperthyroidism in pregnancy: propylthiouracil (PTU) and methimazole. These medications are known as thioamides.^1,2

PTU blocks the oxidation of iodine in the thyroid gland, thereby preventing the synthesis of T₄ and T₃. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 mg/day in three divided doses every 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved with 100 to 150 mg/day in divided doses every 8 to 12 hours.⁹

Methimazole works by blocking the organification of iodide, which decreases thyroid hormone production. The usual dosing, given in three divided doses every 8 hours, is 15 mg/day for mild hyperthyroidism, 30 to 40 mg/day for moderately severe hyperthyroidism, and 60 mg/day for severe hyperthyroidism. Maintenance therapy with methimazole is usually given at a dosage of 5 to 15 mg/day.⁹

In the past, PTU was considered the drug of choice for treatment of hyperthyroidism in pregnancy because clinicians believed it crossed the placenta to a lesser degree than did methimazole, and because methimazole was associated with fetal esophageal and choanal atresia and fetal cutis aplasia (congenital skin defect of the scalp).^1,2 Available evidence does not, however, support these conclusions.^8,10 Whatever medication regimen you choose, thyroid function should be monitored 1) every 4 weeks until TSH and FT₄ levels are within normal limits and 2) every trimester thereafter. FIGURE 3 presents an algorithm for managing hyperthyroidism in pregnancy.

FIGURE 3 Management of hyperthyroidism in pregnancy

CASE Resolved

The patient in thyroid storm described at the beginning of this article requires aggressive management, as outlined in the algorithm in FIGURE 2. As her symptoms diminish, fetal tachycardia resolves. The patient’s FT₄ level begins to decline, consistent with appropriate treatment, and she is discharged home and instructed to continue PTU and labetalol and to follow up at the endocrinology and high-risk obstetrics clinics as soon as possible.

The patient does not follow this advice. Consequently, she presents at 33 5/7 weeks in a hypertensive crisis, with symptoms similar to those she first exhibited plus acute pulmonary edema. Fetal heart rate is initially in the 130s, with good variability and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean section is performed.

A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and 9 at 5 minutes. A 25% placental abruption is noted at the time of delivery.

Mother and fetus are stabilized and discharged.

FIGURE 4 Weakening fetal status in a mother who is in thyroid storm

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.

The authors report no financial relationships relevant to this article.

CASE Life on the line

A 32-year-old woman in the 24th week of her fourth pregnancy arrives at the emergency department complaining of cough and congestion, shortness of breath, and swelling in her face, hands, and feet. The swelling has become worse over the past 2 weeks, and she had several episodes of bloody vomiting the day before her visit. The patient says she has not experienced any leakage of fluid, vaginal bleeding, or contractions. She reports good fetal movement.

The patient’s medical history is unremarkable, but a review of systems reveals a 15-lb weight loss over the past 2 weeks, racing heart, worsening edema and shortness of breath, and diarrhea.

Physical findings include exophthalmia and an enlarged thyroid with a nodule on the right side, as well as bilateral rales, tachycardia, tremor, and increased deep tendon reflexes. There is no evidence of fetal cardiac failure or goiter.

A computed tomography (CT) scan of the mother shows bilateral pleural effusions indicative of high-output cardiac failure. Thyroid ultrasonography (US) reveals a diffusely enlarged thyroid gland with a right-sided mass.

The thyroid-stimulating hormone (TSH) level is undetectable. Fetal heart rate is in the 160s, with normal variability and occasional variable deceleration. Fetal US is consistent with the estimated gestational age and shows adequate amniotic fluid and no gross fetal anomalies.

What is the likely diagnosis?

This is a classic example of undiagnosed hyperthyroidism in pregnancy manifesting as thyroid storm.

As the case illustrates, uncontrolled hyperthyroidism in pregnancy poses a significant challenge for the obstetrician. The condition can cause miscarriage, preterm delivery, intrauterine growth restriction, preeclampsia, and—at its most dangerous—thyroid storm.¹ Thyroid storm is a life-threatening emergency, and treatment must be initiated even before hyperthyroidism is confirmed by thyroid function testing.² The good news is that these complications can be successfully avoided with adequate control of thyroid function.

Overt hyperthyroidism, seen in 0.2% of pregnancies, requires active intervention to avert adverse pregnancy outcome and neurologic damage to the fetus. Subclinical disease, seen in 1.7% of pregnancies, can also create serious obstetrical problems.¹

The effects of hyperthyroidism in pregnancy vary in severity, ranging from the fairly innocuous, transient, and self-limited state called gestational transient thyrotoxicosis to the life-threatening emergency of thyroid storm. This review will update you on how to manage this disorder for optimal pregnancy outcome.

To screen or not to screen

Routine screening for thyroid dysfunction has been recommended for women who have infertility, menstrual disorders, or type 1 diabetes mellitus, and for pregnant women who have signs and symptoms of the disorder. Some authors recommend screening all pregnant women, but routine screening is not endorsed by the American College of Obstetricians and Gynecologists.^2,3

Thyroid testing in pregnancy is recommended in women who:

• have a family history of autoimmune thyroid disease
• are on thyroid therapy
• have a goiter or
• have insulin-dependent diabetes mellitus.

Pregnant women who have a history of high-dose neck radiation, thyroid therapy, postpartum thyroiditis, or an infant born with thyroid disease should also be tested at the first prenatal visit.⁴

Telltale signs and laboratory tests

The signs and symptoms of hyperthyroidism can include nervousness, heat intolerance, tachycardia, palpitations, goiter, weight loss, thyromegaly, exophthalmia, increased appetite, nausea and vomiting, sweating, and tremor.¹ The difficulty here? Many of these symptoms are also seen in pregnant women who have normal thyroid function, so that symptoms alone are not a reliable guide.

Instead, the diagnosis of overt hyperthyroidism is made on the basis of laboratory tests indicating suppressed TSH and elevated levels of free thyroxine (FT₄) and free triiodothyronine (FT₃). Subclinical hyperthyroidism is defined as a suppressed TSH level with normal FT₄ and FT₃ levels.²

The effects of hyperthyroidism on laboratory values are shown in TABLE 1. A form of hyperthyroidism called the T₃– toxicosis syndrome is diagnosed by suppressed TSH, normal FT₄, and elevated FT₃ levels.⁴

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

What are the causes?

The most common cause of hyperthyroidism in pregnancy—accounting for some 95% of cases—is Graves’ disease.² This autoimmune disorder is characterized by autoantibodies that activate the TSH receptor. These autoantibodies cross the placenta and can cause fetal and neonatal thyroid dysfunction even when the mother herself is in a euthyroid condition.⁴

Far less often, hyperthyroidism in pregnancy has a cause other than Graves’ disease; TABLE 2 summarizes the possibilities.¹ Other causes of hyperthyroidism in early pregnancy include choriocarcinoma and gestational trophoblastic disease (partial and complete moles) (TABLE 3).

TABLE 2

Causes of hyperthyroidism in pregnancy

TABLE 3

What causes severe hyperthyroidism before 20 weeks’ gestation?

Signs and symptoms of Graves’ disease

Women who have Graves’ disease usually have thyroid nodules and may have exophthalmia, pretibial myxedema, and tachycardia. They also display other classic signs and symptoms of hyperthyroidism, such as muscle weakness, tremor, and warm and moist skin.

During pregnancy, Graves’ disease usually becomes worse during the first trimester and postpartum period; symptoms resolve during the second and third trimesters.¹

Thyrotoxin receptor and antithyroid antibodies

Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a response to thyroid antigens. The two most common antithyroid antibodies are thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO antibodies are associated with postpartum thyroiditis and fetal and neonatal hyperthyroidism. TSH-receptor antibodies include thyroid-stimulating immunoglobulin (TSI) and TSH-receptor antibody. TSI is associated with Graves’ disease. TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism, and chronic thyroiditis without goiter.⁴

Who do you test for antibodies? Test for maternal thyroid antibodies in patients who:

• had Graves’ disease with fetal or neonatal hyperthyroidism in a previous pregnancy
• have active Graves’ disease being treated with antithyroid drugs
• are euthyroid or have undergone ablative therapy and have fetal tachycardia or intrauterine growth restriction
• have chronic thyroiditis without goiter
• have fetal goiter on ultrasound.

Newborns who have congenital hypothyroidism should also be screened for thyroid antibodies.⁴

What are the consequences?

Hyperthyroidism can have multiple effects on the pregnant patient and her fetus, ranging in severity from the minimal to the catastrophic.

Gestational transient thyrotoxicosis

This condition is presumably related to high levels of human chorionic gonadotropin, a substance known to stimulate TSH receptors. Unhappily for your patient, the condition is usually heralded by severe bouts of nausea and vomiting starting at 4 to 8 weeks’ gestation. Laboratory tests show significantly elevated levels of FT₄ and FT₃ and suppressed TSH. Despite this significant derangement, patients generally have no evidence of a hypermetabolic state.

This condition resolves by 14 to 20 weeks of gestation, is not associated with poor pregnancy outcomes, and does not require treatment with antithyroid medication.¹

Adverse pregnancy outcomes

Pregnant women who have uncontrolled hyperthyroidism are at increased risk of spontaneous miscarriage, congestive heart failure, preterm delivery, intrauterine growth restriction, and preeclampsia.¹ Studies that evaluated pregnancy outcomes in 239 women with overt hyperthyroidism showed increased risk of adverse pregnancy outcomes, compared with treated, euthyroid women (FIGURE 1).^5-7

FIGURE 1 Consequences of uncontrolled hyperthyroidism

Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.^5-7

PTD=preterm delivery; FGR=fetal growth restrictions.

Fetal and neonatal hyperthyroidism

Hyperthyroidism in the fetus or newborn is caused by placental transfer of maternal immunoglobulin antibodies (TSI) to the fetus and is associated with maternal Graves’ disease. The incidence of neonatal hyperthyroidism is less than 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are three to five times higher than they were at the beginning of pregnancy.⁴

Fetal hyperthyroidism develops at about 22 to 24 weeks’ gestation in mothers with a history of Graves’ disease who have been treated surgically or with ablative therapy prior to pregnancy. Even when these therapies achieve a euthyroid state in the mother, TSI levels may remain elevated and lead to fetal hyperthyroidism.

Characteristics of hyperthyroidism in the fetus include tachycardia, intrauterine growth restriction, congestive heart failure, oligohydramnios, and goiter. Treating the mother with antithyroid medications will ameliorate symptoms in the fetus.⁴

Thyroid storm

This is the worst-case scenario—a rare but potentially lethal complication of uncontrolled hyperthyroidism. Thyroid storm is a hypermetabolic state characterized by fever, nausea, vomiting, diarrhea, tachycardia, altered mental status, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It occurs in 1% to 2% of patients receiving thioamide therapy.⁸

In most instances, thyroid storm is a complication of uncontrolled hyperthyroidism, but it can also be precipitated by infection, surgery, thromboembolism, preeclampsia, labor, and delivery.

Thyroid storm is a medical emergency

This manifestation of uncontrolled hyperthyroidism is so urgent that treatment should be initiated before the results of TSH, FT₄, and FT₃ tests are available.^2,8 Delivery should be avoided, if possible, until the mother’s condition can be stabilized but, if the status of the fetus is compromised, delivery is indicated.

Treatment of thyroid storm begins with stabilization of the patient, followed by initiation of a stepwise management approach (FIGURE 2).

FIGURE 2 Management of thyroid storm

Aggressive management of thyroid storm is indicated, following a stepwise approach. Each medication used to treat thyroid storm plays a specific role in suppressing thyroid function. Propylthiouracil (PTU) blocks additional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T₄) to triiodothyronine (T₃). Methimazole blocks additional synthesis of thyroid hormones. Saturated solution of potassium iodide (SSKI), Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used to decrease thyroid hormone release and peripheral conversion of T₄ to T₃. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of excessive thyroid hormones. Finally, phenobarbital is used to treat maternal agitation and restlessness caused by the increased catabolism of thyroid hormones.

SOURCE: Adapted from ACOG.²

Treatment of hyperthyroidism in pregnancy

Two medications are available to treat hyperthyroidism in pregnancy: propylthiouracil (PTU) and methimazole. These medications are known as thioamides.^1,2

PTU blocks the oxidation of iodine in the thyroid gland, thereby preventing the synthesis of T₄ and T₃. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 mg/day in three divided doses every 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved with 100 to 150 mg/day in divided doses every 8 to 12 hours.⁹

Methimazole works by blocking the organification of iodide, which decreases thyroid hormone production. The usual dosing, given in three divided doses every 8 hours, is 15 mg/day for mild hyperthyroidism, 30 to 40 mg/day for moderately severe hyperthyroidism, and 60 mg/day for severe hyperthyroidism. Maintenance therapy with methimazole is usually given at a dosage of 5 to 15 mg/day.⁹

In the past, PTU was considered the drug of choice for treatment of hyperthyroidism in pregnancy because clinicians believed it crossed the placenta to a lesser degree than did methimazole, and because methimazole was associated with fetal esophageal and choanal atresia and fetal cutis aplasia (congenital skin defect of the scalp).^1,2 Available evidence does not, however, support these conclusions.^8,10 Whatever medication regimen you choose, thyroid function should be monitored 1) every 4 weeks until TSH and FT₄ levels are within normal limits and 2) every trimester thereafter. FIGURE 3 presents an algorithm for managing hyperthyroidism in pregnancy.

FIGURE 3 Management of hyperthyroidism in pregnancy

CASE Resolved

The patient in thyroid storm described at the beginning of this article requires aggressive management, as outlined in the algorithm in FIGURE 2. As her symptoms diminish, fetal tachycardia resolves. The patient’s FT₄ level begins to decline, consistent with appropriate treatment, and she is discharged home and instructed to continue PTU and labetalol and to follow up at the endocrinology and high-risk obstetrics clinics as soon as possible.

The patient does not follow this advice. Consequently, she presents at 33 5/7 weeks in a hypertensive crisis, with symptoms similar to those she first exhibited plus acute pulmonary edema. Fetal heart rate is initially in the 130s, with good variability and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean section is performed.

A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and 9 at 5 minutes. A 25% placental abruption is noted at the time of delivery.

Mother and fetus are stabilized and discharged.

FIGURE 4 Weakening fetal status in a mother who is in thyroid storm

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.