Christine Kilgore

Conflict of interest (COI) reporting has moved center stage again in recent months, with some medical journals, professional societies, cancer centers, and academic medical institutions reviewing policies and practices in the wake of a highly publicized disclosure failure last fall at Memorial Sloan Kettering Cancer Center (MSK).

And in some settings, oncologists and other physician researchers are being encouraged to check what the federal Open Payments database says about their payments from industry.

The spotlight is on the field of cancer research and treatment, where MSK’s chief medical officer, José Baselga, MD, PhD, resigned in September 2018 after the New York Times and ProPublica reported that he’d failed to disclose millions of dollars of industry payments and ownership interests in the majority of journal articles he wrote or cowrote over a 4-year period.

Pleas for accuracy

At academic medical institutions, conflicts of interest are identified and then managed; it’s common for researchers’ COI management plans to include requirements for disclosure in all presentations and publications.

Journals and professional medical societies require authors and speakers to submit disclosure forms of varying lengths and with differing questions about relationships with industry, often based on the notion of relevancy to the subject at hand. Disclosure forms are reviewed, but editors and other reviewers rely largely – if not entirely – on the honor system.

Dr. Baselga’s disclosure lapses and his subsequent resignation have rattled leaders in each of these settings. Researchers at MSK were instructed to review their COI disclosures and submit corrections when necessary, and in December 2018 the hospital was reportedly evaluating its process for reviewing conflicts of interest, according to reports in the New York Times and ProPublica. (MSK did not respond to requests for comment about actions taken.)

The Dana Farber Cancer Institute in Boston similarly has “been reminding faculty and other researchers” of their disclosure responsibilities and is conducting a review of “all our policies in this area,” a spokeswoman said. And at Fred Hutchinson Cancer Research Center in Seattle, a spokesman said they have established an internal task force to review individual and institutional COI policies to ensure that COIs are “appropriately managed while also enabling research collaborations that bring scientific advances to our patients.”

Other centers contacted for this article, such as the Cleveland Clinic Cancer Center and the Mayo Clinic Cancer Center, said that they have no new reviews ongoing and no plans to change policies at this time.

The heightened attention to disclosure has, in turn, shone a spotlight on increasingly complex physician-industry relationships and on the Open Payments website run by the Centers for Medicare and Medicaid Services. Open Payments is a disclosure program and database that tracks payments made to physicians and teaching hospitals by drug and device companies.

Journalists, including those who reported on Dr. Baselga’s disclosures, have searched the public database for industry payment data. So have other researchers who have studied financial disclosure statements; a study reported in JAMA Oncology last year, for instance, concluded through the use of Open Payments data that about one-third of authors of cancer drug trial reports did not completely disclose payments from trial sponsors (JAMA Oncol. 2018;4[10]:1426-8).

In a column published in December 2018 in AAMC News, AAMC President and CEO Darrell G. Kirch, MD, wrote that failures to disclose can raise questions about the integrity of research, whether or not there is an actual conflict. He advised institutions to “encourage faculty to review the information posted about them on the Open Payments website” of the CMS to “ensure it is accurate and consistent with disclosures related to all their professional responsibilities.”

ASCO issues similar advice, encouraging authors and CME speakers and participants of other ASCO activities to double-check their disclosures against other sources, including “publicly reported interactions with companies that may have been inadvertently omitted.”

In the world of journals, the New England Journal of Medicine (NEJM) began asking authors at the end of 2018 to “certify that they have reconciled their disclosures” with the Open Payments database, said Jennifer Zeis, a spokeswoman forthe journal.

Time may tell how well such requests work. When the Institute of Medicine (now called the National Academy of Medicine) called on Congress in 2009 to create a national program requiring pharmaceutical, device, and biotechnology companies to publicly report their payments, it envisioned universities, journals, and others using the program to verify disclosures made to them. But the resulting Open Payments database has limitations – for instance, it doesn’t include payments from companies without FDA-approved products, it is not necessarily up to date, and its payment categories do not necessarily match categories of disclosure.

“Some entries in the Open Payments database need further explanation,” said Ms. Zeis of NEJM. “Some authors, for example, have said that the database does not fully and accurately explain that the funds were disbursed not to them personally, but to their academic institutions.” While the database provides transparency, it also “needs context that’s not currently provided,” she said.

Mistakes in the database can also be “very hard to challenge,” said Clifford A. Hudis, MD, CEO of the American Society of Clinical Oncology, which produces the Journal of Clinical Oncology (JCO).

Courtesy American Society of Clinical Oncology

All in all, he said, “there’s really no timely, comprehensive, and fully reliable source of information with which to verify an individual’s disclosures.”

Policies and practices are also under review at the American Association for Cancer Research (AACR) and the American Society of Hematology (ASH).

The AACR has appointed a panel of experts, including physicians, basic scientists, a patient advocate, and others to conduct “a comprehensive review of [its] disclosure policies and to explore whether any current policies need to be revised,” said Rachel Salis-Silverman, director of public relations. It also will convene a session on COI disclosures at its 2019 annual meeting at the end of March, she said.

ASH, which publishes the journal Blood, is exploring possible changes in its “internal processes with regards to ASH publications,” said Matt Gertzog, deputy executive director of the group. COI disclosure is “more of a journey than a destination,” he said. “We are continuously reflecting on and refining our processes.”
 

Moving away from ‘relevancy’

Physicians and others who have relationships with industry have long complained about a patchwork of disclosure requirements, and significant efforts have been made in the last decade to standardize forms and practices. However, the current system is still “a little bit of a Tower of Babel,” said Dr. Hudis of ASCO. “Every day, physicians have to complete from scratch similar, but not identical, disclosure forms that ask similar, but not identical, questions.”

A disclosable compensation amount “might be first dollar, or it might be over $10,000. [Time periods] might cover 1 year, or 3 years. ... Stock ownership might be dollar value, or a percentage of shares,” he explained. “If you want a system that would make it hard to be compliant and easy to mess up, that’s what we have.”

To standardize the COI disclosure process for all Society-related publications and activities – including CME, JCO, and practice guidelines – ASCO moved about 5 years ago to a system of general disclosure, asking physicians and others to disclose all financial interests and industry relationships rather than what they deem relevant.

The thinking was that general disclosure “would be easier for disclosers, and nobody would ever be accused of hiding anything,” Dr. Hudis said.

“We’d [also] recognized,” he explained, “that there was a risk to the relevancy approach in that it put the judgment for the potential conflict in the hands of the potentially conflicted, while others might have a different point of view about what is or isn’t relevant.”

Those concerned about general disclosure worry that it may “obscure [for the reader or listener] what’s really important or the most meaningful,” he said.

Some physicians have expressed in interviews for this article, moreover, the concern that too many disclosures – too long a list of financial relationships – will be viewed negatively. This is something ASCO aims to guard against as it strives to achieve full transparency, Dr. Hudis said. “If one were to suggest that engagement itself is automatically a negative, then you’re starting to put negative pressure on compliance with disclosure.”

And full disclosure matters, he said. “We have to err in the direction of believing that disclosure is good,” he said, “even if we can’t prove it has clear and measurable impact. That is why our goal is to make full disclosure easier. What potential conflicts are acceptable, or not, is an important but entirely separate matter.”

Howard Bauchner, MD, editor in chief of JAMA and the JAMA Network, frames the pros and cons of general and relevant disclosure similarly, and emphasizes that the relationships of authors with industry – particularly with private equity start-up companies – has changed dramatically over the past decade. Editors have “talked about complete versus [more narrowly] relevant disclosures at length,” he said, and have been moving overall “toward more complete disclosure where the reader can make a decision on their own.”

Other journals also are taking this approach. In 2009, in an effort to reduce variability in reporting processes and formats, the International Committee of Medical Journal Editors (ICMJE) developed a uniform electronic disclosure form that asks about financial relationships and interactions with any entity that could be considered “broadly relevant” to the submitted work. The group updated the form in December 2018.

As an example, the form reads, an article about testing an epidermal growth factor receptor (EGFR) antagonist in lung cancer requires the reporting of “all associations with entities pursuing diagnostic or therapeutic strategies in cancer in general, not just in the area of EGFR or lung cancer.” JAMA, NEJM, and The Lancet are among those journals that embrace the ICMJE’s policies and use its form.

To simplify its own disclosure process, JAMA and the network’s journals ended the practice in January 2019 of requiring both the ICMJE form and JAMA’s own separate disclosure form. The journals now use a single electronic form that includes questions from the ICMJE form. And to promote more consistent and complete reporting, the electronic form contains prompts that ask authors each time they answer “no” to one of four specific questions about potential COI whether they are certain of their answers and whether their answers are consistent with other disclosures they recently made.

While relevancy statements “create struggles for authors,” about two-thirds of the disclosure inaccuracies reported by readers and verified by JAMA’s editors (most often through editor-author discussions) involve a complete lack of disclosure rather than questions of relevancy, Dr. Bauchner noted. (JAMA and the network’s journals receive about 30,000 disclosure forms each year.)

The AAMC, in the meantime, has developed a central web-based repository for disclosures called Convey. Physicians and others can maintain secure records of financial interests in the repository, and these records can then be disclosed directly to any journal or organization that uses the system. The tool – born from discussions that followed the 2009 IOM report on COI – is “intended to facilitate more complete, more accurate, and more consistent” disclosures,” said Ms. Pierce of the AAMC. It is now live and in its early stages of use; NEJM assisted in its development and has been one of its pilot testers.
 

Enforcement questions

Some experts believe that institutions should maintain public databases of disclosures and/or that disclosure requirements should be better enforced in-house.

“There often are no clear guidelines in institutions about how to respond to people who are negligent in how they’re managing their disclosures,” said Jeffrey R. Botkin, MD, MPH, professor of pediatrics and associate vice president for research at the University of Utah, Salt Lake City, who has served on a variety of ethics committees and is an elected member of the Hastings Center. Dr. Botkin proposed in a Viewpoint published last October in JAMA that failure to disclose significant COIs should be considered research misconduct (JAMA 2018;320[22]:2307-8).

At the University of Utah, “we’re getting better at saying, ‘show us that you’ve disclosed,’ ” he said. “In some cases we’ll do spot checks of journal articles to make sure [researchers have] followed through with their disclosures.”

John Abramson, MD, a lecturer in the department of health care policy at Harvard Medical School, Boston, contends that incomplete declarations of COI have been shown to correlate with reporting of manufacturer-friendly research results. Journals should have “zero tolerance” standards for incomplete or inaccurate COI declarations and should, among other things, “inform academic institutions of breaches of integrity.”

At JAMA, which in 2017 published a theme issue on COI and COI declarations, editors have been discussing whether they will contact an author’s institution “if there’s a pattern involved [with disclosure problems] or if there’s a lack of declaration of multiple COIs,” Dr. Bauchner said.

Conflict of interest (COI) reporting has moved center stage again in recent months, with some medical journals, professional societies, cancer centers, and academic medical institutions reviewing policies and practices in the wake of a highly publicized disclosure failure last fall at Memorial Sloan Kettering Cancer Center (MSK).

And in some settings, oncologists and other physician researchers are being encouraged to check what the federal Open Payments database says about their payments from industry.

The spotlight is on the field of cancer research and treatment, where MSK’s chief medical officer, José Baselga, MD, PhD, resigned in September 2018 after the New York Times and ProPublica reported that he’d failed to disclose millions of dollars of industry payments and ownership interests in the majority of journal articles he wrote or cowrote over a 4-year period.

Pleas for accuracy

At academic medical institutions, conflicts of interest are identified and then managed; it’s common for researchers’ COI management plans to include requirements for disclosure in all presentations and publications.

Journals and professional medical societies require authors and speakers to submit disclosure forms of varying lengths and with differing questions about relationships with industry, often based on the notion of relevancy to the subject at hand. Disclosure forms are reviewed, but editors and other reviewers rely largely – if not entirely – on the honor system.

Dr. Baselga’s disclosure lapses and his subsequent resignation have rattled leaders in each of these settings. Researchers at MSK were instructed to review their COI disclosures and submit corrections when necessary, and in December 2018 the hospital was reportedly evaluating its process for reviewing conflicts of interest, according to reports in the New York Times and ProPublica. (MSK did not respond to requests for comment about actions taken.)

The Dana Farber Cancer Institute in Boston similarly has “been reminding faculty and other researchers” of their disclosure responsibilities and is conducting a review of “all our policies in this area,” a spokeswoman said. And at Fred Hutchinson Cancer Research Center in Seattle, a spokesman said they have established an internal task force to review individual and institutional COI policies to ensure that COIs are “appropriately managed while also enabling research collaborations that bring scientific advances to our patients.”

Other centers contacted for this article, such as the Cleveland Clinic Cancer Center and the Mayo Clinic Cancer Center, said that they have no new reviews ongoing and no plans to change policies at this time.

The heightened attention to disclosure has, in turn, shone a spotlight on increasingly complex physician-industry relationships and on the Open Payments website run by the Centers for Medicare and Medicaid Services. Open Payments is a disclosure program and database that tracks payments made to physicians and teaching hospitals by drug and device companies.

Journalists, including those who reported on Dr. Baselga’s disclosures, have searched the public database for industry payment data. So have other researchers who have studied financial disclosure statements; a study reported in JAMA Oncology last year, for instance, concluded through the use of Open Payments data that about one-third of authors of cancer drug trial reports did not completely disclose payments from trial sponsors (JAMA Oncol. 2018;4[10]:1426-8).

In a column published in December 2018 in AAMC News, AAMC President and CEO Darrell G. Kirch, MD, wrote that failures to disclose can raise questions about the integrity of research, whether or not there is an actual conflict. He advised institutions to “encourage faculty to review the information posted about them on the Open Payments website” of the CMS to “ensure it is accurate and consistent with disclosures related to all their professional responsibilities.”

ASCO issues similar advice, encouraging authors and CME speakers and participants of other ASCO activities to double-check their disclosures against other sources, including “publicly reported interactions with companies that may have been inadvertently omitted.”

In the world of journals, the New England Journal of Medicine (NEJM) began asking authors at the end of 2018 to “certify that they have reconciled their disclosures” with the Open Payments database, said Jennifer Zeis, a spokeswoman forthe journal.

Time may tell how well such requests work. When the Institute of Medicine (now called the National Academy of Medicine) called on Congress in 2009 to create a national program requiring pharmaceutical, device, and biotechnology companies to publicly report their payments, it envisioned universities, journals, and others using the program to verify disclosures made to them. But the resulting Open Payments database has limitations – for instance, it doesn’t include payments from companies without FDA-approved products, it is not necessarily up to date, and its payment categories do not necessarily match categories of disclosure.

“Some entries in the Open Payments database need further explanation,” said Ms. Zeis of NEJM. “Some authors, for example, have said that the database does not fully and accurately explain that the funds were disbursed not to them personally, but to their academic institutions.” While the database provides transparency, it also “needs context that’s not currently provided,” she said.

Mistakes in the database can also be “very hard to challenge,” said Clifford A. Hudis, MD, CEO of the American Society of Clinical Oncology, which produces the Journal of Clinical Oncology (JCO).

Courtesy American Society of Clinical Oncology

All in all, he said, “there’s really no timely, comprehensive, and fully reliable source of information with which to verify an individual’s disclosures.”

Policies and practices are also under review at the American Association for Cancer Research (AACR) and the American Society of Hematology (ASH).

The AACR has appointed a panel of experts, including physicians, basic scientists, a patient advocate, and others to conduct “a comprehensive review of [its] disclosure policies and to explore whether any current policies need to be revised,” said Rachel Salis-Silverman, director of public relations. It also will convene a session on COI disclosures at its 2019 annual meeting at the end of March, she said.

ASH, which publishes the journal Blood, is exploring possible changes in its “internal processes with regards to ASH publications,” said Matt Gertzog, deputy executive director of the group. COI disclosure is “more of a journey than a destination,” he said. “We are continuously reflecting on and refining our processes.”
 

Moving away from ‘relevancy’

Physicians and others who have relationships with industry have long complained about a patchwork of disclosure requirements, and significant efforts have been made in the last decade to standardize forms and practices. However, the current system is still “a little bit of a Tower of Babel,” said Dr. Hudis of ASCO. “Every day, physicians have to complete from scratch similar, but not identical, disclosure forms that ask similar, but not identical, questions.”

A disclosable compensation amount “might be first dollar, or it might be over $10,000. [Time periods] might cover 1 year, or 3 years. ... Stock ownership might be dollar value, or a percentage of shares,” he explained. “If you want a system that would make it hard to be compliant and easy to mess up, that’s what we have.”

To standardize the COI disclosure process for all Society-related publications and activities – including CME, JCO, and practice guidelines – ASCO moved about 5 years ago to a system of general disclosure, asking physicians and others to disclose all financial interests and industry relationships rather than what they deem relevant.

The thinking was that general disclosure “would be easier for disclosers, and nobody would ever be accused of hiding anything,” Dr. Hudis said.

“We’d [also] recognized,” he explained, “that there was a risk to the relevancy approach in that it put the judgment for the potential conflict in the hands of the potentially conflicted, while others might have a different point of view about what is or isn’t relevant.”

Those concerned about general disclosure worry that it may “obscure [for the reader or listener] what’s really important or the most meaningful,” he said.

Some physicians have expressed in interviews for this article, moreover, the concern that too many disclosures – too long a list of financial relationships – will be viewed negatively. This is something ASCO aims to guard against as it strives to achieve full transparency, Dr. Hudis said. “If one were to suggest that engagement itself is automatically a negative, then you’re starting to put negative pressure on compliance with disclosure.”

And full disclosure matters, he said. “We have to err in the direction of believing that disclosure is good,” he said, “even if we can’t prove it has clear and measurable impact. That is why our goal is to make full disclosure easier. What potential conflicts are acceptable, or not, is an important but entirely separate matter.”

Howard Bauchner, MD, editor in chief of JAMA and the JAMA Network, frames the pros and cons of general and relevant disclosure similarly, and emphasizes that the relationships of authors with industry – particularly with private equity start-up companies – has changed dramatically over the past decade. Editors have “talked about complete versus [more narrowly] relevant disclosures at length,” he said, and have been moving overall “toward more complete disclosure where the reader can make a decision on their own.”

Other journals also are taking this approach. In 2009, in an effort to reduce variability in reporting processes and formats, the International Committee of Medical Journal Editors (ICMJE) developed a uniform electronic disclosure form that asks about financial relationships and interactions with any entity that could be considered “broadly relevant” to the submitted work. The group updated the form in December 2018.

As an example, the form reads, an article about testing an epidermal growth factor receptor (EGFR) antagonist in lung cancer requires the reporting of “all associations with entities pursuing diagnostic or therapeutic strategies in cancer in general, not just in the area of EGFR or lung cancer.” JAMA, NEJM, and The Lancet are among those journals that embrace the ICMJE’s policies and use its form.

To simplify its own disclosure process, JAMA and the network’s journals ended the practice in January 2019 of requiring both the ICMJE form and JAMA’s own separate disclosure form. The journals now use a single electronic form that includes questions from the ICMJE form. And to promote more consistent and complete reporting, the electronic form contains prompts that ask authors each time they answer “no” to one of four specific questions about potential COI whether they are certain of their answers and whether their answers are consistent with other disclosures they recently made.

While relevancy statements “create struggles for authors,” about two-thirds of the disclosure inaccuracies reported by readers and verified by JAMA’s editors (most often through editor-author discussions) involve a complete lack of disclosure rather than questions of relevancy, Dr. Bauchner noted. (JAMA and the network’s journals receive about 30,000 disclosure forms each year.)

The AAMC, in the meantime, has developed a central web-based repository for disclosures called Convey. Physicians and others can maintain secure records of financial interests in the repository, and these records can then be disclosed directly to any journal or organization that uses the system. The tool – born from discussions that followed the 2009 IOM report on COI – is “intended to facilitate more complete, more accurate, and more consistent” disclosures,” said Ms. Pierce of the AAMC. It is now live and in its early stages of use; NEJM assisted in its development and has been one of its pilot testers.
 

Enforcement questions

Some experts believe that institutions should maintain public databases of disclosures and/or that disclosure requirements should be better enforced in-house.

“There often are no clear guidelines in institutions about how to respond to people who are negligent in how they’re managing their disclosures,” said Jeffrey R. Botkin, MD, MPH, professor of pediatrics and associate vice president for research at the University of Utah, Salt Lake City, who has served on a variety of ethics committees and is an elected member of the Hastings Center. Dr. Botkin proposed in a Viewpoint published last October in JAMA that failure to disclose significant COIs should be considered research misconduct (JAMA 2018;320[22]:2307-8).

At the University of Utah, “we’re getting better at saying, ‘show us that you’ve disclosed,’ ” he said. “In some cases we’ll do spot checks of journal articles to make sure [researchers have] followed through with their disclosures.”

John Abramson, MD, a lecturer in the department of health care policy at Harvard Medical School, Boston, contends that incomplete declarations of COI have been shown to correlate with reporting of manufacturer-friendly research results. Journals should have “zero tolerance” standards for incomplete or inaccurate COI declarations and should, among other things, “inform academic institutions of breaches of integrity.”

At JAMA, which in 2017 published a theme issue on COI and COI declarations, editors have been discussing whether they will contact an author’s institution “if there’s a pattern involved [with disclosure problems] or if there’s a lack of declaration of multiple COIs,” Dr. Bauchner said.

Conflict of interest (COI) reporting has moved center stage again in recent months, with some medical journals, professional societies, cancer centers, and academic medical institutions reviewing policies and practices in the wake of a highly publicized disclosure failure last fall at Memorial Sloan Kettering Cancer Center (MSK).

And in some settings, oncologists and other physician researchers are being encouraged to check what the federal Open Payments database says about their payments from industry.

The spotlight is on the field of cancer research and treatment, where MSK’s chief medical officer, José Baselga, MD, PhD, resigned in September 2018 after the New York Times and ProPublica reported that he’d failed to disclose millions of dollars of industry payments and ownership interests in the majority of journal articles he wrote or cowrote over a 4-year period.

Pleas for accuracy

At academic medical institutions, conflicts of interest are identified and then managed; it’s common for researchers’ COI management plans to include requirements for disclosure in all presentations and publications.

Journals and professional medical societies require authors and speakers to submit disclosure forms of varying lengths and with differing questions about relationships with industry, often based on the notion of relevancy to the subject at hand. Disclosure forms are reviewed, but editors and other reviewers rely largely – if not entirely – on the honor system.

Dr. Baselga’s disclosure lapses and his subsequent resignation have rattled leaders in each of these settings. Researchers at MSK were instructed to review their COI disclosures and submit corrections when necessary, and in December 2018 the hospital was reportedly evaluating its process for reviewing conflicts of interest, according to reports in the New York Times and ProPublica. (MSK did not respond to requests for comment about actions taken.)

The Dana Farber Cancer Institute in Boston similarly has “been reminding faculty and other researchers” of their disclosure responsibilities and is conducting a review of “all our policies in this area,” a spokeswoman said. And at Fred Hutchinson Cancer Research Center in Seattle, a spokesman said they have established an internal task force to review individual and institutional COI policies to ensure that COIs are “appropriately managed while also enabling research collaborations that bring scientific advances to our patients.”

Other centers contacted for this article, such as the Cleveland Clinic Cancer Center and the Mayo Clinic Cancer Center, said that they have no new reviews ongoing and no plans to change policies at this time.

The heightened attention to disclosure has, in turn, shone a spotlight on increasingly complex physician-industry relationships and on the Open Payments website run by the Centers for Medicare and Medicaid Services. Open Payments is a disclosure program and database that tracks payments made to physicians and teaching hospitals by drug and device companies.

Journalists, including those who reported on Dr. Baselga’s disclosures, have searched the public database for industry payment data. So have other researchers who have studied financial disclosure statements; a study reported in JAMA Oncology last year, for instance, concluded through the use of Open Payments data that about one-third of authors of cancer drug trial reports did not completely disclose payments from trial sponsors (JAMA Oncol. 2018;4[10]:1426-8).

In a column published in December 2018 in AAMC News, AAMC President and CEO Darrell G. Kirch, MD, wrote that failures to disclose can raise questions about the integrity of research, whether or not there is an actual conflict. He advised institutions to “encourage faculty to review the information posted about them on the Open Payments website” of the CMS to “ensure it is accurate and consistent with disclosures related to all their professional responsibilities.”

ASCO issues similar advice, encouraging authors and CME speakers and participants of other ASCO activities to double-check their disclosures against other sources, including “publicly reported interactions with companies that may have been inadvertently omitted.”

In the world of journals, the New England Journal of Medicine (NEJM) began asking authors at the end of 2018 to “certify that they have reconciled their disclosures” with the Open Payments database, said Jennifer Zeis, a spokeswoman forthe journal.

Time may tell how well such requests work. When the Institute of Medicine (now called the National Academy of Medicine) called on Congress in 2009 to create a national program requiring pharmaceutical, device, and biotechnology companies to publicly report their payments, it envisioned universities, journals, and others using the program to verify disclosures made to them. But the resulting Open Payments database has limitations – for instance, it doesn’t include payments from companies without FDA-approved products, it is not necessarily up to date, and its payment categories do not necessarily match categories of disclosure.

“Some entries in the Open Payments database need further explanation,” said Ms. Zeis of NEJM. “Some authors, for example, have said that the database does not fully and accurately explain that the funds were disbursed not to them personally, but to their academic institutions.” While the database provides transparency, it also “needs context that’s not currently provided,” she said.

Mistakes in the database can also be “very hard to challenge,” said Clifford A. Hudis, MD, CEO of the American Society of Clinical Oncology, which produces the Journal of Clinical Oncology (JCO).

Courtesy American Society of Clinical Oncology

All in all, he said, “there’s really no timely, comprehensive, and fully reliable source of information with which to verify an individual’s disclosures.”

Policies and practices are also under review at the American Association for Cancer Research (AACR) and the American Society of Hematology (ASH).

The AACR has appointed a panel of experts, including physicians, basic scientists, a patient advocate, and others to conduct “a comprehensive review of [its] disclosure policies and to explore whether any current policies need to be revised,” said Rachel Salis-Silverman, director of public relations. It also will convene a session on COI disclosures at its 2019 annual meeting at the end of March, she said.

ASH, which publishes the journal Blood, is exploring possible changes in its “internal processes with regards to ASH publications,” said Matt Gertzog, deputy executive director of the group. COI disclosure is “more of a journey than a destination,” he said. “We are continuously reflecting on and refining our processes.”
 

Moving away from ‘relevancy’

Physicians and others who have relationships with industry have long complained about a patchwork of disclosure requirements, and significant efforts have been made in the last decade to standardize forms and practices. However, the current system is still “a little bit of a Tower of Babel,” said Dr. Hudis of ASCO. “Every day, physicians have to complete from scratch similar, but not identical, disclosure forms that ask similar, but not identical, questions.”

A disclosable compensation amount “might be first dollar, or it might be over $10,000. [Time periods] might cover 1 year, or 3 years. ... Stock ownership might be dollar value, or a percentage of shares,” he explained. “If you want a system that would make it hard to be compliant and easy to mess up, that’s what we have.”

To standardize the COI disclosure process for all Society-related publications and activities – including CME, JCO, and practice guidelines – ASCO moved about 5 years ago to a system of general disclosure, asking physicians and others to disclose all financial interests and industry relationships rather than what they deem relevant.

The thinking was that general disclosure “would be easier for disclosers, and nobody would ever be accused of hiding anything,” Dr. Hudis said.

“We’d [also] recognized,” he explained, “that there was a risk to the relevancy approach in that it put the judgment for the potential conflict in the hands of the potentially conflicted, while others might have a different point of view about what is or isn’t relevant.”

Those concerned about general disclosure worry that it may “obscure [for the reader or listener] what’s really important or the most meaningful,” he said.

Some physicians have expressed in interviews for this article, moreover, the concern that too many disclosures – too long a list of financial relationships – will be viewed negatively. This is something ASCO aims to guard against as it strives to achieve full transparency, Dr. Hudis said. “If one were to suggest that engagement itself is automatically a negative, then you’re starting to put negative pressure on compliance with disclosure.”

And full disclosure matters, he said. “We have to err in the direction of believing that disclosure is good,” he said, “even if we can’t prove it has clear and measurable impact. That is why our goal is to make full disclosure easier. What potential conflicts are acceptable, or not, is an important but entirely separate matter.”

Howard Bauchner, MD, editor in chief of JAMA and the JAMA Network, frames the pros and cons of general and relevant disclosure similarly, and emphasizes that the relationships of authors with industry – particularly with private equity start-up companies – has changed dramatically over the past decade. Editors have “talked about complete versus [more narrowly] relevant disclosures at length,” he said, and have been moving overall “toward more complete disclosure where the reader can make a decision on their own.”

Other journals also are taking this approach. In 2009, in an effort to reduce variability in reporting processes and formats, the International Committee of Medical Journal Editors (ICMJE) developed a uniform electronic disclosure form that asks about financial relationships and interactions with any entity that could be considered “broadly relevant” to the submitted work. The group updated the form in December 2018.

As an example, the form reads, an article about testing an epidermal growth factor receptor (EGFR) antagonist in lung cancer requires the reporting of “all associations with entities pursuing diagnostic or therapeutic strategies in cancer in general, not just in the area of EGFR or lung cancer.” JAMA, NEJM, and The Lancet are among those journals that embrace the ICMJE’s policies and use its form.

To simplify its own disclosure process, JAMA and the network’s journals ended the practice in January 2019 of requiring both the ICMJE form and JAMA’s own separate disclosure form. The journals now use a single electronic form that includes questions from the ICMJE form. And to promote more consistent and complete reporting, the electronic form contains prompts that ask authors each time they answer “no” to one of four specific questions about potential COI whether they are certain of their answers and whether their answers are consistent with other disclosures they recently made.

While relevancy statements “create struggles for authors,” about two-thirds of the disclosure inaccuracies reported by readers and verified by JAMA’s editors (most often through editor-author discussions) involve a complete lack of disclosure rather than questions of relevancy, Dr. Bauchner noted. (JAMA and the network’s journals receive about 30,000 disclosure forms each year.)

The AAMC, in the meantime, has developed a central web-based repository for disclosures called Convey. Physicians and others can maintain secure records of financial interests in the repository, and these records can then be disclosed directly to any journal or organization that uses the system. The tool – born from discussions that followed the 2009 IOM report on COI – is “intended to facilitate more complete, more accurate, and more consistent” disclosures,” said Ms. Pierce of the AAMC. It is now live and in its early stages of use; NEJM assisted in its development and has been one of its pilot testers.
 

Enforcement questions

Some experts believe that institutions should maintain public databases of disclosures and/or that disclosure requirements should be better enforced in-house.

“There often are no clear guidelines in institutions about how to respond to people who are negligent in how they’re managing their disclosures,” said Jeffrey R. Botkin, MD, MPH, professor of pediatrics and associate vice president for research at the University of Utah, Salt Lake City, who has served on a variety of ethics committees and is an elected member of the Hastings Center. Dr. Botkin proposed in a Viewpoint published last October in JAMA that failure to disclose significant COIs should be considered research misconduct (JAMA 2018;320[22]:2307-8).

At the University of Utah, “we’re getting better at saying, ‘show us that you’ve disclosed,’ ” he said. “In some cases we’ll do spot checks of journal articles to make sure [researchers have] followed through with their disclosures.”

John Abramson, MD, a lecturer in the department of health care policy at Harvard Medical School, Boston, contends that incomplete declarations of COI have been shown to correlate with reporting of manufacturer-friendly research results. Journals should have “zero tolerance” standards for incomplete or inaccurate COI declarations and should, among other things, “inform academic institutions of breaches of integrity.”

At JAMA, which in 2017 published a theme issue on COI and COI declarations, editors have been discussing whether they will contact an author’s institution “if there’s a pattern involved [with disclosure problems] or if there’s a lack of declaration of multiple COIs,” Dr. Bauchner said.

Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.

The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.

The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.

“The panel generally believes that both anatomic/objective and subjective outcomes should be used” to assess the effectiveness of mesh repair, “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”

The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.

The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.

In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.

It’s a challenging assessment to make, FDA officials said.

The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.

Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.

The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.

The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.

“The panel generally believes that both anatomic/objective and subjective outcomes should be used” to assess the effectiveness of mesh repair, “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”

The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.

The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.

In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.

It’s a challenging assessment to make, FDA officials said.

The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.

Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.

The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.

The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.

“The panel generally believes that both anatomic/objective and subjective outcomes should be used” to assess the effectiveness of mesh repair, “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”

The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.

The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.

In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.

It’s a challenging assessment to make, FDA officials said.

The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.

Digital single-operator cholangioscopy (D-SOC) with electrohydraulic or laser lithotripsy achieved complete bile duct clearance in more than 95% of 407 consecutive patients who underwent the procedure for difficult bile duct stones in a multicenter retrospective analysis.

“D-SOC with either [electrohydraulic lithotripsy or laser lithotripsy] represents an efficient, highly valuable, safe and minimally invasive alternative to percutaneous or surgical approaches in the management of difficult biliary stones,” reported Olaya I. Brewer Gutierrez, MD, of Johns Hopkins Hospital, Baltimore, and her colleagues.

The study, published in Clinical Gastroenterology and Hepatology, involved 22 tertiary centers in the United States, the United Kingdom, and Korea. Patients had difficult biliary stones, defined as stones greater than 15 mm in size, multiple (more than three) stones, intrahepatic duct/cystic duct stones, impacted stones, and stones associated with Mirizzi syndrome or a difficult biliary anatomy such as stricture below the stone or duodenal diverticula.

Most patients (85.7%) had a prior failed treatment with endoscopic retrograde cholangiopancreatography (ERCP) for stone clearance at outside hospitals, with biliary sphincterotomy and the use of an extraction balloon attempted in 62.2% and 73.2% of these cases, respectively.

Of the 407 study patients, 306 (75.2%) were treated with electrohydraulic lithotripsy (EHL), and 101 (24.8%) were treated with laser lithotripsy (LL). Complete ductal clearance was achieved in 396 (97.3%) of patients with a median of one lithotripsy session (range of one to four sessions), and in 77.4% of patients in a single session. Stone clearance rates and procedure outcomes were similar between the two approaches, but the mean procedure time was significantly longer with EHL than with LL (74 vs. 50 minutes).

Eleven (2.7%) of the 407 patients failed EHL/LL and were treated either with surgery, extracorporeal shock-wave lithotripsy, or both. Adverse events were observed in 15 patients (3.7%), with cholangitis and abdominal pain most commonly reported.

In addition to evaluating the technical success of D-SOC for difficult bile duct stones and comparing the effectiveness of EHL and LL, the investigators looked for predictors of outcomes. On multivariate analysis, they found difficult anatomy/cannulation was associated with incomplete ductal clearance, and the duration of the procedure was a predictor of the need for more than one D-SOC.

The introduction of D-SOC several years ago has “improved the ease of SOC and markedly improved the image quality,” Dr. Gutierrez and her colleagues wrote. “These [improvements] have led to greater use of EHL or LL as part of the ERCP armamentarium to attempt stone clearance in difficult biliary or pancreatic stones.”

Still, given the retrospective nature of the study and subsequent selection bias, randomized controlled trials comparing D-SOC and EHL/LL with conventional techniques for stone extraction are needed, they say.

In an accompanying editorial, Dennis Yang, MD, of the University of Florida, and Jonathan M. Buscaglia, MD, AGAF, of State University of New York at Stony Brook commended the study for critically evaluating a new technology, but said that “it still remains unclear in whom D-SOC with EHL or LL should be considered over conventional ERCP with stone extraction techniques.”

Although most patients in the study had a prior failed ERCP, conventional stone extraction techniques such as endoscopic sphincterotomy with endoscopic papillary large balloon dilation (EPLBD) or mechanical lithotripsy were attempted in less than a quarter of the cases before D-SOC, they wrote. “In the era of high-cost health care, it is important that proven and effective measures for the treatment of stones ... be used adequately before moving up the ladder to cholangioscopy-based techniques.”

Eleven of the study authors reported serving as consultants for Boston Scientific, which manufactures the D-SOC system used at the study sites, and two of the investigators reported serving as speakers for the company. Dr. Gutierrez reported no conflicts of interest.

[email protected]

SOURCE: Brewer Gutierrez OI et al. Clin Gastroenterol Hepatol. 2018;16:918-26.

Digital single-operator cholangioscopy (D-SOC) with electrohydraulic or laser lithotripsy achieved complete bile duct clearance in more than 95% of 407 consecutive patients who underwent the procedure for difficult bile duct stones in a multicenter retrospective analysis.

“D-SOC with either [electrohydraulic lithotripsy or laser lithotripsy] represents an efficient, highly valuable, safe and minimally invasive alternative to percutaneous or surgical approaches in the management of difficult biliary stones,” reported Olaya I. Brewer Gutierrez, MD, of Johns Hopkins Hospital, Baltimore, and her colleagues.

The study, published in Clinical Gastroenterology and Hepatology, involved 22 tertiary centers in the United States, the United Kingdom, and Korea. Patients had difficult biliary stones, defined as stones greater than 15 mm in size, multiple (more than three) stones, intrahepatic duct/cystic duct stones, impacted stones, and stones associated with Mirizzi syndrome or a difficult biliary anatomy such as stricture below the stone or duodenal diverticula.

Most patients (85.7%) had a prior failed treatment with endoscopic retrograde cholangiopancreatography (ERCP) for stone clearance at outside hospitals, with biliary sphincterotomy and the use of an extraction balloon attempted in 62.2% and 73.2% of these cases, respectively.

Of the 407 study patients, 306 (75.2%) were treated with electrohydraulic lithotripsy (EHL), and 101 (24.8%) were treated with laser lithotripsy (LL). Complete ductal clearance was achieved in 396 (97.3%) of patients with a median of one lithotripsy session (range of one to four sessions), and in 77.4% of patients in a single session. Stone clearance rates and procedure outcomes were similar between the two approaches, but the mean procedure time was significantly longer with EHL than with LL (74 vs. 50 minutes).

Eleven (2.7%) of the 407 patients failed EHL/LL and were treated either with surgery, extracorporeal shock-wave lithotripsy, or both. Adverse events were observed in 15 patients (3.7%), with cholangitis and abdominal pain most commonly reported.

In addition to evaluating the technical success of D-SOC for difficult bile duct stones and comparing the effectiveness of EHL and LL, the investigators looked for predictors of outcomes. On multivariate analysis, they found difficult anatomy/cannulation was associated with incomplete ductal clearance, and the duration of the procedure was a predictor of the need for more than one D-SOC.

The introduction of D-SOC several years ago has “improved the ease of SOC and markedly improved the image quality,” Dr. Gutierrez and her colleagues wrote. “These [improvements] have led to greater use of EHL or LL as part of the ERCP armamentarium to attempt stone clearance in difficult biliary or pancreatic stones.”

Still, given the retrospective nature of the study and subsequent selection bias, randomized controlled trials comparing D-SOC and EHL/LL with conventional techniques for stone extraction are needed, they say.

In an accompanying editorial, Dennis Yang, MD, of the University of Florida, and Jonathan M. Buscaglia, MD, AGAF, of State University of New York at Stony Brook commended the study for critically evaluating a new technology, but said that “it still remains unclear in whom D-SOC with EHL or LL should be considered over conventional ERCP with stone extraction techniques.”

Although most patients in the study had a prior failed ERCP, conventional stone extraction techniques such as endoscopic sphincterotomy with endoscopic papillary large balloon dilation (EPLBD) or mechanical lithotripsy were attempted in less than a quarter of the cases before D-SOC, they wrote. “In the era of high-cost health care, it is important that proven and effective measures for the treatment of stones ... be used adequately before moving up the ladder to cholangioscopy-based techniques.”

Eleven of the study authors reported serving as consultants for Boston Scientific, which manufactures the D-SOC system used at the study sites, and two of the investigators reported serving as speakers for the company. Dr. Gutierrez reported no conflicts of interest.

[email protected]

SOURCE: Brewer Gutierrez OI et al. Clin Gastroenterol Hepatol. 2018;16:918-26.

Digital single-operator cholangioscopy (D-SOC) with electrohydraulic or laser lithotripsy achieved complete bile duct clearance in more than 95% of 407 consecutive patients who underwent the procedure for difficult bile duct stones in a multicenter retrospective analysis.

“D-SOC with either [electrohydraulic lithotripsy or laser lithotripsy] represents an efficient, highly valuable, safe and minimally invasive alternative to percutaneous or surgical approaches in the management of difficult biliary stones,” reported Olaya I. Brewer Gutierrez, MD, of Johns Hopkins Hospital, Baltimore, and her colleagues.

The study, published in Clinical Gastroenterology and Hepatology, involved 22 tertiary centers in the United States, the United Kingdom, and Korea. Patients had difficult biliary stones, defined as stones greater than 15 mm in size, multiple (more than three) stones, intrahepatic duct/cystic duct stones, impacted stones, and stones associated with Mirizzi syndrome or a difficult biliary anatomy such as stricture below the stone or duodenal diverticula.

Most patients (85.7%) had a prior failed treatment with endoscopic retrograde cholangiopancreatography (ERCP) for stone clearance at outside hospitals, with biliary sphincterotomy and the use of an extraction balloon attempted in 62.2% and 73.2% of these cases, respectively.

Of the 407 study patients, 306 (75.2%) were treated with electrohydraulic lithotripsy (EHL), and 101 (24.8%) were treated with laser lithotripsy (LL). Complete ductal clearance was achieved in 396 (97.3%) of patients with a median of one lithotripsy session (range of one to four sessions), and in 77.4% of patients in a single session. Stone clearance rates and procedure outcomes were similar between the two approaches, but the mean procedure time was significantly longer with EHL than with LL (74 vs. 50 minutes).

Eleven (2.7%) of the 407 patients failed EHL/LL and were treated either with surgery, extracorporeal shock-wave lithotripsy, or both. Adverse events were observed in 15 patients (3.7%), with cholangitis and abdominal pain most commonly reported.

In addition to evaluating the technical success of D-SOC for difficult bile duct stones and comparing the effectiveness of EHL and LL, the investigators looked for predictors of outcomes. On multivariate analysis, they found difficult anatomy/cannulation was associated with incomplete ductal clearance, and the duration of the procedure was a predictor of the need for more than one D-SOC.

The introduction of D-SOC several years ago has “improved the ease of SOC and markedly improved the image quality,” Dr. Gutierrez and her colleagues wrote. “These [improvements] have led to greater use of EHL or LL as part of the ERCP armamentarium to attempt stone clearance in difficult biliary or pancreatic stones.”

Still, given the retrospective nature of the study and subsequent selection bias, randomized controlled trials comparing D-SOC and EHL/LL with conventional techniques for stone extraction are needed, they say.

In an accompanying editorial, Dennis Yang, MD, of the University of Florida, and Jonathan M. Buscaglia, MD, AGAF, of State University of New York at Stony Brook commended the study for critically evaluating a new technology, but said that “it still remains unclear in whom D-SOC with EHL or LL should be considered over conventional ERCP with stone extraction techniques.”

Although most patients in the study had a prior failed ERCP, conventional stone extraction techniques such as endoscopic sphincterotomy with endoscopic papillary large balloon dilation (EPLBD) or mechanical lithotripsy were attempted in less than a quarter of the cases before D-SOC, they wrote. “In the era of high-cost health care, it is important that proven and effective measures for the treatment of stones ... be used adequately before moving up the ladder to cholangioscopy-based techniques.”

Eleven of the study authors reported serving as consultants for Boston Scientific, which manufactures the D-SOC system used at the study sites, and two of the investigators reported serving as speakers for the company. Dr. Gutierrez reported no conflicts of interest.

[email protected]

SOURCE: Brewer Gutierrez OI et al. Clin Gastroenterol Hepatol. 2018;16:918-26.

E. Albert Reece, MD, PhD, MBA, the dean of the University of Maryland School of Medicine, Baltimore, and medical editor of Ob.Gyn. News, has spoken often in the newspaper’s pages about how the fetus has become a visible and intimate patient – one who, “like the mother, can be interrogated, monitored, and sometimes treated before birth.”

Physician-scientists have been instrumental in lifting the cloud of mystery that surrounded the fetus and fetal outcomes. Yet today, in a trend that Dr. Reece and his colleagues call deeply concerning, the number of physician-scientists is declining. “We’re missing out on a workforce that is dedicated to exploring the biologic basis of disease – knowledge that enables the development of targeted therapeutic interventions,” he said in an interview.

Courtesy of Yale School of Medicine

Courtesy of Yale School of Medicine

E. Albert Reece, MD, PhD, MBA, the dean of the University of Maryland School of Medicine, Baltimore, and medical editor of Ob.Gyn. News, has spoken often in the newspaper’s pages about how the fetus has become a visible and intimate patient – one who, “like the mother, can be interrogated, monitored, and sometimes treated before birth.”

Physician-scientists have been instrumental in lifting the cloud of mystery that surrounded the fetus and fetal outcomes. Yet today, in a trend that Dr. Reece and his colleagues call deeply concerning, the number of physician-scientists is declining. “We’re missing out on a workforce that is dedicated to exploring the biologic basis of disease – knowledge that enables the development of targeted therapeutic interventions,” he said in an interview.

Courtesy of Yale School of Medicine

Courtesy of Yale School of Medicine

E. Albert Reece, MD, PhD, MBA, the dean of the University of Maryland School of Medicine, Baltimore, and medical editor of Ob.Gyn. News, has spoken often in the newspaper’s pages about how the fetus has become a visible and intimate patient – one who, “like the mother, can be interrogated, monitored, and sometimes treated before birth.”

Physician-scientists have been instrumental in lifting the cloud of mystery that surrounded the fetus and fetal outcomes. Yet today, in a trend that Dr. Reece and his colleagues call deeply concerning, the number of physician-scientists is declining. “We’re missing out on a workforce that is dedicated to exploring the biologic basis of disease – knowledge that enables the development of targeted therapeutic interventions,” he said in an interview.

Courtesy of Yale School of Medicine

Courtesy of Yale School of Medicine

Empowering women through a grassroots approach is what Camran Nezhat, MD, a gynecologic surgeon in Palo Alto, Calif., had in mind when he founded the Worldwide Endometriosis March, or EndoMarch, some years ago. In March 2018, the 5th annual international day of marches and calls to action took place across at least eight U.S. cities and dozens of locations across Europe, Africa, the Middle East, and Asia.

Dr. Nezhat founded the 501(c)(3) public charity nonprofit along with his brothers, Farr Nezhat, MD, and Ceana Nezhat, MD; his niece Azadeh Nezhat, MD; and Barbara Page, a graduate of the University of California, Berkeley, who was working in his practice at the time.

“We’d published so much on the disease [in the medical literature], we didn’t know what else to do ... to help these women. We practice in one of the most advanced cultures for medical care ... and yet women come to us who’ve been told it’s all in their heads, or that they have PID [pelvic inflammatory disease] or depression,” Dr. Camran Nezhat said. “We’d get together and talk about this ... and we thought about how not much changed [with civil rights] in this country until people marched and took matters into their own hands.”

Empowering women through a grassroots approach is what Camran Nezhat, MD, a gynecologic surgeon in Palo Alto, Calif., had in mind when he founded the Worldwide Endometriosis March, or EndoMarch, some years ago. In March 2018, the 5th annual international day of marches and calls to action took place across at least eight U.S. cities and dozens of locations across Europe, Africa, the Middle East, and Asia.

Dr. Nezhat founded the 501(c)(3) public charity nonprofit along with his brothers, Farr Nezhat, MD, and Ceana Nezhat, MD; his niece Azadeh Nezhat, MD; and Barbara Page, a graduate of the University of California, Berkeley, who was working in his practice at the time.

“We’d published so much on the disease [in the medical literature], we didn’t know what else to do ... to help these women. We practice in one of the most advanced cultures for medical care ... and yet women come to us who’ve been told it’s all in their heads, or that they have PID [pelvic inflammatory disease] or depression,” Dr. Camran Nezhat said. “We’d get together and talk about this ... and we thought about how not much changed [with civil rights] in this country until people marched and took matters into their own hands.”

Empowering women through a grassroots approach is what Camran Nezhat, MD, a gynecologic surgeon in Palo Alto, Calif., had in mind when he founded the Worldwide Endometriosis March, or EndoMarch, some years ago. In March 2018, the 5th annual international day of marches and calls to action took place across at least eight U.S. cities and dozens of locations across Europe, Africa, the Middle East, and Asia.

Dr. Nezhat founded the 501(c)(3) public charity nonprofit along with his brothers, Farr Nezhat, MD, and Ceana Nezhat, MD; his niece Azadeh Nezhat, MD; and Barbara Page, a graduate of the University of California, Berkeley, who was working in his practice at the time.

“We’d published so much on the disease [in the medical literature], we didn’t know what else to do ... to help these women. We practice in one of the most advanced cultures for medical care ... and yet women come to us who’ve been told it’s all in their heads, or that they have PID [pelvic inflammatory disease] or depression,” Dr. Camran Nezhat said. “We’d get together and talk about this ... and we thought about how not much changed [with civil rights] in this country until people marched and took matters into their own hands.”

Meg Hayden, RN, a school nurse in Oxford, Miss., used to be a labor and delivery nurse and considers herself more attuned to women’s health issues than other school nurses are. Still, a new educational initiative on endometriosis that stresses that menstrual pain is not normal – and that teenagers are not too young to have endometriosis – has helped her “connect the dots.”

“It’s a good reminder for me to look at patterns” and advise those girls who have repeated episodes of pelvic pain and other symptoms to “keep a diary” and to seek care, Ms. Hayden said.

Courtesy Shannon Cohn

Atypical symptoms and presentation

Endometriosis is an enigmatic disease. It traditionally has been associated with retrograde menstruation, but today, there are more nuanced and likely overlapping theories of etiology. Identified in girls even prior to the onset of menses, the disease is generally believed to be progressive, but perhaps not all the time. Patients with significant amounts of disease may have tremendous pain or they may have very little discomfort.

While adolescents can have advanced endometriosis, most have early-stage disease, experts say. Still, adolescence offers its own complexities. Preteen and teen patients with endometriosis tend to present more often with atypical symptoms and with much more subtle and variable laparoscopic findings than do adult patients. Dr. Laufer reported more than 20 years ago that only 9.7% of 46 girls presented classically with dysmenorrhea. In 63%, pain was both acyclic and cyclic, and in 28%, pain was acyclic only (J Pediatr Adolesc Gynecol. 1997;10:199-202).

In a more recent report on adolescents treated by gynecologic surgeon Ceana Nezhat, MD, 64% had dysmenorrhea, 44% had menorrhagia, 60% had abnormal or irregular uterine bleeding, 56% had at least one gastrointestinal symptom, and 52% had at least one genitourinary symptom. The girls had seen a mean of three physicians, including psychiatrists and orthopedic surgeons, and had received diagnoses of pelvic inflammatory disease, irritable bowel syndrome, dysmenorrhea, appendicitis, ovarian cysts, and musculoskeletal pain (JSLS. 2015;19:e2015.00019). Notably, 56% had a family history of endometriosis, Dr. Nezhat, of the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine, and his colleagues found.

Courtesy Dr. Ceana Nezhat

Treatment dilemmas

The first-line treatment for dysmenorrhea and for suspected endometriosis in adolescents has long been empiric treatment with NSAIDs and oral contraceptive pills. Experts commonly recommend today that combined oral contraceptive pills (COCPs) be started cyclically and then changed to continuous dosing if necessary with the goal of inducing amenorrhea.

If symptoms are not well controlled within 3-6 months of compliant medication management with COCPs and NSAIDs and endometriosis is suspected, then laparoscopy by a physician who is familiar with adolescent endometriosis and can simultaneously diagnose and treat the disease should be considered, according to Dr. Laufer and several other experts in pediatric and adolescent gynecology who spoke with Ob.Gyn. News.

“If someone still has pain on one COCP, then switching to another COCP is not going to solve the problem – there is no study that shows that one pill is better than another,” Dr. Laufer said.

Yet extra months and sometimes years of pill-switching and empiric therapy with other medications – rather than surgical evaluation, diagnosis, and treatment – is not uncommon. “Usually, by the time a patient comes to me, they’ve already been on multiple birth control pills, they’ve failed NSAIDs, and they’ve often tried other medications as well,” such as progestins and gonadotropin-releasing hormone agonists, said Iris Kerin Orbuch, MD, director of the Advanced Gynecologic Laparoscopy Centers in New York and Los Angeles.

ACOG under fire

Dr. Sinervo and Dr. Orbuch are among the gynecologic surgeons, other providers, and patients who have signed a petition to ACOG urging it to involve both educated patients and expert, multidisciplinary endometriosis providers in improving their guidance and policies on endometriosis to facilitate earlier diagnosis and more effective treatment.

The petition was organized by advocate Casey Berna in July and supported by more than a half-dozen endometriosis advocacy groups; in early May, it had almost 8,700 signatures. Ms. Berna also co-organized a demonstration outside ACOG headquarters on April 5-6 as leaders were reviewing practice bulletins and deciding which need revision – and a virtual protest (#WeMatterACOG) – to push for better guidelines.

Courtesy of Wendy Bingham, DPT

*This article was updated June 5, 2018. An earlier version of this article misstated Dr. Ken R. Sinervo’s name.

Meg Hayden, RN, a school nurse in Oxford, Miss., used to be a labor and delivery nurse and considers herself more attuned to women’s health issues than other school nurses are. Still, a new educational initiative on endometriosis that stresses that menstrual pain is not normal – and that teenagers are not too young to have endometriosis – has helped her “connect the dots.”

“It’s a good reminder for me to look at patterns” and advise those girls who have repeated episodes of pelvic pain and other symptoms to “keep a diary” and to seek care, Ms. Hayden said.

Courtesy Shannon Cohn

Atypical symptoms and presentation

Endometriosis is an enigmatic disease. It traditionally has been associated with retrograde menstruation, but today, there are more nuanced and likely overlapping theories of etiology. Identified in girls even prior to the onset of menses, the disease is generally believed to be progressive, but perhaps not all the time. Patients with significant amounts of disease may have tremendous pain or they may have very little discomfort.

While adolescents can have advanced endometriosis, most have early-stage disease, experts say. Still, adolescence offers its own complexities. Preteen and teen patients with endometriosis tend to present more often with atypical symptoms and with much more subtle and variable laparoscopic findings than do adult patients. Dr. Laufer reported more than 20 years ago that only 9.7% of 46 girls presented classically with dysmenorrhea. In 63%, pain was both acyclic and cyclic, and in 28%, pain was acyclic only (J Pediatr Adolesc Gynecol. 1997;10:199-202).

In a more recent report on adolescents treated by gynecologic surgeon Ceana Nezhat, MD, 64% had dysmenorrhea, 44% had menorrhagia, 60% had abnormal or irregular uterine bleeding, 56% had at least one gastrointestinal symptom, and 52% had at least one genitourinary symptom. The girls had seen a mean of three physicians, including psychiatrists and orthopedic surgeons, and had received diagnoses of pelvic inflammatory disease, irritable bowel syndrome, dysmenorrhea, appendicitis, ovarian cysts, and musculoskeletal pain (JSLS. 2015;19:e2015.00019). Notably, 56% had a family history of endometriosis, Dr. Nezhat, of the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine, and his colleagues found.

Courtesy Dr. Ceana Nezhat

Treatment dilemmas

The first-line treatment for dysmenorrhea and for suspected endometriosis in adolescents has long been empiric treatment with NSAIDs and oral contraceptive pills. Experts commonly recommend today that combined oral contraceptive pills (COCPs) be started cyclically and then changed to continuous dosing if necessary with the goal of inducing amenorrhea.

If symptoms are not well controlled within 3-6 months of compliant medication management with COCPs and NSAIDs and endometriosis is suspected, then laparoscopy by a physician who is familiar with adolescent endometriosis and can simultaneously diagnose and treat the disease should be considered, according to Dr. Laufer and several other experts in pediatric and adolescent gynecology who spoke with Ob.Gyn. News.

“If someone still has pain on one COCP, then switching to another COCP is not going to solve the problem – there is no study that shows that one pill is better than another,” Dr. Laufer said.

Yet extra months and sometimes years of pill-switching and empiric therapy with other medications – rather than surgical evaluation, diagnosis, and treatment – is not uncommon. “Usually, by the time a patient comes to me, they’ve already been on multiple birth control pills, they’ve failed NSAIDs, and they’ve often tried other medications as well,” such as progestins and gonadotropin-releasing hormone agonists, said Iris Kerin Orbuch, MD, director of the Advanced Gynecologic Laparoscopy Centers in New York and Los Angeles.

ACOG under fire

Dr. Sinervo and Dr. Orbuch are among the gynecologic surgeons, other providers, and patients who have signed a petition to ACOG urging it to involve both educated patients and expert, multidisciplinary endometriosis providers in improving their guidance and policies on endometriosis to facilitate earlier diagnosis and more effective treatment.

The petition was organized by advocate Casey Berna in July and supported by more than a half-dozen endometriosis advocacy groups; in early May, it had almost 8,700 signatures. Ms. Berna also co-organized a demonstration outside ACOG headquarters on April 5-6 as leaders were reviewing practice bulletins and deciding which need revision – and a virtual protest (#WeMatterACOG) – to push for better guidelines.

Courtesy of Wendy Bingham, DPT

*This article was updated June 5, 2018. An earlier version of this article misstated Dr. Ken R. Sinervo’s name.

Meg Hayden, RN, a school nurse in Oxford, Miss., used to be a labor and delivery nurse and considers herself more attuned to women’s health issues than other school nurses are. Still, a new educational initiative on endometriosis that stresses that menstrual pain is not normal – and that teenagers are not too young to have endometriosis – has helped her “connect the dots.”

“It’s a good reminder for me to look at patterns” and advise those girls who have repeated episodes of pelvic pain and other symptoms to “keep a diary” and to seek care, Ms. Hayden said.

Courtesy Shannon Cohn

Atypical symptoms and presentation

Endometriosis is an enigmatic disease. It traditionally has been associated with retrograde menstruation, but today, there are more nuanced and likely overlapping theories of etiology. Identified in girls even prior to the onset of menses, the disease is generally believed to be progressive, but perhaps not all the time. Patients with significant amounts of disease may have tremendous pain or they may have very little discomfort.

While adolescents can have advanced endometriosis, most have early-stage disease, experts say. Still, adolescence offers its own complexities. Preteen and teen patients with endometriosis tend to present more often with atypical symptoms and with much more subtle and variable laparoscopic findings than do adult patients. Dr. Laufer reported more than 20 years ago that only 9.7% of 46 girls presented classically with dysmenorrhea. In 63%, pain was both acyclic and cyclic, and in 28%, pain was acyclic only (J Pediatr Adolesc Gynecol. 1997;10:199-202).

In a more recent report on adolescents treated by gynecologic surgeon Ceana Nezhat, MD, 64% had dysmenorrhea, 44% had menorrhagia, 60% had abnormal or irregular uterine bleeding, 56% had at least one gastrointestinal symptom, and 52% had at least one genitourinary symptom. The girls had seen a mean of three physicians, including psychiatrists and orthopedic surgeons, and had received diagnoses of pelvic inflammatory disease, irritable bowel syndrome, dysmenorrhea, appendicitis, ovarian cysts, and musculoskeletal pain (JSLS. 2015;19:e2015.00019). Notably, 56% had a family history of endometriosis, Dr. Nezhat, of the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine, and his colleagues found.

Courtesy Dr. Ceana Nezhat

Treatment dilemmas

The first-line treatment for dysmenorrhea and for suspected endometriosis in adolescents has long been empiric treatment with NSAIDs and oral contraceptive pills. Experts commonly recommend today that combined oral contraceptive pills (COCPs) be started cyclically and then changed to continuous dosing if necessary with the goal of inducing amenorrhea.

If symptoms are not well controlled within 3-6 months of compliant medication management with COCPs and NSAIDs and endometriosis is suspected, then laparoscopy by a physician who is familiar with adolescent endometriosis and can simultaneously diagnose and treat the disease should be considered, according to Dr. Laufer and several other experts in pediatric and adolescent gynecology who spoke with Ob.Gyn. News.

“If someone still has pain on one COCP, then switching to another COCP is not going to solve the problem – there is no study that shows that one pill is better than another,” Dr. Laufer said.

Yet extra months and sometimes years of pill-switching and empiric therapy with other medications – rather than surgical evaluation, diagnosis, and treatment – is not uncommon. “Usually, by the time a patient comes to me, they’ve already been on multiple birth control pills, they’ve failed NSAIDs, and they’ve often tried other medications as well,” such as progestins and gonadotropin-releasing hormone agonists, said Iris Kerin Orbuch, MD, director of the Advanced Gynecologic Laparoscopy Centers in New York and Los Angeles.

ACOG under fire

Dr. Sinervo and Dr. Orbuch are among the gynecologic surgeons, other providers, and patients who have signed a petition to ACOG urging it to involve both educated patients and expert, multidisciplinary endometriosis providers in improving their guidance and policies on endometriosis to facilitate earlier diagnosis and more effective treatment.

The petition was organized by advocate Casey Berna in July and supported by more than a half-dozen endometriosis advocacy groups; in early May, it had almost 8,700 signatures. Ms. Berna also co-organized a demonstration outside ACOG headquarters on April 5-6 as leaders were reviewing practice bulletins and deciding which need revision – and a virtual protest (#WeMatterACOG) – to push for better guidelines.

Courtesy of Wendy Bingham, DPT

*This article was updated June 5, 2018. An earlier version of this article misstated Dr. Ken R. Sinervo’s name.

WASHINGTON – George R. Saade, MD, wants to see a Time magazine cover story like the 2010 feature titled, “How the first 9 months shape the rest of your life” – except this new story would read “How the first 9 months shape the rest of the mother’s life.”

It’s time, he says, that pregnancy truly be appreciated as a “window to future health” for the mother as well as for the baby, and that the term “maternal care” replaces prenatal care. “How many of your [primary care] providers have asked you if you’ve had any pregnancies and if any of your pregnancies were complicated by hypertension, preterm delivery, growth restriction, or gestational diabetes?” Dr. Saade asked at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“It’s better than before, but not good enough ... Checking with patients 6 weeks postpartum is not enough” to prevent long-term metabolic and cardiovascular disorders, he said. “We need regular screening of women.”

The relationship between gestational diabetes (GDM) and subsequent type 2 diabetes, demonstrated several decades ago, offered the “first evidence that pregnancy is a window to future health,” and evidence of the relationship continues to grow. “We know today that there is no other predictive marker of type 2 diabetes that is better and stronger than gestational diabetes,” said Dr. Saade, chief of obstetrics and maternal-fetal medicine at the University of Texas Medical Branch, Galveston.

GDM has also recently been shown to elevate cardiovascular risk independent of its association with type 2 diabetes and metabolic disease.

And similarly, there is now an incontrovertible body of evidence that women who have had preeclampsia are at significantly higher risk of developing hypertension, stroke, and ischemic heart disease later in life than are women who have not have preeclampsia, Dr. Saade said.

Layered evidence

The study that first caught Dr. Saade’s attention was a large Norwegian population-based study published in 2001 that looked at maternal mortality up to 25 years after pregnancy. Women who had preeclampsia had a 1.2-fold higher long-term risk of death from cardiovascular diseases, cancer, and stroke – and women with a history of both preeclampsia and a preterm delivery had a 2.71-fold higher risk – than that of women without such history.

Looking at cardiovascular causes of death specifically, the risk among women with both preeclampsia and preterm delivery was 8.12-fold higher than in women who did not have preeclampsia.

Since then, studies and reviews conducted in the United States and Europe have shown that a history of preeclampsia doubles the risk of developing cardiovascular disease, more than triples the risk of later hypertension, and also increases the risk of stroke, though more moderately.

Recently, Dr. Saade said, researchers have also begun reporting subclinical cardiac abnormalities in women with a history of preeclampsia. A study of 107 women with preeclampsia and 41 women with uneventful pregnancies found that the prevalence of subclinical heart failure (heart failure Stage B) was approximately 3.5% higher in the short term in the preeclampsia group. The women underwent regular cardiac ultrasound and other cardiovascular risk assessment tests 4-10 years postpartum (Ultrasound Obstet Gynecol. 2017;49[1]:143-9).

Preterm delivery and small for gestational age have also been associated with increased risk of ischemic heart disease and other cardiovascular events later in life. And gestational hypertension, research has shown, is a clear risk factor for later hypertension. “We always think of preeclampsia as a different disease, but as far as long-term health is concerned, it doesn’t matter if a woman had preeclampsia or gestational hypertension; she’s still at [greater] risk for hypertension later,” Dr. Saade said.

“And we don’t have to wait 30 years to see evidence” of the association between pregnancy complications and adverse cardiovascular outcomes, he emphasized. A recent retrospective cohort study of more than 300,000 women in Florida showed that women who experienced a maternal placental syndrome during their first pregnancy were at higher risk of subsequent cardiovascular disease during just 5 years of follow-up (Am J Obstet Gynecol. 2016;215[4]:484.e1-14).

Into practice

Regular screening of women whose pregnancies were complicated by conditions associated with long-term health risks “need not be that sophisticated,” Dr. Saade said. Measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose is often enough for basic maternal health surveillance, he said.

Dr. Saade said he and some other experts in the field are recommending yearly follow-up for patients who’ve had preeclampsia and other complications. Among the other experts urging early heart disease risk screening is Graeme N. Smith, MD, PhD, an ob.gyn in Ontario who has developed surveillance protocols, follow-up forms, and risk prediction tools for use in a maternal health clinic he established at Kingston General Hospital, Queens University. At the meeting, Dr. Saade encouraged the audience to access Dr. Smith’s resources.

The American Heart Association, in its 2011 guidelines for cardiovascular disease prevention in women, includes pregnancy risks factors (specifically a history of preeclampsia, gestational diabetes, or pregnancy-induced hypertension) as part of its list of major factors for use in risk assessment (Circulation. 2011;123:1243-62).

But as Erica P. Gunderson, PhD, MPH, of Kaiser Permanente Northern California’s division of research, pointed out during another presentation at the meeting, there is more work to be done. Reproductive history is not included in existing disease prediction or risk stratification models for atherosclerotic cardiovascular disease, making it hard at this point to devise specific screening protocols and schedules, especially when it comes to a history of GDM, she said.

“We need more coordinated systems, surveillance in younger women, and some prediction models so that we can know who is at highest risk and needs more surveillance,” she said.

The AHA’s inclusion of GDM history is based on its strong link to overt diabetes, but recent evidence has shown that a history of GDM can independently elevate cardiovascular risk, she noted. Research from the Nurses Health Study II cohort, for instance, found a 30% higher relative risk of cardiovascular events (myocardial infarction and stroke) in women with a history of GDM without progression to diabetes, compared with women who did not have GDM or diabetes (JAMA Intern Med. 2017;177[12]:1735-42).

Dr. Gunderson has also found through analyses of the Coronary Artery Risk Development in Young Adults study data that women who had GDM but did not go on to develop overt diabetes or impaired glycemia had greater carotid intima media thickness many years post delivery than did women without a history of gestational diabetes (J Am Heart Assoc. 2014;3[2]:e000490).

In some models, she has written, this difference in carotid intima media thickness could represent 3-5 years of greater vascular aging for women with previous gestational diabetes and no apparent metabolic dysfunction outside of pregnancy (JAMA Intern Med. 2017;177[12]:1742-4).

There’s a question, she and Dr. Saade both noted, of whether pregnancies unmask previous dispositions to cardiovascular disease or whether pregnancy complications more directly drive adverse long-term outcomes. There is evidence that disorders such as GDM, Dr. Gunderson said, are superimposed on already altered metabolism. But at this time, Dr. Saade said, it appears that “the answer is both.”

According to Dr. Saade, at least three studies are currently following women prospectively to learn more about pregnancy as a window to future cardiovascular health. One of them is the National Institute of Child Health and Human Development’s Nulliparous Pregnancy Outcomes Study–Monitoring Mothers-to-Be Heart Health Study; some data from this study will be presented soon, he said.

Both Dr. Saade and Dr. Gunderson reported in their presentations that they had no disclosures.

WASHINGTON – George R. Saade, MD, wants to see a Time magazine cover story like the 2010 feature titled, “How the first 9 months shape the rest of your life” – except this new story would read “How the first 9 months shape the rest of the mother’s life.”

It’s time, he says, that pregnancy truly be appreciated as a “window to future health” for the mother as well as for the baby, and that the term “maternal care” replaces prenatal care. “How many of your [primary care] providers have asked you if you’ve had any pregnancies and if any of your pregnancies were complicated by hypertension, preterm delivery, growth restriction, or gestational diabetes?” Dr. Saade asked at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“It’s better than before, but not good enough ... Checking with patients 6 weeks postpartum is not enough” to prevent long-term metabolic and cardiovascular disorders, he said. “We need regular screening of women.”

The relationship between gestational diabetes (GDM) and subsequent type 2 diabetes, demonstrated several decades ago, offered the “first evidence that pregnancy is a window to future health,” and evidence of the relationship continues to grow. “We know today that there is no other predictive marker of type 2 diabetes that is better and stronger than gestational diabetes,” said Dr. Saade, chief of obstetrics and maternal-fetal medicine at the University of Texas Medical Branch, Galveston.

GDM has also recently been shown to elevate cardiovascular risk independent of its association with type 2 diabetes and metabolic disease.

And similarly, there is now an incontrovertible body of evidence that women who have had preeclampsia are at significantly higher risk of developing hypertension, stroke, and ischemic heart disease later in life than are women who have not have preeclampsia, Dr. Saade said.

Layered evidence

The study that first caught Dr. Saade’s attention was a large Norwegian population-based study published in 2001 that looked at maternal mortality up to 25 years after pregnancy. Women who had preeclampsia had a 1.2-fold higher long-term risk of death from cardiovascular diseases, cancer, and stroke – and women with a history of both preeclampsia and a preterm delivery had a 2.71-fold higher risk – than that of women without such history.

Looking at cardiovascular causes of death specifically, the risk among women with both preeclampsia and preterm delivery was 8.12-fold higher than in women who did not have preeclampsia.

Since then, studies and reviews conducted in the United States and Europe have shown that a history of preeclampsia doubles the risk of developing cardiovascular disease, more than triples the risk of later hypertension, and also increases the risk of stroke, though more moderately.

Recently, Dr. Saade said, researchers have also begun reporting subclinical cardiac abnormalities in women with a history of preeclampsia. A study of 107 women with preeclampsia and 41 women with uneventful pregnancies found that the prevalence of subclinical heart failure (heart failure Stage B) was approximately 3.5% higher in the short term in the preeclampsia group. The women underwent regular cardiac ultrasound and other cardiovascular risk assessment tests 4-10 years postpartum (Ultrasound Obstet Gynecol. 2017;49[1]:143-9).

Preterm delivery and small for gestational age have also been associated with increased risk of ischemic heart disease and other cardiovascular events later in life. And gestational hypertension, research has shown, is a clear risk factor for later hypertension. “We always think of preeclampsia as a different disease, but as far as long-term health is concerned, it doesn’t matter if a woman had preeclampsia or gestational hypertension; she’s still at [greater] risk for hypertension later,” Dr. Saade said.

“And we don’t have to wait 30 years to see evidence” of the association between pregnancy complications and adverse cardiovascular outcomes, he emphasized. A recent retrospective cohort study of more than 300,000 women in Florida showed that women who experienced a maternal placental syndrome during their first pregnancy were at higher risk of subsequent cardiovascular disease during just 5 years of follow-up (Am J Obstet Gynecol. 2016;215[4]:484.e1-14).

Into practice

Regular screening of women whose pregnancies were complicated by conditions associated with long-term health risks “need not be that sophisticated,” Dr. Saade said. Measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose is often enough for basic maternal health surveillance, he said.

Dr. Saade said he and some other experts in the field are recommending yearly follow-up for patients who’ve had preeclampsia and other complications. Among the other experts urging early heart disease risk screening is Graeme N. Smith, MD, PhD, an ob.gyn in Ontario who has developed surveillance protocols, follow-up forms, and risk prediction tools for use in a maternal health clinic he established at Kingston General Hospital, Queens University. At the meeting, Dr. Saade encouraged the audience to access Dr. Smith’s resources.

The American Heart Association, in its 2011 guidelines for cardiovascular disease prevention in women, includes pregnancy risks factors (specifically a history of preeclampsia, gestational diabetes, or pregnancy-induced hypertension) as part of its list of major factors for use in risk assessment (Circulation. 2011;123:1243-62).

But as Erica P. Gunderson, PhD, MPH, of Kaiser Permanente Northern California’s division of research, pointed out during another presentation at the meeting, there is more work to be done. Reproductive history is not included in existing disease prediction or risk stratification models for atherosclerotic cardiovascular disease, making it hard at this point to devise specific screening protocols and schedules, especially when it comes to a history of GDM, she said.

“We need more coordinated systems, surveillance in younger women, and some prediction models so that we can know who is at highest risk and needs more surveillance,” she said.

The AHA’s inclusion of GDM history is based on its strong link to overt diabetes, but recent evidence has shown that a history of GDM can independently elevate cardiovascular risk, she noted. Research from the Nurses Health Study II cohort, for instance, found a 30% higher relative risk of cardiovascular events (myocardial infarction and stroke) in women with a history of GDM without progression to diabetes, compared with women who did not have GDM or diabetes (JAMA Intern Med. 2017;177[12]:1735-42).

Dr. Gunderson has also found through analyses of the Coronary Artery Risk Development in Young Adults study data that women who had GDM but did not go on to develop overt diabetes or impaired glycemia had greater carotid intima media thickness many years post delivery than did women without a history of gestational diabetes (J Am Heart Assoc. 2014;3[2]:e000490).

In some models, she has written, this difference in carotid intima media thickness could represent 3-5 years of greater vascular aging for women with previous gestational diabetes and no apparent metabolic dysfunction outside of pregnancy (JAMA Intern Med. 2017;177[12]:1742-4).

There’s a question, she and Dr. Saade both noted, of whether pregnancies unmask previous dispositions to cardiovascular disease or whether pregnancy complications more directly drive adverse long-term outcomes. There is evidence that disorders such as GDM, Dr. Gunderson said, are superimposed on already altered metabolism. But at this time, Dr. Saade said, it appears that “the answer is both.”

According to Dr. Saade, at least three studies are currently following women prospectively to learn more about pregnancy as a window to future cardiovascular health. One of them is the National Institute of Child Health and Human Development’s Nulliparous Pregnancy Outcomes Study–Monitoring Mothers-to-Be Heart Health Study; some data from this study will be presented soon, he said.

Both Dr. Saade and Dr. Gunderson reported in their presentations that they had no disclosures.

WASHINGTON – George R. Saade, MD, wants to see a Time magazine cover story like the 2010 feature titled, “How the first 9 months shape the rest of your life” – except this new story would read “How the first 9 months shape the rest of the mother’s life.”

It’s time, he says, that pregnancy truly be appreciated as a “window to future health” for the mother as well as for the baby, and that the term “maternal care” replaces prenatal care. “How many of your [primary care] providers have asked you if you’ve had any pregnancies and if any of your pregnancies were complicated by hypertension, preterm delivery, growth restriction, or gestational diabetes?” Dr. Saade asked at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“It’s better than before, but not good enough ... Checking with patients 6 weeks postpartum is not enough” to prevent long-term metabolic and cardiovascular disorders, he said. “We need regular screening of women.”

The relationship between gestational diabetes (GDM) and subsequent type 2 diabetes, demonstrated several decades ago, offered the “first evidence that pregnancy is a window to future health,” and evidence of the relationship continues to grow. “We know today that there is no other predictive marker of type 2 diabetes that is better and stronger than gestational diabetes,” said Dr. Saade, chief of obstetrics and maternal-fetal medicine at the University of Texas Medical Branch, Galveston.

GDM has also recently been shown to elevate cardiovascular risk independent of its association with type 2 diabetes and metabolic disease.

And similarly, there is now an incontrovertible body of evidence that women who have had preeclampsia are at significantly higher risk of developing hypertension, stroke, and ischemic heart disease later in life than are women who have not have preeclampsia, Dr. Saade said.

Layered evidence

The study that first caught Dr. Saade’s attention was a large Norwegian population-based study published in 2001 that looked at maternal mortality up to 25 years after pregnancy. Women who had preeclampsia had a 1.2-fold higher long-term risk of death from cardiovascular diseases, cancer, and stroke – and women with a history of both preeclampsia and a preterm delivery had a 2.71-fold higher risk – than that of women without such history.

Looking at cardiovascular causes of death specifically, the risk among women with both preeclampsia and preterm delivery was 8.12-fold higher than in women who did not have preeclampsia.

Since then, studies and reviews conducted in the United States and Europe have shown that a history of preeclampsia doubles the risk of developing cardiovascular disease, more than triples the risk of later hypertension, and also increases the risk of stroke, though more moderately.

Recently, Dr. Saade said, researchers have also begun reporting subclinical cardiac abnormalities in women with a history of preeclampsia. A study of 107 women with preeclampsia and 41 women with uneventful pregnancies found that the prevalence of subclinical heart failure (heart failure Stage B) was approximately 3.5% higher in the short term in the preeclampsia group. The women underwent regular cardiac ultrasound and other cardiovascular risk assessment tests 4-10 years postpartum (Ultrasound Obstet Gynecol. 2017;49[1]:143-9).

Preterm delivery and small for gestational age have also been associated with increased risk of ischemic heart disease and other cardiovascular events later in life. And gestational hypertension, research has shown, is a clear risk factor for later hypertension. “We always think of preeclampsia as a different disease, but as far as long-term health is concerned, it doesn’t matter if a woman had preeclampsia or gestational hypertension; she’s still at [greater] risk for hypertension later,” Dr. Saade said.

“And we don’t have to wait 30 years to see evidence” of the association between pregnancy complications and adverse cardiovascular outcomes, he emphasized. A recent retrospective cohort study of more than 300,000 women in Florida showed that women who experienced a maternal placental syndrome during their first pregnancy were at higher risk of subsequent cardiovascular disease during just 5 years of follow-up (Am J Obstet Gynecol. 2016;215[4]:484.e1-14).

Into practice

Regular screening of women whose pregnancies were complicated by conditions associated with long-term health risks “need not be that sophisticated,” Dr. Saade said. Measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose is often enough for basic maternal health surveillance, he said.

Dr. Saade said he and some other experts in the field are recommending yearly follow-up for patients who’ve had preeclampsia and other complications. Among the other experts urging early heart disease risk screening is Graeme N. Smith, MD, PhD, an ob.gyn in Ontario who has developed surveillance protocols, follow-up forms, and risk prediction tools for use in a maternal health clinic he established at Kingston General Hospital, Queens University. At the meeting, Dr. Saade encouraged the audience to access Dr. Smith’s resources.

The American Heart Association, in its 2011 guidelines for cardiovascular disease prevention in women, includes pregnancy risks factors (specifically a history of preeclampsia, gestational diabetes, or pregnancy-induced hypertension) as part of its list of major factors for use in risk assessment (Circulation. 2011;123:1243-62).

But as Erica P. Gunderson, PhD, MPH, of Kaiser Permanente Northern California’s division of research, pointed out during another presentation at the meeting, there is more work to be done. Reproductive history is not included in existing disease prediction or risk stratification models for atherosclerotic cardiovascular disease, making it hard at this point to devise specific screening protocols and schedules, especially when it comes to a history of GDM, she said.

“We need more coordinated systems, surveillance in younger women, and some prediction models so that we can know who is at highest risk and needs more surveillance,” she said.

The AHA’s inclusion of GDM history is based on its strong link to overt diabetes, but recent evidence has shown that a history of GDM can independently elevate cardiovascular risk, she noted. Research from the Nurses Health Study II cohort, for instance, found a 30% higher relative risk of cardiovascular events (myocardial infarction and stroke) in women with a history of GDM without progression to diabetes, compared with women who did not have GDM or diabetes (JAMA Intern Med. 2017;177[12]:1735-42).

Dr. Gunderson has also found through analyses of the Coronary Artery Risk Development in Young Adults study data that women who had GDM but did not go on to develop overt diabetes or impaired glycemia had greater carotid intima media thickness many years post delivery than did women without a history of gestational diabetes (J Am Heart Assoc. 2014;3[2]:e000490).

In some models, she has written, this difference in carotid intima media thickness could represent 3-5 years of greater vascular aging for women with previous gestational diabetes and no apparent metabolic dysfunction outside of pregnancy (JAMA Intern Med. 2017;177[12]:1742-4).

There’s a question, she and Dr. Saade both noted, of whether pregnancies unmask previous dispositions to cardiovascular disease or whether pregnancy complications more directly drive adverse long-term outcomes. There is evidence that disorders such as GDM, Dr. Gunderson said, are superimposed on already altered metabolism. But at this time, Dr. Saade said, it appears that “the answer is both.”

According to Dr. Saade, at least three studies are currently following women prospectively to learn more about pregnancy as a window to future cardiovascular health. One of them is the National Institute of Child Health and Human Development’s Nulliparous Pregnancy Outcomes Study–Monitoring Mothers-to-Be Heart Health Study; some data from this study will be presented soon, he said.

Both Dr. Saade and Dr. Gunderson reported in their presentations that they had no disclosures.

Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”

The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.

digitalskillet/Thinkstock

“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.

By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”

Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”

ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.

The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.

Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.

“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”

NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.

Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.

The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.

The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.

“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”

A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.

ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”

Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”

The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.

digitalskillet/Thinkstock

“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.

By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”

Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”

ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.

The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.

Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.

“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”

NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.

Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.

The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.

The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.

“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”

A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.

ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”

Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”

The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.

digitalskillet/Thinkstock

“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.

By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”

Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”

ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.

The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.

Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.

“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”

NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.

Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.

The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.

The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.

“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”

A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.

ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”

WASHINGTON – To predict macrosomia, fetal abdominal circumference is the best single measure to obtain on ultrasound, John C. Hobbins, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“Everything that the estimated fetal weight [EFW] can do, the abdominal circumference can do better,” especially in diabetic mothers, said Dr. Hobbins, who is widely regarded as one of the early pioneers in the development and use of obstetric ultrasound as a diagnostic tool.

Because it reflects liver size and incorporates subcutaneous fat, the abdominal circumference (AC) “concentrates on where the action is,” he said. It also “roughly correlates” with the size of the fetal shoulders and is not affected by genetic factors.

Moreover, “it focuses on one task rather than putting into play four variables, each with its own standard error of the method,” said Dr. Hobbins, referring to the four fetal biometric parameters incorporated into the Hadlock formula for EFW that is provided “upon fire-up of virtually every ultrasound machine.”

These four parameters (biparietal diameter, head circumference, femur length, and AC) each contribute to fetal weight but the AC has been shown to correlate better with weight at birth than the other variables, and it is the only measure that reflects how corpulent the fetus is, he noted.

The “general rule of thumb is that the EFW [as calculated by ultrasound machine–based equations] has a standard error of the method of plus or minus 10%. … which means that an EFW of 4,000 g is associated with a splay of plus or minus 1.2 pounds,” said Dr. Hobbins, professor of obstetrics and gynecology at the University of Colorado at Denver, Aurora.

“But the problem for us is not the failure of the ultrasound – it’s the way we use it,” he said.

An assortment of customized formulas have been developed for macrosomia, including one designed for use in diabetes that incorporates AC, head circumference, femur length, and 3D volumes of the thigh and abdomen. “If one used this and set a cut-off at 4,300 g, you’d pick up 93%. … but at false positive rate of 38%,” he said.

While not perfect, the AC alone is as accurate as more complicated formulas to detect macrosomic fetuses, he emphasized. “It’s a tough [measurement] to get just before the baby is born, but you can do it a little bit earlier,” he said. Research has shown that screening at 30-34 weeks can capture a majority of the fetuses destined to be greater than 4,000 g at birth, with a lower false-positive rate.

He pointed to one “very interesting” recent study in which AC was measured with a handheld ultrasound device at 24-40 weeks’ gestation, prior to formal ultrasound estimation of EFW. Early AC was a better predictor of large-for-gestational age babies at birth than EFW or early fundal height measurement, with sensitivities of 67%, 25%, and 50%, respectively (Am J Obstet Gynecol. 2015 Jun;212[6]:820.e1-8).

“And AC had a false-positive rate of only 10%,” Dr. Hobbins said.

Macrosomia occurs in 20% of cases of gestational diabetes and 25% of pregestational diabetes, he said. “And even if there is adequate glucose control, 17% will be macrosomic.”

The condition correlates with childhood and adulthood metabolic dysfunction and is associated with significantly increased risk of birth injury to the infant and to the mother. The alternative – cesarean delivery – is “not innocuous,” and “[we have] a very low threshold for cesarean if macrosomia is suspected,” Dr. Hobbins said.

Dr. Hobbins reported having no financial disclosures.

WASHINGTON – To predict macrosomia, fetal abdominal circumference is the best single measure to obtain on ultrasound, John C. Hobbins, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“Everything that the estimated fetal weight [EFW] can do, the abdominal circumference can do better,” especially in diabetic mothers, said Dr. Hobbins, who is widely regarded as one of the early pioneers in the development and use of obstetric ultrasound as a diagnostic tool.

Because it reflects liver size and incorporates subcutaneous fat, the abdominal circumference (AC) “concentrates on where the action is,” he said. It also “roughly correlates” with the size of the fetal shoulders and is not affected by genetic factors.

Moreover, “it focuses on one task rather than putting into play four variables, each with its own standard error of the method,” said Dr. Hobbins, referring to the four fetal biometric parameters incorporated into the Hadlock formula for EFW that is provided “upon fire-up of virtually every ultrasound machine.”

These four parameters (biparietal diameter, head circumference, femur length, and AC) each contribute to fetal weight but the AC has been shown to correlate better with weight at birth than the other variables, and it is the only measure that reflects how corpulent the fetus is, he noted.

The “general rule of thumb is that the EFW [as calculated by ultrasound machine–based equations] has a standard error of the method of plus or minus 10%. … which means that an EFW of 4,000 g is associated with a splay of plus or minus 1.2 pounds,” said Dr. Hobbins, professor of obstetrics and gynecology at the University of Colorado at Denver, Aurora.

“But the problem for us is not the failure of the ultrasound – it’s the way we use it,” he said.

An assortment of customized formulas have been developed for macrosomia, including one designed for use in diabetes that incorporates AC, head circumference, femur length, and 3D volumes of the thigh and abdomen. “If one used this and set a cut-off at 4,300 g, you’d pick up 93%. … but at false positive rate of 38%,” he said.

While not perfect, the AC alone is as accurate as more complicated formulas to detect macrosomic fetuses, he emphasized. “It’s a tough [measurement] to get just before the baby is born, but you can do it a little bit earlier,” he said. Research has shown that screening at 30-34 weeks can capture a majority of the fetuses destined to be greater than 4,000 g at birth, with a lower false-positive rate.

He pointed to one “very interesting” recent study in which AC was measured with a handheld ultrasound device at 24-40 weeks’ gestation, prior to formal ultrasound estimation of EFW. Early AC was a better predictor of large-for-gestational age babies at birth than EFW or early fundal height measurement, with sensitivities of 67%, 25%, and 50%, respectively (Am J Obstet Gynecol. 2015 Jun;212[6]:820.e1-8).

“And AC had a false-positive rate of only 10%,” Dr. Hobbins said.

Macrosomia occurs in 20% of cases of gestational diabetes and 25% of pregestational diabetes, he said. “And even if there is adequate glucose control, 17% will be macrosomic.”

The condition correlates with childhood and adulthood metabolic dysfunction and is associated with significantly increased risk of birth injury to the infant and to the mother. The alternative – cesarean delivery – is “not innocuous,” and “[we have] a very low threshold for cesarean if macrosomia is suspected,” Dr. Hobbins said.

Dr. Hobbins reported having no financial disclosures.

WASHINGTON – To predict macrosomia, fetal abdominal circumference is the best single measure to obtain on ultrasound, John C. Hobbins, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“Everything that the estimated fetal weight [EFW] can do, the abdominal circumference can do better,” especially in diabetic mothers, said Dr. Hobbins, who is widely regarded as one of the early pioneers in the development and use of obstetric ultrasound as a diagnostic tool.

Because it reflects liver size and incorporates subcutaneous fat, the abdominal circumference (AC) “concentrates on where the action is,” he said. It also “roughly correlates” with the size of the fetal shoulders and is not affected by genetic factors.

Moreover, “it focuses on one task rather than putting into play four variables, each with its own standard error of the method,” said Dr. Hobbins, referring to the four fetal biometric parameters incorporated into the Hadlock formula for EFW that is provided “upon fire-up of virtually every ultrasound machine.”

These four parameters (biparietal diameter, head circumference, femur length, and AC) each contribute to fetal weight but the AC has been shown to correlate better with weight at birth than the other variables, and it is the only measure that reflects how corpulent the fetus is, he noted.

The “general rule of thumb is that the EFW [as calculated by ultrasound machine–based equations] has a standard error of the method of plus or minus 10%. … which means that an EFW of 4,000 g is associated with a splay of plus or minus 1.2 pounds,” said Dr. Hobbins, professor of obstetrics and gynecology at the University of Colorado at Denver, Aurora.

“But the problem for us is not the failure of the ultrasound – it’s the way we use it,” he said.

An assortment of customized formulas have been developed for macrosomia, including one designed for use in diabetes that incorporates AC, head circumference, femur length, and 3D volumes of the thigh and abdomen. “If one used this and set a cut-off at 4,300 g, you’d pick up 93%. … but at false positive rate of 38%,” he said.

While not perfect, the AC alone is as accurate as more complicated formulas to detect macrosomic fetuses, he emphasized. “It’s a tough [measurement] to get just before the baby is born, but you can do it a little bit earlier,” he said. Research has shown that screening at 30-34 weeks can capture a majority of the fetuses destined to be greater than 4,000 g at birth, with a lower false-positive rate.

He pointed to one “very interesting” recent study in which AC was measured with a handheld ultrasound device at 24-40 weeks’ gestation, prior to formal ultrasound estimation of EFW. Early AC was a better predictor of large-for-gestational age babies at birth than EFW or early fundal height measurement, with sensitivities of 67%, 25%, and 50%, respectively (Am J Obstet Gynecol. 2015 Jun;212[6]:820.e1-8).

“And AC had a false-positive rate of only 10%,” Dr. Hobbins said.

Macrosomia occurs in 20% of cases of gestational diabetes and 25% of pregestational diabetes, he said. “And even if there is adequate glucose control, 17% will be macrosomic.”

The condition correlates with childhood and adulthood metabolic dysfunction and is associated with significantly increased risk of birth injury to the infant and to the mother. The alternative – cesarean delivery – is “not innocuous,” and “[we have] a very low threshold for cesarean if macrosomia is suspected,” Dr. Hobbins said.

Dr. Hobbins reported having no financial disclosures.

WASHINGTON – The American College of Obstetricians and Gynecologists’ conclusion that insulin should be considered the first-line pharmacologic treatment for gestational diabetes came under fire at a recent meeting on diabetes in pregnancy, indicating the extent to which controversy persists over the use of oral antidiabetic medications in pregnancy.

“Like many others, I’m perplexed by the strong endorsement,” Mark Landon, MD, professor and chair of the department of obstetrics and gynecology at Ohio State University, Columbus, said during an open discussion of oral hypoglycemic agents held at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

Dr. Landon and several other researchers and experts in diabetes in pregnancy expressed discontent with any firm prioritization of the drugs most commonly used for gestational diabetes, saying that there are not yet enough data to do so.

Current recommendations

In its practice bulletin, ACOG noted that oral antidiabetic medications, such as glyburide and metformin, are increasingly used among women with GDM, despite not being approved by the Food and Drug Administration for this indication and even though insulin continues to be the recommended as first-line therapy by the American Diabetes Association (ADA).

The ADA, in a summary of its 2017 guideline on the management of diabetes in pregnancy, stated that insulin is the “preferred medication for treating hyperglycemia in gestational diabetes mellitus, as it does not cross the placenta to a measurable extent.” Metformin and glyburide are options, “but both cross the placenta to the fetus, with metformin likely crossing to a greater extent than glyburide” (Diabetes Care. 2017 Jan;40[Suppl 1]:S114- 9).Regarding metformin, the ACOG bulletin cited two trials that randomized women to metformin or insulin – one in which both groups experienced similar rates of a composite outcome of perinatal morbidity, and another in which women receiving metformin had lower mean glucose levels, less gestational weight gain, and neonates with lower rates of hypoglycemia.

ACOG also cited a meta-analysis, that found “minimal differences” between neonates of women randomized to metformin versus insulin, but also noted that “interestingly, women randomized to metformin experienced a higher rate of preterm birth” and a lower rate of gestational hypertension (BMJ. 2015;350:h102).

With respect to glyburide, the ACOG bulletin said that two recent meta-analyses had demonstrated worse neonatal outcomes with glyburide, compared with insulin, and that observational studies have shown higher rates of preeclampsia, hyperbilirubinemia, and stillbirth with the use of glyburide, compared with insulin. However, many other outcomes have not been statistically significantly different, according to the practice bulletin.

Additionally, at least 4%-16% of women eventually require the addition of insulin when glyburide is used as initial treatment, as do 26%-46% of women who take metformin, according to ACOG.

Regarding placental transfer, ACOG’s bulletin said that while one study that analyzed umbilical cord blood revealed no detectable glyburide in exposed pregnancies, another study demonstrated that glyburide does cross the placenta. Metformin has also been found to cross the placenta, with the fetus exposed to concentrations similar to maternal levels, the bulletin noted.

“Although current data demonstrate no adverse short-term effects on maternal or neonatal health from oral diabetic therapy during pregnancy, long-term outcomes are not yet available,” ACOG wrote in the practice bulletin.

Concerns about research

As Thomas Moore, MD, sees it, the quality of available data is insufficient to recommend insulin over oral agents, or one oral agent over another. “We really need to focus [the National Institutes of Health] on putting together proper studies,” he said at the meeting.

In a later interview, Dr. Moore referred to two recent Cochrane reviews. One review, published in January 2017, analyzed eight studies of oral antidiabetic therapies for GDM and concluded there was “insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral antidiabetic pharmacological therapy over another” (Cochrane Database Syst Rev. 2017 Jan 25;1:CD011967).

The other Cochrane review, published in November 2017, concluded that insulin and oral antidiabetic agents have similar effects on key health outcomes, and that each one has minimal harms. The quality of evidence, the authors said, ranged from “very low to moderate, with downgrading decisions due to imprecision, risk of bias, and inconsistency” (Cochrane Database Syst Rev. 2017 Nov 5;11:CD012037).

Dr. Moore, professor of maternal-fetal medicine at the University of California, San Diego, cautioned against presuming that placental transfer of an antidiabetic drug is “ipso facto dangerous or terrible.” Moreover, he said that it’s not yet clear whether glyburide crosses the placenta in the first place.

Dr. Moore, Dr. Landon, and others at the meeting said they are eagerly awaiting long-term follow-up data from the Metformin in Gestational Diabetes (MiG) trial underway in Australia. The prospective randomized trial is designed to compare metformin with insulin and finished recruiting women in 2006. A recently published analysis found similar neurodevelopmental outcomes in offspring at 2 years, but it’s the longer-term data looking into early puberty that experts now want to see (Arch Dis Child Fetal Neonatal Ed. 2016 Feb 24. doi: 10.1136/archdischild-2015-309602).

In the meantime, Dr. Landon said the “short-term safety record for oral antidiabetic medications is actually pretty good.” There are studies “suggesting an increased risk for large babies with glyburide, but these are very small RCTs [randomized controlled trials],” he said in an interview.

Data from population-based studies, moreover, are “flawed in as much as we don’t know the thresholds for initiating glyburide treatment, nor do we know whether the women were really good candidates for this therapy,” Dr. Landon said. “It’s conceivable, and it’s been my experience, that glyburide has been overprescribed and inappropriately prescribed in certain women with GDM who really should receive insulin therapy.”

Whether glyburide and metformin are being prescribed for GDM in optimal doses is another growing question – one that interests Steve N. Caritis, MD. The drugs are typically prescribed to be taken twice a day every 12 hours, but he said he is finding that some patients may need more frequent, individually tailored dosing.

“We may have come to conclusions in [the studies published thus far] that may not be the correct conclusions,” Dr. Caritis, who coleads obstetric pharmacology research at the Magee-Womens Research Institute in Pittsburgh, said at the DPSG meeting. “The question is, If the dosing were appropriate, would we have the same outcomes?”

Individualizing drug choice

Dosing aside, there may be populations of women who respond poorly to a medication because of the underlying pathophysiology of their GDM, said Maisa N. Feghali, MD, assistant professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh.

A study published in 2016 demonstrated the heterogeneity of the physiologic processes underlying hyperglycemia in 67 women with GDM. Almost one-third of women with GDM had predominant insulin secretion deficit, one-half had predominant insulin resistance, and the remaining 20% had a mixed “metabolic profile” (Diabetes Care. 2016 Jun;39[6]:1052-5).

This study prompted Dr. Feghali and her colleagues to design a pilot study aimed at testing an individualized approach that matches treatment to GDM mechanism. “We [currently] have the expectation that all glucose-lowering agents will be similarly effective despite significant variation in underlying GDM pathophysiology,” she said during a presentation at the DPSG meeting. “But I think we have a mismatch between variations in GDM and the uniformity of treatment.”

In her pilot study, women diagnosed with GDM who fail dietary control will be randomized into usual treatment or matched treatment (metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined insulin resistance and insulin secretion defects).

The MATCh-GDM study (Metabolic Analysis for Treatment Choice of GDM) is just getting underway. Patients will be monitored for consistency of GDM mechanism and glucose control, and routine clinical variables (hypertensive diseases, cesarean delivery, and birth weight) will be studied, as well as neonatal body composition, cord blood glucose, and cord blood C-peptide.

WASHINGTON – The American College of Obstetricians and Gynecologists’ conclusion that insulin should be considered the first-line pharmacologic treatment for gestational diabetes came under fire at a recent meeting on diabetes in pregnancy, indicating the extent to which controversy persists over the use of oral antidiabetic medications in pregnancy.

“Like many others, I’m perplexed by the strong endorsement,” Mark Landon, MD, professor and chair of the department of obstetrics and gynecology at Ohio State University, Columbus, said during an open discussion of oral hypoglycemic agents held at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

Dr. Landon and several other researchers and experts in diabetes in pregnancy expressed discontent with any firm prioritization of the drugs most commonly used for gestational diabetes, saying that there are not yet enough data to do so.

Current recommendations

In its practice bulletin, ACOG noted that oral antidiabetic medications, such as glyburide and metformin, are increasingly used among women with GDM, despite not being approved by the Food and Drug Administration for this indication and even though insulin continues to be the recommended as first-line therapy by the American Diabetes Association (ADA).

The ADA, in a summary of its 2017 guideline on the management of diabetes in pregnancy, stated that insulin is the “preferred medication for treating hyperglycemia in gestational diabetes mellitus, as it does not cross the placenta to a measurable extent.” Metformin and glyburide are options, “but both cross the placenta to the fetus, with metformin likely crossing to a greater extent than glyburide” (Diabetes Care. 2017 Jan;40[Suppl 1]:S114- 9).Regarding metformin, the ACOG bulletin cited two trials that randomized women to metformin or insulin – one in which both groups experienced similar rates of a composite outcome of perinatal morbidity, and another in which women receiving metformin had lower mean glucose levels, less gestational weight gain, and neonates with lower rates of hypoglycemia.

ACOG also cited a meta-analysis, that found “minimal differences” between neonates of women randomized to metformin versus insulin, but also noted that “interestingly, women randomized to metformin experienced a higher rate of preterm birth” and a lower rate of gestational hypertension (BMJ. 2015;350:h102).

With respect to glyburide, the ACOG bulletin said that two recent meta-analyses had demonstrated worse neonatal outcomes with glyburide, compared with insulin, and that observational studies have shown higher rates of preeclampsia, hyperbilirubinemia, and stillbirth with the use of glyburide, compared with insulin. However, many other outcomes have not been statistically significantly different, according to the practice bulletin.

Additionally, at least 4%-16% of women eventually require the addition of insulin when glyburide is used as initial treatment, as do 26%-46% of women who take metformin, according to ACOG.

Regarding placental transfer, ACOG’s bulletin said that while one study that analyzed umbilical cord blood revealed no detectable glyburide in exposed pregnancies, another study demonstrated that glyburide does cross the placenta. Metformin has also been found to cross the placenta, with the fetus exposed to concentrations similar to maternal levels, the bulletin noted.

“Although current data demonstrate no adverse short-term effects on maternal or neonatal health from oral diabetic therapy during pregnancy, long-term outcomes are not yet available,” ACOG wrote in the practice bulletin.

Concerns about research

As Thomas Moore, MD, sees it, the quality of available data is insufficient to recommend insulin over oral agents, or one oral agent over another. “We really need to focus [the National Institutes of Health] on putting together proper studies,” he said at the meeting.

In a later interview, Dr. Moore referred to two recent Cochrane reviews. One review, published in January 2017, analyzed eight studies of oral antidiabetic therapies for GDM and concluded there was “insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral antidiabetic pharmacological therapy over another” (Cochrane Database Syst Rev. 2017 Jan 25;1:CD011967).

The other Cochrane review, published in November 2017, concluded that insulin and oral antidiabetic agents have similar effects on key health outcomes, and that each one has minimal harms. The quality of evidence, the authors said, ranged from “very low to moderate, with downgrading decisions due to imprecision, risk of bias, and inconsistency” (Cochrane Database Syst Rev. 2017 Nov 5;11:CD012037).

Dr. Moore, professor of maternal-fetal medicine at the University of California, San Diego, cautioned against presuming that placental transfer of an antidiabetic drug is “ipso facto dangerous or terrible.” Moreover, he said that it’s not yet clear whether glyburide crosses the placenta in the first place.

Dr. Moore, Dr. Landon, and others at the meeting said they are eagerly awaiting long-term follow-up data from the Metformin in Gestational Diabetes (MiG) trial underway in Australia. The prospective randomized trial is designed to compare metformin with insulin and finished recruiting women in 2006. A recently published analysis found similar neurodevelopmental outcomes in offspring at 2 years, but it’s the longer-term data looking into early puberty that experts now want to see (Arch Dis Child Fetal Neonatal Ed. 2016 Feb 24. doi: 10.1136/archdischild-2015-309602).

In the meantime, Dr. Landon said the “short-term safety record for oral antidiabetic medications is actually pretty good.” There are studies “suggesting an increased risk for large babies with glyburide, but these are very small RCTs [randomized controlled trials],” he said in an interview.

Data from population-based studies, moreover, are “flawed in as much as we don’t know the thresholds for initiating glyburide treatment, nor do we know whether the women were really good candidates for this therapy,” Dr. Landon said. “It’s conceivable, and it’s been my experience, that glyburide has been overprescribed and inappropriately prescribed in certain women with GDM who really should receive insulin therapy.”

Whether glyburide and metformin are being prescribed for GDM in optimal doses is another growing question – one that interests Steve N. Caritis, MD. The drugs are typically prescribed to be taken twice a day every 12 hours, but he said he is finding that some patients may need more frequent, individually tailored dosing.

“We may have come to conclusions in [the studies published thus far] that may not be the correct conclusions,” Dr. Caritis, who coleads obstetric pharmacology research at the Magee-Womens Research Institute in Pittsburgh, said at the DPSG meeting. “The question is, If the dosing were appropriate, would we have the same outcomes?”

Individualizing drug choice

Dosing aside, there may be populations of women who respond poorly to a medication because of the underlying pathophysiology of their GDM, said Maisa N. Feghali, MD, assistant professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh.

A study published in 2016 demonstrated the heterogeneity of the physiologic processes underlying hyperglycemia in 67 women with GDM. Almost one-third of women with GDM had predominant insulin secretion deficit, one-half had predominant insulin resistance, and the remaining 20% had a mixed “metabolic profile” (Diabetes Care. 2016 Jun;39[6]:1052-5).

This study prompted Dr. Feghali and her colleagues to design a pilot study aimed at testing an individualized approach that matches treatment to GDM mechanism. “We [currently] have the expectation that all glucose-lowering agents will be similarly effective despite significant variation in underlying GDM pathophysiology,” she said during a presentation at the DPSG meeting. “But I think we have a mismatch between variations in GDM and the uniformity of treatment.”

In her pilot study, women diagnosed with GDM who fail dietary control will be randomized into usual treatment or matched treatment (metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined insulin resistance and insulin secretion defects).

The MATCh-GDM study (Metabolic Analysis for Treatment Choice of GDM) is just getting underway. Patients will be monitored for consistency of GDM mechanism and glucose control, and routine clinical variables (hypertensive diseases, cesarean delivery, and birth weight) will be studied, as well as neonatal body composition, cord blood glucose, and cord blood C-peptide.

WASHINGTON – The American College of Obstetricians and Gynecologists’ conclusion that insulin should be considered the first-line pharmacologic treatment for gestational diabetes came under fire at a recent meeting on diabetes in pregnancy, indicating the extent to which controversy persists over the use of oral antidiabetic medications in pregnancy.

“Like many others, I’m perplexed by the strong endorsement,” Mark Landon, MD, professor and chair of the department of obstetrics and gynecology at Ohio State University, Columbus, said during an open discussion of oral hypoglycemic agents held at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

Dr. Landon and several other researchers and experts in diabetes in pregnancy expressed discontent with any firm prioritization of the drugs most commonly used for gestational diabetes, saying that there are not yet enough data to do so.

Current recommendations

In its practice bulletin, ACOG noted that oral antidiabetic medications, such as glyburide and metformin, are increasingly used among women with GDM, despite not being approved by the Food and Drug Administration for this indication and even though insulin continues to be the recommended as first-line therapy by the American Diabetes Association (ADA).

The ADA, in a summary of its 2017 guideline on the management of diabetes in pregnancy, stated that insulin is the “preferred medication for treating hyperglycemia in gestational diabetes mellitus, as it does not cross the placenta to a measurable extent.” Metformin and glyburide are options, “but both cross the placenta to the fetus, with metformin likely crossing to a greater extent than glyburide” (Diabetes Care. 2017 Jan;40[Suppl 1]:S114- 9).Regarding metformin, the ACOG bulletin cited two trials that randomized women to metformin or insulin – one in which both groups experienced similar rates of a composite outcome of perinatal morbidity, and another in which women receiving metformin had lower mean glucose levels, less gestational weight gain, and neonates with lower rates of hypoglycemia.

ACOG also cited a meta-analysis, that found “minimal differences” between neonates of women randomized to metformin versus insulin, but also noted that “interestingly, women randomized to metformin experienced a higher rate of preterm birth” and a lower rate of gestational hypertension (BMJ. 2015;350:h102).

With respect to glyburide, the ACOG bulletin said that two recent meta-analyses had demonstrated worse neonatal outcomes with glyburide, compared with insulin, and that observational studies have shown higher rates of preeclampsia, hyperbilirubinemia, and stillbirth with the use of glyburide, compared with insulin. However, many other outcomes have not been statistically significantly different, according to the practice bulletin.

Additionally, at least 4%-16% of women eventually require the addition of insulin when glyburide is used as initial treatment, as do 26%-46% of women who take metformin, according to ACOG.

Regarding placental transfer, ACOG’s bulletin said that while one study that analyzed umbilical cord blood revealed no detectable glyburide in exposed pregnancies, another study demonstrated that glyburide does cross the placenta. Metformin has also been found to cross the placenta, with the fetus exposed to concentrations similar to maternal levels, the bulletin noted.

“Although current data demonstrate no adverse short-term effects on maternal or neonatal health from oral diabetic therapy during pregnancy, long-term outcomes are not yet available,” ACOG wrote in the practice bulletin.

Concerns about research

As Thomas Moore, MD, sees it, the quality of available data is insufficient to recommend insulin over oral agents, or one oral agent over another. “We really need to focus [the National Institutes of Health] on putting together proper studies,” he said at the meeting.

In a later interview, Dr. Moore referred to two recent Cochrane reviews. One review, published in January 2017, analyzed eight studies of oral antidiabetic therapies for GDM and concluded there was “insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral antidiabetic pharmacological therapy over another” (Cochrane Database Syst Rev. 2017 Jan 25;1:CD011967).

The other Cochrane review, published in November 2017, concluded that insulin and oral antidiabetic agents have similar effects on key health outcomes, and that each one has minimal harms. The quality of evidence, the authors said, ranged from “very low to moderate, with downgrading decisions due to imprecision, risk of bias, and inconsistency” (Cochrane Database Syst Rev. 2017 Nov 5;11:CD012037).

Dr. Moore, professor of maternal-fetal medicine at the University of California, San Diego, cautioned against presuming that placental transfer of an antidiabetic drug is “ipso facto dangerous or terrible.” Moreover, he said that it’s not yet clear whether glyburide crosses the placenta in the first place.

Dr. Moore, Dr. Landon, and others at the meeting said they are eagerly awaiting long-term follow-up data from the Metformin in Gestational Diabetes (MiG) trial underway in Australia. The prospective randomized trial is designed to compare metformin with insulin and finished recruiting women in 2006. A recently published analysis found similar neurodevelopmental outcomes in offspring at 2 years, but it’s the longer-term data looking into early puberty that experts now want to see (Arch Dis Child Fetal Neonatal Ed. 2016 Feb 24. doi: 10.1136/archdischild-2015-309602).

In the meantime, Dr. Landon said the “short-term safety record for oral antidiabetic medications is actually pretty good.” There are studies “suggesting an increased risk for large babies with glyburide, but these are very small RCTs [randomized controlled trials],” he said in an interview.

Data from population-based studies, moreover, are “flawed in as much as we don’t know the thresholds for initiating glyburide treatment, nor do we know whether the women were really good candidates for this therapy,” Dr. Landon said. “It’s conceivable, and it’s been my experience, that glyburide has been overprescribed and inappropriately prescribed in certain women with GDM who really should receive insulin therapy.”

Whether glyburide and metformin are being prescribed for GDM in optimal doses is another growing question – one that interests Steve N. Caritis, MD. The drugs are typically prescribed to be taken twice a day every 12 hours, but he said he is finding that some patients may need more frequent, individually tailored dosing.

“We may have come to conclusions in [the studies published thus far] that may not be the correct conclusions,” Dr. Caritis, who coleads obstetric pharmacology research at the Magee-Womens Research Institute in Pittsburgh, said at the DPSG meeting. “The question is, If the dosing were appropriate, would we have the same outcomes?”

Individualizing drug choice

Dosing aside, there may be populations of women who respond poorly to a medication because of the underlying pathophysiology of their GDM, said Maisa N. Feghali, MD, assistant professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh.

A study published in 2016 demonstrated the heterogeneity of the physiologic processes underlying hyperglycemia in 67 women with GDM. Almost one-third of women with GDM had predominant insulin secretion deficit, one-half had predominant insulin resistance, and the remaining 20% had a mixed “metabolic profile” (Diabetes Care. 2016 Jun;39[6]:1052-5).

This study prompted Dr. Feghali and her colleagues to design a pilot study aimed at testing an individualized approach that matches treatment to GDM mechanism. “We [currently] have the expectation that all glucose-lowering agents will be similarly effective despite significant variation in underlying GDM pathophysiology,” she said during a presentation at the DPSG meeting. “But I think we have a mismatch between variations in GDM and the uniformity of treatment.”

In her pilot study, women diagnosed with GDM who fail dietary control will be randomized into usual treatment or matched treatment (metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined insulin resistance and insulin secretion defects).

The MATCh-GDM study (Metabolic Analysis for Treatment Choice of GDM) is just getting underway. Patients will be monitored for consistency of GDM mechanism and glucose control, and routine clinical variables (hypertensive diseases, cesarean delivery, and birth weight) will be studied, as well as neonatal body composition, cord blood glucose, and cord blood C-peptide.