Opinion

Question: Choose the best answer regarding physician-assisted suicide in the United States:

A. It is now legal in most states.

B. Under California law, assisting or causing one to commit suicide, including physician-assisted suicide, still remains a felony.

C. Both the U.S. Supreme Court and the New York Court of Appeals have held there is no constitutional right to physician-assisted suicide.

D. The American Medical Association is neutral on the issue.

E. Pain relief is the overriding reason for patients who request physician-assisted suicide.

Answer: C. We reviewed this topic in one of our regular columns in 2013.¹ At that time, efforts to legalize physician-assisted suicide (PAS) appeared to be gathering momentum across the country, with four jurisdictions having legalized the practice, beginning with Oregon in 1994. The other states were Washington, Vermont, and Montana, whose Supreme Court held that there was no public interest reason against the practice.²

Since that time, California, Colorado, and the District of Columbia have joined the group. Currently, PAS – but not euthanasia – is legally available in these jurisdictions and in Switzerland, but both can be legally practiced in Belgium, Canada, Colombia, Luxembourg, and the Netherlands.

All state statutes permitting PAS provide similar provisions and safeguards. Only competent individuals who are terminally ill, i.e., death expected within 6 months, can make a request for a lethal dose of medication to carry out the suicidal act. The request to the doctor is first made verbally, then in writing, and a second opinion must be obtained to confirm the patient’s intent, understanding, and free choice. There is also a waiting period.

Public support for euthanasia and PAS in the United States is said to have plateaued since the 1990s. But a significant number of Americans, 67%, still favor PAS, up from 56% a decade ago.³ However, not many patients resort to PAS – usually those with terminal cancers or neuromuscular conditions – and only a minority of physicians are participants.

For example, 61 physicians in Oregon wrote a total of 115 prescriptions in 2012; there were 77 known Death With Dignity Act deaths in Oregon that year.⁴ In Oregon and Washington State, less than 1% of licensed physicians write prescriptions for physician-assisted suicide each year. In contrast, about half or more of physicians in the Netherlands and Belgium reported ever having received a request, and 60% of Dutch physicians have granted such requests.

The California Department of Public Health reported that 111 terminally ill patients availed themselves of California’s End of Life Option Act in the 7 months after it became effective on June 9, 2016.

In a recent review on euthanasia and PAS for the period 1947-2016, Ezekiel Emanuel, MD, and colleagues noted that typical patients were older, white, and well educated, and pain was mostly not reported as the primary motivation.⁵ A large portion of patients receiving PAS in Oregon and Washington were enrolled in hospice or palliative care. Abuses have not been apparent.

In the vast majority of jurisdictions, assisting or causing one to commit suicide, including PAS, still remains a crime; for example, it is considered manslaughter under Hawaii state law §707-702.

In distinguishing between assisting suicide and withdrawing life-sustaining treatment, the U.S. Supreme Court’s landmark 1997 Vacco v. Quill decision emphasized issues of causation and intent.⁶ On causation, the court reasoned that when a patient refuses life-sustaining treatment, he dies from an underlying fatal disease; but if a patient ingests a lethal medication, he is killed by that medication. As to intent, a physician who honors a patient’s refusal of treatment purposefully intends only to respect his patient’s wishes and to cease doing futile or degrading things. On the other hand, a doctor who assists a suicide “must, necessarily and indubitably, intend primarily that the patient be made dead.”

In its companion case Washington v. Glucksberg, the Supreme Court held that the asserted “right” to assistance in committing suicide is not a fundamental liberty interest protected by the due process clause.⁷

State supreme courts in Florida, New Mexico, and elsewhere have likewise rebuffed claims of any constitutional right to PAS. The latest court to so rule is in New York, which has a long history of criminalizing assisted suicide.⁸ The New York Court of Appeals recently addressed claims brought by three terminally ill individuals, several medical providers, and a nonprofit entity seeking a declaration that New York’s “assisted suicide” statutes exclude physicians from prescribing a lethal dose of drugs to terminally ill, competent patients.

The court unequivocally rejected such claims and affirmed that a physician who assists a suicide by prescribing lethal doses of drugs is subject to criminal prosecution for second-degree manslaughter. It refused to regard PAS as being different from assisted suicide in general, and it rejected the constitutional claim to assisted suicide by a terminally ill person. The state appeals court reiterated the U.S. Supreme Court’s distinction between refusing life-sustaining treatment and assisted suicide, the former being “at least partially rooted in notions of bodily integrity, as the right to refuse treatment is a consequence of a person’s right to resist unwanted bodily invasions.” The New York Court of Appeals also noted that the state has a legitimate purpose and a rational basis for guarding against the risks of mistake and abuse.

These developments may signal a shift away from the legalization of PAS, as recently suggested in a Washington Post article.⁹ According to the end-of-life advocacy organization Compassion and Choices, none of the 27 states where such measures were introduced in 2017 passed them into law, including states such as Connecticut, Hawaii, and Rhode Island. In Central and Eastern Europe, support is decreasing, whereas the opposite is true in Western Europe.

U.S. federal lawmakers also appear to be pushing back. On July 13, 2017, the U.S. House Committee on Appropriations voted to block implementation of a “death with dignity” statute passed by the District of Columbia. Further, 11 House members – including 6 Democrats – have introduced a resolution asserting that PAS undermines a key safeguard that protects our nation’s most vulnerable citizens, including the elderly, people with disabilities, and people experiencing psychiatric diagnoses.¹⁰

The American Medical Association is steadfast in its opposition to PAS and euthanasia. In its latest Code of Ethics, the AMA reaffirmed its long-held position that “allowing physicians to engage in assisted suicide would cause more harm than good. Physician-assisted suicide is fundamentally incompatible with the physician’s role as healer, would be difficult or impossible to control, and would pose serious societal risks. … Instead of participating in assisted suicide, physicians must aggressively respond to the needs of patients at the end of life.”¹¹

 

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from earlier columns in Internal Medicine News. For additional information, readers may contact the author at [email protected].

References

1. “Physician-assisted suicide,” Internal Medicine News, Oct. 14, 2013.

2. Baxter v. State of Montana, 224 P. 3d 1211 (2010).

3. “Majority of Americans Remain Supportive of Euthanasia,” Gallup News, June 12, 2017.

4. Statistics available at public.health.oregon.gov under Oregon Death with Dignity Act.

5. JAMA. 2016 Jul 5;316(1):79-90.

6. Vacco v. Quill, 117 S. Ct. 2293 (1997).

7. Washington v. Glucksberg, 521 U.S. 702 (1997).

8. Myers v. Schneiderman, New York Court of Appeals, 2017.

9. “Legalizing assisted suicide has stalled at every level,” Washington Post, Oct. 24, 2017.

10. H. Con. Res. 80, 115th Congress (2017-2018).

11. AMA Code of Medical Ethics §5.7 (2017).

Question: Choose the best answer regarding physician-assisted suicide in the United States:

A. It is now legal in most states.

B. Under California law, assisting or causing one to commit suicide, including physician-assisted suicide, still remains a felony.

C. Both the U.S. Supreme Court and the New York Court of Appeals have held there is no constitutional right to physician-assisted suicide.

D. The American Medical Association is neutral on the issue.

E. Pain relief is the overriding reason for patients who request physician-assisted suicide.

Answer: C. We reviewed this topic in one of our regular columns in 2013.¹ At that time, efforts to legalize physician-assisted suicide (PAS) appeared to be gathering momentum across the country, with four jurisdictions having legalized the practice, beginning with Oregon in 1994. The other states were Washington, Vermont, and Montana, whose Supreme Court held that there was no public interest reason against the practice.²

Since that time, California, Colorado, and the District of Columbia have joined the group. Currently, PAS – but not euthanasia – is legally available in these jurisdictions and in Switzerland, but both can be legally practiced in Belgium, Canada, Colombia, Luxembourg, and the Netherlands.

All state statutes permitting PAS provide similar provisions and safeguards. Only competent individuals who are terminally ill, i.e., death expected within 6 months, can make a request for a lethal dose of medication to carry out the suicidal act. The request to the doctor is first made verbally, then in writing, and a second opinion must be obtained to confirm the patient’s intent, understanding, and free choice. There is also a waiting period.

Public support for euthanasia and PAS in the United States is said to have plateaued since the 1990s. But a significant number of Americans, 67%, still favor PAS, up from 56% a decade ago.³ However, not many patients resort to PAS – usually those with terminal cancers or neuromuscular conditions – and only a minority of physicians are participants.

For example, 61 physicians in Oregon wrote a total of 115 prescriptions in 2012; there were 77 known Death With Dignity Act deaths in Oregon that year.⁴ In Oregon and Washington State, less than 1% of licensed physicians write prescriptions for physician-assisted suicide each year. In contrast, about half or more of physicians in the Netherlands and Belgium reported ever having received a request, and 60% of Dutch physicians have granted such requests.

The California Department of Public Health reported that 111 terminally ill patients availed themselves of California’s End of Life Option Act in the 7 months after it became effective on June 9, 2016.

In a recent review on euthanasia and PAS for the period 1947-2016, Ezekiel Emanuel, MD, and colleagues noted that typical patients were older, white, and well educated, and pain was mostly not reported as the primary motivation.⁵ A large portion of patients receiving PAS in Oregon and Washington were enrolled in hospice or palliative care. Abuses have not been apparent.

In the vast majority of jurisdictions, assisting or causing one to commit suicide, including PAS, still remains a crime; for example, it is considered manslaughter under Hawaii state law §707-702.

In distinguishing between assisting suicide and withdrawing life-sustaining treatment, the U.S. Supreme Court’s landmark 1997 Vacco v. Quill decision emphasized issues of causation and intent.⁶ On causation, the court reasoned that when a patient refuses life-sustaining treatment, he dies from an underlying fatal disease; but if a patient ingests a lethal medication, he is killed by that medication. As to intent, a physician who honors a patient’s refusal of treatment purposefully intends only to respect his patient’s wishes and to cease doing futile or degrading things. On the other hand, a doctor who assists a suicide “must, necessarily and indubitably, intend primarily that the patient be made dead.”

In its companion case Washington v. Glucksberg, the Supreme Court held that the asserted “right” to assistance in committing suicide is not a fundamental liberty interest protected by the due process clause.⁷

State supreme courts in Florida, New Mexico, and elsewhere have likewise rebuffed claims of any constitutional right to PAS. The latest court to so rule is in New York, which has a long history of criminalizing assisted suicide.⁸ The New York Court of Appeals recently addressed claims brought by three terminally ill individuals, several medical providers, and a nonprofit entity seeking a declaration that New York’s “assisted suicide” statutes exclude physicians from prescribing a lethal dose of drugs to terminally ill, competent patients.

The court unequivocally rejected such claims and affirmed that a physician who assists a suicide by prescribing lethal doses of drugs is subject to criminal prosecution for second-degree manslaughter. It refused to regard PAS as being different from assisted suicide in general, and it rejected the constitutional claim to assisted suicide by a terminally ill person. The state appeals court reiterated the U.S. Supreme Court’s distinction between refusing life-sustaining treatment and assisted suicide, the former being “at least partially rooted in notions of bodily integrity, as the right to refuse treatment is a consequence of a person’s right to resist unwanted bodily invasions.” The New York Court of Appeals also noted that the state has a legitimate purpose and a rational basis for guarding against the risks of mistake and abuse.

These developments may signal a shift away from the legalization of PAS, as recently suggested in a Washington Post article.⁹ According to the end-of-life advocacy organization Compassion and Choices, none of the 27 states where such measures were introduced in 2017 passed them into law, including states such as Connecticut, Hawaii, and Rhode Island. In Central and Eastern Europe, support is decreasing, whereas the opposite is true in Western Europe.

U.S. federal lawmakers also appear to be pushing back. On July 13, 2017, the U.S. House Committee on Appropriations voted to block implementation of a “death with dignity” statute passed by the District of Columbia. Further, 11 House members – including 6 Democrats – have introduced a resolution asserting that PAS undermines a key safeguard that protects our nation’s most vulnerable citizens, including the elderly, people with disabilities, and people experiencing psychiatric diagnoses.¹⁰

The American Medical Association is steadfast in its opposition to PAS and euthanasia. In its latest Code of Ethics, the AMA reaffirmed its long-held position that “allowing physicians to engage in assisted suicide would cause more harm than good. Physician-assisted suicide is fundamentally incompatible with the physician’s role as healer, would be difficult or impossible to control, and would pose serious societal risks. … Instead of participating in assisted suicide, physicians must aggressively respond to the needs of patients at the end of life.”¹¹

 

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from earlier columns in Internal Medicine News. For additional information, readers may contact the author at [email protected].

References

1. “Physician-assisted suicide,” Internal Medicine News, Oct. 14, 2013.

2. Baxter v. State of Montana, 224 P. 3d 1211 (2010).

3. “Majority of Americans Remain Supportive of Euthanasia,” Gallup News, June 12, 2017.

4. Statistics available at public.health.oregon.gov under Oregon Death with Dignity Act.

5. JAMA. 2016 Jul 5;316(1):79-90.

6. Vacco v. Quill, 117 S. Ct. 2293 (1997).

7. Washington v. Glucksberg, 521 U.S. 702 (1997).

8. Myers v. Schneiderman, New York Court of Appeals, 2017.

9. “Legalizing assisted suicide has stalled at every level,” Washington Post, Oct. 24, 2017.

10. H. Con. Res. 80, 115th Congress (2017-2018).

11. AMA Code of Medical Ethics §5.7 (2017).

Question: Choose the best answer regarding physician-assisted suicide in the United States:

A. It is now legal in most states.

B. Under California law, assisting or causing one to commit suicide, including physician-assisted suicide, still remains a felony.

C. Both the U.S. Supreme Court and the New York Court of Appeals have held there is no constitutional right to physician-assisted suicide.

D. The American Medical Association is neutral on the issue.

E. Pain relief is the overriding reason for patients who request physician-assisted suicide.

Answer: C. We reviewed this topic in one of our regular columns in 2013.¹ At that time, efforts to legalize physician-assisted suicide (PAS) appeared to be gathering momentum across the country, with four jurisdictions having legalized the practice, beginning with Oregon in 1994. The other states were Washington, Vermont, and Montana, whose Supreme Court held that there was no public interest reason against the practice.²

Since that time, California, Colorado, and the District of Columbia have joined the group. Currently, PAS – but not euthanasia – is legally available in these jurisdictions and in Switzerland, but both can be legally practiced in Belgium, Canada, Colombia, Luxembourg, and the Netherlands.

All state statutes permitting PAS provide similar provisions and safeguards. Only competent individuals who are terminally ill, i.e., death expected within 6 months, can make a request for a lethal dose of medication to carry out the suicidal act. The request to the doctor is first made verbally, then in writing, and a second opinion must be obtained to confirm the patient’s intent, understanding, and free choice. There is also a waiting period.

Public support for euthanasia and PAS in the United States is said to have plateaued since the 1990s. But a significant number of Americans, 67%, still favor PAS, up from 56% a decade ago.³ However, not many patients resort to PAS – usually those with terminal cancers or neuromuscular conditions – and only a minority of physicians are participants.

For example, 61 physicians in Oregon wrote a total of 115 prescriptions in 2012; there were 77 known Death With Dignity Act deaths in Oregon that year.⁴ In Oregon and Washington State, less than 1% of licensed physicians write prescriptions for physician-assisted suicide each year. In contrast, about half or more of physicians in the Netherlands and Belgium reported ever having received a request, and 60% of Dutch physicians have granted such requests.

The California Department of Public Health reported that 111 terminally ill patients availed themselves of California’s End of Life Option Act in the 7 months after it became effective on June 9, 2016.

In a recent review on euthanasia and PAS for the period 1947-2016, Ezekiel Emanuel, MD, and colleagues noted that typical patients were older, white, and well educated, and pain was mostly not reported as the primary motivation.⁵ A large portion of patients receiving PAS in Oregon and Washington were enrolled in hospice or palliative care. Abuses have not been apparent.

In the vast majority of jurisdictions, assisting or causing one to commit suicide, including PAS, still remains a crime; for example, it is considered manslaughter under Hawaii state law §707-702.

In distinguishing between assisting suicide and withdrawing life-sustaining treatment, the U.S. Supreme Court’s landmark 1997 Vacco v. Quill decision emphasized issues of causation and intent.⁶ On causation, the court reasoned that when a patient refuses life-sustaining treatment, he dies from an underlying fatal disease; but if a patient ingests a lethal medication, he is killed by that medication. As to intent, a physician who honors a patient’s refusal of treatment purposefully intends only to respect his patient’s wishes and to cease doing futile or degrading things. On the other hand, a doctor who assists a suicide “must, necessarily and indubitably, intend primarily that the patient be made dead.”

In its companion case Washington v. Glucksberg, the Supreme Court held that the asserted “right” to assistance in committing suicide is not a fundamental liberty interest protected by the due process clause.⁷

State supreme courts in Florida, New Mexico, and elsewhere have likewise rebuffed claims of any constitutional right to PAS. The latest court to so rule is in New York, which has a long history of criminalizing assisted suicide.⁸ The New York Court of Appeals recently addressed claims brought by three terminally ill individuals, several medical providers, and a nonprofit entity seeking a declaration that New York’s “assisted suicide” statutes exclude physicians from prescribing a lethal dose of drugs to terminally ill, competent patients.

The court unequivocally rejected such claims and affirmed that a physician who assists a suicide by prescribing lethal doses of drugs is subject to criminal prosecution for second-degree manslaughter. It refused to regard PAS as being different from assisted suicide in general, and it rejected the constitutional claim to assisted suicide by a terminally ill person. The state appeals court reiterated the U.S. Supreme Court’s distinction between refusing life-sustaining treatment and assisted suicide, the former being “at least partially rooted in notions of bodily integrity, as the right to refuse treatment is a consequence of a person’s right to resist unwanted bodily invasions.” The New York Court of Appeals also noted that the state has a legitimate purpose and a rational basis for guarding against the risks of mistake and abuse.

These developments may signal a shift away from the legalization of PAS, as recently suggested in a Washington Post article.⁹ According to the end-of-life advocacy organization Compassion and Choices, none of the 27 states where such measures were introduced in 2017 passed them into law, including states such as Connecticut, Hawaii, and Rhode Island. In Central and Eastern Europe, support is decreasing, whereas the opposite is true in Western Europe.

U.S. federal lawmakers also appear to be pushing back. On July 13, 2017, the U.S. House Committee on Appropriations voted to block implementation of a “death with dignity” statute passed by the District of Columbia. Further, 11 House members – including 6 Democrats – have introduced a resolution asserting that PAS undermines a key safeguard that protects our nation’s most vulnerable citizens, including the elderly, people with disabilities, and people experiencing psychiatric diagnoses.¹⁰

The American Medical Association is steadfast in its opposition to PAS and euthanasia. In its latest Code of Ethics, the AMA reaffirmed its long-held position that “allowing physicians to engage in assisted suicide would cause more harm than good. Physician-assisted suicide is fundamentally incompatible with the physician’s role as healer, would be difficult or impossible to control, and would pose serious societal risks. … Instead of participating in assisted suicide, physicians must aggressively respond to the needs of patients at the end of life.”¹¹

 

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from earlier columns in Internal Medicine News. For additional information, readers may contact the author at [email protected].

References

1. “Physician-assisted suicide,” Internal Medicine News, Oct. 14, 2013.

2. Baxter v. State of Montana, 224 P. 3d 1211 (2010).

3. “Majority of Americans Remain Supportive of Euthanasia,” Gallup News, June 12, 2017.

4. Statistics available at public.health.oregon.gov under Oregon Death with Dignity Act.

5. JAMA. 2016 Jul 5;316(1):79-90.

6. Vacco v. Quill, 117 S. Ct. 2293 (1997).

7. Washington v. Glucksberg, 521 U.S. 702 (1997).

8. Myers v. Schneiderman, New York Court of Appeals, 2017.

9. “Legalizing assisted suicide has stalled at every level,” Washington Post, Oct. 24, 2017.

10. H. Con. Res. 80, 115th Congress (2017-2018).

11. AMA Code of Medical Ethics §5.7 (2017).

 

While cases of active tuberculosis are relatively rare in the United States, TB is a major cause of morbidity and mortality worldwide. In the United States, there are an estimated 11 million individuals who have latent TB infection (LTBI). Without prophylactic treatment, somewhere between 4%-6% of individuals with LTBI will develop active disease during their lifetimes; roughly half of these cases will occur within a few years of the initial infection. Treatment of LTBI reduces – but does not eliminate – the risk for active disease, decreasing the consequences of active disease for the patient and the risk of transmitting infection to others.

Guidelines from the American Thoracic Society, the Infectious Diseases Society of America, and the Centers for Disease Control and Prevention have been issued with new recommendations for optimal testing strategies for detecting LTBI. The recommended strategies are based on two criteria: the risk of being infected with TB and, in those with LTBI, the risk of progressing to active disease.
 

Diagnostic tests for LTBI

The tuberculin skin test (TST) has been the standard method of diagnosing LTBI. It involves measuring induration caused by a delayed-type hypersensitivity reaction to Mycobacterium tuberculosis (Mtb) 2 or 3 days after injecting the reagent into the skin. The TST can result in false positives when detecting antibodies to BCG and nontuberculous mycobacteria, and false negatives when the patient does not demonstrate a robust immune response. A newer testing method is the Interferon Gamma Release Assay (IGRA), which involves phlebotomy, followed by a series of laboratory procedures that measure IFN-gamma release by T cells that have been sensitized to Mtb. The sensitivity of IGRA is similar to the TST, but it has better specificity; it is much less likely to react to antigens from BCG or nontuberculous mycobacteria. As detailed below, this guideline suggests a significantly more prominent role for IGRA, compared with previous recommendations.

Recommendation 1. Perform an IGRA, rather than a TST, in individuals 5 years or older who meet the following criteria: 1) are likely to be infected with Mtb; 2) have a low or intermediate risk of disease progression; 3) in whom it has been decided that testing for LTBI is warranted. A TST is an acceptable alternative, particularly if an IGRA is not available, is too costly, or is too burdensome. If an individual either has a history of BCG vaccination or is unlikely to return to have their TST read, then it is strongly recommended to use the IGRA as the test of choice.

Recommendation 2. There are insufficient data to recommend a preference for either a TST or an IGRA as the first-line diagnostic test in individuals 5 years or older who are likely to be infected with Mtb, who have a high risk of progression to active disease, and in whom it has been determined that diagnostic testing for LTBI infection is warranted; either test would be acceptable. In very high-risk patients, consider dual testing, with a positive result from either test (TST or IGRA) being considered positive.

Recommendation 3. Guidelines do not recommend testing for persons at low risk for Mtb infection. However, the authors recognize that testing in such persons may nevertheless be mandated in certain situations (for example in some school or child care settings). In these cases, the authors recommend performing an IGRA instead of a TST, to minimize the chance of a false-positive result, although a TST is an acceptable alternative. Furthermore, if the initial test is positive, they suggest performing a confirmatory test (either an IGRA or TST) and considering the person infected only if both tests are positive.

Recommendation 4. The authors suggest performing a TST rather than an IGRA in healthy children less than 5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted. This recommendation reflects the limited body of evidence regarding IGRA testing in young children and the apparent decreased sensitivity (i.e. more false negatives) in this population, compared with TST use.

In the area of serial testing for TB infection, often done in health care and institutional settings, the guideline points out areas of uncertainty with IGRA testing. Specifically, the IGRA test is subject to variability in readings and boosting with antigen exposure that can complicate interpretation of apparent conversion on repeat testing. One longitudinal study showed conversion rates with IGRA to be six to nine times higher than that seen for the TST, and those conversions were thought to represent false positive tests. The guideline concludes that, “There is insufficient information available to guide the establishment of definitive criteria for the conversion.” The committee thought that a positive test in a low-risk individual was likely to be a false-positive result and recommended repeat testing. Because of the possibility of boosting with antigen exposure in situations where dual testing is anticipated, it may be preferable to obtain a specimen for IGRA prior to, or concurrently with TST placement.
 

 

Bottom line

Current guidelines suggest a more prominent role for IGRA in testing for LTBI, particularly when the likelihood of exposure is low and in situations where a person may have received BCG vaccination, or would be unlikely to return for TST reading.

Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Clark is associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

Reference

Lewisohn DM et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Inf Dis. 2017;64(2):111-5.

 

While cases of active tuberculosis are relatively rare in the United States, TB is a major cause of morbidity and mortality worldwide. In the United States, there are an estimated 11 million individuals who have latent TB infection (LTBI). Without prophylactic treatment, somewhere between 4%-6% of individuals with LTBI will develop active disease during their lifetimes; roughly half of these cases will occur within a few years of the initial infection. Treatment of LTBI reduces – but does not eliminate – the risk for active disease, decreasing the consequences of active disease for the patient and the risk of transmitting infection to others.

Guidelines from the American Thoracic Society, the Infectious Diseases Society of America, and the Centers for Disease Control and Prevention have been issued with new recommendations for optimal testing strategies for detecting LTBI. The recommended strategies are based on two criteria: the risk of being infected with TB and, in those with LTBI, the risk of progressing to active disease.
 

Diagnostic tests for LTBI

The tuberculin skin test (TST) has been the standard method of diagnosing LTBI. It involves measuring induration caused by a delayed-type hypersensitivity reaction to Mycobacterium tuberculosis (Mtb) 2 or 3 days after injecting the reagent into the skin. The TST can result in false positives when detecting antibodies to BCG and nontuberculous mycobacteria, and false negatives when the patient does not demonstrate a robust immune response. A newer testing method is the Interferon Gamma Release Assay (IGRA), which involves phlebotomy, followed by a series of laboratory procedures that measure IFN-gamma release by T cells that have been sensitized to Mtb. The sensitivity of IGRA is similar to the TST, but it has better specificity; it is much less likely to react to antigens from BCG or nontuberculous mycobacteria. As detailed below, this guideline suggests a significantly more prominent role for IGRA, compared with previous recommendations.

Recommendation 1. Perform an IGRA, rather than a TST, in individuals 5 years or older who meet the following criteria: 1) are likely to be infected with Mtb; 2) have a low or intermediate risk of disease progression; 3) in whom it has been decided that testing for LTBI is warranted. A TST is an acceptable alternative, particularly if an IGRA is not available, is too costly, or is too burdensome. If an individual either has a history of BCG vaccination or is unlikely to return to have their TST read, then it is strongly recommended to use the IGRA as the test of choice.

Recommendation 2. There are insufficient data to recommend a preference for either a TST or an IGRA as the first-line diagnostic test in individuals 5 years or older who are likely to be infected with Mtb, who have a high risk of progression to active disease, and in whom it has been determined that diagnostic testing for LTBI infection is warranted; either test would be acceptable. In very high-risk patients, consider dual testing, with a positive result from either test (TST or IGRA) being considered positive.

Recommendation 3. Guidelines do not recommend testing for persons at low risk for Mtb infection. However, the authors recognize that testing in such persons may nevertheless be mandated in certain situations (for example in some school or child care settings). In these cases, the authors recommend performing an IGRA instead of a TST, to minimize the chance of a false-positive result, although a TST is an acceptable alternative. Furthermore, if the initial test is positive, they suggest performing a confirmatory test (either an IGRA or TST) and considering the person infected only if both tests are positive.

Recommendation 4. The authors suggest performing a TST rather than an IGRA in healthy children less than 5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted. This recommendation reflects the limited body of evidence regarding IGRA testing in young children and the apparent decreased sensitivity (i.e. more false negatives) in this population, compared with TST use.

In the area of serial testing for TB infection, often done in health care and institutional settings, the guideline points out areas of uncertainty with IGRA testing. Specifically, the IGRA test is subject to variability in readings and boosting with antigen exposure that can complicate interpretation of apparent conversion on repeat testing. One longitudinal study showed conversion rates with IGRA to be six to nine times higher than that seen for the TST, and those conversions were thought to represent false positive tests. The guideline concludes that, “There is insufficient information available to guide the establishment of definitive criteria for the conversion.” The committee thought that a positive test in a low-risk individual was likely to be a false-positive result and recommended repeat testing. Because of the possibility of boosting with antigen exposure in situations where dual testing is anticipated, it may be preferable to obtain a specimen for IGRA prior to, or concurrently with TST placement.
 

 

Bottom line

Current guidelines suggest a more prominent role for IGRA in testing for LTBI, particularly when the likelihood of exposure is low and in situations where a person may have received BCG vaccination, or would be unlikely to return for TST reading.

Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Clark is associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

Reference

Lewisohn DM et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Inf Dis. 2017;64(2):111-5.

 

While cases of active tuberculosis are relatively rare in the United States, TB is a major cause of morbidity and mortality worldwide. In the United States, there are an estimated 11 million individuals who have latent TB infection (LTBI). Without prophylactic treatment, somewhere between 4%-6% of individuals with LTBI will develop active disease during their lifetimes; roughly half of these cases will occur within a few years of the initial infection. Treatment of LTBI reduces – but does not eliminate – the risk for active disease, decreasing the consequences of active disease for the patient and the risk of transmitting infection to others.

Guidelines from the American Thoracic Society, the Infectious Diseases Society of America, and the Centers for Disease Control and Prevention have been issued with new recommendations for optimal testing strategies for detecting LTBI. The recommended strategies are based on two criteria: the risk of being infected with TB and, in those with LTBI, the risk of progressing to active disease.
 

Diagnostic tests for LTBI

The tuberculin skin test (TST) has been the standard method of diagnosing LTBI. It involves measuring induration caused by a delayed-type hypersensitivity reaction to Mycobacterium tuberculosis (Mtb) 2 or 3 days after injecting the reagent into the skin. The TST can result in false positives when detecting antibodies to BCG and nontuberculous mycobacteria, and false negatives when the patient does not demonstrate a robust immune response. A newer testing method is the Interferon Gamma Release Assay (IGRA), which involves phlebotomy, followed by a series of laboratory procedures that measure IFN-gamma release by T cells that have been sensitized to Mtb. The sensitivity of IGRA is similar to the TST, but it has better specificity; it is much less likely to react to antigens from BCG or nontuberculous mycobacteria. As detailed below, this guideline suggests a significantly more prominent role for IGRA, compared with previous recommendations.

Recommendation 1. Perform an IGRA, rather than a TST, in individuals 5 years or older who meet the following criteria: 1) are likely to be infected with Mtb; 2) have a low or intermediate risk of disease progression; 3) in whom it has been decided that testing for LTBI is warranted. A TST is an acceptable alternative, particularly if an IGRA is not available, is too costly, or is too burdensome. If an individual either has a history of BCG vaccination or is unlikely to return to have their TST read, then it is strongly recommended to use the IGRA as the test of choice.

Recommendation 2. There are insufficient data to recommend a preference for either a TST or an IGRA as the first-line diagnostic test in individuals 5 years or older who are likely to be infected with Mtb, who have a high risk of progression to active disease, and in whom it has been determined that diagnostic testing for LTBI infection is warranted; either test would be acceptable. In very high-risk patients, consider dual testing, with a positive result from either test (TST or IGRA) being considered positive.

Recommendation 3. Guidelines do not recommend testing for persons at low risk for Mtb infection. However, the authors recognize that testing in such persons may nevertheless be mandated in certain situations (for example in some school or child care settings). In these cases, the authors recommend performing an IGRA instead of a TST, to minimize the chance of a false-positive result, although a TST is an acceptable alternative. Furthermore, if the initial test is positive, they suggest performing a confirmatory test (either an IGRA or TST) and considering the person infected only if both tests are positive.

Recommendation 4. The authors suggest performing a TST rather than an IGRA in healthy children less than 5 years of age for whom it has been decided that diagnostic testing for LTBI is warranted. This recommendation reflects the limited body of evidence regarding IGRA testing in young children and the apparent decreased sensitivity (i.e. more false negatives) in this population, compared with TST use.

In the area of serial testing for TB infection, often done in health care and institutional settings, the guideline points out areas of uncertainty with IGRA testing. Specifically, the IGRA test is subject to variability in readings and boosting with antigen exposure that can complicate interpretation of apparent conversion on repeat testing. One longitudinal study showed conversion rates with IGRA to be six to nine times higher than that seen for the TST, and those conversions were thought to represent false positive tests. The guideline concludes that, “There is insufficient information available to guide the establishment of definitive criteria for the conversion.” The committee thought that a positive test in a low-risk individual was likely to be a false-positive result and recommended repeat testing. Because of the possibility of boosting with antigen exposure in situations where dual testing is anticipated, it may be preferable to obtain a specimen for IGRA prior to, or concurrently with TST placement.
 

 

Bottom line

Current guidelines suggest a more prominent role for IGRA in testing for LTBI, particularly when the likelihood of exposure is low and in situations where a person may have received BCG vaccination, or would be unlikely to return for TST reading.

Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Clark is associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

Reference

Lewisohn DM et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Inf Dis. 2017;64(2):111-5.

 

The rise of noninvasive procedures has shifted the aesthetic culture. Patients now are asking for less invasive, less painful, less expensive procedures with short recovery times. Thread-lifts are one of the newest approaches to nonsurgical facial tightening. However, are they of value? Where, and for whom?

Conceptually, the thread-lift is the suspension of ptotic facial soft tissue via a thread subcutaneously inserted in the skin. It is an easy, fast, in-office procedure in which a cone attachment or barbed or nonbarbed suture thread is inserted via a cannula into the skin through a very small incision. The thread is essentially “hooked” to the skin and, with a minimal amount of tightening, the skin is lifted and the suture is cut at the insertion point. The sutures dissolve and, over time, produce scar tissue.

The thread-lifts initially came onto the market in the late 1990s but were difficult to use. The nonabsorbable threads had to be anchored into the scalp, temple, and brow region. The anchoring knots were carefully tied and were permanent. The newest technology threads – NovaThreads and the Silhouette Instalift – have recently received Food and Drug Administration clearance and grown in popularity because of their “lunchtime” appeal and their ease of use. Primarily marketed for the neck, jowls, and lower face, these threads – available in various sizes, lengths, and diameters – can be used almost anywhere. The sutures dissolve over time and do not need any anchoring, making it a very simple in-office procedure.

Side effects include mild procedural pain, edema, erythema, bruising, and rarely, suture granuloma formation; and they may need to be replaced. If not done properly, buckling of the skin can occur and superficially placed sutures can be visible.

Similar to fillers that provide a “liquid face-lift,” the down time is minimal. Common side effects include bruising, and patients should refrain from heavy exercise and opening their mouth wide with chewing for 5-7 days (such as eating a large apple). Soreness, particularly in or near the hairline or jaw line, can occur and can last up to 2 weeks. Dimpling in the skin can occur and usually resolves on its own; however, if threads are placed incorrectly, dimpling can cause some disfigurement.

Results can vary based on the tissue laxity, and the type, amount, and location of the threads used. While results have been reported to last 18 months to 2 years, the procedure is not a replacement for fillers. Facial aging is caused by a combination of skeletal, soft tissue, and skin changes that lead to soft tissue laxity and volume loss. Fillers are essential in restoring lost volume in the aging face and are particularly helpful in combination with tissue tightening lasers, face-lifts and the thread-lift procedures. Fillers used in combination with thread-lifts also increase the longevity of the thread-lift because of additional collagen stimulation.

As the procedure is not indicated for severe laxity, thread-lifts also do not replace the traditional face-lift. Tissue is not released from its underlying attachments, and skin contraction and gravitational pull limit its extent of improvement and its longevity.

Long-term success of the thread-lift procedure for facial rejuvenation was evaluated in a retrospective review of 33 patients who underwent the traditional thread-lift procedure alone or in combination with other facial rejuvenation procedures to the brow, mid-face, jowl, and neck published in 2009.¹ The study compared results in 10 patients who had a thread-lift alone, 23 who had thread-lifts combined with other procedures, and controls, who were 10 ten patients who had non–thread-lift rejuvenation procedures, which included lipotransfer, chemical peels, and rhytidectomies. Independent, blinded, board-certified facial plastic surgeons evaluated pre- and postoperative photos. Patients were followed-up for a mean of 21 months.

At 1 month, aesthetic improvements were observed in all treatment groups. Measurable results through the end of the study period were seen in all the patient groups, with the exception of the group of patients who had the thread-lift procedure alone. Aesthetic improvements observed in the control group were significantly better than were the improvements in the thread-lift only group. In addition, aesthetic improvement scores among those who had the thread-lift plus other procedures were significantly better than were the scores among those who had the thread-lift only. The authors concluded that the thread-lift procedure resulted in only short-term improvements, because of the edema and inflammation related to the procedure. They also concluded that thread-lifts were not effective because they did not produce any volumetric change and only superficially repositioned the soft tissues without addressing excess skin.

While thread-lifts are a beneficial addition to our armamentarium of noninvasive aesthetic procedures, they have better outcomes and higher patient satisfaction when used in combination with fillers, radiofrequency, and fractional lasers and neuromodulators.

Reference

1. Abraham RF et al. Arch Facial Plast Surg. 2009 May-Jun;11(3):178-83.
 

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

 

The rise of noninvasive procedures has shifted the aesthetic culture. Patients now are asking for less invasive, less painful, less expensive procedures with short recovery times. Thread-lifts are one of the newest approaches to nonsurgical facial tightening. However, are they of value? Where, and for whom?

Conceptually, the thread-lift is the suspension of ptotic facial soft tissue via a thread subcutaneously inserted in the skin. It is an easy, fast, in-office procedure in which a cone attachment or barbed or nonbarbed suture thread is inserted via a cannula into the skin through a very small incision. The thread is essentially “hooked” to the skin and, with a minimal amount of tightening, the skin is lifted and the suture is cut at the insertion point. The sutures dissolve and, over time, produce scar tissue.

The thread-lifts initially came onto the market in the late 1990s but were difficult to use. The nonabsorbable threads had to be anchored into the scalp, temple, and brow region. The anchoring knots were carefully tied and were permanent. The newest technology threads – NovaThreads and the Silhouette Instalift – have recently received Food and Drug Administration clearance and grown in popularity because of their “lunchtime” appeal and their ease of use. Primarily marketed for the neck, jowls, and lower face, these threads – available in various sizes, lengths, and diameters – can be used almost anywhere. The sutures dissolve over time and do not need any anchoring, making it a very simple in-office procedure.

Side effects include mild procedural pain, edema, erythema, bruising, and rarely, suture granuloma formation; and they may need to be replaced. If not done properly, buckling of the skin can occur and superficially placed sutures can be visible.

Similar to fillers that provide a “liquid face-lift,” the down time is minimal. Common side effects include bruising, and patients should refrain from heavy exercise and opening their mouth wide with chewing for 5-7 days (such as eating a large apple). Soreness, particularly in or near the hairline or jaw line, can occur and can last up to 2 weeks. Dimpling in the skin can occur and usually resolves on its own; however, if threads are placed incorrectly, dimpling can cause some disfigurement.

Results can vary based on the tissue laxity, and the type, amount, and location of the threads used. While results have been reported to last 18 months to 2 years, the procedure is not a replacement for fillers. Facial aging is caused by a combination of skeletal, soft tissue, and skin changes that lead to soft tissue laxity and volume loss. Fillers are essential in restoring lost volume in the aging face and are particularly helpful in combination with tissue tightening lasers, face-lifts and the thread-lift procedures. Fillers used in combination with thread-lifts also increase the longevity of the thread-lift because of additional collagen stimulation.

As the procedure is not indicated for severe laxity, thread-lifts also do not replace the traditional face-lift. Tissue is not released from its underlying attachments, and skin contraction and gravitational pull limit its extent of improvement and its longevity.

Long-term success of the thread-lift procedure for facial rejuvenation was evaluated in a retrospective review of 33 patients who underwent the traditional thread-lift procedure alone or in combination with other facial rejuvenation procedures to the brow, mid-face, jowl, and neck published in 2009.¹ The study compared results in 10 patients who had a thread-lift alone, 23 who had thread-lifts combined with other procedures, and controls, who were 10 ten patients who had non–thread-lift rejuvenation procedures, which included lipotransfer, chemical peels, and rhytidectomies. Independent, blinded, board-certified facial plastic surgeons evaluated pre- and postoperative photos. Patients were followed-up for a mean of 21 months.

At 1 month, aesthetic improvements were observed in all treatment groups. Measurable results through the end of the study period were seen in all the patient groups, with the exception of the group of patients who had the thread-lift procedure alone. Aesthetic improvements observed in the control group were significantly better than were the improvements in the thread-lift only group. In addition, aesthetic improvement scores among those who had the thread-lift plus other procedures were significantly better than were the scores among those who had the thread-lift only. The authors concluded that the thread-lift procedure resulted in only short-term improvements, because of the edema and inflammation related to the procedure. They also concluded that thread-lifts were not effective because they did not produce any volumetric change and only superficially repositioned the soft tissues without addressing excess skin.

While thread-lifts are a beneficial addition to our armamentarium of noninvasive aesthetic procedures, they have better outcomes and higher patient satisfaction when used in combination with fillers, radiofrequency, and fractional lasers and neuromodulators.

Reference

1. Abraham RF et al. Arch Facial Plast Surg. 2009 May-Jun;11(3):178-83.
 

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

 

The rise of noninvasive procedures has shifted the aesthetic culture. Patients now are asking for less invasive, less painful, less expensive procedures with short recovery times. Thread-lifts are one of the newest approaches to nonsurgical facial tightening. However, are they of value? Where, and for whom?

Conceptually, the thread-lift is the suspension of ptotic facial soft tissue via a thread subcutaneously inserted in the skin. It is an easy, fast, in-office procedure in which a cone attachment or barbed or nonbarbed suture thread is inserted via a cannula into the skin through a very small incision. The thread is essentially “hooked” to the skin and, with a minimal amount of tightening, the skin is lifted and the suture is cut at the insertion point. The sutures dissolve and, over time, produce scar tissue.

The thread-lifts initially came onto the market in the late 1990s but were difficult to use. The nonabsorbable threads had to be anchored into the scalp, temple, and brow region. The anchoring knots were carefully tied and were permanent. The newest technology threads – NovaThreads and the Silhouette Instalift – have recently received Food and Drug Administration clearance and grown in popularity because of their “lunchtime” appeal and their ease of use. Primarily marketed for the neck, jowls, and lower face, these threads – available in various sizes, lengths, and diameters – can be used almost anywhere. The sutures dissolve over time and do not need any anchoring, making it a very simple in-office procedure.

Side effects include mild procedural pain, edema, erythema, bruising, and rarely, suture granuloma formation; and they may need to be replaced. If not done properly, buckling of the skin can occur and superficially placed sutures can be visible.

Similar to fillers that provide a “liquid face-lift,” the down time is minimal. Common side effects include bruising, and patients should refrain from heavy exercise and opening their mouth wide with chewing for 5-7 days (such as eating a large apple). Soreness, particularly in or near the hairline or jaw line, can occur and can last up to 2 weeks. Dimpling in the skin can occur and usually resolves on its own; however, if threads are placed incorrectly, dimpling can cause some disfigurement.

Results can vary based on the tissue laxity, and the type, amount, and location of the threads used. While results have been reported to last 18 months to 2 years, the procedure is not a replacement for fillers. Facial aging is caused by a combination of skeletal, soft tissue, and skin changes that lead to soft tissue laxity and volume loss. Fillers are essential in restoring lost volume in the aging face and are particularly helpful in combination with tissue tightening lasers, face-lifts and the thread-lift procedures. Fillers used in combination with thread-lifts also increase the longevity of the thread-lift because of additional collagen stimulation.

As the procedure is not indicated for severe laxity, thread-lifts also do not replace the traditional face-lift. Tissue is not released from its underlying attachments, and skin contraction and gravitational pull limit its extent of improvement and its longevity.

Long-term success of the thread-lift procedure for facial rejuvenation was evaluated in a retrospective review of 33 patients who underwent the traditional thread-lift procedure alone or in combination with other facial rejuvenation procedures to the brow, mid-face, jowl, and neck published in 2009.¹ The study compared results in 10 patients who had a thread-lift alone, 23 who had thread-lifts combined with other procedures, and controls, who were 10 ten patients who had non–thread-lift rejuvenation procedures, which included lipotransfer, chemical peels, and rhytidectomies. Independent, blinded, board-certified facial plastic surgeons evaluated pre- and postoperative photos. Patients were followed-up for a mean of 21 months.

At 1 month, aesthetic improvements were observed in all treatment groups. Measurable results through the end of the study period were seen in all the patient groups, with the exception of the group of patients who had the thread-lift procedure alone. Aesthetic improvements observed in the control group were significantly better than were the improvements in the thread-lift only group. In addition, aesthetic improvement scores among those who had the thread-lift plus other procedures were significantly better than were the scores among those who had the thread-lift only. The authors concluded that the thread-lift procedure resulted in only short-term improvements, because of the edema and inflammation related to the procedure. They also concluded that thread-lifts were not effective because they did not produce any volumetric change and only superficially repositioned the soft tissues without addressing excess skin.

While thread-lifts are a beneficial addition to our armamentarium of noninvasive aesthetic procedures, they have better outcomes and higher patient satisfaction when used in combination with fillers, radiofrequency, and fractional lasers and neuromodulators.

Reference

1. Abraham RF et al. Arch Facial Plast Surg. 2009 May-Jun;11(3):178-83.
 

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

 

Roughly 6 months ago, a primary care physician referred a patient to our clinic for an assessment for opioid use disorder and a recommendation for treatment. The patient estimated, likely underestimated, his daily heroin use to five bags and dropped positive, in addition to heroin, for benzodiazepines, amphetamines, and cannabis. He was in a profession in which public safety was a critical concern, and he refused to notify his employer’s employee assistance program. He also declined to voluntarily admit himself for detox and treatment at the local, fully accredited addiction program, which was affiliated with a major university medical center. Instead, after an Internet search, the patient opted for an opioid treatment center featuring massage therapy, acupuncture, a stable, a sweat lodge – and a magnificent view of the Pacific Ocean.

When he returned home to his family, with its discord, and his work, with its pressures, he relapsed in 10 days. As it turned out, while a resident at the program, his generalized anxiety disorder and panic attacks never were properly addressed, nor was he offered either Suboxone or naltrexone to manage his cravings and urges. Nor, it appears, did the outpatient treatment center sufficiently emphasize such aftercare basics as a 12-step program, finding a therapist with certification in chemical dependency, and following up with a psychiatrist experienced in addiction. Later investigation uncovered that several of the staff at the outpatient treatment center received their “training” and “certification” from a nonaccredited online university. (I altered key facts and circumstances related to the patient to protect his identity.)

Mental health professionals and lay people alike are aware of the “opioid crisis” – the derailment of lives, the devastation to communities, the death toll. But despite proposals to increase research funding, policies aimed at tightening the prescribing of opioids, and pledges to ramp up interdiction of heroin traffic, there is often an ignorance and confusion regarding the best, evidence-based approaches to getting patients with substance use disorders clean and keeping them clean.

Unfortunately, as with any crisis, there will be opportunists preying on vulnerable patients and their families. And this travesty has reportedly escalated, as outpatient treatment centers take advantage of laws guaranteeing mental health parity and insurance companies paying out tens of thousands of dollars for residential and outpatient opioid treatment. The potential for significant profit is plainly illustrated by the influx of private equity firms, such as Bain Capital, that are investing heavily in treatment centers.

Reports of malfeasance and misconduct, by owners, operators, staff, and others connected with the industry are beginning to get the attention of authorities. There have been reports of outpatient treatment centers that spend lavishly on furnishing, on BMWs and signed art, yet are understaffed, leading to inadequate one-on-one counseling and even sexual transgressions between residents. There are centers that have been investigated for insurance fraud, such as illegally waiving a copay or a deductible or for charging up to $5,000 for a simple urine five drug screen, often multiple times a day. And there is evidence of “junkie hunters” who cruise for people with addictions and brokers who provide such people with fake addresses in order to qualify for insurance plans with excellent benefits for addiction treatment.

Given what is at stake, guidelines are critical in choosing credible programs. For example, despite Google’s recent decision to stop selling ads to rehab centers, looking for an outpatient treatment center on the Internet is not the equivalent of a search for the best local Thai restaurant. Rather, in light of the risk of disinformation and other flaws, online rating tools, a la “Yelp,” should be skipped entirely. Moreover, referral services as a rule should be avoided, as there is little evidence that it adds value and leads to a better outcome for the client, and some of the ways these entities are compensated, (for example, kickbacks), can prejudice the consultation, and cross the line into the unethical and illegal.

Probably the best means to find a suitable outpatient treatment center is by way of a local, experienced, and respected chemical dependency counselor or physician certified in addiction medicine. If people with substance use disorders and their families want to independently conduct a search, as a good rule of thumb, they should be advised to consider programs affiliated with major medical centers and hospitals or outpatient treatment centers that have been established in good standing for years, in contrast to the rash of pop-up, for-profit programs. Of equal, or even greater importance, is that the prospective center ought to be accredited by a national organization, for example, The Joint Commission, and its staff ought to be licensed and credentialed as well.

In addition, there is merit if the staff has been educated, trained, and supervised under the direction of a respected institution. Needless to add, an outpatient treatment center must use evidence-based practices as the bedrock of treatment; this includes pharmacotherapies such as Suboxone and naltrexone (Vivitrol), and behavioral therapies such as cognitive-behavioral therapy, contingency management, and motivational enhancement. To date, massage and essential oils might be relaxing and pleasurable, but they are not considered accepted standard of care.

It is crucial, too, that an outpatient treatment center have both the resources to reliably handle acute medical detox, which can be a potentially life-threatening emergency, and the medical personnel who can assess and treat such medical conditions as hypertension as well as psychiatric illnesses such as bipolar and generalized anxiety disorders. A prospective patient also should inquire whether any of the staff has been the subject of disciplinary action by a licensing board or whether the center has been investigated by the state or a national accrediting organization.

Because addiction so often has facets rooted in the family system, and recovery so often depends on family support, an outpatient treatment center should provide a structured family program integrated into the patient’s treatment and emphasize the importance of continued family involvement after discharge.

Lastly, the best treatment centers often regularly update a patient’s local therapist and physician, spell out the elements of successful aftercare (12-step programs, and so on), and provide amenities, such as calls to a recently discharged patient and an alumni support network.

Dr. Marseille is a psychiatrist who works on the staff of a clinic in Wheaton, Ill. His special interests include adolescent and addiction medicine, eating disorders, trauma, bipolar disorder, and the psychiatric manifestations of acute and chronic medical conditions.

 

This article was updated 12/15/17.

 

Roughly 6 months ago, a primary care physician referred a patient to our clinic for an assessment for opioid use disorder and a recommendation for treatment. The patient estimated, likely underestimated, his daily heroin use to five bags and dropped positive, in addition to heroin, for benzodiazepines, amphetamines, and cannabis. He was in a profession in which public safety was a critical concern, and he refused to notify his employer’s employee assistance program. He also declined to voluntarily admit himself for detox and treatment at the local, fully accredited addiction program, which was affiliated with a major university medical center. Instead, after an Internet search, the patient opted for an opioid treatment center featuring massage therapy, acupuncture, a stable, a sweat lodge – and a magnificent view of the Pacific Ocean.

When he returned home to his family, with its discord, and his work, with its pressures, he relapsed in 10 days. As it turned out, while a resident at the program, his generalized anxiety disorder and panic attacks never were properly addressed, nor was he offered either Suboxone or naltrexone to manage his cravings and urges. Nor, it appears, did the outpatient treatment center sufficiently emphasize such aftercare basics as a 12-step program, finding a therapist with certification in chemical dependency, and following up with a psychiatrist experienced in addiction. Later investigation uncovered that several of the staff at the outpatient treatment center received their “training” and “certification” from a nonaccredited online university. (I altered key facts and circumstances related to the patient to protect his identity.)

Mental health professionals and lay people alike are aware of the “opioid crisis” – the derailment of lives, the devastation to communities, the death toll. But despite proposals to increase research funding, policies aimed at tightening the prescribing of opioids, and pledges to ramp up interdiction of heroin traffic, there is often an ignorance and confusion regarding the best, evidence-based approaches to getting patients with substance use disorders clean and keeping them clean.

Unfortunately, as with any crisis, there will be opportunists preying on vulnerable patients and their families. And this travesty has reportedly escalated, as outpatient treatment centers take advantage of laws guaranteeing mental health parity and insurance companies paying out tens of thousands of dollars for residential and outpatient opioid treatment. The potential for significant profit is plainly illustrated by the influx of private equity firms, such as Bain Capital, that are investing heavily in treatment centers.

Reports of malfeasance and misconduct, by owners, operators, staff, and others connected with the industry are beginning to get the attention of authorities. There have been reports of outpatient treatment centers that spend lavishly on furnishing, on BMWs and signed art, yet are understaffed, leading to inadequate one-on-one counseling and even sexual transgressions between residents. There are centers that have been investigated for insurance fraud, such as illegally waiving a copay or a deductible or for charging up to $5,000 for a simple urine five drug screen, often multiple times a day. And there is evidence of “junkie hunters” who cruise for people with addictions and brokers who provide such people with fake addresses in order to qualify for insurance plans with excellent benefits for addiction treatment.

Given what is at stake, guidelines are critical in choosing credible programs. For example, despite Google’s recent decision to stop selling ads to rehab centers, looking for an outpatient treatment center on the Internet is not the equivalent of a search for the best local Thai restaurant. Rather, in light of the risk of disinformation and other flaws, online rating tools, a la “Yelp,” should be skipped entirely. Moreover, referral services as a rule should be avoided, as there is little evidence that it adds value and leads to a better outcome for the client, and some of the ways these entities are compensated, (for example, kickbacks), can prejudice the consultation, and cross the line into the unethical and illegal.

Probably the best means to find a suitable outpatient treatment center is by way of a local, experienced, and respected chemical dependency counselor or physician certified in addiction medicine. If people with substance use disorders and their families want to independently conduct a search, as a good rule of thumb, they should be advised to consider programs affiliated with major medical centers and hospitals or outpatient treatment centers that have been established in good standing for years, in contrast to the rash of pop-up, for-profit programs. Of equal, or even greater importance, is that the prospective center ought to be accredited by a national organization, for example, The Joint Commission, and its staff ought to be licensed and credentialed as well.

In addition, there is merit if the staff has been educated, trained, and supervised under the direction of a respected institution. Needless to add, an outpatient treatment center must use evidence-based practices as the bedrock of treatment; this includes pharmacotherapies such as Suboxone and naltrexone (Vivitrol), and behavioral therapies such as cognitive-behavioral therapy, contingency management, and motivational enhancement. To date, massage and essential oils might be relaxing and pleasurable, but they are not considered accepted standard of care.

It is crucial, too, that an outpatient treatment center have both the resources to reliably handle acute medical detox, which can be a potentially life-threatening emergency, and the medical personnel who can assess and treat such medical conditions as hypertension as well as psychiatric illnesses such as bipolar and generalized anxiety disorders. A prospective patient also should inquire whether any of the staff has been the subject of disciplinary action by a licensing board or whether the center has been investigated by the state or a national accrediting organization.

Because addiction so often has facets rooted in the family system, and recovery so often depends on family support, an outpatient treatment center should provide a structured family program integrated into the patient’s treatment and emphasize the importance of continued family involvement after discharge.

Lastly, the best treatment centers often regularly update a patient’s local therapist and physician, spell out the elements of successful aftercare (12-step programs, and so on), and provide amenities, such as calls to a recently discharged patient and an alumni support network.

Dr. Marseille is a psychiatrist who works on the staff of a clinic in Wheaton, Ill. His special interests include adolescent and addiction medicine, eating disorders, trauma, bipolar disorder, and the psychiatric manifestations of acute and chronic medical conditions.

 

This article was updated 12/15/17.

 

Roughly 6 months ago, a primary care physician referred a patient to our clinic for an assessment for opioid use disorder and a recommendation for treatment. The patient estimated, likely underestimated, his daily heroin use to five bags and dropped positive, in addition to heroin, for benzodiazepines, amphetamines, and cannabis. He was in a profession in which public safety was a critical concern, and he refused to notify his employer’s employee assistance program. He also declined to voluntarily admit himself for detox and treatment at the local, fully accredited addiction program, which was affiliated with a major university medical center. Instead, after an Internet search, the patient opted for an opioid treatment center featuring massage therapy, acupuncture, a stable, a sweat lodge – and a magnificent view of the Pacific Ocean.

When he returned home to his family, with its discord, and his work, with its pressures, he relapsed in 10 days. As it turned out, while a resident at the program, his generalized anxiety disorder and panic attacks never were properly addressed, nor was he offered either Suboxone or naltrexone to manage his cravings and urges. Nor, it appears, did the outpatient treatment center sufficiently emphasize such aftercare basics as a 12-step program, finding a therapist with certification in chemical dependency, and following up with a psychiatrist experienced in addiction. Later investigation uncovered that several of the staff at the outpatient treatment center received their “training” and “certification” from a nonaccredited online university. (I altered key facts and circumstances related to the patient to protect his identity.)

Mental health professionals and lay people alike are aware of the “opioid crisis” – the derailment of lives, the devastation to communities, the death toll. But despite proposals to increase research funding, policies aimed at tightening the prescribing of opioids, and pledges to ramp up interdiction of heroin traffic, there is often an ignorance and confusion regarding the best, evidence-based approaches to getting patients with substance use disorders clean and keeping them clean.

Unfortunately, as with any crisis, there will be opportunists preying on vulnerable patients and their families. And this travesty has reportedly escalated, as outpatient treatment centers take advantage of laws guaranteeing mental health parity and insurance companies paying out tens of thousands of dollars for residential and outpatient opioid treatment. The potential for significant profit is plainly illustrated by the influx of private equity firms, such as Bain Capital, that are investing heavily in treatment centers.

Reports of malfeasance and misconduct, by owners, operators, staff, and others connected with the industry are beginning to get the attention of authorities. There have been reports of outpatient treatment centers that spend lavishly on furnishing, on BMWs and signed art, yet are understaffed, leading to inadequate one-on-one counseling and even sexual transgressions between residents. There are centers that have been investigated for insurance fraud, such as illegally waiving a copay or a deductible or for charging up to $5,000 for a simple urine five drug screen, often multiple times a day. And there is evidence of “junkie hunters” who cruise for people with addictions and brokers who provide such people with fake addresses in order to qualify for insurance plans with excellent benefits for addiction treatment.

Given what is at stake, guidelines are critical in choosing credible programs. For example, despite Google’s recent decision to stop selling ads to rehab centers, looking for an outpatient treatment center on the Internet is not the equivalent of a search for the best local Thai restaurant. Rather, in light of the risk of disinformation and other flaws, online rating tools, a la “Yelp,” should be skipped entirely. Moreover, referral services as a rule should be avoided, as there is little evidence that it adds value and leads to a better outcome for the client, and some of the ways these entities are compensated, (for example, kickbacks), can prejudice the consultation, and cross the line into the unethical and illegal.

Probably the best means to find a suitable outpatient treatment center is by way of a local, experienced, and respected chemical dependency counselor or physician certified in addiction medicine. If people with substance use disorders and their families want to independently conduct a search, as a good rule of thumb, they should be advised to consider programs affiliated with major medical centers and hospitals or outpatient treatment centers that have been established in good standing for years, in contrast to the rash of pop-up, for-profit programs. Of equal, or even greater importance, is that the prospective center ought to be accredited by a national organization, for example, The Joint Commission, and its staff ought to be licensed and credentialed as well.

In addition, there is merit if the staff has been educated, trained, and supervised under the direction of a respected institution. Needless to add, an outpatient treatment center must use evidence-based practices as the bedrock of treatment; this includes pharmacotherapies such as Suboxone and naltrexone (Vivitrol), and behavioral therapies such as cognitive-behavioral therapy, contingency management, and motivational enhancement. To date, massage and essential oils might be relaxing and pleasurable, but they are not considered accepted standard of care.

It is crucial, too, that an outpatient treatment center have both the resources to reliably handle acute medical detox, which can be a potentially life-threatening emergency, and the medical personnel who can assess and treat such medical conditions as hypertension as well as psychiatric illnesses such as bipolar and generalized anxiety disorders. A prospective patient also should inquire whether any of the staff has been the subject of disciplinary action by a licensing board or whether the center has been investigated by the state or a national accrediting organization.

Because addiction so often has facets rooted in the family system, and recovery so often depends on family support, an outpatient treatment center should provide a structured family program integrated into the patient’s treatment and emphasize the importance of continued family involvement after discharge.

Lastly, the best treatment centers often regularly update a patient’s local therapist and physician, spell out the elements of successful aftercare (12-step programs, and so on), and provide amenities, such as calls to a recently discharged patient and an alumni support network.

Dr. Marseille is a psychiatrist who works on the staff of a clinic in Wheaton, Ill. His special interests include adolescent and addiction medicine, eating disorders, trauma, bipolar disorder, and the psychiatric manifestations of acute and chronic medical conditions.

 

This article was updated 12/15/17.

 

In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.

Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.

Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.

It is no wonder, then, that investigators continue to search for medications to prevent preeclampsia and its associated morbidities. Calcium, vitamins C and E, and fish oil have been shown to be ineffective. Low-dose aspirin is currently recommended for preventing preeclampsia in high-risk women, but it has a modest effect at best and is the subject of much debate.

Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.


 

The commonalities

Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.

Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.

Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.

In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).

Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.
 

Safety issues

So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.

This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.

Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.

Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).

A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).

A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.
 

 

A promising pilot

Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.

This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.

In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).

Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).

Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).

Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).

That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.
 

The future

Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.

With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.

Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).

Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.

Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.

 

In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.

Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.

Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.

It is no wonder, then, that investigators continue to search for medications to prevent preeclampsia and its associated morbidities. Calcium, vitamins C and E, and fish oil have been shown to be ineffective. Low-dose aspirin is currently recommended for preventing preeclampsia in high-risk women, but it has a modest effect at best and is the subject of much debate.

Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.


 

The commonalities

Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.

Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.

Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.

In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).

Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.
 

Safety issues

So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.

This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.

Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.

Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).

A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).

A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.
 

 

A promising pilot

Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.

This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.

In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).

Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).

Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).

Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).

That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.
 

The future

Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.

With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.

Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).

Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.

Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.

 

In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.

Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.

Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.

It is no wonder, then, that investigators continue to search for medications to prevent preeclampsia and its associated morbidities. Calcium, vitamins C and E, and fish oil have been shown to be ineffective. Low-dose aspirin is currently recommended for preventing preeclampsia in high-risk women, but it has a modest effect at best and is the subject of much debate.

Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.


 

The commonalities

Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.

Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.

Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.

In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).

Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.
 

Safety issues

So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.

This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.

Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.

Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).

A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).

A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.
 

 

A promising pilot

Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.

This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.

In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).

Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).

Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).

Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).

That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.
 

The future

Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.

With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.

Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).

Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.

Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.

 

In medicine, there are many diseases and conditions that pose significant challenges to health care practitioners. For example, within brain science, there are patients with debilitating neurodegenerative diseases; within emergency medicine, there are patients who have suffered severe and acute trauma; within pediatrics, there are patients with terminal illnesses, such as cancer. In ob.gyn., one of the great obstetrical syndromes is preeclampsia.

Humans have known about preeclampsia for thousands of years, dating back to the 4th and 5th centuries B.C., since the time of Hippocrates. Ancient writings on medical conditions of women reflect a recognition of preeclampsia and eclampsia, although formal classification of the condition as a hypertensive disorder associated specifically with pregnancy did not occur until the late 1800s. Despite this, the pathology of preeclampsia is significantly underdefined, and because the underlying causes of preeclampsia are largely unknown, prevention and management continue to be hindered.

Our approach to managing women with hypertensive disorders of pregnancy has been one predicated on watchfulness and appropriate timing of delivery. Pharmacologic interventions have been primarily practical and not heavily reliant on scientific evidence. Use of magnesium sulfate is based on temporizing outcomes; use of aspirin and bed rest are similar.

However, recent research indicating an association between statin use and prevention of preeclampsia has given us some hope that targeted management is possible. As ob.gyns. continue to grapple with the intricacies of managing patients with preeclampsia, a condition we increasingly see because of concurrent rises in being overweight, being obese, and having diabetes during pregnancy, so we are eager to see whether the research might confirm an effective role for statins in patient care. Although statins are still quite far from becoming a new standard of care, we are, as a specialty, hungry for a solution to this millennia-old problem.

Therefore, this month we have invited Maged Costantine, MD, an associate professor in the department of obstetrics and gynecology and division of maternal fetal medicine at the University of Texas Medical Branch in Galveston, to discuss this novel and exciting new area of research.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

 

In medicine, there are many diseases and conditions that pose significant challenges to health care practitioners. For example, within brain science, there are patients with debilitating neurodegenerative diseases; within emergency medicine, there are patients who have suffered severe and acute trauma; within pediatrics, there are patients with terminal illnesses, such as cancer. In ob.gyn., one of the great obstetrical syndromes is preeclampsia.

Humans have known about preeclampsia for thousands of years, dating back to the 4th and 5th centuries B.C., since the time of Hippocrates. Ancient writings on medical conditions of women reflect a recognition of preeclampsia and eclampsia, although formal classification of the condition as a hypertensive disorder associated specifically with pregnancy did not occur until the late 1800s. Despite this, the pathology of preeclampsia is significantly underdefined, and because the underlying causes of preeclampsia are largely unknown, prevention and management continue to be hindered.

Our approach to managing women with hypertensive disorders of pregnancy has been one predicated on watchfulness and appropriate timing of delivery. Pharmacologic interventions have been primarily practical and not heavily reliant on scientific evidence. Use of magnesium sulfate is based on temporizing outcomes; use of aspirin and bed rest are similar.

However, recent research indicating an association between statin use and prevention of preeclampsia has given us some hope that targeted management is possible. As ob.gyns. continue to grapple with the intricacies of managing patients with preeclampsia, a condition we increasingly see because of concurrent rises in being overweight, being obese, and having diabetes during pregnancy, so we are eager to see whether the research might confirm an effective role for statins in patient care. Although statins are still quite far from becoming a new standard of care, we are, as a specialty, hungry for a solution to this millennia-old problem.

Therefore, this month we have invited Maged Costantine, MD, an associate professor in the department of obstetrics and gynecology and division of maternal fetal medicine at the University of Texas Medical Branch in Galveston, to discuss this novel and exciting new area of research.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

 

In medicine, there are many diseases and conditions that pose significant challenges to health care practitioners. For example, within brain science, there are patients with debilitating neurodegenerative diseases; within emergency medicine, there are patients who have suffered severe and acute trauma; within pediatrics, there are patients with terminal illnesses, such as cancer. In ob.gyn., one of the great obstetrical syndromes is preeclampsia.

Humans have known about preeclampsia for thousands of years, dating back to the 4th and 5th centuries B.C., since the time of Hippocrates. Ancient writings on medical conditions of women reflect a recognition of preeclampsia and eclampsia, although formal classification of the condition as a hypertensive disorder associated specifically with pregnancy did not occur until the late 1800s. Despite this, the pathology of preeclampsia is significantly underdefined, and because the underlying causes of preeclampsia are largely unknown, prevention and management continue to be hindered.

Our approach to managing women with hypertensive disorders of pregnancy has been one predicated on watchfulness and appropriate timing of delivery. Pharmacologic interventions have been primarily practical and not heavily reliant on scientific evidence. Use of magnesium sulfate is based on temporizing outcomes; use of aspirin and bed rest are similar.

However, recent research indicating an association between statin use and prevention of preeclampsia has given us some hope that targeted management is possible. As ob.gyns. continue to grapple with the intricacies of managing patients with preeclampsia, a condition we increasingly see because of concurrent rises in being overweight, being obese, and having diabetes during pregnancy, so we are eager to see whether the research might confirm an effective role for statins in patient care. Although statins are still quite far from becoming a new standard of care, we are, as a specialty, hungry for a solution to this millennia-old problem.

Therefore, this month we have invited Maged Costantine, MD, an associate professor in the department of obstetrics and gynecology and division of maternal fetal medicine at the University of Texas Medical Branch in Galveston, to discuss this novel and exciting new area of research.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Cutaneous lupus erythematosus can be classified into acute, subacute, and chronic lesions. Chronic cutaneous lupus, or discoid lupus erythematosus (DLE), may occur independently of or in combination with systemic lupus erythematosus (SLE). They are one of the more common skin presentations seen in lupus. Young adults are typically affected, with a female-to-male ratio of 2:1. Progression from DLE to SLE is uncommon. However, patients with SLE will frequently develop discoid lesions.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Lesions generally occur on the head and neck, with scalp and ears (conchal bowls) frequently affected. DLE lesions often begin as erythematous papules or plaques that may become scaly and heal with atrophy, scarring and dyspigmentation (often central hypopigmentation with peripheral hyperpigmentation). Follicular plugging is often seen in lesions. Erosions may occur. A small percentage of patients may have mucosal involvement, including the lips. Sun exposure may have a role in the development of lesions, although lesions may also occur in non–sun exposed areas. Less commonly, DLE may be generalized and involve the trunk and extremities, in addition to the head and neck. Scarring alopecia can be present on the scalp. Scarring may become disfiguring.

The differential diagnosis includes: subacute cutaneous lupus, lichen planus, seborrheic dermatitis, Jessner’s lymphocytic infiltrate, polymorphous light eruption, rosacea, granuloma faciale, and sarcoidosis. Histology of DLE may reveal hyperkeratosis, a thin epidermis with effacement of the rete ridges, a lichenoid and vacuolar interface dermatitis, and follicular plugging. Damaged keratinocytes called colloid bodies may be present. Increased mucin and thickening of the basement membrane are commonly seen. Active lesions will exhibit more of an inflammatory infiltrate. Direct immunofluorescence of lesional skin is positive in more than 75% of cases.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Treatment includes sunscreen and avoidance of sun exposure. Potent or superpotent topical corticosteroids, as well as lesional injections of triamcinolone are helpful. Although, generally, it is not advised to use a high-potency steroid on the face, it can be helpful in DLE. Application should be limited to affected areas for short periods of time, with frequent monitoring for possible side effects. Topical calcineurin inhibitors can be used in addition to topical corticosteroids. If systemic treatment is indicated, hydroxychloroquine is first line. Short-term oral corticosteroid treatment can be used while transitioning to other systemic medications. Our patient had negative serologies and responded to high-dose topical steroids with complete clearing of cutaneous lesions.
This case and the photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Cutaneous lupus erythematosus can be classified into acute, subacute, and chronic lesions. Chronic cutaneous lupus, or discoid lupus erythematosus (DLE), may occur independently of or in combination with systemic lupus erythematosus (SLE). They are one of the more common skin presentations seen in lupus. Young adults are typically affected, with a female-to-male ratio of 2:1. Progression from DLE to SLE is uncommon. However, patients with SLE will frequently develop discoid lesions.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Lesions generally occur on the head and neck, with scalp and ears (conchal bowls) frequently affected. DLE lesions often begin as erythematous papules or plaques that may become scaly and heal with atrophy, scarring and dyspigmentation (often central hypopigmentation with peripheral hyperpigmentation). Follicular plugging is often seen in lesions. Erosions may occur. A small percentage of patients may have mucosal involvement, including the lips. Sun exposure may have a role in the development of lesions, although lesions may also occur in non–sun exposed areas. Less commonly, DLE may be generalized and involve the trunk and extremities, in addition to the head and neck. Scarring alopecia can be present on the scalp. Scarring may become disfiguring.

The differential diagnosis includes: subacute cutaneous lupus, lichen planus, seborrheic dermatitis, Jessner’s lymphocytic infiltrate, polymorphous light eruption, rosacea, granuloma faciale, and sarcoidosis. Histology of DLE may reveal hyperkeratosis, a thin epidermis with effacement of the rete ridges, a lichenoid and vacuolar interface dermatitis, and follicular plugging. Damaged keratinocytes called colloid bodies may be present. Increased mucin and thickening of the basement membrane are commonly seen. Active lesions will exhibit more of an inflammatory infiltrate. Direct immunofluorescence of lesional skin is positive in more than 75% of cases.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Treatment includes sunscreen and avoidance of sun exposure. Potent or superpotent topical corticosteroids, as well as lesional injections of triamcinolone are helpful. Although, generally, it is not advised to use a high-potency steroid on the face, it can be helpful in DLE. Application should be limited to affected areas for short periods of time, with frequent monitoring for possible side effects. Topical calcineurin inhibitors can be used in addition to topical corticosteroids. If systemic treatment is indicated, hydroxychloroquine is first line. Short-term oral corticosteroid treatment can be used while transitioning to other systemic medications. Our patient had negative serologies and responded to high-dose topical steroids with complete clearing of cutaneous lesions.
This case and the photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

Cutaneous lupus erythematosus can be classified into acute, subacute, and chronic lesions. Chronic cutaneous lupus, or discoid lupus erythematosus (DLE), may occur independently of or in combination with systemic lupus erythematosus (SLE). They are one of the more common skin presentations seen in lupus. Young adults are typically affected, with a female-to-male ratio of 2:1. Progression from DLE to SLE is uncommon. However, patients with SLE will frequently develop discoid lesions.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Lesions generally occur on the head and neck, with scalp and ears (conchal bowls) frequently affected. DLE lesions often begin as erythematous papules or plaques that may become scaly and heal with atrophy, scarring and dyspigmentation (often central hypopigmentation with peripheral hyperpigmentation). Follicular plugging is often seen in lesions. Erosions may occur. A small percentage of patients may have mucosal involvement, including the lips. Sun exposure may have a role in the development of lesions, although lesions may also occur in non–sun exposed areas. Less commonly, DLE may be generalized and involve the trunk and extremities, in addition to the head and neck. Scarring alopecia can be present on the scalp. Scarring may become disfiguring.

The differential diagnosis includes: subacute cutaneous lupus, lichen planus, seborrheic dermatitis, Jessner’s lymphocytic infiltrate, polymorphous light eruption, rosacea, granuloma faciale, and sarcoidosis. Histology of DLE may reveal hyperkeratosis, a thin epidermis with effacement of the rete ridges, a lichenoid and vacuolar interface dermatitis, and follicular plugging. Damaged keratinocytes called colloid bodies may be present. Increased mucin and thickening of the basement membrane are commonly seen. Active lesions will exhibit more of an inflammatory infiltrate. Direct immunofluorescence of lesional skin is positive in more than 75% of cases.

Courtesy Dr. Donna Bilu Martin, Premier Dermatology, MD, Aventura, Fla.

Treatment includes sunscreen and avoidance of sun exposure. Potent or superpotent topical corticosteroids, as well as lesional injections of triamcinolone are helpful. Although, generally, it is not advised to use a high-potency steroid on the face, it can be helpful in DLE. Application should be limited to affected areas for short periods of time, with frequent monitoring for possible side effects. Topical calcineurin inhibitors can be used in addition to topical corticosteroids. If systemic treatment is indicated, hydroxychloroquine is first line. Short-term oral corticosteroid treatment can be used while transitioning to other systemic medications. Our patient had negative serologies and responded to high-dose topical steroids with complete clearing of cutaneous lesions.
This case and the photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].

 

More than 20 years ago the Institute of Medicine (recently renamed the National Academy of Medicine, or NAM) issued its landmark report on fetal alcohol syndrome. Since then, there has been an explosion of research on the issue of fetal alcohol exposure – and NAM needs to revisit the issue and release another report.

Recently, NAM has published another important report, “Perspectives on health equity & social determinates of health.” In this report, I contributed a chapter examining the impact of fetal alcohol spectrum disorders (FASD) in the African American community. The chapter underscores several vital issues that are necessary for public health and a strengthening of health equity. It suggests that the problem of fetal alcohol exposure disproportionately affects people of color because of the social determinant of more alcohol flooding low-income communities of color.

Unfortunately, too few physicians and not enough people in the larger society understand public health and that the health status of the unfortunate among us affects the health status of the most fortunate of us. In short, low-income people are the proverbial “canary in the coal mine.”

Accordingly, solving the health care problems of low-income people would solve the health care problems of the middle and upper class. Consider where the United States would be had we paid attention to the opioid epidemic in low-income communities instead of waiting until it spread into everyone’s “safe” communities. We would have tried and tested solutions to the problem as it currently exists.

Another reason NAM needs to revisit FASD – currently proposed to be called neurobehavioral disorders associated with prenatal alcohol exposure in the DSM-5 – are the new findings that link FASD to seizure disorders and other neurodevelopmental disorders of childhood, such as intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, motor disorders, specific learning disorders, and autism. In fact, new research is emerging from Robert Freedman, MD, and his team at the University of Colorado Denver, to suggest that preventing choline deficiency in pregnancy (the mechanism producing neurodevelopmental defects in FASD) may not only prevent neurodevelopmental disorders of childhood but also schizophrenia. Further, it has become abundantly clear that choline deficiency (often generated by FASD), is responsible for affect dysregulation, which is a common thread in various forms of violence and suicide.

A recent report highlighted the findings that inmates incarcerated in Mexican prisons have high rates of intellectual disability, and we know that FASD is one of the leading causes of this problem, but we are not screening for it in our juvenile detention centers, jails, or prisons. Consequently, we need to look for the prevalence of FASD in special education as well as in foster care, because these services often feed our correctional institutions. There also is some recent animal evidence suggesting that sufficient prenatal choline during pregnancy may be protective against Alzheimer’s disease – soon to be an even greater public problem in the United States. Lastly, the neuroscience findings regarding FASD also are emerging.

Hence, there is substantial information growing in various, different but overlapping areas of our systems addressing the nation’s public health and well-being. One of the most respected sources of credible science in America is the National Academy Science. The NAM should convene a meeting of the experts to examine the current state of FASD knowledge. If there is sufficient new information, the NAM needs to develop a new report on FASD. It has been 21 years since the first FAS report from the Institute of Medicine and it needs to be revisited. But it appears that the correctional, child protective services, special education, and mental health fields are not aware of the breadth of available research and its importance to the nation’s public health. Determining how fetal alcohol exposure/choline deficiency affects children and adults in special education, foster care, juvenile and adult corrections systems – along with such other social issues as prematurity, disability, unemployment, homelessness, suicide, violence, and mental health – is critical to our nation’s future.
 

Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago, clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago, former president/CEO of Community Mental Health Council, and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.

 

More than 20 years ago the Institute of Medicine (recently renamed the National Academy of Medicine, or NAM) issued its landmark report on fetal alcohol syndrome. Since then, there has been an explosion of research on the issue of fetal alcohol exposure – and NAM needs to revisit the issue and release another report.

Recently, NAM has published another important report, “Perspectives on health equity & social determinates of health.” In this report, I contributed a chapter examining the impact of fetal alcohol spectrum disorders (FASD) in the African American community. The chapter underscores several vital issues that are necessary for public health and a strengthening of health equity. It suggests that the problem of fetal alcohol exposure disproportionately affects people of color because of the social determinant of more alcohol flooding low-income communities of color.

Unfortunately, too few physicians and not enough people in the larger society understand public health and that the health status of the unfortunate among us affects the health status of the most fortunate of us. In short, low-income people are the proverbial “canary in the coal mine.”

Accordingly, solving the health care problems of low-income people would solve the health care problems of the middle and upper class. Consider where the United States would be had we paid attention to the opioid epidemic in low-income communities instead of waiting until it spread into everyone’s “safe” communities. We would have tried and tested solutions to the problem as it currently exists.

Another reason NAM needs to revisit FASD – currently proposed to be called neurobehavioral disorders associated with prenatal alcohol exposure in the DSM-5 – are the new findings that link FASD to seizure disorders and other neurodevelopmental disorders of childhood, such as intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, motor disorders, specific learning disorders, and autism. In fact, new research is emerging from Robert Freedman, MD, and his team at the University of Colorado Denver, to suggest that preventing choline deficiency in pregnancy (the mechanism producing neurodevelopmental defects in FASD) may not only prevent neurodevelopmental disorders of childhood but also schizophrenia. Further, it has become abundantly clear that choline deficiency (often generated by FASD), is responsible for affect dysregulation, which is a common thread in various forms of violence and suicide.

A recent report highlighted the findings that inmates incarcerated in Mexican prisons have high rates of intellectual disability, and we know that FASD is one of the leading causes of this problem, but we are not screening for it in our juvenile detention centers, jails, or prisons. Consequently, we need to look for the prevalence of FASD in special education as well as in foster care, because these services often feed our correctional institutions. There also is some recent animal evidence suggesting that sufficient prenatal choline during pregnancy may be protective against Alzheimer’s disease – soon to be an even greater public problem in the United States. Lastly, the neuroscience findings regarding FASD also are emerging.

Hence, there is substantial information growing in various, different but overlapping areas of our systems addressing the nation’s public health and well-being. One of the most respected sources of credible science in America is the National Academy Science. The NAM should convene a meeting of the experts to examine the current state of FASD knowledge. If there is sufficient new information, the NAM needs to develop a new report on FASD. It has been 21 years since the first FAS report from the Institute of Medicine and it needs to be revisited. But it appears that the correctional, child protective services, special education, and mental health fields are not aware of the breadth of available research and its importance to the nation’s public health. Determining how fetal alcohol exposure/choline deficiency affects children and adults in special education, foster care, juvenile and adult corrections systems – along with such other social issues as prematurity, disability, unemployment, homelessness, suicide, violence, and mental health – is critical to our nation’s future.
 

Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago, clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago, former president/CEO of Community Mental Health Council, and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.

 

More than 20 years ago the Institute of Medicine (recently renamed the National Academy of Medicine, or NAM) issued its landmark report on fetal alcohol syndrome. Since then, there has been an explosion of research on the issue of fetal alcohol exposure – and NAM needs to revisit the issue and release another report.

Recently, NAM has published another important report, “Perspectives on health equity & social determinates of health.” In this report, I contributed a chapter examining the impact of fetal alcohol spectrum disorders (FASD) in the African American community. The chapter underscores several vital issues that are necessary for public health and a strengthening of health equity. It suggests that the problem of fetal alcohol exposure disproportionately affects people of color because of the social determinant of more alcohol flooding low-income communities of color.

Unfortunately, too few physicians and not enough people in the larger society understand public health and that the health status of the unfortunate among us affects the health status of the most fortunate of us. In short, low-income people are the proverbial “canary in the coal mine.”

Accordingly, solving the health care problems of low-income people would solve the health care problems of the middle and upper class. Consider where the United States would be had we paid attention to the opioid epidemic in low-income communities instead of waiting until it spread into everyone’s “safe” communities. We would have tried and tested solutions to the problem as it currently exists.

Another reason NAM needs to revisit FASD – currently proposed to be called neurobehavioral disorders associated with prenatal alcohol exposure in the DSM-5 – are the new findings that link FASD to seizure disorders and other neurodevelopmental disorders of childhood, such as intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, motor disorders, specific learning disorders, and autism. In fact, new research is emerging from Robert Freedman, MD, and his team at the University of Colorado Denver, to suggest that preventing choline deficiency in pregnancy (the mechanism producing neurodevelopmental defects in FASD) may not only prevent neurodevelopmental disorders of childhood but also schizophrenia. Further, it has become abundantly clear that choline deficiency (often generated by FASD), is responsible for affect dysregulation, which is a common thread in various forms of violence and suicide.

A recent report highlighted the findings that inmates incarcerated in Mexican prisons have high rates of intellectual disability, and we know that FASD is one of the leading causes of this problem, but we are not screening for it in our juvenile detention centers, jails, or prisons. Consequently, we need to look for the prevalence of FASD in special education as well as in foster care, because these services often feed our correctional institutions. There also is some recent animal evidence suggesting that sufficient prenatal choline during pregnancy may be protective against Alzheimer’s disease – soon to be an even greater public problem in the United States. Lastly, the neuroscience findings regarding FASD also are emerging.

Hence, there is substantial information growing in various, different but overlapping areas of our systems addressing the nation’s public health and well-being. One of the most respected sources of credible science in America is the National Academy Science. The NAM should convene a meeting of the experts to examine the current state of FASD knowledge. If there is sufficient new information, the NAM needs to develop a new report on FASD. It has been 21 years since the first FAS report from the Institute of Medicine and it needs to be revisited. But it appears that the correctional, child protective services, special education, and mental health fields are not aware of the breadth of available research and its importance to the nation’s public health. Determining how fetal alcohol exposure/choline deficiency affects children and adults in special education, foster care, juvenile and adult corrections systems – along with such other social issues as prematurity, disability, unemployment, homelessness, suicide, violence, and mental health – is critical to our nation’s future.
 

Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago, clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago, former president/CEO of Community Mental Health Council, and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.

 

Most mature surgeons and surgical educators have been asked by hopeful young medical students: “What can I do to improve my chances of becoming a surgeon?” We all want to give our aspiring students encouraging yet truthful answers. The following are typical questions we get from students, and we have tried to provide responses that are both helpful and realistic given the individual circumstances. Do young hopefuls query you about what it takes to become a surgeon? If so, we invite you to let us know what kinds of questions you get and how you respond. We all want “the best and the brightest” to join our profession, and we can help make that happen by offering sound advice to those who come to us asking “How can I become a surgeon?”

Dear Dr. Hughes,

I am a first-year medical student and want to become a surgeon! Everyone tells me I have to have at least two publications to even be considered for an interview. Is this true? What is the best area of research for me to pursue to assure a match in a surgery residency?

Unpublished in the Midwest


Dear Unpublished,

Like almost everything in life, the answer to your question is “It depends.” Surgery is a field that covers such a wide range of opportunities and training options that there is no “perfect” path to residency. More than anything at the M1 level, you need to keep your options open for any discipline. During the next 3 years, you’ll find out much about yourself and about the breadth of medicine. You need to understand who you are as a person before deciding on a specialty and especially before embarking on a research project. Research is a crucial part of surgery, but research just to have a publication for your resume is not a good enough reason to take this on during medical school.

The pursuit of knowledge through research is best undertaken because you have a passion for a particular subject. Most program directors will see right through “insincere” research – that is, research done to puff up a resume but lacking underlying value or relevance to your personal interests.

In addition, medical school is a process of transforming what you know and how you think. It requires your full attention. Among the keys to being able to choose a residency rather than simply praying you get a slot somewhere is the accumulation of real knowledge, doing well on Step I of the United States Medical Licensing Exam (USMLE) examinations (Step II is actually less important overall), and having teachers and mentors who know you well enough to give honest and accurate letters of reference for the programs to which you apply. If along the way you find an area of study that bears the fruit of research, great – but four mediocre papers will not overcome a low class ranking or a low Step I score. If you instead focus on being the best student of medicine you can be, you are likely to find yourself in the happy position of having good grades and a good academic profile, which may or may not include a publication or poster. While you can try to “game” the match system by filling your application with papers and writing a passionate personal statement, ultimately you’ll be great at your chosen field because you love it. Good luck (and make sure your life on social media is one that doesn’t require complicated explanations).

Tyler Hughes, MD, FACS


Dear Dr. Deveney,

I am in the middle of my third year of medical school. I have wanted to be a rural general surgeon ever since I shadowed the surgeon in my home town and saw the impact he made on the lives of his patients – and they made on his. Unfortunately, I do not do well on standardized tests and scored only 216 on USMLE Step 1. I did earn “Honors” in my surgery clerkship, but only a “Pass” in Medicine, with other clerkships still pending. What can I do to maximize my chances of a successful match in a surgical residency?

Discouraged in Denver


Dear Discouraged,

Since medical students are applying to a larger number of programs every year, surgical training programs receive far more applicants than they can interview. Most programs use USMLE Step 1 score as a convenient way to filter applicants and interview only students who have scored above an arbitrary threshold, such as 220, 230, or 240. We all know that USMLE Step 1 score does not correlate well with how good a surgeon you will be, but it does correlate with the likelihood of passing the American Board of Surgery Qualifying Exam on the first attempt. Programs are in part judged on their Board passage rate by both applicants and by accrediting agencies. Your score of 216 means that you will need to apply widely to programs across the country.

Given your interest in rural surgery, you should focus on community and independent programs that often have fewer fellows and specialty residencies to expand the breadth of your clinical experience. Look at the list of residencies that have a rural track or focus. You can find information about these programs on the American College of Surgeons’ website in the online guide entitled “So You Want to be a Surgeon.” Apply now to do a visiting rotation at one or more of the programs that most appeal to you. Ask the program director at your school which programs he/she recommends that would be within your reach.

I urge you to join the American College of Surgeons as a student member and attend the 2018 Clinical Congress meeting. Attend its medical student program, and meet as many program directors as you can at the “Meet and Greet” receptions.

Programs in which you will thrive are ones that value a person who pitches in and helps the team get the daily work done. Surgery is a team sport! You need to be unfailingly pleasant and positive and be able to tie a knot and suture an incision smoothly. Chance favors the prepared mind and hands! Good luck!

Karen E. Deveney, MD, FACS

 

Most mature surgeons and surgical educators have been asked by hopeful young medical students: “What can I do to improve my chances of becoming a surgeon?” We all want to give our aspiring students encouraging yet truthful answers. The following are typical questions we get from students, and we have tried to provide responses that are both helpful and realistic given the individual circumstances. Do young hopefuls query you about what it takes to become a surgeon? If so, we invite you to let us know what kinds of questions you get and how you respond. We all want “the best and the brightest” to join our profession, and we can help make that happen by offering sound advice to those who come to us asking “How can I become a surgeon?”

Dear Dr. Hughes,

I am a first-year medical student and want to become a surgeon! Everyone tells me I have to have at least two publications to even be considered for an interview. Is this true? What is the best area of research for me to pursue to assure a match in a surgery residency?

Unpublished in the Midwest


Dear Unpublished,

Like almost everything in life, the answer to your question is “It depends.” Surgery is a field that covers such a wide range of opportunities and training options that there is no “perfect” path to residency. More than anything at the M1 level, you need to keep your options open for any discipline. During the next 3 years, you’ll find out much about yourself and about the breadth of medicine. You need to understand who you are as a person before deciding on a specialty and especially before embarking on a research project. Research is a crucial part of surgery, but research just to have a publication for your resume is not a good enough reason to take this on during medical school.

The pursuit of knowledge through research is best undertaken because you have a passion for a particular subject. Most program directors will see right through “insincere” research – that is, research done to puff up a resume but lacking underlying value or relevance to your personal interests.

In addition, medical school is a process of transforming what you know and how you think. It requires your full attention. Among the keys to being able to choose a residency rather than simply praying you get a slot somewhere is the accumulation of real knowledge, doing well on Step I of the United States Medical Licensing Exam (USMLE) examinations (Step II is actually less important overall), and having teachers and mentors who know you well enough to give honest and accurate letters of reference for the programs to which you apply. If along the way you find an area of study that bears the fruit of research, great – but four mediocre papers will not overcome a low class ranking or a low Step I score. If you instead focus on being the best student of medicine you can be, you are likely to find yourself in the happy position of having good grades and a good academic profile, which may or may not include a publication or poster. While you can try to “game” the match system by filling your application with papers and writing a passionate personal statement, ultimately you’ll be great at your chosen field because you love it. Good luck (and make sure your life on social media is one that doesn’t require complicated explanations).

Tyler Hughes, MD, FACS


Dear Dr. Deveney,

I am in the middle of my third year of medical school. I have wanted to be a rural general surgeon ever since I shadowed the surgeon in my home town and saw the impact he made on the lives of his patients – and they made on his. Unfortunately, I do not do well on standardized tests and scored only 216 on USMLE Step 1. I did earn “Honors” in my surgery clerkship, but only a “Pass” in Medicine, with other clerkships still pending. What can I do to maximize my chances of a successful match in a surgical residency?

Discouraged in Denver


Dear Discouraged,

Since medical students are applying to a larger number of programs every year, surgical training programs receive far more applicants than they can interview. Most programs use USMLE Step 1 score as a convenient way to filter applicants and interview only students who have scored above an arbitrary threshold, such as 220, 230, or 240. We all know that USMLE Step 1 score does not correlate well with how good a surgeon you will be, but it does correlate with the likelihood of passing the American Board of Surgery Qualifying Exam on the first attempt. Programs are in part judged on their Board passage rate by both applicants and by accrediting agencies. Your score of 216 means that you will need to apply widely to programs across the country.

Given your interest in rural surgery, you should focus on community and independent programs that often have fewer fellows and specialty residencies to expand the breadth of your clinical experience. Look at the list of residencies that have a rural track or focus. You can find information about these programs on the American College of Surgeons’ website in the online guide entitled “So You Want to be a Surgeon.” Apply now to do a visiting rotation at one or more of the programs that most appeal to you. Ask the program director at your school which programs he/she recommends that would be within your reach.

I urge you to join the American College of Surgeons as a student member and attend the 2018 Clinical Congress meeting. Attend its medical student program, and meet as many program directors as you can at the “Meet and Greet” receptions.

Programs in which you will thrive are ones that value a person who pitches in and helps the team get the daily work done. Surgery is a team sport! You need to be unfailingly pleasant and positive and be able to tie a knot and suture an incision smoothly. Chance favors the prepared mind and hands! Good luck!

Karen E. Deveney, MD, FACS

 

Most mature surgeons and surgical educators have been asked by hopeful young medical students: “What can I do to improve my chances of becoming a surgeon?” We all want to give our aspiring students encouraging yet truthful answers. The following are typical questions we get from students, and we have tried to provide responses that are both helpful and realistic given the individual circumstances. Do young hopefuls query you about what it takes to become a surgeon? If so, we invite you to let us know what kinds of questions you get and how you respond. We all want “the best and the brightest” to join our profession, and we can help make that happen by offering sound advice to those who come to us asking “How can I become a surgeon?”

Dear Dr. Hughes,

I am a first-year medical student and want to become a surgeon! Everyone tells me I have to have at least two publications to even be considered for an interview. Is this true? What is the best area of research for me to pursue to assure a match in a surgery residency?

Unpublished in the Midwest


Dear Unpublished,

Like almost everything in life, the answer to your question is “It depends.” Surgery is a field that covers such a wide range of opportunities and training options that there is no “perfect” path to residency. More than anything at the M1 level, you need to keep your options open for any discipline. During the next 3 years, you’ll find out much about yourself and about the breadth of medicine. You need to understand who you are as a person before deciding on a specialty and especially before embarking on a research project. Research is a crucial part of surgery, but research just to have a publication for your resume is not a good enough reason to take this on during medical school.

The pursuit of knowledge through research is best undertaken because you have a passion for a particular subject. Most program directors will see right through “insincere” research – that is, research done to puff up a resume but lacking underlying value or relevance to your personal interests.

In addition, medical school is a process of transforming what you know and how you think. It requires your full attention. Among the keys to being able to choose a residency rather than simply praying you get a slot somewhere is the accumulation of real knowledge, doing well on Step I of the United States Medical Licensing Exam (USMLE) examinations (Step II is actually less important overall), and having teachers and mentors who know you well enough to give honest and accurate letters of reference for the programs to which you apply. If along the way you find an area of study that bears the fruit of research, great – but four mediocre papers will not overcome a low class ranking or a low Step I score. If you instead focus on being the best student of medicine you can be, you are likely to find yourself in the happy position of having good grades and a good academic profile, which may or may not include a publication or poster. While you can try to “game” the match system by filling your application with papers and writing a passionate personal statement, ultimately you’ll be great at your chosen field because you love it. Good luck (and make sure your life on social media is one that doesn’t require complicated explanations).

Tyler Hughes, MD, FACS


Dear Dr. Deveney,

I am in the middle of my third year of medical school. I have wanted to be a rural general surgeon ever since I shadowed the surgeon in my home town and saw the impact he made on the lives of his patients – and they made on his. Unfortunately, I do not do well on standardized tests and scored only 216 on USMLE Step 1. I did earn “Honors” in my surgery clerkship, but only a “Pass” in Medicine, with other clerkships still pending. What can I do to maximize my chances of a successful match in a surgical residency?

Discouraged in Denver


Dear Discouraged,

Since medical students are applying to a larger number of programs every year, surgical training programs receive far more applicants than they can interview. Most programs use USMLE Step 1 score as a convenient way to filter applicants and interview only students who have scored above an arbitrary threshold, such as 220, 230, or 240. We all know that USMLE Step 1 score does not correlate well with how good a surgeon you will be, but it does correlate with the likelihood of passing the American Board of Surgery Qualifying Exam on the first attempt. Programs are in part judged on their Board passage rate by both applicants and by accrediting agencies. Your score of 216 means that you will need to apply widely to programs across the country.

Given your interest in rural surgery, you should focus on community and independent programs that often have fewer fellows and specialty residencies to expand the breadth of your clinical experience. Look at the list of residencies that have a rural track or focus. You can find information about these programs on the American College of Surgeons’ website in the online guide entitled “So You Want to be a Surgeon.” Apply now to do a visiting rotation at one or more of the programs that most appeal to you. Ask the program director at your school which programs he/she recommends that would be within your reach.

I urge you to join the American College of Surgeons as a student member and attend the 2018 Clinical Congress meeting. Attend its medical student program, and meet as many program directors as you can at the “Meet and Greet” receptions.

Programs in which you will thrive are ones that value a person who pitches in and helps the team get the daily work done. Surgery is a team sport! You need to be unfailingly pleasant and positive and be able to tie a knot and suture an incision smoothly. Chance favors the prepared mind and hands! Good luck!

Karen E. Deveney, MD, FACS

 

There are currently 15 drugs indicated for adverse conditions of the urinary tract. The reported frequency of use in pregnancy and during breastfeeding for most of these agents is very low or completely absent.

The five subclasses of urinary tract agents are analgesics, antispasmodics, urinary acidifiers, urinary alkalinizers, and urinary germicides. With the exception of the three urinary germicides, anti-infectives are not covered in this column.

 

Analgesics

The analgesic subclass includes pentosan and phenazopyridine. Pentosan (Elmiron), a heparinlike compound, is an oral drug that is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. Systemic absorption is low, at about 6%. Because of the high molecular weight (4,000-6,000), it does not appear to cross the placenta, at least in the first half of pregnancy. A 1975 reference described its use in five women with preeclampsia. Each patient received 100 mg intramuscularly every 8 hours for about 5 days in the last weeks of pregnancy. No maternal benefit from the therapy was observed. There was apparently no fetal harm, but the neonatal outcomes were not described.

There are substantial – more than 900 – human pregnancy exposures in the first trimester with phenazopyridine. The exposures were not related to an increased risk of embryo-fetal harm and so use of the drug in pregnancy can be classified as compatible. However, the low molecular weight (about 214 for the free base) suggests that the drug will cross to the embryo and fetus.
 

Antispasmodics

The eight antispasmodics are darifenacin (Enablex), fesoterodine (Toviaz), flavoxate, mirabegron (Myrbetriq), oxybutynin (Ditropan XL), solifenacin (Vesicare), tolterodine (Detrol LA), and trospium.

These agents are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The molecular weights range between 342 and 508, suggesting that all will cross the human placenta. There are no human pregnancy data for six of these agents and very limited data for flavoxate and oxybutynin. There is no evidence of embryo-fetal harm from these two drugs, but only one case involved exposure in the first trimester.

In seven of these drugs, the animal data suggested low risk. There was no embryo harm from doses that were equal to or less than 10 times the human dose based on body surface area (BSA) or area under the concentration curve (AUC). Solifenacin did cause embryo toxicity in pregnant mice. There was no embryo toxicity in pregnant rats and rabbits, but the maximum doses used were very low. Overall, the available data suggest that exposure to an antispasmodic in pregnancy is low risk for embryo, fetal, and newborn harm.
 

Urinary acidifiers

Ammonium chloride is a urinary acidifier as well as a respiratory expectorant. There is a large amount of data related to when the drug was used as an expectorant. There was no evidence that this use was associated with large categories of major or minor malformations. However, there were possible associations with three individual defects: inguinal hernia, cataract, and any benign tumor. No reports describing its use as a urinary acidifier have been located. When large amounts are consumed near term, the drug may cause acidosis in the mother and fetus. The molecular weight (about 53) suggests that it will cross the placenta.

Urinary alkalinizers

Potassium citrate (Urocit-K) is indicated for the management of renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate with nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones. The molecular weight (about 307) suggests it will cross the placenta. Only one case of its use in pregnancy has been located. The newborn had an unspecified defect but no other information was provided. The animal data in four species suggest low risk.

Urinary germicides

There are three urinary germicides: methenamine, methylene blue, and nitrofurantoin. Methenamine is available as methenamine mandelate (molecular weight abut 292) and methenamine hippurate (molecular weight about 319). Both are metabolized to formaldehyde (molecular weight about 30), the active agent. The molecular weights suggest that all will cross the placenta. The use of methenamine during pregnancy has been reported in more than 750 pregnancies. There have been no embryo or fetal adverse effects attributed to the drug.

The human data involving oral methylene blue, a weak urinary germicide, is limited to 55 exposures. There were three infants with birth defects (type not specified). Several reports have described the use of intra-amniotic injections to assist in the diagnosis of suspected membrane rupture. This use has resulted in newborns with hemolytic anemia, hyperbilirubinemia with or without Heinz body formation, blue staining of the skin, and methemoglobinemia. Fetal deaths have also been described. Recommendations to avoid the intra-amniotic use of methylene blue were issued more than 10 years ago. Moreover, the use of oral methylene blue as a urinary germicide is no longer recommended.

The low molecular weight (about 238) of nitrofurantoin suggests that it will cross the placenta. It is commonly used in pregnancy for the treatment or prophylaxis of urinary tract infections. The large amount of human data indicates that the risk of drug-induced birth defects is low. Several cohort studies have found no increased risk for birth defects. However, some case-control studies have found increased risks for hypoplastic left heart syndrome and oral clefts. A 2015 review concluded that this difference was due to the increased sensitivity of case-control studies to detect adverse effects (J Obstet Gynaecol Can. 2015 Feb;37[2]:150-6).

Use of the drug close to term may cause hemolytic anemia in newborns who are glucose-6-phosphate dehydrogenase (G6PD) deficient. Although rare, this may also occur in newborns who are not G6PD deficient. The best course is to avoid use of the drug close to delivery. As for use of the drug in the first trimester, ACOG’s Committee on Obstetric Practice stated in Committee Opinion No. 717 that nitrofurantoin was still thought to be appropriate when no other suitable alternative antibiotics were available (Obstet Gynecol. 2017 Sept;130[3]:666-7).
 

Breastfeeding

Except for methenamine and nitrofurantoin, there are no data related to the use of the urinary tract drugs during breastfeeding. Peak levels of methenamine occur at 1 hour, but no reports of adverse effects on nursing infants have been located. Several reports have described the use of nitrofurantoin during breastfeeding. Minor diarrhea was noted in two infants. However, breastfeeding an infant with G6PD deficiency could lead to hemolytic anemia.

Phenazopyridine should be used with caution especially for an infant younger than 1 month or with G6PD deficiency because of the risk for methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia.

Although there have been no reports of the use of mirabegron during lactation, the characteristics of the drug – low molecular weight (about 397), long elimination half life (50 hours), and moderate plasma protein binding (about 71%) – suggest that the drug will be excreted into milk, potentially in clinically significant amounts. There is also concern with use of tolterodine (molecular weight about 476) because both the primary drug and its equipotent metabolite may be excreted into milk.
 

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

There are currently 15 drugs indicated for adverse conditions of the urinary tract. The reported frequency of use in pregnancy and during breastfeeding for most of these agents is very low or completely absent.

The five subclasses of urinary tract agents are analgesics, antispasmodics, urinary acidifiers, urinary alkalinizers, and urinary germicides. With the exception of the three urinary germicides, anti-infectives are not covered in this column.

 

Analgesics

The analgesic subclass includes pentosan and phenazopyridine. Pentosan (Elmiron), a heparinlike compound, is an oral drug that is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. Systemic absorption is low, at about 6%. Because of the high molecular weight (4,000-6,000), it does not appear to cross the placenta, at least in the first half of pregnancy. A 1975 reference described its use in five women with preeclampsia. Each patient received 100 mg intramuscularly every 8 hours for about 5 days in the last weeks of pregnancy. No maternal benefit from the therapy was observed. There was apparently no fetal harm, but the neonatal outcomes were not described.

There are substantial – more than 900 – human pregnancy exposures in the first trimester with phenazopyridine. The exposures were not related to an increased risk of embryo-fetal harm and so use of the drug in pregnancy can be classified as compatible. However, the low molecular weight (about 214 for the free base) suggests that the drug will cross to the embryo and fetus.
 

Antispasmodics

The eight antispasmodics are darifenacin (Enablex), fesoterodine (Toviaz), flavoxate, mirabegron (Myrbetriq), oxybutynin (Ditropan XL), solifenacin (Vesicare), tolterodine (Detrol LA), and trospium.

These agents are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The molecular weights range between 342 and 508, suggesting that all will cross the human placenta. There are no human pregnancy data for six of these agents and very limited data for flavoxate and oxybutynin. There is no evidence of embryo-fetal harm from these two drugs, but only one case involved exposure in the first trimester.

In seven of these drugs, the animal data suggested low risk. There was no embryo harm from doses that were equal to or less than 10 times the human dose based on body surface area (BSA) or area under the concentration curve (AUC). Solifenacin did cause embryo toxicity in pregnant mice. There was no embryo toxicity in pregnant rats and rabbits, but the maximum doses used were very low. Overall, the available data suggest that exposure to an antispasmodic in pregnancy is low risk for embryo, fetal, and newborn harm.
 

Urinary acidifiers

Ammonium chloride is a urinary acidifier as well as a respiratory expectorant. There is a large amount of data related to when the drug was used as an expectorant. There was no evidence that this use was associated with large categories of major or minor malformations. However, there were possible associations with three individual defects: inguinal hernia, cataract, and any benign tumor. No reports describing its use as a urinary acidifier have been located. When large amounts are consumed near term, the drug may cause acidosis in the mother and fetus. The molecular weight (about 53) suggests that it will cross the placenta.

Urinary alkalinizers

Potassium citrate (Urocit-K) is indicated for the management of renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate with nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones. The molecular weight (about 307) suggests it will cross the placenta. Only one case of its use in pregnancy has been located. The newborn had an unspecified defect but no other information was provided. The animal data in four species suggest low risk.

Urinary germicides

There are three urinary germicides: methenamine, methylene blue, and nitrofurantoin. Methenamine is available as methenamine mandelate (molecular weight abut 292) and methenamine hippurate (molecular weight about 319). Both are metabolized to formaldehyde (molecular weight about 30), the active agent. The molecular weights suggest that all will cross the placenta. The use of methenamine during pregnancy has been reported in more than 750 pregnancies. There have been no embryo or fetal adverse effects attributed to the drug.

The human data involving oral methylene blue, a weak urinary germicide, is limited to 55 exposures. There were three infants with birth defects (type not specified). Several reports have described the use of intra-amniotic injections to assist in the diagnosis of suspected membrane rupture. This use has resulted in newborns with hemolytic anemia, hyperbilirubinemia with or without Heinz body formation, blue staining of the skin, and methemoglobinemia. Fetal deaths have also been described. Recommendations to avoid the intra-amniotic use of methylene blue were issued more than 10 years ago. Moreover, the use of oral methylene blue as a urinary germicide is no longer recommended.

The low molecular weight (about 238) of nitrofurantoin suggests that it will cross the placenta. It is commonly used in pregnancy for the treatment or prophylaxis of urinary tract infections. The large amount of human data indicates that the risk of drug-induced birth defects is low. Several cohort studies have found no increased risk for birth defects. However, some case-control studies have found increased risks for hypoplastic left heart syndrome and oral clefts. A 2015 review concluded that this difference was due to the increased sensitivity of case-control studies to detect adverse effects (J Obstet Gynaecol Can. 2015 Feb;37[2]:150-6).

Use of the drug close to term may cause hemolytic anemia in newborns who are glucose-6-phosphate dehydrogenase (G6PD) deficient. Although rare, this may also occur in newborns who are not G6PD deficient. The best course is to avoid use of the drug close to delivery. As for use of the drug in the first trimester, ACOG’s Committee on Obstetric Practice stated in Committee Opinion No. 717 that nitrofurantoin was still thought to be appropriate when no other suitable alternative antibiotics were available (Obstet Gynecol. 2017 Sept;130[3]:666-7).
 

Breastfeeding

Except for methenamine and nitrofurantoin, there are no data related to the use of the urinary tract drugs during breastfeeding. Peak levels of methenamine occur at 1 hour, but no reports of adverse effects on nursing infants have been located. Several reports have described the use of nitrofurantoin during breastfeeding. Minor diarrhea was noted in two infants. However, breastfeeding an infant with G6PD deficiency could lead to hemolytic anemia.

Phenazopyridine should be used with caution especially for an infant younger than 1 month or with G6PD deficiency because of the risk for methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia.

Although there have been no reports of the use of mirabegron during lactation, the characteristics of the drug – low molecular weight (about 397), long elimination half life (50 hours), and moderate plasma protein binding (about 71%) – suggest that the drug will be excreted into milk, potentially in clinically significant amounts. There is also concern with use of tolterodine (molecular weight about 476) because both the primary drug and its equipotent metabolite may be excreted into milk.
 

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

There are currently 15 drugs indicated for adverse conditions of the urinary tract. The reported frequency of use in pregnancy and during breastfeeding for most of these agents is very low or completely absent.

The five subclasses of urinary tract agents are analgesics, antispasmodics, urinary acidifiers, urinary alkalinizers, and urinary germicides. With the exception of the three urinary germicides, anti-infectives are not covered in this column.

 

Analgesics

The analgesic subclass includes pentosan and phenazopyridine. Pentosan (Elmiron), a heparinlike compound, is an oral drug that is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. Systemic absorption is low, at about 6%. Because of the high molecular weight (4,000-6,000), it does not appear to cross the placenta, at least in the first half of pregnancy. A 1975 reference described its use in five women with preeclampsia. Each patient received 100 mg intramuscularly every 8 hours for about 5 days in the last weeks of pregnancy. No maternal benefit from the therapy was observed. There was apparently no fetal harm, but the neonatal outcomes were not described.

There are substantial – more than 900 – human pregnancy exposures in the first trimester with phenazopyridine. The exposures were not related to an increased risk of embryo-fetal harm and so use of the drug in pregnancy can be classified as compatible. However, the low molecular weight (about 214 for the free base) suggests that the drug will cross to the embryo and fetus.
 

Antispasmodics

The eight antispasmodics are darifenacin (Enablex), fesoterodine (Toviaz), flavoxate, mirabegron (Myrbetriq), oxybutynin (Ditropan XL), solifenacin (Vesicare), tolterodine (Detrol LA), and trospium.

These agents are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The molecular weights range between 342 and 508, suggesting that all will cross the human placenta. There are no human pregnancy data for six of these agents and very limited data for flavoxate and oxybutynin. There is no evidence of embryo-fetal harm from these two drugs, but only one case involved exposure in the first trimester.

In seven of these drugs, the animal data suggested low risk. There was no embryo harm from doses that were equal to or less than 10 times the human dose based on body surface area (BSA) or area under the concentration curve (AUC). Solifenacin did cause embryo toxicity in pregnant mice. There was no embryo toxicity in pregnant rats and rabbits, but the maximum doses used were very low. Overall, the available data suggest that exposure to an antispasmodic in pregnancy is low risk for embryo, fetal, and newborn harm.
 

Urinary acidifiers

Ammonium chloride is a urinary acidifier as well as a respiratory expectorant. There is a large amount of data related to when the drug was used as an expectorant. There was no evidence that this use was associated with large categories of major or minor malformations. However, there were possible associations with three individual defects: inguinal hernia, cataract, and any benign tumor. No reports describing its use as a urinary acidifier have been located. When large amounts are consumed near term, the drug may cause acidosis in the mother and fetus. The molecular weight (about 53) suggests that it will cross the placenta.

Urinary alkalinizers

Potassium citrate (Urocit-K) is indicated for the management of renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate with nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones. The molecular weight (about 307) suggests it will cross the placenta. Only one case of its use in pregnancy has been located. The newborn had an unspecified defect but no other information was provided. The animal data in four species suggest low risk.

Urinary germicides

There are three urinary germicides: methenamine, methylene blue, and nitrofurantoin. Methenamine is available as methenamine mandelate (molecular weight abut 292) and methenamine hippurate (molecular weight about 319). Both are metabolized to formaldehyde (molecular weight about 30), the active agent. The molecular weights suggest that all will cross the placenta. The use of methenamine during pregnancy has been reported in more than 750 pregnancies. There have been no embryo or fetal adverse effects attributed to the drug.

The human data involving oral methylene blue, a weak urinary germicide, is limited to 55 exposures. There were three infants with birth defects (type not specified). Several reports have described the use of intra-amniotic injections to assist in the diagnosis of suspected membrane rupture. This use has resulted in newborns with hemolytic anemia, hyperbilirubinemia with or without Heinz body formation, blue staining of the skin, and methemoglobinemia. Fetal deaths have also been described. Recommendations to avoid the intra-amniotic use of methylene blue were issued more than 10 years ago. Moreover, the use of oral methylene blue as a urinary germicide is no longer recommended.

The low molecular weight (about 238) of nitrofurantoin suggests that it will cross the placenta. It is commonly used in pregnancy for the treatment or prophylaxis of urinary tract infections. The large amount of human data indicates that the risk of drug-induced birth defects is low. Several cohort studies have found no increased risk for birth defects. However, some case-control studies have found increased risks for hypoplastic left heart syndrome and oral clefts. A 2015 review concluded that this difference was due to the increased sensitivity of case-control studies to detect adverse effects (J Obstet Gynaecol Can. 2015 Feb;37[2]:150-6).

Use of the drug close to term may cause hemolytic anemia in newborns who are glucose-6-phosphate dehydrogenase (G6PD) deficient. Although rare, this may also occur in newborns who are not G6PD deficient. The best course is to avoid use of the drug close to delivery. As for use of the drug in the first trimester, ACOG’s Committee on Obstetric Practice stated in Committee Opinion No. 717 that nitrofurantoin was still thought to be appropriate when no other suitable alternative antibiotics were available (Obstet Gynecol. 2017 Sept;130[3]:666-7).
 

Breastfeeding

Except for methenamine and nitrofurantoin, there are no data related to the use of the urinary tract drugs during breastfeeding. Peak levels of methenamine occur at 1 hour, but no reports of adverse effects on nursing infants have been located. Several reports have described the use of nitrofurantoin during breastfeeding. Minor diarrhea was noted in two infants. However, breastfeeding an infant with G6PD deficiency could lead to hemolytic anemia.

Phenazopyridine should be used with caution especially for an infant younger than 1 month or with G6PD deficiency because of the risk for methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia.

Although there have been no reports of the use of mirabegron during lactation, the characteristics of the drug – low molecular weight (about 397), long elimination half life (50 hours), and moderate plasma protein binding (about 71%) – suggest that the drug will be excreted into milk, potentially in clinically significant amounts. There is also concern with use of tolterodine (molecular weight about 476) because both the primary drug and its equipotent metabolite may be excreted into milk.
 

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.