Clinical Review

As soon as next year, the human papillomavirus (HPV) vaccine could transform clinical practice more than anything since the Pap smear was introduced 60 years ago.

A second large trial has shown extraordinary efficacy, and now 2 manufacturers, GlaxoSmithKline and Merck, are conducting late-phase clinical trials and working toward registering their vaccines for clinical use in 2006. Only last month, Merck and GSK signed an agreement that resolves their competing intellectual property claims—removing one more barrier to rapid commercialization.

But there are other important new developments that apply to practice now:

• Colposcopy, it appears, is far less reliable for identifying cervical intraepithelial neoplasia (CIN) 2,3 than we thought.
• The long-term risk of preterm delivery with loop electrosurgical excision procedures (LEEP) points to a need to counsel patients and consider all management options for women with CIN 1.
• The high rates of spontaneous regression of low-grade squamous intraepithelial lesion (LSIL) cytologic changes in young women are now better defined, and indicate colposcopy is not always needed.

Colposcopy not as sensitive as we thought

Pretorius R, Zhang W, Bellinson J, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004; 191:430–434.

We need to carefully follow up whenever colposcopy does not identify a CIN 2,3 lesion. This study also reinforces the need for diagnostic excisional procedures in women with an HSIL Pap result, and who are found after colposcopy to have CIN 1 or less (FIGURE 1).

Unfortunately, colposcopy is highly subjective. Accuracy depends on training and experience. Nevertheless, it is the standard of care for identifying CIN 2,3 and invasive cervical cancer in women with abnormal Pap results. Colposcopy was thought to be a sensitive but rather nonspecific method for identifying high-grade neoplasia. A 1998 comprehensive meta-analysis estimated that colposcopy had a weighted mean sensitivity for distinguishing normal tissue from abnormal tissue of 0.96 (95% confidence interval [CI], 0.95-0.97) and a weighted mean specificity of 0.48 (95% CI, 0.47-0.49).¹ This means that colposcopy would miss a biopsy-confirmed cervical abnormality in only about 4% of patients. However, more recent follow-up studies have reported much higher false negative rates for colposcopy.

Pretorius and colleagues studied women enrolled in a cervical cancer screening trial conducted in Shanxi, China. The colposcopy in this study was performed by attending gynecologic oncologists who worked closely with a team of US-based gynecologic oncologists. The women in the study had biopsies taken of all areas classified as abnormal by colposcopy. In addition, random 4-quadrant cervical biopsies were obtained from colposcopically normal regions of the cervix.

A total of 364 women with a satisfactory colposcopy and biopsy-confirmed CIN 2 or greater lesions were identified. Even though all 364 women had a satisfactory colposcopic examination, only 57.1% of the women with biopsy-confirmed CIN 2 or worse were detected by the colposcopically-directed biopsy; the remaining 42.9% were detected by the random biopsies of colposcopically normal-appearing tissue. The lesions that were missed by colposcopy tended to be smaller than those identified by colposcopy and were more frequently CIN 2 rather than CIN 3 lesions.

This study also evaluated the role of endocervical curettage, and found that even among women with a satisfactory colposcopic examination, a significant proportion (5.5%) of cases of CIN 2,3 or worse were detected only by using endocervical curettage.

FIGURE 1 Repeat colposcopy and biopsy may reveal high-grade lesion

Low-grade cervical intraepithelial neoplasia (CIN 1) of the cervix. This young woman has a well-defined acetowhite lesion of her cervix that was diagnosed as a CIN 1 on cervical biopsy. In many such cases, repeat colposcopy and biopsy identifies an area of high-grade lesion that was missed at the initial colposcopy.

REFERENCE

1. Mitchell MF, Schottenfeld D, Tortolero-Luna G, Cantor SB, Richards-Kortum R. Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;91:626-631.

LEEP raises risk of preterm birth

Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA. 2004;291:2100-2106.

We need to counsel women that LEEP will increase their risk for preterm premature rupture of membranes (PPROM) and preterm delivery. We must recognize that it is desirable to follow, rather than treat, biopsy-confirmed CIN 1, and to limit the depth of excision to 1 cm or less whenever possible.

 

Although Consensus Guidelines state that both ablative and excisional methods are acceptable forms of managing women with satisfactory colposcopy and CIN 2,3, for most clinicians, LEEP has completely replaced laser ablation and cryotherapy for treatment of CIN.¹ Because LEEP is so widely utilized, its effects on fertility and preterm delivery, as well as other adverse pregnancy outcomes, are of great concern.

LEEP became widely adopted since its introduction in the early 1990s because it yields a tissue specimen for histological evaluation and is less expensive and easier to perform than laser ablation.

Unfortunately, most studies of the impact of LEEP on fertility and pregnancy have been limited or inconclusive, and most lacked statistical power to detect a doubling of risk. The New Zealand study conducted by Sadler and colleagues—a large retrospective cohort study—compared delivery outcomes of 426 untreated women with 652 women treated by laser conization, laser ablation, or LEEP. Women who had LEEP or laser cone treatment were at significantly increased risk of rupture of membranes before 37 weeks’ gestation. Notably, in women who had undergone a LEEP, the adjusted relative risk (RR) for PPROM was 1.9 (95% CI, 1.0-3.8) compared to the untreated women. Laser ablation did not increase risk (RR 1.1). This study demonstrate that women who have undergone LEEP have almost twice the risk for PPROM as untreated women, should be of concern to all gynecologists.

Risk of both PPROM and preterm delivery increased as depth of cervical tissue removed increased. Women in whom 1 cm or less of tissue was excised had no increased risk of PPROM or preterm birth; women in whom more than 1.7 cm of tissue was excised had an adjusted relative risk of 3.6 (95% CI, 1.8-7.5).

In a Canadian study published only last month, Samson and colleagues found PPROM was almost 4 times more common among women who had had a LEEP.²

REFERENCES

1. Wright TC, Jr, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

2. Samson S, Bentley JR, Fahey T, McKay D, Gill G. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325-332.

LSIL cytology meaningless?

Moscicki A, Shiboski S, Hills N, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678–1683.

This study shows just how meaningless LSIL cytology is in young women—and it portends changes in the next Consensus Guidelines. Colposcopy for all adolescents and young women is unwarranted, the authors stated. They recommend monitoring with repeat cytology instead.

For over a decade it has been widely appreciated that many CIN 1 lesions spontaneously regress in the absence of therapy.¹ Based on what we recently learned from natural history studies of HPV, we know that the majority of LSIL cytology results and biopsy-confirmed CIN 1 lesions represent nothing more than the morphological manifestation of a productive HPV infection.² HPV infections, including those with high-risk types of HPV, are typically self-limited (FIGURE 2). In approximately 90% of women, HPV shedding stops spontaneously within 24 months.

However, in the United States, most women with LSIL undergo colposcopy, and many clinicians continue to treat women with biopsy-confirmed CIN 1. These approaches do correspond to the most recent Consensus Guidelines, which recommend colposcopy for women with LSIL, and state that follow-up with treatment, as well as treatment with ablative or excisional methods, are acceptable management options for women with CIN 1.³

Regarding adolescents with LSIL, the guidelines made an exception to performing a colposcopy. For these patients, an acceptable management option is follow-up without initial colposcopy, using a protocol of repeat cytological testing at 6 and 12 months, or HPV testing at 12 months.

 

To better define the best way to manage young women with LSIL, Moscicki and colleagues followed a cohort of 204 young women (ages 13 to 22 years), who had an LSIL Pap result, for up to 80 months (median 61 months). HSIL cytology (N=6) or biopsy-confirmed CIN 2,3 (N=17) was found in only 11.3% of the women. After 36 months, only 6% had persistent LSIL.

The remainder had had 3 consecutive negative Pap results, and the median time to developing the first of 3 negative Pap results was only 8 months.

FIGURE 2 Even high-risk HPV types usually abate in young women

Liquid-based cytology specimen diagnosed as low-grade squamous intraepithelial lesion (LSIL), with marked koilocytosis with multinucleation, perinuclear halos, and nuclear atypia. These features typify productive HPV infection that usually regresses spontaneously in young women.

REFERENCES

1. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;92:727-735.

2. Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.

3. Wright TC, Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

Bivalent vaccine vanquishes HPV

Harper D, Franco E, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757–1765.

HPV vaccine may be registered for clinical use next year. Since two-thirds of cervical cancers are caused by only 2 types of high-risk HPV—HPV 16 and HPV 18—a vaccine that prevents infection with HPV 16 and 18 could reduce cervical cancer and high-grade precursor lesions by more than half.

Extraordinary efficacy—100% against persistent infections and 91.6% against incident HPV 16 or 18 infections—was found in this Phase II trial of a bivalent HPV vaccine made by GlaxoSmithKline—the second such trial to show high efficacy for an HPV vaccine. Merck found high efficacy for its monovalent vaccine. Both companies are conducting Phase III registration trials.

Harper and colleagues observed these efficacy rates in women who took all their scheduled vaccinations. They used bivalent HPV 16 and 18 vaccine in a study of 1,113 women randomized to receive 3 doses of vaccine or placebo over a 6-month period. All were followed for up to 27 months.

The vaccine was also highly effective against cytological abnormalities associated with HPV 16 or 18 and was generally safe, well tolerated, and highly immunogenic.

In 2002, a Phase II trial of a monovalent HPV 16 vaccine produced by Merck demonstrated efficacy of 100% over 18 months in preventing persistent HPV 16 infection or CIN associated with HPV 16.¹

Both companies’ vaccines consist of viral-like particles that are made by producing recombinant L1 capsid protein of the specific HPV type and then allowing the recombinant L1 capsid proteins to assemble into a structure that appears identical to the native virus, but lacks infectious DNA.

Each year, 470,000 women develop invasive cervical cancer, and 230,000 die, globally. Vaccination is a particularly attractive strategy for preventing cervical cancer in developing countries, where less than 5% of women have ever been screened.

Yet these numbers do not begin to take into account the huge costs and burden of disease due to noninvasive cervical cancer precursors and abnormal screening cytology. In the United States alone, we spend up to $6 billion a year on prevention and treatment of cervical cancer.

The author reports no financial relationships relevant to this article.

REFERENCE

1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.

As soon as next year, the human papillomavirus (HPV) vaccine could transform clinical practice more than anything since the Pap smear was introduced 60 years ago.

A second large trial has shown extraordinary efficacy, and now 2 manufacturers, GlaxoSmithKline and Merck, are conducting late-phase clinical trials and working toward registering their vaccines for clinical use in 2006. Only last month, Merck and GSK signed an agreement that resolves their competing intellectual property claims—removing one more barrier to rapid commercialization.

But there are other important new developments that apply to practice now:

• Colposcopy, it appears, is far less reliable for identifying cervical intraepithelial neoplasia (CIN) 2,3 than we thought.
• The long-term risk of preterm delivery with loop electrosurgical excision procedures (LEEP) points to a need to counsel patients and consider all management options for women with CIN 1.
• The high rates of spontaneous regression of low-grade squamous intraepithelial lesion (LSIL) cytologic changes in young women are now better defined, and indicate colposcopy is not always needed.

Colposcopy not as sensitive as we thought

Pretorius R, Zhang W, Bellinson J, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004; 191:430–434.

We need to carefully follow up whenever colposcopy does not identify a CIN 2,3 lesion. This study also reinforces the need for diagnostic excisional procedures in women with an HSIL Pap result, and who are found after colposcopy to have CIN 1 or less (FIGURE 1).

Unfortunately, colposcopy is highly subjective. Accuracy depends on training and experience. Nevertheless, it is the standard of care for identifying CIN 2,3 and invasive cervical cancer in women with abnormal Pap results. Colposcopy was thought to be a sensitive but rather nonspecific method for identifying high-grade neoplasia. A 1998 comprehensive meta-analysis estimated that colposcopy had a weighted mean sensitivity for distinguishing normal tissue from abnormal tissue of 0.96 (95% confidence interval [CI], 0.95-0.97) and a weighted mean specificity of 0.48 (95% CI, 0.47-0.49).¹ This means that colposcopy would miss a biopsy-confirmed cervical abnormality in only about 4% of patients. However, more recent follow-up studies have reported much higher false negative rates for colposcopy.

Pretorius and colleagues studied women enrolled in a cervical cancer screening trial conducted in Shanxi, China. The colposcopy in this study was performed by attending gynecologic oncologists who worked closely with a team of US-based gynecologic oncologists. The women in the study had biopsies taken of all areas classified as abnormal by colposcopy. In addition, random 4-quadrant cervical biopsies were obtained from colposcopically normal regions of the cervix.

A total of 364 women with a satisfactory colposcopy and biopsy-confirmed CIN 2 or greater lesions were identified. Even though all 364 women had a satisfactory colposcopic examination, only 57.1% of the women with biopsy-confirmed CIN 2 or worse were detected by the colposcopically-directed biopsy; the remaining 42.9% were detected by the random biopsies of colposcopically normal-appearing tissue. The lesions that were missed by colposcopy tended to be smaller than those identified by colposcopy and were more frequently CIN 2 rather than CIN 3 lesions.

This study also evaluated the role of endocervical curettage, and found that even among women with a satisfactory colposcopic examination, a significant proportion (5.5%) of cases of CIN 2,3 or worse were detected only by using endocervical curettage.

FIGURE 1 Repeat colposcopy and biopsy may reveal high-grade lesion

Low-grade cervical intraepithelial neoplasia (CIN 1) of the cervix. This young woman has a well-defined acetowhite lesion of her cervix that was diagnosed as a CIN 1 on cervical biopsy. In many such cases, repeat colposcopy and biopsy identifies an area of high-grade lesion that was missed at the initial colposcopy.

REFERENCE

1. Mitchell MF, Schottenfeld D, Tortolero-Luna G, Cantor SB, Richards-Kortum R. Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;91:626-631.

LEEP raises risk of preterm birth

Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA. 2004;291:2100-2106.

We need to counsel women that LEEP will increase their risk for preterm premature rupture of membranes (PPROM) and preterm delivery. We must recognize that it is desirable to follow, rather than treat, biopsy-confirmed CIN 1, and to limit the depth of excision to 1 cm or less whenever possible.

 

Although Consensus Guidelines state that both ablative and excisional methods are acceptable forms of managing women with satisfactory colposcopy and CIN 2,3, for most clinicians, LEEP has completely replaced laser ablation and cryotherapy for treatment of CIN.¹ Because LEEP is so widely utilized, its effects on fertility and preterm delivery, as well as other adverse pregnancy outcomes, are of great concern.

LEEP became widely adopted since its introduction in the early 1990s because it yields a tissue specimen for histological evaluation and is less expensive and easier to perform than laser ablation.

Unfortunately, most studies of the impact of LEEP on fertility and pregnancy have been limited or inconclusive, and most lacked statistical power to detect a doubling of risk. The New Zealand study conducted by Sadler and colleagues—a large retrospective cohort study—compared delivery outcomes of 426 untreated women with 652 women treated by laser conization, laser ablation, or LEEP. Women who had LEEP or laser cone treatment were at significantly increased risk of rupture of membranes before 37 weeks’ gestation. Notably, in women who had undergone a LEEP, the adjusted relative risk (RR) for PPROM was 1.9 (95% CI, 1.0-3.8) compared to the untreated women. Laser ablation did not increase risk (RR 1.1). This study demonstrate that women who have undergone LEEP have almost twice the risk for PPROM as untreated women, should be of concern to all gynecologists.

Risk of both PPROM and preterm delivery increased as depth of cervical tissue removed increased. Women in whom 1 cm or less of tissue was excised had no increased risk of PPROM or preterm birth; women in whom more than 1.7 cm of tissue was excised had an adjusted relative risk of 3.6 (95% CI, 1.8-7.5).

In a Canadian study published only last month, Samson and colleagues found PPROM was almost 4 times more common among women who had had a LEEP.²

REFERENCES

1. Wright TC, Jr, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

2. Samson S, Bentley JR, Fahey T, McKay D, Gill G. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325-332.

LSIL cytology meaningless?

Moscicki A, Shiboski S, Hills N, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678–1683.

This study shows just how meaningless LSIL cytology is in young women—and it portends changes in the next Consensus Guidelines. Colposcopy for all adolescents and young women is unwarranted, the authors stated. They recommend monitoring with repeat cytology instead.

For over a decade it has been widely appreciated that many CIN 1 lesions spontaneously regress in the absence of therapy.¹ Based on what we recently learned from natural history studies of HPV, we know that the majority of LSIL cytology results and biopsy-confirmed CIN 1 lesions represent nothing more than the morphological manifestation of a productive HPV infection.² HPV infections, including those with high-risk types of HPV, are typically self-limited (FIGURE 2). In approximately 90% of women, HPV shedding stops spontaneously within 24 months.

However, in the United States, most women with LSIL undergo colposcopy, and many clinicians continue to treat women with biopsy-confirmed CIN 1. These approaches do correspond to the most recent Consensus Guidelines, which recommend colposcopy for women with LSIL, and state that follow-up with treatment, as well as treatment with ablative or excisional methods, are acceptable management options for women with CIN 1.³

Regarding adolescents with LSIL, the guidelines made an exception to performing a colposcopy. For these patients, an acceptable management option is follow-up without initial colposcopy, using a protocol of repeat cytological testing at 6 and 12 months, or HPV testing at 12 months.

 

To better define the best way to manage young women with LSIL, Moscicki and colleagues followed a cohort of 204 young women (ages 13 to 22 years), who had an LSIL Pap result, for up to 80 months (median 61 months). HSIL cytology (N=6) or biopsy-confirmed CIN 2,3 (N=17) was found in only 11.3% of the women. After 36 months, only 6% had persistent LSIL.

The remainder had had 3 consecutive negative Pap results, and the median time to developing the first of 3 negative Pap results was only 8 months.

FIGURE 2 Even high-risk HPV types usually abate in young women

Liquid-based cytology specimen diagnosed as low-grade squamous intraepithelial lesion (LSIL), with marked koilocytosis with multinucleation, perinuclear halos, and nuclear atypia. These features typify productive HPV infection that usually regresses spontaneously in young women.

REFERENCES

1. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;92:727-735.

2. Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.

3. Wright TC, Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

Bivalent vaccine vanquishes HPV

Harper D, Franco E, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757–1765.

HPV vaccine may be registered for clinical use next year. Since two-thirds of cervical cancers are caused by only 2 types of high-risk HPV—HPV 16 and HPV 18—a vaccine that prevents infection with HPV 16 and 18 could reduce cervical cancer and high-grade precursor lesions by more than half.

Extraordinary efficacy—100% against persistent infections and 91.6% against incident HPV 16 or 18 infections—was found in this Phase II trial of a bivalent HPV vaccine made by GlaxoSmithKline—the second such trial to show high efficacy for an HPV vaccine. Merck found high efficacy for its monovalent vaccine. Both companies are conducting Phase III registration trials.

Harper and colleagues observed these efficacy rates in women who took all their scheduled vaccinations. They used bivalent HPV 16 and 18 vaccine in a study of 1,113 women randomized to receive 3 doses of vaccine or placebo over a 6-month period. All were followed for up to 27 months.

The vaccine was also highly effective against cytological abnormalities associated with HPV 16 or 18 and was generally safe, well tolerated, and highly immunogenic.

In 2002, a Phase II trial of a monovalent HPV 16 vaccine produced by Merck demonstrated efficacy of 100% over 18 months in preventing persistent HPV 16 infection or CIN associated with HPV 16.¹

Both companies’ vaccines consist of viral-like particles that are made by producing recombinant L1 capsid protein of the specific HPV type and then allowing the recombinant L1 capsid proteins to assemble into a structure that appears identical to the native virus, but lacks infectious DNA.

Each year, 470,000 women develop invasive cervical cancer, and 230,000 die, globally. Vaccination is a particularly attractive strategy for preventing cervical cancer in developing countries, where less than 5% of women have ever been screened.

Yet these numbers do not begin to take into account the huge costs and burden of disease due to noninvasive cervical cancer precursors and abnormal screening cytology. In the United States alone, we spend up to $6 billion a year on prevention and treatment of cervical cancer.

The author reports no financial relationships relevant to this article.

REFERENCE

1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.

As soon as next year, the human papillomavirus (HPV) vaccine could transform clinical practice more than anything since the Pap smear was introduced 60 years ago.

A second large trial has shown extraordinary efficacy, and now 2 manufacturers, GlaxoSmithKline and Merck, are conducting late-phase clinical trials and working toward registering their vaccines for clinical use in 2006. Only last month, Merck and GSK signed an agreement that resolves their competing intellectual property claims—removing one more barrier to rapid commercialization.

But there are other important new developments that apply to practice now:

• Colposcopy, it appears, is far less reliable for identifying cervical intraepithelial neoplasia (CIN) 2,3 than we thought.
• The long-term risk of preterm delivery with loop electrosurgical excision procedures (LEEP) points to a need to counsel patients and consider all management options for women with CIN 1.
• The high rates of spontaneous regression of low-grade squamous intraepithelial lesion (LSIL) cytologic changes in young women are now better defined, and indicate colposcopy is not always needed.

Colposcopy not as sensitive as we thought

Pretorius R, Zhang W, Bellinson J, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004; 191:430–434.

We need to carefully follow up whenever colposcopy does not identify a CIN 2,3 lesion. This study also reinforces the need for diagnostic excisional procedures in women with an HSIL Pap result, and who are found after colposcopy to have CIN 1 or less (FIGURE 1).

Unfortunately, colposcopy is highly subjective. Accuracy depends on training and experience. Nevertheless, it is the standard of care for identifying CIN 2,3 and invasive cervical cancer in women with abnormal Pap results. Colposcopy was thought to be a sensitive but rather nonspecific method for identifying high-grade neoplasia. A 1998 comprehensive meta-analysis estimated that colposcopy had a weighted mean sensitivity for distinguishing normal tissue from abnormal tissue of 0.96 (95% confidence interval [CI], 0.95-0.97) and a weighted mean specificity of 0.48 (95% CI, 0.47-0.49).¹ This means that colposcopy would miss a biopsy-confirmed cervical abnormality in only about 4% of patients. However, more recent follow-up studies have reported much higher false negative rates for colposcopy.

Pretorius and colleagues studied women enrolled in a cervical cancer screening trial conducted in Shanxi, China. The colposcopy in this study was performed by attending gynecologic oncologists who worked closely with a team of US-based gynecologic oncologists. The women in the study had biopsies taken of all areas classified as abnormal by colposcopy. In addition, random 4-quadrant cervical biopsies were obtained from colposcopically normal regions of the cervix.

A total of 364 women with a satisfactory colposcopy and biopsy-confirmed CIN 2 or greater lesions were identified. Even though all 364 women had a satisfactory colposcopic examination, only 57.1% of the women with biopsy-confirmed CIN 2 or worse were detected by the colposcopically-directed biopsy; the remaining 42.9% were detected by the random biopsies of colposcopically normal-appearing tissue. The lesions that were missed by colposcopy tended to be smaller than those identified by colposcopy and were more frequently CIN 2 rather than CIN 3 lesions.

This study also evaluated the role of endocervical curettage, and found that even among women with a satisfactory colposcopic examination, a significant proportion (5.5%) of cases of CIN 2,3 or worse were detected only by using endocervical curettage.

FIGURE 1 Repeat colposcopy and biopsy may reveal high-grade lesion

Low-grade cervical intraepithelial neoplasia (CIN 1) of the cervix. This young woman has a well-defined acetowhite lesion of her cervix that was diagnosed as a CIN 1 on cervical biopsy. In many such cases, repeat colposcopy and biopsy identifies an area of high-grade lesion that was missed at the initial colposcopy.

REFERENCE

1. Mitchell MF, Schottenfeld D, Tortolero-Luna G, Cantor SB, Richards-Kortum R. Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;91:626-631.

LEEP raises risk of preterm birth

Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA. 2004;291:2100-2106.

We need to counsel women that LEEP will increase their risk for preterm premature rupture of membranes (PPROM) and preterm delivery. We must recognize that it is desirable to follow, rather than treat, biopsy-confirmed CIN 1, and to limit the depth of excision to 1 cm or less whenever possible.

 

Although Consensus Guidelines state that both ablative and excisional methods are acceptable forms of managing women with satisfactory colposcopy and CIN 2,3, for most clinicians, LEEP has completely replaced laser ablation and cryotherapy for treatment of CIN.¹ Because LEEP is so widely utilized, its effects on fertility and preterm delivery, as well as other adverse pregnancy outcomes, are of great concern.

LEEP became widely adopted since its introduction in the early 1990s because it yields a tissue specimen for histological evaluation and is less expensive and easier to perform than laser ablation.

Unfortunately, most studies of the impact of LEEP on fertility and pregnancy have been limited or inconclusive, and most lacked statistical power to detect a doubling of risk. The New Zealand study conducted by Sadler and colleagues—a large retrospective cohort study—compared delivery outcomes of 426 untreated women with 652 women treated by laser conization, laser ablation, or LEEP. Women who had LEEP or laser cone treatment were at significantly increased risk of rupture of membranes before 37 weeks’ gestation. Notably, in women who had undergone a LEEP, the adjusted relative risk (RR) for PPROM was 1.9 (95% CI, 1.0-3.8) compared to the untreated women. Laser ablation did not increase risk (RR 1.1). This study demonstrate that women who have undergone LEEP have almost twice the risk for PPROM as untreated women, should be of concern to all gynecologists.

Risk of both PPROM and preterm delivery increased as depth of cervical tissue removed increased. Women in whom 1 cm or less of tissue was excised had no increased risk of PPROM or preterm birth; women in whom more than 1.7 cm of tissue was excised had an adjusted relative risk of 3.6 (95% CI, 1.8-7.5).

In a Canadian study published only last month, Samson and colleagues found PPROM was almost 4 times more common among women who had had a LEEP.²

REFERENCES

1. Wright TC, Jr, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

2. Samson S, Bentley JR, Fahey T, McKay D, Gill G. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325-332.

LSIL cytology meaningless?

Moscicki A, Shiboski S, Hills N, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678–1683.

This study shows just how meaningless LSIL cytology is in young women—and it portends changes in the next Consensus Guidelines. Colposcopy for all adolescents and young women is unwarranted, the authors stated. They recommend monitoring with repeat cytology instead.

For over a decade it has been widely appreciated that many CIN 1 lesions spontaneously regress in the absence of therapy.¹ Based on what we recently learned from natural history studies of HPV, we know that the majority of LSIL cytology results and biopsy-confirmed CIN 1 lesions represent nothing more than the morphological manifestation of a productive HPV infection.² HPV infections, including those with high-risk types of HPV, are typically self-limited (FIGURE 2). In approximately 90% of women, HPV shedding stops spontaneously within 24 months.

However, in the United States, most women with LSIL undergo colposcopy, and many clinicians continue to treat women with biopsy-confirmed CIN 1. These approaches do correspond to the most recent Consensus Guidelines, which recommend colposcopy for women with LSIL, and state that follow-up with treatment, as well as treatment with ablative or excisional methods, are acceptable management options for women with CIN 1.³

Regarding adolescents with LSIL, the guidelines made an exception to performing a colposcopy. For these patients, an acceptable management option is follow-up without initial colposcopy, using a protocol of repeat cytological testing at 6 and 12 months, or HPV testing at 12 months.

 

To better define the best way to manage young women with LSIL, Moscicki and colleagues followed a cohort of 204 young women (ages 13 to 22 years), who had an LSIL Pap result, for up to 80 months (median 61 months). HSIL cytology (N=6) or biopsy-confirmed CIN 2,3 (N=17) was found in only 11.3% of the women. After 36 months, only 6% had persistent LSIL.

The remainder had had 3 consecutive negative Pap results, and the median time to developing the first of 3 negative Pap results was only 8 months.

FIGURE 2 Even high-risk HPV types usually abate in young women

Liquid-based cytology specimen diagnosed as low-grade squamous intraepithelial lesion (LSIL), with marked koilocytosis with multinucleation, perinuclear halos, and nuclear atypia. These features typify productive HPV infection that usually regresses spontaneously in young women.

REFERENCES

1. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;92:727-735.

2. Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.

3. Wright TC, Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

Bivalent vaccine vanquishes HPV

Harper D, Franco E, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757–1765.

HPV vaccine may be registered for clinical use next year. Since two-thirds of cervical cancers are caused by only 2 types of high-risk HPV—HPV 16 and HPV 18—a vaccine that prevents infection with HPV 16 and 18 could reduce cervical cancer and high-grade precursor lesions by more than half.

Extraordinary efficacy—100% against persistent infections and 91.6% against incident HPV 16 or 18 infections—was found in this Phase II trial of a bivalent HPV vaccine made by GlaxoSmithKline—the second such trial to show high efficacy for an HPV vaccine. Merck found high efficacy for its monovalent vaccine. Both companies are conducting Phase III registration trials.

Harper and colleagues observed these efficacy rates in women who took all their scheduled vaccinations. They used bivalent HPV 16 and 18 vaccine in a study of 1,113 women randomized to receive 3 doses of vaccine or placebo over a 6-month period. All were followed for up to 27 months.

The vaccine was also highly effective against cytological abnormalities associated with HPV 16 or 18 and was generally safe, well tolerated, and highly immunogenic.

In 2002, a Phase II trial of a monovalent HPV 16 vaccine produced by Merck demonstrated efficacy of 100% over 18 months in preventing persistent HPV 16 infection or CIN associated with HPV 16.¹

Both companies’ vaccines consist of viral-like particles that are made by producing recombinant L1 capsid protein of the specific HPV type and then allowing the recombinant L1 capsid proteins to assemble into a structure that appears identical to the native virus, but lacks infectious DNA.

Each year, 470,000 women develop invasive cervical cancer, and 230,000 die, globally. Vaccination is a particularly attractive strategy for preventing cervical cancer in developing countries, where less than 5% of women have ever been screened.

Yet these numbers do not begin to take into account the huge costs and burden of disease due to noninvasive cervical cancer precursors and abnormal screening cytology. In the United States alone, we spend up to $6 billion a year on prevention and treatment of cervical cancer.

The author reports no financial relationships relevant to this article.

REFERENCE

1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.

This question begs for a simple yes or no, but it is best answered by asking a second question, “Do I need to know my patient’s bone density to give her the best care possible at menopause?” If the answer is yes, then bone density testing is a must, because there is no other way to know what her bone density actually is.

How, then, does this knowledge affect clinical decision-making?

Our concern, of course, is whether we need to intervene pharmacologically to preserve the strength of the skeleton. Even though bone mineral density (BMD) does not completely account for bone strength, it does determine some 60% to 80% of bone strength, and it is still the best predictor of an initial fracture.

Of immediate concern to the physician caring for a woman entering the postmenopausal period is whether she has sufficient bone mass to withstand the bone loss that estrogen deficiency will impose—without developing a dangerously fragile skeletal structure.

Women start losing bone mass years before menopause. While she is still in her mid-40s, a woman’s spinal bone density begins to diminish due to accumulating dietary calcium deficiency, declining physical activity, and declining estradiol levels. (Unless menopause occurs earlier for any reason, however, bone density in the spine is thought to remain relatively stable from the time peak bone mass is attained, before age 30 in most skeletal sites,¹ until the mid-40s.) The exact age at which the proximal femur begins to lose bone is more controversial. Cross-sectional studies have suggested that bone loss may in fact begin in a woman’s 20s, almost immediately after reaching peak bone mass. Others have suggested that bone loss does not begin until later, in her 30s.²

A variety of risk factors are modifiable, but one that we cannot modify—genetics— may play the predominant role in determining peak bone mass. Other factors include nutrition, physical activity, intervening illnesses, medications, and lifestyle factors like smoking and alcohol use.

Expect bone loss with any cause of estrogen decline

Postmenopausal bone loss is inexorable in the absence of estrogen replacement, as well as after stopping estrogen replacement therapy (ERT) or hormone replacement therapy (HRT). If your patient stops ERT or HRT, from a skeletal perspective she has just become postmenopausal again. By measuring her bone density, you can ascertain whether bone loss— which will certainly occur—will further deplete bone mass that is already less than ideal. If so, immediate intervention to prevent bone loss is appropriate.

One key longitudinal study,³ for example, found that perimenopausal women lost an average of 2.3% per year from the spine; postmenopausal women, 0.5%. The authors observed these losses in peri- and postmenopausal women, assessed over an average of 27 months. (Women were classified as perimenopausal if they became postmenopausal during the study.)

Calcium intake of 1,000 mg/day or more does not stop bone loss

In a study designed to evaluate the effectiveness of alendronate compared with placebo in preventing bone loss in women within 3 years of menopause, McClung et al⁴ found a 3% to 4% bone loss at the end of 3 years in the placebo group, despite total calcium intakes of 1,000 mg per day or more.

Stopping HT merits equal concern

Estrogen deficiency precipitated by stopping hormone therapy is due the same concern as that created by menopause itself. Although the exact rates vary in studies, it is clear that bone loss begins when ERT or HRT stops, just as it does with onset of menopause. Hysterectomized postmenopausal women who received ERT for 2 years were found to have a 4.5% decline in posterior-anterior (PA) lumbar spine bone density and a 1.2% decline in total hip bone density only 1 year after estrogen withdrawal.⁵ This loss occurred despite calcium supplementation.

Trémollieres et al found a 1.64% per year loss of bone density from the spine for the first 2 years after discontinuing HRT, which was similar to that seen in estrogen-deficient women for the first 2 years immediately after menopause.⁶ In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, women who stopped HRT after 3 years lost bone density at an annual rate of 1.04% from the spine and 1.01% from the hip during 4 years of follow-up.⁷

 

A conservative assessment of the rate of bone loss in the first few years after menopause or cessation of hormone therapy is about 1% per year from the spine and proximal femur. At first glance, 1% per year does not appear worrisome. But within 10 years of menopause, at or about the age of only 60, 10% of the bone mass that was present at menopause is gone. In 15 years, at least 15% is gone because of estrogen deficiency.

Unquestionably, many women have stopped ERT or HRT or are choosing not to begin, due to media attention on negative findings from trials such as the combined-continuous HRT arm of the Wo men’s Health Initiative (WHI) and the Heart and Estrogen Replacement Study (HERS-I). Reviews of the National Prescription Audit database and National Disease and Therapeutic Index database confirmed a subsequent marked drop in prescriptions for ERT or HRT,⁸ despite WHI findings showing that combined-continuous HRT significantly reduces the risk of spine and hip fracture.⁹

Anne:Onset of hot flashes is a “teachable moment”

“Anne,” a 53-year-old Caucasian woman, has come to see you because of hot flashes that have begun to trouble her since her menstrual periods stopped 8 months ago.

Although she knows that estrogen replacement would help relieve her hot flashes, she is uncertain whether to use it, having heard negative media reports about WHI findings. She has no family or personal history of breast cancer, but is very frightened at even the slightest possibility of increasing her personal risk for breast cancer. She is 5’5” tall and weighs 120 lb. She broke her right wrist in a fall at age 46.

Don’t miss this opportunity!

Though Anne’s visit was prompted by distress over hot flashes, night sweats, and related symptoms of sleep disruption, daytime fatigue, mental lapses, and irritability, it’s a “teachable moment” to discuss osteoporosis prevention and testing. As is typical, her primary desire is relief from hot flashes, yet bone loss is a more serious threat.

If long-term inter vention starts early, bone loss and osteoporosis are preventable; in that context, onset of hot flashes can be seen as a positive force, since they prompted her to seek medical help.

Beth:Concerned because of her mother’s hip fracture

Occasionally a patient will raise the issue of osteoporosis herself. “Beth” is a 49-year-old woman who reports that her last menstrual period 3 months ago was very light in comparison to what she considers normal. Her periods have become irregular over the last year, initially being about 21 days apart, but now 10 to 12 weeks apart. She says she may have noticed an occasional hot flash, but it was not troublesome. She is concerned about the menstrual irregularity and wonders if she is close to menopause.

While she is not psychologically troubled about cessation of menstrual periods, she is concerned about potential bone loss due to estrogen deficiency. With additional questioning, you discover that her mother had a hip fracture.

Carol:Believes her risk low and refuses BMD test

“Carol,” on the other hand, says she doesn’t need bone density testing, because she is not interested in taking any medication to prevent or treat osteoporosis.

If Carol truly will not consider preventive medications, then bone density testing is certainly not indicated. The few patients who refuse to consider medications or testing tend to think their risk is slight. Careful questioning often elicits this belief. They may exercise, avoid cigarette smoke, and consume more than adequate amounts of calcium supplements or dairy products.

Unfortunately, such admirable habits in no way prevent estrogen-deficient bone loss.

Genetically determined low BMD

And no woman can overcome the effects of a genetically determined lower-than-average peak bone density, which may exist without the patient’s knowledge. Without a bone density test, the patient is making an uninformed decision and it is from this perspective that this situation is best approached. Her decision should always be respected, but it is our responsibility to insure that it is an informed decision.

Drug intervention based on T-score

By measuring the bone density at menopause, we can determine if pharmacologic intervention to prevent bone loss needs to start immediately. According to the National Osteoporosis Foundation (NOF) and the American Association of Clinical Endocrinologists (AACE) guidelines, if a woman’s T-score is below -1.5 and she has even 1 other risk factor, pharmacologic intervention is warranted.^12,13

This level of bone density is clearly above the threshold for a diagnosis of osteoporosis based on the WHO criteria. Nevertheless, this patient’s estrogen deficiency will further deplete her already lower-than-normal bone density, and could be rapidly devastating. Knowledge of her T-score gives us potential to prevent fractures, now that we have drugs to prevent such devastation.

 

Three guidelines (TABLE)^12-14 recommend pharmacologic intervention if the T-score is -2.5 or lower, and these guidelines differ only in the intervention threshold that also requires an additional risk factor. Note that all 3 recommend pharmacologic intervention when there is only a single risk factor in addition to a bone density level that would not be considered osteoporotic by WHO criteria.

The Food and Drug Administration (FDA) has approved drugs for prevention or treatment of postmenopausal osteoporosis, or both, based on whether data demonstrate that a drug:

• inhibits or stops bone loss, for the prevention indication, or
• reduces fracture risk, for the treatment indication.

The FDA-approved dosages of nonestrogen agents may vary by indication (TABLE). In clinical practice, however, the distinction between prevention and treatment is often less clear, leaving the dosage to the judgment of the clinician.

The complete list of clinical risk factors to consider in initiating therapy based on the T-score is lengthy; furthermore, an ever-increasing number of medications and diseases are now known to contribute to bone loss. The 5 major risk factors listed in the margin below are some of the most important to consider along with the T-score.

TABLE

Drug intervention is appropriate when there are…

	NO RISK FACTORS AND A T-SCORE:	RISK FACTORS AND A T-SCORE:
National Osteoporosis Foundation	Below -2.0	Below -1.5
American Association of Clinical Endocrinologists	At or below -2.5	-1.5 or poorer
North American Menopause Society	Below -2.5	-2.0 or poorer
FDA-approved agents for prevention and treatment of postmenopausal osteoporosis*
Alendronate
Prevention	5 mg po qd or 35 mg po qw
Treatment	10 mg po qd or 70 mg po qw
Ibandronate†	2.5 mg po qd
Risedronate	5 mg po qd or 35 mg po qw
Raloxifene	60 mg po qd
*Unless otherwise noted, doses are the same for prevention or treatment
†Although FDA-approved, ibandronate is not currently marketed in the United States

Follow-up testing intervals

Once your patient begins drug therapy, it is appropriate to follow up periodically with bone densitometry. The skeletal site measured at follow-up and the intervals between are dictated by reimbursement, as well as scientific issues. Many insurers, including Medicare, reimburse only once every 2 years.¹⁶ Exceptions are few.

From a scientific standpoint, BMD increases at the PA lumbar spine may be sufficiently great to be detected in only 1 year, with potent agents like the bisphosphonates or teriparatide. Since changes in PA lumbar spine density are generally less with raloxifene or salmon calcitonin, waiting 2 years to remeasure the PA lumbar spine is entirely appropriate here.

The PA lumbar spine is the preferred site for monitoring therapy because its higher percentage of trabecular bone generally results in a greater magnitude of change than at the proximal femur.

However, the slower rate of change at the proximal femur means that it need not be measured more often than 2 or even 3 years.

If your patient’s bone density is above the pharmacologic intervention threshold, it is always appropriate to counsel her on nonpharmacologic measures to preserve her skeleton: adequate dietary or supplemental calcium and vitamin D, regular weight-bearing or resistance exercise, and avoidance of cigarette smoke.

But we cannot assume that these are sufficient to protect her skeleton. Follow-up bone density studies are recommended to identify women who will lose bone despite these measures, and for whom pharmacologic intervention is warranted. AACE and the North American Menopause Society (NAMS) recommend follow-up bone density studies every 3 to 5 years in postmenopausal women in whom pharmacologic intervention is not deemed immediately necessary.^13,14

A more specific approach based on the patient’s lowest T-score at either the PA lumbar spine or femoral neck has been suggested.¹⁷ If her T-score is greater than 0, a repeat study is suggested in 5 years. If however, the T-score is 0 to -0.5, a repeat study is suggested in 3 years. A repeat study should be done in only 1 year if the T-score is -0.5 to -1.

This approach assumes that you wish to know when the patient’s T-score might fall below the normal range established by the WHO, that is, below a T-score of -1, and assumes a rate of bone loss of approximately 0.5 SD (or 0.5 T-score units) per year. If you know you would not intervene until the T-score reaches -1.5 or -2, you can adjust the interval accordingly.

Precision in bone density testing is integral to accurate drug therapy monitoring. When properly performed, dual energy x-ray absorptiometry (DXA) bone density measurements are highly, but not perfectly, reproducible. To reflect actual biologic changes, a measured change i n BMD must have sufficient magnitude.

In general, for measurements at the PA lumbar spine or total hip, a change of 2.77% is needed for 95% confidence. The bone densitometry testing facility should provide the clinician with the exact magnitude of the change necessary for a given level of statistical confidence.¹⁸ It is also important to remember that while increases in BMD are desirable and reassuring, no loss of BMD may also be considered efficacious.

 

The guidelines

The NOF, AACE, the American College of Obstetricians and Gynecologists (ACOG), NAMS and the United States Preventive Services Task Force (USPSTF) guidelines^12-14,19,20 agree that all postmenopausal women age 65 and older should have bone density testing. With the exception of the USPSTF, they also agree that all postmenopausal women under age 65 with risk factors should be tested. (The USPSTF limits this recommendation to women age 60 to 64.)

In reality, all postmenopausal women should have bone density testing because the list of risk factors is so comprehensive that it is unusual to find a woman who does not have at least 1 risk factor for osteoporosis.

Anne:Test again in 1 year

With this information in mind, let’s again consider Anne, the 53-year-old woman who sought help for hot flashes. Her visit was an opportunity to discuss osteoporosis prevention. Of the major risk factors, Anne has 2: weight less than 127 lb and a fracture after age 40. Based on the recommendations from the NOF, AACE, ACOG, and NAMS, bone density testing is appropriate.

A DXA study of both proximal femurs shows bone density data for each femur individually as well as the mean BMD value for each region of interest for both femurs. There are 5 regions of interest in the proximal femur: the total hip (or total femur), the femoral neck, Wa rd’s area, the trochanter, and the shaft. The total hip or femoral neck is preferred for diagnosis. Based on her normal T-scores, Anne does not meet any of the pharmacologic intervention guidelines. She should nevertheless be counseled on nonpharmacologic interventions to prevent bone loss.

She should have another bone density study in 1 year. Anne’s PA lumbar spine DXA study is not shown, but it provided no additional information. The PA lumbar spine would be the preferred site for follow-up in 1 year, however.

The recommendation for follow-up in 1 year would not change even if you elected to begin low-dose combined-continuous HRT for relief of hot flashes. Although HRT would be expected to preserve her skeleton, follow-up testing in 1 year for confirmation is appropriate.²¹

Beth:Treat now, test in 1 yr

Beth has an important risk factor: her mother’s hip fracture. This raises the possibility that she is genetically predisposed to lowerthan-average peak bone density. She meets NOF, AACE, NAMS, and ACOG guidelines for bone density testing.

At the PA lumbar spine, it is preferable to use either the L1-L4 BMD or the L2-L4 BMD and the corresponding T-score. In either case, Beth’s T-score is disturbingly low at -3.7 and -3.6, respectively. Either T-score meets the diagnosis of osteoporosis based on WHO criteria.

This single bone density study does not reveal whether she has lost bone density from a previously higher level or whether her current bone density represents her peak bone density. It is incumbent on the physician to evaluate her medically to exclude possible causes of bone loss other than estrogen deficiency, which might require a different or additional therapy.

Beth certainly meets NOF, AACE, and NAMS guidelines for drug intervention.

A follow-up PA lumbar spine DXA study is indicated in 1 year. Although she has osteoporosis, she has not yet had a fracture. For now, her diagnosis is nothing more than a test result. An osteoporotic fracture will change that. Immediate intervention with drug therapy can preserve her skeletal mass and her quality of life.

Donna:Borderline T-scores

Treatment decisions are not always as clear as in the cases of Anne, Beth, and Carol. Consider Donna, age 54, who is 2 years postmenopausal and in good health. However, her mother reportedly had a dowager’s hump at the time of her death. Although Donna was never told that her mother had osteoporosis, you suspect that she did because of the kyphosis. Donna is fairly sedentary, thin, and continues to smoke. She is not using HRT and rarely takes nutritional supplements of any kind. L 1 - L 4 PA lumbar spine T-score is -1.4; total hip is -1.3.

The dilemma is that Donna does not meet any guideline for pharmacologic intervention based on T-score, even in the presence of risk factors. Both T-scores are just above the NOF and AACE cutoff points, even in the presence of risk factors.

But the guidelines are not hard and fast rules. T- score cutoff points, with or without other risk factors, were chosen to balance the potential benefit and any potential harm of pharmacologic therapy with the risk of fracture if untreated. So, while it may seem arbitrary to recommend treatment when the T- score is -1.5 with risk factors, yet not if the T-score is -1.4 or -1.3, there is a substantive rationale behind the recommendation. Still, there is no substitute for your judgment.

 

What is a reasonable course?

She has 6 risk factors for bone loss and osteoporosis: estrogen deficiency, current smoking, probable family history, thinness, sedentary lifestyle, and probable calcium deficiency. Every attempt to modify the risk factors that can be modified is worth the effort—smoking cessation, exercise, and calcium and vitamin D supplementation would benefit her skeleton.

Important: Test again in 1 year. It is extremely important to repeat bone density testing at the lumbar spine in 1 year. If the nonpharmacologic interventions you recommend prove insufficient to radically slow the anticipated bone loss, she will fall below a T-score of -1.5 in the next year.

On the other hand, if she demonstrates that she can maintain her bone density with nonpharmacologic measures, a prescription may not be warranted. It would not be unreasonable to allow her this 1 year, because at her relatively young age of 54, at this bone density, her short-term risk of fracture is actually quite low.

“Yes” to both questions

If bone density is low—particularly if it is low and a woman has risk factors for osteoporosis—pharmacologic intervention can be reasonably expected to prevent the devastating consequences of osteoporosis. The question, “Does this menopausal woman need pharmacologic intervention to prevent or treat osteoporosis now, or might she need it later?” can be answered by measuring bone density. It is a question we would be remiss not to ask. Bone density measurement, preferably at the PA lumbar spine and proximal femur by DXA, is the only way to answer this all-important question. To provide the best care possible for a woman who has just become menopausal, you do need to know her bone density. The simple answer to both original questions then, is yes.

 

Dr. Bonnick reports research support from Merck and Roche/GSK; consultant fees from Merck, Roche/GSK, and Wyeth; and speaking fees from Merck, Roche/GSK, and Procter & Gamble.

This question begs for a simple yes or no, but it is best answered by asking a second question, “Do I need to know my patient’s bone density to give her the best care possible at menopause?” If the answer is yes, then bone density testing is a must, because there is no other way to know what her bone density actually is.

How, then, does this knowledge affect clinical decision-making?

Our concern, of course, is whether we need to intervene pharmacologically to preserve the strength of the skeleton. Even though bone mineral density (BMD) does not completely account for bone strength, it does determine some 60% to 80% of bone strength, and it is still the best predictor of an initial fracture.

Of immediate concern to the physician caring for a woman entering the postmenopausal period is whether she has sufficient bone mass to withstand the bone loss that estrogen deficiency will impose—without developing a dangerously fragile skeletal structure.

Women start losing bone mass years before menopause. While she is still in her mid-40s, a woman’s spinal bone density begins to diminish due to accumulating dietary calcium deficiency, declining physical activity, and declining estradiol levels. (Unless menopause occurs earlier for any reason, however, bone density in the spine is thought to remain relatively stable from the time peak bone mass is attained, before age 30 in most skeletal sites,¹ until the mid-40s.) The exact age at which the proximal femur begins to lose bone is more controversial. Cross-sectional studies have suggested that bone loss may in fact begin in a woman’s 20s, almost immediately after reaching peak bone mass. Others have suggested that bone loss does not begin until later, in her 30s.²

A variety of risk factors are modifiable, but one that we cannot modify—genetics— may play the predominant role in determining peak bone mass. Other factors include nutrition, physical activity, intervening illnesses, medications, and lifestyle factors like smoking and alcohol use.

Expect bone loss with any cause of estrogen decline

Postmenopausal bone loss is inexorable in the absence of estrogen replacement, as well as after stopping estrogen replacement therapy (ERT) or hormone replacement therapy (HRT). If your patient stops ERT or HRT, from a skeletal perspective she has just become postmenopausal again. By measuring her bone density, you can ascertain whether bone loss— which will certainly occur—will further deplete bone mass that is already less than ideal. If so, immediate intervention to prevent bone loss is appropriate.

One key longitudinal study,³ for example, found that perimenopausal women lost an average of 2.3% per year from the spine; postmenopausal women, 0.5%. The authors observed these losses in peri- and postmenopausal women, assessed over an average of 27 months. (Women were classified as perimenopausal if they became postmenopausal during the study.)

Calcium intake of 1,000 mg/day or more does not stop bone loss

In a study designed to evaluate the effectiveness of alendronate compared with placebo in preventing bone loss in women within 3 years of menopause, McClung et al⁴ found a 3% to 4% bone loss at the end of 3 years in the placebo group, despite total calcium intakes of 1,000 mg per day or more.

Stopping HT merits equal concern

Estrogen deficiency precipitated by stopping hormone therapy is due the same concern as that created by menopause itself. Although the exact rates vary in studies, it is clear that bone loss begins when ERT or HRT stops, just as it does with onset of menopause. Hysterectomized postmenopausal women who received ERT for 2 years were found to have a 4.5% decline in posterior-anterior (PA) lumbar spine bone density and a 1.2% decline in total hip bone density only 1 year after estrogen withdrawal.⁵ This loss occurred despite calcium supplementation.

Trémollieres et al found a 1.64% per year loss of bone density from the spine for the first 2 years after discontinuing HRT, which was similar to that seen in estrogen-deficient women for the first 2 years immediately after menopause.⁶ In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, women who stopped HRT after 3 years lost bone density at an annual rate of 1.04% from the spine and 1.01% from the hip during 4 years of follow-up.⁷

 

A conservative assessment of the rate of bone loss in the first few years after menopause or cessation of hormone therapy is about 1% per year from the spine and proximal femur. At first glance, 1% per year does not appear worrisome. But within 10 years of menopause, at or about the age of only 60, 10% of the bone mass that was present at menopause is gone. In 15 years, at least 15% is gone because of estrogen deficiency.

Unquestionably, many women have stopped ERT or HRT or are choosing not to begin, due to media attention on negative findings from trials such as the combined-continuous HRT arm of the Wo men’s Health Initiative (WHI) and the Heart and Estrogen Replacement Study (HERS-I). Reviews of the National Prescription Audit database and National Disease and Therapeutic Index database confirmed a subsequent marked drop in prescriptions for ERT or HRT,⁸ despite WHI findings showing that combined-continuous HRT significantly reduces the risk of spine and hip fracture.⁹

Anne:Onset of hot flashes is a “teachable moment”

“Anne,” a 53-year-old Caucasian woman, has come to see you because of hot flashes that have begun to trouble her since her menstrual periods stopped 8 months ago.

Although she knows that estrogen replacement would help relieve her hot flashes, she is uncertain whether to use it, having heard negative media reports about WHI findings. She has no family or personal history of breast cancer, but is very frightened at even the slightest possibility of increasing her personal risk for breast cancer. She is 5’5” tall and weighs 120 lb. She broke her right wrist in a fall at age 46.

Don’t miss this opportunity!

Though Anne’s visit was prompted by distress over hot flashes, night sweats, and related symptoms of sleep disruption, daytime fatigue, mental lapses, and irritability, it’s a “teachable moment” to discuss osteoporosis prevention and testing. As is typical, her primary desire is relief from hot flashes, yet bone loss is a more serious threat.

If long-term inter vention starts early, bone loss and osteoporosis are preventable; in that context, onset of hot flashes can be seen as a positive force, since they prompted her to seek medical help.

Beth:Concerned because of her mother’s hip fracture

Occasionally a patient will raise the issue of osteoporosis herself. “Beth” is a 49-year-old woman who reports that her last menstrual period 3 months ago was very light in comparison to what she considers normal. Her periods have become irregular over the last year, initially being about 21 days apart, but now 10 to 12 weeks apart. She says she may have noticed an occasional hot flash, but it was not troublesome. She is concerned about the menstrual irregularity and wonders if she is close to menopause.

While she is not psychologically troubled about cessation of menstrual periods, she is concerned about potential bone loss due to estrogen deficiency. With additional questioning, you discover that her mother had a hip fracture.

Carol:Believes her risk low and refuses BMD test

“Carol,” on the other hand, says she doesn’t need bone density testing, because she is not interested in taking any medication to prevent or treat osteoporosis.

If Carol truly will not consider preventive medications, then bone density testing is certainly not indicated. The few patients who refuse to consider medications or testing tend to think their risk is slight. Careful questioning often elicits this belief. They may exercise, avoid cigarette smoke, and consume more than adequate amounts of calcium supplements or dairy products.

Unfortunately, such admirable habits in no way prevent estrogen-deficient bone loss.

Genetically determined low BMD

And no woman can overcome the effects of a genetically determined lower-than-average peak bone density, which may exist without the patient’s knowledge. Without a bone density test, the patient is making an uninformed decision and it is from this perspective that this situation is best approached. Her decision should always be respected, but it is our responsibility to insure that it is an informed decision.

Drug intervention based on T-score

By measuring the bone density at menopause, we can determine if pharmacologic intervention to prevent bone loss needs to start immediately. According to the National Osteoporosis Foundation (NOF) and the American Association of Clinical Endocrinologists (AACE) guidelines, if a woman’s T-score is below -1.5 and she has even 1 other risk factor, pharmacologic intervention is warranted.^12,13

This level of bone density is clearly above the threshold for a diagnosis of osteoporosis based on the WHO criteria. Nevertheless, this patient’s estrogen deficiency will further deplete her already lower-than-normal bone density, and could be rapidly devastating. Knowledge of her T-score gives us potential to prevent fractures, now that we have drugs to prevent such devastation.

 

Three guidelines (TABLE)^12-14 recommend pharmacologic intervention if the T-score is -2.5 or lower, and these guidelines differ only in the intervention threshold that also requires an additional risk factor. Note that all 3 recommend pharmacologic intervention when there is only a single risk factor in addition to a bone density level that would not be considered osteoporotic by WHO criteria.

The Food and Drug Administration (FDA) has approved drugs for prevention or treatment of postmenopausal osteoporosis, or both, based on whether data demonstrate that a drug:

• inhibits or stops bone loss, for the prevention indication, or
• reduces fracture risk, for the treatment indication.

The FDA-approved dosages of nonestrogen agents may vary by indication (TABLE). In clinical practice, however, the distinction between prevention and treatment is often less clear, leaving the dosage to the judgment of the clinician.

The complete list of clinical risk factors to consider in initiating therapy based on the T-score is lengthy; furthermore, an ever-increasing number of medications and diseases are now known to contribute to bone loss. The 5 major risk factors listed in the margin below are some of the most important to consider along with the T-score.

TABLE

Drug intervention is appropriate when there are…

	NO RISK FACTORS AND A T-SCORE:	RISK FACTORS AND A T-SCORE:
National Osteoporosis Foundation	Below -2.0	Below -1.5
American Association of Clinical Endocrinologists	At or below -2.5	-1.5 or poorer
North American Menopause Society	Below -2.5	-2.0 or poorer
FDA-approved agents for prevention and treatment of postmenopausal osteoporosis*
Alendronate
Prevention	5 mg po qd or 35 mg po qw
Treatment	10 mg po qd or 70 mg po qw
Ibandronate†	2.5 mg po qd
Risedronate	5 mg po qd or 35 mg po qw
Raloxifene	60 mg po qd
*Unless otherwise noted, doses are the same for prevention or treatment
†Although FDA-approved, ibandronate is not currently marketed in the United States

Follow-up testing intervals

Once your patient begins drug therapy, it is appropriate to follow up periodically with bone densitometry. The skeletal site measured at follow-up and the intervals between are dictated by reimbursement, as well as scientific issues. Many insurers, including Medicare, reimburse only once every 2 years.¹⁶ Exceptions are few.

From a scientific standpoint, BMD increases at the PA lumbar spine may be sufficiently great to be detected in only 1 year, with potent agents like the bisphosphonates or teriparatide. Since changes in PA lumbar spine density are generally less with raloxifene or salmon calcitonin, waiting 2 years to remeasure the PA lumbar spine is entirely appropriate here.

The PA lumbar spine is the preferred site for monitoring therapy because its higher percentage of trabecular bone generally results in a greater magnitude of change than at the proximal femur.

However, the slower rate of change at the proximal femur means that it need not be measured more often than 2 or even 3 years.

If your patient’s bone density is above the pharmacologic intervention threshold, it is always appropriate to counsel her on nonpharmacologic measures to preserve her skeleton: adequate dietary or supplemental calcium and vitamin D, regular weight-bearing or resistance exercise, and avoidance of cigarette smoke.

But we cannot assume that these are sufficient to protect her skeleton. Follow-up bone density studies are recommended to identify women who will lose bone despite these measures, and for whom pharmacologic intervention is warranted. AACE and the North American Menopause Society (NAMS) recommend follow-up bone density studies every 3 to 5 years in postmenopausal women in whom pharmacologic intervention is not deemed immediately necessary.^13,14

A more specific approach based on the patient’s lowest T-score at either the PA lumbar spine or femoral neck has been suggested.¹⁷ If her T-score is greater than 0, a repeat study is suggested in 5 years. If however, the T-score is 0 to -0.5, a repeat study is suggested in 3 years. A repeat study should be done in only 1 year if the T-score is -0.5 to -1.

This approach assumes that you wish to know when the patient’s T-score might fall below the normal range established by the WHO, that is, below a T-score of -1, and assumes a rate of bone loss of approximately 0.5 SD (or 0.5 T-score units) per year. If you know you would not intervene until the T-score reaches -1.5 or -2, you can adjust the interval accordingly.

Precision in bone density testing is integral to accurate drug therapy monitoring. When properly performed, dual energy x-ray absorptiometry (DXA) bone density measurements are highly, but not perfectly, reproducible. To reflect actual biologic changes, a measured change i n BMD must have sufficient magnitude.

In general, for measurements at the PA lumbar spine or total hip, a change of 2.77% is needed for 95% confidence. The bone densitometry testing facility should provide the clinician with the exact magnitude of the change necessary for a given level of statistical confidence.¹⁸ It is also important to remember that while increases in BMD are desirable and reassuring, no loss of BMD may also be considered efficacious.

 

The guidelines

The NOF, AACE, the American College of Obstetricians and Gynecologists (ACOG), NAMS and the United States Preventive Services Task Force (USPSTF) guidelines^12-14,19,20 agree that all postmenopausal women age 65 and older should have bone density testing. With the exception of the USPSTF, they also agree that all postmenopausal women under age 65 with risk factors should be tested. (The USPSTF limits this recommendation to women age 60 to 64.)

In reality, all postmenopausal women should have bone density testing because the list of risk factors is so comprehensive that it is unusual to find a woman who does not have at least 1 risk factor for osteoporosis.

Anne:Test again in 1 year

With this information in mind, let’s again consider Anne, the 53-year-old woman who sought help for hot flashes. Her visit was an opportunity to discuss osteoporosis prevention. Of the major risk factors, Anne has 2: weight less than 127 lb and a fracture after age 40. Based on the recommendations from the NOF, AACE, ACOG, and NAMS, bone density testing is appropriate.

A DXA study of both proximal femurs shows bone density data for each femur individually as well as the mean BMD value for each region of interest for both femurs. There are 5 regions of interest in the proximal femur: the total hip (or total femur), the femoral neck, Wa rd’s area, the trochanter, and the shaft. The total hip or femoral neck is preferred for diagnosis. Based on her normal T-scores, Anne does not meet any of the pharmacologic intervention guidelines. She should nevertheless be counseled on nonpharmacologic interventions to prevent bone loss.

She should have another bone density study in 1 year. Anne’s PA lumbar spine DXA study is not shown, but it provided no additional information. The PA lumbar spine would be the preferred site for follow-up in 1 year, however.

The recommendation for follow-up in 1 year would not change even if you elected to begin low-dose combined-continuous HRT for relief of hot flashes. Although HRT would be expected to preserve her skeleton, follow-up testing in 1 year for confirmation is appropriate.²¹

Beth:Treat now, test in 1 yr

Beth has an important risk factor: her mother’s hip fracture. This raises the possibility that she is genetically predisposed to lowerthan-average peak bone density. She meets NOF, AACE, NAMS, and ACOG guidelines for bone density testing.

At the PA lumbar spine, it is preferable to use either the L1-L4 BMD or the L2-L4 BMD and the corresponding T-score. In either case, Beth’s T-score is disturbingly low at -3.7 and -3.6, respectively. Either T-score meets the diagnosis of osteoporosis based on WHO criteria.

This single bone density study does not reveal whether she has lost bone density from a previously higher level or whether her current bone density represents her peak bone density. It is incumbent on the physician to evaluate her medically to exclude possible causes of bone loss other than estrogen deficiency, which might require a different or additional therapy.

Beth certainly meets NOF, AACE, and NAMS guidelines for drug intervention.

A follow-up PA lumbar spine DXA study is indicated in 1 year. Although she has osteoporosis, she has not yet had a fracture. For now, her diagnosis is nothing more than a test result. An osteoporotic fracture will change that. Immediate intervention with drug therapy can preserve her skeletal mass and her quality of life.

Donna:Borderline T-scores

Treatment decisions are not always as clear as in the cases of Anne, Beth, and Carol. Consider Donna, age 54, who is 2 years postmenopausal and in good health. However, her mother reportedly had a dowager’s hump at the time of her death. Although Donna was never told that her mother had osteoporosis, you suspect that she did because of the kyphosis. Donna is fairly sedentary, thin, and continues to smoke. She is not using HRT and rarely takes nutritional supplements of any kind. L 1 - L 4 PA lumbar spine T-score is -1.4; total hip is -1.3.

The dilemma is that Donna does not meet any guideline for pharmacologic intervention based on T-score, even in the presence of risk factors. Both T-scores are just above the NOF and AACE cutoff points, even in the presence of risk factors.

But the guidelines are not hard and fast rules. T- score cutoff points, with or without other risk factors, were chosen to balance the potential benefit and any potential harm of pharmacologic therapy with the risk of fracture if untreated. So, while it may seem arbitrary to recommend treatment when the T- score is -1.5 with risk factors, yet not if the T-score is -1.4 or -1.3, there is a substantive rationale behind the recommendation. Still, there is no substitute for your judgment.

 

What is a reasonable course?

She has 6 risk factors for bone loss and osteoporosis: estrogen deficiency, current smoking, probable family history, thinness, sedentary lifestyle, and probable calcium deficiency. Every attempt to modify the risk factors that can be modified is worth the effort—smoking cessation, exercise, and calcium and vitamin D supplementation would benefit her skeleton.

Important: Test again in 1 year. It is extremely important to repeat bone density testing at the lumbar spine in 1 year. If the nonpharmacologic interventions you recommend prove insufficient to radically slow the anticipated bone loss, she will fall below a T-score of -1.5 in the next year.

On the other hand, if she demonstrates that she can maintain her bone density with nonpharmacologic measures, a prescription may not be warranted. It would not be unreasonable to allow her this 1 year, because at her relatively young age of 54, at this bone density, her short-term risk of fracture is actually quite low.

“Yes” to both questions

If bone density is low—particularly if it is low and a woman has risk factors for osteoporosis—pharmacologic intervention can be reasonably expected to prevent the devastating consequences of osteoporosis. The question, “Does this menopausal woman need pharmacologic intervention to prevent or treat osteoporosis now, or might she need it later?” can be answered by measuring bone density. It is a question we would be remiss not to ask. Bone density measurement, preferably at the PA lumbar spine and proximal femur by DXA, is the only way to answer this all-important question. To provide the best care possible for a woman who has just become menopausal, you do need to know her bone density. The simple answer to both original questions then, is yes.

 

Dr. Bonnick reports research support from Merck and Roche/GSK; consultant fees from Merck, Roche/GSK, and Wyeth; and speaking fees from Merck, Roche/GSK, and Procter & Gamble.

This question begs for a simple yes or no, but it is best answered by asking a second question, “Do I need to know my patient’s bone density to give her the best care possible at menopause?” If the answer is yes, then bone density testing is a must, because there is no other way to know what her bone density actually is.

How, then, does this knowledge affect clinical decision-making?

Our concern, of course, is whether we need to intervene pharmacologically to preserve the strength of the skeleton. Even though bone mineral density (BMD) does not completely account for bone strength, it does determine some 60% to 80% of bone strength, and it is still the best predictor of an initial fracture.

Of immediate concern to the physician caring for a woman entering the postmenopausal period is whether she has sufficient bone mass to withstand the bone loss that estrogen deficiency will impose—without developing a dangerously fragile skeletal structure.

Women start losing bone mass years before menopause. While she is still in her mid-40s, a woman’s spinal bone density begins to diminish due to accumulating dietary calcium deficiency, declining physical activity, and declining estradiol levels. (Unless menopause occurs earlier for any reason, however, bone density in the spine is thought to remain relatively stable from the time peak bone mass is attained, before age 30 in most skeletal sites,¹ until the mid-40s.) The exact age at which the proximal femur begins to lose bone is more controversial. Cross-sectional studies have suggested that bone loss may in fact begin in a woman’s 20s, almost immediately after reaching peak bone mass. Others have suggested that bone loss does not begin until later, in her 30s.²

A variety of risk factors are modifiable, but one that we cannot modify—genetics— may play the predominant role in determining peak bone mass. Other factors include nutrition, physical activity, intervening illnesses, medications, and lifestyle factors like smoking and alcohol use.

Expect bone loss with any cause of estrogen decline

Postmenopausal bone loss is inexorable in the absence of estrogen replacement, as well as after stopping estrogen replacement therapy (ERT) or hormone replacement therapy (HRT). If your patient stops ERT or HRT, from a skeletal perspective she has just become postmenopausal again. By measuring her bone density, you can ascertain whether bone loss— which will certainly occur—will further deplete bone mass that is already less than ideal. If so, immediate intervention to prevent bone loss is appropriate.

One key longitudinal study,³ for example, found that perimenopausal women lost an average of 2.3% per year from the spine; postmenopausal women, 0.5%. The authors observed these losses in peri- and postmenopausal women, assessed over an average of 27 months. (Women were classified as perimenopausal if they became postmenopausal during the study.)

Calcium intake of 1,000 mg/day or more does not stop bone loss

In a study designed to evaluate the effectiveness of alendronate compared with placebo in preventing bone loss in women within 3 years of menopause, McClung et al⁴ found a 3% to 4% bone loss at the end of 3 years in the placebo group, despite total calcium intakes of 1,000 mg per day or more.

Stopping HT merits equal concern

Estrogen deficiency precipitated by stopping hormone therapy is due the same concern as that created by menopause itself. Although the exact rates vary in studies, it is clear that bone loss begins when ERT or HRT stops, just as it does with onset of menopause. Hysterectomized postmenopausal women who received ERT for 2 years were found to have a 4.5% decline in posterior-anterior (PA) lumbar spine bone density and a 1.2% decline in total hip bone density only 1 year after estrogen withdrawal.⁵ This loss occurred despite calcium supplementation.

Trémollieres et al found a 1.64% per year loss of bone density from the spine for the first 2 years after discontinuing HRT, which was similar to that seen in estrogen-deficient women for the first 2 years immediately after menopause.⁶ In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, women who stopped HRT after 3 years lost bone density at an annual rate of 1.04% from the spine and 1.01% from the hip during 4 years of follow-up.⁷

 

A conservative assessment of the rate of bone loss in the first few years after menopause or cessation of hormone therapy is about 1% per year from the spine and proximal femur. At first glance, 1% per year does not appear worrisome. But within 10 years of menopause, at or about the age of only 60, 10% of the bone mass that was present at menopause is gone. In 15 years, at least 15% is gone because of estrogen deficiency.

Unquestionably, many women have stopped ERT or HRT or are choosing not to begin, due to media attention on negative findings from trials such as the combined-continuous HRT arm of the Wo men’s Health Initiative (WHI) and the Heart and Estrogen Replacement Study (HERS-I). Reviews of the National Prescription Audit database and National Disease and Therapeutic Index database confirmed a subsequent marked drop in prescriptions for ERT or HRT,⁸ despite WHI findings showing that combined-continuous HRT significantly reduces the risk of spine and hip fracture.⁹

Anne:Onset of hot flashes is a “teachable moment”

“Anne,” a 53-year-old Caucasian woman, has come to see you because of hot flashes that have begun to trouble her since her menstrual periods stopped 8 months ago.

Although she knows that estrogen replacement would help relieve her hot flashes, she is uncertain whether to use it, having heard negative media reports about WHI findings. She has no family or personal history of breast cancer, but is very frightened at even the slightest possibility of increasing her personal risk for breast cancer. She is 5’5” tall and weighs 120 lb. She broke her right wrist in a fall at age 46.

Don’t miss this opportunity!

Though Anne’s visit was prompted by distress over hot flashes, night sweats, and related symptoms of sleep disruption, daytime fatigue, mental lapses, and irritability, it’s a “teachable moment” to discuss osteoporosis prevention and testing. As is typical, her primary desire is relief from hot flashes, yet bone loss is a more serious threat.

If long-term inter vention starts early, bone loss and osteoporosis are preventable; in that context, onset of hot flashes can be seen as a positive force, since they prompted her to seek medical help.

Beth:Concerned because of her mother’s hip fracture

Occasionally a patient will raise the issue of osteoporosis herself. “Beth” is a 49-year-old woman who reports that her last menstrual period 3 months ago was very light in comparison to what she considers normal. Her periods have become irregular over the last year, initially being about 21 days apart, but now 10 to 12 weeks apart. She says she may have noticed an occasional hot flash, but it was not troublesome. She is concerned about the menstrual irregularity and wonders if she is close to menopause.

While she is not psychologically troubled about cessation of menstrual periods, she is concerned about potential bone loss due to estrogen deficiency. With additional questioning, you discover that her mother had a hip fracture.

Carol:Believes her risk low and refuses BMD test

“Carol,” on the other hand, says she doesn’t need bone density testing, because she is not interested in taking any medication to prevent or treat osteoporosis.

If Carol truly will not consider preventive medications, then bone density testing is certainly not indicated. The few patients who refuse to consider medications or testing tend to think their risk is slight. Careful questioning often elicits this belief. They may exercise, avoid cigarette smoke, and consume more than adequate amounts of calcium supplements or dairy products.

Unfortunately, such admirable habits in no way prevent estrogen-deficient bone loss.

Genetically determined low BMD

And no woman can overcome the effects of a genetically determined lower-than-average peak bone density, which may exist without the patient’s knowledge. Without a bone density test, the patient is making an uninformed decision and it is from this perspective that this situation is best approached. Her decision should always be respected, but it is our responsibility to insure that it is an informed decision.

Drug intervention based on T-score

By measuring the bone density at menopause, we can determine if pharmacologic intervention to prevent bone loss needs to start immediately. According to the National Osteoporosis Foundation (NOF) and the American Association of Clinical Endocrinologists (AACE) guidelines, if a woman’s T-score is below -1.5 and she has even 1 other risk factor, pharmacologic intervention is warranted.^12,13

This level of bone density is clearly above the threshold for a diagnosis of osteoporosis based on the WHO criteria. Nevertheless, this patient’s estrogen deficiency will further deplete her already lower-than-normal bone density, and could be rapidly devastating. Knowledge of her T-score gives us potential to prevent fractures, now that we have drugs to prevent such devastation.

 

Three guidelines (TABLE)^12-14 recommend pharmacologic intervention if the T-score is -2.5 or lower, and these guidelines differ only in the intervention threshold that also requires an additional risk factor. Note that all 3 recommend pharmacologic intervention when there is only a single risk factor in addition to a bone density level that would not be considered osteoporotic by WHO criteria.

The Food and Drug Administration (FDA) has approved drugs for prevention or treatment of postmenopausal osteoporosis, or both, based on whether data demonstrate that a drug:

• inhibits or stops bone loss, for the prevention indication, or
• reduces fracture risk, for the treatment indication.

The FDA-approved dosages of nonestrogen agents may vary by indication (TABLE). In clinical practice, however, the distinction between prevention and treatment is often less clear, leaving the dosage to the judgment of the clinician.

The complete list of clinical risk factors to consider in initiating therapy based on the T-score is lengthy; furthermore, an ever-increasing number of medications and diseases are now known to contribute to bone loss. The 5 major risk factors listed in the margin below are some of the most important to consider along with the T-score.

TABLE

Drug intervention is appropriate when there are…

	NO RISK FACTORS AND A T-SCORE:	RISK FACTORS AND A T-SCORE:
National Osteoporosis Foundation	Below -2.0	Below -1.5
American Association of Clinical Endocrinologists	At or below -2.5	-1.5 or poorer
North American Menopause Society	Below -2.5	-2.0 or poorer
FDA-approved agents for prevention and treatment of postmenopausal osteoporosis*
Alendronate
Prevention	5 mg po qd or 35 mg po qw
Treatment	10 mg po qd or 70 mg po qw
Ibandronate†	2.5 mg po qd
Risedronate	5 mg po qd or 35 mg po qw
Raloxifene	60 mg po qd
*Unless otherwise noted, doses are the same for prevention or treatment
†Although FDA-approved, ibandronate is not currently marketed in the United States

Follow-up testing intervals

Once your patient begins drug therapy, it is appropriate to follow up periodically with bone densitometry. The skeletal site measured at follow-up and the intervals between are dictated by reimbursement, as well as scientific issues. Many insurers, including Medicare, reimburse only once every 2 years.¹⁶ Exceptions are few.

From a scientific standpoint, BMD increases at the PA lumbar spine may be sufficiently great to be detected in only 1 year, with potent agents like the bisphosphonates or teriparatide. Since changes in PA lumbar spine density are generally less with raloxifene or salmon calcitonin, waiting 2 years to remeasure the PA lumbar spine is entirely appropriate here.

The PA lumbar spine is the preferred site for monitoring therapy because its higher percentage of trabecular bone generally results in a greater magnitude of change than at the proximal femur.

However, the slower rate of change at the proximal femur means that it need not be measured more often than 2 or even 3 years.

If your patient’s bone density is above the pharmacologic intervention threshold, it is always appropriate to counsel her on nonpharmacologic measures to preserve her skeleton: adequate dietary or supplemental calcium and vitamin D, regular weight-bearing or resistance exercise, and avoidance of cigarette smoke.

But we cannot assume that these are sufficient to protect her skeleton. Follow-up bone density studies are recommended to identify women who will lose bone despite these measures, and for whom pharmacologic intervention is warranted. AACE and the North American Menopause Society (NAMS) recommend follow-up bone density studies every 3 to 5 years in postmenopausal women in whom pharmacologic intervention is not deemed immediately necessary.^13,14

A more specific approach based on the patient’s lowest T-score at either the PA lumbar spine or femoral neck has been suggested.¹⁷ If her T-score is greater than 0, a repeat study is suggested in 5 years. If however, the T-score is 0 to -0.5, a repeat study is suggested in 3 years. A repeat study should be done in only 1 year if the T-score is -0.5 to -1.

This approach assumes that you wish to know when the patient’s T-score might fall below the normal range established by the WHO, that is, below a T-score of -1, and assumes a rate of bone loss of approximately 0.5 SD (or 0.5 T-score units) per year. If you know you would not intervene until the T-score reaches -1.5 or -2, you can adjust the interval accordingly.

Precision in bone density testing is integral to accurate drug therapy monitoring. When properly performed, dual energy x-ray absorptiometry (DXA) bone density measurements are highly, but not perfectly, reproducible. To reflect actual biologic changes, a measured change i n BMD must have sufficient magnitude.

In general, for measurements at the PA lumbar spine or total hip, a change of 2.77% is needed for 95% confidence. The bone densitometry testing facility should provide the clinician with the exact magnitude of the change necessary for a given level of statistical confidence.¹⁸ It is also important to remember that while increases in BMD are desirable and reassuring, no loss of BMD may also be considered efficacious.

 

The guidelines

The NOF, AACE, the American College of Obstetricians and Gynecologists (ACOG), NAMS and the United States Preventive Services Task Force (USPSTF) guidelines^12-14,19,20 agree that all postmenopausal women age 65 and older should have bone density testing. With the exception of the USPSTF, they also agree that all postmenopausal women under age 65 with risk factors should be tested. (The USPSTF limits this recommendation to women age 60 to 64.)

In reality, all postmenopausal women should have bone density testing because the list of risk factors is so comprehensive that it is unusual to find a woman who does not have at least 1 risk factor for osteoporosis.

Anne:Test again in 1 year

With this information in mind, let’s again consider Anne, the 53-year-old woman who sought help for hot flashes. Her visit was an opportunity to discuss osteoporosis prevention. Of the major risk factors, Anne has 2: weight less than 127 lb and a fracture after age 40. Based on the recommendations from the NOF, AACE, ACOG, and NAMS, bone density testing is appropriate.

A DXA study of both proximal femurs shows bone density data for each femur individually as well as the mean BMD value for each region of interest for both femurs. There are 5 regions of interest in the proximal femur: the total hip (or total femur), the femoral neck, Wa rd’s area, the trochanter, and the shaft. The total hip or femoral neck is preferred for diagnosis. Based on her normal T-scores, Anne does not meet any of the pharmacologic intervention guidelines. She should nevertheless be counseled on nonpharmacologic interventions to prevent bone loss.

She should have another bone density study in 1 year. Anne’s PA lumbar spine DXA study is not shown, but it provided no additional information. The PA lumbar spine would be the preferred site for follow-up in 1 year, however.

The recommendation for follow-up in 1 year would not change even if you elected to begin low-dose combined-continuous HRT for relief of hot flashes. Although HRT would be expected to preserve her skeleton, follow-up testing in 1 year for confirmation is appropriate.²¹

Beth:Treat now, test in 1 yr

Beth has an important risk factor: her mother’s hip fracture. This raises the possibility that she is genetically predisposed to lowerthan-average peak bone density. She meets NOF, AACE, NAMS, and ACOG guidelines for bone density testing.

At the PA lumbar spine, it is preferable to use either the L1-L4 BMD or the L2-L4 BMD and the corresponding T-score. In either case, Beth’s T-score is disturbingly low at -3.7 and -3.6, respectively. Either T-score meets the diagnosis of osteoporosis based on WHO criteria.

This single bone density study does not reveal whether she has lost bone density from a previously higher level or whether her current bone density represents her peak bone density. It is incumbent on the physician to evaluate her medically to exclude possible causes of bone loss other than estrogen deficiency, which might require a different or additional therapy.

Beth certainly meets NOF, AACE, and NAMS guidelines for drug intervention.

A follow-up PA lumbar spine DXA study is indicated in 1 year. Although she has osteoporosis, she has not yet had a fracture. For now, her diagnosis is nothing more than a test result. An osteoporotic fracture will change that. Immediate intervention with drug therapy can preserve her skeletal mass and her quality of life.

Donna:Borderline T-scores

Treatment decisions are not always as clear as in the cases of Anne, Beth, and Carol. Consider Donna, age 54, who is 2 years postmenopausal and in good health. However, her mother reportedly had a dowager’s hump at the time of her death. Although Donna was never told that her mother had osteoporosis, you suspect that she did because of the kyphosis. Donna is fairly sedentary, thin, and continues to smoke. She is not using HRT and rarely takes nutritional supplements of any kind. L 1 - L 4 PA lumbar spine T-score is -1.4; total hip is -1.3.

The dilemma is that Donna does not meet any guideline for pharmacologic intervention based on T-score, even in the presence of risk factors. Both T-scores are just above the NOF and AACE cutoff points, even in the presence of risk factors.

But the guidelines are not hard and fast rules. T- score cutoff points, with or without other risk factors, were chosen to balance the potential benefit and any potential harm of pharmacologic therapy with the risk of fracture if untreated. So, while it may seem arbitrary to recommend treatment when the T- score is -1.5 with risk factors, yet not if the T-score is -1.4 or -1.3, there is a substantive rationale behind the recommendation. Still, there is no substitute for your judgment.

 

What is a reasonable course?

She has 6 risk factors for bone loss and osteoporosis: estrogen deficiency, current smoking, probable family history, thinness, sedentary lifestyle, and probable calcium deficiency. Every attempt to modify the risk factors that can be modified is worth the effort—smoking cessation, exercise, and calcium and vitamin D supplementation would benefit her skeleton.

Important: Test again in 1 year. It is extremely important to repeat bone density testing at the lumbar spine in 1 year. If the nonpharmacologic interventions you recommend prove insufficient to radically slow the anticipated bone loss, she will fall below a T-score of -1.5 in the next year.

On the other hand, if she demonstrates that she can maintain her bone density with nonpharmacologic measures, a prescription may not be warranted. It would not be unreasonable to allow her this 1 year, because at her relatively young age of 54, at this bone density, her short-term risk of fracture is actually quite low.

“Yes” to both questions

If bone density is low—particularly if it is low and a woman has risk factors for osteoporosis—pharmacologic intervention can be reasonably expected to prevent the devastating consequences of osteoporosis. The question, “Does this menopausal woman need pharmacologic intervention to prevent or treat osteoporosis now, or might she need it later?” can be answered by measuring bone density. It is a question we would be remiss not to ask. Bone density measurement, preferably at the PA lumbar spine and proximal femur by DXA, is the only way to answer this all-important question. To provide the best care possible for a woman who has just become menopausal, you do need to know her bone density. The simple answer to both original questions then, is yes.

 

Dr. Bonnick reports research support from Merck and Roche/GSK; consultant fees from Merck, Roche/GSK, and Wyeth; and speaking fees from Merck, Roche/GSK, and Procter & Gamble.

Once you decide to expectantly manage a patient with preeclampsia, the balancing act begins. That means weighing fetal benefits against maternal risks, since the only justification for expectant management is to prolong pregnancy for fetal gain—there is no advantage to the mother.

The best approach is to classify the woman’s preeclampsia by the degree of severity and gestational age at the time of diagnosis, then follow recommendations tailored to that particular category.

This article offers guidelines for expectant management of mild and severe preeclampsia, preeclampsia superimposed on a preexisting medical condition, and intrapartum and postpartum care.

Mild preeclampsia

The earlier preeclampsia develops, the greater the risk it will become severe. The need for hospitalization depends on gestational age, blood pressure, proteinuria levels, maternal symptoms, and reliability of the patient.

Preeclampsia is mild when systolic blood pressure reaches 140 to 159 mm Hg or diastolic pressure measures 90 to 109 mm Hg on at least 2 occasions more than 6 hours apart after 20 weeks’ gestation in a woman who previously had normal blood pressure. In preeclampsia, this hypertension is accompanied by proteinuria of 0.3 to 4.9 g in a 24-hour urine sample (1+ or 2+ by dipstick on 2 occasions).

At or beyond 37 weeks’ gestation

In general, women diagnosed with preeclampsia at this gestational age have pregnancy outcomes similar to those of normotensive gravidas. Thus, they benefit from induction of labor and delivery.

32 to 36 weeks’ gestation

Close maternal and fetal evaluation is essential. (It is assumed these women have no labor or membrane rupture and normal fetal testing; otherwise, delivery is indicated at 34 weeks or beyond.)

In general, hospitalization is indicated when any of the following circumstances are present (FIGURE 1):

• the patient is unreliable,
• 2 or more systolic blood pressure readings exceed 150 mm Hg,
• 2 or more diastolic blood pressure readings exceed 100 mm Hg,
• proteinuria occurs at a rate exceeding 1 g/24 hours, or
• persistent maternal symptoms are present.

FIGURE 1 Treatment of mild preeclampsia in healthy women

Before 32 weeks’ gestation

These women are at high risk of progressing to severe disease. They also are more likely to have adverse perinatal outcomes such as intrauterine growth restriction (IUGR) (15% to 20%), preterm delivery (50%), and abruptio placentae (1% to 2%), compared with women diagnosed with preeclampsia at 32 to 36 weeks. In addition, they require more antenatal surveillance than women who develop preeclampsia later in pregnancy.

I recommend hospitalization at the time of diagnosis when women develop mild preeclampsia before 32 weeks.

What and when to monitor

Maternal evaluation should include:

• monitoring of blood pressure at least daily (at home or in the hospital),
• daily urine dipstick evaluation to monitor changes in proteinuria,
• twice-weekly platelet count and liver enzymes, and
• documentation of symptoms. (Instruct all women to report the onset of severe headaches, visual changes, altered mental status, epigastric or right upper quadrant pain, and any nausea or vomiting.)

Fetal evaluation should include:

• serial ultrasound every 3 weeks to estimate fetal weight and amniotic fluid status,
• nonstress testing every week, and
• daily fetal movement counts.

If a nonstress test is nonreactive, it should be confirmed by biophysical profile.

All testing should be promptly repeated if the maternal clinical condition deteriorates.

No need for bed rest, diuretics, or antihypertensive medications

Although expectantly managed patients with mild preeclampsia should be advised to restrict daily activity, there is no need for complete bed rest. Nor have diuretics or other antihypertensive drugs been shown to prolong gestation. On the contrary, these medications may mask severe preeclampsia.

Antihypertensive medications reduce the rate of severe hypertension but do not improve perinatal outcome. If these drugs are used to treat mild disease remote from term, hospitalize the patient and manage her as though she has severe preeclampsia.

Hospitalization versus outpatient management

Although she may be hospitalized at the time of diagnosis, a woman with preeclampsia may switch to outpatient management if systolic or diastolic blood pressure declines, proteinuria diminishes to 1 g/24 hours or less, and there are no maternal symptoms or evidence of severe IUGR. Otherwise, these women should remain hospitalized until delivery.

 

In cases that begin with outpatient management, prompt hospitalization is indicated if there is clinical evidence that the disease is progressing (ie, new symptoms, labor or rupture of membranes, vaginal bleeding, or increased blood pressures or proteinuria) or IUGR and/or oligohydramnios.

Instruct all women to report symptoms and changes in fetal movement.

When to deliver

Whether the gravida is hospitalized or an outpatient, delivery is indicated at 37 weeks. Earlier delivery may be warranted if nonreassuring maternal or fetal conditions develop. (FIGURE 1 summarizes management of mild preeclampsia.)

Severe preeclampsia

Expectant management is safe in properly selected women with severe disease, although maternal and fetal conditions can deteriorate. Hospitalization and daily monitoring are required.

Preeclampsia is severe when any of the following are present:

• systolic blood pressure of 160 mm Hg or higher or diastolic pressure of 110 mm Hg or above on 2 occasions at least 6 hours apart while the patient is on bed rest
• proteinuria of 5 g or more in a 24-hour urine specimen,
• oliguria of less than 500 mL in 24 hours,
• cerebral or visual disturbances,
• pulmonary edema or cyanosis,
• severe epigastric or right upper-quadrant pain, or
• thrombocytopenia.

When gestational hypertension or preeclampsia is severe, hospitalization in the labor and delivery suite is warranted. These women should receive intravenous (IV) magnesium sulfate to reduce the risk of convulsions and antihypertensive drugs to treat severe levels of hypertension, if present. The aim of antihypertensive treatment is to keep diastolic blood pressure between 90 and 105 mm Hg and systolic blood pressure below 160 mm Hg.

During observation, assess maternal and fetal conditions and decide whether delivery is indicated (FIGURE 2).

Expectant management is warranted only for gestations between 23 and 32 weeks’ gestation, provided maternal and fetal conditions are stable (FIGURE 2).

Keep in mind that both maternal and fetal conditions may progressively deteriorate. Thus, these pregnancies involve higher rates of maternal morbidity and significant risk of neonatal morbidity. For this reason, expectant management should proceed only in a tertiary-care center with adequate maternal and neonatal facilities.

Recommended counseling

Advise these patients of the potential risks and benefits of expectant management, which requires daily monitoring of maternal and fetal conditions. Also explain that the decision to continue expectant management will be revisited on a daily basis and that the median number of days pregnancy is prolonged in these cases is 7 (range 2 to 35).

Another important fact to relay: Only 2 randomized trials involving 133 women have compared expectant management to aggressive management in early-onset preeclampsia. However, retrospective and observational studies involving more than 700 women suggest expectant management reduces short-term neonatal morbidity with minimal risk to the mother.

Superimposed preeclampsia

Women who develop preeclampsia on top of chronic hypertension, renal disease, or type 1 diabetes have a markedly higher risk of morbidity, including perinatal morbidity, than women without preexisting conditions.

Women with superimposed preeclampsia may be managed in the hospital, since these pregnancies are associated with higher rates of abruptio placentae (2% to 5%), preterm delivery (56%), IUGR (13% to 15%), and perinatal death (8%). Thus, these women benefit from very close maternal and fetal monitoring.

Superimposed preeclampsia is not classified according to severity.

In general, maternal and perinatal morbidities are substantially higher in women who have preexisting conditions than in healthy women who develop preeclampsia.

Chronic hypertension

Indications for delivery are similar to those described for healthy women with preeclampsia, as is antihypertensive therapy.

If the woman develops preeclampsia while using antihypertensive drugs, delivery should be considered beyond 34 weeks’ gestation.

How preeclampsia affects renal function

Women with renal disease or dysfunction (serum creatinine ≥1.2 mg/dL) prior to or early in pregnancy face an increased risk of adverse neonatal outcomes, regardless of whether preeclampsia also develops. These women also face an increased risk of deteriorating renal function during pregnancy (particularly if preeclampsia or severe hypertension develops) and beyond (more than 6 months postpartum).

Start antihypertensive medications as soon as possible, with the goal of keeping systolic blood pressure below 140 mm Hg and diastolic blood pressure below 90 mm Hg throughout gestation.

Delivery is indicated with the onset of preeclampsia or significant deterioration in renal function.

Diabetes warrants aggressive therapy

Women with type 1 diabetes have a higher risk of preeclampsia, maternal and fetal morbidity, and perinatal mortality. These risks multiply in women who have hypertension and/or diabetic nephropathy. Worsening of retinopathy and nephropathy also is more likely in women who have hypertension. Thus, aggressive management of blood sugars with insulin should be accompanied by aggressive control of blood pressure, with the goal of keeping systolic pressure below 130 mm Hg and diastolic pressure below 85 mm Hg.

 

Choosing antihypertensive drugs. Calcium-channel blockers are preferred to control blood pressure during pregnancy in women with diabetes. Outside of pregnancy, angiotensin-converting enzyme (ACE) inhibitors are best to avert long-term complications, but avoid these drugs in pregnancy (along with angiotensin-receptor blockers), particularly beyond 16 weeks.

Delivery is indicated in all women with vascular diabetes mellitus beyond 34 weeks when preeclampsia is present.

Intrapartum management

Close fetal heart rate and maternal blood pressure monitoring are mainstays, along with magnesium sulfate and antihypertensive therapy.

All women with preeclampsia should receive continuous monitoring of fetal heart rate and uterine activity, with special vigilance for hyperstimulation and onset of vaginal bleeding during labor. (For a description of potential maternal complications, see TABLE 1; fetal complications are described in FIGURE 3.)

Uterine irritability, recurrent variable or late decelerations, and the development of vaginal bleeding may be the first signs of abruptio placentae.

I recommend recording maternal blood pressure at least hourly to detect progression from mild to severe hypertension and to determine the need for antihypertensive therapy.

TABLE 1

Likelihood of maternal complications

Disease progresses during labor (from mild to severe)	10%
Eclampsia
• Mild disease	<0.5%
• Severe preeclampsia	1–2%
Stroke (encephalopathy or hemorrhage)	<1%
Mainly with severe or early onset disease
Pulmonary edema	1–2%
Usually associated with fluid overload or long-standing chronic hypertension

Prevent progression to eclampsia

Magnesium sulfate is the drug of choice in women with preeclampsia. Recent reviews indicate that it reduces the rate of convulsions from 2% to 0.6% in women with severe preeclampsia. In women with mild preeclampsia, the benefit of magnesium sulfate remains unclear.

I recommend IV magnesium sulfate during labor and postpartum when a woman has the indications listed in TABLE 2.

The dose of magnesium sulfate is 6 g IV loading over 20 minutes, followed by a maintenance dose of 2 g/hour.

Magnesium sulfate should be started before surgery (elective cesarean delivery) and continued for at least 12 hours postpartum (I prefer 24 hours).

TABLE 2

When to give prophylactic magnesium sulfate

Use intrapartum and for at least 12 hours postpartum
When the patient has: Severe hypertension or preeclampsia Mild preeclampsia with symptoms Mild hypertension plus symptoms or thrombocytopenia HELLP syndrome (Hemolysis, elevated liver enzymes, and low platelets)

When treating hypertension in labor, avoid “hypotensive overshoot”

The goal of intrapartum treatment is to lower maternal blood pressure without causing precipitous hypotensive overshoot that may lead to reduced maternal organ perfusion, particularly uteroplacental blood flow. Such acute lowering of maternal blood pressure is a common cause of nonreassuring fetal heart rate patterns during labor.

What blood pressure necessitates treatment? There is no doubt that severe levels of hypertension should be treated to avoid potential cerebrovascular and cardiovascular complications in healthy women. However, there is disagreement about what constitutes severe hypertension.

In previously healthy women, I recommend antihypertensive therapy for systolic pressures of 170 mm Hg or above and/or for diastolic pressures of 110 mm Hg or above.

For women with thrombocytopenia, disseminated intravascular coagulation, or pulmonary edema, I recommend treatment for systolic pressures of 160 mm Hg or above and diastolic pressures of 105 mm Hg or above. This latter group should also be given IV furosemide (20 to 40 mg) to promote diuresis. I also recommend treatment at these levels in the postpartum period.

For women with diabetes, renal disease, or left ventricular cardiac disease, antihypertensive medications should be used to keep systolic pressure below 140 mm Hg and diastolic pressure below 90 mm Hg during labor and postpartum. Further, patients in congestive heart failure or with left ventricular diastolic dysfunction should receive furosemide in addition to antihypertensive drugs.

Choosing a drug. My drugs of choice are IV labetalol and oral nifedipine. These 2 drugs, along with IV hydralazine, are the most commonly recommended medications for severe hypertension in pregnancy (TABLE 3).

Although many authorities prefer hydralazine, recent data indicate that, compared with IV labetalol and oral nifedipine, IV hydralazine is associated with more maternal side effects and worse perinatal outcomes (more fetal distress in labor).

TABLE 3

Drug profiles: Dosing and side effects of antihypertensives used in pregnancy

MEDICATION	ONSET OF ACTION	DOSE	SIDE EFFECTS
Hydralazine	10-20 minutes	5-10 mg intravenously every 20 minutes up to maximum dose of 30 mg	More maternal side effects and worse perinatal outcomes than labetalol or nifedipine.
			Skin blisters; chest pain; general feeling of discomfort, illness, or weakness; joint or muscle pain; sore throat and fever; swollen lymph glands
Labetalol*	10-15 minutes	10-20 mg intravenously, then 40-80 mg every 10 minutes up to maximum dose of 220 mg/hour or continuous infusion of 1-2 mg/minute	Breathing difficulty and/or wheezing, cold hands and feet, mental depression, shortness of breath, slow heartbeat, swelling of lower extremities, back or joint pain, chest pain, confusion, fever and sore throat, hallucinations, irregular heartbeat, unusual bleeding and bruising, yellow eyes or skin
Nifedipine	5-10 minutes	10-20 mg orally, repeated in 30 minutes, up to maximum dose of 50 mg/hour	Breathing difficulty, coughing, or wheezing; irregular or fast, poundingheartbeat; skin rash; swelling of lower extremities; chest pain; fainting; painful, swollen joints; vision impairment
Sodium nitroprusside†	0.5-5 minutes	0.25-5 μg/kg/minute by intravenous infusion	Risk of fetal cyanide poisoning with prolonged treatment.
			Maternal effects include symptoms of hypothyroidism, headache, abdominal pain, drowsiness, nausea, involuntary muscle movements, perspiration, restlessness, paraesthesia, palpitations, dizziness, retching, tachycardia
*In women with asthma and congestive heart failure
†Rarely needed except in hypertensive encephalopathy or cerebral hemorrhage

 

Postpartum management

Because preeclampsia can worsen, or first appear, in the postpartum period, extra vigilance is important, and pharmacotherapy may be appropriate.

Management of preeclampsia does not end with delivery of the fetus and the placenta. These events do signal the beginning of the curative process, but complications can occur in the postpartum period. Indeed, in some women, the disease process worsens immediately postpartum. Therefore, women with diagnosed preeclampsia or severe gestational hypertension require close monitoring of blood pressure and maternal symptoms and accurate measurement of fluid intake and urine output. Some of these women are at increased risk for pulmonary edema; exacerbation of severe hypertension; eclampsia; and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.

Treating postpartum hypertension

Women who continue to have severe hypertension (systolic pressure at or above 155 mm Hg or diastolic pressure of 105 mm Hg or higher) will benefit from oral nifedipine (10 mg every 6 hours) or long-acting nifedipine (10 to 20 mg twice daily), the drugs of choice because of their favorable effects on renal function.

Women with severe hypertension also may require diuretics for better control of blood pressure, as may women with a history of congestive heart failure or left ventricular dysfunction.

Start women with vascular diabetes mellitus or diabetic nephropathy on ACE inhibitors immediately postpartum.

Patients can be discharged home once blood pressure is stable, provided there are no maternal symptoms of preeclampsia.

Postpartum preeclampsia can develop even in healthy women

Because severe hypertension or preeclampsia may develop for the first time in the postpartum period, it is important to educate all gravidas about the signs and symptoms. All health-care providers should be on the lookout for these symptoms as well.

The author reports no financial relationships relevant to this article.

Once you decide to expectantly manage a patient with preeclampsia, the balancing act begins. That means weighing fetal benefits against maternal risks, since the only justification for expectant management is to prolong pregnancy for fetal gain—there is no advantage to the mother.

The best approach is to classify the woman’s preeclampsia by the degree of severity and gestational age at the time of diagnosis, then follow recommendations tailored to that particular category.

This article offers guidelines for expectant management of mild and severe preeclampsia, preeclampsia superimposed on a preexisting medical condition, and intrapartum and postpartum care.

Mild preeclampsia

The earlier preeclampsia develops, the greater the risk it will become severe. The need for hospitalization depends on gestational age, blood pressure, proteinuria levels, maternal symptoms, and reliability of the patient.

Preeclampsia is mild when systolic blood pressure reaches 140 to 159 mm Hg or diastolic pressure measures 90 to 109 mm Hg on at least 2 occasions more than 6 hours apart after 20 weeks’ gestation in a woman who previously had normal blood pressure. In preeclampsia, this hypertension is accompanied by proteinuria of 0.3 to 4.9 g in a 24-hour urine sample (1+ or 2+ by dipstick on 2 occasions).

At or beyond 37 weeks’ gestation

In general, women diagnosed with preeclampsia at this gestational age have pregnancy outcomes similar to those of normotensive gravidas. Thus, they benefit from induction of labor and delivery.

32 to 36 weeks’ gestation

Close maternal and fetal evaluation is essential. (It is assumed these women have no labor or membrane rupture and normal fetal testing; otherwise, delivery is indicated at 34 weeks or beyond.)

In general, hospitalization is indicated when any of the following circumstances are present (FIGURE 1):

• the patient is unreliable,
• 2 or more systolic blood pressure readings exceed 150 mm Hg,
• 2 or more diastolic blood pressure readings exceed 100 mm Hg,
• proteinuria occurs at a rate exceeding 1 g/24 hours, or
• persistent maternal symptoms are present.

FIGURE 1 Treatment of mild preeclampsia in healthy women

Before 32 weeks’ gestation

These women are at high risk of progressing to severe disease. They also are more likely to have adverse perinatal outcomes such as intrauterine growth restriction (IUGR) (15% to 20%), preterm delivery (50%), and abruptio placentae (1% to 2%), compared with women diagnosed with preeclampsia at 32 to 36 weeks. In addition, they require more antenatal surveillance than women who develop preeclampsia later in pregnancy.

I recommend hospitalization at the time of diagnosis when women develop mild preeclampsia before 32 weeks.

What and when to monitor

Maternal evaluation should include:

• monitoring of blood pressure at least daily (at home or in the hospital),
• daily urine dipstick evaluation to monitor changes in proteinuria,
• twice-weekly platelet count and liver enzymes, and
• documentation of symptoms. (Instruct all women to report the onset of severe headaches, visual changes, altered mental status, epigastric or right upper quadrant pain, and any nausea or vomiting.)

Fetal evaluation should include:

• serial ultrasound every 3 weeks to estimate fetal weight and amniotic fluid status,
• nonstress testing every week, and
• daily fetal movement counts.

If a nonstress test is nonreactive, it should be confirmed by biophysical profile.

All testing should be promptly repeated if the maternal clinical condition deteriorates.

No need for bed rest, diuretics, or antihypertensive medications

Although expectantly managed patients with mild preeclampsia should be advised to restrict daily activity, there is no need for complete bed rest. Nor have diuretics or other antihypertensive drugs been shown to prolong gestation. On the contrary, these medications may mask severe preeclampsia.

Antihypertensive medications reduce the rate of severe hypertension but do not improve perinatal outcome. If these drugs are used to treat mild disease remote from term, hospitalize the patient and manage her as though she has severe preeclampsia.

Hospitalization versus outpatient management

Although she may be hospitalized at the time of diagnosis, a woman with preeclampsia may switch to outpatient management if systolic or diastolic blood pressure declines, proteinuria diminishes to 1 g/24 hours or less, and there are no maternal symptoms or evidence of severe IUGR. Otherwise, these women should remain hospitalized until delivery.

 

In cases that begin with outpatient management, prompt hospitalization is indicated if there is clinical evidence that the disease is progressing (ie, new symptoms, labor or rupture of membranes, vaginal bleeding, or increased blood pressures or proteinuria) or IUGR and/or oligohydramnios.

Instruct all women to report symptoms and changes in fetal movement.

When to deliver

Whether the gravida is hospitalized or an outpatient, delivery is indicated at 37 weeks. Earlier delivery may be warranted if nonreassuring maternal or fetal conditions develop. (FIGURE 1 summarizes management of mild preeclampsia.)

Severe preeclampsia

Expectant management is safe in properly selected women with severe disease, although maternal and fetal conditions can deteriorate. Hospitalization and daily monitoring are required.

Preeclampsia is severe when any of the following are present:

• systolic blood pressure of 160 mm Hg or higher or diastolic pressure of 110 mm Hg or above on 2 occasions at least 6 hours apart while the patient is on bed rest
• proteinuria of 5 g or more in a 24-hour urine specimen,
• oliguria of less than 500 mL in 24 hours,
• cerebral or visual disturbances,
• pulmonary edema or cyanosis,
• severe epigastric or right upper-quadrant pain, or
• thrombocytopenia.

When gestational hypertension or preeclampsia is severe, hospitalization in the labor and delivery suite is warranted. These women should receive intravenous (IV) magnesium sulfate to reduce the risk of convulsions and antihypertensive drugs to treat severe levels of hypertension, if present. The aim of antihypertensive treatment is to keep diastolic blood pressure between 90 and 105 mm Hg and systolic blood pressure below 160 mm Hg.

During observation, assess maternal and fetal conditions and decide whether delivery is indicated (FIGURE 2).

Expectant management is warranted only for gestations between 23 and 32 weeks’ gestation, provided maternal and fetal conditions are stable (FIGURE 2).

Keep in mind that both maternal and fetal conditions may progressively deteriorate. Thus, these pregnancies involve higher rates of maternal morbidity and significant risk of neonatal morbidity. For this reason, expectant management should proceed only in a tertiary-care center with adequate maternal and neonatal facilities.

Recommended counseling

Advise these patients of the potential risks and benefits of expectant management, which requires daily monitoring of maternal and fetal conditions. Also explain that the decision to continue expectant management will be revisited on a daily basis and that the median number of days pregnancy is prolonged in these cases is 7 (range 2 to 35).

Another important fact to relay: Only 2 randomized trials involving 133 women have compared expectant management to aggressive management in early-onset preeclampsia. However, retrospective and observational studies involving more than 700 women suggest expectant management reduces short-term neonatal morbidity with minimal risk to the mother.

Superimposed preeclampsia

Women who develop preeclampsia on top of chronic hypertension, renal disease, or type 1 diabetes have a markedly higher risk of morbidity, including perinatal morbidity, than women without preexisting conditions.

Women with superimposed preeclampsia may be managed in the hospital, since these pregnancies are associated with higher rates of abruptio placentae (2% to 5%), preterm delivery (56%), IUGR (13% to 15%), and perinatal death (8%). Thus, these women benefit from very close maternal and fetal monitoring.

Superimposed preeclampsia is not classified according to severity.

In general, maternal and perinatal morbidities are substantially higher in women who have preexisting conditions than in healthy women who develop preeclampsia.

Chronic hypertension

Indications for delivery are similar to those described for healthy women with preeclampsia, as is antihypertensive therapy.

If the woman develops preeclampsia while using antihypertensive drugs, delivery should be considered beyond 34 weeks’ gestation.

How preeclampsia affects renal function

Women with renal disease or dysfunction (serum creatinine ≥1.2 mg/dL) prior to or early in pregnancy face an increased risk of adverse neonatal outcomes, regardless of whether preeclampsia also develops. These women also face an increased risk of deteriorating renal function during pregnancy (particularly if preeclampsia or severe hypertension develops) and beyond (more than 6 months postpartum).

Start antihypertensive medications as soon as possible, with the goal of keeping systolic blood pressure below 140 mm Hg and diastolic blood pressure below 90 mm Hg throughout gestation.

Delivery is indicated with the onset of preeclampsia or significant deterioration in renal function.

Diabetes warrants aggressive therapy

Women with type 1 diabetes have a higher risk of preeclampsia, maternal and fetal morbidity, and perinatal mortality. These risks multiply in women who have hypertension and/or diabetic nephropathy. Worsening of retinopathy and nephropathy also is more likely in women who have hypertension. Thus, aggressive management of blood sugars with insulin should be accompanied by aggressive control of blood pressure, with the goal of keeping systolic pressure below 130 mm Hg and diastolic pressure below 85 mm Hg.

 

Choosing antihypertensive drugs. Calcium-channel blockers are preferred to control blood pressure during pregnancy in women with diabetes. Outside of pregnancy, angiotensin-converting enzyme (ACE) inhibitors are best to avert long-term complications, but avoid these drugs in pregnancy (along with angiotensin-receptor blockers), particularly beyond 16 weeks.

Delivery is indicated in all women with vascular diabetes mellitus beyond 34 weeks when preeclampsia is present.

Intrapartum management

Close fetal heart rate and maternal blood pressure monitoring are mainstays, along with magnesium sulfate and antihypertensive therapy.

All women with preeclampsia should receive continuous monitoring of fetal heart rate and uterine activity, with special vigilance for hyperstimulation and onset of vaginal bleeding during labor. (For a description of potential maternal complications, see TABLE 1; fetal complications are described in FIGURE 3.)

Uterine irritability, recurrent variable or late decelerations, and the development of vaginal bleeding may be the first signs of abruptio placentae.

I recommend recording maternal blood pressure at least hourly to detect progression from mild to severe hypertension and to determine the need for antihypertensive therapy.

TABLE 1

Likelihood of maternal complications

Disease progresses during labor (from mild to severe)	10%
Eclampsia
• Mild disease	<0.5%
• Severe preeclampsia	1–2%
Stroke (encephalopathy or hemorrhage)	<1%
Mainly with severe or early onset disease
Pulmonary edema	1–2%
Usually associated with fluid overload or long-standing chronic hypertension

Prevent progression to eclampsia

Magnesium sulfate is the drug of choice in women with preeclampsia. Recent reviews indicate that it reduces the rate of convulsions from 2% to 0.6% in women with severe preeclampsia. In women with mild preeclampsia, the benefit of magnesium sulfate remains unclear.

I recommend IV magnesium sulfate during labor and postpartum when a woman has the indications listed in TABLE 2.

The dose of magnesium sulfate is 6 g IV loading over 20 minutes, followed by a maintenance dose of 2 g/hour.

Magnesium sulfate should be started before surgery (elective cesarean delivery) and continued for at least 12 hours postpartum (I prefer 24 hours).

TABLE 2

When to give prophylactic magnesium sulfate

Use intrapartum and for at least 12 hours postpartum
When the patient has: Severe hypertension or preeclampsia Mild preeclampsia with symptoms Mild hypertension plus symptoms or thrombocytopenia HELLP syndrome (Hemolysis, elevated liver enzymes, and low platelets)

When treating hypertension in labor, avoid “hypotensive overshoot”

The goal of intrapartum treatment is to lower maternal blood pressure without causing precipitous hypotensive overshoot that may lead to reduced maternal organ perfusion, particularly uteroplacental blood flow. Such acute lowering of maternal blood pressure is a common cause of nonreassuring fetal heart rate patterns during labor.

What blood pressure necessitates treatment? There is no doubt that severe levels of hypertension should be treated to avoid potential cerebrovascular and cardiovascular complications in healthy women. However, there is disagreement about what constitutes severe hypertension.

In previously healthy women, I recommend antihypertensive therapy for systolic pressures of 170 mm Hg or above and/or for diastolic pressures of 110 mm Hg or above.

For women with thrombocytopenia, disseminated intravascular coagulation, or pulmonary edema, I recommend treatment for systolic pressures of 160 mm Hg or above and diastolic pressures of 105 mm Hg or above. This latter group should also be given IV furosemide (20 to 40 mg) to promote diuresis. I also recommend treatment at these levels in the postpartum period.

For women with diabetes, renal disease, or left ventricular cardiac disease, antihypertensive medications should be used to keep systolic pressure below 140 mm Hg and diastolic pressure below 90 mm Hg during labor and postpartum. Further, patients in congestive heart failure or with left ventricular diastolic dysfunction should receive furosemide in addition to antihypertensive drugs.

Choosing a drug. My drugs of choice are IV labetalol and oral nifedipine. These 2 drugs, along with IV hydralazine, are the most commonly recommended medications for severe hypertension in pregnancy (TABLE 3).

Although many authorities prefer hydralazine, recent data indicate that, compared with IV labetalol and oral nifedipine, IV hydralazine is associated with more maternal side effects and worse perinatal outcomes (more fetal distress in labor).

TABLE 3

Drug profiles: Dosing and side effects of antihypertensives used in pregnancy

MEDICATION	ONSET OF ACTION	DOSE	SIDE EFFECTS
Hydralazine	10-20 minutes	5-10 mg intravenously every 20 minutes up to maximum dose of 30 mg	More maternal side effects and worse perinatal outcomes than labetalol or nifedipine.
			Skin blisters; chest pain; general feeling of discomfort, illness, or weakness; joint or muscle pain; sore throat and fever; swollen lymph glands
Labetalol*	10-15 minutes	10-20 mg intravenously, then 40-80 mg every 10 minutes up to maximum dose of 220 mg/hour or continuous infusion of 1-2 mg/minute	Breathing difficulty and/or wheezing, cold hands and feet, mental depression, shortness of breath, slow heartbeat, swelling of lower extremities, back or joint pain, chest pain, confusion, fever and sore throat, hallucinations, irregular heartbeat, unusual bleeding and bruising, yellow eyes or skin
Nifedipine	5-10 minutes	10-20 mg orally, repeated in 30 minutes, up to maximum dose of 50 mg/hour	Breathing difficulty, coughing, or wheezing; irregular or fast, poundingheartbeat; skin rash; swelling of lower extremities; chest pain; fainting; painful, swollen joints; vision impairment
Sodium nitroprusside†	0.5-5 minutes	0.25-5 μg/kg/minute by intravenous infusion	Risk of fetal cyanide poisoning with prolonged treatment.
			Maternal effects include symptoms of hypothyroidism, headache, abdominal pain, drowsiness, nausea, involuntary muscle movements, perspiration, restlessness, paraesthesia, palpitations, dizziness, retching, tachycardia
*In women with asthma and congestive heart failure
†Rarely needed except in hypertensive encephalopathy or cerebral hemorrhage

 

Postpartum management

Because preeclampsia can worsen, or first appear, in the postpartum period, extra vigilance is important, and pharmacotherapy may be appropriate.

Management of preeclampsia does not end with delivery of the fetus and the placenta. These events do signal the beginning of the curative process, but complications can occur in the postpartum period. Indeed, in some women, the disease process worsens immediately postpartum. Therefore, women with diagnosed preeclampsia or severe gestational hypertension require close monitoring of blood pressure and maternal symptoms and accurate measurement of fluid intake and urine output. Some of these women are at increased risk for pulmonary edema; exacerbation of severe hypertension; eclampsia; and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.

Treating postpartum hypertension

Women who continue to have severe hypertension (systolic pressure at or above 155 mm Hg or diastolic pressure of 105 mm Hg or higher) will benefit from oral nifedipine (10 mg every 6 hours) or long-acting nifedipine (10 to 20 mg twice daily), the drugs of choice because of their favorable effects on renal function.

Women with severe hypertension also may require diuretics for better control of blood pressure, as may women with a history of congestive heart failure or left ventricular dysfunction.

Start women with vascular diabetes mellitus or diabetic nephropathy on ACE inhibitors immediately postpartum.

Patients can be discharged home once blood pressure is stable, provided there are no maternal symptoms of preeclampsia.

Postpartum preeclampsia can develop even in healthy women

Because severe hypertension or preeclampsia may develop for the first time in the postpartum period, it is important to educate all gravidas about the signs and symptoms. All health-care providers should be on the lookout for these symptoms as well.

The author reports no financial relationships relevant to this article.

Once you decide to expectantly manage a patient with preeclampsia, the balancing act begins. That means weighing fetal benefits against maternal risks, since the only justification for expectant management is to prolong pregnancy for fetal gain—there is no advantage to the mother.

The best approach is to classify the woman’s preeclampsia by the degree of severity and gestational age at the time of diagnosis, then follow recommendations tailored to that particular category.

This article offers guidelines for expectant management of mild and severe preeclampsia, preeclampsia superimposed on a preexisting medical condition, and intrapartum and postpartum care.

Mild preeclampsia

The earlier preeclampsia develops, the greater the risk it will become severe. The need for hospitalization depends on gestational age, blood pressure, proteinuria levels, maternal symptoms, and reliability of the patient.

Preeclampsia is mild when systolic blood pressure reaches 140 to 159 mm Hg or diastolic pressure measures 90 to 109 mm Hg on at least 2 occasions more than 6 hours apart after 20 weeks’ gestation in a woman who previously had normal blood pressure. In preeclampsia, this hypertension is accompanied by proteinuria of 0.3 to 4.9 g in a 24-hour urine sample (1+ or 2+ by dipstick on 2 occasions).

At or beyond 37 weeks’ gestation

In general, women diagnosed with preeclampsia at this gestational age have pregnancy outcomes similar to those of normotensive gravidas. Thus, they benefit from induction of labor and delivery.

32 to 36 weeks’ gestation

Close maternal and fetal evaluation is essential. (It is assumed these women have no labor or membrane rupture and normal fetal testing; otherwise, delivery is indicated at 34 weeks or beyond.)

In general, hospitalization is indicated when any of the following circumstances are present (FIGURE 1):

• the patient is unreliable,
• 2 or more systolic blood pressure readings exceed 150 mm Hg,
• 2 or more diastolic blood pressure readings exceed 100 mm Hg,
• proteinuria occurs at a rate exceeding 1 g/24 hours, or
• persistent maternal symptoms are present.

FIGURE 1 Treatment of mild preeclampsia in healthy women

Before 32 weeks’ gestation

These women are at high risk of progressing to severe disease. They also are more likely to have adverse perinatal outcomes such as intrauterine growth restriction (IUGR) (15% to 20%), preterm delivery (50%), and abruptio placentae (1% to 2%), compared with women diagnosed with preeclampsia at 32 to 36 weeks. In addition, they require more antenatal surveillance than women who develop preeclampsia later in pregnancy.

I recommend hospitalization at the time of diagnosis when women develop mild preeclampsia before 32 weeks.

What and when to monitor

Maternal evaluation should include:

• monitoring of blood pressure at least daily (at home or in the hospital),
• daily urine dipstick evaluation to monitor changes in proteinuria,
• twice-weekly platelet count and liver enzymes, and
• documentation of symptoms. (Instruct all women to report the onset of severe headaches, visual changes, altered mental status, epigastric or right upper quadrant pain, and any nausea or vomiting.)

Fetal evaluation should include:

• serial ultrasound every 3 weeks to estimate fetal weight and amniotic fluid status,
• nonstress testing every week, and
• daily fetal movement counts.

If a nonstress test is nonreactive, it should be confirmed by biophysical profile.

All testing should be promptly repeated if the maternal clinical condition deteriorates.

No need for bed rest, diuretics, or antihypertensive medications

Although expectantly managed patients with mild preeclampsia should be advised to restrict daily activity, there is no need for complete bed rest. Nor have diuretics or other antihypertensive drugs been shown to prolong gestation. On the contrary, these medications may mask severe preeclampsia.

Antihypertensive medications reduce the rate of severe hypertension but do not improve perinatal outcome. If these drugs are used to treat mild disease remote from term, hospitalize the patient and manage her as though she has severe preeclampsia.

Hospitalization versus outpatient management

Although she may be hospitalized at the time of diagnosis, a woman with preeclampsia may switch to outpatient management if systolic or diastolic blood pressure declines, proteinuria diminishes to 1 g/24 hours or less, and there are no maternal symptoms or evidence of severe IUGR. Otherwise, these women should remain hospitalized until delivery.

 

In cases that begin with outpatient management, prompt hospitalization is indicated if there is clinical evidence that the disease is progressing (ie, new symptoms, labor or rupture of membranes, vaginal bleeding, or increased blood pressures or proteinuria) or IUGR and/or oligohydramnios.

Instruct all women to report symptoms and changes in fetal movement.

When to deliver

Whether the gravida is hospitalized or an outpatient, delivery is indicated at 37 weeks. Earlier delivery may be warranted if nonreassuring maternal or fetal conditions develop. (FIGURE 1 summarizes management of mild preeclampsia.)

Severe preeclampsia

Expectant management is safe in properly selected women with severe disease, although maternal and fetal conditions can deteriorate. Hospitalization and daily monitoring are required.

Preeclampsia is severe when any of the following are present:

• systolic blood pressure of 160 mm Hg or higher or diastolic pressure of 110 mm Hg or above on 2 occasions at least 6 hours apart while the patient is on bed rest
• proteinuria of 5 g or more in a 24-hour urine specimen,
• oliguria of less than 500 mL in 24 hours,
• cerebral or visual disturbances,
• pulmonary edema or cyanosis,
• severe epigastric or right upper-quadrant pain, or
• thrombocytopenia.

When gestational hypertension or preeclampsia is severe, hospitalization in the labor and delivery suite is warranted. These women should receive intravenous (IV) magnesium sulfate to reduce the risk of convulsions and antihypertensive drugs to treat severe levels of hypertension, if present. The aim of antihypertensive treatment is to keep diastolic blood pressure between 90 and 105 mm Hg and systolic blood pressure below 160 mm Hg.

During observation, assess maternal and fetal conditions and decide whether delivery is indicated (FIGURE 2).

Expectant management is warranted only for gestations between 23 and 32 weeks’ gestation, provided maternal and fetal conditions are stable (FIGURE 2).

Keep in mind that both maternal and fetal conditions may progressively deteriorate. Thus, these pregnancies involve higher rates of maternal morbidity and significant risk of neonatal morbidity. For this reason, expectant management should proceed only in a tertiary-care center with adequate maternal and neonatal facilities.

Recommended counseling

Advise these patients of the potential risks and benefits of expectant management, which requires daily monitoring of maternal and fetal conditions. Also explain that the decision to continue expectant management will be revisited on a daily basis and that the median number of days pregnancy is prolonged in these cases is 7 (range 2 to 35).

Another important fact to relay: Only 2 randomized trials involving 133 women have compared expectant management to aggressive management in early-onset preeclampsia. However, retrospective and observational studies involving more than 700 women suggest expectant management reduces short-term neonatal morbidity with minimal risk to the mother.

Superimposed preeclampsia

Women who develop preeclampsia on top of chronic hypertension, renal disease, or type 1 diabetes have a markedly higher risk of morbidity, including perinatal morbidity, than women without preexisting conditions.

Women with superimposed preeclampsia may be managed in the hospital, since these pregnancies are associated with higher rates of abruptio placentae (2% to 5%), preterm delivery (56%), IUGR (13% to 15%), and perinatal death (8%). Thus, these women benefit from very close maternal and fetal monitoring.

Superimposed preeclampsia is not classified according to severity.

In general, maternal and perinatal morbidities are substantially higher in women who have preexisting conditions than in healthy women who develop preeclampsia.

Chronic hypertension

Indications for delivery are similar to those described for healthy women with preeclampsia, as is antihypertensive therapy.

If the woman develops preeclampsia while using antihypertensive drugs, delivery should be considered beyond 34 weeks’ gestation.

How preeclampsia affects renal function

Women with renal disease or dysfunction (serum creatinine ≥1.2 mg/dL) prior to or early in pregnancy face an increased risk of adverse neonatal outcomes, regardless of whether preeclampsia also develops. These women also face an increased risk of deteriorating renal function during pregnancy (particularly if preeclampsia or severe hypertension develops) and beyond (more than 6 months postpartum).

Start antihypertensive medications as soon as possible, with the goal of keeping systolic blood pressure below 140 mm Hg and diastolic blood pressure below 90 mm Hg throughout gestation.

Delivery is indicated with the onset of preeclampsia or significant deterioration in renal function.

Diabetes warrants aggressive therapy

Women with type 1 diabetes have a higher risk of preeclampsia, maternal and fetal morbidity, and perinatal mortality. These risks multiply in women who have hypertension and/or diabetic nephropathy. Worsening of retinopathy and nephropathy also is more likely in women who have hypertension. Thus, aggressive management of blood sugars with insulin should be accompanied by aggressive control of blood pressure, with the goal of keeping systolic pressure below 130 mm Hg and diastolic pressure below 85 mm Hg.

 

Choosing antihypertensive drugs. Calcium-channel blockers are preferred to control blood pressure during pregnancy in women with diabetes. Outside of pregnancy, angiotensin-converting enzyme (ACE) inhibitors are best to avert long-term complications, but avoid these drugs in pregnancy (along with angiotensin-receptor blockers), particularly beyond 16 weeks.

Delivery is indicated in all women with vascular diabetes mellitus beyond 34 weeks when preeclampsia is present.

Intrapartum management

Close fetal heart rate and maternal blood pressure monitoring are mainstays, along with magnesium sulfate and antihypertensive therapy.

All women with preeclampsia should receive continuous monitoring of fetal heart rate and uterine activity, with special vigilance for hyperstimulation and onset of vaginal bleeding during labor. (For a description of potential maternal complications, see TABLE 1; fetal complications are described in FIGURE 3.)

Uterine irritability, recurrent variable or late decelerations, and the development of vaginal bleeding may be the first signs of abruptio placentae.

I recommend recording maternal blood pressure at least hourly to detect progression from mild to severe hypertension and to determine the need for antihypertensive therapy.

TABLE 1

Likelihood of maternal complications

Disease progresses during labor (from mild to severe)	10%
Eclampsia
• Mild disease	<0.5%
• Severe preeclampsia	1–2%
Stroke (encephalopathy or hemorrhage)	<1%
Mainly with severe or early onset disease
Pulmonary edema	1–2%
Usually associated with fluid overload or long-standing chronic hypertension

Prevent progression to eclampsia

Magnesium sulfate is the drug of choice in women with preeclampsia. Recent reviews indicate that it reduces the rate of convulsions from 2% to 0.6% in women with severe preeclampsia. In women with mild preeclampsia, the benefit of magnesium sulfate remains unclear.

I recommend IV magnesium sulfate during labor and postpartum when a woman has the indications listed in TABLE 2.

The dose of magnesium sulfate is 6 g IV loading over 20 minutes, followed by a maintenance dose of 2 g/hour.

Magnesium sulfate should be started before surgery (elective cesarean delivery) and continued for at least 12 hours postpartum (I prefer 24 hours).

TABLE 2

When to give prophylactic magnesium sulfate

Use intrapartum and for at least 12 hours postpartum
When the patient has: Severe hypertension or preeclampsia Mild preeclampsia with symptoms Mild hypertension plus symptoms or thrombocytopenia HELLP syndrome (Hemolysis, elevated liver enzymes, and low platelets)

When treating hypertension in labor, avoid “hypotensive overshoot”

The goal of intrapartum treatment is to lower maternal blood pressure without causing precipitous hypotensive overshoot that may lead to reduced maternal organ perfusion, particularly uteroplacental blood flow. Such acute lowering of maternal blood pressure is a common cause of nonreassuring fetal heart rate patterns during labor.

What blood pressure necessitates treatment? There is no doubt that severe levels of hypertension should be treated to avoid potential cerebrovascular and cardiovascular complications in healthy women. However, there is disagreement about what constitutes severe hypertension.

In previously healthy women, I recommend antihypertensive therapy for systolic pressures of 170 mm Hg or above and/or for diastolic pressures of 110 mm Hg or above.

For women with thrombocytopenia, disseminated intravascular coagulation, or pulmonary edema, I recommend treatment for systolic pressures of 160 mm Hg or above and diastolic pressures of 105 mm Hg or above. This latter group should also be given IV furosemide (20 to 40 mg) to promote diuresis. I also recommend treatment at these levels in the postpartum period.

For women with diabetes, renal disease, or left ventricular cardiac disease, antihypertensive medications should be used to keep systolic pressure below 140 mm Hg and diastolic pressure below 90 mm Hg during labor and postpartum. Further, patients in congestive heart failure or with left ventricular diastolic dysfunction should receive furosemide in addition to antihypertensive drugs.

Choosing a drug. My drugs of choice are IV labetalol and oral nifedipine. These 2 drugs, along with IV hydralazine, are the most commonly recommended medications for severe hypertension in pregnancy (TABLE 3).

Although many authorities prefer hydralazine, recent data indicate that, compared with IV labetalol and oral nifedipine, IV hydralazine is associated with more maternal side effects and worse perinatal outcomes (more fetal distress in labor).

TABLE 3

Drug profiles: Dosing and side effects of antihypertensives used in pregnancy

MEDICATION	ONSET OF ACTION	DOSE	SIDE EFFECTS
Hydralazine	10-20 minutes	5-10 mg intravenously every 20 minutes up to maximum dose of 30 mg	More maternal side effects and worse perinatal outcomes than labetalol or nifedipine.
			Skin blisters; chest pain; general feeling of discomfort, illness, or weakness; joint or muscle pain; sore throat and fever; swollen lymph glands
Labetalol*	10-15 minutes	10-20 mg intravenously, then 40-80 mg every 10 minutes up to maximum dose of 220 mg/hour or continuous infusion of 1-2 mg/minute	Breathing difficulty and/or wheezing, cold hands and feet, mental depression, shortness of breath, slow heartbeat, swelling of lower extremities, back or joint pain, chest pain, confusion, fever and sore throat, hallucinations, irregular heartbeat, unusual bleeding and bruising, yellow eyes or skin
Nifedipine	5-10 minutes	10-20 mg orally, repeated in 30 minutes, up to maximum dose of 50 mg/hour	Breathing difficulty, coughing, or wheezing; irregular or fast, poundingheartbeat; skin rash; swelling of lower extremities; chest pain; fainting; painful, swollen joints; vision impairment
Sodium nitroprusside†	0.5-5 minutes	0.25-5 μg/kg/minute by intravenous infusion	Risk of fetal cyanide poisoning with prolonged treatment.
			Maternal effects include symptoms of hypothyroidism, headache, abdominal pain, drowsiness, nausea, involuntary muscle movements, perspiration, restlessness, paraesthesia, palpitations, dizziness, retching, tachycardia
*In women with asthma and congestive heart failure
†Rarely needed except in hypertensive encephalopathy or cerebral hemorrhage

 

Postpartum management

Because preeclampsia can worsen, or first appear, in the postpartum period, extra vigilance is important, and pharmacotherapy may be appropriate.

Management of preeclampsia does not end with delivery of the fetus and the placenta. These events do signal the beginning of the curative process, but complications can occur in the postpartum period. Indeed, in some women, the disease process worsens immediately postpartum. Therefore, women with diagnosed preeclampsia or severe gestational hypertension require close monitoring of blood pressure and maternal symptoms and accurate measurement of fluid intake and urine output. Some of these women are at increased risk for pulmonary edema; exacerbation of severe hypertension; eclampsia; and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.

Treating postpartum hypertension

Women who continue to have severe hypertension (systolic pressure at or above 155 mm Hg or diastolic pressure of 105 mm Hg or higher) will benefit from oral nifedipine (10 mg every 6 hours) or long-acting nifedipine (10 to 20 mg twice daily), the drugs of choice because of their favorable effects on renal function.

Women with severe hypertension also may require diuretics for better control of blood pressure, as may women with a history of congestive heart failure or left ventricular dysfunction.

Start women with vascular diabetes mellitus or diabetic nephropathy on ACE inhibitors immediately postpartum.

Patients can be discharged home once blood pressure is stable, provided there are no maternal symptoms of preeclampsia.

Postpartum preeclampsia can develop even in healthy women

Because severe hypertension or preeclampsia may develop for the first time in the postpartum period, it is important to educate all gravidas about the signs and symptoms. All health-care providers should be on the lookout for these symptoms as well.

The author reports no financial relationships relevant to this article.

As predicted in this column a year ago, 2004 saw the emergence of human oocyte cryopreservation as a hot topic. Now, it is generally agreed that human oocyte cryopreservation is a technique that can be applied to clinical practice in certain circumstances, although general application will be hotly debated pending further adequate clinical trials.

Be prepared for questions when the marketing starts

We can expect younger patients wishing to preserve reproductive capacity to ask our advice on freezing their eggs. (This technology is of limited applicability to the average reproductive-aged woman). The official position of the American Society for Reproductive Medicine is that, until outcome data are available, it is too early to incorporate this practice into general use.

However, a growing number of assisted reproductive technology (ART) centers will be offering—and marketing—the procedure.

Related to the growing interest in preserving female fertility so that women can delay childbearing: a momentous discovery reported in 2004 suggests that our time-honored dogma on growth of new human oocytes may be wrong.

In addition, 2 laboratory studies suggest a future for assisted reproductive technologies, when every embryo is assessed for its likelihood to result in a healthy infant.

These reports demonstrate the excitement of translational research in bringing basic discoveries into the clinical arena. They highlight the incredible development of both stem cell biology and nanotechnology, and suggest how such fields are rapidly becoming relevant in the modern practice of infertility. While it is difficult to predict an accurate timeline, or certainty, of the application of these discoveries to a modern infertility practice, it is safe to say that these and similar discoveries will influence our usual practice in the foreseeable future.

Oocytes unlimited after all?

Johnson J, Canning J, Kaneko T, Pru J, Tilly J. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–150.

Along-held belief is that women reach their peak oocyte number at midgestation, and that number continuously declines until oocytes are depleted, sometime after menopause. This study from Jonathan Tilly’s group at Harvard Medical School presents evidence for germline stem cells in the ovaries of mice capable of replenishing oocytes into adult life. Removal of these germline stem cells caused a rapid depletion of primordial follicles, suggesting that the primordial follicle reserve was continuously replenished from germline stem cells.

While it is quite a leap to assume that human ovaries contain similar germline stem cells, the possibility that reproductive age woman may be able to develop new oocytes is truly exciting. If such oogonial stem cells exist in women—and could be harvested and cryopreserved, as mature oocytes are now being harvested and preserved—it opens the possibility that a renewable supply of oocytes may be available for women who wish to preserve the capacity to reproduce.

Practical implications

Whether for personal use following cancer therapy or oophorectomy, or as a source of oocytes for donation to women who have lost ovarian function, the potential holds great promise. However, extensive further work is required, not the least of which is independent verification of Dr. Tilly’s findings and the extension of that discovery to women.

For the practicing obstetrician/gynecologist fielding a question about “growing new eggs” from a savvy patient surfing the Net, know that the concept has a scientific basis but is definitely not ready for prime time.

New standard ahead for embryo assessment

In vivo assessment without injury

Kulkarni RN, Roper MG, Dahlgren G, Shih DQ, Kauri LM, Peters JL, Stoffel M, Kennedy RT. Islet secretory defect in insulin receptor substrate 1 null mice is linked with reduced calcium signaling and expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SECA)-2b and -3. Diabetes. 2004;53:1517–1525.

The assessment of human embryos for their viability and the likelihood of implanting and developing into a healthy baby has been a challenge for in vitro fertilization programs worldwide. Recent interest has focused on removing single cells from embryos and performing genetic studies. However, this is expensive, time consuming, and runs the risk of damaging embryos in the process of removing single blastomeres.

This study by Kennedy and colleagues, while not immediately applicable to human ART programs, demonstrates a technique for monitoring the secretion products from individual pancreatic beta cells. Using microelectrodes placed adjacent to individually cultured beta cells, insulin secretion from each cell was estimated by measuring the number of exocytotic events in normal and IRS-1 knock-out mice. The in vivo measurement of specific secretion products from individual cells without injuring them is an exciting example of the miniaturization of clinical science.

 

Practical implications

The extension of this technique to the safe assessment of human embryos in vivo while they are in culture is logical and opens up an entire area of both investigation and potential clinical practice. If the metabolic activity of the individual embryos indicates the likelihood of implantation and development, then this could become a new standard in the assessment of every embryo resulting from an ART cycle.

Much work will be required to translate this exciting new technique to human embryos, but it does offer a logical approach to the longstanding problem of embryo assessment.

Real-time assessment

Schuster TG, Cho B, Keller LM, Takayama S, Smith GD. Isolation of motile spermatozoa from semen samples using microfluidics. Reproductive Biomedicine Online. 2004;1(Jul-Aug):75–81.

One of the challenges of assessing individual human embryos in vivo is the dilution effect on any secretion products secreted from an embryo into the relatively vast amount of media in a traditional ART Petri dish. This report describes the first of a series of microfluidic devices designed to separate motile from nonmotile spermatozoa in very small volumes. Such devices can be used to isolate motile sperm from nonmotile sperm and debris for ART procedures when numbers are exceptionally low.

However, similar microfluidic devices are being developed to include tiny chambers that could be used to contain individual human embryos receiving a constant stream of nutrient media with a constant output of spent media and secretory products. In conjunction with the capacity to analyze such tiny amounts of secretory products in vivo from individual cells, this suggests a system for evaluating all human embryos in modern microchambers and continually monitoring for appropriate secretion and subsequent selection for optimal reproductive capacity.

Practical implications

The promise of real-time embryo assessment is certainly upon us, though much work needs to be done to develop these microfluidic incubation chambers before they will be clinically applicable.

For the practicing Ob/Gyn, it is useful to know that the era of preimplantation evaluation of all embryos is not far off. Whether that will translate into fewer fetal/neonatal defects remains to be seen.

The author reports no financial relationships relevant to this article.

As predicted in this column a year ago, 2004 saw the emergence of human oocyte cryopreservation as a hot topic. Now, it is generally agreed that human oocyte cryopreservation is a technique that can be applied to clinical practice in certain circumstances, although general application will be hotly debated pending further adequate clinical trials.

Be prepared for questions when the marketing starts

We can expect younger patients wishing to preserve reproductive capacity to ask our advice on freezing their eggs. (This technology is of limited applicability to the average reproductive-aged woman). The official position of the American Society for Reproductive Medicine is that, until outcome data are available, it is too early to incorporate this practice into general use.

However, a growing number of assisted reproductive technology (ART) centers will be offering—and marketing—the procedure.

Related to the growing interest in preserving female fertility so that women can delay childbearing: a momentous discovery reported in 2004 suggests that our time-honored dogma on growth of new human oocytes may be wrong.

In addition, 2 laboratory studies suggest a future for assisted reproductive technologies, when every embryo is assessed for its likelihood to result in a healthy infant.

These reports demonstrate the excitement of translational research in bringing basic discoveries into the clinical arena. They highlight the incredible development of both stem cell biology and nanotechnology, and suggest how such fields are rapidly becoming relevant in the modern practice of infertility. While it is difficult to predict an accurate timeline, or certainty, of the application of these discoveries to a modern infertility practice, it is safe to say that these and similar discoveries will influence our usual practice in the foreseeable future.

Oocytes unlimited after all?

Johnson J, Canning J, Kaneko T, Pru J, Tilly J. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–150.

Along-held belief is that women reach their peak oocyte number at midgestation, and that number continuously declines until oocytes are depleted, sometime after menopause. This study from Jonathan Tilly’s group at Harvard Medical School presents evidence for germline stem cells in the ovaries of mice capable of replenishing oocytes into adult life. Removal of these germline stem cells caused a rapid depletion of primordial follicles, suggesting that the primordial follicle reserve was continuously replenished from germline stem cells.

While it is quite a leap to assume that human ovaries contain similar germline stem cells, the possibility that reproductive age woman may be able to develop new oocytes is truly exciting. If such oogonial stem cells exist in women—and could be harvested and cryopreserved, as mature oocytes are now being harvested and preserved—it opens the possibility that a renewable supply of oocytes may be available for women who wish to preserve the capacity to reproduce.

Practical implications

Whether for personal use following cancer therapy or oophorectomy, or as a source of oocytes for donation to women who have lost ovarian function, the potential holds great promise. However, extensive further work is required, not the least of which is independent verification of Dr. Tilly’s findings and the extension of that discovery to women.

For the practicing obstetrician/gynecologist fielding a question about “growing new eggs” from a savvy patient surfing the Net, know that the concept has a scientific basis but is definitely not ready for prime time.

New standard ahead for embryo assessment

In vivo assessment without injury

Kulkarni RN, Roper MG, Dahlgren G, Shih DQ, Kauri LM, Peters JL, Stoffel M, Kennedy RT. Islet secretory defect in insulin receptor substrate 1 null mice is linked with reduced calcium signaling and expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SECA)-2b and -3. Diabetes. 2004;53:1517–1525.

The assessment of human embryos for their viability and the likelihood of implanting and developing into a healthy baby has been a challenge for in vitro fertilization programs worldwide. Recent interest has focused on removing single cells from embryos and performing genetic studies. However, this is expensive, time consuming, and runs the risk of damaging embryos in the process of removing single blastomeres.

This study by Kennedy and colleagues, while not immediately applicable to human ART programs, demonstrates a technique for monitoring the secretion products from individual pancreatic beta cells. Using microelectrodes placed adjacent to individually cultured beta cells, insulin secretion from each cell was estimated by measuring the number of exocytotic events in normal and IRS-1 knock-out mice. The in vivo measurement of specific secretion products from individual cells without injuring them is an exciting example of the miniaturization of clinical science.

 

Practical implications

The extension of this technique to the safe assessment of human embryos in vivo while they are in culture is logical and opens up an entire area of both investigation and potential clinical practice. If the metabolic activity of the individual embryos indicates the likelihood of implantation and development, then this could become a new standard in the assessment of every embryo resulting from an ART cycle.

Much work will be required to translate this exciting new technique to human embryos, but it does offer a logical approach to the longstanding problem of embryo assessment.

Real-time assessment

Schuster TG, Cho B, Keller LM, Takayama S, Smith GD. Isolation of motile spermatozoa from semen samples using microfluidics. Reproductive Biomedicine Online. 2004;1(Jul-Aug):75–81.

One of the challenges of assessing individual human embryos in vivo is the dilution effect on any secretion products secreted from an embryo into the relatively vast amount of media in a traditional ART Petri dish. This report describes the first of a series of microfluidic devices designed to separate motile from nonmotile spermatozoa in very small volumes. Such devices can be used to isolate motile sperm from nonmotile sperm and debris for ART procedures when numbers are exceptionally low.

However, similar microfluidic devices are being developed to include tiny chambers that could be used to contain individual human embryos receiving a constant stream of nutrient media with a constant output of spent media and secretory products. In conjunction with the capacity to analyze such tiny amounts of secretory products in vivo from individual cells, this suggests a system for evaluating all human embryos in modern microchambers and continually monitoring for appropriate secretion and subsequent selection for optimal reproductive capacity.

Practical implications

The promise of real-time embryo assessment is certainly upon us, though much work needs to be done to develop these microfluidic incubation chambers before they will be clinically applicable.

For the practicing Ob/Gyn, it is useful to know that the era of preimplantation evaluation of all embryos is not far off. Whether that will translate into fewer fetal/neonatal defects remains to be seen.

The author reports no financial relationships relevant to this article.

As predicted in this column a year ago, 2004 saw the emergence of human oocyte cryopreservation as a hot topic. Now, it is generally agreed that human oocyte cryopreservation is a technique that can be applied to clinical practice in certain circumstances, although general application will be hotly debated pending further adequate clinical trials.

Be prepared for questions when the marketing starts

We can expect younger patients wishing to preserve reproductive capacity to ask our advice on freezing their eggs. (This technology is of limited applicability to the average reproductive-aged woman). The official position of the American Society for Reproductive Medicine is that, until outcome data are available, it is too early to incorporate this practice into general use.

However, a growing number of assisted reproductive technology (ART) centers will be offering—and marketing—the procedure.

Related to the growing interest in preserving female fertility so that women can delay childbearing: a momentous discovery reported in 2004 suggests that our time-honored dogma on growth of new human oocytes may be wrong.

In addition, 2 laboratory studies suggest a future for assisted reproductive technologies, when every embryo is assessed for its likelihood to result in a healthy infant.

These reports demonstrate the excitement of translational research in bringing basic discoveries into the clinical arena. They highlight the incredible development of both stem cell biology and nanotechnology, and suggest how such fields are rapidly becoming relevant in the modern practice of infertility. While it is difficult to predict an accurate timeline, or certainty, of the application of these discoveries to a modern infertility practice, it is safe to say that these and similar discoveries will influence our usual practice in the foreseeable future.

Oocytes unlimited after all?

Johnson J, Canning J, Kaneko T, Pru J, Tilly J. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–150.

Along-held belief is that women reach their peak oocyte number at midgestation, and that number continuously declines until oocytes are depleted, sometime after menopause. This study from Jonathan Tilly’s group at Harvard Medical School presents evidence for germline stem cells in the ovaries of mice capable of replenishing oocytes into adult life. Removal of these germline stem cells caused a rapid depletion of primordial follicles, suggesting that the primordial follicle reserve was continuously replenished from germline stem cells.

While it is quite a leap to assume that human ovaries contain similar germline stem cells, the possibility that reproductive age woman may be able to develop new oocytes is truly exciting. If such oogonial stem cells exist in women—and could be harvested and cryopreserved, as mature oocytes are now being harvested and preserved—it opens the possibility that a renewable supply of oocytes may be available for women who wish to preserve the capacity to reproduce.

Practical implications

Whether for personal use following cancer therapy or oophorectomy, or as a source of oocytes for donation to women who have lost ovarian function, the potential holds great promise. However, extensive further work is required, not the least of which is independent verification of Dr. Tilly’s findings and the extension of that discovery to women.

For the practicing obstetrician/gynecologist fielding a question about “growing new eggs” from a savvy patient surfing the Net, know that the concept has a scientific basis but is definitely not ready for prime time.

New standard ahead for embryo assessment

In vivo assessment without injury

Kulkarni RN, Roper MG, Dahlgren G, Shih DQ, Kauri LM, Peters JL, Stoffel M, Kennedy RT. Islet secretory defect in insulin receptor substrate 1 null mice is linked with reduced calcium signaling and expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SECA)-2b and -3. Diabetes. 2004;53:1517–1525.

The assessment of human embryos for their viability and the likelihood of implanting and developing into a healthy baby has been a challenge for in vitro fertilization programs worldwide. Recent interest has focused on removing single cells from embryos and performing genetic studies. However, this is expensive, time consuming, and runs the risk of damaging embryos in the process of removing single blastomeres.

This study by Kennedy and colleagues, while not immediately applicable to human ART programs, demonstrates a technique for monitoring the secretion products from individual pancreatic beta cells. Using microelectrodes placed adjacent to individually cultured beta cells, insulin secretion from each cell was estimated by measuring the number of exocytotic events in normal and IRS-1 knock-out mice. The in vivo measurement of specific secretion products from individual cells without injuring them is an exciting example of the miniaturization of clinical science.

 

Practical implications

The extension of this technique to the safe assessment of human embryos in vivo while they are in culture is logical and opens up an entire area of both investigation and potential clinical practice. If the metabolic activity of the individual embryos indicates the likelihood of implantation and development, then this could become a new standard in the assessment of every embryo resulting from an ART cycle.

Much work will be required to translate this exciting new technique to human embryos, but it does offer a logical approach to the longstanding problem of embryo assessment.

Real-time assessment

Schuster TG, Cho B, Keller LM, Takayama S, Smith GD. Isolation of motile spermatozoa from semen samples using microfluidics. Reproductive Biomedicine Online. 2004;1(Jul-Aug):75–81.

One of the challenges of assessing individual human embryos in vivo is the dilution effect on any secretion products secreted from an embryo into the relatively vast amount of media in a traditional ART Petri dish. This report describes the first of a series of microfluidic devices designed to separate motile from nonmotile spermatozoa in very small volumes. Such devices can be used to isolate motile sperm from nonmotile sperm and debris for ART procedures when numbers are exceptionally low.

However, similar microfluidic devices are being developed to include tiny chambers that could be used to contain individual human embryos receiving a constant stream of nutrient media with a constant output of spent media and secretory products. In conjunction with the capacity to analyze such tiny amounts of secretory products in vivo from individual cells, this suggests a system for evaluating all human embryos in modern microchambers and continually monitoring for appropriate secretion and subsequent selection for optimal reproductive capacity.

Practical implications

The promise of real-time embryo assessment is certainly upon us, though much work needs to be done to develop these microfluidic incubation chambers before they will be clinically applicable.

For the practicing Ob/Gyn, it is useful to know that the era of preimplantation evaluation of all embryos is not far off. Whether that will translate into fewer fetal/neonatal defects remains to be seen.

The author reports no financial relationships relevant to this article.

We routinely use every means possible to overcome the complications of hypertensive disorders and related preterm births. Yet our best opportunity to reduce morbidity and mortality could be before preeclampsia develops.

Preemptive tactics can be effective in preventing or reducing severity of preeclampsia. The patient’s active cooperation is a must, but the effort to recruit her cooperation can mean a better outcome.

If a diabetic or hypertensive woman doesn’t take her medications properly or if an obese woman postpones weight loss until after preeclampsia develops, it is too late to reduce the level of risk.

At-risk patients can benefit from being informed of any other ways to reduce risk as well; for example, by controlling the number of fetuses transferred via assisted reproductive techniques.

Trends that are driving up the prevalence of risk factors will only increase the number of preconception and obstetric cases with high-risk potential:

• The increased proportion of births among nulliparous women and women older than 35 years.
• The increased proportion of multifetal gestation as a result of assisted reproductive therapy.
• The increased prevalence of obesity in women, which is likely to lead to greater frequency of gestational diabetes, insulin resistance, and chronic hypertension.

Step 1Start risk-reducing tactics as early as possible

Retrospective studies have identified factors that multiply the risk of preeclampsia. Some are identifiable—and modifiable—before conception or beginning at the first prenatal visit (TABLE 1).

Preconception risk factors

Obesity carries a 10 to 15% risk for preeclampsia. Prevention or effective treatment can greatly reduce risk.

Hypertension.Women with uncontrolled hypertension should have their blood pressure controlled prior to conception and as early as possible in the first trimester. In these women, the risk of preeclampsia may be reduced to below the 10 to 40% rate, depending on severity.

Renal disease. Risk for an adverse pregnancy outcome depends on maternal renal function at time of conception. Women should be encouraged to conceive while serum creatinine is less than 1.2 mg/dl.

Pregestational diabetes mellitus. Risk for preeclampsia and adverse outcomes depends on duration of diabetes, as well as vascular complications and blood sugar control prior to conception and early in pregnancy. Encourage these women to complete childbearing as early as possible and before vascular complications develop, and to aggressively control their diabetes and hypertension (if present) at least a few months prior to conception and throughout pregnancy.

Maternal age older than 35 years increases risk depending on associated medical conditions, nulliparity, and need for assisted reproductive therapy. These women are more likely to be nulliparous, overweight, chronically hypertensive, and to require assisted reproductive therapy. ART may involve multifetal gestation and donor insemination or oocyte donation—both of which increase risk and severity of preeclampsia. Therefore, these patients need to be made aware of their risks and helped to take steps to minimize risks.

TABLE 1

Preconception risk factors for preeclampsia

20 to 30%	Previous preeclampsia
50%	Previous preeclampsia at 28 weeks
15 to 25%	Chronic hypertension
40%	Severe hypertension
25%	Renal disease
20%	Pregestational diabetes mellitus
10 to 15%	Class B/C diabetes
35%	Class F/R diabetes
10 to 40%	Thrombophilia
10 to 15%	Obesity/insulin resistance
10 to 20%	Age >35 years
10 to 15%	Family history of preeclampsia
6 to 7%	Nulliparity/primipaternity

Pregnancy-related risk factors

Many risk factors may be identified for the first time during pregnancy (TABLE 2). It is important to realize that the magnitude of risk depends on number of risk factors.

Nulliparity and primipaternity. Over the past decade, several epidemiologic studies suggested that immune maladaptation plays an important pathogenetic role in development of preeclampsia.

Generally, preeclampsia is considered a disease of first pregnancy. Indeed, a previous miscarriage of a previous normotensive pregnancy with the same partner is has a lowered frequency of preeclampsia. This protective effect is lost, however, with change of partner, suggesting that primipaternity increases the rate of preeclampsia.

 

A large prospective study on the relation between duration of sperm exposure with a partner and the rate of preeclampsia showed that women who conceive after a cohabitation period of 0 to 4 months have a 10-fold rate of preeclampsia, compared to those who conceive after a cohabitation period of at least 12 months. A similar study confirmed these findings.

The protective effects of long-term sperm exposure could explain the high frequency of preeclampsia in teenage pregnancy. (These women tend to have limited sperm exposure with a partner, or multiple partners). Thus, it is important to teach these women about their risks and the need for regular prenatal care.

Multifetal gestation increases the rate as well as the severity of preeclampsia, and the rate increases with the number of fetuses. Lowering the number of embryos transferred will substantially reduce the risk of preeclampsia and adverse outcomes.

There is no therapy to prevent preeclampsia in these women; however, we should acknowledge the increased risk and develop antenatal-care programs that allow close observation and early detection of preeclampsia in these women.

Hydropic degeneration of placenta. It is well-established that pregnancies complicated by fetal hydrops or hydropic degeneration of the placenta (with or without a coexisting fetus) are at very high risk for preeclampsia. In these cases, preeclampsia usually develops in the second trimester and is usually severe, and therefore causes substantial maternal and perinatal morbidities. Development of preeclampsia in such pregnancies requires immediate hospitalization and consideration for prompt delivery.

Unexplained elevated serum markers in the second trimester. Maternal serum screening with alpha fetoprotein (AFP), human chorionic gonadotropin (HCG) and inhibin A is commonly used to identify those at risk for aneuploidy or neural tube defects.

Unexplained elevations in AFP, HCG or inhibin A have been associated with increased adverse pregnancy outcome such as fetal death, intrauterine growth restriction (IUGR), preterm delivery, and preeclampsia. However, the data on the association between abnormalities in these biomarkers and preeclampsia have been inconsistent. Nevertheless, retrospective studies suggest that elevation in these serum markers during the second trimester increases the risk of preeclampsia by at least twofold. The risk is probably higher in those who have abnormalities in more than 1 of these markers. Since unexplained abnormalities of these serum markers may reflect early placental pathology, it is suggested that these pregnancies may benefit from close obstetric surveillance.

Serum and urinary markers of abnormal angiogenesis and subsequent preeclampsia were strongly associate, in newly published studies reported by Levine and colleagues. For example, circulating soluble fms-like tyrosine kinase (sFLt1) is elevated in pregnant women prior to onset of preeclampsia, whereas urinary placental growth factor is reduced several weeks prior to clinical onset of preeclampsia. Both of these markers appear to hold some promise.

Unexplained proteinuria or hematuria. Generally, proteinuria is considered a late manifestation of preeclampsia. However, recent retrospective studies suggest that some women with preeclampsia, particularly those with HELLP syndrome, might not have hypertension (>140 mm Hg systolic or >90 mm Hg diastolic). In some women, persistent proteinuria (3+ on dipstick) or >300 mg/24 hour may be the first sign of preeclampsia or could be a marker of silent renal disease.

No prospective studies have evaluated the risk of preeclampsia in asymptomatic women with persistent proteinuria. I suggest, however, that women with this finding will benefit from intensified obstetric surveillance (more frequent prenatal visits) and/or biochemical evaluation (platelet count, liver enzymes), particularly if they have headaches, visual changes, epigastric or right upper quadrant pain, nausea or vomiting, or respiratory symptoms (chest pain or shortness of breath)—likewise, for pregnant women with persistent hematuria of unknown origin.

Unexplained fetal growth restriction. Impaired trophoblast invasion is a key features of pregnancies complicated by preeclampsia or unexplained IUGR. Preeclampsia can manifest either as a maternal syndrome (hypertension and proteinuria with or without symptoms) or a fetal abnormal growth syndrome.

In clinical practice, most cases of unexplained IUGR are probably delivered before the maternal syndrome develops. In some cases, unexplained IUGR may be the first manifestation of preeclampsia, particularly those with IUGR before 34 weeks’ gestation. The absolute risk of clinical preeclampsia in such women is unknown because of lack of prospective data. Nevertheless, a woman with idiopathic IUGR prior to 34 weeks’ gestation whose pregnancy is managed expectantly is at increased risk for future preeclampsia. These women should receive intensive maternal surveillance for preeclampsia, and a diagnosis of preeclampsia should be considered in those who develop maternal symptoms or abnormal blood tests.

Abnormal uterine artery Doppler velocimetry at 18 to 24 weeks’ gestation. Several observational studies reported an association between elevated uterine artery resistance as measured by Doppler (with or without presence of a notch) in the second trimester and subsequent preeclampsia and/or IUGR. The reported rates of preeclampsia among women with abnormal Doppler results range from 6% to 40%. The risk varies depending on the site measured, gestational age at time of measurement, normal indices used, abnormality on repeat measurement, and population studied.

 

A systemic review of 27 studies, which included approximately 13,000 women, revealed that an abnormal uterine artery Doppler waveform increases the risk of preeclampsia by 4- to 6-fold, compared to normal Doppler results. The review concluded that uterine artery Doppler evaluation has a limited value as a screening test to predict preeclampsia.

What should the physician do when faced with an ultrasound report indicating an abnormal uterine artery Doppler finding?

Is low-dose aspirin helpful? Several randomized trials evaluated the potential role of low-dose aspirin in reducing the risk of preeclampsia in women with abnormal uterine artery Doppler indices. A meta-analysis suggested that low-dose aspirin significantly reduced the rate of preeclampsia (16% in placebo versus 10% with aspirin, odds ratio of 0.55). This analysis included a total of 498 subjects.

In contrast, a recent randomized trial in 560 women with abnormal uterine artery Doppler at 23 weeks’, who were assigned to aspirin 150 mg or placebo, found no differences in rates of preeclampsia (18% versus 19%) or in preeclampsia requiring delivery before 34 weeks’ (6% versus 8%). A similar randomized trial using 100 mg aspirin daily in 237 women with abnormal uterine artery Doppler at 22 to 24 weeks revealed no reduction in rate of preeclampsia compared to placebo.

Consequently, low-dose aspirin is not recommended for prevention of preeclamp-sia in these women.

Close surveillance is warranted. Although there is no available proven therapy to reduce the risk of preeclampsia in these women, they should be closely observed because of the increased rate of adverse outcomes, including preeclampsia.

TABLE 2

Pregnancy-related risk factors for preeclampsia

Magnitude of risk depends on the number of factors
2-fold normal	Unexplained midtrimester elevations of serum AFP, HCG, inhibin-A
10 to 30%	Abnormal uterine artery Doppler velocimetry
0 to 30%	Hydrops/hydropic degeneration of placenta
10 to 20%	Multifetal gestation (depends on number of fetuses and maternal age)
10%	Partner who fathered preeclampsia in another woman
8 to 10%	Gestational diabetes mellitus
8 to 10%	Limited sperm exposure (teenage pregnancy)
6 to 7%	Nulliparity/primipaternity
Limited data	Donor insemination, oocyte donation
Limited data	Unexplained persistent proteinuria or hematuria
Unknown	Unexplained fetal growth restriction

Step 2Watch for signal findings, diagnose preeclampsia early

Signs and symptoms may call for close surveillance at any time. Early detection of preeclampsia is the best way to reduce adverse outcomes.

Prenatal care does not prevent preeclampsia, of course. All pregnant women are at risk, some more than others. Still, adequate and proper prenatal care is the best strategy to detect preeclampsia early.

We may need to modify the frequency and type of maternal and fetal surveillance at any time. Thus, patients with multiple risk factors or risk exceeding 10% should have more frequent visits, especially beyond 24 weeks. Maternal blood pressure (both systolic and diastolic), urine protein values, abrupt and excessive weight gain, maternal symptoms, and fetal growth warrant particular attention.

Diagnostic criteria vary with risk

The diagnosis of preeclampsia is different in patients with different risk factors. In healthy nulliparous women, the diagnosis requires persistent hypertension and proteinuria (new onset after 20 weeks’ gestation). However, in some patients the diagnosis should be made based on new onset hypertension and maternal symptoms or abnormal blood tests (low platelets or elevated liver enzymes).

Urine dipstick is a reliable screening test in women who remain normotensive.

24-hour urine measurement is the best test to confirm proteinuria if hypertension develops. Several studies found that urine dipstick values less than (1+) and random urine protein to creatinine ratio measurements are not accurate to predict proteinuria in women with gestational hypertension.

When is it gestational hypertension? The term applies only women with all of these findings:

• mild hypertension <160/<110 mm Hg
• proteinuria <300 mg/24-hour urine
• normal platelet count
• normal liver enzymes
• normal fetal growth
• no maternal symptoms

Once gestational hypertension is diagnosed, obtain blood tests and ultrasound evaluation to document fetal growth and amniotic fluid status.

Women with severe gestational hypertension and those with abnormal tests should be diagnosed as having preeclampsia and managed as such.

Women with gestational hypertension are at high risk for preeclampsia, and risk of progression depends on gestational age at time of diagnosis. Women who develop gestational hypertension at 24 to 35 weeks have a 46% chance of developing preeclampsia with a high rate of preterm delivery (32% <36 weeks and 12.5% <34 weeks) (FIGURE). These women require very close surveillance. In contrast, maternal and perinatal outcome is usually favorable when only mild gestational hypertension develops at or beyond 36 weeks.

When hypertension, proteinuria occur before 20 weeks

The traditional diagnostic criteria for preeclampsia in healthy women are not reliable in women who have either hypertension or proteinuria prior to 20 weeks’ gestation, particularly in those taking antihypertensive medications and in those who have class F diabetes mellitus. Because of the physiologic changes during pregnancy, women with diabetes and renal disease will have serial increases in blood pressure as well as protein excretion with advanced gestational age, particularly in the third trimester. Diagnostic criteria (TABLE 3) should be individualized based on medical conditions and current therapy. Antihypertensive drugs and preexisting proteinuria make it more difficult to classify preeclampsia as mild or severe.

 

TABLE 3

Diagnostic criteria

GESTATIONAL HYPERTENSION IN HEALTHY WOMEN
Blood pressure <160 mm Hg diastolic and <110 mm Hg systolic
Proteinuria <300 mg/24-hour collection
Platelet count >100,000/mm3
Normal liver enzymes
No maternal symptoms
No intrauterine growth restriction or oligohydraminos by ultrasound
PREECLAMPSIA IN WOMEN WITH PREEXISTING MEDICAL CONDITIONS
Condition	Criteria
Hypertension only	Proteinuria >500 mg/24-hours or thrombocytopenia
Proteinuria only	New onset hypertension plus symptoms or thrombocytopenia or elevated liver enzymes
Hypertension plus proteinuria (renal disease or class F diabetes)	Worsening severe hypertension and/or new onset of symptoms, thrombocytopenia, elevated liver enzymes

FIGURE Whether preeclampsia will develop depends on when gestational hypertension begins

Adapted from Barton JR, et al. Am J Obstet Gynecol. 2001;184:979-983.

Step 3Consider how to balance risk to mother and fetus

Once a diagnosis is made, promptly evaluate mother and fetus, continue close surveillance, select those who will benefit from hospitalization, and identify indications for delivery (TABLE 4).

Delivery will always reduce the risks for the mother, but in certain situations, it might not be the best option for an extremely premature fetus. Sometimes delivery is best for both mother and fetus.

The best strategy takes into consideration:

• maternal and fetal status at initial evaluation,
• preexisting medical conditions that could affect pregnancy outcome,
• fetal gestational age at time of diagnosis,
• labor or rupture of fetal membranes (both could affect management), and
• maternal choice of available options.

Women who remain undelivered require close maternal and fetal evaluation. In otherwise healthy women, management depends on whether the preeclampsia is mild or severe, and, if there are other medical conditions, on the status of those conditions, as well.

TABLE 4

Indications for delivery

Consider delivery in gravidas with 1 or more indications
Gestational age ≥38 weeks for mild disease
Gestational age ≥34 weeks for severe disease
33-34 weeks with severe disease after steroids
Onset of labor and/or membrane rupture ≥34 weeks
Eclampsia or pulmonary edema (any gestational age)
HELLP syndrome (any gestational age)
Severe cerebral symptoms or epigastric pain
Acute renal insufficiency (serum creatinine >1.2 mg/dl)
Persistent thrombocytopenia (platelet count <100,000)
Maternal desire for delivery
Severe oligohydraminos or IUGR < 5th percentile
Nonreassuring fetal testing

The author reports no financial relationships relevant to this article.

We routinely use every means possible to overcome the complications of hypertensive disorders and related preterm births. Yet our best opportunity to reduce morbidity and mortality could be before preeclampsia develops.

Preemptive tactics can be effective in preventing or reducing severity of preeclampsia. The patient’s active cooperation is a must, but the effort to recruit her cooperation can mean a better outcome.

If a diabetic or hypertensive woman doesn’t take her medications properly or if an obese woman postpones weight loss until after preeclampsia develops, it is too late to reduce the level of risk.

At-risk patients can benefit from being informed of any other ways to reduce risk as well; for example, by controlling the number of fetuses transferred via assisted reproductive techniques.

Trends that are driving up the prevalence of risk factors will only increase the number of preconception and obstetric cases with high-risk potential:

• The increased proportion of births among nulliparous women and women older than 35 years.
• The increased proportion of multifetal gestation as a result of assisted reproductive therapy.
• The increased prevalence of obesity in women, which is likely to lead to greater frequency of gestational diabetes, insulin resistance, and chronic hypertension.

Step 1Start risk-reducing tactics as early as possible

Retrospective studies have identified factors that multiply the risk of preeclampsia. Some are identifiable—and modifiable—before conception or beginning at the first prenatal visit (TABLE 1).

Preconception risk factors

Obesity carries a 10 to 15% risk for preeclampsia. Prevention or effective treatment can greatly reduce risk.

Hypertension.Women with uncontrolled hypertension should have their blood pressure controlled prior to conception and as early as possible in the first trimester. In these women, the risk of preeclampsia may be reduced to below the 10 to 40% rate, depending on severity.

Renal disease. Risk for an adverse pregnancy outcome depends on maternal renal function at time of conception. Women should be encouraged to conceive while serum creatinine is less than 1.2 mg/dl.

Pregestational diabetes mellitus. Risk for preeclampsia and adverse outcomes depends on duration of diabetes, as well as vascular complications and blood sugar control prior to conception and early in pregnancy. Encourage these women to complete childbearing as early as possible and before vascular complications develop, and to aggressively control their diabetes and hypertension (if present) at least a few months prior to conception and throughout pregnancy.

Maternal age older than 35 years increases risk depending on associated medical conditions, nulliparity, and need for assisted reproductive therapy. These women are more likely to be nulliparous, overweight, chronically hypertensive, and to require assisted reproductive therapy. ART may involve multifetal gestation and donor insemination or oocyte donation—both of which increase risk and severity of preeclampsia. Therefore, these patients need to be made aware of their risks and helped to take steps to minimize risks.

TABLE 1

Preconception risk factors for preeclampsia

20 to 30%	Previous preeclampsia
50%	Previous preeclampsia at 28 weeks
15 to 25%	Chronic hypertension
40%	Severe hypertension
25%	Renal disease
20%	Pregestational diabetes mellitus
10 to 15%	Class B/C diabetes
35%	Class F/R diabetes
10 to 40%	Thrombophilia
10 to 15%	Obesity/insulin resistance
10 to 20%	Age >35 years
10 to 15%	Family history of preeclampsia
6 to 7%	Nulliparity/primipaternity

Pregnancy-related risk factors

Many risk factors may be identified for the first time during pregnancy (TABLE 2). It is important to realize that the magnitude of risk depends on number of risk factors.

Nulliparity and primipaternity. Over the past decade, several epidemiologic studies suggested that immune maladaptation plays an important pathogenetic role in development of preeclampsia.

Generally, preeclampsia is considered a disease of first pregnancy. Indeed, a previous miscarriage of a previous normotensive pregnancy with the same partner is has a lowered frequency of preeclampsia. This protective effect is lost, however, with change of partner, suggesting that primipaternity increases the rate of preeclampsia.

 

A large prospective study on the relation between duration of sperm exposure with a partner and the rate of preeclampsia showed that women who conceive after a cohabitation period of 0 to 4 months have a 10-fold rate of preeclampsia, compared to those who conceive after a cohabitation period of at least 12 months. A similar study confirmed these findings.

The protective effects of long-term sperm exposure could explain the high frequency of preeclampsia in teenage pregnancy. (These women tend to have limited sperm exposure with a partner, or multiple partners). Thus, it is important to teach these women about their risks and the need for regular prenatal care.

Multifetal gestation increases the rate as well as the severity of preeclampsia, and the rate increases with the number of fetuses. Lowering the number of embryos transferred will substantially reduce the risk of preeclampsia and adverse outcomes.

There is no therapy to prevent preeclampsia in these women; however, we should acknowledge the increased risk and develop antenatal-care programs that allow close observation and early detection of preeclampsia in these women.

Hydropic degeneration of placenta. It is well-established that pregnancies complicated by fetal hydrops or hydropic degeneration of the placenta (with or without a coexisting fetus) are at very high risk for preeclampsia. In these cases, preeclampsia usually develops in the second trimester and is usually severe, and therefore causes substantial maternal and perinatal morbidities. Development of preeclampsia in such pregnancies requires immediate hospitalization and consideration for prompt delivery.

Unexplained elevated serum markers in the second trimester. Maternal serum screening with alpha fetoprotein (AFP), human chorionic gonadotropin (HCG) and inhibin A is commonly used to identify those at risk for aneuploidy or neural tube defects.

Unexplained elevations in AFP, HCG or inhibin A have been associated with increased adverse pregnancy outcome such as fetal death, intrauterine growth restriction (IUGR), preterm delivery, and preeclampsia. However, the data on the association between abnormalities in these biomarkers and preeclampsia have been inconsistent. Nevertheless, retrospective studies suggest that elevation in these serum markers during the second trimester increases the risk of preeclampsia by at least twofold. The risk is probably higher in those who have abnormalities in more than 1 of these markers. Since unexplained abnormalities of these serum markers may reflect early placental pathology, it is suggested that these pregnancies may benefit from close obstetric surveillance.

Serum and urinary markers of abnormal angiogenesis and subsequent preeclampsia were strongly associate, in newly published studies reported by Levine and colleagues. For example, circulating soluble fms-like tyrosine kinase (sFLt1) is elevated in pregnant women prior to onset of preeclampsia, whereas urinary placental growth factor is reduced several weeks prior to clinical onset of preeclampsia. Both of these markers appear to hold some promise.

Unexplained proteinuria or hematuria. Generally, proteinuria is considered a late manifestation of preeclampsia. However, recent retrospective studies suggest that some women with preeclampsia, particularly those with HELLP syndrome, might not have hypertension (>140 mm Hg systolic or >90 mm Hg diastolic). In some women, persistent proteinuria (3+ on dipstick) or >300 mg/24 hour may be the first sign of preeclampsia or could be a marker of silent renal disease.

No prospective studies have evaluated the risk of preeclampsia in asymptomatic women with persistent proteinuria. I suggest, however, that women with this finding will benefit from intensified obstetric surveillance (more frequent prenatal visits) and/or biochemical evaluation (platelet count, liver enzymes), particularly if they have headaches, visual changes, epigastric or right upper quadrant pain, nausea or vomiting, or respiratory symptoms (chest pain or shortness of breath)—likewise, for pregnant women with persistent hematuria of unknown origin.

Unexplained fetal growth restriction. Impaired trophoblast invasion is a key features of pregnancies complicated by preeclampsia or unexplained IUGR. Preeclampsia can manifest either as a maternal syndrome (hypertension and proteinuria with or without symptoms) or a fetal abnormal growth syndrome.

In clinical practice, most cases of unexplained IUGR are probably delivered before the maternal syndrome develops. In some cases, unexplained IUGR may be the first manifestation of preeclampsia, particularly those with IUGR before 34 weeks’ gestation. The absolute risk of clinical preeclampsia in such women is unknown because of lack of prospective data. Nevertheless, a woman with idiopathic IUGR prior to 34 weeks’ gestation whose pregnancy is managed expectantly is at increased risk for future preeclampsia. These women should receive intensive maternal surveillance for preeclampsia, and a diagnosis of preeclampsia should be considered in those who develop maternal symptoms or abnormal blood tests.

Abnormal uterine artery Doppler velocimetry at 18 to 24 weeks’ gestation. Several observational studies reported an association between elevated uterine artery resistance as measured by Doppler (with or without presence of a notch) in the second trimester and subsequent preeclampsia and/or IUGR. The reported rates of preeclampsia among women with abnormal Doppler results range from 6% to 40%. The risk varies depending on the site measured, gestational age at time of measurement, normal indices used, abnormality on repeat measurement, and population studied.

 

A systemic review of 27 studies, which included approximately 13,000 women, revealed that an abnormal uterine artery Doppler waveform increases the risk of preeclampsia by 4- to 6-fold, compared to normal Doppler results. The review concluded that uterine artery Doppler evaluation has a limited value as a screening test to predict preeclampsia.

What should the physician do when faced with an ultrasound report indicating an abnormal uterine artery Doppler finding?

Is low-dose aspirin helpful? Several randomized trials evaluated the potential role of low-dose aspirin in reducing the risk of preeclampsia in women with abnormal uterine artery Doppler indices. A meta-analysis suggested that low-dose aspirin significantly reduced the rate of preeclampsia (16% in placebo versus 10% with aspirin, odds ratio of 0.55). This analysis included a total of 498 subjects.

In contrast, a recent randomized trial in 560 women with abnormal uterine artery Doppler at 23 weeks’, who were assigned to aspirin 150 mg or placebo, found no differences in rates of preeclampsia (18% versus 19%) or in preeclampsia requiring delivery before 34 weeks’ (6% versus 8%). A similar randomized trial using 100 mg aspirin daily in 237 women with abnormal uterine artery Doppler at 22 to 24 weeks revealed no reduction in rate of preeclampsia compared to placebo.

Consequently, low-dose aspirin is not recommended for prevention of preeclamp-sia in these women.

Close surveillance is warranted. Although there is no available proven therapy to reduce the risk of preeclampsia in these women, they should be closely observed because of the increased rate of adverse outcomes, including preeclampsia.

TABLE 2

Pregnancy-related risk factors for preeclampsia

Magnitude of risk depends on the number of factors
2-fold normal	Unexplained midtrimester elevations of serum AFP, HCG, inhibin-A
10 to 30%	Abnormal uterine artery Doppler velocimetry
0 to 30%	Hydrops/hydropic degeneration of placenta
10 to 20%	Multifetal gestation (depends on number of fetuses and maternal age)
10%	Partner who fathered preeclampsia in another woman
8 to 10%	Gestational diabetes mellitus
8 to 10%	Limited sperm exposure (teenage pregnancy)
6 to 7%	Nulliparity/primipaternity
Limited data	Donor insemination, oocyte donation
Limited data	Unexplained persistent proteinuria or hematuria
Unknown	Unexplained fetal growth restriction

Step 2Watch for signal findings, diagnose preeclampsia early

Signs and symptoms may call for close surveillance at any time. Early detection of preeclampsia is the best way to reduce adverse outcomes.

Prenatal care does not prevent preeclampsia, of course. All pregnant women are at risk, some more than others. Still, adequate and proper prenatal care is the best strategy to detect preeclampsia early.

We may need to modify the frequency and type of maternal and fetal surveillance at any time. Thus, patients with multiple risk factors or risk exceeding 10% should have more frequent visits, especially beyond 24 weeks. Maternal blood pressure (both systolic and diastolic), urine protein values, abrupt and excessive weight gain, maternal symptoms, and fetal growth warrant particular attention.

Diagnostic criteria vary with risk

The diagnosis of preeclampsia is different in patients with different risk factors. In healthy nulliparous women, the diagnosis requires persistent hypertension and proteinuria (new onset after 20 weeks’ gestation). However, in some patients the diagnosis should be made based on new onset hypertension and maternal symptoms or abnormal blood tests (low platelets or elevated liver enzymes).

Urine dipstick is a reliable screening test in women who remain normotensive.

24-hour urine measurement is the best test to confirm proteinuria if hypertension develops. Several studies found that urine dipstick values less than (1+) and random urine protein to creatinine ratio measurements are not accurate to predict proteinuria in women with gestational hypertension.

When is it gestational hypertension? The term applies only women with all of these findings:

• mild hypertension <160/<110 mm Hg
• proteinuria <300 mg/24-hour urine
• normal platelet count
• normal liver enzymes
• normal fetal growth
• no maternal symptoms

Once gestational hypertension is diagnosed, obtain blood tests and ultrasound evaluation to document fetal growth and amniotic fluid status.

Women with severe gestational hypertension and those with abnormal tests should be diagnosed as having preeclampsia and managed as such.

Women with gestational hypertension are at high risk for preeclampsia, and risk of progression depends on gestational age at time of diagnosis. Women who develop gestational hypertension at 24 to 35 weeks have a 46% chance of developing preeclampsia with a high rate of preterm delivery (32% <36 weeks and 12.5% <34 weeks) (FIGURE). These women require very close surveillance. In contrast, maternal and perinatal outcome is usually favorable when only mild gestational hypertension develops at or beyond 36 weeks.

When hypertension, proteinuria occur before 20 weeks

The traditional diagnostic criteria for preeclampsia in healthy women are not reliable in women who have either hypertension or proteinuria prior to 20 weeks’ gestation, particularly in those taking antihypertensive medications and in those who have class F diabetes mellitus. Because of the physiologic changes during pregnancy, women with diabetes and renal disease will have serial increases in blood pressure as well as protein excretion with advanced gestational age, particularly in the third trimester. Diagnostic criteria (TABLE 3) should be individualized based on medical conditions and current therapy. Antihypertensive drugs and preexisting proteinuria make it more difficult to classify preeclampsia as mild or severe.

 

TABLE 3

Diagnostic criteria

GESTATIONAL HYPERTENSION IN HEALTHY WOMEN
Blood pressure <160 mm Hg diastolic and <110 mm Hg systolic
Proteinuria <300 mg/24-hour collection
Platelet count >100,000/mm3
Normal liver enzymes
No maternal symptoms
No intrauterine growth restriction or oligohydraminos by ultrasound
PREECLAMPSIA IN WOMEN WITH PREEXISTING MEDICAL CONDITIONS
Condition	Criteria
Hypertension only	Proteinuria >500 mg/24-hours or thrombocytopenia
Proteinuria only	New onset hypertension plus symptoms or thrombocytopenia or elevated liver enzymes
Hypertension plus proteinuria (renal disease or class F diabetes)	Worsening severe hypertension and/or new onset of symptoms, thrombocytopenia, elevated liver enzymes

FIGURE Whether preeclampsia will develop depends on when gestational hypertension begins

Adapted from Barton JR, et al. Am J Obstet Gynecol. 2001;184:979-983.

Step 3Consider how to balance risk to mother and fetus

Once a diagnosis is made, promptly evaluate mother and fetus, continue close surveillance, select those who will benefit from hospitalization, and identify indications for delivery (TABLE 4).

Delivery will always reduce the risks for the mother, but in certain situations, it might not be the best option for an extremely premature fetus. Sometimes delivery is best for both mother and fetus.

The best strategy takes into consideration:

• maternal and fetal status at initial evaluation,
• preexisting medical conditions that could affect pregnancy outcome,
• fetal gestational age at time of diagnosis,
• labor or rupture of fetal membranes (both could affect management), and
• maternal choice of available options.

Women who remain undelivered require close maternal and fetal evaluation. In otherwise healthy women, management depends on whether the preeclampsia is mild or severe, and, if there are other medical conditions, on the status of those conditions, as well.

TABLE 4

Indications for delivery

Consider delivery in gravidas with 1 or more indications
Gestational age ≥38 weeks for mild disease
Gestational age ≥34 weeks for severe disease
33-34 weeks with severe disease after steroids
Onset of labor and/or membrane rupture ≥34 weeks
Eclampsia or pulmonary edema (any gestational age)
HELLP syndrome (any gestational age)
Severe cerebral symptoms or epigastric pain
Acute renal insufficiency (serum creatinine >1.2 mg/dl)
Persistent thrombocytopenia (platelet count <100,000)
Maternal desire for delivery
Severe oligohydraminos or IUGR < 5th percentile
Nonreassuring fetal testing

The author reports no financial relationships relevant to this article.

We routinely use every means possible to overcome the complications of hypertensive disorders and related preterm births. Yet our best opportunity to reduce morbidity and mortality could be before preeclampsia develops.

Preemptive tactics can be effective in preventing or reducing severity of preeclampsia. The patient’s active cooperation is a must, but the effort to recruit her cooperation can mean a better outcome.

If a diabetic or hypertensive woman doesn’t take her medications properly or if an obese woman postpones weight loss until after preeclampsia develops, it is too late to reduce the level of risk.

At-risk patients can benefit from being informed of any other ways to reduce risk as well; for example, by controlling the number of fetuses transferred via assisted reproductive techniques.

Trends that are driving up the prevalence of risk factors will only increase the number of preconception and obstetric cases with high-risk potential:

• The increased proportion of births among nulliparous women and women older than 35 years.
• The increased proportion of multifetal gestation as a result of assisted reproductive therapy.
• The increased prevalence of obesity in women, which is likely to lead to greater frequency of gestational diabetes, insulin resistance, and chronic hypertension.

Step 1Start risk-reducing tactics as early as possible

Retrospective studies have identified factors that multiply the risk of preeclampsia. Some are identifiable—and modifiable—before conception or beginning at the first prenatal visit (TABLE 1).

Preconception risk factors

Obesity carries a 10 to 15% risk for preeclampsia. Prevention or effective treatment can greatly reduce risk.

Hypertension.Women with uncontrolled hypertension should have their blood pressure controlled prior to conception and as early as possible in the first trimester. In these women, the risk of preeclampsia may be reduced to below the 10 to 40% rate, depending on severity.

Renal disease. Risk for an adverse pregnancy outcome depends on maternal renal function at time of conception. Women should be encouraged to conceive while serum creatinine is less than 1.2 mg/dl.

Pregestational diabetes mellitus. Risk for preeclampsia and adverse outcomes depends on duration of diabetes, as well as vascular complications and blood sugar control prior to conception and early in pregnancy. Encourage these women to complete childbearing as early as possible and before vascular complications develop, and to aggressively control their diabetes and hypertension (if present) at least a few months prior to conception and throughout pregnancy.

Maternal age older than 35 years increases risk depending on associated medical conditions, nulliparity, and need for assisted reproductive therapy. These women are more likely to be nulliparous, overweight, chronically hypertensive, and to require assisted reproductive therapy. ART may involve multifetal gestation and donor insemination or oocyte donation—both of which increase risk and severity of preeclampsia. Therefore, these patients need to be made aware of their risks and helped to take steps to minimize risks.

TABLE 1

Preconception risk factors for preeclampsia

20 to 30%	Previous preeclampsia
50%	Previous preeclampsia at 28 weeks
15 to 25%	Chronic hypertension
40%	Severe hypertension
25%	Renal disease
20%	Pregestational diabetes mellitus
10 to 15%	Class B/C diabetes
35%	Class F/R diabetes
10 to 40%	Thrombophilia
10 to 15%	Obesity/insulin resistance
10 to 20%	Age >35 years
10 to 15%	Family history of preeclampsia
6 to 7%	Nulliparity/primipaternity

Pregnancy-related risk factors

Many risk factors may be identified for the first time during pregnancy (TABLE 2). It is important to realize that the magnitude of risk depends on number of risk factors.

Nulliparity and primipaternity. Over the past decade, several epidemiologic studies suggested that immune maladaptation plays an important pathogenetic role in development of preeclampsia.

Generally, preeclampsia is considered a disease of first pregnancy. Indeed, a previous miscarriage of a previous normotensive pregnancy with the same partner is has a lowered frequency of preeclampsia. This protective effect is lost, however, with change of partner, suggesting that primipaternity increases the rate of preeclampsia.

 

A large prospective study on the relation between duration of sperm exposure with a partner and the rate of preeclampsia showed that women who conceive after a cohabitation period of 0 to 4 months have a 10-fold rate of preeclampsia, compared to those who conceive after a cohabitation period of at least 12 months. A similar study confirmed these findings.

The protective effects of long-term sperm exposure could explain the high frequency of preeclampsia in teenage pregnancy. (These women tend to have limited sperm exposure with a partner, or multiple partners). Thus, it is important to teach these women about their risks and the need for regular prenatal care.

Multifetal gestation increases the rate as well as the severity of preeclampsia, and the rate increases with the number of fetuses. Lowering the number of embryos transferred will substantially reduce the risk of preeclampsia and adverse outcomes.

There is no therapy to prevent preeclampsia in these women; however, we should acknowledge the increased risk and develop antenatal-care programs that allow close observation and early detection of preeclampsia in these women.

Hydropic degeneration of placenta. It is well-established that pregnancies complicated by fetal hydrops or hydropic degeneration of the placenta (with or without a coexisting fetus) are at very high risk for preeclampsia. In these cases, preeclampsia usually develops in the second trimester and is usually severe, and therefore causes substantial maternal and perinatal morbidities. Development of preeclampsia in such pregnancies requires immediate hospitalization and consideration for prompt delivery.

Unexplained elevated serum markers in the second trimester. Maternal serum screening with alpha fetoprotein (AFP), human chorionic gonadotropin (HCG) and inhibin A is commonly used to identify those at risk for aneuploidy or neural tube defects.

Unexplained elevations in AFP, HCG or inhibin A have been associated with increased adverse pregnancy outcome such as fetal death, intrauterine growth restriction (IUGR), preterm delivery, and preeclampsia. However, the data on the association between abnormalities in these biomarkers and preeclampsia have been inconsistent. Nevertheless, retrospective studies suggest that elevation in these serum markers during the second trimester increases the risk of preeclampsia by at least twofold. The risk is probably higher in those who have abnormalities in more than 1 of these markers. Since unexplained abnormalities of these serum markers may reflect early placental pathology, it is suggested that these pregnancies may benefit from close obstetric surveillance.

Serum and urinary markers of abnormal angiogenesis and subsequent preeclampsia were strongly associate, in newly published studies reported by Levine and colleagues. For example, circulating soluble fms-like tyrosine kinase (sFLt1) is elevated in pregnant women prior to onset of preeclampsia, whereas urinary placental growth factor is reduced several weeks prior to clinical onset of preeclampsia. Both of these markers appear to hold some promise.

Unexplained proteinuria or hematuria. Generally, proteinuria is considered a late manifestation of preeclampsia. However, recent retrospective studies suggest that some women with preeclampsia, particularly those with HELLP syndrome, might not have hypertension (>140 mm Hg systolic or >90 mm Hg diastolic). In some women, persistent proteinuria (3+ on dipstick) or >300 mg/24 hour may be the first sign of preeclampsia or could be a marker of silent renal disease.

No prospective studies have evaluated the risk of preeclampsia in asymptomatic women with persistent proteinuria. I suggest, however, that women with this finding will benefit from intensified obstetric surveillance (more frequent prenatal visits) and/or biochemical evaluation (platelet count, liver enzymes), particularly if they have headaches, visual changes, epigastric or right upper quadrant pain, nausea or vomiting, or respiratory symptoms (chest pain or shortness of breath)—likewise, for pregnant women with persistent hematuria of unknown origin.

Unexplained fetal growth restriction. Impaired trophoblast invasion is a key features of pregnancies complicated by preeclampsia or unexplained IUGR. Preeclampsia can manifest either as a maternal syndrome (hypertension and proteinuria with or without symptoms) or a fetal abnormal growth syndrome.

In clinical practice, most cases of unexplained IUGR are probably delivered before the maternal syndrome develops. In some cases, unexplained IUGR may be the first manifestation of preeclampsia, particularly those with IUGR before 34 weeks’ gestation. The absolute risk of clinical preeclampsia in such women is unknown because of lack of prospective data. Nevertheless, a woman with idiopathic IUGR prior to 34 weeks’ gestation whose pregnancy is managed expectantly is at increased risk for future preeclampsia. These women should receive intensive maternal surveillance for preeclampsia, and a diagnosis of preeclampsia should be considered in those who develop maternal symptoms or abnormal blood tests.

Abnormal uterine artery Doppler velocimetry at 18 to 24 weeks’ gestation. Several observational studies reported an association between elevated uterine artery resistance as measured by Doppler (with or without presence of a notch) in the second trimester and subsequent preeclampsia and/or IUGR. The reported rates of preeclampsia among women with abnormal Doppler results range from 6% to 40%. The risk varies depending on the site measured, gestational age at time of measurement, normal indices used, abnormality on repeat measurement, and population studied.

 

A systemic review of 27 studies, which included approximately 13,000 women, revealed that an abnormal uterine artery Doppler waveform increases the risk of preeclampsia by 4- to 6-fold, compared to normal Doppler results. The review concluded that uterine artery Doppler evaluation has a limited value as a screening test to predict preeclampsia.

What should the physician do when faced with an ultrasound report indicating an abnormal uterine artery Doppler finding?

Is low-dose aspirin helpful? Several randomized trials evaluated the potential role of low-dose aspirin in reducing the risk of preeclampsia in women with abnormal uterine artery Doppler indices. A meta-analysis suggested that low-dose aspirin significantly reduced the rate of preeclampsia (16% in placebo versus 10% with aspirin, odds ratio of 0.55). This analysis included a total of 498 subjects.

In contrast, a recent randomized trial in 560 women with abnormal uterine artery Doppler at 23 weeks’, who were assigned to aspirin 150 mg or placebo, found no differences in rates of preeclampsia (18% versus 19%) or in preeclampsia requiring delivery before 34 weeks’ (6% versus 8%). A similar randomized trial using 100 mg aspirin daily in 237 women with abnormal uterine artery Doppler at 22 to 24 weeks revealed no reduction in rate of preeclampsia compared to placebo.

Consequently, low-dose aspirin is not recommended for prevention of preeclamp-sia in these women.

Close surveillance is warranted. Although there is no available proven therapy to reduce the risk of preeclampsia in these women, they should be closely observed because of the increased rate of adverse outcomes, including preeclampsia.

TABLE 2

Pregnancy-related risk factors for preeclampsia

Magnitude of risk depends on the number of factors
2-fold normal	Unexplained midtrimester elevations of serum AFP, HCG, inhibin-A
10 to 30%	Abnormal uterine artery Doppler velocimetry
0 to 30%	Hydrops/hydropic degeneration of placenta
10 to 20%	Multifetal gestation (depends on number of fetuses and maternal age)
10%	Partner who fathered preeclampsia in another woman
8 to 10%	Gestational diabetes mellitus
8 to 10%	Limited sperm exposure (teenage pregnancy)
6 to 7%	Nulliparity/primipaternity
Limited data	Donor insemination, oocyte donation
Limited data	Unexplained persistent proteinuria or hematuria
Unknown	Unexplained fetal growth restriction

Step 2Watch for signal findings, diagnose preeclampsia early

Signs and symptoms may call for close surveillance at any time. Early detection of preeclampsia is the best way to reduce adverse outcomes.

Prenatal care does not prevent preeclampsia, of course. All pregnant women are at risk, some more than others. Still, adequate and proper prenatal care is the best strategy to detect preeclampsia early.

We may need to modify the frequency and type of maternal and fetal surveillance at any time. Thus, patients with multiple risk factors or risk exceeding 10% should have more frequent visits, especially beyond 24 weeks. Maternal blood pressure (both systolic and diastolic), urine protein values, abrupt and excessive weight gain, maternal symptoms, and fetal growth warrant particular attention.

Diagnostic criteria vary with risk

The diagnosis of preeclampsia is different in patients with different risk factors. In healthy nulliparous women, the diagnosis requires persistent hypertension and proteinuria (new onset after 20 weeks’ gestation). However, in some patients the diagnosis should be made based on new onset hypertension and maternal symptoms or abnormal blood tests (low platelets or elevated liver enzymes).

Urine dipstick is a reliable screening test in women who remain normotensive.

24-hour urine measurement is the best test to confirm proteinuria if hypertension develops. Several studies found that urine dipstick values less than (1+) and random urine protein to creatinine ratio measurements are not accurate to predict proteinuria in women with gestational hypertension.

When is it gestational hypertension? The term applies only women with all of these findings:

• mild hypertension <160/<110 mm Hg
• proteinuria <300 mg/24-hour urine
• normal platelet count
• normal liver enzymes
• normal fetal growth
• no maternal symptoms

Once gestational hypertension is diagnosed, obtain blood tests and ultrasound evaluation to document fetal growth and amniotic fluid status.

Women with severe gestational hypertension and those with abnormal tests should be diagnosed as having preeclampsia and managed as such.

Women with gestational hypertension are at high risk for preeclampsia, and risk of progression depends on gestational age at time of diagnosis. Women who develop gestational hypertension at 24 to 35 weeks have a 46% chance of developing preeclampsia with a high rate of preterm delivery (32% <36 weeks and 12.5% <34 weeks) (FIGURE). These women require very close surveillance. In contrast, maternal and perinatal outcome is usually favorable when only mild gestational hypertension develops at or beyond 36 weeks.

When hypertension, proteinuria occur before 20 weeks

The traditional diagnostic criteria for preeclampsia in healthy women are not reliable in women who have either hypertension or proteinuria prior to 20 weeks’ gestation, particularly in those taking antihypertensive medications and in those who have class F diabetes mellitus. Because of the physiologic changes during pregnancy, women with diabetes and renal disease will have serial increases in blood pressure as well as protein excretion with advanced gestational age, particularly in the third trimester. Diagnostic criteria (TABLE 3) should be individualized based on medical conditions and current therapy. Antihypertensive drugs and preexisting proteinuria make it more difficult to classify preeclampsia as mild or severe.

 

TABLE 3

Diagnostic criteria

GESTATIONAL HYPERTENSION IN HEALTHY WOMEN
Blood pressure <160 mm Hg diastolic and <110 mm Hg systolic
Proteinuria <300 mg/24-hour collection
Platelet count >100,000/mm3
Normal liver enzymes
No maternal symptoms
No intrauterine growth restriction or oligohydraminos by ultrasound
PREECLAMPSIA IN WOMEN WITH PREEXISTING MEDICAL CONDITIONS
Condition	Criteria
Hypertension only	Proteinuria >500 mg/24-hours or thrombocytopenia
Proteinuria only	New onset hypertension plus symptoms or thrombocytopenia or elevated liver enzymes
Hypertension plus proteinuria (renal disease or class F diabetes)	Worsening severe hypertension and/or new onset of symptoms, thrombocytopenia, elevated liver enzymes

FIGURE Whether preeclampsia will develop depends on when gestational hypertension begins

Adapted from Barton JR, et al. Am J Obstet Gynecol. 2001;184:979-983.

Step 3Consider how to balance risk to mother and fetus

Once a diagnosis is made, promptly evaluate mother and fetus, continue close surveillance, select those who will benefit from hospitalization, and identify indications for delivery (TABLE 4).

Delivery will always reduce the risks for the mother, but in certain situations, it might not be the best option for an extremely premature fetus. Sometimes delivery is best for both mother and fetus.

The best strategy takes into consideration:

• maternal and fetal status at initial evaluation,
• preexisting medical conditions that could affect pregnancy outcome,
• fetal gestational age at time of diagnosis,
• labor or rupture of fetal membranes (both could affect management), and
• maternal choice of available options.

Women who remain undelivered require close maternal and fetal evaluation. In otherwise healthy women, management depends on whether the preeclampsia is mild or severe, and, if there are other medical conditions, on the status of those conditions, as well.

TABLE 4

Indications for delivery

Consider delivery in gravidas with 1 or more indications
Gestational age ≥38 weeks for mild disease
Gestational age ≥34 weeks for severe disease
33-34 weeks with severe disease after steroids
Onset of labor and/or membrane rupture ≥34 weeks
Eclampsia or pulmonary edema (any gestational age)
HELLP syndrome (any gestational age)
Severe cerebral symptoms or epigastric pain
Acute renal insufficiency (serum creatinine >1.2 mg/dl)
Persistent thrombocytopenia (platelet count <100,000)
Maternal desire for delivery
Severe oligohydraminos or IUGR < 5th percentile
Nonreassuring fetal testing

The author reports no financial relationships relevant to this article.