Clinical Review

As 2007 draws to a close, we are still awaiting the World Health Organization’s fracture risk-assessment tool. The much-anticipated instrument will calculate 5- and 10-year fracture risks using an individual’s femoral neck T-score, age, history of low-trauma fracture, body mass index, steroid exposure, family history of hip fracture, smoking status, and alcohol intake. Once it is implemented, the tool will eliminate much of the confusion that arises when the T-score is the only variable used to determine the need for pharmacotherapy.

Why is the ability to stratify risk important? Although the incidence of fragility fractures is highest in osteoporotic women (as defined by the T-score), the absolute number of fractures is greater in those who have osteopenia. All clinicians should realize that the current definitions of normal bone density, osteopenia, and osteoporosis apply to the postmenopausal population only:

• normal – T-score above -1.0
• osteopenia – T-score below -1.0 but above -2.5
• osteoporosis – T-score below -2.5.

Indications added for raloxifene

The year did bring new indications for raloxifene, based on data from the RUTH and STAR trials,^1,2 which were mentioned in this Update 1 year ago. On September 14, the Food and Drug Administration approved two new indications:

• reduction of risk of invasive breast cancer in postmenopausal women with osteoporosis
• reduction of risk of invasive breast cancer in postmenopausal women at high risk of breast cancer.

These new indications are very important for clinicians who prescribe agents to prevent fragility fractures. Raloxifene should be considered for breast cancer risk reduction when deciding which agent to prescribe.

REAL study finds real advantage with risedronate

Silverman SL, Watts NB, Delmas PD, et al. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int. 2007;18(1):25–34.

Patients who take risedronate have lower rates of hip and nonvertebral fracture during their first year of therapy than do those who take alendronate. That is the finding of the RisedronatE and ALendronate (REAL) cohort study, a retrospective observation of the records of health-care utilization among women in the United States. Silverman and colleagues analyzed data sets for women older than age 65 who had ever used once-weekly dosing of risedronate or alendronate. The risedronate cohort included 12,215 women who were followed for a mean of 226 days of therapy. The alendronate cohort included 21,615 women followed for a mean of 238 days of therapy.

Risedronate group had more risk factors for fracture

At baseline, women taking risedronate had a statistically greater incidence of:

• advanced age
• use of concomitant medications
• glucocorticoid use
• rheumatoid arthritis.

Each of these characteristics might have been expected to increase the risk of fragility fracture. However, through 1 year of therapy, women using risedronate had an incidence of nonvertebral fractures 18% lower than those using alendronate (2.0% versus 2.3%; 95% confidence interval [CI], 0.02–0.32). They also had an incidence of hip fracture 43% lower than those using alendronate (0.4% versus 0.6%; 95% CI, 0.13–0.63). Overall, there were 507 nonvertebral fractures and 109 hip fractures.

Footnote: Large database analyses complement randomized trials

Randomized clinical trials (RCTs) are, of course, the gold standard for determining drug safety and efficacy and the key requisite for regulatory approval of new drugs. By design, RCTs have strict inclusion and exclusion criteria to meet the regulatory standard for evaluating drug efficacy and safety and to exclude internal bias. Often, the majority of patients are deemed ineligible for entry into an RCT because of comorbidity, concomitant medication use, age, or severity of disease. Therefore, database analyses are often more “real world” than RCTs.

As clinical practice data accumulate over time, observational, or outcomes, studies can be conducted to complement the data that have been generated by RCTs. For example, over the past decade, large databases of health-care utilization claims have become available in the United States and are being tapped to conduct effectiveness studies. These observational studies can supplement the efficacy measures obtained from the carefully controlled environment of a placebo-controlled RCT. They also provide a measure of effectiveness over a wide range of patients and health-care practices. Data generated from the REAL study are just another piece of the huge puzzle we must grapple with as we seek good information about agents to treat osteoporosis and prevent fragility fractures.

Annual infusion of zoledronic acid reduces risk of fracture

Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–1822.

Lyles KW, Colon-Emeris C, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357. DOI: 10.1056/NEJMoa074941.

Zoledronic acid (Zometa) is indicated for the treatment of high levels of serum calcium associated with Paget’s disease and various malignancies (multiple myeloma, breast, prostate, and lung). These two studies explore use of this agent to prevent fracture in postmenopausal women with osteoporosis—a use for which it proved effective. Other benefits may include improved compliance and ease of administration in some women.

Black and colleagues conducted their randomized, double-blind, placebo-controlled trial to assess the effect of annual infusion of zoledronic acid on the risk of fracture over a 3-year period. A total of 3,889 postmenopausal women with osteoporosis (mean age, 73 years; range, 65–89 years) were assigned to receive a single 15-minute, 5-mg infusion of the drug at baseline, 12 months, and 24 months, and a total of 3,876 women received placebo. Approximately half the women were from Europe, and the other half were from North and South America and Asia. All women received oral daily calcium (1,000–1,500 mg) and vitamin D (400–1,200 U), and all were monitored for 36 months.

The risk of vertebral fracture was reduced in the treatment group by 70% over 3 years, compared with the placebo group (3.3% or 92 women in the treatment group versus 10.9% or 310 women receiving placebo). The risk of hip fracture was reduced by 41% in the treatment group (1.4% or 52 women receiving zoledronic acid versus 2.5% or 88 women in the placebo group). (For all comparisons, P<.001.)

The most common postdose symptoms, seen within 3 days of infusion, included fever, flu-like symptoms, myalgia, headache, and arthralgias. There were more serious adverse events related to atrial fibrillation in the women receiving zoledronic acid (50 women receiving zoledronic acid versus 20 in the placebo group; P<.001).

Treatment is a valuable option for carefully selected populations

The trial by Black and colleagues holds great promise for some patients, especially those who have (or appear to have) upper gastrointestinal intolerance of oral bisphosphonates or who may have difficulty adhering to the positional requirements (i.e., remaining upright) of oral therapy. This may be especially true of patients in nursing homes. Once-yearly intravenous (IV) infusion may also make compliance easier for these patients.

One important detail of this trial: Of almost 8,000 women studied, the youngest was age 65. The implication: Don’t automatically assume this regimen is an appropriate alternative for younger osteopenic women who perceive themselves to have acid reflux.

Women at extremely high risk of fracture also benefit

Fracture is most likely to occur in women who have already experienced it (FIGURE 1). Lyles and colleagues chose this population for their study of once-yearly infusion of zoledronic acid. The study involved 2,127 patients within 90 days after repair of low-trauma hip fracture. Subjects were randomized to receive 5-mg IV zoledronic acid annually or placebo in a blinded fashion. All patients also received vitamin D and calcium supplements. Mean age was 74.5 years, as might be expected in a hip-fracture cohort, and median follow-up was 1.9 years.

New clinical fractures occurred in 8.6% of women in the zoledronic acid group and 13.9% of the placebo group—a 35% risk reduction with IV zoledronic acid (P=.001). Deaths occurred in 101 of 1,054 patients (9.6%) in the zoledronic acid group and 141 of 1,057 patients (13.3%) in the placebo group. This was a reduction of 28% in death from any cause in the zoledronic acid group (P=.01).

The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported. Rates of atrial fibrillation and stroke were similar in both the zoledronic acid and placebo groups.

This study provides further evidence that, for extremely high-risk women (those who have already suffered hip fracture), yearly zoledronic acid may be an extremely useful tool, especially for elderly women, in whom compliance with any medication—weekly or monthly—may be difficult.

FIGURE 1 Once a fracture occurs, another is likely

Although the risk of new fractures is heightened in women who have already experienced one, Lyles and colleagues found a 35% risk reduction with zoledronic acid.

Parathyroid hormone reduces vertebral fractures in osteoporotic women

Greenspan SL, Bone HG, Ettinger MP, et al, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326–339.

Teriparatide (Forteo) is a synthetic portion (1-34) of the parathyroid hormone (PTH) molecule that is identical in sequence to the biologically active segment of the 84-amino acid human PTH.

It has been shown to prevent fracture in women with low bone mineral density (BMD). Teriparatide is the only anabolic bone agent approved for clinical use; all other pharmacotherapies are antiresorptive.

The study by Greenspan and associates—the Treatment of Osteoporosis with Parathyroid Hormone, or TOP trial—involved the full-length PTH molecule (1–84) and provides evidence that it, too, can prevent vertebral fracture in women who have low BMD (FIGURE 2). This agent is used in Europe but not yet available in the United States.

TOP was an 18-month, randomized, double-blind, placebo-controlled, parallel-group study of 2,532 women with low BMD at the hip or lumbar spine. It was conducted at 168 centers in nine countries.

The primary outcome measure was new or worsened vertebral fracture; secondary outcomes were changes in BMD and safety. The trial investigated the safety of recombinant PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.

FIGURE 2 Fracture-prone bone responds to PTH

PTH prevented vertebral fracture in women with low BMD, existing fractures, or both.

Women had very low BMD, or low BMD and existing fractures

Participants were postmenopausal women aged 45 to 54 years. They had a BMD 3 standard deviations or more (T-score ≤ -3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip, with no vertebral fractures, or they had a BMD T-score of -2.5 and 1 to 4 vertebral fractures. Postmenopausal women aged 55 years or older were included if their BMD T-score was -2.5 and they had no vertebral fractures, or if their BMD T-score was -2.0 and they had 1 to 4 vertebral fractures before enrollment. The women were given 100 μg of recombinant human PTH or placebo daily, as well as calcium (700 mg/day) and vitamin D₃ (400 U/day).

PTH reduced the risk of new fractures or prevented worsening of existing fractures. The reduction in relative risk (RR) for vertebral fracture was 0.42 (95% CI, 0.24–0.72; P=.001). Women who received PTH had an increase in mean BMD of 6.9% at the spine (95% CI, 6.4–7.4) and 2.1% at the hip (95% CI, 1.7–2.5). Adverse events included a higher incidence of hypercalciuria, hypercalcemia, and nausea.

Although it is unlikely that many gynecologists will be ordering or monitoring injectable PTH therapy, we should be aware of the data. All too often such therapy is not even considered for women with severe osteoporosis (T-score < -2.5 and preexisting fracture), who may be excellent candidates.

Long-term alendronate users can sometimes take a “drug holiday”

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

As early as 2002, Greenspan and colleagues³ demonstrated that women on alendronate for 21 months maintained femoral-neck BMD through 15 months of crossover to placebo. This study by Black and associates, known as the FLEX trial, is a long-term extension of the Fracture Intervention Trial (FIT). A total of 1,099 women who had participated in FIT and taken alendronate for 5 years were then randomized to one of two doses of alendronate or placebo for an additional 5 years. To qualify for the FLEX trial, all women had to have low bone mass at the beginning of FIT. The average age of women in the FLEX trial was 73 years. The primary outcome was total hip BMD; secondary outcomes were BMD at other sites and biochemical markers.

Women who remained on alendronate maintained a higher BMD of the hip and spine than women on placebo, but all patients’ levels remained at or above pretreatment levels of 10 years earlier. The same was true for markers of bone remodeling. The cumulative risk of nonvertebral fractures did not differ between the two groups (19% for placebo, 18.9% for alendronate; RR, 1.0; 95% CI, 0.76–1.32). The risk of clinically recognized vertebral fractures was lower in the women who continued alendronate (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24–0.85), but there was no significant reduction in morphometric vertebral fractures.

Data can aid in determining duration of therapy

These data are extremely helpful, especially for clinicians who are trying to determine how long to continue bisphosphonate therapy and which patients may be candidates for a “drug holiday.” We have all had women whose response to a bisphosphonate has been so robust that follow-up BMD measurements have climbed to a range in which therapy would not have been initiated. This study clearly shows that the cumulative effect of 5 years of alendronate followed by 5 years of placebo is positive, compared with the bone loss one would expect in untreated women.

As 2007 draws to a close, we are still awaiting the World Health Organization’s fracture risk-assessment tool. The much-anticipated instrument will calculate 5- and 10-year fracture risks using an individual’s femoral neck T-score, age, history of low-trauma fracture, body mass index, steroid exposure, family history of hip fracture, smoking status, and alcohol intake. Once it is implemented, the tool will eliminate much of the confusion that arises when the T-score is the only variable used to determine the need for pharmacotherapy.

Why is the ability to stratify risk important? Although the incidence of fragility fractures is highest in osteoporotic women (as defined by the T-score), the absolute number of fractures is greater in those who have osteopenia. All clinicians should realize that the current definitions of normal bone density, osteopenia, and osteoporosis apply to the postmenopausal population only:

• normal – T-score above -1.0
• osteopenia – T-score below -1.0 but above -2.5
• osteoporosis – T-score below -2.5.

Indications added for raloxifene

The year did bring new indications for raloxifene, based on data from the RUTH and STAR trials,^1,2 which were mentioned in this Update 1 year ago. On September 14, the Food and Drug Administration approved two new indications:

• reduction of risk of invasive breast cancer in postmenopausal women with osteoporosis
• reduction of risk of invasive breast cancer in postmenopausal women at high risk of breast cancer.

These new indications are very important for clinicians who prescribe agents to prevent fragility fractures. Raloxifene should be considered for breast cancer risk reduction when deciding which agent to prescribe.

REAL study finds real advantage with risedronate

Silverman SL, Watts NB, Delmas PD, et al. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int. 2007;18(1):25–34.

Patients who take risedronate have lower rates of hip and nonvertebral fracture during their first year of therapy than do those who take alendronate. That is the finding of the RisedronatE and ALendronate (REAL) cohort study, a retrospective observation of the records of health-care utilization among women in the United States. Silverman and colleagues analyzed data sets for women older than age 65 who had ever used once-weekly dosing of risedronate or alendronate. The risedronate cohort included 12,215 women who were followed for a mean of 226 days of therapy. The alendronate cohort included 21,615 women followed for a mean of 238 days of therapy.

Risedronate group had more risk factors for fracture

At baseline, women taking risedronate had a statistically greater incidence of:

• advanced age
• use of concomitant medications
• glucocorticoid use
• rheumatoid arthritis.

Each of these characteristics might have been expected to increase the risk of fragility fracture. However, through 1 year of therapy, women using risedronate had an incidence of nonvertebral fractures 18% lower than those using alendronate (2.0% versus 2.3%; 95% confidence interval [CI], 0.02–0.32). They also had an incidence of hip fracture 43% lower than those using alendronate (0.4% versus 0.6%; 95% CI, 0.13–0.63). Overall, there were 507 nonvertebral fractures and 109 hip fractures.

Footnote: Large database analyses complement randomized trials

Randomized clinical trials (RCTs) are, of course, the gold standard for determining drug safety and efficacy and the key requisite for regulatory approval of new drugs. By design, RCTs have strict inclusion and exclusion criteria to meet the regulatory standard for evaluating drug efficacy and safety and to exclude internal bias. Often, the majority of patients are deemed ineligible for entry into an RCT because of comorbidity, concomitant medication use, age, or severity of disease. Therefore, database analyses are often more “real world” than RCTs.

As clinical practice data accumulate over time, observational, or outcomes, studies can be conducted to complement the data that have been generated by RCTs. For example, over the past decade, large databases of health-care utilization claims have become available in the United States and are being tapped to conduct effectiveness studies. These observational studies can supplement the efficacy measures obtained from the carefully controlled environment of a placebo-controlled RCT. They also provide a measure of effectiveness over a wide range of patients and health-care practices. Data generated from the REAL study are just another piece of the huge puzzle we must grapple with as we seek good information about agents to treat osteoporosis and prevent fragility fractures.

Annual infusion of zoledronic acid reduces risk of fracture

Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–1822.

Lyles KW, Colon-Emeris C, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357. DOI: 10.1056/NEJMoa074941.

Zoledronic acid (Zometa) is indicated for the treatment of high levels of serum calcium associated with Paget’s disease and various malignancies (multiple myeloma, breast, prostate, and lung). These two studies explore use of this agent to prevent fracture in postmenopausal women with osteoporosis—a use for which it proved effective. Other benefits may include improved compliance and ease of administration in some women.

Black and colleagues conducted their randomized, double-blind, placebo-controlled trial to assess the effect of annual infusion of zoledronic acid on the risk of fracture over a 3-year period. A total of 3,889 postmenopausal women with osteoporosis (mean age, 73 years; range, 65–89 years) were assigned to receive a single 15-minute, 5-mg infusion of the drug at baseline, 12 months, and 24 months, and a total of 3,876 women received placebo. Approximately half the women were from Europe, and the other half were from North and South America and Asia. All women received oral daily calcium (1,000–1,500 mg) and vitamin D (400–1,200 U), and all were monitored for 36 months.

The risk of vertebral fracture was reduced in the treatment group by 70% over 3 years, compared with the placebo group (3.3% or 92 women in the treatment group versus 10.9% or 310 women receiving placebo). The risk of hip fracture was reduced by 41% in the treatment group (1.4% or 52 women receiving zoledronic acid versus 2.5% or 88 women in the placebo group). (For all comparisons, P<.001.)

The most common postdose symptoms, seen within 3 days of infusion, included fever, flu-like symptoms, myalgia, headache, and arthralgias. There were more serious adverse events related to atrial fibrillation in the women receiving zoledronic acid (50 women receiving zoledronic acid versus 20 in the placebo group; P<.001).

Treatment is a valuable option for carefully selected populations

The trial by Black and colleagues holds great promise for some patients, especially those who have (or appear to have) upper gastrointestinal intolerance of oral bisphosphonates or who may have difficulty adhering to the positional requirements (i.e., remaining upright) of oral therapy. This may be especially true of patients in nursing homes. Once-yearly intravenous (IV) infusion may also make compliance easier for these patients.

One important detail of this trial: Of almost 8,000 women studied, the youngest was age 65. The implication: Don’t automatically assume this regimen is an appropriate alternative for younger osteopenic women who perceive themselves to have acid reflux.

Women at extremely high risk of fracture also benefit

Fracture is most likely to occur in women who have already experienced it (FIGURE 1). Lyles and colleagues chose this population for their study of once-yearly infusion of zoledronic acid. The study involved 2,127 patients within 90 days after repair of low-trauma hip fracture. Subjects were randomized to receive 5-mg IV zoledronic acid annually or placebo in a blinded fashion. All patients also received vitamin D and calcium supplements. Mean age was 74.5 years, as might be expected in a hip-fracture cohort, and median follow-up was 1.9 years.

New clinical fractures occurred in 8.6% of women in the zoledronic acid group and 13.9% of the placebo group—a 35% risk reduction with IV zoledronic acid (P=.001). Deaths occurred in 101 of 1,054 patients (9.6%) in the zoledronic acid group and 141 of 1,057 patients (13.3%) in the placebo group. This was a reduction of 28% in death from any cause in the zoledronic acid group (P=.01).

The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported. Rates of atrial fibrillation and stroke were similar in both the zoledronic acid and placebo groups.

This study provides further evidence that, for extremely high-risk women (those who have already suffered hip fracture), yearly zoledronic acid may be an extremely useful tool, especially for elderly women, in whom compliance with any medication—weekly or monthly—may be difficult.

FIGURE 1 Once a fracture occurs, another is likely

Although the risk of new fractures is heightened in women who have already experienced one, Lyles and colleagues found a 35% risk reduction with zoledronic acid.

Parathyroid hormone reduces vertebral fractures in osteoporotic women

Greenspan SL, Bone HG, Ettinger MP, et al, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326–339.

Teriparatide (Forteo) is a synthetic portion (1-34) of the parathyroid hormone (PTH) molecule that is identical in sequence to the biologically active segment of the 84-amino acid human PTH.

It has been shown to prevent fracture in women with low bone mineral density (BMD). Teriparatide is the only anabolic bone agent approved for clinical use; all other pharmacotherapies are antiresorptive.

The study by Greenspan and associates—the Treatment of Osteoporosis with Parathyroid Hormone, or TOP trial—involved the full-length PTH molecule (1–84) and provides evidence that it, too, can prevent vertebral fracture in women who have low BMD (FIGURE 2). This agent is used in Europe but not yet available in the United States.

TOP was an 18-month, randomized, double-blind, placebo-controlled, parallel-group study of 2,532 women with low BMD at the hip or lumbar spine. It was conducted at 168 centers in nine countries.

The primary outcome measure was new or worsened vertebral fracture; secondary outcomes were changes in BMD and safety. The trial investigated the safety of recombinant PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.

FIGURE 2 Fracture-prone bone responds to PTH

PTH prevented vertebral fracture in women with low BMD, existing fractures, or both.

Women had very low BMD, or low BMD and existing fractures

Participants were postmenopausal women aged 45 to 54 years. They had a BMD 3 standard deviations or more (T-score ≤ -3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip, with no vertebral fractures, or they had a BMD T-score of -2.5 and 1 to 4 vertebral fractures. Postmenopausal women aged 55 years or older were included if their BMD T-score was -2.5 and they had no vertebral fractures, or if their BMD T-score was -2.0 and they had 1 to 4 vertebral fractures before enrollment. The women were given 100 μg of recombinant human PTH or placebo daily, as well as calcium (700 mg/day) and vitamin D₃ (400 U/day).

PTH reduced the risk of new fractures or prevented worsening of existing fractures. The reduction in relative risk (RR) for vertebral fracture was 0.42 (95% CI, 0.24–0.72; P=.001). Women who received PTH had an increase in mean BMD of 6.9% at the spine (95% CI, 6.4–7.4) and 2.1% at the hip (95% CI, 1.7–2.5). Adverse events included a higher incidence of hypercalciuria, hypercalcemia, and nausea.

Although it is unlikely that many gynecologists will be ordering or monitoring injectable PTH therapy, we should be aware of the data. All too often such therapy is not even considered for women with severe osteoporosis (T-score < -2.5 and preexisting fracture), who may be excellent candidates.

Long-term alendronate users can sometimes take a “drug holiday”

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

As early as 2002, Greenspan and colleagues³ demonstrated that women on alendronate for 21 months maintained femoral-neck BMD through 15 months of crossover to placebo. This study by Black and associates, known as the FLEX trial, is a long-term extension of the Fracture Intervention Trial (FIT). A total of 1,099 women who had participated in FIT and taken alendronate for 5 years were then randomized to one of two doses of alendronate or placebo for an additional 5 years. To qualify for the FLEX trial, all women had to have low bone mass at the beginning of FIT. The average age of women in the FLEX trial was 73 years. The primary outcome was total hip BMD; secondary outcomes were BMD at other sites and biochemical markers.

Women who remained on alendronate maintained a higher BMD of the hip and spine than women on placebo, but all patients’ levels remained at or above pretreatment levels of 10 years earlier. The same was true for markers of bone remodeling. The cumulative risk of nonvertebral fractures did not differ between the two groups (19% for placebo, 18.9% for alendronate; RR, 1.0; 95% CI, 0.76–1.32). The risk of clinically recognized vertebral fractures was lower in the women who continued alendronate (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24–0.85), but there was no significant reduction in morphometric vertebral fractures.

Data can aid in determining duration of therapy

These data are extremely helpful, especially for clinicians who are trying to determine how long to continue bisphosphonate therapy and which patients may be candidates for a “drug holiday.” We have all had women whose response to a bisphosphonate has been so robust that follow-up BMD measurements have climbed to a range in which therapy would not have been initiated. This study clearly shows that the cumulative effect of 5 years of alendronate followed by 5 years of placebo is positive, compared with the bone loss one would expect in untreated women.

As 2007 draws to a close, we are still awaiting the World Health Organization’s fracture risk-assessment tool. The much-anticipated instrument will calculate 5- and 10-year fracture risks using an individual’s femoral neck T-score, age, history of low-trauma fracture, body mass index, steroid exposure, family history of hip fracture, smoking status, and alcohol intake. Once it is implemented, the tool will eliminate much of the confusion that arises when the T-score is the only variable used to determine the need for pharmacotherapy.

Why is the ability to stratify risk important? Although the incidence of fragility fractures is highest in osteoporotic women (as defined by the T-score), the absolute number of fractures is greater in those who have osteopenia. All clinicians should realize that the current definitions of normal bone density, osteopenia, and osteoporosis apply to the postmenopausal population only:

• normal – T-score above -1.0
• osteopenia – T-score below -1.0 but above -2.5
• osteoporosis – T-score below -2.5.

Indications added for raloxifene

The year did bring new indications for raloxifene, based on data from the RUTH and STAR trials,^1,2 which were mentioned in this Update 1 year ago. On September 14, the Food and Drug Administration approved two new indications:

• reduction of risk of invasive breast cancer in postmenopausal women with osteoporosis
• reduction of risk of invasive breast cancer in postmenopausal women at high risk of breast cancer.

These new indications are very important for clinicians who prescribe agents to prevent fragility fractures. Raloxifene should be considered for breast cancer risk reduction when deciding which agent to prescribe.

REAL study finds real advantage with risedronate

Silverman SL, Watts NB, Delmas PD, et al. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int. 2007;18(1):25–34.

Patients who take risedronate have lower rates of hip and nonvertebral fracture during their first year of therapy than do those who take alendronate. That is the finding of the RisedronatE and ALendronate (REAL) cohort study, a retrospective observation of the records of health-care utilization among women in the United States. Silverman and colleagues analyzed data sets for women older than age 65 who had ever used once-weekly dosing of risedronate or alendronate. The risedronate cohort included 12,215 women who were followed for a mean of 226 days of therapy. The alendronate cohort included 21,615 women followed for a mean of 238 days of therapy.

Risedronate group had more risk factors for fracture

At baseline, women taking risedronate had a statistically greater incidence of:

• advanced age
• use of concomitant medications
• glucocorticoid use
• rheumatoid arthritis.

Each of these characteristics might have been expected to increase the risk of fragility fracture. However, through 1 year of therapy, women using risedronate had an incidence of nonvertebral fractures 18% lower than those using alendronate (2.0% versus 2.3%; 95% confidence interval [CI], 0.02–0.32). They also had an incidence of hip fracture 43% lower than those using alendronate (0.4% versus 0.6%; 95% CI, 0.13–0.63). Overall, there were 507 nonvertebral fractures and 109 hip fractures.

Footnote: Large database analyses complement randomized trials

Randomized clinical trials (RCTs) are, of course, the gold standard for determining drug safety and efficacy and the key requisite for regulatory approval of new drugs. By design, RCTs have strict inclusion and exclusion criteria to meet the regulatory standard for evaluating drug efficacy and safety and to exclude internal bias. Often, the majority of patients are deemed ineligible for entry into an RCT because of comorbidity, concomitant medication use, age, or severity of disease. Therefore, database analyses are often more “real world” than RCTs.

As clinical practice data accumulate over time, observational, or outcomes, studies can be conducted to complement the data that have been generated by RCTs. For example, over the past decade, large databases of health-care utilization claims have become available in the United States and are being tapped to conduct effectiveness studies. These observational studies can supplement the efficacy measures obtained from the carefully controlled environment of a placebo-controlled RCT. They also provide a measure of effectiveness over a wide range of patients and health-care practices. Data generated from the REAL study are just another piece of the huge puzzle we must grapple with as we seek good information about agents to treat osteoporosis and prevent fragility fractures.

Annual infusion of zoledronic acid reduces risk of fracture

Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–1822.

Lyles KW, Colon-Emeris C, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357. DOI: 10.1056/NEJMoa074941.

Zoledronic acid (Zometa) is indicated for the treatment of high levels of serum calcium associated with Paget’s disease and various malignancies (multiple myeloma, breast, prostate, and lung). These two studies explore use of this agent to prevent fracture in postmenopausal women with osteoporosis—a use for which it proved effective. Other benefits may include improved compliance and ease of administration in some women.

Black and colleagues conducted their randomized, double-blind, placebo-controlled trial to assess the effect of annual infusion of zoledronic acid on the risk of fracture over a 3-year period. A total of 3,889 postmenopausal women with osteoporosis (mean age, 73 years; range, 65–89 years) were assigned to receive a single 15-minute, 5-mg infusion of the drug at baseline, 12 months, and 24 months, and a total of 3,876 women received placebo. Approximately half the women were from Europe, and the other half were from North and South America and Asia. All women received oral daily calcium (1,000–1,500 mg) and vitamin D (400–1,200 U), and all were monitored for 36 months.

The risk of vertebral fracture was reduced in the treatment group by 70% over 3 years, compared with the placebo group (3.3% or 92 women in the treatment group versus 10.9% or 310 women receiving placebo). The risk of hip fracture was reduced by 41% in the treatment group (1.4% or 52 women receiving zoledronic acid versus 2.5% or 88 women in the placebo group). (For all comparisons, P<.001.)

The most common postdose symptoms, seen within 3 days of infusion, included fever, flu-like symptoms, myalgia, headache, and arthralgias. There were more serious adverse events related to atrial fibrillation in the women receiving zoledronic acid (50 women receiving zoledronic acid versus 20 in the placebo group; P<.001).

Treatment is a valuable option for carefully selected populations

The trial by Black and colleagues holds great promise for some patients, especially those who have (or appear to have) upper gastrointestinal intolerance of oral bisphosphonates or who may have difficulty adhering to the positional requirements (i.e., remaining upright) of oral therapy. This may be especially true of patients in nursing homes. Once-yearly intravenous (IV) infusion may also make compliance easier for these patients.

One important detail of this trial: Of almost 8,000 women studied, the youngest was age 65. The implication: Don’t automatically assume this regimen is an appropriate alternative for younger osteopenic women who perceive themselves to have acid reflux.

Women at extremely high risk of fracture also benefit

Fracture is most likely to occur in women who have already experienced it (FIGURE 1). Lyles and colleagues chose this population for their study of once-yearly infusion of zoledronic acid. The study involved 2,127 patients within 90 days after repair of low-trauma hip fracture. Subjects were randomized to receive 5-mg IV zoledronic acid annually or placebo in a blinded fashion. All patients also received vitamin D and calcium supplements. Mean age was 74.5 years, as might be expected in a hip-fracture cohort, and median follow-up was 1.9 years.

New clinical fractures occurred in 8.6% of women in the zoledronic acid group and 13.9% of the placebo group—a 35% risk reduction with IV zoledronic acid (P=.001). Deaths occurred in 101 of 1,054 patients (9.6%) in the zoledronic acid group and 141 of 1,057 patients (13.3%) in the placebo group. This was a reduction of 28% in death from any cause in the zoledronic acid group (P=.01).

The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported. Rates of atrial fibrillation and stroke were similar in both the zoledronic acid and placebo groups.

This study provides further evidence that, for extremely high-risk women (those who have already suffered hip fracture), yearly zoledronic acid may be an extremely useful tool, especially for elderly women, in whom compliance with any medication—weekly or monthly—may be difficult.

FIGURE 1 Once a fracture occurs, another is likely

Although the risk of new fractures is heightened in women who have already experienced one, Lyles and colleagues found a 35% risk reduction with zoledronic acid.

Parathyroid hormone reduces vertebral fractures in osteoporotic women

Greenspan SL, Bone HG, Ettinger MP, et al, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326–339.

Teriparatide (Forteo) is a synthetic portion (1-34) of the parathyroid hormone (PTH) molecule that is identical in sequence to the biologically active segment of the 84-amino acid human PTH.

It has been shown to prevent fracture in women with low bone mineral density (BMD). Teriparatide is the only anabolic bone agent approved for clinical use; all other pharmacotherapies are antiresorptive.

The study by Greenspan and associates—the Treatment of Osteoporosis with Parathyroid Hormone, or TOP trial—involved the full-length PTH molecule (1–84) and provides evidence that it, too, can prevent vertebral fracture in women who have low BMD (FIGURE 2). This agent is used in Europe but not yet available in the United States.

TOP was an 18-month, randomized, double-blind, placebo-controlled, parallel-group study of 2,532 women with low BMD at the hip or lumbar spine. It was conducted at 168 centers in nine countries.

The primary outcome measure was new or worsened vertebral fracture; secondary outcomes were changes in BMD and safety. The trial investigated the safety of recombinant PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.

FIGURE 2 Fracture-prone bone responds to PTH

PTH prevented vertebral fracture in women with low BMD, existing fractures, or both.

Women had very low BMD, or low BMD and existing fractures

Participants were postmenopausal women aged 45 to 54 years. They had a BMD 3 standard deviations or more (T-score ≤ -3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip, with no vertebral fractures, or they had a BMD T-score of -2.5 and 1 to 4 vertebral fractures. Postmenopausal women aged 55 years or older were included if their BMD T-score was -2.5 and they had no vertebral fractures, or if their BMD T-score was -2.0 and they had 1 to 4 vertebral fractures before enrollment. The women were given 100 μg of recombinant human PTH or placebo daily, as well as calcium (700 mg/day) and vitamin D₃ (400 U/day).

PTH reduced the risk of new fractures or prevented worsening of existing fractures. The reduction in relative risk (RR) for vertebral fracture was 0.42 (95% CI, 0.24–0.72; P=.001). Women who received PTH had an increase in mean BMD of 6.9% at the spine (95% CI, 6.4–7.4) and 2.1% at the hip (95% CI, 1.7–2.5). Adverse events included a higher incidence of hypercalciuria, hypercalcemia, and nausea.

Although it is unlikely that many gynecologists will be ordering or monitoring injectable PTH therapy, we should be aware of the data. All too often such therapy is not even considered for women with severe osteoporosis (T-score < -2.5 and preexisting fracture), who may be excellent candidates.

Long-term alendronate users can sometimes take a “drug holiday”

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

As early as 2002, Greenspan and colleagues³ demonstrated that women on alendronate for 21 months maintained femoral-neck BMD through 15 months of crossover to placebo. This study by Black and associates, known as the FLEX trial, is a long-term extension of the Fracture Intervention Trial (FIT). A total of 1,099 women who had participated in FIT and taken alendronate for 5 years were then randomized to one of two doses of alendronate or placebo for an additional 5 years. To qualify for the FLEX trial, all women had to have low bone mass at the beginning of FIT. The average age of women in the FLEX trial was 73 years. The primary outcome was total hip BMD; secondary outcomes were BMD at other sites and biochemical markers.

Women who remained on alendronate maintained a higher BMD of the hip and spine than women on placebo, but all patients’ levels remained at or above pretreatment levels of 10 years earlier. The same was true for markers of bone remodeling. The cumulative risk of nonvertebral fractures did not differ between the two groups (19% for placebo, 18.9% for alendronate; RR, 1.0; 95% CI, 0.76–1.32). The risk of clinically recognized vertebral fractures was lower in the women who continued alendronate (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24–0.85), but there was no significant reduction in morphometric vertebral fractures.

Data can aid in determining duration of therapy

These data are extremely helpful, especially for clinicians who are trying to determine how long to continue bisphosphonate therapy and which patients may be candidates for a “drug holiday.” We have all had women whose response to a bisphosphonate has been so robust that follow-up BMD measurements have climbed to a range in which therapy would not have been initiated. This study clearly shows that the cumulative effect of 5 years of alendronate followed by 5 years of placebo is positive, compared with the bone loss one would expect in untreated women.

CASE: Difficulty inserting a catheter suggests an unyielding cervix

A.W. is a 38-year-old nulliparous woman who seeks treatment for persistent irregular vaginal bleeding. Her physician attempts an endometrial biopsy in the office but is unable to pass the catheter through the internal cervical os. She schedules office hysteroscopy as follow-up.

What steps can the ObGyn take to reduce the difficulty of the procedure, particularly insertion of the hysteroscope through the cervical canal?

Successful hysteroscopy requires a cervical canal sufficiently dilated to allow passage of the hysteroscope. And because of inevitable variation in anatomy—and even in models of hysteroscopes, which range in diameter from 2.7 to 10 mm—passage is not always easily accomplished. Many of the complications related to hysteroscopy, including cervical tears, creation of a false passage, uterine perforation, vasovagal reaction, pain, and inability to complete the procedure, are caused by inadequate cervical dilation and an inability to insert the hysteroscope.^1-6 One study noted that almost half of complications were related to cervical entry.⁶

In this article, I describe ways to overcome the challenging cervix for hysteroscopic procedures and endometrial biopsy (TABLES 1 and 2).

TABLE 1

10 actions that can ease entry to the cervix for hysteroscopy

TABLE 2

6 ways to prepare the cervix for endometrial biopsy

Hysteroscopy failure rate: 3.4% to 4.2%

Hysteroscopy is, of course, common in gynecologic practice, its indications extending across a range of investigations and treatments—for menstrual disorders, postmenopausal bleeding, infertility, and recurrent pregnancy loss.^1,7 Flexible hysteroscopes range in diameter from 2.7 to 5 mm; rigid hysteroscopes, from 1 to 5 mm; and operative hysteroscopes can be as large as 8 to 10 mm.^2,7

A systematic review of diagnostic hysteroscopy in more than 26,000 women reported a failure rate of 4.2% for ambulatory hysteroscopy and 3.4% for inpatient procedures.⁴ Failed ambulatory procedures were mainly attributed to technical problems, including:

• cervical stenosis
• anatomic and structural abnormalities
• pain and intolerance.⁴

Ideally, hysteroscopy is performed with minimal or no cervical dilation,⁷ but this may not always be possible.

Things to consider before embarking
Close attention to cervical and uterine anatomy is critical because insertion of the hysteroscope can be the most difficult aspect of the procedure. A bimanual examination is imperative to assess uterine size and position. It also is useful to sound the uterus to determine its depth.

An accurate medical, gynecologic, and obstetric history is essential, including information on pregnancies, dilation and curettage, cervical procedures such as cryotherapy, and any other procedures that may increase the risk of cervical stenosis, or difficulty dilating the cervix.

Is stenosis present? Stenosis is most common in nulliparous and postmenopausal women and in those who have undergone cervical procedures such as cryotherapy. Stenosis increases the risk of laceration and uterine perforation.

Consider a mechanical dilator. When cervical dilation is difficult, a series of small Hagar or lacrimal duct dilators may be helpful (FIGURE).

FIGURE Mechanical dilation is one antidote to cervical stenosis

In challenging cases, such as cervical stenosis, mechanical dilation with a series of Hagar or lacrimal duct dilators may facilitate entry into the cervix.

Pain can be mild—or it can thwart your work

Although many women tolerate placement of a small hysteroscope without analgesia or anesthesia, pain and vasovagal reaction sometimes occur. Indeed, the level of pain experienced by the patient is a major determinant of the overall success of the procedure.^3,8-10 Pain can occur when a tenaculum is used to grasp the anterior cervix, as well as during cervical dilation, injection of local anesthetic, or insertion of the hysteroscope. In some cases, a smaller scope may be all that is needed to solve the problem.¹¹

Analgesia may not always be necessary

Some researchers have studied office hysteroscopy without analgesia or anesthesia, finding a high level of acceptance.^12,13 Others have found a significant percentage of women requesting anesthesia or analgesia (16.5%)¹⁰ or requiring local anesthesia (28.8%).⁸

Preoperative NSAIDs may suffice. Use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) 1 hour before office hysteroscopy may reduce intraoperative and postoperative pain.⁷ Nagele and colleagues⁸ compared use of mefenamic acid 1 hour before the procedure with placebo in 95 women undergoing outpatient diagnostic hysteroscopy. Mefenamic acid reduced pain at 30 and 60 minutes after—but not during—the procedure. Other studies have found that pain is reduced when an oral NSAID is taken 1 to 2 hours before insertion of an intrauterine device and before suction curettage.^14,15

Other perioperative medications may help reduce discomfort and patient anxiety, including anxiolytics, such as lorazepam, analgesics, and conscious sedation.³

Paracervical block may be appropriate when pain is very likely

A number of investigators have evaluated use of paracervical anesthesia during out-patient hysteroscopy.^9,13,16,17 They injected lignocaine or mepivacaine using a 21- or 22-gauge needle at 3, 5, 7, and 9 o’clock or 4 and 8 o’clock paracervically.¹³ One study found paracervical block to be effective in reducing the pain of tenaculum placement and insertion of the hysteroscope.¹⁷ However, some studies suggested a reduction of pain in postmenopausal women only.⁹ These women may be more likely to have cervical stenosis.

Paracervical block does pose a risk of complications. Studies have reported bleeding in some women¹⁶ and pain with injection of the paracervical block, as well as bradycardia and hypotension possibly secondary to intravascular injection.¹⁷

Other methods are inconsistent

Intracervical injection. Some researchers have recommended injection of local anesthetic into the cervix.¹³ One study found no benefit—in fact, the injection appeared to be the most painful part of the procedure.¹⁸ A case series suggested that injection of local anesthetic may be effective, but the series lacked a placebo or control arm.¹³

Topical intrauterine anesthetic has been investigated after administration through the channel of the hysteroscope or by a catheter passed through the cervix into the uterine cavity.¹³ Findings have been mixed, with some researchers demonstrating reduced pain^19,20 and others showing no relief.²¹

Topical cervical anesthesia. Some hysteroscopists have recommended application of anesthetic cream, gel, or spray directly to the cervix immediately before the procedure.^13,22 The results have been mixed, with some studies noting decreased pain overall,¹³ one finding decreased pain only during tenaculum placement,²² and others finding no significant reduction in pain any time during the procedure.^13,23,24 A review concluded that topical cervical lignocaine spray may reduce the discomfort of tenaculum placement.¹³

Topical anesthesia may minimize vasovagal reaction

In one study, 1.1% of women undergoing office hysteroscopy experienced a vasovagal reaction, caused by stimulation of the parasympathetic nervous system with cervical manipulation and passage of the scope through the internal os of the cervix.²⁵ The reaction led to hypotension and bradycardia. Several studies have suggested that a local anesthetic can reduce this complication.^19,20

Cicinelli and associates found that topical local anesthesia reduced the incidence of vasovagal reaction from 32.5% in the control arm to 5%.²⁰ They suggest that a local anesthetic be considered in selected women, such as postmenopausal patients, who are at increased risk of vasovagal attack.

In contrast, Lau and associates¹⁷ found an increased rate of bradycardia and hypotension with paracervical lignocaine (31% versus 10%), but it may have been caused by inadvertent intravascular injection.¹⁷

Researchers have also suggested that the use of smaller hysteroscopes may reduce the incidence of vasovagal reactions.²⁶

How to prime the cervix for hysteroscopy

The use of vaginal misoprostol, a prostaglandin E₁ analogue, 9 to 12 hours before hysteroscopy may help increase preprocedural cervical dilation in premenopausal women, especially in nulliparas and women undergoing operative hysteroscopy. Misoprostol, used to prevent and treat NSAID-induced gastric ulcers, is gaining favor as a cervical ripening agent. We performed a meta-analysis to assess its effectiveness in dilating the cervix and reducing the need for mechanical dilation.⁵

We identified 10 studies that met inclusion criteria; five of them included premenopausal women, four included postmenopausal women or women receiving a gonadotropin-releasing hormone (GnRH) agonist, and one study included both groups.⁵ A variety of dosing protocols were used, with dosages ranging from 100 μg to 1,000 μg of intravaginal or oral misoprostol 4 to 24 hours preoperatively (most studies evaluated the vaginal route).

We found that misoprostol significantly reduced the need for further cervical dilation, and was associated with a lower rate of cervical laceration. However, this was true only for the premenopausal group: 42.6% of premenopausal women given misoprostol needed further dilation, compared with 71.7% in the control group, and 2% of premenopausal women given misoprostol suffered cervical laceration, compared with 11% in the control group. Among postmenopausal women and those receiving a GnRH agonist, misoprostol lacked clear benefit and was associated with side effects such as nausea, diarrhea, abdominal cramping, and fever.

For every premenopausal woman who received misoprostol before hysteroscopy, one woman avoided the need for further cervical dilation. For every 12 premenopausal women receiving misoprostol, one cervical laceration was avoided.

The ideal dosing regimen could not be determined because of variations in protocols. Nor was it clear whether misoprostol had any benefit among postmenopausal women or those receiving a GnRH agonist.

Most studies of misoprostol for cervical ripening have involved intravaginal administration, with dosages of 200 μg to 400 μg given 9 to 12 hours before hysteroscopy showing the greatest benefit.

Ultrasonography may help guide dilation

Transabdominal ultrasonography has been used to guide dilation in difficult dilation and curettage procedures, and is especially useful in women with a history of uterine perforation.²⁷ It may be helpful in cases involving difficult cervical dilation during hysteroscopy or endometrial biopsy.

Steady the cervix. A tenaculum is not always required, but its use on the anterior lip of the cervix may help steady the cervix and provide countertraction during insertion of the hysteroscope through the cervical canal, especially if the cervix is not in an axial position.⁷

CASE Resolved!

Because she is nulliparous and may benefit from cervical priming, the patient is given 400 μg of intravaginal misoprostol 12 hours before hysteroscopy, as well as an oral NSAID 1 hour before the procedure. A bimanual examination reveals a sharply anteverted uterus, so a topical cervical anesthetic spray is applied to the anterior cervix, and a tenaculum is placed to help straighten the uterine position. The hysteroscope passes easily through the cervical canal, making further dilation unnecessary. The procedure is completed without difficulty and is well tolerated by the patient.

Difficult entry can also hamper endometrial biopsy

Every ObGyn has used endometrial biopsy to assess abnormal uterine bleeding, postmenopausal bleeding, infertility, or recurrent pregnancy loss, or to monitor women on hormone replacement therapy^28,29 —so its advantages over dilation and curettage should come as no surprise. They include the ability to perform it in an office setting, usually with minimal cervical dilation, often without anesthesia, and at less expense.²⁸ Complications include cramping and pain,^29-32 vasovagal reaction,²⁹ bleeding,²⁹ and inability to pass the biopsy catheter through the cervix into the uterine cavity. Another rare complication is uterine perforation.²⁹

As with hysteroscopy, many of these complications are related to difficulty entering the uterine cavity through the cervix.

Prerequisites include thorough assessment of the uterus

As with hysteroscopy, an accurate and detailed history is necessary to identify risk factors for a difficult procedure. Assess uterine size and position with a bimanual examination. Although a tenaculum is often unnecessary, its placement on the anterior lip of the cervix may help steady the cervix and allow the catheter to pass through the cervical canal into the uterine cavity, especially if the uterus is not in the axial position.^28,29 Again, it is useful to sound the uterine cavity to ascertain its depth. This may be done with the biopsy catheter.

Cervical dilation may be necessary

Even when women with cervical stenosis were excluded in one study, it was difficult to pass the Pipelle endometrial biopsy through the cervix in 41.7% of women.³⁰

If the sampling device does not pass easily through the cervix, use a tenaculum and a lacrimal duct probe or small Hagar dilators to dilate the cervix.²⁸

Pain may again be an issue

Almost 50% of women experience moderate or severe pain during endometrial biopsy.³² Many clinicians recommend giving an oral NSAID 60 minutes before the procedure to decrease discomfort. One study found that the use of naproxen sodium before Vabra curettage reduced the severity of pain at 30 and 60 minutes after the procedure, but did not alleviate discomfort arising during the biopsy itself.¹⁴ Another study suggested the combination of naproxen sodium and intrauterine lidocaine (5 mL of 2% lidocaine) to reduce discomfort associated with the procedure.³⁰

Use of anesthesia is controversial

A study by Lau and colleagues¹⁷ found paracervical lignocaine to be ineffective at reducing pain during hysteroscopy and endometrial biopsy, but the drug did increase the risk of bradycardia and hypotension. Another study demonstrated a decrease in procedure-related discomfort in postmenopausal women who were given 2 mL of 2% intrauterine mepivacaine.²⁰ These findings are similar to those of Zupi and associates.¹⁹

Consider the tool

Discomfort may be related to the size of the biopsy catheter. Pain scores appear to be significantly lower with the Pipelle biopsy catheter than with the larger Novak biopsy curette.³²

Vasovagal reaction usually resolves after the procedure

As with hysteroscopy, women may occasionally experience a vasovagal reaction during endometrial biopsy. This complication usually resolves quickly once the procedure is completed.²⁹ Some clinicians suggest that the patient be allowed to eat and drink before the procedure and be given an analgesic before it begins.²⁸

Cervical priming is not a proven strategy

Misoprostol has been considered as a preprocedure adjunct to endometrial biopsy. Only one small randomized, controlled trial involving 42 women has evaluated the drug for this indication. It found no benefit when 400 μg of misoprostol was given orally 3 hours before the procedure, as well as cramping and increased pain during the biopsy.³³ This study had several shortcomings, including its small sample size and the inclusion of both pre- and postmenopausal women. Further research is needed—separately in premenopausal and postmenopausal women and with adequately large samples—to assess the use of misoprostol.

The author reports no financial relationships relevant to this article.

CASE: Difficulty inserting a catheter suggests an unyielding cervix

A.W. is a 38-year-old nulliparous woman who seeks treatment for persistent irregular vaginal bleeding. Her physician attempts an endometrial biopsy in the office but is unable to pass the catheter through the internal cervical os. She schedules office hysteroscopy as follow-up.

What steps can the ObGyn take to reduce the difficulty of the procedure, particularly insertion of the hysteroscope through the cervical canal?

Successful hysteroscopy requires a cervical canal sufficiently dilated to allow passage of the hysteroscope. And because of inevitable variation in anatomy—and even in models of hysteroscopes, which range in diameter from 2.7 to 10 mm—passage is not always easily accomplished. Many of the complications related to hysteroscopy, including cervical tears, creation of a false passage, uterine perforation, vasovagal reaction, pain, and inability to complete the procedure, are caused by inadequate cervical dilation and an inability to insert the hysteroscope.^1-6 One study noted that almost half of complications were related to cervical entry.⁶

In this article, I describe ways to overcome the challenging cervix for hysteroscopic procedures and endometrial biopsy (TABLES 1 and 2).

TABLE 1

10 actions that can ease entry to the cervix for hysteroscopy

TABLE 2

6 ways to prepare the cervix for endometrial biopsy

Hysteroscopy failure rate: 3.4% to 4.2%

Hysteroscopy is, of course, common in gynecologic practice, its indications extending across a range of investigations and treatments—for menstrual disorders, postmenopausal bleeding, infertility, and recurrent pregnancy loss.^1,7 Flexible hysteroscopes range in diameter from 2.7 to 5 mm; rigid hysteroscopes, from 1 to 5 mm; and operative hysteroscopes can be as large as 8 to 10 mm.^2,7

A systematic review of diagnostic hysteroscopy in more than 26,000 women reported a failure rate of 4.2% for ambulatory hysteroscopy and 3.4% for inpatient procedures.⁴ Failed ambulatory procedures were mainly attributed to technical problems, including:

• cervical stenosis
• anatomic and structural abnormalities
• pain and intolerance.⁴

Ideally, hysteroscopy is performed with minimal or no cervical dilation,⁷ but this may not always be possible.

Things to consider before embarking
Close attention to cervical and uterine anatomy is critical because insertion of the hysteroscope can be the most difficult aspect of the procedure. A bimanual examination is imperative to assess uterine size and position. It also is useful to sound the uterus to determine its depth.

An accurate medical, gynecologic, and obstetric history is essential, including information on pregnancies, dilation and curettage, cervical procedures such as cryotherapy, and any other procedures that may increase the risk of cervical stenosis, or difficulty dilating the cervix.

Is stenosis present? Stenosis is most common in nulliparous and postmenopausal women and in those who have undergone cervical procedures such as cryotherapy. Stenosis increases the risk of laceration and uterine perforation.

Consider a mechanical dilator. When cervical dilation is difficult, a series of small Hagar or lacrimal duct dilators may be helpful (FIGURE).

FIGURE Mechanical dilation is one antidote to cervical stenosis

In challenging cases, such as cervical stenosis, mechanical dilation with a series of Hagar or lacrimal duct dilators may facilitate entry into the cervix.

Pain can be mild—or it can thwart your work

Although many women tolerate placement of a small hysteroscope without analgesia or anesthesia, pain and vasovagal reaction sometimes occur. Indeed, the level of pain experienced by the patient is a major determinant of the overall success of the procedure.^3,8-10 Pain can occur when a tenaculum is used to grasp the anterior cervix, as well as during cervical dilation, injection of local anesthetic, or insertion of the hysteroscope. In some cases, a smaller scope may be all that is needed to solve the problem.¹¹

Analgesia may not always be necessary

Some researchers have studied office hysteroscopy without analgesia or anesthesia, finding a high level of acceptance.^12,13 Others have found a significant percentage of women requesting anesthesia or analgesia (16.5%)¹⁰ or requiring local anesthesia (28.8%).⁸

Preoperative NSAIDs may suffice. Use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) 1 hour before office hysteroscopy may reduce intraoperative and postoperative pain.⁷ Nagele and colleagues⁸ compared use of mefenamic acid 1 hour before the procedure with placebo in 95 women undergoing outpatient diagnostic hysteroscopy. Mefenamic acid reduced pain at 30 and 60 minutes after—but not during—the procedure. Other studies have found that pain is reduced when an oral NSAID is taken 1 to 2 hours before insertion of an intrauterine device and before suction curettage.^14,15

Other perioperative medications may help reduce discomfort and patient anxiety, including anxiolytics, such as lorazepam, analgesics, and conscious sedation.³

Paracervical block may be appropriate when pain is very likely

A number of investigators have evaluated use of paracervical anesthesia during out-patient hysteroscopy.^9,13,16,17 They injected lignocaine or mepivacaine using a 21- or 22-gauge needle at 3, 5, 7, and 9 o’clock or 4 and 8 o’clock paracervically.¹³ One study found paracervical block to be effective in reducing the pain of tenaculum placement and insertion of the hysteroscope.¹⁷ However, some studies suggested a reduction of pain in postmenopausal women only.⁹ These women may be more likely to have cervical stenosis.

Paracervical block does pose a risk of complications. Studies have reported bleeding in some women¹⁶ and pain with injection of the paracervical block, as well as bradycardia and hypotension possibly secondary to intravascular injection.¹⁷

Other methods are inconsistent

Intracervical injection. Some researchers have recommended injection of local anesthetic into the cervix.¹³ One study found no benefit—in fact, the injection appeared to be the most painful part of the procedure.¹⁸ A case series suggested that injection of local anesthetic may be effective, but the series lacked a placebo or control arm.¹³

Topical intrauterine anesthetic has been investigated after administration through the channel of the hysteroscope or by a catheter passed through the cervix into the uterine cavity.¹³ Findings have been mixed, with some researchers demonstrating reduced pain^19,20 and others showing no relief.²¹

Topical cervical anesthesia. Some hysteroscopists have recommended application of anesthetic cream, gel, or spray directly to the cervix immediately before the procedure.^13,22 The results have been mixed, with some studies noting decreased pain overall,¹³ one finding decreased pain only during tenaculum placement,²² and others finding no significant reduction in pain any time during the procedure.^13,23,24 A review concluded that topical cervical lignocaine spray may reduce the discomfort of tenaculum placement.¹³

Topical anesthesia may minimize vasovagal reaction

In one study, 1.1% of women undergoing office hysteroscopy experienced a vasovagal reaction, caused by stimulation of the parasympathetic nervous system with cervical manipulation and passage of the scope through the internal os of the cervix.²⁵ The reaction led to hypotension and bradycardia. Several studies have suggested that a local anesthetic can reduce this complication.^19,20

Cicinelli and associates found that topical local anesthesia reduced the incidence of vasovagal reaction from 32.5% in the control arm to 5%.²⁰ They suggest that a local anesthetic be considered in selected women, such as postmenopausal patients, who are at increased risk of vasovagal attack.

In contrast, Lau and associates¹⁷ found an increased rate of bradycardia and hypotension with paracervical lignocaine (31% versus 10%), but it may have been caused by inadvertent intravascular injection.¹⁷

Researchers have also suggested that the use of smaller hysteroscopes may reduce the incidence of vasovagal reactions.²⁶

How to prime the cervix for hysteroscopy

The use of vaginal misoprostol, a prostaglandin E₁ analogue, 9 to 12 hours before hysteroscopy may help increase preprocedural cervical dilation in premenopausal women, especially in nulliparas and women undergoing operative hysteroscopy. Misoprostol, used to prevent and treat NSAID-induced gastric ulcers, is gaining favor as a cervical ripening agent. We performed a meta-analysis to assess its effectiveness in dilating the cervix and reducing the need for mechanical dilation.⁵

We identified 10 studies that met inclusion criteria; five of them included premenopausal women, four included postmenopausal women or women receiving a gonadotropin-releasing hormone (GnRH) agonist, and one study included both groups.⁵ A variety of dosing protocols were used, with dosages ranging from 100 μg to 1,000 μg of intravaginal or oral misoprostol 4 to 24 hours preoperatively (most studies evaluated the vaginal route).

We found that misoprostol significantly reduced the need for further cervical dilation, and was associated with a lower rate of cervical laceration. However, this was true only for the premenopausal group: 42.6% of premenopausal women given misoprostol needed further dilation, compared with 71.7% in the control group, and 2% of premenopausal women given misoprostol suffered cervical laceration, compared with 11% in the control group. Among postmenopausal women and those receiving a GnRH agonist, misoprostol lacked clear benefit and was associated with side effects such as nausea, diarrhea, abdominal cramping, and fever.

For every premenopausal woman who received misoprostol before hysteroscopy, one woman avoided the need for further cervical dilation. For every 12 premenopausal women receiving misoprostol, one cervical laceration was avoided.

The ideal dosing regimen could not be determined because of variations in protocols. Nor was it clear whether misoprostol had any benefit among postmenopausal women or those receiving a GnRH agonist.

Most studies of misoprostol for cervical ripening have involved intravaginal administration, with dosages of 200 μg to 400 μg given 9 to 12 hours before hysteroscopy showing the greatest benefit.

Ultrasonography may help guide dilation

Transabdominal ultrasonography has been used to guide dilation in difficult dilation and curettage procedures, and is especially useful in women with a history of uterine perforation.²⁷ It may be helpful in cases involving difficult cervical dilation during hysteroscopy or endometrial biopsy.

Steady the cervix. A tenaculum is not always required, but its use on the anterior lip of the cervix may help steady the cervix and provide countertraction during insertion of the hysteroscope through the cervical canal, especially if the cervix is not in an axial position.⁷

CASE Resolved!

Because she is nulliparous and may benefit from cervical priming, the patient is given 400 μg of intravaginal misoprostol 12 hours before hysteroscopy, as well as an oral NSAID 1 hour before the procedure. A bimanual examination reveals a sharply anteverted uterus, so a topical cervical anesthetic spray is applied to the anterior cervix, and a tenaculum is placed to help straighten the uterine position. The hysteroscope passes easily through the cervical canal, making further dilation unnecessary. The procedure is completed without difficulty and is well tolerated by the patient.

Difficult entry can also hamper endometrial biopsy

Every ObGyn has used endometrial biopsy to assess abnormal uterine bleeding, postmenopausal bleeding, infertility, or recurrent pregnancy loss, or to monitor women on hormone replacement therapy^28,29 —so its advantages over dilation and curettage should come as no surprise. They include the ability to perform it in an office setting, usually with minimal cervical dilation, often without anesthesia, and at less expense.²⁸ Complications include cramping and pain,^29-32 vasovagal reaction,²⁹ bleeding,²⁹ and inability to pass the biopsy catheter through the cervix into the uterine cavity. Another rare complication is uterine perforation.²⁹

As with hysteroscopy, many of these complications are related to difficulty entering the uterine cavity through the cervix.

Prerequisites include thorough assessment of the uterus

As with hysteroscopy, an accurate and detailed history is necessary to identify risk factors for a difficult procedure. Assess uterine size and position with a bimanual examination. Although a tenaculum is often unnecessary, its placement on the anterior lip of the cervix may help steady the cervix and allow the catheter to pass through the cervical canal into the uterine cavity, especially if the uterus is not in the axial position.^28,29 Again, it is useful to sound the uterine cavity to ascertain its depth. This may be done with the biopsy catheter.

Cervical dilation may be necessary

Even when women with cervical stenosis were excluded in one study, it was difficult to pass the Pipelle endometrial biopsy through the cervix in 41.7% of women.³⁰

If the sampling device does not pass easily through the cervix, use a tenaculum and a lacrimal duct probe or small Hagar dilators to dilate the cervix.²⁸

Pain may again be an issue

Almost 50% of women experience moderate or severe pain during endometrial biopsy.³² Many clinicians recommend giving an oral NSAID 60 minutes before the procedure to decrease discomfort. One study found that the use of naproxen sodium before Vabra curettage reduced the severity of pain at 30 and 60 minutes after the procedure, but did not alleviate discomfort arising during the biopsy itself.¹⁴ Another study suggested the combination of naproxen sodium and intrauterine lidocaine (5 mL of 2% lidocaine) to reduce discomfort associated with the procedure.³⁰

Use of anesthesia is controversial

A study by Lau and colleagues¹⁷ found paracervical lignocaine to be ineffective at reducing pain during hysteroscopy and endometrial biopsy, but the drug did increase the risk of bradycardia and hypotension. Another study demonstrated a decrease in procedure-related discomfort in postmenopausal women who were given 2 mL of 2% intrauterine mepivacaine.²⁰ These findings are similar to those of Zupi and associates.¹⁹

Consider the tool

Discomfort may be related to the size of the biopsy catheter. Pain scores appear to be significantly lower with the Pipelle biopsy catheter than with the larger Novak biopsy curette.³²

Vasovagal reaction usually resolves after the procedure

As with hysteroscopy, women may occasionally experience a vasovagal reaction during endometrial biopsy. This complication usually resolves quickly once the procedure is completed.²⁹ Some clinicians suggest that the patient be allowed to eat and drink before the procedure and be given an analgesic before it begins.²⁸

Cervical priming is not a proven strategy

Misoprostol has been considered as a preprocedure adjunct to endometrial biopsy. Only one small randomized, controlled trial involving 42 women has evaluated the drug for this indication. It found no benefit when 400 μg of misoprostol was given orally 3 hours before the procedure, as well as cramping and increased pain during the biopsy.³³ This study had several shortcomings, including its small sample size and the inclusion of both pre- and postmenopausal women. Further research is needed—separately in premenopausal and postmenopausal women and with adequately large samples—to assess the use of misoprostol.

The author reports no financial relationships relevant to this article.

CASE: Difficulty inserting a catheter suggests an unyielding cervix

A.W. is a 38-year-old nulliparous woman who seeks treatment for persistent irregular vaginal bleeding. Her physician attempts an endometrial biopsy in the office but is unable to pass the catheter through the internal cervical os. She schedules office hysteroscopy as follow-up.

What steps can the ObGyn take to reduce the difficulty of the procedure, particularly insertion of the hysteroscope through the cervical canal?

Successful hysteroscopy requires a cervical canal sufficiently dilated to allow passage of the hysteroscope. And because of inevitable variation in anatomy—and even in models of hysteroscopes, which range in diameter from 2.7 to 10 mm—passage is not always easily accomplished. Many of the complications related to hysteroscopy, including cervical tears, creation of a false passage, uterine perforation, vasovagal reaction, pain, and inability to complete the procedure, are caused by inadequate cervical dilation and an inability to insert the hysteroscope.^1-6 One study noted that almost half of complications were related to cervical entry.⁶

In this article, I describe ways to overcome the challenging cervix for hysteroscopic procedures and endometrial biopsy (TABLES 1 and 2).

TABLE 1

10 actions that can ease entry to the cervix for hysteroscopy

TABLE 2

6 ways to prepare the cervix for endometrial biopsy

Hysteroscopy failure rate: 3.4% to 4.2%

Hysteroscopy is, of course, common in gynecologic practice, its indications extending across a range of investigations and treatments—for menstrual disorders, postmenopausal bleeding, infertility, and recurrent pregnancy loss.^1,7 Flexible hysteroscopes range in diameter from 2.7 to 5 mm; rigid hysteroscopes, from 1 to 5 mm; and operative hysteroscopes can be as large as 8 to 10 mm.^2,7

A systematic review of diagnostic hysteroscopy in more than 26,000 women reported a failure rate of 4.2% for ambulatory hysteroscopy and 3.4% for inpatient procedures.⁴ Failed ambulatory procedures were mainly attributed to technical problems, including:

• cervical stenosis
• anatomic and structural abnormalities
• pain and intolerance.⁴

Ideally, hysteroscopy is performed with minimal or no cervical dilation,⁷ but this may not always be possible.

Things to consider before embarking
Close attention to cervical and uterine anatomy is critical because insertion of the hysteroscope can be the most difficult aspect of the procedure. A bimanual examination is imperative to assess uterine size and position. It also is useful to sound the uterus to determine its depth.

An accurate medical, gynecologic, and obstetric history is essential, including information on pregnancies, dilation and curettage, cervical procedures such as cryotherapy, and any other procedures that may increase the risk of cervical stenosis, or difficulty dilating the cervix.

Is stenosis present? Stenosis is most common in nulliparous and postmenopausal women and in those who have undergone cervical procedures such as cryotherapy. Stenosis increases the risk of laceration and uterine perforation.

Consider a mechanical dilator. When cervical dilation is difficult, a series of small Hagar or lacrimal duct dilators may be helpful (FIGURE).

FIGURE Mechanical dilation is one antidote to cervical stenosis

In challenging cases, such as cervical stenosis, mechanical dilation with a series of Hagar or lacrimal duct dilators may facilitate entry into the cervix.

Pain can be mild—or it can thwart your work

Although many women tolerate placement of a small hysteroscope without analgesia or anesthesia, pain and vasovagal reaction sometimes occur. Indeed, the level of pain experienced by the patient is a major determinant of the overall success of the procedure.^3,8-10 Pain can occur when a tenaculum is used to grasp the anterior cervix, as well as during cervical dilation, injection of local anesthetic, or insertion of the hysteroscope. In some cases, a smaller scope may be all that is needed to solve the problem.¹¹

Analgesia may not always be necessary

Some researchers have studied office hysteroscopy without analgesia or anesthesia, finding a high level of acceptance.^12,13 Others have found a significant percentage of women requesting anesthesia or analgesia (16.5%)¹⁰ or requiring local anesthesia (28.8%).⁸

Preoperative NSAIDs may suffice. Use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) 1 hour before office hysteroscopy may reduce intraoperative and postoperative pain.⁷ Nagele and colleagues⁸ compared use of mefenamic acid 1 hour before the procedure with placebo in 95 women undergoing outpatient diagnostic hysteroscopy. Mefenamic acid reduced pain at 30 and 60 minutes after—but not during—the procedure. Other studies have found that pain is reduced when an oral NSAID is taken 1 to 2 hours before insertion of an intrauterine device and before suction curettage.^14,15

Other perioperative medications may help reduce discomfort and patient anxiety, including anxiolytics, such as lorazepam, analgesics, and conscious sedation.³

Paracervical block may be appropriate when pain is very likely

A number of investigators have evaluated use of paracervical anesthesia during out-patient hysteroscopy.^9,13,16,17 They injected lignocaine or mepivacaine using a 21- or 22-gauge needle at 3, 5, 7, and 9 o’clock or 4 and 8 o’clock paracervically.¹³ One study found paracervical block to be effective in reducing the pain of tenaculum placement and insertion of the hysteroscope.¹⁷ However, some studies suggested a reduction of pain in postmenopausal women only.⁹ These women may be more likely to have cervical stenosis.

Paracervical block does pose a risk of complications. Studies have reported bleeding in some women¹⁶ and pain with injection of the paracervical block, as well as bradycardia and hypotension possibly secondary to intravascular injection.¹⁷

Other methods are inconsistent

Intracervical injection. Some researchers have recommended injection of local anesthetic into the cervix.¹³ One study found no benefit—in fact, the injection appeared to be the most painful part of the procedure.¹⁸ A case series suggested that injection of local anesthetic may be effective, but the series lacked a placebo or control arm.¹³

Topical intrauterine anesthetic has been investigated after administration through the channel of the hysteroscope or by a catheter passed through the cervix into the uterine cavity.¹³ Findings have been mixed, with some researchers demonstrating reduced pain^19,20 and others showing no relief.²¹

Topical cervical anesthesia. Some hysteroscopists have recommended application of anesthetic cream, gel, or spray directly to the cervix immediately before the procedure.^13,22 The results have been mixed, with some studies noting decreased pain overall,¹³ one finding decreased pain only during tenaculum placement,²² and others finding no significant reduction in pain any time during the procedure.^13,23,24 A review concluded that topical cervical lignocaine spray may reduce the discomfort of tenaculum placement.¹³

Topical anesthesia may minimize vasovagal reaction

In one study, 1.1% of women undergoing office hysteroscopy experienced a vasovagal reaction, caused by stimulation of the parasympathetic nervous system with cervical manipulation and passage of the scope through the internal os of the cervix.²⁵ The reaction led to hypotension and bradycardia. Several studies have suggested that a local anesthetic can reduce this complication.^19,20

Cicinelli and associates found that topical local anesthesia reduced the incidence of vasovagal reaction from 32.5% in the control arm to 5%.²⁰ They suggest that a local anesthetic be considered in selected women, such as postmenopausal patients, who are at increased risk of vasovagal attack.

In contrast, Lau and associates¹⁷ found an increased rate of bradycardia and hypotension with paracervical lignocaine (31% versus 10%), but it may have been caused by inadvertent intravascular injection.¹⁷

Researchers have also suggested that the use of smaller hysteroscopes may reduce the incidence of vasovagal reactions.²⁶

How to prime the cervix for hysteroscopy

The use of vaginal misoprostol, a prostaglandin E₁ analogue, 9 to 12 hours before hysteroscopy may help increase preprocedural cervical dilation in premenopausal women, especially in nulliparas and women undergoing operative hysteroscopy. Misoprostol, used to prevent and treat NSAID-induced gastric ulcers, is gaining favor as a cervical ripening agent. We performed a meta-analysis to assess its effectiveness in dilating the cervix and reducing the need for mechanical dilation.⁵

We identified 10 studies that met inclusion criteria; five of them included premenopausal women, four included postmenopausal women or women receiving a gonadotropin-releasing hormone (GnRH) agonist, and one study included both groups.⁵ A variety of dosing protocols were used, with dosages ranging from 100 μg to 1,000 μg of intravaginal or oral misoprostol 4 to 24 hours preoperatively (most studies evaluated the vaginal route).

We found that misoprostol significantly reduced the need for further cervical dilation, and was associated with a lower rate of cervical laceration. However, this was true only for the premenopausal group: 42.6% of premenopausal women given misoprostol needed further dilation, compared with 71.7% in the control group, and 2% of premenopausal women given misoprostol suffered cervical laceration, compared with 11% in the control group. Among postmenopausal women and those receiving a GnRH agonist, misoprostol lacked clear benefit and was associated with side effects such as nausea, diarrhea, abdominal cramping, and fever.

For every premenopausal woman who received misoprostol before hysteroscopy, one woman avoided the need for further cervical dilation. For every 12 premenopausal women receiving misoprostol, one cervical laceration was avoided.

The ideal dosing regimen could not be determined because of variations in protocols. Nor was it clear whether misoprostol had any benefit among postmenopausal women or those receiving a GnRH agonist.

Most studies of misoprostol for cervical ripening have involved intravaginal administration, with dosages of 200 μg to 400 μg given 9 to 12 hours before hysteroscopy showing the greatest benefit.

Ultrasonography may help guide dilation

Transabdominal ultrasonography has been used to guide dilation in difficult dilation and curettage procedures, and is especially useful in women with a history of uterine perforation.²⁷ It may be helpful in cases involving difficult cervical dilation during hysteroscopy or endometrial biopsy.

Steady the cervix. A tenaculum is not always required, but its use on the anterior lip of the cervix may help steady the cervix and provide countertraction during insertion of the hysteroscope through the cervical canal, especially if the cervix is not in an axial position.⁷

CASE Resolved!

Because she is nulliparous and may benefit from cervical priming, the patient is given 400 μg of intravaginal misoprostol 12 hours before hysteroscopy, as well as an oral NSAID 1 hour before the procedure. A bimanual examination reveals a sharply anteverted uterus, so a topical cervical anesthetic spray is applied to the anterior cervix, and a tenaculum is placed to help straighten the uterine position. The hysteroscope passes easily through the cervical canal, making further dilation unnecessary. The procedure is completed without difficulty and is well tolerated by the patient.

Difficult entry can also hamper endometrial biopsy

Every ObGyn has used endometrial biopsy to assess abnormal uterine bleeding, postmenopausal bleeding, infertility, or recurrent pregnancy loss, or to monitor women on hormone replacement therapy^28,29 —so its advantages over dilation and curettage should come as no surprise. They include the ability to perform it in an office setting, usually with minimal cervical dilation, often without anesthesia, and at less expense.²⁸ Complications include cramping and pain,^29-32 vasovagal reaction,²⁹ bleeding,²⁹ and inability to pass the biopsy catheter through the cervix into the uterine cavity. Another rare complication is uterine perforation.²⁹

As with hysteroscopy, many of these complications are related to difficulty entering the uterine cavity through the cervix.

Prerequisites include thorough assessment of the uterus

As with hysteroscopy, an accurate and detailed history is necessary to identify risk factors for a difficult procedure. Assess uterine size and position with a bimanual examination. Although a tenaculum is often unnecessary, its placement on the anterior lip of the cervix may help steady the cervix and allow the catheter to pass through the cervical canal into the uterine cavity, especially if the uterus is not in the axial position.^28,29 Again, it is useful to sound the uterine cavity to ascertain its depth. This may be done with the biopsy catheter.

Cervical dilation may be necessary

Even when women with cervical stenosis were excluded in one study, it was difficult to pass the Pipelle endometrial biopsy through the cervix in 41.7% of women.³⁰

If the sampling device does not pass easily through the cervix, use a tenaculum and a lacrimal duct probe or small Hagar dilators to dilate the cervix.²⁸

Pain may again be an issue

Almost 50% of women experience moderate or severe pain during endometrial biopsy.³² Many clinicians recommend giving an oral NSAID 60 minutes before the procedure to decrease discomfort. One study found that the use of naproxen sodium before Vabra curettage reduced the severity of pain at 30 and 60 minutes after the procedure, but did not alleviate discomfort arising during the biopsy itself.¹⁴ Another study suggested the combination of naproxen sodium and intrauterine lidocaine (5 mL of 2% lidocaine) to reduce discomfort associated with the procedure.³⁰

Use of anesthesia is controversial

A study by Lau and colleagues¹⁷ found paracervical lignocaine to be ineffective at reducing pain during hysteroscopy and endometrial biopsy, but the drug did increase the risk of bradycardia and hypotension. Another study demonstrated a decrease in procedure-related discomfort in postmenopausal women who were given 2 mL of 2% intrauterine mepivacaine.²⁰ These findings are similar to those of Zupi and associates.¹⁹

Consider the tool

Discomfort may be related to the size of the biopsy catheter. Pain scores appear to be significantly lower with the Pipelle biopsy catheter than with the larger Novak biopsy curette.³²

Vasovagal reaction usually resolves after the procedure

As with hysteroscopy, women may occasionally experience a vasovagal reaction during endometrial biopsy. This complication usually resolves quickly once the procedure is completed.²⁹ Some clinicians suggest that the patient be allowed to eat and drink before the procedure and be given an analgesic before it begins.²⁸

Cervical priming is not a proven strategy

Misoprostol has been considered as a preprocedure adjunct to endometrial biopsy. Only one small randomized, controlled trial involving 42 women has evaluated the drug for this indication. It found no benefit when 400 μg of misoprostol was given orally 3 hours before the procedure, as well as cramping and increased pain during the biopsy.³³ This study had several shortcomings, including its small sample size and the inclusion of both pre- and postmenopausal women. Further research is needed—separately in premenopausal and postmenopausal women and with adequately large samples—to assess the use of misoprostol.

The author reports no financial relationships relevant to this article.

The author reports no financial relationships relevant to this article.

Fifty years ago, the thalidomide experience—a high incidence of major birth defects following prenatal use of the drug—made clear the devastating potential of drug exposure during pregnancy. Since that disaster, healthcare providers and patients have adopted a conservative approach to medication use during pregnancy, especially during the first trimester and lactation. That is a wise strategy, although very few medications are associated with abnormal fetal development.

In this article, I’ll guide you through some of the issues that must be considered when assessing a drug’s teratogenicity, help you find information on a host of medications, and familiarize you with some of the challenges involved in counseling the patient. I also present a table listing the adverse effects known to be associated with selected drugs during the first, second, and third trimesters and lactation (TABLE). We are fortunate that a large body of information about medication use during pregnancy and lactation is readily available on the Web and in books and medical journals. This information is far from definitive, however, because much of the evidence concerning prescribed drugs is anecdotal or presented with insufficient warning about their use during pregnancy and lactation.

A discussion of these issues with the patient will help set the risks and benefits of a particular drug into proper perspective, alleviate fears, and improve compliance. Nonprescription medications should also be discussed, and the patient should be advised that we have very little data concerning their use during pregnancy.

Assignment of risk is an uncertain science

Major structural defects are apparent at birth in about 3% of all pregnancies and in about 4.5% of all children by the age of 5 years.¹ A cause or proposed mechanism for the defects can be determined in fewer than 50% of these cases. Nor can we count on expert consensus about the safety of many medications during pregnancy because it rarely occurs and, in some cases, may be impossible to achieve.

Animal studies are the means of assessing the teratogenicity of most drugs. Animals commonly used to study fetal effects include rodents (fertility, birth defects, birth weight, behavior), rabbits (birth defects), baboons (uterine blood flow), and sheep (uterine blood flow, cardiovascular effects, fetal hypoxia, and acidosis). Dosages are often much higher (in relation to body weight or surface area) to “test the systems” for any possible reproductive harm. Although these studies may be helpful, they do not reliably predict the human response.

Even when humans are the subject of study, conclusions must be viewed with caution. To determine the risk of teratogenesis, it is necessary to know the stage of development during which the exposure occurred, as well as the identity and dose of the medication and the genetic susceptibility of the mother and fetus.

Three critical stages. In utero exposure to a drug occurs in one of three periods of fetal development:

• ovum – from fertilization to implantation
• embryo – from the second through the eighth week of gestation
• fetus – from the eighth completed week until delivery.

An “all-or-none” effect (i.e., spontaneous abortion or not) is believed to arise from exposure during the first period, but the embryo stage is the most critical time because it involves organogenesis. Detrimental effects may occur even beyond this period as cells continue to divide in the hematologic, reproductive, and central nervous systems.

Many fine points of exposure are difficult to clarify

Retrospective and uncontrolled studies, as well as individual case reports or small series, may overestimate the risk to the fetus of exposure to a specific drug or combination of medications. Case reports do not establish causation.

It can also be difficult to differentiate between the risks of a specific drug and the hazards of maternal illness to explain an unfavorable outcome. For example, is a particular case of stillbirth the result of fetal exposure to enoxaparin or maternal thrombophilia, or both? Can fetal growth restriction be attributed to use of azathioprine during pregnancy or to the mother’s underlying illness? And so on.

In addition, it is necessary to distinguish between a defect’s natural prevalence—i.e., the rate at which it occurs in a population—and the additional risk posed by exposure to a particular drug. Studies in large populations are needed—but usually unattainable—to determine the relative risk from specific potential teratogens.

Finally, it is very difficult to assess neurobehavioral effects of in utero exposure to centrally acting drugs beyond the immediate neonatal period. The dose, offspring’s age and gender, and behavioral test system must all be considered.

Few drugs are implicated in restricting fetal growth or reducing organ size. We also lack consistent information about long-term effects such as learning or behavioral problems (i.e., functional teratogenesis) that may result from chronic prenatal exposure to a certain medication.

All drugs cross the placenta

Most medications are easily absorbed during pregnancy, and serum concentrations of albumin for drug binding are lower than in the nonpregnant state. Pharmacokinetic changes during pregnancy include:

• higher volume of distribution
• lower maximum plasma concentration
• lower steady-state serum concentration
• shorter plasma half-life
• higher clearance rate.¹

The small spatial configuration and high lipid solubility of most medications permit easy transfer of an unbound drug or its metabolite across the placenta or into breast milk. Virtually all drugs and their end products cross the placenta, with unbound concentrations of the drug in the fetal serum similar to the level in maternal serum—sometimes even higher (FIGURE).

A few drugs with high molecular weight do not cross the placenta in significant amounts (e.g., glyburide, interferon, thyroid supplements, insulin).

FIGURE An elaborate nutrient (and drug) delivery system

The placenta and umbilical cord deliver the nutrients and oxygen the fetus needs for normal growth—as well as most medications used by the mother.

Medication use tends to increase as pregnancy progresses

The drugs most commonly taken during pregnancy include vitamins, iron preparations, calcium, analgesics, antibiotics, and antacids. Excluding vitamins and mineral supplements, an average of one to two medications are taken during gestation. Over-the-counter formulations account for about half of these drugs, with acetaminophen being the single most commonly used medication during pregnancy. Antibiotics are the most widely prescribed drugs.

Although caffeine, tobacco, alcohol, and illicit substance use tends to diminish as pregnancy progresses, medications are usually taken at the same frequency or more often during gestation.

My colleagues and I found a significantly higher mean number of medications (3.3 and 4.1, respectively) used during the second and third trimesters of gestation than were taken before pregnancy (2.6).²

How to counsel the patient

Counseling a woman before or during pregnancy about the continuation or initiation of a medication should take place in an open, supportive, and informative manner. Most inquiries relate to exposures involving very low levels of relative and absolute risk.

A detailed fetal ultrasonographic examination is often used to accurately date the pregnancy and, if possible, screen for any structural defects. The patient should be advised that first-trimester screening, chorionic villus sampling, maternal serum quadruple screening, amniocentesis, and fetal blood sampling are not very predictive of a drug’s fetal effects. Exceptions may be the observation of open neural tube defects (approximate 1% risk associated with valproic acid and carbamazepine) by maternal serum quadruple screening and facial clefting by targeted ultrasonography.

When a patient inquires about a particular drug, it is important to gather the following information:

• When did she take the medication?
• Why did she take it?
• For how long did she take the medication?
• Did she take other medications, or any substances of abuse, at the same time?

A number of sources of information about potential teratogens are available.^3-5 These include national computerized databases that are accessible on the Web:

• National Library of Medicine (http://sis.nlm.nih.gov/enviro.html)
• pregnancy exposure registries (www.fda.gov/womens/registries/default.htm)
• Reproductive Toxicology Center (http://reprotox.org) (access requires a paid subscription)
• LactMed, National Library of Medicine guide to drug safety in lactation (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT)
• Organization of Teratology Information Specialists (OTIS) (www.otispregnancy.org).

The last source (OTIS) consolidates teratology information nationwide and reports it by state or region. It also publishes a host of fact sheets on various drugs that may be useful to dispense to the patient during counseling. In addition, many teratogen information services or poison control centers (often at children’s hospitals) are available throughout the United States to serve specific geographic areas. And teratogen registries at pharmaceutical companies may provide limited information about newer medications.

The Physician’s Desk Reference (PDR) is a common source of information about the use of prescription drugs in pregnancy.³ But be aware that, to avoid liability, pharmaceutical manufacturers do not encourage use of their drugs during pregnancy unless the benefit clearly outweighs the risk. It would be unrealistic for them to market a medication for specific use during pregnancy because it would require considerable time and cost, and raise ethical objections, to conduct research in a vulnerable population that is limited in number.

Effects of agents used more than 40 years ago were reported by the Collaborative Perinatal Project or the Boston Collaborative Drug Surveillance Program.⁶ Those findings are often inconclusive, reflect bias in study designs, and do not help a clinician evaluate current medications or those less commonly prescribed during pregnancy.

The risks and experience associated with new drugs are usually not well explored in regard to pregnancy. As a result, older medications are more likely to be prescribed as maintenance therapy during gestation for the simple reason that they have a larger body of information regarding their effects. These older drugs may no longer be preferred once the patient delivers.

Most drugs are not teratogens

The TABLE lists adverse effects in the human fetus known to arise from exposure to specific drugs. The information comes largely from the Reprotox database, which was reviewed as recently as 2006, describes human data only, and is reported by first trimester (anomalies, abortion) and the second and third trimesters (fetal growth restriction, stillbirth, low birth weight, preterm delivery, immediate neonatal problems).⁷ Typical dosages of most drugs are not anticipated to increase the risk of congenital anomalies.

Most human data come from small series or case reports. Although these types of studies are helpful, they tend to be biased or reflect the pregnancy’s background risk of birth defects rather than the risk posed by a specific drug. In addition, case reports of malformation after prenatal exposure to a certain drug may involve exposures to other agents and a lack of uniformity of abnormalities, making the association between adverse effects and a single agent unlikely. Dissimilarities in the dosage and route of delivery also limit interpretation. for example, short-term intravenous or sublingual administration of a drug may pose a different risk than taking that medication orally or vaginally, in a lower dose, for a longer period, or at a different period of gestation.

Randomized controlled trials of drugs are rare during pregnancy, as are prospective cohort investigations. Because a control population is often impossible to identify, it becomes difficult to separate any heightened risk identified during use of the medication from the underlying disease. When the gravida has significant medical problems, it is important to assess the potential risk of a drug—or its omission—in her as well as her fetus. The lowest effective dose is preferred, but keep in mind that inadequate treatment may lead to minimal benefit and potentially greater risk to the pregnancy.

When reviewing or planning maintenance drug therapy, follow the same principles as you would in a nonpregnant patient. Be familiar with more than one medication for each disorder. Also be aware that some drugs may need to be prescribed at a higher dose or greater frequency to attain a therapeutic concentration in the expanded intravascular volume of pregnancy. In addition, side effects such as nausea, fatigue, and gastrointestinal disturbance may mimic symptoms arising from physiologic changes of pregnancy.

Assessing the risks associated with over-the-counter medications and natural food products is even harder. The PDR for Nonprescription Drugs, Dietary Supplements, and Herbs⁸ contains little or no information about the reproductive hazards of most of these products. Many agents contain multiple ingredients, both active and inactive, thereby complicating counseling about their risks during pregnancy. Although the recommended dosage is usually low, many product labels do not specify what it should be.

Most drugs enter breast milk

The amount of drug that an infant consumes from breast milk depends on the medication’s chemical properties as well as the dosage, frequency, and duration of exposure.² Contraindications and cautions are usually either theoretical or based on findings from case reports that often conflict or confuse. In theory, it is safer for the mother to take the medication just after infant feeding or just before the infant’s longest sleep period.

The TABLE also lists the effects of drugs in the breastfed human infant. Again, the information comes from the Reprotox database, access to which requires a subscription. For additional information, try the free LactMed site at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT.

Nearly all drugs are excreted in breast milk, usually in small amounts (often less than 5% of the weight-adjusted maternal daily dose). The amount of drug or metabolite in an infant’s serum also is determined by the volume of breast milk, age of the infant, and other exposures.

Suspect a drug-related effect

A medication may be the cause in any newborn manifesting signs of anemia, hepatitis, hepatotoxicity, hepatorenal dysfunction, and hyperbilirubinemia. This includes breastfed infants. An adverse drug-related effect should also be suspected when an infant exhibits signs of jaundice, floppiness, jitteriness, poor suck, diarrhea, or growth restriction.

The author reports no financial relationships relevant to this article.

Fifty years ago, the thalidomide experience—a high incidence of major birth defects following prenatal use of the drug—made clear the devastating potential of drug exposure during pregnancy. Since that disaster, healthcare providers and patients have adopted a conservative approach to medication use during pregnancy, especially during the first trimester and lactation. That is a wise strategy, although very few medications are associated with abnormal fetal development.

In this article, I’ll guide you through some of the issues that must be considered when assessing a drug’s teratogenicity, help you find information on a host of medications, and familiarize you with some of the challenges involved in counseling the patient. I also present a table listing the adverse effects known to be associated with selected drugs during the first, second, and third trimesters and lactation (TABLE). We are fortunate that a large body of information about medication use during pregnancy and lactation is readily available on the Web and in books and medical journals. This information is far from definitive, however, because much of the evidence concerning prescribed drugs is anecdotal or presented with insufficient warning about their use during pregnancy and lactation.

A discussion of these issues with the patient will help set the risks and benefits of a particular drug into proper perspective, alleviate fears, and improve compliance. Nonprescription medications should also be discussed, and the patient should be advised that we have very little data concerning their use during pregnancy.

Assignment of risk is an uncertain science

Major structural defects are apparent at birth in about 3% of all pregnancies and in about 4.5% of all children by the age of 5 years.¹ A cause or proposed mechanism for the defects can be determined in fewer than 50% of these cases. Nor can we count on expert consensus about the safety of many medications during pregnancy because it rarely occurs and, in some cases, may be impossible to achieve.

Animal studies are the means of assessing the teratogenicity of most drugs. Animals commonly used to study fetal effects include rodents (fertility, birth defects, birth weight, behavior), rabbits (birth defects), baboons (uterine blood flow), and sheep (uterine blood flow, cardiovascular effects, fetal hypoxia, and acidosis). Dosages are often much higher (in relation to body weight or surface area) to “test the systems” for any possible reproductive harm. Although these studies may be helpful, they do not reliably predict the human response.

Even when humans are the subject of study, conclusions must be viewed with caution. To determine the risk of teratogenesis, it is necessary to know the stage of development during which the exposure occurred, as well as the identity and dose of the medication and the genetic susceptibility of the mother and fetus.

Three critical stages. In utero exposure to a drug occurs in one of three periods of fetal development:

• ovum – from fertilization to implantation
• embryo – from the second through the eighth week of gestation
• fetus – from the eighth completed week until delivery.

An “all-or-none” effect (i.e., spontaneous abortion or not) is believed to arise from exposure during the first period, but the embryo stage is the most critical time because it involves organogenesis. Detrimental effects may occur even beyond this period as cells continue to divide in the hematologic, reproductive, and central nervous systems.

Many fine points of exposure are difficult to clarify

Retrospective and uncontrolled studies, as well as individual case reports or small series, may overestimate the risk to the fetus of exposure to a specific drug or combination of medications. Case reports do not establish causation.

It can also be difficult to differentiate between the risks of a specific drug and the hazards of maternal illness to explain an unfavorable outcome. For example, is a particular case of stillbirth the result of fetal exposure to enoxaparin or maternal thrombophilia, or both? Can fetal growth restriction be attributed to use of azathioprine during pregnancy or to the mother’s underlying illness? And so on.

In addition, it is necessary to distinguish between a defect’s natural prevalence—i.e., the rate at which it occurs in a population—and the additional risk posed by exposure to a particular drug. Studies in large populations are needed—but usually unattainable—to determine the relative risk from specific potential teratogens.

Finally, it is very difficult to assess neurobehavioral effects of in utero exposure to centrally acting drugs beyond the immediate neonatal period. The dose, offspring’s age and gender, and behavioral test system must all be considered.

Few drugs are implicated in restricting fetal growth or reducing organ size. We also lack consistent information about long-term effects such as learning or behavioral problems (i.e., functional teratogenesis) that may result from chronic prenatal exposure to a certain medication.

All drugs cross the placenta

Most medications are easily absorbed during pregnancy, and serum concentrations of albumin for drug binding are lower than in the nonpregnant state. Pharmacokinetic changes during pregnancy include:

• higher volume of distribution
• lower maximum plasma concentration
• lower steady-state serum concentration
• shorter plasma half-life
• higher clearance rate.¹

The small spatial configuration and high lipid solubility of most medications permit easy transfer of an unbound drug or its metabolite across the placenta or into breast milk. Virtually all drugs and their end products cross the placenta, with unbound concentrations of the drug in the fetal serum similar to the level in maternal serum—sometimes even higher (FIGURE).

A few drugs with high molecular weight do not cross the placenta in significant amounts (e.g., glyburide, interferon, thyroid supplements, insulin).

FIGURE An elaborate nutrient (and drug) delivery system

The placenta and umbilical cord deliver the nutrients and oxygen the fetus needs for normal growth—as well as most medications used by the mother.

Medication use tends to increase as pregnancy progresses

The drugs most commonly taken during pregnancy include vitamins, iron preparations, calcium, analgesics, antibiotics, and antacids. Excluding vitamins and mineral supplements, an average of one to two medications are taken during gestation. Over-the-counter formulations account for about half of these drugs, with acetaminophen being the single most commonly used medication during pregnancy. Antibiotics are the most widely prescribed drugs.

Although caffeine, tobacco, alcohol, and illicit substance use tends to diminish as pregnancy progresses, medications are usually taken at the same frequency or more often during gestation.

My colleagues and I found a significantly higher mean number of medications (3.3 and 4.1, respectively) used during the second and third trimesters of gestation than were taken before pregnancy (2.6).²

How to counsel the patient

Counseling a woman before or during pregnancy about the continuation or initiation of a medication should take place in an open, supportive, and informative manner. Most inquiries relate to exposures involving very low levels of relative and absolute risk.

A detailed fetal ultrasonographic examination is often used to accurately date the pregnancy and, if possible, screen for any structural defects. The patient should be advised that first-trimester screening, chorionic villus sampling, maternal serum quadruple screening, amniocentesis, and fetal blood sampling are not very predictive of a drug’s fetal effects. Exceptions may be the observation of open neural tube defects (approximate 1% risk associated with valproic acid and carbamazepine) by maternal serum quadruple screening and facial clefting by targeted ultrasonography.

When a patient inquires about a particular drug, it is important to gather the following information:

• When did she take the medication?
• Why did she take it?
• For how long did she take the medication?
• Did she take other medications, or any substances of abuse, at the same time?

A number of sources of information about potential teratogens are available.^3-5 These include national computerized databases that are accessible on the Web:

• National Library of Medicine (http://sis.nlm.nih.gov/enviro.html)
• pregnancy exposure registries (www.fda.gov/womens/registries/default.htm)
• Reproductive Toxicology Center (http://reprotox.org) (access requires a paid subscription)
• LactMed, National Library of Medicine guide to drug safety in lactation (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT)
• Organization of Teratology Information Specialists (OTIS) (www.otispregnancy.org).

The last source (OTIS) consolidates teratology information nationwide and reports it by state or region. It also publishes a host of fact sheets on various drugs that may be useful to dispense to the patient during counseling. In addition, many teratogen information services or poison control centers (often at children’s hospitals) are available throughout the United States to serve specific geographic areas. And teratogen registries at pharmaceutical companies may provide limited information about newer medications.

The Physician’s Desk Reference (PDR) is a common source of information about the use of prescription drugs in pregnancy.³ But be aware that, to avoid liability, pharmaceutical manufacturers do not encourage use of their drugs during pregnancy unless the benefit clearly outweighs the risk. It would be unrealistic for them to market a medication for specific use during pregnancy because it would require considerable time and cost, and raise ethical objections, to conduct research in a vulnerable population that is limited in number.

Effects of agents used more than 40 years ago were reported by the Collaborative Perinatal Project or the Boston Collaborative Drug Surveillance Program.⁶ Those findings are often inconclusive, reflect bias in study designs, and do not help a clinician evaluate current medications or those less commonly prescribed during pregnancy.

The risks and experience associated with new drugs are usually not well explored in regard to pregnancy. As a result, older medications are more likely to be prescribed as maintenance therapy during gestation for the simple reason that they have a larger body of information regarding their effects. These older drugs may no longer be preferred once the patient delivers.

Most drugs are not teratogens

The TABLE lists adverse effects in the human fetus known to arise from exposure to specific drugs. The information comes largely from the Reprotox database, which was reviewed as recently as 2006, describes human data only, and is reported by first trimester (anomalies, abortion) and the second and third trimesters (fetal growth restriction, stillbirth, low birth weight, preterm delivery, immediate neonatal problems).⁷ Typical dosages of most drugs are not anticipated to increase the risk of congenital anomalies.

Most human data come from small series or case reports. Although these types of studies are helpful, they tend to be biased or reflect the pregnancy’s background risk of birth defects rather than the risk posed by a specific drug. In addition, case reports of malformation after prenatal exposure to a certain drug may involve exposures to other agents and a lack of uniformity of abnormalities, making the association between adverse effects and a single agent unlikely. Dissimilarities in the dosage and route of delivery also limit interpretation. for example, short-term intravenous or sublingual administration of a drug may pose a different risk than taking that medication orally or vaginally, in a lower dose, for a longer period, or at a different period of gestation.

Randomized controlled trials of drugs are rare during pregnancy, as are prospective cohort investigations. Because a control population is often impossible to identify, it becomes difficult to separate any heightened risk identified during use of the medication from the underlying disease. When the gravida has significant medical problems, it is important to assess the potential risk of a drug—or its omission—in her as well as her fetus. The lowest effective dose is preferred, but keep in mind that inadequate treatment may lead to minimal benefit and potentially greater risk to the pregnancy.

When reviewing or planning maintenance drug therapy, follow the same principles as you would in a nonpregnant patient. Be familiar with more than one medication for each disorder. Also be aware that some drugs may need to be prescribed at a higher dose or greater frequency to attain a therapeutic concentration in the expanded intravascular volume of pregnancy. In addition, side effects such as nausea, fatigue, and gastrointestinal disturbance may mimic symptoms arising from physiologic changes of pregnancy.

Assessing the risks associated with over-the-counter medications and natural food products is even harder. The PDR for Nonprescription Drugs, Dietary Supplements, and Herbs⁸ contains little or no information about the reproductive hazards of most of these products. Many agents contain multiple ingredients, both active and inactive, thereby complicating counseling about their risks during pregnancy. Although the recommended dosage is usually low, many product labels do not specify what it should be.

Most drugs enter breast milk

The amount of drug that an infant consumes from breast milk depends on the medication’s chemical properties as well as the dosage, frequency, and duration of exposure.² Contraindications and cautions are usually either theoretical or based on findings from case reports that often conflict or confuse. In theory, it is safer for the mother to take the medication just after infant feeding or just before the infant’s longest sleep period.

The TABLE also lists the effects of drugs in the breastfed human infant. Again, the information comes from the Reprotox database, access to which requires a subscription. For additional information, try the free LactMed site at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT.

Nearly all drugs are excreted in breast milk, usually in small amounts (often less than 5% of the weight-adjusted maternal daily dose). The amount of drug or metabolite in an infant’s serum also is determined by the volume of breast milk, age of the infant, and other exposures.

Suspect a drug-related effect

A medication may be the cause in any newborn manifesting signs of anemia, hepatitis, hepatotoxicity, hepatorenal dysfunction, and hyperbilirubinemia. This includes breastfed infants. An adverse drug-related effect should also be suspected when an infant exhibits signs of jaundice, floppiness, jitteriness, poor suck, diarrhea, or growth restriction.

The author reports no financial relationships relevant to this article.

Fifty years ago, the thalidomide experience—a high incidence of major birth defects following prenatal use of the drug—made clear the devastating potential of drug exposure during pregnancy. Since that disaster, healthcare providers and patients have adopted a conservative approach to medication use during pregnancy, especially during the first trimester and lactation. That is a wise strategy, although very few medications are associated with abnormal fetal development.

In this article, I’ll guide you through some of the issues that must be considered when assessing a drug’s teratogenicity, help you find information on a host of medications, and familiarize you with some of the challenges involved in counseling the patient. I also present a table listing the adverse effects known to be associated with selected drugs during the first, second, and third trimesters and lactation (TABLE). We are fortunate that a large body of information about medication use during pregnancy and lactation is readily available on the Web and in books and medical journals. This information is far from definitive, however, because much of the evidence concerning prescribed drugs is anecdotal or presented with insufficient warning about their use during pregnancy and lactation.

A discussion of these issues with the patient will help set the risks and benefits of a particular drug into proper perspective, alleviate fears, and improve compliance. Nonprescription medications should also be discussed, and the patient should be advised that we have very little data concerning their use during pregnancy.

Assignment of risk is an uncertain science

Major structural defects are apparent at birth in about 3% of all pregnancies and in about 4.5% of all children by the age of 5 years.¹ A cause or proposed mechanism for the defects can be determined in fewer than 50% of these cases. Nor can we count on expert consensus about the safety of many medications during pregnancy because it rarely occurs and, in some cases, may be impossible to achieve.

Animal studies are the means of assessing the teratogenicity of most drugs. Animals commonly used to study fetal effects include rodents (fertility, birth defects, birth weight, behavior), rabbits (birth defects), baboons (uterine blood flow), and sheep (uterine blood flow, cardiovascular effects, fetal hypoxia, and acidosis). Dosages are often much higher (in relation to body weight or surface area) to “test the systems” for any possible reproductive harm. Although these studies may be helpful, they do not reliably predict the human response.

Even when humans are the subject of study, conclusions must be viewed with caution. To determine the risk of teratogenesis, it is necessary to know the stage of development during which the exposure occurred, as well as the identity and dose of the medication and the genetic susceptibility of the mother and fetus.

Three critical stages. In utero exposure to a drug occurs in one of three periods of fetal development:

• ovum – from fertilization to implantation
• embryo – from the second through the eighth week of gestation
• fetus – from the eighth completed week until delivery.

An “all-or-none” effect (i.e., spontaneous abortion or not) is believed to arise from exposure during the first period, but the embryo stage is the most critical time because it involves organogenesis. Detrimental effects may occur even beyond this period as cells continue to divide in the hematologic, reproductive, and central nervous systems.

Many fine points of exposure are difficult to clarify

Retrospective and uncontrolled studies, as well as individual case reports or small series, may overestimate the risk to the fetus of exposure to a specific drug or combination of medications. Case reports do not establish causation.

It can also be difficult to differentiate between the risks of a specific drug and the hazards of maternal illness to explain an unfavorable outcome. For example, is a particular case of stillbirth the result of fetal exposure to enoxaparin or maternal thrombophilia, or both? Can fetal growth restriction be attributed to use of azathioprine during pregnancy or to the mother’s underlying illness? And so on.

In addition, it is necessary to distinguish between a defect’s natural prevalence—i.e., the rate at which it occurs in a population—and the additional risk posed by exposure to a particular drug. Studies in large populations are needed—but usually unattainable—to determine the relative risk from specific potential teratogens.

Finally, it is very difficult to assess neurobehavioral effects of in utero exposure to centrally acting drugs beyond the immediate neonatal period. The dose, offspring’s age and gender, and behavioral test system must all be considered.

Few drugs are implicated in restricting fetal growth or reducing organ size. We also lack consistent information about long-term effects such as learning or behavioral problems (i.e., functional teratogenesis) that may result from chronic prenatal exposure to a certain medication.

All drugs cross the placenta

Most medications are easily absorbed during pregnancy, and serum concentrations of albumin for drug binding are lower than in the nonpregnant state. Pharmacokinetic changes during pregnancy include:

• higher volume of distribution
• lower maximum plasma concentration
• lower steady-state serum concentration
• shorter plasma half-life
• higher clearance rate.¹

The small spatial configuration and high lipid solubility of most medications permit easy transfer of an unbound drug or its metabolite across the placenta or into breast milk. Virtually all drugs and their end products cross the placenta, with unbound concentrations of the drug in the fetal serum similar to the level in maternal serum—sometimes even higher (FIGURE).

A few drugs with high molecular weight do not cross the placenta in significant amounts (e.g., glyburide, interferon, thyroid supplements, insulin).

FIGURE An elaborate nutrient (and drug) delivery system

The placenta and umbilical cord deliver the nutrients and oxygen the fetus needs for normal growth—as well as most medications used by the mother.

Medication use tends to increase as pregnancy progresses

The drugs most commonly taken during pregnancy include vitamins, iron preparations, calcium, analgesics, antibiotics, and antacids. Excluding vitamins and mineral supplements, an average of one to two medications are taken during gestation. Over-the-counter formulations account for about half of these drugs, with acetaminophen being the single most commonly used medication during pregnancy. Antibiotics are the most widely prescribed drugs.

Although caffeine, tobacco, alcohol, and illicit substance use tends to diminish as pregnancy progresses, medications are usually taken at the same frequency or more often during gestation.

My colleagues and I found a significantly higher mean number of medications (3.3 and 4.1, respectively) used during the second and third trimesters of gestation than were taken before pregnancy (2.6).²

How to counsel the patient

Counseling a woman before or during pregnancy about the continuation or initiation of a medication should take place in an open, supportive, and informative manner. Most inquiries relate to exposures involving very low levels of relative and absolute risk.

A detailed fetal ultrasonographic examination is often used to accurately date the pregnancy and, if possible, screen for any structural defects. The patient should be advised that first-trimester screening, chorionic villus sampling, maternal serum quadruple screening, amniocentesis, and fetal blood sampling are not very predictive of a drug’s fetal effects. Exceptions may be the observation of open neural tube defects (approximate 1% risk associated with valproic acid and carbamazepine) by maternal serum quadruple screening and facial clefting by targeted ultrasonography.

When a patient inquires about a particular drug, it is important to gather the following information:

• When did she take the medication?
• Why did she take it?
• For how long did she take the medication?
• Did she take other medications, or any substances of abuse, at the same time?

A number of sources of information about potential teratogens are available.^3-5 These include national computerized databases that are accessible on the Web:

• National Library of Medicine (http://sis.nlm.nih.gov/enviro.html)
• pregnancy exposure registries (www.fda.gov/womens/registries/default.htm)
• Reproductive Toxicology Center (http://reprotox.org) (access requires a paid subscription)
• LactMed, National Library of Medicine guide to drug safety in lactation (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT)
• Organization of Teratology Information Specialists (OTIS) (www.otispregnancy.org).

The last source (OTIS) consolidates teratology information nationwide and reports it by state or region. It also publishes a host of fact sheets on various drugs that may be useful to dispense to the patient during counseling. In addition, many teratogen information services or poison control centers (often at children’s hospitals) are available throughout the United States to serve specific geographic areas. And teratogen registries at pharmaceutical companies may provide limited information about newer medications.

The Physician’s Desk Reference (PDR) is a common source of information about the use of prescription drugs in pregnancy.³ But be aware that, to avoid liability, pharmaceutical manufacturers do not encourage use of their drugs during pregnancy unless the benefit clearly outweighs the risk. It would be unrealistic for them to market a medication for specific use during pregnancy because it would require considerable time and cost, and raise ethical objections, to conduct research in a vulnerable population that is limited in number.

Effects of agents used more than 40 years ago were reported by the Collaborative Perinatal Project or the Boston Collaborative Drug Surveillance Program.⁶ Those findings are often inconclusive, reflect bias in study designs, and do not help a clinician evaluate current medications or those less commonly prescribed during pregnancy.

The risks and experience associated with new drugs are usually not well explored in regard to pregnancy. As a result, older medications are more likely to be prescribed as maintenance therapy during gestation for the simple reason that they have a larger body of information regarding their effects. These older drugs may no longer be preferred once the patient delivers.

Most drugs are not teratogens

The TABLE lists adverse effects in the human fetus known to arise from exposure to specific drugs. The information comes largely from the Reprotox database, which was reviewed as recently as 2006, describes human data only, and is reported by first trimester (anomalies, abortion) and the second and third trimesters (fetal growth restriction, stillbirth, low birth weight, preterm delivery, immediate neonatal problems).⁷ Typical dosages of most drugs are not anticipated to increase the risk of congenital anomalies.

Most human data come from small series or case reports. Although these types of studies are helpful, they tend to be biased or reflect the pregnancy’s background risk of birth defects rather than the risk posed by a specific drug. In addition, case reports of malformation after prenatal exposure to a certain drug may involve exposures to other agents and a lack of uniformity of abnormalities, making the association between adverse effects and a single agent unlikely. Dissimilarities in the dosage and route of delivery also limit interpretation. for example, short-term intravenous or sublingual administration of a drug may pose a different risk than taking that medication orally or vaginally, in a lower dose, for a longer period, or at a different period of gestation.

Randomized controlled trials of drugs are rare during pregnancy, as are prospective cohort investigations. Because a control population is often impossible to identify, it becomes difficult to separate any heightened risk identified during use of the medication from the underlying disease. When the gravida has significant medical problems, it is important to assess the potential risk of a drug—or its omission—in her as well as her fetus. The lowest effective dose is preferred, but keep in mind that inadequate treatment may lead to minimal benefit and potentially greater risk to the pregnancy.

When reviewing or planning maintenance drug therapy, follow the same principles as you would in a nonpregnant patient. Be familiar with more than one medication for each disorder. Also be aware that some drugs may need to be prescribed at a higher dose or greater frequency to attain a therapeutic concentration in the expanded intravascular volume of pregnancy. In addition, side effects such as nausea, fatigue, and gastrointestinal disturbance may mimic symptoms arising from physiologic changes of pregnancy.

Assessing the risks associated with over-the-counter medications and natural food products is even harder. The PDR for Nonprescription Drugs, Dietary Supplements, and Herbs⁸ contains little or no information about the reproductive hazards of most of these products. Many agents contain multiple ingredients, both active and inactive, thereby complicating counseling about their risks during pregnancy. Although the recommended dosage is usually low, many product labels do not specify what it should be.

Most drugs enter breast milk

The amount of drug that an infant consumes from breast milk depends on the medication’s chemical properties as well as the dosage, frequency, and duration of exposure.² Contraindications and cautions are usually either theoretical or based on findings from case reports that often conflict or confuse. In theory, it is safer for the mother to take the medication just after infant feeding or just before the infant’s longest sleep period.

The TABLE also lists the effects of drugs in the breastfed human infant. Again, the information comes from the Reprotox database, access to which requires a subscription. For additional information, try the free LactMed site at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT.

Nearly all drugs are excreted in breast milk, usually in small amounts (often less than 5% of the weight-adjusted maternal daily dose). The amount of drug or metabolite in an infant’s serum also is determined by the volume of breast milk, age of the infant, and other exposures.

Suspect a drug-related effect

A medication may be the cause in any newborn manifesting signs of anemia, hepatitis, hepatotoxicity, hepatorenal dysfunction, and hyperbilirubinemia. This includes breastfed infants. An adverse drug-related effect should also be suspected when an infant exhibits signs of jaundice, floppiness, jitteriness, poor suck, diarrhea, or growth restriction.

The author reports no financial relationships relevant to this article.

Brachial plexus injury is a dreaded sequela of shoulder dystocia, one that lies at the root of many medical liability disputes. Although brachial plexus injury cannot be prevented, most of the commonly used maneuvers for freeing a stuck shoulder are designed to maximize fetal safety and minimize injury.

What is the standard of care when dystocia occurs? Several respected sources have offered conflicting recommendations, particularly in regard to maternal pushing once dystocia is diagnosed. My aim in this article is to clarify the issue.

Endogenous force versus exogenous force

The introduction to the American College of Obstetricians and Gynecologists’ practice bulletin on shoulder dystocia, published in November 2002, provides a useful summary of much of our current knowledge:

Shoulder dystocia is most often an unpredictable and unpreventable obstetric emergency. Failure of the shoulders to deliver spontaneously places both the pregnant woman and fetus at risk for injury. Several maneuvers to release impacted shoulders have been developed, but the urgency of this event makes prospective studies impractical for comparing their effectiveness.¹

Because prospective studies are unlikely ever to be performed, some investigators have turned to mathematical modeling to learn more about the forces exerted on the fetal neck overlying the roots of the brachial plexus when a shoulder is impacted against the symphysis pubis.

Gonik and colleagues² performed elegant modeling of the pressure between the base of the fetal neck and symphysis pubis during dystocia. They utilized data on birth forces gathered by CaldeyroBarcia and Poseiro³ in their classic work on intrauterine pressure. Gonik and colleagues also used data from Allen and associates,⁴ who measured the force of clinician-applied traction after delivery of the head by having clinicians wear sensory gloves that recorded the force of traction applied.

Gonik and associates² concluded that the pressure resulting from endogenous forces is four to nine times greater than the pressure generated by a clinician. “Neonatal brachial plexus injury is not a priori explained by iatrogenically induced excessive traction,” they wrote. “Spontaneous endogenous forces may contribute substantially to this type of neonatal trauma.”

How an understanding of endogenous forces alters management

Although fewer than 10% of cases of shoulder dystocia result in permanent brachial plexus injury,¹ such injuries are a major source of malpractice litigation in obstetrics, as I noted at the beginning of this article. In most such cases, injury is blamed on excessive traction by the physician (FIGURE). Newer data, such as the study by Gonik and colleagues,² may implicate expulsive force (ie, maternal pushing) as another, perhaps greater, cause.

As long ago as 1988, Acker and colleagues⁵ reported on their experience with Erb’s palsy, which was associated with rapid delivery and unusually forceful expulsive effort in one third of cases. Their findings suggest that, when shoulder dystocia occurs and additional maneuvers are necessary to deliver the impacted anterior shoulder, the contribution of potentially harmful endogenous forces should be kept in mind. Counterintuitive strategies, including having the mother stop pushing until the anterior shoulder is freed, may help limit injury.

FIGURE Maternal pushing may contribute to injury

When shoulder dystocia occurs, the progress of labor is interrupted and brachial plexus injury can result, a common cause of litigation. Until now, plaintiff’s attorneys have tended to blame these injuries on the obstetrician and “excess” traction, but it now appears that maternal pushing contributes as well—possibly, to a greater degree than any effort by the physician.

How confusion crept into the literature

The 21st (current) edition of Williams Obstetrics,⁶ in the section on management of shoulder dystocia, states that “an initial gentle attempt at traction assisted by maternal expulsive efforts is recommended.” There is no reference for this statement. However, a look at the 19th edition of the textbook⁷ reveals identical wording, and the reference cited is ACOG Technical Bulletin No. 152 (August 1991), entitled Operative Vaginal Delivery. A subsequent version of the same bulletin (no. 196 from August 1994) contains identical wording. By the time that version was replaced by ACOG Practice Bulletin No. 17 (June 2000), however, it no longer contained any information on shoulder dystocia. Instead, ACOG published Practice Pattern No. 7 (October 1997), entitled Shoulder Dystocia. This document did not recommend maternal expulsive force after a diagnosis of shoulder dystocia—in fact, maternal force was not even mentioned. Nor is it mentioned in the current practice bulletin (no. 40 from November 2002), which replaced the previous version of Shoulder Dystocia.

Confusion doesn’t end there

In its section on shoulder dystocia, ACOG’s publication Precis (1998) states:

Management of shoulder dystocia involves both anticipation of and preparation for problems. The key to preventing fetal injury is avoidance of excess traction on the fetal head. When shoulder dystocia is diagnosed, a deliberate and planned sequence of events should be initiated. Pushing should be halted and obstructive causes should be considered. Aggressive fundal pressure or continued pushing will only further impact the anterior shoulder.

We are left with the paradox that the current edition of Williams Obstetrics, in its discussion of shoulder dystocia, carries a statement recommending maternal pushing based on a 1994 ACOG document—a statement that subsequent ACOG documents no longer contain. In fact, one of those documents—Precis—tells us that pushing should be halted, an instruction supported by the mathematical modeling of Gonik and colleagues.² And a popular online text (UpToDate.com) advises: “The mother should be told not to push during attempts to reposition the fetus.”⁸ Once the fetus is successfully repositioned, maternal pushing or traction, or both, can be reinstated.

Putting it all into clinical perspective

The current ACOG practice bulletin on shoulder dystocia (no. 40 from November 2002) observes that “retraction of the delivered fetal head against the maternal perineum (turtle sign) may be present and may assist in the diagnosis of shoulder dystocia.” When present, the turtle sign strongly suggests that the anterior shoulder is already impacted against the symphysis pubis. Maternal expulsive forces may have already put enough pressure on the nerve roots of the brachial plexus to cause damage. Any degree of traction or continued maternal pushing is likely to compound an already potentially serious problem.

In such cases, it is prudent to resort to known maneuvers, avoid encouraging continued maternal pushing, and simply support and guide the head without supplying any real traction.

When the turtle sign is absent, shoulder dystocia can be diagnosed only after the head is delivered, when the usual methods (ie, downward traction and continued maternal pushing) fail to advance delivery. Diagnosis in these cases requires recognition on the part of the delivering physician that shoulder dystocia is present. At that point, continued expulsive force and any real degree of traction no longer are appropriate.

The author reports no financial relationships relevant to this article.

Brachial plexus injury is a dreaded sequela of shoulder dystocia, one that lies at the root of many medical liability disputes. Although brachial plexus injury cannot be prevented, most of the commonly used maneuvers for freeing a stuck shoulder are designed to maximize fetal safety and minimize injury.

What is the standard of care when dystocia occurs? Several respected sources have offered conflicting recommendations, particularly in regard to maternal pushing once dystocia is diagnosed. My aim in this article is to clarify the issue.

Endogenous force versus exogenous force

The introduction to the American College of Obstetricians and Gynecologists’ practice bulletin on shoulder dystocia, published in November 2002, provides a useful summary of much of our current knowledge:

Shoulder dystocia is most often an unpredictable and unpreventable obstetric emergency. Failure of the shoulders to deliver spontaneously places both the pregnant woman and fetus at risk for injury. Several maneuvers to release impacted shoulders have been developed, but the urgency of this event makes prospective studies impractical for comparing their effectiveness.¹

Because prospective studies are unlikely ever to be performed, some investigators have turned to mathematical modeling to learn more about the forces exerted on the fetal neck overlying the roots of the brachial plexus when a shoulder is impacted against the symphysis pubis.

Gonik and colleagues² performed elegant modeling of the pressure between the base of the fetal neck and symphysis pubis during dystocia. They utilized data on birth forces gathered by CaldeyroBarcia and Poseiro³ in their classic work on intrauterine pressure. Gonik and colleagues also used data from Allen and associates,⁴ who measured the force of clinician-applied traction after delivery of the head by having clinicians wear sensory gloves that recorded the force of traction applied.

Gonik and associates² concluded that the pressure resulting from endogenous forces is four to nine times greater than the pressure generated by a clinician. “Neonatal brachial plexus injury is not a priori explained by iatrogenically induced excessive traction,” they wrote. “Spontaneous endogenous forces may contribute substantially to this type of neonatal trauma.”

How an understanding of endogenous forces alters management

Although fewer than 10% of cases of shoulder dystocia result in permanent brachial plexus injury,¹ such injuries are a major source of malpractice litigation in obstetrics, as I noted at the beginning of this article. In most such cases, injury is blamed on excessive traction by the physician (FIGURE). Newer data, such as the study by Gonik and colleagues,² may implicate expulsive force (ie, maternal pushing) as another, perhaps greater, cause.

As long ago as 1988, Acker and colleagues⁵ reported on their experience with Erb’s palsy, which was associated with rapid delivery and unusually forceful expulsive effort in one third of cases. Their findings suggest that, when shoulder dystocia occurs and additional maneuvers are necessary to deliver the impacted anterior shoulder, the contribution of potentially harmful endogenous forces should be kept in mind. Counterintuitive strategies, including having the mother stop pushing until the anterior shoulder is freed, may help limit injury.

FIGURE Maternal pushing may contribute to injury

When shoulder dystocia occurs, the progress of labor is interrupted and brachial plexus injury can result, a common cause of litigation. Until now, plaintiff’s attorneys have tended to blame these injuries on the obstetrician and “excess” traction, but it now appears that maternal pushing contributes as well—possibly, to a greater degree than any effort by the physician.

How confusion crept into the literature

The 21st (current) edition of Williams Obstetrics,⁶ in the section on management of shoulder dystocia, states that “an initial gentle attempt at traction assisted by maternal expulsive efforts is recommended.” There is no reference for this statement. However, a look at the 19th edition of the textbook⁷ reveals identical wording, and the reference cited is ACOG Technical Bulletin No. 152 (August 1991), entitled Operative Vaginal Delivery. A subsequent version of the same bulletin (no. 196 from August 1994) contains identical wording. By the time that version was replaced by ACOG Practice Bulletin No. 17 (June 2000), however, it no longer contained any information on shoulder dystocia. Instead, ACOG published Practice Pattern No. 7 (October 1997), entitled Shoulder Dystocia. This document did not recommend maternal expulsive force after a diagnosis of shoulder dystocia—in fact, maternal force was not even mentioned. Nor is it mentioned in the current practice bulletin (no. 40 from November 2002), which replaced the previous version of Shoulder Dystocia.

Confusion doesn’t end there

In its section on shoulder dystocia, ACOG’s publication Precis (1998) states:

Management of shoulder dystocia involves both anticipation of and preparation for problems. The key to preventing fetal injury is avoidance of excess traction on the fetal head. When shoulder dystocia is diagnosed, a deliberate and planned sequence of events should be initiated. Pushing should be halted and obstructive causes should be considered. Aggressive fundal pressure or continued pushing will only further impact the anterior shoulder.

We are left with the paradox that the current edition of Williams Obstetrics, in its discussion of shoulder dystocia, carries a statement recommending maternal pushing based on a 1994 ACOG document—a statement that subsequent ACOG documents no longer contain. In fact, one of those documents—Precis—tells us that pushing should be halted, an instruction supported by the mathematical modeling of Gonik and colleagues.² And a popular online text (UpToDate.com) advises: “The mother should be told not to push during attempts to reposition the fetus.”⁸ Once the fetus is successfully repositioned, maternal pushing or traction, or both, can be reinstated.

Putting it all into clinical perspective

The current ACOG practice bulletin on shoulder dystocia (no. 40 from November 2002) observes that “retraction of the delivered fetal head against the maternal perineum (turtle sign) may be present and may assist in the diagnosis of shoulder dystocia.” When present, the turtle sign strongly suggests that the anterior shoulder is already impacted against the symphysis pubis. Maternal expulsive forces may have already put enough pressure on the nerve roots of the brachial plexus to cause damage. Any degree of traction or continued maternal pushing is likely to compound an already potentially serious problem.

In such cases, it is prudent to resort to known maneuvers, avoid encouraging continued maternal pushing, and simply support and guide the head without supplying any real traction.

When the turtle sign is absent, shoulder dystocia can be diagnosed only after the head is delivered, when the usual methods (ie, downward traction and continued maternal pushing) fail to advance delivery. Diagnosis in these cases requires recognition on the part of the delivering physician that shoulder dystocia is present. At that point, continued expulsive force and any real degree of traction no longer are appropriate.

The author reports no financial relationships relevant to this article.

Brachial plexus injury is a dreaded sequela of shoulder dystocia, one that lies at the root of many medical liability disputes. Although brachial plexus injury cannot be prevented, most of the commonly used maneuvers for freeing a stuck shoulder are designed to maximize fetal safety and minimize injury.

What is the standard of care when dystocia occurs? Several respected sources have offered conflicting recommendations, particularly in regard to maternal pushing once dystocia is diagnosed. My aim in this article is to clarify the issue.

Endogenous force versus exogenous force

The introduction to the American College of Obstetricians and Gynecologists’ practice bulletin on shoulder dystocia, published in November 2002, provides a useful summary of much of our current knowledge:

Shoulder dystocia is most often an unpredictable and unpreventable obstetric emergency. Failure of the shoulders to deliver spontaneously places both the pregnant woman and fetus at risk for injury. Several maneuvers to release impacted shoulders have been developed, but the urgency of this event makes prospective studies impractical for comparing their effectiveness.¹

Because prospective studies are unlikely ever to be performed, some investigators have turned to mathematical modeling to learn more about the forces exerted on the fetal neck overlying the roots of the brachial plexus when a shoulder is impacted against the symphysis pubis.

Gonik and colleagues² performed elegant modeling of the pressure between the base of the fetal neck and symphysis pubis during dystocia. They utilized data on birth forces gathered by CaldeyroBarcia and Poseiro³ in their classic work on intrauterine pressure. Gonik and colleagues also used data from Allen and associates,⁴ who measured the force of clinician-applied traction after delivery of the head by having clinicians wear sensory gloves that recorded the force of traction applied.

Gonik and associates² concluded that the pressure resulting from endogenous forces is four to nine times greater than the pressure generated by a clinician. “Neonatal brachial plexus injury is not a priori explained by iatrogenically induced excessive traction,” they wrote. “Spontaneous endogenous forces may contribute substantially to this type of neonatal trauma.”

How an understanding of endogenous forces alters management

Although fewer than 10% of cases of shoulder dystocia result in permanent brachial plexus injury,¹ such injuries are a major source of malpractice litigation in obstetrics, as I noted at the beginning of this article. In most such cases, injury is blamed on excessive traction by the physician (FIGURE). Newer data, such as the study by Gonik and colleagues,² may implicate expulsive force (ie, maternal pushing) as another, perhaps greater, cause.

As long ago as 1988, Acker and colleagues⁵ reported on their experience with Erb’s palsy, which was associated with rapid delivery and unusually forceful expulsive effort in one third of cases. Their findings suggest that, when shoulder dystocia occurs and additional maneuvers are necessary to deliver the impacted anterior shoulder, the contribution of potentially harmful endogenous forces should be kept in mind. Counterintuitive strategies, including having the mother stop pushing until the anterior shoulder is freed, may help limit injury.

FIGURE Maternal pushing may contribute to injury

When shoulder dystocia occurs, the progress of labor is interrupted and brachial plexus injury can result, a common cause of litigation. Until now, plaintiff’s attorneys have tended to blame these injuries on the obstetrician and “excess” traction, but it now appears that maternal pushing contributes as well—possibly, to a greater degree than any effort by the physician.

How confusion crept into the literature

The 21st (current) edition of Williams Obstetrics,⁶ in the section on management of shoulder dystocia, states that “an initial gentle attempt at traction assisted by maternal expulsive efforts is recommended.” There is no reference for this statement. However, a look at the 19th edition of the textbook⁷ reveals identical wording, and the reference cited is ACOG Technical Bulletin No. 152 (August 1991), entitled Operative Vaginal Delivery. A subsequent version of the same bulletin (no. 196 from August 1994) contains identical wording. By the time that version was replaced by ACOG Practice Bulletin No. 17 (June 2000), however, it no longer contained any information on shoulder dystocia. Instead, ACOG published Practice Pattern No. 7 (October 1997), entitled Shoulder Dystocia. This document did not recommend maternal expulsive force after a diagnosis of shoulder dystocia—in fact, maternal force was not even mentioned. Nor is it mentioned in the current practice bulletin (no. 40 from November 2002), which replaced the previous version of Shoulder Dystocia.

Confusion doesn’t end there

In its section on shoulder dystocia, ACOG’s publication Precis (1998) states:

Management of shoulder dystocia involves both anticipation of and preparation for problems. The key to preventing fetal injury is avoidance of excess traction on the fetal head. When shoulder dystocia is diagnosed, a deliberate and planned sequence of events should be initiated. Pushing should be halted and obstructive causes should be considered. Aggressive fundal pressure or continued pushing will only further impact the anterior shoulder.

We are left with the paradox that the current edition of Williams Obstetrics, in its discussion of shoulder dystocia, carries a statement recommending maternal pushing based on a 1994 ACOG document—a statement that subsequent ACOG documents no longer contain. In fact, one of those documents—Precis—tells us that pushing should be halted, an instruction supported by the mathematical modeling of Gonik and colleagues.² And a popular online text (UpToDate.com) advises: “The mother should be told not to push during attempts to reposition the fetus.”⁸ Once the fetus is successfully repositioned, maternal pushing or traction, or both, can be reinstated.

Putting it all into clinical perspective

The current ACOG practice bulletin on shoulder dystocia (no. 40 from November 2002) observes that “retraction of the delivered fetal head against the maternal perineum (turtle sign) may be present and may assist in the diagnosis of shoulder dystocia.” When present, the turtle sign strongly suggests that the anterior shoulder is already impacted against the symphysis pubis. Maternal expulsive forces may have already put enough pressure on the nerve roots of the brachial plexus to cause damage. Any degree of traction or continued maternal pushing is likely to compound an already potentially serious problem.

In such cases, it is prudent to resort to known maneuvers, avoid encouraging continued maternal pushing, and simply support and guide the head without supplying any real traction.

When the turtle sign is absent, shoulder dystocia can be diagnosed only after the head is delivered, when the usual methods (ie, downward traction and continued maternal pushing) fail to advance delivery. Diagnosis in these cases requires recognition on the part of the delivering physician that shoulder dystocia is present. At that point, continued expulsive force and any real degree of traction no longer are appropriate.

The authors report no financial relationships relevant to this article.

The use of transvaginal mesh—with or without trocar placement—is surrounded by controversy. A number of minimally invasive vaginal mesh kits are commercially available for the repair of pelvic organ prolapse, and new kits are entering the market rapidly. The challenge is determining whether these new techniques are as effective and safe as traditional prolapse repairs.

Although the use of permanent mesh to repair prolapse has been explored in retrospective and prospective studies, no rigorous controlled trials have compared these new procedures with abdominal sacrocolpopexy or uterosacral ligament suspension, for example. The current body of literature does suggest a high rate of recurrent prolapse after traditional anterior or posterior colporrhaphy, and the use of allograft material has not been shown to improve outcomes. Surgeons are now turning their attention to permanent polypropylene mesh as a possible alternative. In addition, repair of the vaginal apex at the time of anterior and posterior vaginal wall repair is being explored as a way to increase durability of the repair. The new trocar-delivered mesh kits address this issue by suspending the vaginal vault while providing support to the vaginal walls.

This article highlights three recent studies that focus on a new trocar-delivered, protected, low-weight polypropylene mesh (Ugytex, distributed by Bard as Pelvitex) and three trocar-delivered mesh kits (Prolift, Apogee, and Perigee).

One-year outcomes encouraging for low-weight polypropylene mesh

De Tayrac R, Devoldere G, Renaudie J, Villard P, Guilbaud O, Eglin G. Prolapse repair by vaginal route using a new protected low-weight polypropylene mesh: 1-year functional and anatomical outcome in a prospective multicentre study. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:251–256.

This study evaluated functional and anatomic outcomes after placement for prolapse repair of low-weight polypropylene mesh protected by absorbable hydrophilic film. The film, a combination of atelocollagen, polyethylene glycol, and glycerol, is designed to protect pelvic organs from acute inflammation during healing. In a separate investigation of unprotected, heavyweight polypropylene mesh in prolapse repair, the anatomic success rate ranged from 75% to 100%, but the rate of mesh erosion (13%) and dyspareunia (69%) seemed unacceptably high.¹

Rigorous preoperative assessment

In this trial, 230 women with symptomatic vaginal wall prolapse were recruited at 13 centers in a consecutive fashion. At enrollment, all patients were measured using the pelvic organ prolapse quantitative staging system (POP-Q). They also completed the validated Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire. The presence and severity of dyspareunia were also recorded, as well as the Urinary Dysfunction Measurement Scale. All participants had prolapse equal to or exceeding stage II.

Surgeons used trocars to percutaneously place a low-weight (38 g/m²) and highly porous polypropylene monofilament mesh (Ugytex/Pelvitex) for vaginal repair and performed any concomitant procedures. Perioperative and postoperative complications were recorded. Patients were evaluated at 6 weeks, 6 months, and 1 year. The first 143 patients with at least 10 months of follow-up were analyzed, with a mean follow-up of 13±2 months (range: 10–19). Anatomic cure was defined as no prolapse greater than or equal to stage II.

Patient satisfaction was high

The anatomic cure rate was 92.3%, with a 6.8% recurrence of anterior vaginal wall prolapse and 2.6% recurrence of posterior vaginal wall prolapse. Only one patient with recurrence was symptomatic.

Six of 143 patients (4.2%) sustained an intraoperative complication: three bladder injuries, one rectal injury, one uterine artery hemorrhage (during hysterectomy), and one vaginal sulcus perforation (during transobturator tape placement). The most significant postoperative complication related to the vaginal mesh kit was vaginal hematoma; one of the two cases required reoperation and partial removal of the mesh.

Nine patients developed mesh erosion in the first 3 months, for an erosion rate of 6.3%. Six required partial excision of the mesh. Overall, symptoms and quality of life improved significantly, with an overall satisfaction rate at follow-up of 96.5%. No significant difference was noted between pre- and postoperative rates of dyspareunia.

Further evaluation is warranted

The authors are already conducting a randomized trial to compare anterior vaginal wall repair using this low-weight polypropylene mesh with traditional anterior colporrhaphy to confirm and explore these results.

Note: Bard now offers a kit called Avaulta Plus that uses the same mesh material with a trocar delivery system, previously lacking (although investigators used trocars in this study).

Perioperative complications were uncommon with Prolift system

Altman D, Falconer C. Perioperative morbidity using transvaginal mesh in pelvic organ prolapse repair. Obstet Gynecol. 2007;109:303–308.

This study explored the frequency and characteristics of perioperative complications associated with the use of Prolift, a transvaginal mesh system for the repair of pelvic organ prolapse (FIGURE). Twenty-five centers participated by registering a standardized safety protocol form for 248 women who underwent surgery using the system over a 6-month period. The form included information about perioperative complications, adverse intraoperative events, and the associated hospital stay, as well as obstetric and gynecologic medical history and previous pelvic surgery.

Pelvic organ perforation (lower urinary tract or anorectal injury) and blood loss greater than 1,000 mL were recorded as major complications, and any other adverse events related to the hospital stay were documented as minor complications. Most of the cohort had already undergone prolapse repair, and prolapse had recurred in the same vaginal compartment.

One author was an educational adviser for Gynecare Sweden AB, and the other an adviser for Johnson & Johnson. Although the study was funded entirely by university-administered research funds, pretrial scientific meetings were paid for by Gynecare Sweden AB.

FIGURE: Mesh support of pelvic organs

Prolift mesh in final position, with extension arms passed through the sacrospinous ligaments and the obturator foramen bilaterally.

4.4% rate of serious complications

Serious complications occurred in 4.4% (11 of 248) of cases (95% confidence interval [CI], 2.5–7.8). The predominant complication was visceral injury, which included bladder, urethral, and rectal perforation. One patient had blood loss exceeding 1,000 mL.

Minor complications occurred in 44 patients (18%). The most common minor complication was urinary tract infection. Adverse events included urinary retention requiring catheterization, anemia, transfusion, fever, groin and buttock pain, and vaginal hematoma, among others.

Concurrent pelvic floor surgery increased the risk for minor complications (odds ratio, 2.8; 95% CI, 1.1–6.9). Concurrent procedures included vaginal hysterectomy, sling procedure with tension-free vaginal tape or transobturator tension-free tape, sacrospinal fixation, repair of vaginal enterocele, and bilateral salpingo-oophorectomy. This risk analysis identified no other predictors of outcome.

Key points for successful placement of trocar-delivered mesh

Posterior/apical repair

• Adequately infiltrate the vaginal epithelium with diluted epinephrine solution, especially toward the lateral apices, to facilitate hemostasis and dissection
• Be thorough in lateral dissection toward the ischial spine and stay in the proper surgical plane to create a thick vaginal epithelial flap
• Palpate the ischial spine, with the preoperatively packed rectum retracted medially
• During passage of the trocar, place an index finger along the vaginal dissection to palpate the trocar in the ischiorectal fossa and deep to the levator ani muscles until the tip is palpated at the level of the ischial spine
• Pass the trocar through the arcus tendineus/levator fascia at the level of the ischial spine, as shown below:

• Do not apply excess tension to the straps of the graft material
• Do not trim the vaginal epithelium

Anterior wall (obturator foramen trocar passage)

• Same key points as posterior wall technique, but in anterior repair, there are two passes through the obturator foramen
• The first trocar is inserted into the inferior obturator foramen, rotated, and guided with the surgeon’s finger inserted into and held in the vaginal dissection, as shown below:

• The superior passage exits close to the bladder neck, and the inferior passage approximates the ischial spine. Penetrate along the arcus tendineus approximately 1 cm from the ischial spine

Caution! Keep summary points in context

These key points are not intended as formal medical training, but as general information only. Continued research into these techniques is needed to assess long-term outcomes.

Short-term outcomes data only

Because this study focused on immediate complications, no long-term data on such complications as persistent pain, mesh erosion, or infection were collected.

All surgeons underwent hands-on training with the transvaginal repair system before patients were enrolled in the study. Nevertheless, the authors observe that many repair procedures were performed at the beginning of the physicians’ learning curve, with a higher number of complications than would be expected from more experienced surgeons.

The data may also have been affected by selection bias (ie, toward more complicated cases), given that most patients had already undergone prolapse repair.

Two systems yield excellent short-term results in women with recurrent prolapse

Gauruder-Burmester A, Koutouzidou P, Rohne J, Gronewold M, Tunn R. Follow-up after polypropylene mesh repair of anterior and posterior compartments in patients with recurrent prolapse. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:1059–1064.

This retrospective study involved women who had already undergone one or more prolapse repairs. These patients then underwent reoperation with mesh-reinforced repair. The authors hypothesized that recurrent prolapse represents poor tissue quality, necessitating the use of mesh in subsequent repairs. Both pre- and postoperative symptoms and functional changes were analyzed, with a special focus on mesh erosion and sexual function.

Details of the study

Of 145 women who underwent repair with the Apogee (apical posterior) or Perigee (anterior wall) system during a 1-year period, 120 were included in the analysis. The other 25 patients were excluded because they did not return for follow-up, were missing urodynamic data, or had inaccurate POP-Q staging. All patients had recurrent stage III posterior or anterior vaginal wall prolapse. Forty percent of patients had an apical posterior repair, and 60% had anterior wall repair. None had both procedures performed simultaneously.

All patients had undergone hysterectomy and received vaginal estrogen before and after surgery. Urinary incontinence was treated in a two-step fashion; that is, it was not addressed until 3 months after repair of the prolapse. Routine follow-up occurred at 1 month and 1 year after surgery.

One-year cure rate was 93%

No perioperative or intraoperative complications occurred, and mean operative time was 35±4.5 minutes. Mesh erosion occurred in four patients (3%) and involved anterior mesh placement only. No mesh infections were noted.

At 1 year, 93% of women were anatomically cured of prolapse (ie, they had less than stage II prolapse). Prolapse recurred in eight women; all cases involved the anterior compartment.

No dyspareunia was associated with the repair. In fact, prolapse-associated dyspareunia resolved in all 15 women who reported this symptom before surgery. In addition, questionnaires about quality of life and satisfaction revealed significant improvement after mesh placement (P=.023).

The authors attribute the positive results to the fact that both surgeons involved in the study used the technique on 15 patients before operating on study participants, minimizing the effect of the learning curve. The authors were also careful about patient selection.

Results merit cautious optimism

The authors propose that the low erosion rate and lack of new-onset dyspareunia after surgery may be misleading because long-term results have not yet been obtained. We also speculate that precise dissection in the proper surgical plane likely minimized early erosions.

The authors report no financial relationships relevant to this article.

The use of transvaginal mesh—with or without trocar placement—is surrounded by controversy. A number of minimally invasive vaginal mesh kits are commercially available for the repair of pelvic organ prolapse, and new kits are entering the market rapidly. The challenge is determining whether these new techniques are as effective and safe as traditional prolapse repairs.

Although the use of permanent mesh to repair prolapse has been explored in retrospective and prospective studies, no rigorous controlled trials have compared these new procedures with abdominal sacrocolpopexy or uterosacral ligament suspension, for example. The current body of literature does suggest a high rate of recurrent prolapse after traditional anterior or posterior colporrhaphy, and the use of allograft material has not been shown to improve outcomes. Surgeons are now turning their attention to permanent polypropylene mesh as a possible alternative. In addition, repair of the vaginal apex at the time of anterior and posterior vaginal wall repair is being explored as a way to increase durability of the repair. The new trocar-delivered mesh kits address this issue by suspending the vaginal vault while providing support to the vaginal walls.

This article highlights three recent studies that focus on a new trocar-delivered, protected, low-weight polypropylene mesh (Ugytex, distributed by Bard as Pelvitex) and three trocar-delivered mesh kits (Prolift, Apogee, and Perigee).

One-year outcomes encouraging for low-weight polypropylene mesh

De Tayrac R, Devoldere G, Renaudie J, Villard P, Guilbaud O, Eglin G. Prolapse repair by vaginal route using a new protected low-weight polypropylene mesh: 1-year functional and anatomical outcome in a prospective multicentre study. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:251–256.

This study evaluated functional and anatomic outcomes after placement for prolapse repair of low-weight polypropylene mesh protected by absorbable hydrophilic film. The film, a combination of atelocollagen, polyethylene glycol, and glycerol, is designed to protect pelvic organs from acute inflammation during healing. In a separate investigation of unprotected, heavyweight polypropylene mesh in prolapse repair, the anatomic success rate ranged from 75% to 100%, but the rate of mesh erosion (13%) and dyspareunia (69%) seemed unacceptably high.¹

Rigorous preoperative assessment

In this trial, 230 women with symptomatic vaginal wall prolapse were recruited at 13 centers in a consecutive fashion. At enrollment, all patients were measured using the pelvic organ prolapse quantitative staging system (POP-Q). They also completed the validated Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire. The presence and severity of dyspareunia were also recorded, as well as the Urinary Dysfunction Measurement Scale. All participants had prolapse equal to or exceeding stage II.

Surgeons used trocars to percutaneously place a low-weight (38 g/m²) and highly porous polypropylene monofilament mesh (Ugytex/Pelvitex) for vaginal repair and performed any concomitant procedures. Perioperative and postoperative complications were recorded. Patients were evaluated at 6 weeks, 6 months, and 1 year. The first 143 patients with at least 10 months of follow-up were analyzed, with a mean follow-up of 13±2 months (range: 10–19). Anatomic cure was defined as no prolapse greater than or equal to stage II.

Patient satisfaction was high

The anatomic cure rate was 92.3%, with a 6.8% recurrence of anterior vaginal wall prolapse and 2.6% recurrence of posterior vaginal wall prolapse. Only one patient with recurrence was symptomatic.

Six of 143 patients (4.2%) sustained an intraoperative complication: three bladder injuries, one rectal injury, one uterine artery hemorrhage (during hysterectomy), and one vaginal sulcus perforation (during transobturator tape placement). The most significant postoperative complication related to the vaginal mesh kit was vaginal hematoma; one of the two cases required reoperation and partial removal of the mesh.

Nine patients developed mesh erosion in the first 3 months, for an erosion rate of 6.3%. Six required partial excision of the mesh. Overall, symptoms and quality of life improved significantly, with an overall satisfaction rate at follow-up of 96.5%. No significant difference was noted between pre- and postoperative rates of dyspareunia.

Further evaluation is warranted

The authors are already conducting a randomized trial to compare anterior vaginal wall repair using this low-weight polypropylene mesh with traditional anterior colporrhaphy to confirm and explore these results.

Note: Bard now offers a kit called Avaulta Plus that uses the same mesh material with a trocar delivery system, previously lacking (although investigators used trocars in this study).

Perioperative complications were uncommon with Prolift system

Altman D, Falconer C. Perioperative morbidity using transvaginal mesh in pelvic organ prolapse repair. Obstet Gynecol. 2007;109:303–308.

This study explored the frequency and characteristics of perioperative complications associated with the use of Prolift, a transvaginal mesh system for the repair of pelvic organ prolapse (FIGURE). Twenty-five centers participated by registering a standardized safety protocol form for 248 women who underwent surgery using the system over a 6-month period. The form included information about perioperative complications, adverse intraoperative events, and the associated hospital stay, as well as obstetric and gynecologic medical history and previous pelvic surgery.

Pelvic organ perforation (lower urinary tract or anorectal injury) and blood loss greater than 1,000 mL were recorded as major complications, and any other adverse events related to the hospital stay were documented as minor complications. Most of the cohort had already undergone prolapse repair, and prolapse had recurred in the same vaginal compartment.

One author was an educational adviser for Gynecare Sweden AB, and the other an adviser for Johnson & Johnson. Although the study was funded entirely by university-administered research funds, pretrial scientific meetings were paid for by Gynecare Sweden AB.

FIGURE: Mesh support of pelvic organs

Prolift mesh in final position, with extension arms passed through the sacrospinous ligaments and the obturator foramen bilaterally.

4.4% rate of serious complications

Serious complications occurred in 4.4% (11 of 248) of cases (95% confidence interval [CI], 2.5–7.8). The predominant complication was visceral injury, which included bladder, urethral, and rectal perforation. One patient had blood loss exceeding 1,000 mL.

Minor complications occurred in 44 patients (18%). The most common minor complication was urinary tract infection. Adverse events included urinary retention requiring catheterization, anemia, transfusion, fever, groin and buttock pain, and vaginal hematoma, among others.

Concurrent pelvic floor surgery increased the risk for minor complications (odds ratio, 2.8; 95% CI, 1.1–6.9). Concurrent procedures included vaginal hysterectomy, sling procedure with tension-free vaginal tape or transobturator tension-free tape, sacrospinal fixation, repair of vaginal enterocele, and bilateral salpingo-oophorectomy. This risk analysis identified no other predictors of outcome.

Key points for successful placement of trocar-delivered mesh

Posterior/apical repair

• Adequately infiltrate the vaginal epithelium with diluted epinephrine solution, especially toward the lateral apices, to facilitate hemostasis and dissection
• Be thorough in lateral dissection toward the ischial spine and stay in the proper surgical plane to create a thick vaginal epithelial flap
• Palpate the ischial spine, with the preoperatively packed rectum retracted medially
• During passage of the trocar, place an index finger along the vaginal dissection to palpate the trocar in the ischiorectal fossa and deep to the levator ani muscles until the tip is palpated at the level of the ischial spine
• Pass the trocar through the arcus tendineus/levator fascia at the level of the ischial spine, as shown below:

• Do not apply excess tension to the straps of the graft material
• Do not trim the vaginal epithelium

Anterior wall (obturator foramen trocar passage)

• Same key points as posterior wall technique, but in anterior repair, there are two passes through the obturator foramen
• The first trocar is inserted into the inferior obturator foramen, rotated, and guided with the surgeon’s finger inserted into and held in the vaginal dissection, as shown below:

• The superior passage exits close to the bladder neck, and the inferior passage approximates the ischial spine. Penetrate along the arcus tendineus approximately 1 cm from the ischial spine

Caution! Keep summary points in context

These key points are not intended as formal medical training, but as general information only. Continued research into these techniques is needed to assess long-term outcomes.

Short-term outcomes data only

Because this study focused on immediate complications, no long-term data on such complications as persistent pain, mesh erosion, or infection were collected.

All surgeons underwent hands-on training with the transvaginal repair system before patients were enrolled in the study. Nevertheless, the authors observe that many repair procedures were performed at the beginning of the physicians’ learning curve, with a higher number of complications than would be expected from more experienced surgeons.

The data may also have been affected by selection bias (ie, toward more complicated cases), given that most patients had already undergone prolapse repair.

Two systems yield excellent short-term results in women with recurrent prolapse

Gauruder-Burmester A, Koutouzidou P, Rohne J, Gronewold M, Tunn R. Follow-up after polypropylene mesh repair of anterior and posterior compartments in patients with recurrent prolapse. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:1059–1064.

This retrospective study involved women who had already undergone one or more prolapse repairs. These patients then underwent reoperation with mesh-reinforced repair. The authors hypothesized that recurrent prolapse represents poor tissue quality, necessitating the use of mesh in subsequent repairs. Both pre- and postoperative symptoms and functional changes were analyzed, with a special focus on mesh erosion and sexual function.

Details of the study

Of 145 women who underwent repair with the Apogee (apical posterior) or Perigee (anterior wall) system during a 1-year period, 120 were included in the analysis. The other 25 patients were excluded because they did not return for follow-up, were missing urodynamic data, or had inaccurate POP-Q staging. All patients had recurrent stage III posterior or anterior vaginal wall prolapse. Forty percent of patients had an apical posterior repair, and 60% had anterior wall repair. None had both procedures performed simultaneously.

All patients had undergone hysterectomy and received vaginal estrogen before and after surgery. Urinary incontinence was treated in a two-step fashion; that is, it was not addressed until 3 months after repair of the prolapse. Routine follow-up occurred at 1 month and 1 year after surgery.

One-year cure rate was 93%

No perioperative or intraoperative complications occurred, and mean operative time was 35±4.5 minutes. Mesh erosion occurred in four patients (3%) and involved anterior mesh placement only. No mesh infections were noted.

At 1 year, 93% of women were anatomically cured of prolapse (ie, they had less than stage II prolapse). Prolapse recurred in eight women; all cases involved the anterior compartment.

No dyspareunia was associated with the repair. In fact, prolapse-associated dyspareunia resolved in all 15 women who reported this symptom before surgery. In addition, questionnaires about quality of life and satisfaction revealed significant improvement after mesh placement (P=.023).

The authors attribute the positive results to the fact that both surgeons involved in the study used the technique on 15 patients before operating on study participants, minimizing the effect of the learning curve. The authors were also careful about patient selection.

Results merit cautious optimism

The authors propose that the low erosion rate and lack of new-onset dyspareunia after surgery may be misleading because long-term results have not yet been obtained. We also speculate that precise dissection in the proper surgical plane likely minimized early erosions.

The authors report no financial relationships relevant to this article.

The use of transvaginal mesh—with or without trocar placement—is surrounded by controversy. A number of minimally invasive vaginal mesh kits are commercially available for the repair of pelvic organ prolapse, and new kits are entering the market rapidly. The challenge is determining whether these new techniques are as effective and safe as traditional prolapse repairs.

Although the use of permanent mesh to repair prolapse has been explored in retrospective and prospective studies, no rigorous controlled trials have compared these new procedures with abdominal sacrocolpopexy or uterosacral ligament suspension, for example. The current body of literature does suggest a high rate of recurrent prolapse after traditional anterior or posterior colporrhaphy, and the use of allograft material has not been shown to improve outcomes. Surgeons are now turning their attention to permanent polypropylene mesh as a possible alternative. In addition, repair of the vaginal apex at the time of anterior and posterior vaginal wall repair is being explored as a way to increase durability of the repair. The new trocar-delivered mesh kits address this issue by suspending the vaginal vault while providing support to the vaginal walls.

This article highlights three recent studies that focus on a new trocar-delivered, protected, low-weight polypropylene mesh (Ugytex, distributed by Bard as Pelvitex) and three trocar-delivered mesh kits (Prolift, Apogee, and Perigee).

One-year outcomes encouraging for low-weight polypropylene mesh

De Tayrac R, Devoldere G, Renaudie J, Villard P, Guilbaud O, Eglin G. Prolapse repair by vaginal route using a new protected low-weight polypropylene mesh: 1-year functional and anatomical outcome in a prospective multicentre study. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:251–256.

This study evaluated functional and anatomic outcomes after placement for prolapse repair of low-weight polypropylene mesh protected by absorbable hydrophilic film. The film, a combination of atelocollagen, polyethylene glycol, and glycerol, is designed to protect pelvic organs from acute inflammation during healing. In a separate investigation of unprotected, heavyweight polypropylene mesh in prolapse repair, the anatomic success rate ranged from 75% to 100%, but the rate of mesh erosion (13%) and dyspareunia (69%) seemed unacceptably high.¹

Rigorous preoperative assessment

In this trial, 230 women with symptomatic vaginal wall prolapse were recruited at 13 centers in a consecutive fashion. At enrollment, all patients were measured using the pelvic organ prolapse quantitative staging system (POP-Q). They also completed the validated Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire. The presence and severity of dyspareunia were also recorded, as well as the Urinary Dysfunction Measurement Scale. All participants had prolapse equal to or exceeding stage II.

Surgeons used trocars to percutaneously place a low-weight (38 g/m²) and highly porous polypropylene monofilament mesh (Ugytex/Pelvitex) for vaginal repair and performed any concomitant procedures. Perioperative and postoperative complications were recorded. Patients were evaluated at 6 weeks, 6 months, and 1 year. The first 143 patients with at least 10 months of follow-up were analyzed, with a mean follow-up of 13±2 months (range: 10–19). Anatomic cure was defined as no prolapse greater than or equal to stage II.

Patient satisfaction was high

The anatomic cure rate was 92.3%, with a 6.8% recurrence of anterior vaginal wall prolapse and 2.6% recurrence of posterior vaginal wall prolapse. Only one patient with recurrence was symptomatic.

Six of 143 patients (4.2%) sustained an intraoperative complication: three bladder injuries, one rectal injury, one uterine artery hemorrhage (during hysterectomy), and one vaginal sulcus perforation (during transobturator tape placement). The most significant postoperative complication related to the vaginal mesh kit was vaginal hematoma; one of the two cases required reoperation and partial removal of the mesh.

Nine patients developed mesh erosion in the first 3 months, for an erosion rate of 6.3%. Six required partial excision of the mesh. Overall, symptoms and quality of life improved significantly, with an overall satisfaction rate at follow-up of 96.5%. No significant difference was noted between pre- and postoperative rates of dyspareunia.

Further evaluation is warranted

The authors are already conducting a randomized trial to compare anterior vaginal wall repair using this low-weight polypropylene mesh with traditional anterior colporrhaphy to confirm and explore these results.

Note: Bard now offers a kit called Avaulta Plus that uses the same mesh material with a trocar delivery system, previously lacking (although investigators used trocars in this study).

Perioperative complications were uncommon with Prolift system

Altman D, Falconer C. Perioperative morbidity using transvaginal mesh in pelvic organ prolapse repair. Obstet Gynecol. 2007;109:303–308.

This study explored the frequency and characteristics of perioperative complications associated with the use of Prolift, a transvaginal mesh system for the repair of pelvic organ prolapse (FIGURE). Twenty-five centers participated by registering a standardized safety protocol form for 248 women who underwent surgery using the system over a 6-month period. The form included information about perioperative complications, adverse intraoperative events, and the associated hospital stay, as well as obstetric and gynecologic medical history and previous pelvic surgery.

Pelvic organ perforation (lower urinary tract or anorectal injury) and blood loss greater than 1,000 mL were recorded as major complications, and any other adverse events related to the hospital stay were documented as minor complications. Most of the cohort had already undergone prolapse repair, and prolapse had recurred in the same vaginal compartment.

One author was an educational adviser for Gynecare Sweden AB, and the other an adviser for Johnson & Johnson. Although the study was funded entirely by university-administered research funds, pretrial scientific meetings were paid for by Gynecare Sweden AB.

FIGURE: Mesh support of pelvic organs

Prolift mesh in final position, with extension arms passed through the sacrospinous ligaments and the obturator foramen bilaterally.

4.4% rate of serious complications

Serious complications occurred in 4.4% (11 of 248) of cases (95% confidence interval [CI], 2.5–7.8). The predominant complication was visceral injury, which included bladder, urethral, and rectal perforation. One patient had blood loss exceeding 1,000 mL.

Minor complications occurred in 44 patients (18%). The most common minor complication was urinary tract infection. Adverse events included urinary retention requiring catheterization, anemia, transfusion, fever, groin and buttock pain, and vaginal hematoma, among others.

Concurrent pelvic floor surgery increased the risk for minor complications (odds ratio, 2.8; 95% CI, 1.1–6.9). Concurrent procedures included vaginal hysterectomy, sling procedure with tension-free vaginal tape or transobturator tension-free tape, sacrospinal fixation, repair of vaginal enterocele, and bilateral salpingo-oophorectomy. This risk analysis identified no other predictors of outcome.

Key points for successful placement of trocar-delivered mesh

Posterior/apical repair

• Adequately infiltrate the vaginal epithelium with diluted epinephrine solution, especially toward the lateral apices, to facilitate hemostasis and dissection
• Be thorough in lateral dissection toward the ischial spine and stay in the proper surgical plane to create a thick vaginal epithelial flap
• Palpate the ischial spine, with the preoperatively packed rectum retracted medially
• During passage of the trocar, place an index finger along the vaginal dissection to palpate the trocar in the ischiorectal fossa and deep to the levator ani muscles until the tip is palpated at the level of the ischial spine
• Pass the trocar through the arcus tendineus/levator fascia at the level of the ischial spine, as shown below:

• Do not apply excess tension to the straps of the graft material
• Do not trim the vaginal epithelium

Anterior wall (obturator foramen trocar passage)

• Same key points as posterior wall technique, but in anterior repair, there are two passes through the obturator foramen
• The first trocar is inserted into the inferior obturator foramen, rotated, and guided with the surgeon’s finger inserted into and held in the vaginal dissection, as shown below:

• The superior passage exits close to the bladder neck, and the inferior passage approximates the ischial spine. Penetrate along the arcus tendineus approximately 1 cm from the ischial spine

Caution! Keep summary points in context

These key points are not intended as formal medical training, but as general information only. Continued research into these techniques is needed to assess long-term outcomes.

Short-term outcomes data only

Because this study focused on immediate complications, no long-term data on such complications as persistent pain, mesh erosion, or infection were collected.

All surgeons underwent hands-on training with the transvaginal repair system before patients were enrolled in the study. Nevertheless, the authors observe that many repair procedures were performed at the beginning of the physicians’ learning curve, with a higher number of complications than would be expected from more experienced surgeons.

The data may also have been affected by selection bias (ie, toward more complicated cases), given that most patients had already undergone prolapse repair.

Two systems yield excellent short-term results in women with recurrent prolapse

Gauruder-Burmester A, Koutouzidou P, Rohne J, Gronewold M, Tunn R. Follow-up after polypropylene mesh repair of anterior and posterior compartments in patients with recurrent prolapse. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:1059–1064.

This retrospective study involved women who had already undergone one or more prolapse repairs. These patients then underwent reoperation with mesh-reinforced repair. The authors hypothesized that recurrent prolapse represents poor tissue quality, necessitating the use of mesh in subsequent repairs. Both pre- and postoperative symptoms and functional changes were analyzed, with a special focus on mesh erosion and sexual function.

Details of the study

Of 145 women who underwent repair with the Apogee (apical posterior) or Perigee (anterior wall) system during a 1-year period, 120 were included in the analysis. The other 25 patients were excluded because they did not return for follow-up, were missing urodynamic data, or had inaccurate POP-Q staging. All patients had recurrent stage III posterior or anterior vaginal wall prolapse. Forty percent of patients had an apical posterior repair, and 60% had anterior wall repair. None had both procedures performed simultaneously.

All patients had undergone hysterectomy and received vaginal estrogen before and after surgery. Urinary incontinence was treated in a two-step fashion; that is, it was not addressed until 3 months after repair of the prolapse. Routine follow-up occurred at 1 month and 1 year after surgery.

One-year cure rate was 93%

No perioperative or intraoperative complications occurred, and mean operative time was 35±4.5 minutes. Mesh erosion occurred in four patients (3%) and involved anterior mesh placement only. No mesh infections were noted.

At 1 year, 93% of women were anatomically cured of prolapse (ie, they had less than stage II prolapse). Prolapse recurred in eight women; all cases involved the anterior compartment.

No dyspareunia was associated with the repair. In fact, prolapse-associated dyspareunia resolved in all 15 women who reported this symptom before surgery. In addition, questionnaires about quality of life and satisfaction revealed significant improvement after mesh placement (P=.023).

The authors attribute the positive results to the fact that both surgeons involved in the study used the technique on 15 patients before operating on study participants, minimizing the effect of the learning curve. The authors were also careful about patient selection.

Results merit cautious optimism

The authors propose that the low erosion rate and lack of new-onset dyspareunia after surgery may be misleading because long-term results have not yet been obtained. We also speculate that precise dissection in the proper surgical plane likely minimized early erosions.