OBG Management

Most physicians know that migraine with aura is a risk factor for ischemic stroke and that the use of an estrogen-containing contraceptive further increases this risk.^1-3 Additional important and prevalent risk factors for ischemic stroke include cigarette smoking, hypertension, diabetes, and ischemic heart disease.¹ The American College of Obstetricians and Gynecologists (ACOG)² and the Centers for Disease Control and Prevention (CDC)³ recommend against the use of estrogen-containing contraceptives for women with migraine with aura because of the increased risk of ischemic stroke (Medical Eligibility Criteria [MEC] category 4—unacceptable health risk, method not to be used).

However, those who have migraine with aura can use nonhormonal and progestin-only forms of contraception, including copper- and levonorgestrel-intrauterine devices, the etonogestrel subdermal implant, depot medroxyprogesterone acetate, and progestin-only pills (MEC category 1—no restriction).^2,3 ACOG and the CDC advise that estrogen-containing contraceptives can be used for those with migraine without aura who have no other risk factors for stroke (MEC category 2—advantages generally outweigh theoretical or proven risks).^2,3 Given the high prevalence of migraine in reproductive-age women, accurate diagnosis of aura is of paramount importance in order to provide appropriate contraceptive counseling.

When is migraine with aura the right diagnosis?

In clinical practice, there is a high level of confusion about the migraine symptoms that warrant a diagnosis of migraine with aura. One approach to improving the accuracy of such a diagnosis is to refer every woman seeking contraceptive counseling who has migraine headaches to a neurologist for expert adjudication of the presence or absence of aura. But in the clinical context of contraceptive counseling, neurology consultation is not always readily available, and requiring consultation increases barriers to care. However, there are tools—such as the Visual Aura Rating Scale (VARS), which is discussed below—that may help non-neurologists identify migraine with aura.⁴ First, let us review the data that links migraine with aura with increased risk of ischemic stroke.

Migraine with aura is a risk factor for stroke

Multiple case-control studies report that migraine with aura is a risk factor for ischemic stroke.^1,5,6 Studies also report that women with migraine with aura who use estrogen-containing contraceptives have an even greater risk of ischemic stroke. For example, one recent case-control study used a commercial claims database of 1,884 cases of ischemic stroke among individuals who identify as women 15 to 49 years of age matched to 7,536 controls without ischemic stroke.¹ In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR], 2.59), hypertension (aOR, 2.73), diabetes (aOR, 2.78), migraine with aura (aOR, 2.89), and ischemic heart disease (aOR, 5.49). For those with migraine with aura who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with migraine with aura who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with migraine without aura, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.

Continue to: Although women with migraine...

Although women with migraine with and without aura are at increased risk for stroke, the absolute risk is still very low. For example, one review reported that the incidence of ischemic stroke per 100,000 person-years among women 20 to 44 years of age was 2.5 for those without migraine not taking estrogen-containing contraceptives, 5.9 for those with migraine with aura not taking estrogen-containing contraceptives, and 14.5 among those with migraine with aura and taking estrogen-containing contraceptives.⁶ Another important observation is that the incidence of thrombotic stroke dramatically increases from adolescence (3.4 per 100,000 person-years) to 45-49 years of age (64.4 per 100,000 person-years).⁷ Therefore, older women with migraine are at greater risk for stroke than adolescents.

Diagnostic criteria for migraine with and without aura

In contraceptive counseling, if an estrogen-containing contraceptive is being considered, it is important to identify women with migraine headache, determine migraine subtype, assess the frequency of migraines and identify other cardiovascular risk factors, such as hypertension and cigarette smoking. The International Headache Society has evolved the diagnostic criteria for migraine with and without aura, and now endorses the criteria published in the 3rd edition of the International Classification of Headache Disorders (ICHD-3; TABLES 1 and 2).⁸ For non-neurologists, these criteria may be difficult to remember and impractical to utilize in daily contraceptive counseling. Two simplified tools, the ID Migraine Questionnaire⁹ and the Visual Aura Rating Scale (TABLE 3)⁴ may help identify women who have migraine headaches and assess for the presence of aura.

The ID Migraine Questionnaire

In a study of 563 people seeking primary care who had headaches in the past 3 months, 3 questions were identified as being helpful in identifying women with migraine. This 3-question screening tool had reasonable sensitivity (81%), specificity (75%), and positive predictive value (93%) compared with expert diagnosis using the ICHD-3.⁹ The 3 questions in this screening tool, which are answered “Yes” or “No,” are:

During the last 3 months did you have the following symptoms with your headaches:

1. Feel nauseated or sick to your stomach?
2. Light bothered you?
3. Your headaches limited your ability to work, study or do what you needed to do for at least 1 day?

If two questions are answered “Yes” the patient may have migraine headaches.

Visual Aura Rating Scale for the diagnosis of migraine with aura

More than 90% of women with migraine with aura have visual auras, leaving only a minority with non–visual aura, such as tingling or numbness in a limb, speech or language problems, or muscle weakness. Hence for non-neurologists, it is reasonable to focus on the accurate diagnosis of visual aura to identify those with migraine with aura.

In the clinical context of contraceptive counseling, the Visual Aura Rating Scale (VARS) is especially useful because it has good sensitivity and specificity, and it is easy to use in practice (TABLE 3).⁴ VARS assesses for 5 characteristics of a visual aura, and each characteristic is associated with a weighted risk score. The 5 symptoms assessed include:

1. duration of visual symptom between 5 and 60 minutes (3 points)
2. visual symptom develops gradually over 5 minutes (2 points)
3. scotoma (2 points)
4. zig-zag line (2 points)
5. unilateral (1 point).

Continue to: Of note, visual aura is usually...

Of note, visual aura is usually slow-spreading and persists for more than 5 minutes but less than 60 minutes. If a visual symptom has a sudden onset and persists for much longer than 60 minutes, concern is heightened for a more serious neurologic diagnosis such as transient ischemic attack or stroke. A summed score of 5 or more points supports the diagnosis of migraine with aura. In one study, VARS had a sensitivity of 91% and specificity of 96% for identifying women with migraine with aura diagnosed by the ICHD-3 criteria.⁴

Consider using VARS to identify migraine with aura

Epidemiologic studies report that about 17% of adults have migraine, and about 5% have migraine with aura.^10,11 Consequently, migraine with aura is one of the most common medical conditions encountered during contraceptive counseling. The CDC MEC recommend against the use of estrogen-containing contraceptives in women with migraine with aura (Category 4 rating). The VARS may help clinicians identify those who have migraine with aura who should not be offered estrogen-containing contraceptives. Equally important, the use of VARS could help reduce the number of women who are inappropriately diagnosed as having migraine with aura based on fleeting visual symptoms lasting far less than 5 minutes during a migraine headache.

Most physicians know that migraine with aura is a risk factor for ischemic stroke and that the use of an estrogen-containing contraceptive further increases this risk.^1-3 Additional important and prevalent risk factors for ischemic stroke include cigarette smoking, hypertension, diabetes, and ischemic heart disease.¹ The American College of Obstetricians and Gynecologists (ACOG)² and the Centers for Disease Control and Prevention (CDC)³ recommend against the use of estrogen-containing contraceptives for women with migraine with aura because of the increased risk of ischemic stroke (Medical Eligibility Criteria [MEC] category 4—unacceptable health risk, method not to be used).

However, those who have migraine with aura can use nonhormonal and progestin-only forms of contraception, including copper- and levonorgestrel-intrauterine devices, the etonogestrel subdermal implant, depot medroxyprogesterone acetate, and progestin-only pills (MEC category 1—no restriction).^2,3 ACOG and the CDC advise that estrogen-containing contraceptives can be used for those with migraine without aura who have no other risk factors for stroke (MEC category 2—advantages generally outweigh theoretical or proven risks).^2,3 Given the high prevalence of migraine in reproductive-age women, accurate diagnosis of aura is of paramount importance in order to provide appropriate contraceptive counseling.

When is migraine with aura the right diagnosis?

In clinical practice, there is a high level of confusion about the migraine symptoms that warrant a diagnosis of migraine with aura. One approach to improving the accuracy of such a diagnosis is to refer every woman seeking contraceptive counseling who has migraine headaches to a neurologist for expert adjudication of the presence or absence of aura. But in the clinical context of contraceptive counseling, neurology consultation is not always readily available, and requiring consultation increases barriers to care. However, there are tools—such as the Visual Aura Rating Scale (VARS), which is discussed below—that may help non-neurologists identify migraine with aura.⁴ First, let us review the data that links migraine with aura with increased risk of ischemic stroke.

Migraine with aura is a risk factor for stroke

Multiple case-control studies report that migraine with aura is a risk factor for ischemic stroke.^1,5,6 Studies also report that women with migraine with aura who use estrogen-containing contraceptives have an even greater risk of ischemic stroke. For example, one recent case-control study used a commercial claims database of 1,884 cases of ischemic stroke among individuals who identify as women 15 to 49 years of age matched to 7,536 controls without ischemic stroke.¹ In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR], 2.59), hypertension (aOR, 2.73), diabetes (aOR, 2.78), migraine with aura (aOR, 2.89), and ischemic heart disease (aOR, 5.49). For those with migraine with aura who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with migraine with aura who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with migraine without aura, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.

Continue to: Although women with migraine...

Although women with migraine with and without aura are at increased risk for stroke, the absolute risk is still very low. For example, one review reported that the incidence of ischemic stroke per 100,000 person-years among women 20 to 44 years of age was 2.5 for those without migraine not taking estrogen-containing contraceptives, 5.9 for those with migraine with aura not taking estrogen-containing contraceptives, and 14.5 among those with migraine with aura and taking estrogen-containing contraceptives.⁶ Another important observation is that the incidence of thrombotic stroke dramatically increases from adolescence (3.4 per 100,000 person-years) to 45-49 years of age (64.4 per 100,000 person-years).⁷ Therefore, older women with migraine are at greater risk for stroke than adolescents.

Diagnostic criteria for migraine with and without aura

In contraceptive counseling, if an estrogen-containing contraceptive is being considered, it is important to identify women with migraine headache, determine migraine subtype, assess the frequency of migraines and identify other cardiovascular risk factors, such as hypertension and cigarette smoking. The International Headache Society has evolved the diagnostic criteria for migraine with and without aura, and now endorses the criteria published in the 3rd edition of the International Classification of Headache Disorders (ICHD-3; TABLES 1 and 2).⁸ For non-neurologists, these criteria may be difficult to remember and impractical to utilize in daily contraceptive counseling. Two simplified tools, the ID Migraine Questionnaire⁹ and the Visual Aura Rating Scale (TABLE 3)⁴ may help identify women who have migraine headaches and assess for the presence of aura.

The ID Migraine Questionnaire

In a study of 563 people seeking primary care who had headaches in the past 3 months, 3 questions were identified as being helpful in identifying women with migraine. This 3-question screening tool had reasonable sensitivity (81%), specificity (75%), and positive predictive value (93%) compared with expert diagnosis using the ICHD-3.⁹ The 3 questions in this screening tool, which are answered “Yes” or “No,” are:

During the last 3 months did you have the following symptoms with your headaches:

1. Feel nauseated or sick to your stomach?
2. Light bothered you?
3. Your headaches limited your ability to work, study or do what you needed to do for at least 1 day?

If two questions are answered “Yes” the patient may have migraine headaches.

Visual Aura Rating Scale for the diagnosis of migraine with aura

More than 90% of women with migraine with aura have visual auras, leaving only a minority with non–visual aura, such as tingling or numbness in a limb, speech or language problems, or muscle weakness. Hence for non-neurologists, it is reasonable to focus on the accurate diagnosis of visual aura to identify those with migraine with aura.

In the clinical context of contraceptive counseling, the Visual Aura Rating Scale (VARS) is especially useful because it has good sensitivity and specificity, and it is easy to use in practice (TABLE 3).⁴ VARS assesses for 5 characteristics of a visual aura, and each characteristic is associated with a weighted risk score. The 5 symptoms assessed include:

1. duration of visual symptom between 5 and 60 minutes (3 points)
2. visual symptom develops gradually over 5 minutes (2 points)
3. scotoma (2 points)
4. zig-zag line (2 points)
5. unilateral (1 point).

Continue to: Of note, visual aura is usually...

Of note, visual aura is usually slow-spreading and persists for more than 5 minutes but less than 60 minutes. If a visual symptom has a sudden onset and persists for much longer than 60 minutes, concern is heightened for a more serious neurologic diagnosis such as transient ischemic attack or stroke. A summed score of 5 or more points supports the diagnosis of migraine with aura. In one study, VARS had a sensitivity of 91% and specificity of 96% for identifying women with migraine with aura diagnosed by the ICHD-3 criteria.⁴

Consider using VARS to identify migraine with aura

Epidemiologic studies report that about 17% of adults have migraine, and about 5% have migraine with aura.^10,11 Consequently, migraine with aura is one of the most common medical conditions encountered during contraceptive counseling. The CDC MEC recommend against the use of estrogen-containing contraceptives in women with migraine with aura (Category 4 rating). The VARS may help clinicians identify those who have migraine with aura who should not be offered estrogen-containing contraceptives. Equally important, the use of VARS could help reduce the number of women who are inappropriately diagnosed as having migraine with aura based on fleeting visual symptoms lasting far less than 5 minutes during a migraine headache.

Most physicians know that migraine with aura is a risk factor for ischemic stroke and that the use of an estrogen-containing contraceptive further increases this risk.^1-3 Additional important and prevalent risk factors for ischemic stroke include cigarette smoking, hypertension, diabetes, and ischemic heart disease.¹ The American College of Obstetricians and Gynecologists (ACOG)² and the Centers for Disease Control and Prevention (CDC)³ recommend against the use of estrogen-containing contraceptives for women with migraine with aura because of the increased risk of ischemic stroke (Medical Eligibility Criteria [MEC] category 4—unacceptable health risk, method not to be used).

However, those who have migraine with aura can use nonhormonal and progestin-only forms of contraception, including copper- and levonorgestrel-intrauterine devices, the etonogestrel subdermal implant, depot medroxyprogesterone acetate, and progestin-only pills (MEC category 1—no restriction).^2,3 ACOG and the CDC advise that estrogen-containing contraceptives can be used for those with migraine without aura who have no other risk factors for stroke (MEC category 2—advantages generally outweigh theoretical or proven risks).^2,3 Given the high prevalence of migraine in reproductive-age women, accurate diagnosis of aura is of paramount importance in order to provide appropriate contraceptive counseling.

When is migraine with aura the right diagnosis?

In clinical practice, there is a high level of confusion about the migraine symptoms that warrant a diagnosis of migraine with aura. One approach to improving the accuracy of such a diagnosis is to refer every woman seeking contraceptive counseling who has migraine headaches to a neurologist for expert adjudication of the presence or absence of aura. But in the clinical context of contraceptive counseling, neurology consultation is not always readily available, and requiring consultation increases barriers to care. However, there are tools—such as the Visual Aura Rating Scale (VARS), which is discussed below—that may help non-neurologists identify migraine with aura.⁴ First, let us review the data that links migraine with aura with increased risk of ischemic stroke.

Migraine with aura is a risk factor for stroke

Multiple case-control studies report that migraine with aura is a risk factor for ischemic stroke.^1,5,6 Studies also report that women with migraine with aura who use estrogen-containing contraceptives have an even greater risk of ischemic stroke. For example, one recent case-control study used a commercial claims database of 1,884 cases of ischemic stroke among individuals who identify as women 15 to 49 years of age matched to 7,536 controls without ischemic stroke.¹ In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR], 2.59), hypertension (aOR, 2.73), diabetes (aOR, 2.78), migraine with aura (aOR, 2.89), and ischemic heart disease (aOR, 5.49). For those with migraine with aura who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with migraine with aura who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with migraine without aura, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.

Continue to: Although women with migraine...

Although women with migraine with and without aura are at increased risk for stroke, the absolute risk is still very low. For example, one review reported that the incidence of ischemic stroke per 100,000 person-years among women 20 to 44 years of age was 2.5 for those without migraine not taking estrogen-containing contraceptives, 5.9 for those with migraine with aura not taking estrogen-containing contraceptives, and 14.5 among those with migraine with aura and taking estrogen-containing contraceptives.⁶ Another important observation is that the incidence of thrombotic stroke dramatically increases from adolescence (3.4 per 100,000 person-years) to 45-49 years of age (64.4 per 100,000 person-years).⁷ Therefore, older women with migraine are at greater risk for stroke than adolescents.

Diagnostic criteria for migraine with and without aura

In contraceptive counseling, if an estrogen-containing contraceptive is being considered, it is important to identify women with migraine headache, determine migraine subtype, assess the frequency of migraines and identify other cardiovascular risk factors, such as hypertension and cigarette smoking. The International Headache Society has evolved the diagnostic criteria for migraine with and without aura, and now endorses the criteria published in the 3rd edition of the International Classification of Headache Disorders (ICHD-3; TABLES 1 and 2).⁸ For non-neurologists, these criteria may be difficult to remember and impractical to utilize in daily contraceptive counseling. Two simplified tools, the ID Migraine Questionnaire⁹ and the Visual Aura Rating Scale (TABLE 3)⁴ may help identify women who have migraine headaches and assess for the presence of aura.

The ID Migraine Questionnaire

In a study of 563 people seeking primary care who had headaches in the past 3 months, 3 questions were identified as being helpful in identifying women with migraine. This 3-question screening tool had reasonable sensitivity (81%), specificity (75%), and positive predictive value (93%) compared with expert diagnosis using the ICHD-3.⁹ The 3 questions in this screening tool, which are answered “Yes” or “No,” are:

During the last 3 months did you have the following symptoms with your headaches:

1. Feel nauseated or sick to your stomach?
2. Light bothered you?
3. Your headaches limited your ability to work, study or do what you needed to do for at least 1 day?

If two questions are answered “Yes” the patient may have migraine headaches.

Visual Aura Rating Scale for the diagnosis of migraine with aura

More than 90% of women with migraine with aura have visual auras, leaving only a minority with non–visual aura, such as tingling or numbness in a limb, speech or language problems, or muscle weakness. Hence for non-neurologists, it is reasonable to focus on the accurate diagnosis of visual aura to identify those with migraine with aura.

In the clinical context of contraceptive counseling, the Visual Aura Rating Scale (VARS) is especially useful because it has good sensitivity and specificity, and it is easy to use in practice (TABLE 3).⁴ VARS assesses for 5 characteristics of a visual aura, and each characteristic is associated with a weighted risk score. The 5 symptoms assessed include:

1. duration of visual symptom between 5 and 60 minutes (3 points)
2. visual symptom develops gradually over 5 minutes (2 points)
3. scotoma (2 points)
4. zig-zag line (2 points)
5. unilateral (1 point).

Continue to: Of note, visual aura is usually...

Of note, visual aura is usually slow-spreading and persists for more than 5 minutes but less than 60 minutes. If a visual symptom has a sudden onset and persists for much longer than 60 minutes, concern is heightened for a more serious neurologic diagnosis such as transient ischemic attack or stroke. A summed score of 5 or more points supports the diagnosis of migraine with aura. In one study, VARS had a sensitivity of 91% and specificity of 96% for identifying women with migraine with aura diagnosed by the ICHD-3 criteria.⁴

Consider using VARS to identify migraine with aura

Epidemiologic studies report that about 17% of adults have migraine, and about 5% have migraine with aura.^10,11 Consequently, migraine with aura is one of the most common medical conditions encountered during contraceptive counseling. The CDC MEC recommend against the use of estrogen-containing contraceptives in women with migraine with aura (Category 4 rating). The VARS may help clinicians identify those who have migraine with aura who should not be offered estrogen-containing contraceptives. Equally important, the use of VARS could help reduce the number of women who are inappropriately diagnosed as having migraine with aura based on fleeting visual symptoms lasting far less than 5 minutes during a migraine headache.

In a recent systematic review, Fink and colleagues attempted to summarize the published evidence of the efficacy and safety of long-term (> 3 years) therapy for osteoporosis.¹ Unfortunately, they arrived at very limited and tentative conclusions because, as they point out, of the paucity of such evidence.

Why long-term studies stop short

Only 3 of the several tens of placebo-controlled fracture end-point studies (about 58 trials and observational studies) that Fink and colleagues reviewed evaluated treatment for more than 3 years. The nonavailability of longer-term studies is the direct consequence of a requirement by regulatory agencies for a 3-year fracture end-point study in order to register a new drug for osteoporosis. Hence, longer, placebo-controlled studies do not benefit the industry sponsor, and enrolling patients with osteoporosis or who are at high risk for fracture in any, much less long, placebo-controlled trials is now considered to be unethical.

What the authors did observe

From this limited set of information with which to evaluate, Fink and colleagues observed that long-term therapy with raloxifene reduces the risk of vertebral fractures but is associated with thromboembolic complications. In addition, treatment for more than 3 years with bisphosphonates reduces the risk of vertebral and nonvertebral fractures but may increase risk of rare adverse events (including femoral shaft fractures with atypical radiographic features).

The bisphosphonate holiday. The authors refer to the even more limited evidence about the effects of discontinuing bisphosphonate therapy. Unlike the rapid loss of bone mass density (BMD) and fracture protection upon stopping estrogen or denosumab, the offset of these treatment benefits is slower when bisphosphonates are discontinued. This, coupled with concern about increasing risk with long-term bisphosphonate therapy, led to the confusing concept of a “bisphosphonate holiday.” While recommendations to consider temporary discontinuation of bisphosphonates in patients at low risk for fracture have been made by expert panels,² very little information exists about the benefits/risks of this strategy, how long the treatment interruption should be, or how to decide when and with what to restart therapy. Unfortunately, overall, Fink and colleagues’ observations provide little practical guidance for clinicians.

Continue to: What we can learn from longer term and recent studies of ideal treatment...

What we can learn from longer term and recent studies of ideal treatment

Since we have no “cure” for osteoporosis, and since the benefits of therapy, including protection from fractures, abate upon stopping treatment (as they do when we stop treating hypertension or diabetes), very long term if not lifelong management is required for patients with osteoporosis. Persistent or even greater reduction of fracture risk with treatment up to 10 years, compared with the rate of fracture in the placebo or treated group during the first 3 years of the study, has been observed with zoledronate and denosumab.^3-5 Denosumab was not included in the systematic review by Fink and colleagues since the pivotal fracture trial with that agent was placebo-controlled for only 3 years.⁶

Sequential drug treatment may be best. Fink and colleagues also did not consider new evidence, which suggests that the use of osteoporosis drugs in sequence—rather than a single agent for a long time—may be the most effective management strategy.^7,8

More consideration should be given to the use of estrogen and raloxifene in younger postmenopausal women at risk for vertebral but not hip fracture.

Only treat high-risk patients. Using osteoporosis therapies to only treat patients at high risk for fracture will optimize the benefit:risk ratio and cost-effectiveness of therapy.

Bisphosphonate holidays may not be as important as once thought. BMD and fracture risk reduction does not improve after 5 years of bisphosphonate therapy, and longer treatment may increase the risk of atypical fractures, while switching to another agent can increase BMD and perhaps mitigate the safety concern, suggesting that there is little justification for continuous use of bisphosphonates for more than 5 years, thereby minimizing the importance of a bisphosphonate holiday.

Hip BMD may serve as indicator for treatment decisions. Recent evidence indicating that the change in hip BMD with treatment or the level of hip BMD achieved on treatment correlates with fracture risk reduction may provide a useful clinical target to guide treatment decisions.^9,10

Because we have a lack of pristine evidence does not mean that we shouldn’t treat osteoporosis; we have to do the best we can with the limited evidence we have. Therapy must be individualized, for we are not just treating osteoporosis, we are treating patients with osteoporosis.

In a recent systematic review, Fink and colleagues attempted to summarize the published evidence of the efficacy and safety of long-term (> 3 years) therapy for osteoporosis.¹ Unfortunately, they arrived at very limited and tentative conclusions because, as they point out, of the paucity of such evidence.

Why long-term studies stop short

Only 3 of the several tens of placebo-controlled fracture end-point studies (about 58 trials and observational studies) that Fink and colleagues reviewed evaluated treatment for more than 3 years. The nonavailability of longer-term studies is the direct consequence of a requirement by regulatory agencies for a 3-year fracture end-point study in order to register a new drug for osteoporosis. Hence, longer, placebo-controlled studies do not benefit the industry sponsor, and enrolling patients with osteoporosis or who are at high risk for fracture in any, much less long, placebo-controlled trials is now considered to be unethical.

What the authors did observe

From this limited set of information with which to evaluate, Fink and colleagues observed that long-term therapy with raloxifene reduces the risk of vertebral fractures but is associated with thromboembolic complications. In addition, treatment for more than 3 years with bisphosphonates reduces the risk of vertebral and nonvertebral fractures but may increase risk of rare adverse events (including femoral shaft fractures with atypical radiographic features).

The bisphosphonate holiday. The authors refer to the even more limited evidence about the effects of discontinuing bisphosphonate therapy. Unlike the rapid loss of bone mass density (BMD) and fracture protection upon stopping estrogen or denosumab, the offset of these treatment benefits is slower when bisphosphonates are discontinued. This, coupled with concern about increasing risk with long-term bisphosphonate therapy, led to the confusing concept of a “bisphosphonate holiday.” While recommendations to consider temporary discontinuation of bisphosphonates in patients at low risk for fracture have been made by expert panels,² very little information exists about the benefits/risks of this strategy, how long the treatment interruption should be, or how to decide when and with what to restart therapy. Unfortunately, overall, Fink and colleagues’ observations provide little practical guidance for clinicians.

Continue to: What we can learn from longer term and recent studies of ideal treatment...

What we can learn from longer term and recent studies of ideal treatment

Since we have no “cure” for osteoporosis, and since the benefits of therapy, including protection from fractures, abate upon stopping treatment (as they do when we stop treating hypertension or diabetes), very long term if not lifelong management is required for patients with osteoporosis. Persistent or even greater reduction of fracture risk with treatment up to 10 years, compared with the rate of fracture in the placebo or treated group during the first 3 years of the study, has been observed with zoledronate and denosumab.^3-5 Denosumab was not included in the systematic review by Fink and colleagues since the pivotal fracture trial with that agent was placebo-controlled for only 3 years.⁶

Sequential drug treatment may be best. Fink and colleagues also did not consider new evidence, which suggests that the use of osteoporosis drugs in sequence—rather than a single agent for a long time—may be the most effective management strategy.^7,8

More consideration should be given to the use of estrogen and raloxifene in younger postmenopausal women at risk for vertebral but not hip fracture.

Only treat high-risk patients. Using osteoporosis therapies to only treat patients at high risk for fracture will optimize the benefit:risk ratio and cost-effectiveness of therapy.

Bisphosphonate holidays may not be as important as once thought. BMD and fracture risk reduction does not improve after 5 years of bisphosphonate therapy, and longer treatment may increase the risk of atypical fractures, while switching to another agent can increase BMD and perhaps mitigate the safety concern, suggesting that there is little justification for continuous use of bisphosphonates for more than 5 years, thereby minimizing the importance of a bisphosphonate holiday.

Hip BMD may serve as indicator for treatment decisions. Recent evidence indicating that the change in hip BMD with treatment or the level of hip BMD achieved on treatment correlates with fracture risk reduction may provide a useful clinical target to guide treatment decisions.^9,10

Because we have a lack of pristine evidence does not mean that we shouldn’t treat osteoporosis; we have to do the best we can with the limited evidence we have. Therapy must be individualized, for we are not just treating osteoporosis, we are treating patients with osteoporosis.

In a recent systematic review, Fink and colleagues attempted to summarize the published evidence of the efficacy and safety of long-term (> 3 years) therapy for osteoporosis.¹ Unfortunately, they arrived at very limited and tentative conclusions because, as they point out, of the paucity of such evidence.

Why long-term studies stop short

Only 3 of the several tens of placebo-controlled fracture end-point studies (about 58 trials and observational studies) that Fink and colleagues reviewed evaluated treatment for more than 3 years. The nonavailability of longer-term studies is the direct consequence of a requirement by regulatory agencies for a 3-year fracture end-point study in order to register a new drug for osteoporosis. Hence, longer, placebo-controlled studies do not benefit the industry sponsor, and enrolling patients with osteoporosis or who are at high risk for fracture in any, much less long, placebo-controlled trials is now considered to be unethical.

What the authors did observe

From this limited set of information with which to evaluate, Fink and colleagues observed that long-term therapy with raloxifene reduces the risk of vertebral fractures but is associated with thromboembolic complications. In addition, treatment for more than 3 years with bisphosphonates reduces the risk of vertebral and nonvertebral fractures but may increase risk of rare adverse events (including femoral shaft fractures with atypical radiographic features).

The bisphosphonate holiday. The authors refer to the even more limited evidence about the effects of discontinuing bisphosphonate therapy. Unlike the rapid loss of bone mass density (BMD) and fracture protection upon stopping estrogen or denosumab, the offset of these treatment benefits is slower when bisphosphonates are discontinued. This, coupled with concern about increasing risk with long-term bisphosphonate therapy, led to the confusing concept of a “bisphosphonate holiday.” While recommendations to consider temporary discontinuation of bisphosphonates in patients at low risk for fracture have been made by expert panels,² very little information exists about the benefits/risks of this strategy, how long the treatment interruption should be, or how to decide when and with what to restart therapy. Unfortunately, overall, Fink and colleagues’ observations provide little practical guidance for clinicians.

Continue to: What we can learn from longer term and recent studies of ideal treatment...

What we can learn from longer term and recent studies of ideal treatment

Since we have no “cure” for osteoporosis, and since the benefits of therapy, including protection from fractures, abate upon stopping treatment (as they do when we stop treating hypertension or diabetes), very long term if not lifelong management is required for patients with osteoporosis. Persistent or even greater reduction of fracture risk with treatment up to 10 years, compared with the rate of fracture in the placebo or treated group during the first 3 years of the study, has been observed with zoledronate and denosumab.^3-5 Denosumab was not included in the systematic review by Fink and colleagues since the pivotal fracture trial with that agent was placebo-controlled for only 3 years.⁶

Sequential drug treatment may be best. Fink and colleagues also did not consider new evidence, which suggests that the use of osteoporosis drugs in sequence—rather than a single agent for a long time—may be the most effective management strategy.^7,8

More consideration should be given to the use of estrogen and raloxifene in younger postmenopausal women at risk for vertebral but not hip fracture.

Only treat high-risk patients. Using osteoporosis therapies to only treat patients at high risk for fracture will optimize the benefit:risk ratio and cost-effectiveness of therapy.

Bisphosphonate holidays may not be as important as once thought. BMD and fracture risk reduction does not improve after 5 years of bisphosphonate therapy, and longer treatment may increase the risk of atypical fractures, while switching to another agent can increase BMD and perhaps mitigate the safety concern, suggesting that there is little justification for continuous use of bisphosphonates for more than 5 years, thereby minimizing the importance of a bisphosphonate holiday.

Hip BMD may serve as indicator for treatment decisions. Recent evidence indicating that the change in hip BMD with treatment or the level of hip BMD achieved on treatment correlates with fracture risk reduction may provide a useful clinical target to guide treatment decisions.^9,10

Because we have a lack of pristine evidence does not mean that we shouldn’t treat osteoporosis; we have to do the best we can with the limited evidence we have. Therapy must be individualized, for we are not just treating osteoporosis, we are treating patients with osteoporosis.

De Vivo V, Carbone L, Saccone G, et al. Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol. 2019. doi: 10.1016/j.ajog.2019.07.049.

EXPERT COMMENTARY

Induction of labor has doubled over the past 2 decades, with almost 25% of parturients currently undergoing induction in the United States.¹ Labor induction at term is associated with perinatal outcomes similar to those with spontaneous labor, without an increase in the CD rate.^1-3 Although numerous methods for cervical ripening have been evaluated, the safest and most effective method has yet to be determined.²

Amniotomy—or artificial rupture of membranes (AROM)—has long been used as a technique for labor induction and for augmentation in women in spontaneous labor. Purported benefits include an increased responsiveness to exogenous oxytocin, decreased interval to delivery, and an increased likelihood of spontaneous vaginal delivery. Risks of amniotomy include injury to the fetus or surrounding tissues, bleeding, nonreassuring fetal testing, cord prolapse, and prolonged rupture of membranes (defined as longer than 18 hours), which is a risk factor for intra-amniotic infection.

The optimal timing of amniotomy is not known. The recent study by De Vivo and colleagues was designed to better understand the risk/benefit ratio of early amniotomy after cervical ripening in women undergoing induction of labor.

Details of the study

The authors conducted a systematic review and meta-analysis that included 1,273 women in 4 randomized controlled trials to determine the effectiveness of routine early amniotomy versus late amniotomy/spontaneous rupture of membranes after cervical ripening (with either a Foley catheter or prostaglandins) in women with a singleton vertex fetus undergoing induction of labor in the term or late preterm period.

Early amniotomy was defined as AROM “soon after cervical ripening” (cases); late amniotomy was defined as AROM after the active phase of labor or spontaneous rupture of membranes (controls).

The primary outcome was the incidence of CD. Secondary outcomes included the overall length of labor, latency from induction to delivery, and neonatal morbidity (a composite of birth weight, Apgar scores, meconium-stained amniotic fluid, neonatal sepsis, need for resuscitation, and admission to the neonatal intensive care unit).

Continue to: Findings...

Findings. Women randomly assigned to early amniotomy had a similar risk of CD compared with controls (31.1% vs 30.9% [relative risk (RR), 1.05; 95% confidence interval (CI), 0.71–1.56]) and a shorter interval from induction to delivery of about 5 hours (mean difference, -4.95 hours [95% CI, -8.12 to -1.78]).

There was no difference in any of the secondary outcome measures, although the number of events was small. Specifically, there was no significant difference in rates of chorioamnionitis between the early and late amniotomy cohorts (7.3% vs 4.8% [RR, 1.47; 95% CI, 0.95–2.28]).

Study strengths and limitations

This is the first systematic review to evaluate early versus late amniotomy after cervical ripening for induction of labor. “Systematic review and meta-analysis” is not synonymous with a review of the literature. It has its own methodology and is regarded as original research. A strength of this study is that it was performed by a highly credible team who followed established Cochrane and PRISMA methodological and reporting guidelines.

Study weaknesses include the fact that the meta-analysis contained a relatively small number of trials and study participants. It was significantly underpowered to address issues related to neonatal outcome. The 4 trials included were highly variable in terms of maternal parity and indications for labor induction and CD. The definition of “early amniotomy” was inconsistent, and the overall rate of CD varied greatly among the studies (7.9%–41.1%). Multiple pregnancies were excluded. Taken together, these findings may have limited generalizability.

De Vivo V, Carbone L, Saccone G, et al. Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol. 2019. doi: 10.1016/j.ajog.2019.07.049.

EXPERT COMMENTARY

Induction of labor has doubled over the past 2 decades, with almost 25% of parturients currently undergoing induction in the United States.¹ Labor induction at term is associated with perinatal outcomes similar to those with spontaneous labor, without an increase in the CD rate.^1-3 Although numerous methods for cervical ripening have been evaluated, the safest and most effective method has yet to be determined.²

Amniotomy—or artificial rupture of membranes (AROM)—has long been used as a technique for labor induction and for augmentation in women in spontaneous labor. Purported benefits include an increased responsiveness to exogenous oxytocin, decreased interval to delivery, and an increased likelihood of spontaneous vaginal delivery. Risks of amniotomy include injury to the fetus or surrounding tissues, bleeding, nonreassuring fetal testing, cord prolapse, and prolonged rupture of membranes (defined as longer than 18 hours), which is a risk factor for intra-amniotic infection.

The optimal timing of amniotomy is not known. The recent study by De Vivo and colleagues was designed to better understand the risk/benefit ratio of early amniotomy after cervical ripening in women undergoing induction of labor.

Details of the study

The authors conducted a systematic review and meta-analysis that included 1,273 women in 4 randomized controlled trials to determine the effectiveness of routine early amniotomy versus late amniotomy/spontaneous rupture of membranes after cervical ripening (with either a Foley catheter or prostaglandins) in women with a singleton vertex fetus undergoing induction of labor in the term or late preterm period.

Early amniotomy was defined as AROM “soon after cervical ripening” (cases); late amniotomy was defined as AROM after the active phase of labor or spontaneous rupture of membranes (controls).

The primary outcome was the incidence of CD. Secondary outcomes included the overall length of labor, latency from induction to delivery, and neonatal morbidity (a composite of birth weight, Apgar scores, meconium-stained amniotic fluid, neonatal sepsis, need for resuscitation, and admission to the neonatal intensive care unit).

Continue to: Findings...

Findings. Women randomly assigned to early amniotomy had a similar risk of CD compared with controls (31.1% vs 30.9% [relative risk (RR), 1.05; 95% confidence interval (CI), 0.71–1.56]) and a shorter interval from induction to delivery of about 5 hours (mean difference, -4.95 hours [95% CI, -8.12 to -1.78]).

There was no difference in any of the secondary outcome measures, although the number of events was small. Specifically, there was no significant difference in rates of chorioamnionitis between the early and late amniotomy cohorts (7.3% vs 4.8% [RR, 1.47; 95% CI, 0.95–2.28]).

Study strengths and limitations

This is the first systematic review to evaluate early versus late amniotomy after cervical ripening for induction of labor. “Systematic review and meta-analysis” is not synonymous with a review of the literature. It has its own methodology and is regarded as original research. A strength of this study is that it was performed by a highly credible team who followed established Cochrane and PRISMA methodological and reporting guidelines.

Study weaknesses include the fact that the meta-analysis contained a relatively small number of trials and study participants. It was significantly underpowered to address issues related to neonatal outcome. The 4 trials included were highly variable in terms of maternal parity and indications for labor induction and CD. The definition of “early amniotomy” was inconsistent, and the overall rate of CD varied greatly among the studies (7.9%–41.1%). Multiple pregnancies were excluded. Taken together, these findings may have limited generalizability.

De Vivo V, Carbone L, Saccone G, et al. Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol. 2019. doi: 10.1016/j.ajog.2019.07.049.

EXPERT COMMENTARY

Induction of labor has doubled over the past 2 decades, with almost 25% of parturients currently undergoing induction in the United States.¹ Labor induction at term is associated with perinatal outcomes similar to those with spontaneous labor, without an increase in the CD rate.^1-3 Although numerous methods for cervical ripening have been evaluated, the safest and most effective method has yet to be determined.²

Amniotomy—or artificial rupture of membranes (AROM)—has long been used as a technique for labor induction and for augmentation in women in spontaneous labor. Purported benefits include an increased responsiveness to exogenous oxytocin, decreased interval to delivery, and an increased likelihood of spontaneous vaginal delivery. Risks of amniotomy include injury to the fetus or surrounding tissues, bleeding, nonreassuring fetal testing, cord prolapse, and prolonged rupture of membranes (defined as longer than 18 hours), which is a risk factor for intra-amniotic infection.

The optimal timing of amniotomy is not known. The recent study by De Vivo and colleagues was designed to better understand the risk/benefit ratio of early amniotomy after cervical ripening in women undergoing induction of labor.

Details of the study

The authors conducted a systematic review and meta-analysis that included 1,273 women in 4 randomized controlled trials to determine the effectiveness of routine early amniotomy versus late amniotomy/spontaneous rupture of membranes after cervical ripening (with either a Foley catheter or prostaglandins) in women with a singleton vertex fetus undergoing induction of labor in the term or late preterm period.

Early amniotomy was defined as AROM “soon after cervical ripening” (cases); late amniotomy was defined as AROM after the active phase of labor or spontaneous rupture of membranes (controls).

The primary outcome was the incidence of CD. Secondary outcomes included the overall length of labor, latency from induction to delivery, and neonatal morbidity (a composite of birth weight, Apgar scores, meconium-stained amniotic fluid, neonatal sepsis, need for resuscitation, and admission to the neonatal intensive care unit).

Continue to: Findings...

Findings. Women randomly assigned to early amniotomy had a similar risk of CD compared with controls (31.1% vs 30.9% [relative risk (RR), 1.05; 95% confidence interval (CI), 0.71–1.56]) and a shorter interval from induction to delivery of about 5 hours (mean difference, -4.95 hours [95% CI, -8.12 to -1.78]).

There was no difference in any of the secondary outcome measures, although the number of events was small. Specifically, there was no significant difference in rates of chorioamnionitis between the early and late amniotomy cohorts (7.3% vs 4.8% [RR, 1.47; 95% CI, 0.95–2.28]).

Study strengths and limitations

This is the first systematic review to evaluate early versus late amniotomy after cervical ripening for induction of labor. “Systematic review and meta-analysis” is not synonymous with a review of the literature. It has its own methodology and is regarded as original research. A strength of this study is that it was performed by a highly credible team who followed established Cochrane and PRISMA methodological and reporting guidelines.

Study weaknesses include the fact that the meta-analysis contained a relatively small number of trials and study participants. It was significantly underpowered to address issues related to neonatal outcome. The 4 trials included were highly variable in terms of maternal parity and indications for labor induction and CD. The definition of “early amniotomy” was inconsistent, and the overall rate of CD varied greatly among the studies (7.9%–41.1%). Multiple pregnancies were excluded. Taken together, these findings may have limited generalizability.

CASE Patient has adverse effects from halted estrogen pills

JR twists her hands nervously as you step into the room. “They stopped my hormones,” she sighs as you pull up her lab results.

JR recently had been admitted to an inpatient cardiology unit for several days for a heart failure exacerbation. Her ankles are still swollen beneath her floral print skirt, but she is breathing much easier now. She is back at your primary care office, hoping to get clearance to restart her estrogen pills.

JR reports having mood swings and terrible nightmares while not taking her hormones, which she has been taking for more than 3 years. She hesitates before sharing, “One of the doctors kept asking me questions about my sex life that had nothing to do with my heart condition. I don’t want to go back there.”

Providing compassionate and comprehensive care to gender-nonconforming individuals is challenging for a multitude of reasons, from clinician ignorance to systemic discrimination. About 33% of transgender patients reported being harassed, denied care, or even being assaulted when seeking health care, while 23% reported avoiding going to the doctor altogether when sick or injured out of fear of discrimination.¹

Unfortunately, now, further increases to barriers to care may be put in place. In late May of this year, the Department of Health and Human Services (HHS) proposed new regulations that would reverse previous regulations granted through section 1557 of the Affordable Care Act (ACA)—the Health Care Rights Law—which affirmed the rights of gender nonbinary persons to medical care. Among the proposed changes is the elimination of protections against discrimination in health care based on gender identity.² The proposed regulation changes come on the heels of a federal court case, which seeks to declare that hospital systems may turn away patients based on gender identity.³

Unraveling rights afforded under the ACA

The Health Care Rights Law was passed under the ACA; it prohibits discrimination based on race, color, national origin, sex, age, and disability in health programs and activities receiving federal financial assistance. Multiple lower courts have supported that the rights of transgender individuals is included within these protections against discrimination on the basis of sex.⁴ These court rulings not only have ensured the ability of gender-diverse individuals to access care but also have enforced insurance coverage of therapies for gender dysphoria. It was only in 2014 that Medicaid began providing coverage for gender-affirming surgeries and eliminating language that such procedures were “experimental” or “cosmetic.” The 2016 passage of the ACA mandated that private insurance companies follow suit. Unfortunately, the recent proposed regulation changes to the Health Care Rights Law may spark a reversal from insurance companies as well. Such a setback would affect gender-diverse individuals’ hormone treatments as well as their ability to access a full spectrum of care within the health care system.

Continue to: ACOG urges nondiscriminatory practices...

ACOG urges nondiscriminatory practices

The proposed regulation changes to the Health Care Rights Law are from the Conscience and Religious Freedom Division of the HHS Office for Civil Rights, which was established in 2018 and has been advocating for the rights of health care providers to refuse to treat patients based on their own religious beliefs.⁵ We argue, however, that providing care to persons of varying backgrounds is not an assault on our individual liberties but rather a privilege as providers. As obstetrician-gynecologists, it may be easy to only consider cis-gendered women our responsibility. But our field also emphasizes individual empowerment above all else—we fight every day for our patients’ rights to contraception, fertility, pregnancy, parenthood, and sexual freedoms. Let us continue speaking up for the rights of all those who need gynecologic care, regardless of the pronouns they use.

“The American College of Obstetricians and Gynecologists urges health care providers to foster nondiscriminatory practices and policies to increase identification and to facilitate quality health care for transgender individuals, both in assisting with the transition if desired as well as providing long-term preventive health care.”⁶

We urge you to take action

• Reach out to your local representatives about protecting transgender health access
• Educate yourself on the unique needs of transgender individuals
• Read personal accounts
• Share your personal story
• Find referring providers near your practice

CASE Patient has adverse effects from halted estrogen pills

JR twists her hands nervously as you step into the room. “They stopped my hormones,” she sighs as you pull up her lab results.

JR recently had been admitted to an inpatient cardiology unit for several days for a heart failure exacerbation. Her ankles are still swollen beneath her floral print skirt, but she is breathing much easier now. She is back at your primary care office, hoping to get clearance to restart her estrogen pills.

JR reports having mood swings and terrible nightmares while not taking her hormones, which she has been taking for more than 3 years. She hesitates before sharing, “One of the doctors kept asking me questions about my sex life that had nothing to do with my heart condition. I don’t want to go back there.”

Providing compassionate and comprehensive care to gender-nonconforming individuals is challenging for a multitude of reasons, from clinician ignorance to systemic discrimination. About 33% of transgender patients reported being harassed, denied care, or even being assaulted when seeking health care, while 23% reported avoiding going to the doctor altogether when sick or injured out of fear of discrimination.¹

Unfortunately, now, further increases to barriers to care may be put in place. In late May of this year, the Department of Health and Human Services (HHS) proposed new regulations that would reverse previous regulations granted through section 1557 of the Affordable Care Act (ACA)—the Health Care Rights Law—which affirmed the rights of gender nonbinary persons to medical care. Among the proposed changes is the elimination of protections against discrimination in health care based on gender identity.² The proposed regulation changes come on the heels of a federal court case, which seeks to declare that hospital systems may turn away patients based on gender identity.³

Unraveling rights afforded under the ACA

The Health Care Rights Law was passed under the ACA; it prohibits discrimination based on race, color, national origin, sex, age, and disability in health programs and activities receiving federal financial assistance. Multiple lower courts have supported that the rights of transgender individuals is included within these protections against discrimination on the basis of sex.⁴ These court rulings not only have ensured the ability of gender-diverse individuals to access care but also have enforced insurance coverage of therapies for gender dysphoria. It was only in 2014 that Medicaid began providing coverage for gender-affirming surgeries and eliminating language that such procedures were “experimental” or “cosmetic.” The 2016 passage of the ACA mandated that private insurance companies follow suit. Unfortunately, the recent proposed regulation changes to the Health Care Rights Law may spark a reversal from insurance companies as well. Such a setback would affect gender-diverse individuals’ hormone treatments as well as their ability to access a full spectrum of care within the health care system.

Continue to: ACOG urges nondiscriminatory practices...

ACOG urges nondiscriminatory practices

The proposed regulation changes to the Health Care Rights Law are from the Conscience and Religious Freedom Division of the HHS Office for Civil Rights, which was established in 2018 and has been advocating for the rights of health care providers to refuse to treat patients based on their own religious beliefs.⁵ We argue, however, that providing care to persons of varying backgrounds is not an assault on our individual liberties but rather a privilege as providers. As obstetrician-gynecologists, it may be easy to only consider cis-gendered women our responsibility. But our field also emphasizes individual empowerment above all else—we fight every day for our patients’ rights to contraception, fertility, pregnancy, parenthood, and sexual freedoms. Let us continue speaking up for the rights of all those who need gynecologic care, regardless of the pronouns they use.

“The American College of Obstetricians and Gynecologists urges health care providers to foster nondiscriminatory practices and policies to increase identification and to facilitate quality health care for transgender individuals, both in assisting with the transition if desired as well as providing long-term preventive health care.”⁶

We urge you to take action

• Reach out to your local representatives about protecting transgender health access
• Educate yourself on the unique needs of transgender individuals
• Read personal accounts
• Share your personal story
• Find referring providers near your practice

CASE Patient has adverse effects from halted estrogen pills

JR twists her hands nervously as you step into the room. “They stopped my hormones,” she sighs as you pull up her lab results.

JR recently had been admitted to an inpatient cardiology unit for several days for a heart failure exacerbation. Her ankles are still swollen beneath her floral print skirt, but she is breathing much easier now. She is back at your primary care office, hoping to get clearance to restart her estrogen pills.

JR reports having mood swings and terrible nightmares while not taking her hormones, which she has been taking for more than 3 years. She hesitates before sharing, “One of the doctors kept asking me questions about my sex life that had nothing to do with my heart condition. I don’t want to go back there.”

Providing compassionate and comprehensive care to gender-nonconforming individuals is challenging for a multitude of reasons, from clinician ignorance to systemic discrimination. About 33% of transgender patients reported being harassed, denied care, or even being assaulted when seeking health care, while 23% reported avoiding going to the doctor altogether when sick or injured out of fear of discrimination.¹

Unfortunately, now, further increases to barriers to care may be put in place. In late May of this year, the Department of Health and Human Services (HHS) proposed new regulations that would reverse previous regulations granted through section 1557 of the Affordable Care Act (ACA)—the Health Care Rights Law—which affirmed the rights of gender nonbinary persons to medical care. Among the proposed changes is the elimination of protections against discrimination in health care based on gender identity.² The proposed regulation changes come on the heels of a federal court case, which seeks to declare that hospital systems may turn away patients based on gender identity.³

Unraveling rights afforded under the ACA

The Health Care Rights Law was passed under the ACA; it prohibits discrimination based on race, color, national origin, sex, age, and disability in health programs and activities receiving federal financial assistance. Multiple lower courts have supported that the rights of transgender individuals is included within these protections against discrimination on the basis of sex.⁴ These court rulings not only have ensured the ability of gender-diverse individuals to access care but also have enforced insurance coverage of therapies for gender dysphoria. It was only in 2014 that Medicaid began providing coverage for gender-affirming surgeries and eliminating language that such procedures were “experimental” or “cosmetic.” The 2016 passage of the ACA mandated that private insurance companies follow suit. Unfortunately, the recent proposed regulation changes to the Health Care Rights Law may spark a reversal from insurance companies as well. Such a setback would affect gender-diverse individuals’ hormone treatments as well as their ability to access a full spectrum of care within the health care system.

Continue to: ACOG urges nondiscriminatory practices...

ACOG urges nondiscriminatory practices

The proposed regulation changes to the Health Care Rights Law are from the Conscience and Religious Freedom Division of the HHS Office for Civil Rights, which was established in 2018 and has been advocating for the rights of health care providers to refuse to treat patients based on their own religious beliefs.⁵ We argue, however, that providing care to persons of varying backgrounds is not an assault on our individual liberties but rather a privilege as providers. As obstetrician-gynecologists, it may be easy to only consider cis-gendered women our responsibility. But our field also emphasizes individual empowerment above all else—we fight every day for our patients’ rights to contraception, fertility, pregnancy, parenthood, and sexual freedoms. Let us continue speaking up for the rights of all those who need gynecologic care, regardless of the pronouns they use.

“The American College of Obstetricians and Gynecologists urges health care providers to foster nondiscriminatory practices and policies to increase identification and to facilitate quality health care for transgender individuals, both in assisting with the transition if desired as well as providing long-term preventive health care.”⁶

We urge you to take action

• Reach out to your local representatives about protecting transgender health access
• Educate yourself on the unique needs of transgender individuals
• Read personal accounts
• Share your personal story
• Find referring providers near your practice

In 2015, 1.2% of the US population was estimated to have active epilepsy.¹ For neurologists, key goals in the treatment of epilepsy include: controlling seizures, minimizing adverse effects of antiepileptic drugs (AEDs) and optimizing quality of life. For obstetrician-gynecologists, women with epilepsy (WWE) have unique contraceptive, preconception, and obstetric needs that require highly specialized approaches to care. Here, I highlight 5 care points that are important to keep in mind when counseling WWE.  

1. Enzyme-inducing AEDs reduce the effectiveness of estrogen-progestin and some progestin contraceptives. 

AEDs can induce hepatic enzymes that accelerate steroid hormone metabolism, producing clinically important reductions in bioavailable steroid hormone concentration (TABLE 1). According to Lexicomp, AEDs that are inducers of hepatic enzymes that metabolize steroid hormones include: carbamazepine (Tegretol), eslicarbazepine (Aptiom), felbamate (Felbatol), oxcarbazepine (Trileptal), perampanel (Fycompa), phenobarbital, phenytoin (Dilantin), primidone (Mysoline), rufinamide (Banzel), and topiramate (Topamax) (at dosages >200 mg daily). According to Lexicomp, the following AEDs do not cause clinically significant changes in hepatic enzymes that metabolize steroid hormones: acetazolamide (Diamox), clonazepam (Klonopin), ethosuximide (Zarontin), gabapentin (Neurontin), lacosamide (Vimpat), levetiracetam (Keppra), pregabalin (Lyrica), tiagabine (Gabitril), vigabatrin (Vigadrone), and zonisamide (Zonegran).^2,3 In addition, lamotrigine (Lamictal) and valproate (Depakote) do not significantly influence the metabolism of contraceptive steroids,^4,5 but contraceptive steroids significantly influence their metabolism (TABLE 2). 

For WWE taking an AED that accelerates steroid hormone metabolism, estrogen-progestin contraceptive failure is common. In a survey of 111 WWE taking both an oral contraceptive and an AED, 27 reported becoming pregnant while taking the oral contraceptive.⁶ Carbamazepine, a strong inducer of hepatic enzymes, was the most frequently used AED in this sample.  

Many studies report that carbamazepine accelerates the metabolisms of estrogen and progestins and reduces contraceptive efficacy. For example, in one study 20 healthy women were administered an ethinyl estradiol (20 µg)-levonorgestrel (100 µg) contraceptive, and randomly assigned to either receive carbamazepine 600 mg daily or a placebo pill.⁷ In this study, based on serum progesterone measurements, 5 of 10 women in the carbamazepine group ovulated, compared with 1 of 10 women in the placebo group. Women taking carbamazepine had integrated serum ethinyl estradiol and levonorgestrel concentrations approximately 45% lower than women taking placebo.⁷ Other studies also report that carbamazepine accelerates steroid hormone metabolism and reduces the circulating concentration of ethinyl estradiol, norethindrone, and levonorgestrel by about 50%.^5,8  

WWE taking an AED that induces hepatic enzymes should be counseled to use a copper or levonorgestrel (LNG) intrauterine device (IUD) or depot medroxyprogesterone acetate (DMPA) for contraception.⁹ WWE taking AEDs that do not induce hepatic enzymes can be offered the full array of contraceptive options, as outlined in Table 1.  Occasionally, a WWE taking an AED that is an inducer of hepatic enzymes may strongly prefer to use an estrogen-progestin contraceptive and decline the preferred option of using an IUD or DMPA. If an estrogen-progestin contraceptive is to be prescribed, safeguards to reduce the risk of pregnancy include:  

• prescribe a contraceptive with ≥35 µg of ethinyl estradiol  
• prescribe a contraceptive with the highest dose of progestin with a long half-life (drospirenone, desogestrel, levonorgestrel)  
• consider continuous hormonal contraception rather than 4 or 7 days off hormones and  
• recommend use of a barrier contraceptive in addition to the hormonal contraceptive. 

The effectiveness of levonorgestrel emergency contraception may also be reduced in WWE taking an enzyme-inducing AED. In these cases, some experts recommend a regimen of two doses of levonorgestrel 1.5 mg, separated by 12 hours.¹⁰ The effectiveness of progestin subdermal contraceptives may be reduced in women taking phenytoin. In one study of 9 WWE using a progestin subdermal implant, phenytoin reduced the circulating levonorgestrel level by approximately 40%.¹¹  

Continue to: 2. Do not use lamotrigine with cyclic estrogen-progestin contraceptives...

2. Do not use lamotrigine with cyclic estrogen-progestin contraceptives. 

Estrogens, but not progestins, are known to reduce the serum concentration of lamotrigine by about 50%.^12,13 This is a clinically significant pharmacologic interaction. Consequently, when a cyclic estrogen-progestin contraceptive is prescribed to a woman taking lamotrigine, oscillation in lamotrigine serum concentration can occur. When the woman is taking estrogen-containing pills, lamotrigine levels decrease, which increases the risk of seizure. When the woman is not taking the estrogen-containing pills, lamotrigine levels increase, possibly causing such adverse effects as nausea and vomiting. If a woman taking lamotrigine insists on using an estrogen-progestin contraceptive, the medication should be prescribed in a continuous regimen and the neurologist alerted so that they can increase the dose of lamotrigine and intensify their monitoring of lamotrigine levels. Lamotrigine does not change the metabolism of ethinyl estradiol and has minimal impact on the metabolism of levonorgestrel.⁴  

3. Estrogen-progestin contraceptives require valproate dosage adjustment. 

A few studies report that estrogen-progestin contraceptives accelerate the metabolism of valproate and reduce circulating valproate concentration,^14,15 as noted in Table 2.In one study, estrogen-progestin contraceptive was associated with 18% and 29% decreases in total and unbound valproate concentrations, respectively.¹⁴ Valproate may induce polycystic ovary syndrome in women.¹⁶ Therefore, it is common that valproate and an estrogen-progestin contraceptive are co-prescribed. In these situations, the neurologist should be alerted prior to prescribing an estrogen-progestin contraceptive to WWE taking valproate so that dosage adjustment may occur, if indicated. Valproate does not appear to change the metabolism of ethinyl estradiol or levonorgestrel.⁵  

4. Preconception counseling: Before conception consider using an AED with low teratogenicity. 

Valproate is a potent teratogen, and consideration should be given to discontinuing valproate prior to conception. In a study of 1,788 pregnancies exposed to valproate, the risk of a major congenital malformation was 10% for valproate monotherapy, 11.3% for valproate combined with lamotrigine, and 11.7% for valproate combined with another AED, but not lamotrigine.¹⁷ At a valproate dose of ≥1,500 mg daily, the risk of major malformation was 24% for valproate monotherapy, 31% for valproate plus lamotrigine, and 19% for valproate plus another AED, but not lamotrigine.¹⁷ Valproate is reported to be associated with the following major congenital malformations: spina bifida, ventricular and atrial septal defects, pulmonary valve atresia, hypoplastic left heart syndrome, cleft palate, anorectal atresia, and hypospadias.¹⁸  

In a study of 7,555 pregnancies in women using a single AED, the risk of major congenital anomalies varied greatly among the AEDs, including: valproate (10.3%), phenobarbital (6.5%), phenytoin (6.4%), carbamazepine (5.5%), topiramate (3.9%), oxcarbazepine (3.0%), lamotrigine (2.9%), and levetiracetam (2.8%).¹⁹ For WWE considering pregnancy, many experts recommend use of lamotrigine, levetiracetam, or oxcarbazepine to minimize the risk of fetal anomalies.  

Continue to: 5. Folic acid...

5. Folic acid: Although the optimal dose for WWE taking an AED and planning to become pregnant is unknown, a high dose is reasonable. 

The American College of Obstetricians and Gynecologists (ACOG) recommends that women planning pregnancy take 0.4 mg of folic acid daily, starting at least 1 month before pregnancy and continuing through at least the 12th week of gestation.²⁰ ACOG also recommends that women at high risk of a neural tube defect should take 4 mg of folic acid daily. WWE taking a teratogenic AED are known to be at increased risk for fetal malformations, including neural tube defects. Should these women take 4 mg of folic acid daily? ACOG notes that, for women taking valproate, the benefit of high-dose folic acid (4 mg daily) has not been definitively proven,²¹ and guidelines from the American Academy of Neurology do not recommend high-dose folic acid for women receiving AEDs.22 Hence, ACOG does not recommend that WWE taking an AED take high-dose folic acid.  

By contrast, the Royal College of Obstetricians and Gynecologists (RCOG) recommends that all WWE planning a pregnancy take folic acid 5 mg daily, initiated 3 months before conception and continued through the first trimester of pregnancy.²³ The RCOG notes that among WWE taking an AED, intelligence quotient is greater in children whose mothers took folic acid during pregnancy.²⁴ Given the potential benefit of folic acid on long-term outcomes and the known safety of folic acid, it is reasonable to recommend high-dose folic acid for WWE. 

Final takeaways 

Surveys consistently report that WWE have a low-level of awareness about the interaction between AEDs and hormonal contraceptives and the teratogenicity of AEDs. For example, in a survey of 2,000 WWE, 45% who were taking an enzyme-inducing AED and an estrogen-progestin oral contraceptive reported that they had not been warned about the potential interaction between the medications.²⁵ Surprisingly, surveys of neurologists and obstetrician-gynecologists also report that there is a low level of awareness about the interaction between AEDs and hormonal contraceptives.²⁶ When providing contraceptive counseling for WWE, prioritize the use of a copper or levonorgestrel IUD. When providing preconception counseling for WWE, educate the patient about the high teratogenicity of valproate and the lower risk of malformations associated with the use of lamotrigine, levetiracetam, and oxcarbazepine.  
 

In 2015, 1.2% of the US population was estimated to have active epilepsy.¹ For neurologists, key goals in the treatment of epilepsy include: controlling seizures, minimizing adverse effects of antiepileptic drugs (AEDs) and optimizing quality of life. For obstetrician-gynecologists, women with epilepsy (WWE) have unique contraceptive, preconception, and obstetric needs that require highly specialized approaches to care. Here, I highlight 5 care points that are important to keep in mind when counseling WWE.  

1. Enzyme-inducing AEDs reduce the effectiveness of estrogen-progestin and some progestin contraceptives. 

AEDs can induce hepatic enzymes that accelerate steroid hormone metabolism, producing clinically important reductions in bioavailable steroid hormone concentration (TABLE 1). According to Lexicomp, AEDs that are inducers of hepatic enzymes that metabolize steroid hormones include: carbamazepine (Tegretol), eslicarbazepine (Aptiom), felbamate (Felbatol), oxcarbazepine (Trileptal), perampanel (Fycompa), phenobarbital, phenytoin (Dilantin), primidone (Mysoline), rufinamide (Banzel), and topiramate (Topamax) (at dosages >200 mg daily). According to Lexicomp, the following AEDs do not cause clinically significant changes in hepatic enzymes that metabolize steroid hormones: acetazolamide (Diamox), clonazepam (Klonopin), ethosuximide (Zarontin), gabapentin (Neurontin), lacosamide (Vimpat), levetiracetam (Keppra), pregabalin (Lyrica), tiagabine (Gabitril), vigabatrin (Vigadrone), and zonisamide (Zonegran).^2,3 In addition, lamotrigine (Lamictal) and valproate (Depakote) do not significantly influence the metabolism of contraceptive steroids,^4,5 but contraceptive steroids significantly influence their metabolism (TABLE 2). 

For WWE taking an AED that accelerates steroid hormone metabolism, estrogen-progestin contraceptive failure is common. In a survey of 111 WWE taking both an oral contraceptive and an AED, 27 reported becoming pregnant while taking the oral contraceptive.⁶ Carbamazepine, a strong inducer of hepatic enzymes, was the most frequently used AED in this sample.  

Many studies report that carbamazepine accelerates the metabolisms of estrogen and progestins and reduces contraceptive efficacy. For example, in one study 20 healthy women were administered an ethinyl estradiol (20 µg)-levonorgestrel (100 µg) contraceptive, and randomly assigned to either receive carbamazepine 600 mg daily or a placebo pill.⁷ In this study, based on serum progesterone measurements, 5 of 10 women in the carbamazepine group ovulated, compared with 1 of 10 women in the placebo group. Women taking carbamazepine had integrated serum ethinyl estradiol and levonorgestrel concentrations approximately 45% lower than women taking placebo.⁷ Other studies also report that carbamazepine accelerates steroid hormone metabolism and reduces the circulating concentration of ethinyl estradiol, norethindrone, and levonorgestrel by about 50%.^5,8  

WWE taking an AED that induces hepatic enzymes should be counseled to use a copper or levonorgestrel (LNG) intrauterine device (IUD) or depot medroxyprogesterone acetate (DMPA) for contraception.⁹ WWE taking AEDs that do not induce hepatic enzymes can be offered the full array of contraceptive options, as outlined in Table 1.  Occasionally, a WWE taking an AED that is an inducer of hepatic enzymes may strongly prefer to use an estrogen-progestin contraceptive and decline the preferred option of using an IUD or DMPA. If an estrogen-progestin contraceptive is to be prescribed, safeguards to reduce the risk of pregnancy include:  

• prescribe a contraceptive with ≥35 µg of ethinyl estradiol  
• prescribe a contraceptive with the highest dose of progestin with a long half-life (drospirenone, desogestrel, levonorgestrel)  
• consider continuous hormonal contraception rather than 4 or 7 days off hormones and  
• recommend use of a barrier contraceptive in addition to the hormonal contraceptive. 

The effectiveness of levonorgestrel emergency contraception may also be reduced in WWE taking an enzyme-inducing AED. In these cases, some experts recommend a regimen of two doses of levonorgestrel 1.5 mg, separated by 12 hours.¹⁰ The effectiveness of progestin subdermal contraceptives may be reduced in women taking phenytoin. In one study of 9 WWE using a progestin subdermal implant, phenytoin reduced the circulating levonorgestrel level by approximately 40%.¹¹  

Continue to: 2. Do not use lamotrigine with cyclic estrogen-progestin contraceptives...

2. Do not use lamotrigine with cyclic estrogen-progestin contraceptives. 

Estrogens, but not progestins, are known to reduce the serum concentration of lamotrigine by about 50%.^12,13 This is a clinically significant pharmacologic interaction. Consequently, when a cyclic estrogen-progestin contraceptive is prescribed to a woman taking lamotrigine, oscillation in lamotrigine serum concentration can occur. When the woman is taking estrogen-containing pills, lamotrigine levels decrease, which increases the risk of seizure. When the woman is not taking the estrogen-containing pills, lamotrigine levels increase, possibly causing such adverse effects as nausea and vomiting. If a woman taking lamotrigine insists on using an estrogen-progestin contraceptive, the medication should be prescribed in a continuous regimen and the neurologist alerted so that they can increase the dose of lamotrigine and intensify their monitoring of lamotrigine levels. Lamotrigine does not change the metabolism of ethinyl estradiol and has minimal impact on the metabolism of levonorgestrel.⁴  

3. Estrogen-progestin contraceptives require valproate dosage adjustment. 

A few studies report that estrogen-progestin contraceptives accelerate the metabolism of valproate and reduce circulating valproate concentration,^14,15 as noted in Table 2.In one study, estrogen-progestin contraceptive was associated with 18% and 29% decreases in total and unbound valproate concentrations, respectively.¹⁴ Valproate may induce polycystic ovary syndrome in women.¹⁶ Therefore, it is common that valproate and an estrogen-progestin contraceptive are co-prescribed. In these situations, the neurologist should be alerted prior to prescribing an estrogen-progestin contraceptive to WWE taking valproate so that dosage adjustment may occur, if indicated. Valproate does not appear to change the metabolism of ethinyl estradiol or levonorgestrel.⁵  

4. Preconception counseling: Before conception consider using an AED with low teratogenicity. 

Valproate is a potent teratogen, and consideration should be given to discontinuing valproate prior to conception. In a study of 1,788 pregnancies exposed to valproate, the risk of a major congenital malformation was 10% for valproate monotherapy, 11.3% for valproate combined with lamotrigine, and 11.7% for valproate combined with another AED, but not lamotrigine.¹⁷ At a valproate dose of ≥1,500 mg daily, the risk of major malformation was 24% for valproate monotherapy, 31% for valproate plus lamotrigine, and 19% for valproate plus another AED, but not lamotrigine.¹⁷ Valproate is reported to be associated with the following major congenital malformations: spina bifida, ventricular and atrial septal defects, pulmonary valve atresia, hypoplastic left heart syndrome, cleft palate, anorectal atresia, and hypospadias.¹⁸  

In a study of 7,555 pregnancies in women using a single AED, the risk of major congenital anomalies varied greatly among the AEDs, including: valproate (10.3%), phenobarbital (6.5%), phenytoin (6.4%), carbamazepine (5.5%), topiramate (3.9%), oxcarbazepine (3.0%), lamotrigine (2.9%), and levetiracetam (2.8%).¹⁹ For WWE considering pregnancy, many experts recommend use of lamotrigine, levetiracetam, or oxcarbazepine to minimize the risk of fetal anomalies.  

Continue to: 5. Folic acid...

5. Folic acid: Although the optimal dose for WWE taking an AED and planning to become pregnant is unknown, a high dose is reasonable. 

The American College of Obstetricians and Gynecologists (ACOG) recommends that women planning pregnancy take 0.4 mg of folic acid daily, starting at least 1 month before pregnancy and continuing through at least the 12th week of gestation.²⁰ ACOG also recommends that women at high risk of a neural tube defect should take 4 mg of folic acid daily. WWE taking a teratogenic AED are known to be at increased risk for fetal malformations, including neural tube defects. Should these women take 4 mg of folic acid daily? ACOG notes that, for women taking valproate, the benefit of high-dose folic acid (4 mg daily) has not been definitively proven,²¹ and guidelines from the American Academy of Neurology do not recommend high-dose folic acid for women receiving AEDs.22 Hence, ACOG does not recommend that WWE taking an AED take high-dose folic acid.  

By contrast, the Royal College of Obstetricians and Gynecologists (RCOG) recommends that all WWE planning a pregnancy take folic acid 5 mg daily, initiated 3 months before conception and continued through the first trimester of pregnancy.²³ The RCOG notes that among WWE taking an AED, intelligence quotient is greater in children whose mothers took folic acid during pregnancy.²⁴ Given the potential benefit of folic acid on long-term outcomes and the known safety of folic acid, it is reasonable to recommend high-dose folic acid for WWE. 

Final takeaways 

Surveys consistently report that WWE have a low-level of awareness about the interaction between AEDs and hormonal contraceptives and the teratogenicity of AEDs. For example, in a survey of 2,000 WWE, 45% who were taking an enzyme-inducing AED and an estrogen-progestin oral contraceptive reported that they had not been warned about the potential interaction between the medications.²⁵ Surprisingly, surveys of neurologists and obstetrician-gynecologists also report that there is a low level of awareness about the interaction between AEDs and hormonal contraceptives.²⁶ When providing contraceptive counseling for WWE, prioritize the use of a copper or levonorgestrel IUD. When providing preconception counseling for WWE, educate the patient about the high teratogenicity of valproate and the lower risk of malformations associated with the use of lamotrigine, levetiracetam, and oxcarbazepine.  
 

In 2015, 1.2% of the US population was estimated to have active epilepsy.¹ For neurologists, key goals in the treatment of epilepsy include: controlling seizures, minimizing adverse effects of antiepileptic drugs (AEDs) and optimizing quality of life. For obstetrician-gynecologists, women with epilepsy (WWE) have unique contraceptive, preconception, and obstetric needs that require highly specialized approaches to care. Here, I highlight 5 care points that are important to keep in mind when counseling WWE.  

1. Enzyme-inducing AEDs reduce the effectiveness of estrogen-progestin and some progestin contraceptives. 

AEDs can induce hepatic enzymes that accelerate steroid hormone metabolism, producing clinically important reductions in bioavailable steroid hormone concentration (TABLE 1). According to Lexicomp, AEDs that are inducers of hepatic enzymes that metabolize steroid hormones include: carbamazepine (Tegretol), eslicarbazepine (Aptiom), felbamate (Felbatol), oxcarbazepine (Trileptal), perampanel (Fycompa), phenobarbital, phenytoin (Dilantin), primidone (Mysoline), rufinamide (Banzel), and topiramate (Topamax) (at dosages >200 mg daily). According to Lexicomp, the following AEDs do not cause clinically significant changes in hepatic enzymes that metabolize steroid hormones: acetazolamide (Diamox), clonazepam (Klonopin), ethosuximide (Zarontin), gabapentin (Neurontin), lacosamide (Vimpat), levetiracetam (Keppra), pregabalin (Lyrica), tiagabine (Gabitril), vigabatrin (Vigadrone), and zonisamide (Zonegran).^2,3 In addition, lamotrigine (Lamictal) and valproate (Depakote) do not significantly influence the metabolism of contraceptive steroids,^4,5 but contraceptive steroids significantly influence their metabolism (TABLE 2). 

For WWE taking an AED that accelerates steroid hormone metabolism, estrogen-progestin contraceptive failure is common. In a survey of 111 WWE taking both an oral contraceptive and an AED, 27 reported becoming pregnant while taking the oral contraceptive.⁶ Carbamazepine, a strong inducer of hepatic enzymes, was the most frequently used AED in this sample.  

Many studies report that carbamazepine accelerates the metabolisms of estrogen and progestins and reduces contraceptive efficacy. For example, in one study 20 healthy women were administered an ethinyl estradiol (20 µg)-levonorgestrel (100 µg) contraceptive, and randomly assigned to either receive carbamazepine 600 mg daily or a placebo pill.⁷ In this study, based on serum progesterone measurements, 5 of 10 women in the carbamazepine group ovulated, compared with 1 of 10 women in the placebo group. Women taking carbamazepine had integrated serum ethinyl estradiol and levonorgestrel concentrations approximately 45% lower than women taking placebo.⁷ Other studies also report that carbamazepine accelerates steroid hormone metabolism and reduces the circulating concentration of ethinyl estradiol, norethindrone, and levonorgestrel by about 50%.^5,8  

WWE taking an AED that induces hepatic enzymes should be counseled to use a copper or levonorgestrel (LNG) intrauterine device (IUD) or depot medroxyprogesterone acetate (DMPA) for contraception.⁹ WWE taking AEDs that do not induce hepatic enzymes can be offered the full array of contraceptive options, as outlined in Table 1.  Occasionally, a WWE taking an AED that is an inducer of hepatic enzymes may strongly prefer to use an estrogen-progestin contraceptive and decline the preferred option of using an IUD or DMPA. If an estrogen-progestin contraceptive is to be prescribed, safeguards to reduce the risk of pregnancy include:  

• prescribe a contraceptive with ≥35 µg of ethinyl estradiol  
• prescribe a contraceptive with the highest dose of progestin with a long half-life (drospirenone, desogestrel, levonorgestrel)  
• consider continuous hormonal contraception rather than 4 or 7 days off hormones and  
• recommend use of a barrier contraceptive in addition to the hormonal contraceptive. 

The effectiveness of levonorgestrel emergency contraception may also be reduced in WWE taking an enzyme-inducing AED. In these cases, some experts recommend a regimen of two doses of levonorgestrel 1.5 mg, separated by 12 hours.¹⁰ The effectiveness of progestin subdermal contraceptives may be reduced in women taking phenytoin. In one study of 9 WWE using a progestin subdermal implant, phenytoin reduced the circulating levonorgestrel level by approximately 40%.¹¹  

Continue to: 2. Do not use lamotrigine with cyclic estrogen-progestin contraceptives...

2. Do not use lamotrigine with cyclic estrogen-progestin contraceptives. 

Estrogens, but not progestins, are known to reduce the serum concentration of lamotrigine by about 50%.^12,13 This is a clinically significant pharmacologic interaction. Consequently, when a cyclic estrogen-progestin contraceptive is prescribed to a woman taking lamotrigine, oscillation in lamotrigine serum concentration can occur. When the woman is taking estrogen-containing pills, lamotrigine levels decrease, which increases the risk of seizure. When the woman is not taking the estrogen-containing pills, lamotrigine levels increase, possibly causing such adverse effects as nausea and vomiting. If a woman taking lamotrigine insists on using an estrogen-progestin contraceptive, the medication should be prescribed in a continuous regimen and the neurologist alerted so that they can increase the dose of lamotrigine and intensify their monitoring of lamotrigine levels. Lamotrigine does not change the metabolism of ethinyl estradiol and has minimal impact on the metabolism of levonorgestrel.⁴  

3. Estrogen-progestin contraceptives require valproate dosage adjustment. 

A few studies report that estrogen-progestin contraceptives accelerate the metabolism of valproate and reduce circulating valproate concentration,^14,15 as noted in Table 2.In one study, estrogen-progestin contraceptive was associated with 18% and 29% decreases in total and unbound valproate concentrations, respectively.¹⁴ Valproate may induce polycystic ovary syndrome in women.¹⁶ Therefore, it is common that valproate and an estrogen-progestin contraceptive are co-prescribed. In these situations, the neurologist should be alerted prior to prescribing an estrogen-progestin contraceptive to WWE taking valproate so that dosage adjustment may occur, if indicated. Valproate does not appear to change the metabolism of ethinyl estradiol or levonorgestrel.⁵  

4. Preconception counseling: Before conception consider using an AED with low teratogenicity. 

Valproate is a potent teratogen, and consideration should be given to discontinuing valproate prior to conception. In a study of 1,788 pregnancies exposed to valproate, the risk of a major congenital malformation was 10% for valproate monotherapy, 11.3% for valproate combined with lamotrigine, and 11.7% for valproate combined with another AED, but not lamotrigine.¹⁷ At a valproate dose of ≥1,500 mg daily, the risk of major malformation was 24% for valproate monotherapy, 31% for valproate plus lamotrigine, and 19% for valproate plus another AED, but not lamotrigine.¹⁷ Valproate is reported to be associated with the following major congenital malformations: spina bifida, ventricular and atrial septal defects, pulmonary valve atresia, hypoplastic left heart syndrome, cleft palate, anorectal atresia, and hypospadias.¹⁸  

In a study of 7,555 pregnancies in women using a single AED, the risk of major congenital anomalies varied greatly among the AEDs, including: valproate (10.3%), phenobarbital (6.5%), phenytoin (6.4%), carbamazepine (5.5%), topiramate (3.9%), oxcarbazepine (3.0%), lamotrigine (2.9%), and levetiracetam (2.8%).¹⁹ For WWE considering pregnancy, many experts recommend use of lamotrigine, levetiracetam, or oxcarbazepine to minimize the risk of fetal anomalies.  

Continue to: 5. Folic acid...

5. Folic acid: Although the optimal dose for WWE taking an AED and planning to become pregnant is unknown, a high dose is reasonable. 

The American College of Obstetricians and Gynecologists (ACOG) recommends that women planning pregnancy take 0.4 mg of folic acid daily, starting at least 1 month before pregnancy and continuing through at least the 12th week of gestation.²⁰ ACOG also recommends that women at high risk of a neural tube defect should take 4 mg of folic acid daily. WWE taking a teratogenic AED are known to be at increased risk for fetal malformations, including neural tube defects. Should these women take 4 mg of folic acid daily? ACOG notes that, for women taking valproate, the benefit of high-dose folic acid (4 mg daily) has not been definitively proven,²¹ and guidelines from the American Academy of Neurology do not recommend high-dose folic acid for women receiving AEDs.22 Hence, ACOG does not recommend that WWE taking an AED take high-dose folic acid.  

By contrast, the Royal College of Obstetricians and Gynecologists (RCOG) recommends that all WWE planning a pregnancy take folic acid 5 mg daily, initiated 3 months before conception and continued through the first trimester of pregnancy.²³ The RCOG notes that among WWE taking an AED, intelligence quotient is greater in children whose mothers took folic acid during pregnancy.²⁴ Given the potential benefit of folic acid on long-term outcomes and the known safety of folic acid, it is reasonable to recommend high-dose folic acid for WWE. 

Final takeaways 

Surveys consistently report that WWE have a low-level of awareness about the interaction between AEDs and hormonal contraceptives and the teratogenicity of AEDs. For example, in a survey of 2,000 WWE, 45% who were taking an enzyme-inducing AED and an estrogen-progestin oral contraceptive reported that they had not been warned about the potential interaction between the medications.²⁵ Surprisingly, surveys of neurologists and obstetrician-gynecologists also report that there is a low level of awareness about the interaction between AEDs and hormonal contraceptives.²⁶ When providing contraceptive counseling for WWE, prioritize the use of a copper or levonorgestrel IUD. When providing preconception counseling for WWE, educate the patient about the high teratogenicity of valproate and the lower risk of malformations associated with the use of lamotrigine, levetiracetam, and oxcarbazepine.