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Low-risk prenatal testing gives 12 times more false positives than cell-free DNA testing
The current prenatal screening standard of care for Down syndrome and other trisomies in low-risk pregnancies is more than three times as likely to return a false positive, compared with false positive rates from noninvasive, cell-free DNA testing, according to a new study.
The findings likely will strengthen public demand for the novel testing to become routine, according to Dr. Diana W. Bianchi, lead author of the CARE (Comparison of Aneuploidy Risk Evaluation) study.
"The pregnant women social media groups are very aware of the false positives. I think everybody knows somebody who has had one, since there’s 1 in 20 chance of that [happening]," Dr. Bianchi said in an interview.
Surprising results
Also revealed in the study was cell-free DNA testing’s essentially 100% negative predictive value for aneuploidies in low-risk populations.
The results are "very impressive," said Dr. Michael F. Greene, associate editor of the New England Journal of Medicine, in an interview. "I do think this is going to sweep the table in terms of what is offered to pregnant women," particularly if other studies demonstrate the same level of efficacy, he said. The study was published online (N. Engl. J. Med. 2014;370:799-808).
To compare false positive rates in the two methods of screening, Dr. Bianchi and her team analyzed test results from 1,914 women (average age, 30 years) enrolled from the general obstetrical population across 21 centers in 14 states. Participants either had or planned to have standard aneuploidy serum screening. All women were risk classified according to standard screening and had a singleton fetus without aneuploidy and a gestational age of at least 8 weeks. A second serum sample was taken from each woman, and massively parallel sequencing was used by laboratory personnel blinded to fetal karyotype to determine the chromosome dosage. Birth outcomes or karyotypes were used as the reference standard.
For trisomies 21 and 18, the false positive rates returned by cell-free DNA testing were significantly lower than those returned by standard screening: 6 patients vs. 69 out of 1,909 for trisomy 21 (0.3% vs. 3.6%; P less than .001), and 3 vs. 11 out of 1,905 for trisomy 18 (0.2% vs. 0.6%, P = .03).
The positive detection rate for cell-free DNA testing of all aneuploidies (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13) was 100% (95% confidence interval, 99.8-100). The positive predictive values for the cell-free DNA testing, compared with standard screening, were 45.5% vs. 4.2% for trisomy 21, and 40.0% vs. 8.3% for trisomy 18.
These positive predictive values, Dr. Greene and Dr. Elizabeth G. Phimister wrote in an accompanying editorial, "underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention." However, they concluded, "the observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false positive rates with cell-free DNA screening than with standard screening, augur well for pregnant women and their fetuses" (N. Engl. J. Med. 2014;370:874-5).
"I think it is going to surprise people when they see that the current standard of care has such a low positive predictive value in a general obstetrical population," said Dr. Bianchi, who also directs the Mother Infant Research Institute at Tufts Medical Center, Boston.
The primary outcome was determined by newborn physical examination in 1,857 patients (97.0%) and by karyotype in 57 patients (3.0%). Of these, chorionic villus sampling was performed in 10 patients, amniocentesis in 38, testing of the products of conception in 3, and postnatal evaluation in 6. The women whose cell-free DNA tests came back with false positive readings all had live births with normal physical examinations.
The secondary endpoint was a similar comparison of detection rates for trisomy 13 (Patau syndrome). There was one false positive result for trisomy 13 with cell-free DNA testing, as compared with six false positive results on standard screening, thus showing a trend toward significance (P = .059) in the 899 patients who underwent standard screening for trisomy 13.
Fetal fraction not maternal age–related
The researchers found that cell-free DNA testing had the same high-sensitivity detection rates in low-risk obstetrical populations as has been previously established in high-risk ones. Generally considered at higher risk for trisomy 21, women 35 years and older who were tested in either the first or second trimesters had results that were nearly identical to results from women under age 35 in terms of both their mean percentage of free fetal DNA and their standard screening results and/or cell-free DNA results (11.3% and 11.6%, respectively). For women tested in the third trimester, the fetal fraction was higher (mean, 24.6%).
This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."
The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.
Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.
‘Throwing down the gauntlet’
The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.
When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."
The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."
As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.
For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.
Market pressures
For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.
"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.
"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."
However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.
Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."
According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "
Although some women will still need an invasive procedure to resolve a screen positive test, Dr. Bianchi said most pregnant women, including older women, are going to be reassured with the 100% negative predictive value.
"The younger woman’s benefit will primarily be the reduced false positive rate, because overwhelmingly, she is going to have a normal fetus, so her major benefit is not being made anxious and being sent for all the subsequent testing."
Dr. Bianchi and her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. Dr. Greene stated that he had no conflict of interest disclosures. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.
The good news out of this is the much lower rate of false positives compared with traditional screening. But what I think is important here is that it’s potentially so easy and accurate to do this testing, that I hope it will continue to be done with full discussion and informed consent regarding the implications, and without judgment about whether or not women ought to pursue this testing. What’s in the background of decisions about testing is the question of abortion, which is as personal and value-laden a decision as anyone can make. As a result, discussion of the fact that testing may lead inevitably to decisions about abortion has to be a part of the conversation from the beginning.
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The concepts of prenatal screening and diagnostic testing have been around for a long time, so in principle they are not new to obstetricians and their patients. Prenatal screening should be performed only with full consent, and with discussion of the potential downstream implications and questions that women and their partners may need to confront, similar to chess where you are thinking three moves ahead. The discussion should address what will happen at the point of the first test, including the possibility of a further diagnostic test, and then where things will go if the fetus is found to have one of these trisomies.
My concern is that because this new testing technology is easy and accurate, and greatly reduces the potential for anxiety caused by false positives, there might be the assumption that it’s a good thing to do for all women. My own view is that it will be good for some, and not for others. You want to be sure where your patient stands before you embark on this pathway. You want to be sure of the woman’s and her partner’s values before you offer this testing as something that will inform decisions about whether to bring the pregnancy to term.
In addition, I suspect it is inevitable that we will move in the direction of using this technology to test or screen for a whole list of other genetic conditions. We should be talking about whether or not that’s a good thing. For example, some women know that they are BRCA1 carriers, and they will ask their obstetricians if they can use this technology to test for conditions like that. Clinicians will need to start expanding their resources for patient education about genetics, and for genetic counseling of these patients, in order to be prepared for these kinds of questions.
Dr. Steven Joffe, a pediatric oncologist and bioethicist, is vice chair of medical ethics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician at the Children’s Hospital of Philadelphia. Dr. Joffe had no conflict of interest disclosures.
The good news out of this is the much lower rate of false positives compared with traditional screening. But what I think is important here is that it’s potentially so easy and accurate to do this testing, that I hope it will continue to be done with full discussion and informed consent regarding the implications, and without judgment about whether or not women ought to pursue this testing. What’s in the background of decisions about testing is the question of abortion, which is as personal and value-laden a decision as anyone can make. As a result, discussion of the fact that testing may lead inevitably to decisions about abortion has to be a part of the conversation from the beginning.
|
|
|
The concepts of prenatal screening and diagnostic testing have been around for a long time, so in principle they are not new to obstetricians and their patients. Prenatal screening should be performed only with full consent, and with discussion of the potential downstream implications and questions that women and their partners may need to confront, similar to chess where you are thinking three moves ahead. The discussion should address what will happen at the point of the first test, including the possibility of a further diagnostic test, and then where things will go if the fetus is found to have one of these trisomies.
My concern is that because this new testing technology is easy and accurate, and greatly reduces the potential for anxiety caused by false positives, there might be the assumption that it’s a good thing to do for all women. My own view is that it will be good for some, and not for others. You want to be sure where your patient stands before you embark on this pathway. You want to be sure of the woman’s and her partner’s values before you offer this testing as something that will inform decisions about whether to bring the pregnancy to term.
In addition, I suspect it is inevitable that we will move in the direction of using this technology to test or screen for a whole list of other genetic conditions. We should be talking about whether or not that’s a good thing. For example, some women know that they are BRCA1 carriers, and they will ask their obstetricians if they can use this technology to test for conditions like that. Clinicians will need to start expanding their resources for patient education about genetics, and for genetic counseling of these patients, in order to be prepared for these kinds of questions.
Dr. Steven Joffe, a pediatric oncologist and bioethicist, is vice chair of medical ethics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician at the Children’s Hospital of Philadelphia. Dr. Joffe had no conflict of interest disclosures.
The good news out of this is the much lower rate of false positives compared with traditional screening. But what I think is important here is that it’s potentially so easy and accurate to do this testing, that I hope it will continue to be done with full discussion and informed consent regarding the implications, and without judgment about whether or not women ought to pursue this testing. What’s in the background of decisions about testing is the question of abortion, which is as personal and value-laden a decision as anyone can make. As a result, discussion of the fact that testing may lead inevitably to decisions about abortion has to be a part of the conversation from the beginning.
|
|
|
The concepts of prenatal screening and diagnostic testing have been around for a long time, so in principle they are not new to obstetricians and their patients. Prenatal screening should be performed only with full consent, and with discussion of the potential downstream implications and questions that women and their partners may need to confront, similar to chess where you are thinking three moves ahead. The discussion should address what will happen at the point of the first test, including the possibility of a further diagnostic test, and then where things will go if the fetus is found to have one of these trisomies.
My concern is that because this new testing technology is easy and accurate, and greatly reduces the potential for anxiety caused by false positives, there might be the assumption that it’s a good thing to do for all women. My own view is that it will be good for some, and not for others. You want to be sure where your patient stands before you embark on this pathway. You want to be sure of the woman’s and her partner’s values before you offer this testing as something that will inform decisions about whether to bring the pregnancy to term.
In addition, I suspect it is inevitable that we will move in the direction of using this technology to test or screen for a whole list of other genetic conditions. We should be talking about whether or not that’s a good thing. For example, some women know that they are BRCA1 carriers, and they will ask their obstetricians if they can use this technology to test for conditions like that. Clinicians will need to start expanding their resources for patient education about genetics, and for genetic counseling of these patients, in order to be prepared for these kinds of questions.
Dr. Steven Joffe, a pediatric oncologist and bioethicist, is vice chair of medical ethics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician at the Children’s Hospital of Philadelphia. Dr. Joffe had no conflict of interest disclosures.
The current prenatal screening standard of care for Down syndrome and other trisomies in low-risk pregnancies is more than three times as likely to return a false positive, compared with false positive rates from noninvasive, cell-free DNA testing, according to a new study.
The findings likely will strengthen public demand for the novel testing to become routine, according to Dr. Diana W. Bianchi, lead author of the CARE (Comparison of Aneuploidy Risk Evaluation) study.
"The pregnant women social media groups are very aware of the false positives. I think everybody knows somebody who has had one, since there’s 1 in 20 chance of that [happening]," Dr. Bianchi said in an interview.
Surprising results
Also revealed in the study was cell-free DNA testing’s essentially 100% negative predictive value for aneuploidies in low-risk populations.
The results are "very impressive," said Dr. Michael F. Greene, associate editor of the New England Journal of Medicine, in an interview. "I do think this is going to sweep the table in terms of what is offered to pregnant women," particularly if other studies demonstrate the same level of efficacy, he said. The study was published online (N. Engl. J. Med. 2014;370:799-808).
To compare false positive rates in the two methods of screening, Dr. Bianchi and her team analyzed test results from 1,914 women (average age, 30 years) enrolled from the general obstetrical population across 21 centers in 14 states. Participants either had or planned to have standard aneuploidy serum screening. All women were risk classified according to standard screening and had a singleton fetus without aneuploidy and a gestational age of at least 8 weeks. A second serum sample was taken from each woman, and massively parallel sequencing was used by laboratory personnel blinded to fetal karyotype to determine the chromosome dosage. Birth outcomes or karyotypes were used as the reference standard.
For trisomies 21 and 18, the false positive rates returned by cell-free DNA testing were significantly lower than those returned by standard screening: 6 patients vs. 69 out of 1,909 for trisomy 21 (0.3% vs. 3.6%; P less than .001), and 3 vs. 11 out of 1,905 for trisomy 18 (0.2% vs. 0.6%, P = .03).
The positive detection rate for cell-free DNA testing of all aneuploidies (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13) was 100% (95% confidence interval, 99.8-100). The positive predictive values for the cell-free DNA testing, compared with standard screening, were 45.5% vs. 4.2% for trisomy 21, and 40.0% vs. 8.3% for trisomy 18.
These positive predictive values, Dr. Greene and Dr. Elizabeth G. Phimister wrote in an accompanying editorial, "underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention." However, they concluded, "the observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false positive rates with cell-free DNA screening than with standard screening, augur well for pregnant women and their fetuses" (N. Engl. J. Med. 2014;370:874-5).
"I think it is going to surprise people when they see that the current standard of care has such a low positive predictive value in a general obstetrical population," said Dr. Bianchi, who also directs the Mother Infant Research Institute at Tufts Medical Center, Boston.
The primary outcome was determined by newborn physical examination in 1,857 patients (97.0%) and by karyotype in 57 patients (3.0%). Of these, chorionic villus sampling was performed in 10 patients, amniocentesis in 38, testing of the products of conception in 3, and postnatal evaluation in 6. The women whose cell-free DNA tests came back with false positive readings all had live births with normal physical examinations.
The secondary endpoint was a similar comparison of detection rates for trisomy 13 (Patau syndrome). There was one false positive result for trisomy 13 with cell-free DNA testing, as compared with six false positive results on standard screening, thus showing a trend toward significance (P = .059) in the 899 patients who underwent standard screening for trisomy 13.
Fetal fraction not maternal age–related
The researchers found that cell-free DNA testing had the same high-sensitivity detection rates in low-risk obstetrical populations as has been previously established in high-risk ones. Generally considered at higher risk for trisomy 21, women 35 years and older who were tested in either the first or second trimesters had results that were nearly identical to results from women under age 35 in terms of both their mean percentage of free fetal DNA and their standard screening results and/or cell-free DNA results (11.3% and 11.6%, respectively). For women tested in the third trimester, the fetal fraction was higher (mean, 24.6%).
This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."
The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.
Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.
‘Throwing down the gauntlet’
The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.
When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."
The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."
As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.
For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.
Market pressures
For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.
"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.
"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."
However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.
Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."
According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "
Although some women will still need an invasive procedure to resolve a screen positive test, Dr. Bianchi said most pregnant women, including older women, are going to be reassured with the 100% negative predictive value.
"The younger woman’s benefit will primarily be the reduced false positive rate, because overwhelmingly, she is going to have a normal fetus, so her major benefit is not being made anxious and being sent for all the subsequent testing."
Dr. Bianchi and her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. Dr. Greene stated that he had no conflict of interest disclosures. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.
The current prenatal screening standard of care for Down syndrome and other trisomies in low-risk pregnancies is more than three times as likely to return a false positive, compared with false positive rates from noninvasive, cell-free DNA testing, according to a new study.
The findings likely will strengthen public demand for the novel testing to become routine, according to Dr. Diana W. Bianchi, lead author of the CARE (Comparison of Aneuploidy Risk Evaluation) study.
"The pregnant women social media groups are very aware of the false positives. I think everybody knows somebody who has had one, since there’s 1 in 20 chance of that [happening]," Dr. Bianchi said in an interview.
Surprising results
Also revealed in the study was cell-free DNA testing’s essentially 100% negative predictive value for aneuploidies in low-risk populations.
The results are "very impressive," said Dr. Michael F. Greene, associate editor of the New England Journal of Medicine, in an interview. "I do think this is going to sweep the table in terms of what is offered to pregnant women," particularly if other studies demonstrate the same level of efficacy, he said. The study was published online (N. Engl. J. Med. 2014;370:799-808).
To compare false positive rates in the two methods of screening, Dr. Bianchi and her team analyzed test results from 1,914 women (average age, 30 years) enrolled from the general obstetrical population across 21 centers in 14 states. Participants either had or planned to have standard aneuploidy serum screening. All women were risk classified according to standard screening and had a singleton fetus without aneuploidy and a gestational age of at least 8 weeks. A second serum sample was taken from each woman, and massively parallel sequencing was used by laboratory personnel blinded to fetal karyotype to determine the chromosome dosage. Birth outcomes or karyotypes were used as the reference standard.
For trisomies 21 and 18, the false positive rates returned by cell-free DNA testing were significantly lower than those returned by standard screening: 6 patients vs. 69 out of 1,909 for trisomy 21 (0.3% vs. 3.6%; P less than .001), and 3 vs. 11 out of 1,905 for trisomy 18 (0.2% vs. 0.6%, P = .03).
The positive detection rate for cell-free DNA testing of all aneuploidies (5 for trisomy 21, 2 for trisomy 18, and 1 for trisomy 13) was 100% (95% confidence interval, 99.8-100). The positive predictive values for the cell-free DNA testing, compared with standard screening, were 45.5% vs. 4.2% for trisomy 21, and 40.0% vs. 8.3% for trisomy 18.
These positive predictive values, Dr. Greene and Dr. Elizabeth G. Phimister wrote in an accompanying editorial, "underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention." However, they concluded, "the observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false positive rates with cell-free DNA screening than with standard screening, augur well for pregnant women and their fetuses" (N. Engl. J. Med. 2014;370:874-5).
"I think it is going to surprise people when they see that the current standard of care has such a low positive predictive value in a general obstetrical population," said Dr. Bianchi, who also directs the Mother Infant Research Institute at Tufts Medical Center, Boston.
The primary outcome was determined by newborn physical examination in 1,857 patients (97.0%) and by karyotype in 57 patients (3.0%). Of these, chorionic villus sampling was performed in 10 patients, amniocentesis in 38, testing of the products of conception in 3, and postnatal evaluation in 6. The women whose cell-free DNA tests came back with false positive readings all had live births with normal physical examinations.
The secondary endpoint was a similar comparison of detection rates for trisomy 13 (Patau syndrome). There was one false positive result for trisomy 13 with cell-free DNA testing, as compared with six false positive results on standard screening, thus showing a trend toward significance (P = .059) in the 899 patients who underwent standard screening for trisomy 13.
Fetal fraction not maternal age–related
The researchers found that cell-free DNA testing had the same high-sensitivity detection rates in low-risk obstetrical populations as has been previously established in high-risk ones. Generally considered at higher risk for trisomy 21, women 35 years and older who were tested in either the first or second trimesters had results that were nearly identical to results from women under age 35 in terms of both their mean percentage of free fetal DNA and their standard screening results and/or cell-free DNA results (11.3% and 11.6%, respectively). For women tested in the third trimester, the fetal fraction was higher (mean, 24.6%).
This finding further strengthens the argument that the technology should be available to the general obstetric population. "The amount of the DNA was the same when we stratified the relatively high risk from the relatively low risk," said Dr. Bianchi. "That will be a surprise to some people who postulated that the high-risk women would have more DNA circulating. They don’t."
The consistent fetal fraction also lends itself to greater flexibility when prenatal screening occurs, allowing women to be screened anytime between 10 and 40 weeks gestational age. This could mean better prenatal care for women who do not have their first prenatal visit until late in the second trimester, for example. Because the current screening methods are specific to certain gestational times, if a woman is erratic with her prenatal visits, testing may be impossible.
Regarding its utility in women carrying multiple fetuses, Dr. Bianchi said that about 10% of the time, the fetal fraction per fetus tends to be too low to get an accurate reading.
‘Throwing down the gauntlet’
The test’s unparalleled accuracy could give greater peace of mind to women who might have had difficulty getting pregnant and so are wary of the miscarriage risks posed by invasive diagnostic testing, according to Dr. Bianchi. Fewer invasive diagnostic tests could also lower costs across the system.
When all results for trisomies 21 and 18 were combined, the researchers found that the false positive rates for standard screening were 4.2%, compared with 0.5% for cell-free DNA testing. "If all pregnant women had undergone cell-free DNA testing as a primary screening method and if all women with positive results had undergone post-test counseling and had decided to undergo an invasive procedure," wrote the authors, "there would have been a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result."
The data should move professional societies to take action, according to Dr. Bianchi. "That’s kind of the gauntlet that we’re throwing down." More data are on the way, she said, which will "enable the professional societies to take a cumulative look and decide what their recommendations are going to be."
As it stands, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists state that the testing be used only in women at higher risk for giving birth to children with aneuploidies, such as women aged 35 years or older or those with a history of pregnancy with trisomy, and that positive cell-free DNA results should be confirmed by invasive diagnostic testing.
For now, because the tests are not considered routine prenatal care, low-risk patients usually pay out of pocket for these tests, which Dr. Bianchi said many women are willing to do. The cost of the test ranges anywhere from $1,200 to upward of $2,700, although some careful Internet searching for deals can net tests at substantially lower prices, she said.
Market pressures
For some physicians in the field, this public demand for a screening test not subject to Food and Drug Administration (FDA) regulation has not outweighed the level of proof it offers in the clinical setting. One of these critics was, until recently, Dr. Greene.
"Companies have been free to build consumer demand for cell-free DNA testing by aggressively marketing the tests, emphasizing data that do not answer key questions," wrote Dr. Greene in July 2013, in an editorial he coauthored (N. Engl. J. Med. 2013;369:499-501). "As a result, cell-free DNA testing seems to be drifting into routine practice ahead of the evidence," stated Dr. Greene, who is also chief of obstetrics at Massachusetts General Hospital in Boston, and who wrote with his colleagues that the test’s positive predictive value, largely unreported by manufacturers, was still in question.
"The problem is that the proof-of-principle studies that all these companies have published to date have been with ratios of ‘Down’s’ to ‘normals’ ranging from 1 to 7, 1 to 13, or 1 to 20," said Dr. Greene in an interview. "All were done in retrospective populations at extraordinarily high risk."
However, with the CARE study, "what’s impressive is the positive predictive value in a low-incidence group of patients," he said.
Sponsored by Illumina/Verinata, the study puts pressure on other companies to publish their own data in peer-reviewed journals, said Dr. Greene. "Once this paper appears in print, [Verinata] will get a leg up, and the other companies won’t want to let them get too far ahead of them."
According to Dr. Bianchi, Verinata is now seeking FDA approval to market the testing as an in vitro diagnostic product. She expects demand for the testing to be led not by physicians but by patients. "People often ask me why the DNA testing took off so quickly," said Dr. Bianchi. "I think a factor is social media. I find there is a discrepancy between what the average patient knows and the general obstetrician knows because of the discussions [online]. "
Although some women will still need an invasive procedure to resolve a screen positive test, Dr. Bianchi said most pregnant women, including older women, are going to be reassured with the 100% negative predictive value.
"The younger woman’s benefit will primarily be the reduced false positive rate, because overwhelmingly, she is going to have a normal fetus, so her major benefit is not being made anxious and being sent for all the subsequent testing."
Dr. Bianchi and her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. Dr. Greene stated that he had no conflict of interest disclosures. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: Cell-free DNA testing bested standard prenatal screening false positive rates for trisomy 21 (0.3% vs. 3.6%; P less than .001) and for trisomy 18 (0.2% vs. 0.6%; P = .03). Positive predictive values for cell-free DNA were 45.5% vs. 4.2% for trisomy 21 and 40.0% vs. 8.3% for trisomy 18.
Data source: Prospective, blinded, multisite observational study of blood samples from 1,914 women with low-risk singleton pregnancies.
Disclosures: Dr. Bianchi and all her coauthors disclosed relationships with Verinata/Illumina, maker of the Verifi cell-free DNA prenatal test. Dr. Bianchi is also on the clinical advisory board of Verinata. The study was sponsored by Illumina, ClinicalTrials.gov number NCT01663350.
Weak link found between induction and high C-section rates
NEW ORLEANS – The link between labor induction and cesarean deliveries was found to be negatively correlated, according to data presented at this year’s Pregnancy Meeting, sponsored by the Society for Maternal-Fetal Medicine.
The findings that a woman’s odds of delivering by C-section are 30% greater (confidence interval, 1.26-1.31; P = less than .01) if she delivers at a hospital with low rates of labor induction, independent of other obstetric risk factors and hospital characteristics, were unexpected by the study’s presenter, Dr. Sarah E. Little of Brigham and Women’s Hospital in Boston. "I was quite surprised by the findings. It suggests to me that inductions themselves may not be the culprit behind the rising rate of cesarean delivery in the United States."
Dr. Little and her colleagues conducted the research to help close the gap between this commonly held belief that an overreliance on induction is at least in part responsible for why the rate of C-section deliveries performed in the United States rose from 20.7% in 1996 to 32.8% in 2011, making it the most commonly performed surgical procedure in the nation. The increased risk has not been shown in prospective trials because the control group would be women with expectant management, according to Dr. Little.
"In retrospective trials, the comparison group is often spontaneous labor, but you can’t choose to be in spontaneous labor," she said. "During expectant management, things can arise – the babies get bigger, the placentas get worse, moms can develop bleeding or preeclampsia – all of which increase the risk of cesarean section, so if you don’t take this into account, then inductions look worse."
For the study, Dr. Little and her colleagues calculated hospital rates of C-sections using the 2010 Nationwide Inpatient Sample of 813,693 deliveries at 604 hospitals. The sample was representative of roughly 20% of all American hospitals, according to Dr. Little and included women at low risk for emergency C-section, and those with no preexisting comorbidities.
The investigators classified hospital level inductions as any induction; low-risk inductions, excluding anyone with preexisting comorbidities; and elective inductions if they were performed when not medically indicated, according to Joint Commission guidelines.
Hospitals in the study were characterized according to location, number of beds, and whether they were teaching facilities. Hospitals that performed fewer than 100 C-sections or did not perform labor inductions were excluded.
The researchers then conducted unadjusted and adjusted hospital cesarean rates according to hospital induction quartile. They also conducted a logistic regression analysis across quartiles to determine the correlation between the hospital rate of induction and the individual’s risk for C-section.
Dr. Little and her team found that hospitals had an average cesarean rate of 31%, with a range of 5.1%-75.7% (mean, 30.5%); rates of labor induction varied from 0% to 50% (mean 19.1%).
Hospitals with high induction rates had lower cesarean delivery rates (Pearson, –0.18; P = less than .001), a negative correlation that held even when only low-risk C-sections and low-risk inductions were studied (Pearson –0.31; P = less than .001). Hospitals in the highest quartile of labor inductions had an average cesarean rate of 32.6%, compared with 29.7% at hospitals in the lowest quartile of inductions.
"There is wide variation in the induction rates across hospitals," said Dr. Little. "I think this speaks to the wide variation in physician practices across the U.S."
The findings were presented during a time when the society is actively encouraging physicians to think twice before inducing labor and is conducting workshops that specifically draw a connection between the two procedures. "This study provides helpful information, and is potentially reassuring to those who require labor induction, but I would continue to encourage a practice of limiting labor induction to those with an indication for delivery and no contraindication to labor," Dr. Brian Mercer, the society’s immediate past president, responded when asked about the results.
The society’s suggested protocols are outlined in the paper, "Preventing the first cesarean delivery" (Obstet. Gynecol. 2012;120:1181-93), which includes an algorithm for when to induce labor – typically, only when medically indicated, such as in the case of membrane rupture.
"I think [our study] supports the SMFM initiative as there is clearly a large variation in practice which could potentially be targeted for change," said Dr. Little. "Also, there are other downsides to labor induction – iatrogenic prematurity if done prior to 39 weeks and increased cost and resource utilization. So even if inductions don’t lead to increased cesareans directly, there are a number of reasons you might want to avoid them."
Because birth certificate data is not kept at the hospital level, the investigators used billing data from the Nationwide Inpatient Sample. "This is not perfect, as it lacks some covariates, such as parity and gestational age, but it is the best national data available currently at the hospital level," Dr. Little said. "The next step might be to look at data sets, which combine birth certificate and discharge data, or collect this data prospectively at a hospital level."
I applaud Dr. Little and her coauthors for conducting this evaluation, which highlights significant variation in the rates of induction (0%-50%), elective induction (0%-47%), and total cesarean delivery (5%-50%) between hospitals.
|
|
Induction and cesarean delivery are both important interventions that can improve outcomes for mothers and/or their baby when medically indicated. The study highlights the importance of attention to this issue, and the importance of informed decision making regarding the potential benefits and risks of intervening in an otherwise uncomplicated pregnancy.
This is a complex issue. The need for labor induction may change over time. For example, a woman with an uncomplicated pregnancy at 39 weeks may develop preeclampsia a week later, at 40 weeks, and require induction of labor. This patient would be included in the induction group rather than the noninduction group, even though a decision had previously been made not to induce electively at 39 weeks’ gestation.
While the authors found a weak association between lower hospital induction rates and higher hospital cesarean rates, they did not specifically study the rates of cesarean delivery among those being induced versus those who were allowed to labor spontaneously; especially those without medical reasons for induction or early delivery. Including women who may have required a cesarean delivery (for placenta previa, prior classical cesarean delivery, or arrest of labor) but were not induced potentially confuses the relationship, as these would not be related to whether labor was induced or not.
Dr. Brian Mercer is the immediate past president of the Society for Maternal-Fetal Medicine, and a member of its Executive Committee. He is chair of the department of obstetrics and gynecology and director of maternal-fetal medicine at Metrohealth Medical Center and professor of reproductive biology at Case Western Reserve University, Cleveland.
I applaud Dr. Little and her coauthors for conducting this evaluation, which highlights significant variation in the rates of induction (0%-50%), elective induction (0%-47%), and total cesarean delivery (5%-50%) between hospitals.
|
|
|
Induction and cesarean delivery are both important interventions that can improve outcomes for mothers and/or their baby when medically indicated. The study highlights the importance of attention to this issue, and the importance of informed decision making regarding the potential benefits and risks of intervening in an otherwise uncomplicated pregnancy.
This is a complex issue. The need for labor induction may change over time. For example, a woman with an uncomplicated pregnancy at 39 weeks may develop preeclampsia a week later, at 40 weeks, and require induction of labor. This patient would be included in the induction group rather than the noninduction group, even though a decision had previously been made not to induce electively at 39 weeks’ gestation.
While the authors found a weak association between lower hospital induction rates and higher hospital cesarean rates, they did not specifically study the rates of cesarean delivery among those being induced versus those who were allowed to labor spontaneously; especially those without medical reasons for induction or early delivery. Including women who may have required a cesarean delivery (for placenta previa, prior classical cesarean delivery, or arrest of labor) but were not induced potentially confuses the relationship, as these would not be related to whether labor was induced or not.
Dr. Brian Mercer is the immediate past president of the Society for Maternal-Fetal Medicine, and a member of its Executive Committee. He is chair of the department of obstetrics and gynecology and director of maternal-fetal medicine at Metrohealth Medical Center and professor of reproductive biology at Case Western Reserve University, Cleveland.
I applaud Dr. Little and her coauthors for conducting this evaluation, which highlights significant variation in the rates of induction (0%-50%), elective induction (0%-47%), and total cesarean delivery (5%-50%) between hospitals.
|
|
|
Induction and cesarean delivery are both important interventions that can improve outcomes for mothers and/or their baby when medically indicated. The study highlights the importance of attention to this issue, and the importance of informed decision making regarding the potential benefits and risks of intervening in an otherwise uncomplicated pregnancy.
This is a complex issue. The need for labor induction may change over time. For example, a woman with an uncomplicated pregnancy at 39 weeks may develop preeclampsia a week later, at 40 weeks, and require induction of labor. This patient would be included in the induction group rather than the noninduction group, even though a decision had previously been made not to induce electively at 39 weeks’ gestation.
While the authors found a weak association between lower hospital induction rates and higher hospital cesarean rates, they did not specifically study the rates of cesarean delivery among those being induced versus those who were allowed to labor spontaneously; especially those without medical reasons for induction or early delivery. Including women who may have required a cesarean delivery (for placenta previa, prior classical cesarean delivery, or arrest of labor) but were not induced potentially confuses the relationship, as these would not be related to whether labor was induced or not.
Dr. Brian Mercer is the immediate past president of the Society for Maternal-Fetal Medicine, and a member of its Executive Committee. He is chair of the department of obstetrics and gynecology and director of maternal-fetal medicine at Metrohealth Medical Center and professor of reproductive biology at Case Western Reserve University, Cleveland.
NEW ORLEANS – The link between labor induction and cesarean deliveries was found to be negatively correlated, according to data presented at this year’s Pregnancy Meeting, sponsored by the Society for Maternal-Fetal Medicine.
The findings that a woman’s odds of delivering by C-section are 30% greater (confidence interval, 1.26-1.31; P = less than .01) if she delivers at a hospital with low rates of labor induction, independent of other obstetric risk factors and hospital characteristics, were unexpected by the study’s presenter, Dr. Sarah E. Little of Brigham and Women’s Hospital in Boston. "I was quite surprised by the findings. It suggests to me that inductions themselves may not be the culprit behind the rising rate of cesarean delivery in the United States."
Dr. Little and her colleagues conducted the research to help close the gap between this commonly held belief that an overreliance on induction is at least in part responsible for why the rate of C-section deliveries performed in the United States rose from 20.7% in 1996 to 32.8% in 2011, making it the most commonly performed surgical procedure in the nation. The increased risk has not been shown in prospective trials because the control group would be women with expectant management, according to Dr. Little.
"In retrospective trials, the comparison group is often spontaneous labor, but you can’t choose to be in spontaneous labor," she said. "During expectant management, things can arise – the babies get bigger, the placentas get worse, moms can develop bleeding or preeclampsia – all of which increase the risk of cesarean section, so if you don’t take this into account, then inductions look worse."
For the study, Dr. Little and her colleagues calculated hospital rates of C-sections using the 2010 Nationwide Inpatient Sample of 813,693 deliveries at 604 hospitals. The sample was representative of roughly 20% of all American hospitals, according to Dr. Little and included women at low risk for emergency C-section, and those with no preexisting comorbidities.
The investigators classified hospital level inductions as any induction; low-risk inductions, excluding anyone with preexisting comorbidities; and elective inductions if they were performed when not medically indicated, according to Joint Commission guidelines.
Hospitals in the study were characterized according to location, number of beds, and whether they were teaching facilities. Hospitals that performed fewer than 100 C-sections or did not perform labor inductions were excluded.
The researchers then conducted unadjusted and adjusted hospital cesarean rates according to hospital induction quartile. They also conducted a logistic regression analysis across quartiles to determine the correlation between the hospital rate of induction and the individual’s risk for C-section.
Dr. Little and her team found that hospitals had an average cesarean rate of 31%, with a range of 5.1%-75.7% (mean, 30.5%); rates of labor induction varied from 0% to 50% (mean 19.1%).
Hospitals with high induction rates had lower cesarean delivery rates (Pearson, –0.18; P = less than .001), a negative correlation that held even when only low-risk C-sections and low-risk inductions were studied (Pearson –0.31; P = less than .001). Hospitals in the highest quartile of labor inductions had an average cesarean rate of 32.6%, compared with 29.7% at hospitals in the lowest quartile of inductions.
"There is wide variation in the induction rates across hospitals," said Dr. Little. "I think this speaks to the wide variation in physician practices across the U.S."
The findings were presented during a time when the society is actively encouraging physicians to think twice before inducing labor and is conducting workshops that specifically draw a connection between the two procedures. "This study provides helpful information, and is potentially reassuring to those who require labor induction, but I would continue to encourage a practice of limiting labor induction to those with an indication for delivery and no contraindication to labor," Dr. Brian Mercer, the society’s immediate past president, responded when asked about the results.
The society’s suggested protocols are outlined in the paper, "Preventing the first cesarean delivery" (Obstet. Gynecol. 2012;120:1181-93), which includes an algorithm for when to induce labor – typically, only when medically indicated, such as in the case of membrane rupture.
"I think [our study] supports the SMFM initiative as there is clearly a large variation in practice which could potentially be targeted for change," said Dr. Little. "Also, there are other downsides to labor induction – iatrogenic prematurity if done prior to 39 weeks and increased cost and resource utilization. So even if inductions don’t lead to increased cesareans directly, there are a number of reasons you might want to avoid them."
Because birth certificate data is not kept at the hospital level, the investigators used billing data from the Nationwide Inpatient Sample. "This is not perfect, as it lacks some covariates, such as parity and gestational age, but it is the best national data available currently at the hospital level," Dr. Little said. "The next step might be to look at data sets, which combine birth certificate and discharge data, or collect this data prospectively at a hospital level."
NEW ORLEANS – The link between labor induction and cesarean deliveries was found to be negatively correlated, according to data presented at this year’s Pregnancy Meeting, sponsored by the Society for Maternal-Fetal Medicine.
The findings that a woman’s odds of delivering by C-section are 30% greater (confidence interval, 1.26-1.31; P = less than .01) if she delivers at a hospital with low rates of labor induction, independent of other obstetric risk factors and hospital characteristics, were unexpected by the study’s presenter, Dr. Sarah E. Little of Brigham and Women’s Hospital in Boston. "I was quite surprised by the findings. It suggests to me that inductions themselves may not be the culprit behind the rising rate of cesarean delivery in the United States."
Dr. Little and her colleagues conducted the research to help close the gap between this commonly held belief that an overreliance on induction is at least in part responsible for why the rate of C-section deliveries performed in the United States rose from 20.7% in 1996 to 32.8% in 2011, making it the most commonly performed surgical procedure in the nation. The increased risk has not been shown in prospective trials because the control group would be women with expectant management, according to Dr. Little.
"In retrospective trials, the comparison group is often spontaneous labor, but you can’t choose to be in spontaneous labor," she said. "During expectant management, things can arise – the babies get bigger, the placentas get worse, moms can develop bleeding or preeclampsia – all of which increase the risk of cesarean section, so if you don’t take this into account, then inductions look worse."
For the study, Dr. Little and her colleagues calculated hospital rates of C-sections using the 2010 Nationwide Inpatient Sample of 813,693 deliveries at 604 hospitals. The sample was representative of roughly 20% of all American hospitals, according to Dr. Little and included women at low risk for emergency C-section, and those with no preexisting comorbidities.
The investigators classified hospital level inductions as any induction; low-risk inductions, excluding anyone with preexisting comorbidities; and elective inductions if they were performed when not medically indicated, according to Joint Commission guidelines.
Hospitals in the study were characterized according to location, number of beds, and whether they were teaching facilities. Hospitals that performed fewer than 100 C-sections or did not perform labor inductions were excluded.
The researchers then conducted unadjusted and adjusted hospital cesarean rates according to hospital induction quartile. They also conducted a logistic regression analysis across quartiles to determine the correlation between the hospital rate of induction and the individual’s risk for C-section.
Dr. Little and her team found that hospitals had an average cesarean rate of 31%, with a range of 5.1%-75.7% (mean, 30.5%); rates of labor induction varied from 0% to 50% (mean 19.1%).
Hospitals with high induction rates had lower cesarean delivery rates (Pearson, –0.18; P = less than .001), a negative correlation that held even when only low-risk C-sections and low-risk inductions were studied (Pearson –0.31; P = less than .001). Hospitals in the highest quartile of labor inductions had an average cesarean rate of 32.6%, compared with 29.7% at hospitals in the lowest quartile of inductions.
"There is wide variation in the induction rates across hospitals," said Dr. Little. "I think this speaks to the wide variation in physician practices across the U.S."
The findings were presented during a time when the society is actively encouraging physicians to think twice before inducing labor and is conducting workshops that specifically draw a connection between the two procedures. "This study provides helpful information, and is potentially reassuring to those who require labor induction, but I would continue to encourage a practice of limiting labor induction to those with an indication for delivery and no contraindication to labor," Dr. Brian Mercer, the society’s immediate past president, responded when asked about the results.
The society’s suggested protocols are outlined in the paper, "Preventing the first cesarean delivery" (Obstet. Gynecol. 2012;120:1181-93), which includes an algorithm for when to induce labor – typically, only when medically indicated, such as in the case of membrane rupture.
"I think [our study] supports the SMFM initiative as there is clearly a large variation in practice which could potentially be targeted for change," said Dr. Little. "Also, there are other downsides to labor induction – iatrogenic prematurity if done prior to 39 weeks and increased cost and resource utilization. So even if inductions don’t lead to increased cesareans directly, there are a number of reasons you might want to avoid them."
Because birth certificate data is not kept at the hospital level, the investigators used billing data from the Nationwide Inpatient Sample. "This is not perfect, as it lacks some covariates, such as parity and gestational age, but it is the best national data available currently at the hospital level," Dr. Little said. "The next step might be to look at data sets, which combine birth certificate and discharge data, or collect this data prospectively at a hospital level."
FROM THE 2014 PREGNANCY MEETING
Major finding: The mean C-section rate was 31% (5.1%-75.7%); rates of labor induction varied from 0% to 50%.
Data source: A logistic regression analysis of 813,693 deliveries at 604 hospitals using the 2010 Nationwide Inpatient Sample.
Disclosures: Dr. Little and Dr. Robinson reported they had no relevant financial disclosures.
Let expectant mothers labor longer to avoid C-sections
WASHINGTON – Longer labors lead to fewer cesarean sections.
That’s according to the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine who have jointly issued the Obstetric Care Consensus guideline, urging physicians to allow women with low-risk pregnancies to remain in latent labor longer before elevating their delivery to surgical status. The report and the consensus guideline appear in the March issue of Obstetrics & Gynecology (Obstet. Gynecol. 2014;123:693-711).
"Evidence now shows that labor actually progresses slower than we thought in the past, so many women might just need a little more time to labor and deliver vaginally instead of moving to a cesarean delivery," Dr. Aaron B. Caughey, a member of ACOG’s Committee on Obstetric Practice, said in a statement.
The document calls on physicians to consider that active labor has begun at 6 cm of cervical dilation, rather than 4, and stresses that doctors should allow more time for progression of labor during the active phase. Whether a woman chooses to use an epidural should also be factored into laboring times because the analgesia can slow contractions.
Although no absolute specific time for allowing a woman to remain in the active labor phase has been determined, the document states that women who have never delivered should be given at least 3 hours to push, while women who have delivered previously should be given a minimum of 2 hours.
‘Fear and convenience’
The recommendations are specifically concerned with avoiding the primary cesarean section because more than one-third of all births in the United States are cesarean deliveries, two-thirds of which are among nulliparous women. Avoiding the first cesarean section is important, "because if the woman labors with a scar from a previous C-section, there is a risk that the uterus will rupture," SMFM president Dr. Vincenzo Berghella, director of maternal-fetal medicine at Thomas Jefferson Medical Center in Philadelphia, said in an interview. "It only happens one-half to one percent [of the time], but it can be catastrophic. The baby could even die. A lot of women, understandably, are afraid of [that]."
In addition, sometimes the procedure is medically indicated, as in the case of placenta previa or uterine rupture. However, according to the document, in most pregnancies, which are typically low risk, cesarean delivery carries with it greater overall severe morbidity and mortality risks for the mother compared with vaginal delivery: 9.2% vs. 8.6% and 2.7% vs. 0.9%, respectively.
A combination of fear of being sued for malpractice, convenience, and lack of manpower, are partially responsible for the astronomical rise in C-sections, now the most common surgical procedure performed in the United States, according to the Centers for Disease Control and Prevention.
Dr. Berghella said a scenario that plays out in a physician’s mind could run along the lines of, "You know what, maybe 99% of things are fine here, but I am just worried a little bit here. So I am just going to do a C-section just to cover my behind."
In the past, solo practitioners also were pressed in ways that today’s doctors who belong to an entire practice are not, said Dr. Berghella.
"There are many, many factors that can lead to a longer labor," Dr. Berghella said, adding it was his "hope" that the document will help doctors make decisions based on the patient and how she presents as an individual. "This is to empower doctors, and reassure everyone on the team, including that patient, that if everything is going well, there is no rush."
Redefining active labor and ‘failed’ induction
The use of alternative methods to assist with stalled labors, such as vaginally delivering the baby with forceps or vacuum, is no longer as common as it once was. So residents were taught these techniques less and less. But now Dr. Berghella and his colleagues at the college and the society are urging residency training programs to offer more training in these techniques, including with vacuum birth simulations. "It’s better to do it the first time on a simulator than to try it out on the patient and put the woman at risk. But [residents] need to learn how to do these things," he said.
Physicians also are urged in the statement to reconsider whether there is a failed induction, noting that if the maternal and fetal status allow, cesarean deliveries should be postponed up to 24 hours or longer, and that "oxytocin [should] be administered for at least 12-18 hours after membrane rupture before deeming induction a failure"
A commonly held misperception is that induction and C-section rates are positively correlated, according to the document. "That is a big, big change. The better data seem to say that if you get to 39 weeks, if you do an induction, it actually decreases the chance for a cesarean," said Dr. Berghella. "It was painted as a terrible thing, but if you do it at the right time, it is beneficial."
Into practice
Prenatal counseling should stress weight maintenance, because more than a third of women of reproductive age in the United States are obese, a factor that Dr. Berghella said contributes to the rise in C-sections. Infection risk is higher in this population, and the abundance of adipose tissues makes it harder for the baby to be delivered vaginally. "The higher your weight, the higher your chance of C-section," said Dr. Berghella.
In addition to tort reform, which the document states is "necessary" to prompt physicians to overcome their fears of being sued in case of an adverse event during vaginal delivery, Dr. Berghella said that the culture change rests on communication between office-based obstetricians, midwives, nurse practitioners, and their patients. "Doing a better job of educating women [prenatally] about labor in general, including that it can take a while, will prepare them and help avoid frustration and impatience because they will know what is going on," he said, noting that even a woman who has given birth before can have a completely different experience the next time.
Dr. Berghella said he had no relevant financial disclosures.
WASHINGTON – Longer labors lead to fewer cesarean sections.
That’s according to the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine who have jointly issued the Obstetric Care Consensus guideline, urging physicians to allow women with low-risk pregnancies to remain in latent labor longer before elevating their delivery to surgical status. The report and the consensus guideline appear in the March issue of Obstetrics & Gynecology (Obstet. Gynecol. 2014;123:693-711).
"Evidence now shows that labor actually progresses slower than we thought in the past, so many women might just need a little more time to labor and deliver vaginally instead of moving to a cesarean delivery," Dr. Aaron B. Caughey, a member of ACOG’s Committee on Obstetric Practice, said in a statement.
The document calls on physicians to consider that active labor has begun at 6 cm of cervical dilation, rather than 4, and stresses that doctors should allow more time for progression of labor during the active phase. Whether a woman chooses to use an epidural should also be factored into laboring times because the analgesia can slow contractions.
Although no absolute specific time for allowing a woman to remain in the active labor phase has been determined, the document states that women who have never delivered should be given at least 3 hours to push, while women who have delivered previously should be given a minimum of 2 hours.
‘Fear and convenience’
The recommendations are specifically concerned with avoiding the primary cesarean section because more than one-third of all births in the United States are cesarean deliveries, two-thirds of which are among nulliparous women. Avoiding the first cesarean section is important, "because if the woman labors with a scar from a previous C-section, there is a risk that the uterus will rupture," SMFM president Dr. Vincenzo Berghella, director of maternal-fetal medicine at Thomas Jefferson Medical Center in Philadelphia, said in an interview. "It only happens one-half to one percent [of the time], but it can be catastrophic. The baby could even die. A lot of women, understandably, are afraid of [that]."
In addition, sometimes the procedure is medically indicated, as in the case of placenta previa or uterine rupture. However, according to the document, in most pregnancies, which are typically low risk, cesarean delivery carries with it greater overall severe morbidity and mortality risks for the mother compared with vaginal delivery: 9.2% vs. 8.6% and 2.7% vs. 0.9%, respectively.
A combination of fear of being sued for malpractice, convenience, and lack of manpower, are partially responsible for the astronomical rise in C-sections, now the most common surgical procedure performed in the United States, according to the Centers for Disease Control and Prevention.
Dr. Berghella said a scenario that plays out in a physician’s mind could run along the lines of, "You know what, maybe 99% of things are fine here, but I am just worried a little bit here. So I am just going to do a C-section just to cover my behind."
In the past, solo practitioners also were pressed in ways that today’s doctors who belong to an entire practice are not, said Dr. Berghella.
"There are many, many factors that can lead to a longer labor," Dr. Berghella said, adding it was his "hope" that the document will help doctors make decisions based on the patient and how she presents as an individual. "This is to empower doctors, and reassure everyone on the team, including that patient, that if everything is going well, there is no rush."
Redefining active labor and ‘failed’ induction
The use of alternative methods to assist with stalled labors, such as vaginally delivering the baby with forceps or vacuum, is no longer as common as it once was. So residents were taught these techniques less and less. But now Dr. Berghella and his colleagues at the college and the society are urging residency training programs to offer more training in these techniques, including with vacuum birth simulations. "It’s better to do it the first time on a simulator than to try it out on the patient and put the woman at risk. But [residents] need to learn how to do these things," he said.
Physicians also are urged in the statement to reconsider whether there is a failed induction, noting that if the maternal and fetal status allow, cesarean deliveries should be postponed up to 24 hours or longer, and that "oxytocin [should] be administered for at least 12-18 hours after membrane rupture before deeming induction a failure"
A commonly held misperception is that induction and C-section rates are positively correlated, according to the document. "That is a big, big change. The better data seem to say that if you get to 39 weeks, if you do an induction, it actually decreases the chance for a cesarean," said Dr. Berghella. "It was painted as a terrible thing, but if you do it at the right time, it is beneficial."
Into practice
Prenatal counseling should stress weight maintenance, because more than a third of women of reproductive age in the United States are obese, a factor that Dr. Berghella said contributes to the rise in C-sections. Infection risk is higher in this population, and the abundance of adipose tissues makes it harder for the baby to be delivered vaginally. "The higher your weight, the higher your chance of C-section," said Dr. Berghella.
In addition to tort reform, which the document states is "necessary" to prompt physicians to overcome their fears of being sued in case of an adverse event during vaginal delivery, Dr. Berghella said that the culture change rests on communication between office-based obstetricians, midwives, nurse practitioners, and their patients. "Doing a better job of educating women [prenatally] about labor in general, including that it can take a while, will prepare them and help avoid frustration and impatience because they will know what is going on," he said, noting that even a woman who has given birth before can have a completely different experience the next time.
Dr. Berghella said he had no relevant financial disclosures.
WASHINGTON – Longer labors lead to fewer cesarean sections.
That’s according to the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine who have jointly issued the Obstetric Care Consensus guideline, urging physicians to allow women with low-risk pregnancies to remain in latent labor longer before elevating their delivery to surgical status. The report and the consensus guideline appear in the March issue of Obstetrics & Gynecology (Obstet. Gynecol. 2014;123:693-711).
"Evidence now shows that labor actually progresses slower than we thought in the past, so many women might just need a little more time to labor and deliver vaginally instead of moving to a cesarean delivery," Dr. Aaron B. Caughey, a member of ACOG’s Committee on Obstetric Practice, said in a statement.
The document calls on physicians to consider that active labor has begun at 6 cm of cervical dilation, rather than 4, and stresses that doctors should allow more time for progression of labor during the active phase. Whether a woman chooses to use an epidural should also be factored into laboring times because the analgesia can slow contractions.
Although no absolute specific time for allowing a woman to remain in the active labor phase has been determined, the document states that women who have never delivered should be given at least 3 hours to push, while women who have delivered previously should be given a minimum of 2 hours.
‘Fear and convenience’
The recommendations are specifically concerned with avoiding the primary cesarean section because more than one-third of all births in the United States are cesarean deliveries, two-thirds of which are among nulliparous women. Avoiding the first cesarean section is important, "because if the woman labors with a scar from a previous C-section, there is a risk that the uterus will rupture," SMFM president Dr. Vincenzo Berghella, director of maternal-fetal medicine at Thomas Jefferson Medical Center in Philadelphia, said in an interview. "It only happens one-half to one percent [of the time], but it can be catastrophic. The baby could even die. A lot of women, understandably, are afraid of [that]."
In addition, sometimes the procedure is medically indicated, as in the case of placenta previa or uterine rupture. However, according to the document, in most pregnancies, which are typically low risk, cesarean delivery carries with it greater overall severe morbidity and mortality risks for the mother compared with vaginal delivery: 9.2% vs. 8.6% and 2.7% vs. 0.9%, respectively.
A combination of fear of being sued for malpractice, convenience, and lack of manpower, are partially responsible for the astronomical rise in C-sections, now the most common surgical procedure performed in the United States, according to the Centers for Disease Control and Prevention.
Dr. Berghella said a scenario that plays out in a physician’s mind could run along the lines of, "You know what, maybe 99% of things are fine here, but I am just worried a little bit here. So I am just going to do a C-section just to cover my behind."
In the past, solo practitioners also were pressed in ways that today’s doctors who belong to an entire practice are not, said Dr. Berghella.
"There are many, many factors that can lead to a longer labor," Dr. Berghella said, adding it was his "hope" that the document will help doctors make decisions based on the patient and how she presents as an individual. "This is to empower doctors, and reassure everyone on the team, including that patient, that if everything is going well, there is no rush."
Redefining active labor and ‘failed’ induction
The use of alternative methods to assist with stalled labors, such as vaginally delivering the baby with forceps or vacuum, is no longer as common as it once was. So residents were taught these techniques less and less. But now Dr. Berghella and his colleagues at the college and the society are urging residency training programs to offer more training in these techniques, including with vacuum birth simulations. "It’s better to do it the first time on a simulator than to try it out on the patient and put the woman at risk. But [residents] need to learn how to do these things," he said.
Physicians also are urged in the statement to reconsider whether there is a failed induction, noting that if the maternal and fetal status allow, cesarean deliveries should be postponed up to 24 hours or longer, and that "oxytocin [should] be administered for at least 12-18 hours after membrane rupture before deeming induction a failure"
A commonly held misperception is that induction and C-section rates are positively correlated, according to the document. "That is a big, big change. The better data seem to say that if you get to 39 weeks, if you do an induction, it actually decreases the chance for a cesarean," said Dr. Berghella. "It was painted as a terrible thing, but if you do it at the right time, it is beneficial."
Into practice
Prenatal counseling should stress weight maintenance, because more than a third of women of reproductive age in the United States are obese, a factor that Dr. Berghella said contributes to the rise in C-sections. Infection risk is higher in this population, and the abundance of adipose tissues makes it harder for the baby to be delivered vaginally. "The higher your weight, the higher your chance of C-section," said Dr. Berghella.
In addition to tort reform, which the document states is "necessary" to prompt physicians to overcome their fears of being sued in case of an adverse event during vaginal delivery, Dr. Berghella said that the culture change rests on communication between office-based obstetricians, midwives, nurse practitioners, and their patients. "Doing a better job of educating women [prenatally] about labor in general, including that it can take a while, will prepare them and help avoid frustration and impatience because they will know what is going on," he said, noting that even a woman who has given birth before can have a completely different experience the next time.
Dr. Berghella said he had no relevant financial disclosures.
FROM OBSTETRICS & GYNECOLOGY
Noninvasive prenatal testing detects more than 80% of chromosomal abnormalities
NEW ORLEANS – Noninvasive prenatal testing using cell-free fetal DNA found in the maternal bloodstream detects more than 80% of the most common trisomies, including the one for Down syndrome, according to results presented at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
Expectant mothers and their treating physicians now may have a wider range of options for balancing the risks inherent in the more invasive kinds of diagnostic testing, such as chorionic villus sampling and amniocentesis, against the desire for such tests’ near-perfect diagnostic accuracy, according to Dr. Mary Norton.
"Some of the other screening tests that we use, some of the ultrasound screens and some blood tests, have a number of false positives," the study’s presenter, Dr. Norton, vice chair of clinical and translational genetics at the University of California, San Francisco, said in an interview.
For the majority of women, the screening tests show no fetal abnormalities, but the experience can unnerve some women, who find that the test just isn’t worth the risk, said Dr. Norton. Current recommendations from the American College of Obstetricians and Gynecologists (ACOG) are that noninvasive prenatal testing (NIPT) only be offered to high-risk pregnant women as an alternative to invasive testing if integrated ultrasound/blood test screens come back positive.
While diagnostic invasive testing offers "near 100% accuracy," there is a 1 in 500 chance the woman will miscarry after having such a procedure, Dr. Norton said. NIPT, which was introduced into clinical practice in 2011, relies on a simple blood test and is typically performed during the second trimester.
"For a woman who is losing sleep with worry that her fetus may have a chromosome problem, having a test like an amniocentesis that comes back normal may allow her to enjoy the rest of her pregnancy," said Dr. Norton. "For someone whose goal is to avoid diagnostic testing at all costs, to avoid the fear of having a false positive, [NIPT] may be better to detect fewer things but to avoid false positives."
Using the California Prenatal Screening Program database from March 2009 through December 2012, Dr. Norton and her colleagues reviewed all karyotype results from invasive diagnostic tests of singleton pregnancies performed after a prenatal screen indicated possible abnormalities. In all, 26,059 results were analyzed and divided according to either the abnormalities that NIPT is currently able to detect, including nonmosaic trisomies 13, 18, and 21 and sex-chromosomal aneuploidy; or abnormalities currently undetectable by NIPT, such as mosaicism.
During the study period, more than 1.3 million women were screened, with just over 5% (68,990) screening positive for trisomy 18 or 21. Of screen-positive women, nearly 38% (26,059) assented to an invasive prenatal test; of these, 12% (2,993) came back with abnormal results. Just more than 83% (2,488) of those abnormalities were ones detectable by NIPT, while just less than 17% (511) were not. The most common abnormal result, at 53% (1,592), was trisomy 21 (Down syndrome), which has been shown to comprise more than half of all abnormalities detected prenatally.
Women aged 35-39 years composed more than a third of all women studied. While in women under age 30, NIPT misses about 22% of aneuploidies, Dr. Norton said in her presentation that in women over age 45, that number drops dramatically to 8%, largely because of the correlative risk for trisomy 18 and 21 and advanced maternal age.
She noted that one of the limitations of the study was the fact that it included only screen-positive women, and thus the study group was "enriched" for trisomy 21; hence, the results cannot be generalized to the unscreened population, which has a different rate and spectrum of fetal abnormalities.
"Our calculations are for potential detection by NIPT for the target disorders. While the sensitivity is high, it is not 100%; therefore, the overall detection for all chromosomal abnormalities will be less than the 83% we report," Dr. Norton told the audience. "In addition, only 38% of screen-positive women chose to have invasive testing, and those declining such testing might have had different risks, and therefore different outcomes."
NEW ORLEANS – Noninvasive prenatal testing using cell-free fetal DNA found in the maternal bloodstream detects more than 80% of the most common trisomies, including the one for Down syndrome, according to results presented at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
Expectant mothers and their treating physicians now may have a wider range of options for balancing the risks inherent in the more invasive kinds of diagnostic testing, such as chorionic villus sampling and amniocentesis, against the desire for such tests’ near-perfect diagnostic accuracy, according to Dr. Mary Norton.
"Some of the other screening tests that we use, some of the ultrasound screens and some blood tests, have a number of false positives," the study’s presenter, Dr. Norton, vice chair of clinical and translational genetics at the University of California, San Francisco, said in an interview.
For the majority of women, the screening tests show no fetal abnormalities, but the experience can unnerve some women, who find that the test just isn’t worth the risk, said Dr. Norton. Current recommendations from the American College of Obstetricians and Gynecologists (ACOG) are that noninvasive prenatal testing (NIPT) only be offered to high-risk pregnant women as an alternative to invasive testing if integrated ultrasound/blood test screens come back positive.
While diagnostic invasive testing offers "near 100% accuracy," there is a 1 in 500 chance the woman will miscarry after having such a procedure, Dr. Norton said. NIPT, which was introduced into clinical practice in 2011, relies on a simple blood test and is typically performed during the second trimester.
"For a woman who is losing sleep with worry that her fetus may have a chromosome problem, having a test like an amniocentesis that comes back normal may allow her to enjoy the rest of her pregnancy," said Dr. Norton. "For someone whose goal is to avoid diagnostic testing at all costs, to avoid the fear of having a false positive, [NIPT] may be better to detect fewer things but to avoid false positives."
Using the California Prenatal Screening Program database from March 2009 through December 2012, Dr. Norton and her colleagues reviewed all karyotype results from invasive diagnostic tests of singleton pregnancies performed after a prenatal screen indicated possible abnormalities. In all, 26,059 results were analyzed and divided according to either the abnormalities that NIPT is currently able to detect, including nonmosaic trisomies 13, 18, and 21 and sex-chromosomal aneuploidy; or abnormalities currently undetectable by NIPT, such as mosaicism.
During the study period, more than 1.3 million women were screened, with just over 5% (68,990) screening positive for trisomy 18 or 21. Of screen-positive women, nearly 38% (26,059) assented to an invasive prenatal test; of these, 12% (2,993) came back with abnormal results. Just more than 83% (2,488) of those abnormalities were ones detectable by NIPT, while just less than 17% (511) were not. The most common abnormal result, at 53% (1,592), was trisomy 21 (Down syndrome), which has been shown to comprise more than half of all abnormalities detected prenatally.
Women aged 35-39 years composed more than a third of all women studied. While in women under age 30, NIPT misses about 22% of aneuploidies, Dr. Norton said in her presentation that in women over age 45, that number drops dramatically to 8%, largely because of the correlative risk for trisomy 18 and 21 and advanced maternal age.
She noted that one of the limitations of the study was the fact that it included only screen-positive women, and thus the study group was "enriched" for trisomy 21; hence, the results cannot be generalized to the unscreened population, which has a different rate and spectrum of fetal abnormalities.
"Our calculations are for potential detection by NIPT for the target disorders. While the sensitivity is high, it is not 100%; therefore, the overall detection for all chromosomal abnormalities will be less than the 83% we report," Dr. Norton told the audience. "In addition, only 38% of screen-positive women chose to have invasive testing, and those declining such testing might have had different risks, and therefore different outcomes."
NEW ORLEANS – Noninvasive prenatal testing using cell-free fetal DNA found in the maternal bloodstream detects more than 80% of the most common trisomies, including the one for Down syndrome, according to results presented at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
Expectant mothers and their treating physicians now may have a wider range of options for balancing the risks inherent in the more invasive kinds of diagnostic testing, such as chorionic villus sampling and amniocentesis, against the desire for such tests’ near-perfect diagnostic accuracy, according to Dr. Mary Norton.
"Some of the other screening tests that we use, some of the ultrasound screens and some blood tests, have a number of false positives," the study’s presenter, Dr. Norton, vice chair of clinical and translational genetics at the University of California, San Francisco, said in an interview.
For the majority of women, the screening tests show no fetal abnormalities, but the experience can unnerve some women, who find that the test just isn’t worth the risk, said Dr. Norton. Current recommendations from the American College of Obstetricians and Gynecologists (ACOG) are that noninvasive prenatal testing (NIPT) only be offered to high-risk pregnant women as an alternative to invasive testing if integrated ultrasound/blood test screens come back positive.
While diagnostic invasive testing offers "near 100% accuracy," there is a 1 in 500 chance the woman will miscarry after having such a procedure, Dr. Norton said. NIPT, which was introduced into clinical practice in 2011, relies on a simple blood test and is typically performed during the second trimester.
"For a woman who is losing sleep with worry that her fetus may have a chromosome problem, having a test like an amniocentesis that comes back normal may allow her to enjoy the rest of her pregnancy," said Dr. Norton. "For someone whose goal is to avoid diagnostic testing at all costs, to avoid the fear of having a false positive, [NIPT] may be better to detect fewer things but to avoid false positives."
Using the California Prenatal Screening Program database from March 2009 through December 2012, Dr. Norton and her colleagues reviewed all karyotype results from invasive diagnostic tests of singleton pregnancies performed after a prenatal screen indicated possible abnormalities. In all, 26,059 results were analyzed and divided according to either the abnormalities that NIPT is currently able to detect, including nonmosaic trisomies 13, 18, and 21 and sex-chromosomal aneuploidy; or abnormalities currently undetectable by NIPT, such as mosaicism.
During the study period, more than 1.3 million women were screened, with just over 5% (68,990) screening positive for trisomy 18 or 21. Of screen-positive women, nearly 38% (26,059) assented to an invasive prenatal test; of these, 12% (2,993) came back with abnormal results. Just more than 83% (2,488) of those abnormalities were ones detectable by NIPT, while just less than 17% (511) were not. The most common abnormal result, at 53% (1,592), was trisomy 21 (Down syndrome), which has been shown to comprise more than half of all abnormalities detected prenatally.
Women aged 35-39 years composed more than a third of all women studied. While in women under age 30, NIPT misses about 22% of aneuploidies, Dr. Norton said in her presentation that in women over age 45, that number drops dramatically to 8%, largely because of the correlative risk for trisomy 18 and 21 and advanced maternal age.
She noted that one of the limitations of the study was the fact that it included only screen-positive women, and thus the study group was "enriched" for trisomy 21; hence, the results cannot be generalized to the unscreened population, which has a different rate and spectrum of fetal abnormalities.
"Our calculations are for potential detection by NIPT for the target disorders. While the sensitivity is high, it is not 100%; therefore, the overall detection for all chromosomal abnormalities will be less than the 83% we report," Dr. Norton told the audience. "In addition, only 38% of screen-positive women chose to have invasive testing, and those declining such testing might have had different risks, and therefore different outcomes."
FROM THE PREGNANCY MEETING
Cervicovaginal microbiome may be involved in some preterm births
NEW ORLEANS – Could the cervicovaginal microbiome be responsible for some preterm births?
"It is a hot topic because there is increasing interest in medicine with regard to the microbiome and how our health is affected by it," said Dr. William Grobman, program chair for the Society for Maternal-Fetal Medicine’s annual meeting. "Preterm birth remains poorly understood, but there is intriguing evidence that its occurrence may be related to alterations in the microbiome."
To explore the potential relationship between cervicovaginal microbiota and preterm birth, Dr. Michal Elovitz, director of the maternal and child health research program at the University of Pennsylvania, Philadelphia, led a team in a nested case-control study of 46 women. She presented her results at the meeting.
Dr. Elovitz and her colleagues tested vaginal swabs taken from pregnant women during 20-24 weeks’ gestation, and again during 24-28 weeks. After the women delivered, the cervicovaginal specimens from women who had preterm deliveries were compared with those taken from women who delivered at term.
The researchers tested the DNA from the samples and characterized the microbial communities. Vaginal samples were characterized into community state types (CSTs) based on which bacteria dominated the microbial community. The first group, CST I, is dominated by Lactobacillus crispatus, which according to the Dr. Elovitz is traditionally considered a beneficial bacteria. CST III is dominated by L. iners, and CST IV is dominated by anaerobic bacteria, typical in bacterial vaginosis.
In the 14 women who had a preterm birth, the CST proportions were significantly different than those who delivered at term. In the preterm cohort, 17% had CST I, 61% had CST III, and 22% had CST IV.
In the term cohort, 35% had CST I, 37% had CST III, and 33% had CST IV (P = .012). The percentage of women who had no CST III was higher in women delivering at term than in those who delivered prematurely: 68% vs. 39% (P =.002).
"The percent of non–CST-III was significantly lower in samples from women delivering preterm than term. Notably, the differences in these microbial communities were evident in the late second trimester of pregnancy, weeks if not months prior to the preterm birth," said Dr. Elovitz.
Seventy-eight percent of the women in the study were black; Dr. Elovitz and her colleagues conducted a subanalysis of only those women. "And what we found is that the results were even stronger."
"The implications are very broad, and hopefully very clinically impactful. The microbiome is modifiable. We can find ways to change it," said Dr. Elovitz. The challenge now, she said, is to determine whether the microbiome is just a marker, or if it’s a cause. If microbiota are implicated, "there is a whole new window of opportunity for therapeutics to reduce preterm birth."
Dr. Elovitz did not have any relevant disclosures.
NEW ORLEANS – Could the cervicovaginal microbiome be responsible for some preterm births?
"It is a hot topic because there is increasing interest in medicine with regard to the microbiome and how our health is affected by it," said Dr. William Grobman, program chair for the Society for Maternal-Fetal Medicine’s annual meeting. "Preterm birth remains poorly understood, but there is intriguing evidence that its occurrence may be related to alterations in the microbiome."
To explore the potential relationship between cervicovaginal microbiota and preterm birth, Dr. Michal Elovitz, director of the maternal and child health research program at the University of Pennsylvania, Philadelphia, led a team in a nested case-control study of 46 women. She presented her results at the meeting.
Dr. Elovitz and her colleagues tested vaginal swabs taken from pregnant women during 20-24 weeks’ gestation, and again during 24-28 weeks. After the women delivered, the cervicovaginal specimens from women who had preterm deliveries were compared with those taken from women who delivered at term.
The researchers tested the DNA from the samples and characterized the microbial communities. Vaginal samples were characterized into community state types (CSTs) based on which bacteria dominated the microbial community. The first group, CST I, is dominated by Lactobacillus crispatus, which according to the Dr. Elovitz is traditionally considered a beneficial bacteria. CST III is dominated by L. iners, and CST IV is dominated by anaerobic bacteria, typical in bacterial vaginosis.
In the 14 women who had a preterm birth, the CST proportions were significantly different than those who delivered at term. In the preterm cohort, 17% had CST I, 61% had CST III, and 22% had CST IV.
In the term cohort, 35% had CST I, 37% had CST III, and 33% had CST IV (P = .012). The percentage of women who had no CST III was higher in women delivering at term than in those who delivered prematurely: 68% vs. 39% (P =.002).
"The percent of non–CST-III was significantly lower in samples from women delivering preterm than term. Notably, the differences in these microbial communities were evident in the late second trimester of pregnancy, weeks if not months prior to the preterm birth," said Dr. Elovitz.
Seventy-eight percent of the women in the study were black; Dr. Elovitz and her colleagues conducted a subanalysis of only those women. "And what we found is that the results were even stronger."
"The implications are very broad, and hopefully very clinically impactful. The microbiome is modifiable. We can find ways to change it," said Dr. Elovitz. The challenge now, she said, is to determine whether the microbiome is just a marker, or if it’s a cause. If microbiota are implicated, "there is a whole new window of opportunity for therapeutics to reduce preterm birth."
Dr. Elovitz did not have any relevant disclosures.
NEW ORLEANS – Could the cervicovaginal microbiome be responsible for some preterm births?
"It is a hot topic because there is increasing interest in medicine with regard to the microbiome and how our health is affected by it," said Dr. William Grobman, program chair for the Society for Maternal-Fetal Medicine’s annual meeting. "Preterm birth remains poorly understood, but there is intriguing evidence that its occurrence may be related to alterations in the microbiome."
To explore the potential relationship between cervicovaginal microbiota and preterm birth, Dr. Michal Elovitz, director of the maternal and child health research program at the University of Pennsylvania, Philadelphia, led a team in a nested case-control study of 46 women. She presented her results at the meeting.
Dr. Elovitz and her colleagues tested vaginal swabs taken from pregnant women during 20-24 weeks’ gestation, and again during 24-28 weeks. After the women delivered, the cervicovaginal specimens from women who had preterm deliveries were compared with those taken from women who delivered at term.
The researchers tested the DNA from the samples and characterized the microbial communities. Vaginal samples were characterized into community state types (CSTs) based on which bacteria dominated the microbial community. The first group, CST I, is dominated by Lactobacillus crispatus, which according to the Dr. Elovitz is traditionally considered a beneficial bacteria. CST III is dominated by L. iners, and CST IV is dominated by anaerobic bacteria, typical in bacterial vaginosis.
In the 14 women who had a preterm birth, the CST proportions were significantly different than those who delivered at term. In the preterm cohort, 17% had CST I, 61% had CST III, and 22% had CST IV.
In the term cohort, 35% had CST I, 37% had CST III, and 33% had CST IV (P = .012). The percentage of women who had no CST III was higher in women delivering at term than in those who delivered prematurely: 68% vs. 39% (P =.002).
"The percent of non–CST-III was significantly lower in samples from women delivering preterm than term. Notably, the differences in these microbial communities were evident in the late second trimester of pregnancy, weeks if not months prior to the preterm birth," said Dr. Elovitz.
Seventy-eight percent of the women in the study were black; Dr. Elovitz and her colleagues conducted a subanalysis of only those women. "And what we found is that the results were even stronger."
"The implications are very broad, and hopefully very clinically impactful. The microbiome is modifiable. We can find ways to change it," said Dr. Elovitz. The challenge now, she said, is to determine whether the microbiome is just a marker, or if it’s a cause. If microbiota are implicated, "there is a whole new window of opportunity for therapeutics to reduce preterm birth."
Dr. Elovitz did not have any relevant disclosures.
AT THE PREGNANCY MEETING
Major finding: Of the 14 women in the preterm group, 17% had CST I, 61% had CST III, and 22% had CST IV. In the term cohort, 35% had CST I, 37% had CST III, and 33% had CST IV.
Data source: Nested case-controlled study of 14 women who delivered preterm and 32 who delivered at term.
Disclosures: Dr. Elovitz did not have any relevant disclosures.
Video: Cervicovaginal microbiome implicated in some preterm births
NEW ORLEANS – Could the cervicovaginal microbiome be responsible for some preterm births?
In a video interview, Dr. Michal Elovitz of the University of Pennsylvania, Philadelphia, discussed a study exploring the role the microbiome plays in high-risk pregnancies and preterm births, and she outlines how better understanding could reshape clinical practice.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NEW ORLEANS – Could the cervicovaginal microbiome be responsible for some preterm births?
In a video interview, Dr. Michal Elovitz of the University of Pennsylvania, Philadelphia, discussed a study exploring the role the microbiome plays in high-risk pregnancies and preterm births, and she outlines how better understanding could reshape clinical practice.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NEW ORLEANS – Could the cervicovaginal microbiome be responsible for some preterm births?
In a video interview, Dr. Michal Elovitz of the University of Pennsylvania, Philadelphia, discussed a study exploring the role the microbiome plays in high-risk pregnancies and preterm births, and she outlines how better understanding could reshape clinical practice.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE SMFM ANNUAL PREGNANCY MEETING
Video: What can be done to reverse rise in C-sections?
NEW ORLEANS – The rate of cesarean section in the United States has risen dramatically in the past 2 decades, accounting for 30% of all deliveries in 2011.
Several factors are driving the increase, according to the Society for Maternal-Fetal Medicine, which sponsored the annual Pregnancy Meeting. Women are waiting until later in life to have children, and their obesity rates are higher than ever before – both of which increase the risk of medical complications during pregnancy. Fear of malpractice also motivates some ob.gyns. to rely on C-sections.
But the most common reason for a woman to have a C-section is that she has had one before, explained Dr. George Saade, director of the division of maternal-fetal medicine at the University of Texas Medical Branch, Galveston. In a video interview, Dr. Saade discussed what’s fueling the rise, and what physicians must do to reduce C-section rates.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NEW ORLEANS – The rate of cesarean section in the United States has risen dramatically in the past 2 decades, accounting for 30% of all deliveries in 2011.
Several factors are driving the increase, according to the Society for Maternal-Fetal Medicine, which sponsored the annual Pregnancy Meeting. Women are waiting until later in life to have children, and their obesity rates are higher than ever before – both of which increase the risk of medical complications during pregnancy. Fear of malpractice also motivates some ob.gyns. to rely on C-sections.
But the most common reason for a woman to have a C-section is that she has had one before, explained Dr. George Saade, director of the division of maternal-fetal medicine at the University of Texas Medical Branch, Galveston. In a video interview, Dr. Saade discussed what’s fueling the rise, and what physicians must do to reduce C-section rates.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NEW ORLEANS – The rate of cesarean section in the United States has risen dramatically in the past 2 decades, accounting for 30% of all deliveries in 2011.
Several factors are driving the increase, according to the Society for Maternal-Fetal Medicine, which sponsored the annual Pregnancy Meeting. Women are waiting until later in life to have children, and their obesity rates are higher than ever before – both of which increase the risk of medical complications during pregnancy. Fear of malpractice also motivates some ob.gyns. to rely on C-sections.
But the most common reason for a woman to have a C-section is that she has had one before, explained Dr. George Saade, director of the division of maternal-fetal medicine at the University of Texas Medical Branch, Galveston. In a video interview, Dr. Saade discussed what’s fueling the rise, and what physicians must do to reduce C-section rates.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE PREGNANCY MEETING
The politics of food addiction: Who wins, who 'loses'
ATLANTA – It’s too soon to disrupt current obesity treatment by declaring food addiction to be a clinical condition, according to Dr. Paul Fletcher.
"If we are to employ [the term] food addiction ... it needs a firm scientific basis," said Dr. Fletcher, who is the Bernard Wolfe Professor of Health Neuroscience in the department of psychiatry at University of Cambridge (England).
Organized medicine took the first step toward recognizing food addiction as a clinical diagnosis with the 2013 inclusion of binge eating disorder (BED) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). That recognition has the potential to set the stage for an overhaul in delivery and funding of obesity treatment as well as how people with pathologic eating behaviors are viewed.
Obesogenic environment
For some, the answer to obesity and food addiction is to remove unhealthful foods from the environment. And to address "powerful environmental drives to consume them," Dr. Hisham Ziauddeen, a Wellcome Trust Fellow in Translational Medicine and Therapeutics at Cambridge, said in an interview.
In a separate presentation at a meeting, sponsored by the Obesity Society and the Society for the Study of Ingestive Behavior, Ashley Gearhardt, Ph.D., noted that researchers do not know whether food addiction exists. "The science is emerging." Foods high in fat and sugar, especially when aggressively marketed to children, are the chief culprits of the obesity epidemic, according to Dr. Gearhardt, a clinical psychologist at the University of Michigan, Ann Arbor.
"If scientific evidence identifies that certain foods are also capable of hijacking the brain in an addictive manner, it would likely be a landmark change that would support bold policy approaches that focus on improving the food environment," she has said (Biol. Psychiatry 2013;73:802-3).
Current research in the field is focused on the individual risk factors for compulsive eating, such as impulsivity or reward sensitivity, Dr. Gearhardt said. However, the lack of addictive behaviors associated with "minimally processed foods that are relatively low in sugar and fat, such as apples or chicken breasts," means research now needs to determine if there is something about the food or behavior "that leads to compulsive problematic use," she said in an interview.
"Individual approaches may be helpful in developing clinical interventions but will touch the lives of far fewer people than will policy changes that affect entire populations," she said.
Dr. Gearhardt and her associates sought to link obesity to addictive patterning in the brain through the combined use of functional neuroimaging (fMRI) and scores on the Yale Food Addiction Scale (YFAS), which applies substance-dependence criteria in the DSM-IV-TR as a type of metric for addictive eating behaviors.
The investigators used fMRI maps of participants’ brain activation when they were given food cues of either a tasteless substance or a chocolate milkshake high in fat and sugar. These images were then compared with the participants’ scores from the YFAS. The group was a mixture of both lean and obese women (Arch. Gen. Psychiatry. 2011;68:808-16).
The researchers found that when presented with a chocolate milkshake, those with higher YFAS scores, regardless of body mass index, experienced "significantly greater activation" in brain regions associated with dopaminergic release, including the anterior cingulate cortex. Those with the highest YFAS scores experienced a significant increase in activity of the dorsolateral prefrontal cortex.
‘Elegant experiments’
While fMRI research into the neurobiologic response to food has "generated some very elegant experiments," according to Dr. Fletcher, he is concerned that food addiction proponents have neglected to see these data in a larger context. "The literature is hugely inconsistent, and ignoring this fact may be inconvenient ... but if we continue to do so, it will come back to slap us in the face."
Because neuroimages "are often ambiguous, unless they are constrained by a specific hypothesis, it becomes more like reading tarot cards than interpreting scientific data," he said. "There is a dangerous tendency for people to have a particular perspective and then, no matter what the fMRI data show, to interpret them according to the perspective with which they started out."
And while this free hand with data interpretation happens generally, Dr. Fletcher said he has been "particularly struck" by its occurrence in the food addiction field. "There seem to be very few constraints on interpretation of the regional activation," he said, noting that whether researchers are looking at obesity, binge-eating, or anyone assumed to have a food addition. "Inevitably, [the researchers] find differences in neural activation in such groups but the interpretations of those activations are often post hoc and heavily biased by what the researchers believed in the first place."
As an example, he cited how activity in the anterior cingulate cortex in overweight people given food cues may be interpreted as a sign of craving. "But this is an unjustified inference because we do not know what the anterior cingulate cortex does and it far more frequently related to other processes than to craving."
Dr. Fletcher and his colleagues’ alarm over this "oversimplification of data" prompted a polite, but impassioned, back and forth with Dr. Gearhardt and her associates, published in Nature Reviews Neuroscience (2012;13:279-86 [doi:10.1038/nrn3212]); (2012;13:514 [doi:10.1038/nrn3212-c1]); (2012;13:514 [doi:10.1038/nrn3212-c2]).
In the first of these editorials, Dr. Fletcher and his coauthors wrote that "the messages now emerging from the neuroscientific research community may therefore have an unprecedented impact on policy development," and in another, urged the adoption of "a more detailed consideration" of how to explore food addiction, particularly since cognitive neuroscience is already moving the field beyond ideas based "purely on clinical overlap" and the model of addiction as delineated in the DSM-IV-TR.
Obesity subsets
"Dr. Fletcher and I agree that the concept of ‘food addiction’ is still an open question," Dr. Gearhardt said in an interview. "My group believes that there is evidence building that suggests it is plausible that an addictive process contributes to problematic eating in some circumstances, especially for eaters who exhibit behavioral phenotypes."
Binge eating, emotional eating, and other pathologies surrounding attitudes toward food also were noted in participants with high YFAS scores in Dr. Gearhardt’s study. "We see evidence of addictive-like processes contributing to problematic eating even for individuals who do not meet the criteria for BED," she said.
Dr. Fletcher noted that "there is a clear degree of clinical overlap between obesity and binge eating, particularly binge eating disorder and drug addiction." Specifically, tolerance, withdrawal, persistent desire for food, eating more than intended, and the diminishment of social engagement in exchange for more time spent acquiring and ingesting food all parallel drug addiction. "However, we don’t know what the overlap is," said Dr. Fletcher. "Is it sugar? Is it fat? Is it a combination? We really don’t know yet."
Populations vs. individuals
"If certain foods are addictive, this may partially explain the difficulty people experience in achieving sustainable weight loss," according to Dr. Gearhardt in commenting on the fMRI study results. "Ubiquitous food advertising and the availability of inexpensive palatable foods may make it extremely difficult to adhere to healthier food choices because the omnipresent food cues trigger the reward system."
Dr. Gearhardt speculated that a focus on specific food ingredients being at the root of addiction-linked obesity may spur activism by manufacturers. "The food industry will likely use any inconsistency in the food addiction literature to plant doubt, attack scientists’ credibility, or fund negative studies," they wrote.
By focusing on how detrimental the food environment has become as a result of "heavily marketed foods that interact with the brain in harmful ways," the public may be more likely to support restrictive policies such as "taxing addictive foods, limiting marketing of these foods to children, and enacting zoning laws that limit the number of vendors selling such foods" among other measures, she wrote.
Dr. Fletcher acknowledged that there is likely a legitimate "battle to be joined" against marketers of junk food and other agents contributing to a deleterious food environment, but attacking the problem at the societal level without consideration of the potential impact on the individual will ultimately backfire. "We must be very careful about how we line up our troops," he said.
"Changing behavior at a population level, which indubitably is required, is not going to be easy," said Dr. Ziauddeen. "As well as the resistance of those with vested interests, such changes will be considered widely unacceptable if they are perceived to entail a loss of liberty."
Although Dr. Fletcher and Dr. Ziauddeen agree a lack of willpower and moral frailty are antiquated notions of why people become obese, assuming that diagnosing people as food addicts will protect them, either from stigmatization or any unforeseen effects of policy changes, is short-sighted.
"Based on our experience with drug addictions over the centuries, it is hard to think that food addiction will not come with some stigma and the consequences thereof," he said.
And Dr. Ziauddeen agreed that, "If the science is shaky and hard to defend, it will be ripped apart." Beyond it possibly being "indefensible" in the face of the opposition from processed food manufacturers, thus setting the field back on its heels, there is the danger of a loss of personal liberty that results, not for the sake of the greater good, but solely from policies based on shoddy science.
"The removal of choice is less threatening if it is done to protect against a situation in which the individual has no real choice anyway, as is the case with addictive substances," said Dr. Ziauddeen. "In short, if there is an addictive agent in some foods, then policy change and legislation can be seen as protective rather than restrictive." This is only possible however, he said, if there is "clear, consistent evidence that there is indeed an addictive substance in food."
And yet, regarding a connection between obesity and food addiction, "the most striking finding is complete inconsistency," said Dr. Fletcher. "I would like to see the same sorts of changes that those supporting food addiction would like, but I do not think that we are going to succeed by using a poorly specified concept with little real evidence to back it up."
Dopamine response not reliable measure
"Food addiction may well exist, [but] even then, it may only explain a tiny fraction of obesity and overeating," according to Dr. Fletcher. "Perhaps the major problem is our general limitations in our often dopaminergically centered views of what constitutes addiction."
A full understanding of the brain’s pathophysiology is still under development, he said. But in addition to classic behavioral manifestations, such as persistent use of a substance, accepted components of addiction include reduced dopamine-receptor density in the ventral striatum and a flip in the neurocircuitry for decision making from the ventral to the dorsal striatum.
Otherwise, he said, conclusive statements about the neurobiology of addiction are suspect. "When we run a functional neuroimaging experiment, we are looking at many different brain regions and, for pretty much all of these, there is a fairly dense ambiguity about what processes they carry out."
In addition, said Dr. Fletcher, although several researchers have tried to replicate one particular study showing that that showed those with severe obesity had reduced raclopride, an indication their dopamine reception was suppressed, the various findings have been inconsistent, thus, said Dr. Fletcher, "there is no proof that there is reduced dopamine in obesity" (Lancet 2001;357:354-7).
As the field of addiction research advances, there will be a shift in the viewpoint that dopamine is the "end all and be all," in part because there will be a deeper understanding of individual variability to different substances that lead to different forms of eating pathologies, he said. "We need to entertain the notion that no single characteristic will define the nature of reward-processing in obesity and that there may be many routes to positive calorie balance."
Longitudinal studies of individual variability to certain foods also could help better determine the impact of certain foods on the brain, he said.
Winners and ‘losers’
"In terms of those who stand to gain from the acceptance of food addiction," said Dr. Fletcher, "At first glance, this would seem to be the people who offer treatments for food addiction and the people who might make some money by suing [processed food] companies."
Yet, for Dr. Gearhardt, if food addiction is proved, and a direct line can be drawn between the food industry’s intentional manipulation of ingredients to profit from this "brain hijacking," Dr. Gearhardt said, "This brings up the question of industry culpability and the ethics of aggressively marketing it to children."
Dr. Gearhardt also believes the possibility of a clinical food addiction diagnosis for those who struggle with pathological eating might "encourage more people ... to receive professional help rather than beat themselves up for not being able to stick to diet after diet on their own."
Conversely, Dr. Ziauddeen noted what while a food addiction diagnosis may offer someone consolation and motivation to seek help, "What if the person is subject to restrictions or treatments based on the diagnosis?" Specifically, he cited ineligibility for bariatric surgery or less clout in the eyes of the court for child custody. "This does not require a stretch of the imagination," he said. "If you have a diagnosis of alcohol dependence, it influences your chances of receiving a liver transplant. If you have a diagnosis of drug or alcohol addiction, it impacts social care decisions made about your children."
Accepting food addiction as real will affect not only those given the diagnosis, but also the so-called "unaffected" public, said Dr. Fletcher. "If food ‘X’ is addictive, to what extent should it be controlled?" He also suggested that health care provision would experience overhaul: "What will be the effect of diverting funding to food addiction treatment from other obesity-related treatments?"
Food addiction "may help us think of novel and hopefully more effective strategies for treating eating-related concerns," said Dr. Gearhardt.
Regardless, Dr. Fletcher warned that because obesity is multifactorial, and includes molecular, metabolic, behavioral, societal and environmental elements, we should not rush to accept "simplistic" answers, or force things to fit where they actually might not. "The thing I think we need to stop right now is this selective citing because we like the narrative."
Dr. Fletcher, Dr. Ziauddeen, and Dr. Gearhardt had no relevant disclosures.
ATLANTA – It’s too soon to disrupt current obesity treatment by declaring food addiction to be a clinical condition, according to Dr. Paul Fletcher.
"If we are to employ [the term] food addiction ... it needs a firm scientific basis," said Dr. Fletcher, who is the Bernard Wolfe Professor of Health Neuroscience in the department of psychiatry at University of Cambridge (England).
Organized medicine took the first step toward recognizing food addiction as a clinical diagnosis with the 2013 inclusion of binge eating disorder (BED) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). That recognition has the potential to set the stage for an overhaul in delivery and funding of obesity treatment as well as how people with pathologic eating behaviors are viewed.
Obesogenic environment
For some, the answer to obesity and food addiction is to remove unhealthful foods from the environment. And to address "powerful environmental drives to consume them," Dr. Hisham Ziauddeen, a Wellcome Trust Fellow in Translational Medicine and Therapeutics at Cambridge, said in an interview.
In a separate presentation at a meeting, sponsored by the Obesity Society and the Society for the Study of Ingestive Behavior, Ashley Gearhardt, Ph.D., noted that researchers do not know whether food addiction exists. "The science is emerging." Foods high in fat and sugar, especially when aggressively marketed to children, are the chief culprits of the obesity epidemic, according to Dr. Gearhardt, a clinical psychologist at the University of Michigan, Ann Arbor.
"If scientific evidence identifies that certain foods are also capable of hijacking the brain in an addictive manner, it would likely be a landmark change that would support bold policy approaches that focus on improving the food environment," she has said (Biol. Psychiatry 2013;73:802-3).
Current research in the field is focused on the individual risk factors for compulsive eating, such as impulsivity or reward sensitivity, Dr. Gearhardt said. However, the lack of addictive behaviors associated with "minimally processed foods that are relatively low in sugar and fat, such as apples or chicken breasts," means research now needs to determine if there is something about the food or behavior "that leads to compulsive problematic use," she said in an interview.
"Individual approaches may be helpful in developing clinical interventions but will touch the lives of far fewer people than will policy changes that affect entire populations," she said.
Dr. Gearhardt and her associates sought to link obesity to addictive patterning in the brain through the combined use of functional neuroimaging (fMRI) and scores on the Yale Food Addiction Scale (YFAS), which applies substance-dependence criteria in the DSM-IV-TR as a type of metric for addictive eating behaviors.
The investigators used fMRI maps of participants’ brain activation when they were given food cues of either a tasteless substance or a chocolate milkshake high in fat and sugar. These images were then compared with the participants’ scores from the YFAS. The group was a mixture of both lean and obese women (Arch. Gen. Psychiatry. 2011;68:808-16).
The researchers found that when presented with a chocolate milkshake, those with higher YFAS scores, regardless of body mass index, experienced "significantly greater activation" in brain regions associated with dopaminergic release, including the anterior cingulate cortex. Those with the highest YFAS scores experienced a significant increase in activity of the dorsolateral prefrontal cortex.
‘Elegant experiments’
While fMRI research into the neurobiologic response to food has "generated some very elegant experiments," according to Dr. Fletcher, he is concerned that food addiction proponents have neglected to see these data in a larger context. "The literature is hugely inconsistent, and ignoring this fact may be inconvenient ... but if we continue to do so, it will come back to slap us in the face."
Because neuroimages "are often ambiguous, unless they are constrained by a specific hypothesis, it becomes more like reading tarot cards than interpreting scientific data," he said. "There is a dangerous tendency for people to have a particular perspective and then, no matter what the fMRI data show, to interpret them according to the perspective with which they started out."
And while this free hand with data interpretation happens generally, Dr. Fletcher said he has been "particularly struck" by its occurrence in the food addiction field. "There seem to be very few constraints on interpretation of the regional activation," he said, noting that whether researchers are looking at obesity, binge-eating, or anyone assumed to have a food addition. "Inevitably, [the researchers] find differences in neural activation in such groups but the interpretations of those activations are often post hoc and heavily biased by what the researchers believed in the first place."
As an example, he cited how activity in the anterior cingulate cortex in overweight people given food cues may be interpreted as a sign of craving. "But this is an unjustified inference because we do not know what the anterior cingulate cortex does and it far more frequently related to other processes than to craving."
Dr. Fletcher and his colleagues’ alarm over this "oversimplification of data" prompted a polite, but impassioned, back and forth with Dr. Gearhardt and her associates, published in Nature Reviews Neuroscience (2012;13:279-86 [doi:10.1038/nrn3212]); (2012;13:514 [doi:10.1038/nrn3212-c1]); (2012;13:514 [doi:10.1038/nrn3212-c2]).
In the first of these editorials, Dr. Fletcher and his coauthors wrote that "the messages now emerging from the neuroscientific research community may therefore have an unprecedented impact on policy development," and in another, urged the adoption of "a more detailed consideration" of how to explore food addiction, particularly since cognitive neuroscience is already moving the field beyond ideas based "purely on clinical overlap" and the model of addiction as delineated in the DSM-IV-TR.
Obesity subsets
"Dr. Fletcher and I agree that the concept of ‘food addiction’ is still an open question," Dr. Gearhardt said in an interview. "My group believes that there is evidence building that suggests it is plausible that an addictive process contributes to problematic eating in some circumstances, especially for eaters who exhibit behavioral phenotypes."
Binge eating, emotional eating, and other pathologies surrounding attitudes toward food also were noted in participants with high YFAS scores in Dr. Gearhardt’s study. "We see evidence of addictive-like processes contributing to problematic eating even for individuals who do not meet the criteria for BED," she said.
Dr. Fletcher noted that "there is a clear degree of clinical overlap between obesity and binge eating, particularly binge eating disorder and drug addiction." Specifically, tolerance, withdrawal, persistent desire for food, eating more than intended, and the diminishment of social engagement in exchange for more time spent acquiring and ingesting food all parallel drug addiction. "However, we don’t know what the overlap is," said Dr. Fletcher. "Is it sugar? Is it fat? Is it a combination? We really don’t know yet."
Populations vs. individuals
"If certain foods are addictive, this may partially explain the difficulty people experience in achieving sustainable weight loss," according to Dr. Gearhardt in commenting on the fMRI study results. "Ubiquitous food advertising and the availability of inexpensive palatable foods may make it extremely difficult to adhere to healthier food choices because the omnipresent food cues trigger the reward system."
Dr. Gearhardt speculated that a focus on specific food ingredients being at the root of addiction-linked obesity may spur activism by manufacturers. "The food industry will likely use any inconsistency in the food addiction literature to plant doubt, attack scientists’ credibility, or fund negative studies," they wrote.
By focusing on how detrimental the food environment has become as a result of "heavily marketed foods that interact with the brain in harmful ways," the public may be more likely to support restrictive policies such as "taxing addictive foods, limiting marketing of these foods to children, and enacting zoning laws that limit the number of vendors selling such foods" among other measures, she wrote.
Dr. Fletcher acknowledged that there is likely a legitimate "battle to be joined" against marketers of junk food and other agents contributing to a deleterious food environment, but attacking the problem at the societal level without consideration of the potential impact on the individual will ultimately backfire. "We must be very careful about how we line up our troops," he said.
"Changing behavior at a population level, which indubitably is required, is not going to be easy," said Dr. Ziauddeen. "As well as the resistance of those with vested interests, such changes will be considered widely unacceptable if they are perceived to entail a loss of liberty."
Although Dr. Fletcher and Dr. Ziauddeen agree a lack of willpower and moral frailty are antiquated notions of why people become obese, assuming that diagnosing people as food addicts will protect them, either from stigmatization or any unforeseen effects of policy changes, is short-sighted.
"Based on our experience with drug addictions over the centuries, it is hard to think that food addiction will not come with some stigma and the consequences thereof," he said.
And Dr. Ziauddeen agreed that, "If the science is shaky and hard to defend, it will be ripped apart." Beyond it possibly being "indefensible" in the face of the opposition from processed food manufacturers, thus setting the field back on its heels, there is the danger of a loss of personal liberty that results, not for the sake of the greater good, but solely from policies based on shoddy science.
"The removal of choice is less threatening if it is done to protect against a situation in which the individual has no real choice anyway, as is the case with addictive substances," said Dr. Ziauddeen. "In short, if there is an addictive agent in some foods, then policy change and legislation can be seen as protective rather than restrictive." This is only possible however, he said, if there is "clear, consistent evidence that there is indeed an addictive substance in food."
And yet, regarding a connection between obesity and food addiction, "the most striking finding is complete inconsistency," said Dr. Fletcher. "I would like to see the same sorts of changes that those supporting food addiction would like, but I do not think that we are going to succeed by using a poorly specified concept with little real evidence to back it up."
Dopamine response not reliable measure
"Food addiction may well exist, [but] even then, it may only explain a tiny fraction of obesity and overeating," according to Dr. Fletcher. "Perhaps the major problem is our general limitations in our often dopaminergically centered views of what constitutes addiction."
A full understanding of the brain’s pathophysiology is still under development, he said. But in addition to classic behavioral manifestations, such as persistent use of a substance, accepted components of addiction include reduced dopamine-receptor density in the ventral striatum and a flip in the neurocircuitry for decision making from the ventral to the dorsal striatum.
Otherwise, he said, conclusive statements about the neurobiology of addiction are suspect. "When we run a functional neuroimaging experiment, we are looking at many different brain regions and, for pretty much all of these, there is a fairly dense ambiguity about what processes they carry out."
In addition, said Dr. Fletcher, although several researchers have tried to replicate one particular study showing that that showed those with severe obesity had reduced raclopride, an indication their dopamine reception was suppressed, the various findings have been inconsistent, thus, said Dr. Fletcher, "there is no proof that there is reduced dopamine in obesity" (Lancet 2001;357:354-7).
As the field of addiction research advances, there will be a shift in the viewpoint that dopamine is the "end all and be all," in part because there will be a deeper understanding of individual variability to different substances that lead to different forms of eating pathologies, he said. "We need to entertain the notion that no single characteristic will define the nature of reward-processing in obesity and that there may be many routes to positive calorie balance."
Longitudinal studies of individual variability to certain foods also could help better determine the impact of certain foods on the brain, he said.
Winners and ‘losers’
"In terms of those who stand to gain from the acceptance of food addiction," said Dr. Fletcher, "At first glance, this would seem to be the people who offer treatments for food addiction and the people who might make some money by suing [processed food] companies."
Yet, for Dr. Gearhardt, if food addiction is proved, and a direct line can be drawn between the food industry’s intentional manipulation of ingredients to profit from this "brain hijacking," Dr. Gearhardt said, "This brings up the question of industry culpability and the ethics of aggressively marketing it to children."
Dr. Gearhardt also believes the possibility of a clinical food addiction diagnosis for those who struggle with pathological eating might "encourage more people ... to receive professional help rather than beat themselves up for not being able to stick to diet after diet on their own."
Conversely, Dr. Ziauddeen noted what while a food addiction diagnosis may offer someone consolation and motivation to seek help, "What if the person is subject to restrictions or treatments based on the diagnosis?" Specifically, he cited ineligibility for bariatric surgery or less clout in the eyes of the court for child custody. "This does not require a stretch of the imagination," he said. "If you have a diagnosis of alcohol dependence, it influences your chances of receiving a liver transplant. If you have a diagnosis of drug or alcohol addiction, it impacts social care decisions made about your children."
Accepting food addiction as real will affect not only those given the diagnosis, but also the so-called "unaffected" public, said Dr. Fletcher. "If food ‘X’ is addictive, to what extent should it be controlled?" He also suggested that health care provision would experience overhaul: "What will be the effect of diverting funding to food addiction treatment from other obesity-related treatments?"
Food addiction "may help us think of novel and hopefully more effective strategies for treating eating-related concerns," said Dr. Gearhardt.
Regardless, Dr. Fletcher warned that because obesity is multifactorial, and includes molecular, metabolic, behavioral, societal and environmental elements, we should not rush to accept "simplistic" answers, or force things to fit where they actually might not. "The thing I think we need to stop right now is this selective citing because we like the narrative."
Dr. Fletcher, Dr. Ziauddeen, and Dr. Gearhardt had no relevant disclosures.
ATLANTA – It’s too soon to disrupt current obesity treatment by declaring food addiction to be a clinical condition, according to Dr. Paul Fletcher.
"If we are to employ [the term] food addiction ... it needs a firm scientific basis," said Dr. Fletcher, who is the Bernard Wolfe Professor of Health Neuroscience in the department of psychiatry at University of Cambridge (England).
Organized medicine took the first step toward recognizing food addiction as a clinical diagnosis with the 2013 inclusion of binge eating disorder (BED) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). That recognition has the potential to set the stage for an overhaul in delivery and funding of obesity treatment as well as how people with pathologic eating behaviors are viewed.
Obesogenic environment
For some, the answer to obesity and food addiction is to remove unhealthful foods from the environment. And to address "powerful environmental drives to consume them," Dr. Hisham Ziauddeen, a Wellcome Trust Fellow in Translational Medicine and Therapeutics at Cambridge, said in an interview.
In a separate presentation at a meeting, sponsored by the Obesity Society and the Society for the Study of Ingestive Behavior, Ashley Gearhardt, Ph.D., noted that researchers do not know whether food addiction exists. "The science is emerging." Foods high in fat and sugar, especially when aggressively marketed to children, are the chief culprits of the obesity epidemic, according to Dr. Gearhardt, a clinical psychologist at the University of Michigan, Ann Arbor.
"If scientific evidence identifies that certain foods are also capable of hijacking the brain in an addictive manner, it would likely be a landmark change that would support bold policy approaches that focus on improving the food environment," she has said (Biol. Psychiatry 2013;73:802-3).
Current research in the field is focused on the individual risk factors for compulsive eating, such as impulsivity or reward sensitivity, Dr. Gearhardt said. However, the lack of addictive behaviors associated with "minimally processed foods that are relatively low in sugar and fat, such as apples or chicken breasts," means research now needs to determine if there is something about the food or behavior "that leads to compulsive problematic use," she said in an interview.
"Individual approaches may be helpful in developing clinical interventions but will touch the lives of far fewer people than will policy changes that affect entire populations," she said.
Dr. Gearhardt and her associates sought to link obesity to addictive patterning in the brain through the combined use of functional neuroimaging (fMRI) and scores on the Yale Food Addiction Scale (YFAS), which applies substance-dependence criteria in the DSM-IV-TR as a type of metric for addictive eating behaviors.
The investigators used fMRI maps of participants’ brain activation when they were given food cues of either a tasteless substance or a chocolate milkshake high in fat and sugar. These images were then compared with the participants’ scores from the YFAS. The group was a mixture of both lean and obese women (Arch. Gen. Psychiatry. 2011;68:808-16).
The researchers found that when presented with a chocolate milkshake, those with higher YFAS scores, regardless of body mass index, experienced "significantly greater activation" in brain regions associated with dopaminergic release, including the anterior cingulate cortex. Those with the highest YFAS scores experienced a significant increase in activity of the dorsolateral prefrontal cortex.
‘Elegant experiments’
While fMRI research into the neurobiologic response to food has "generated some very elegant experiments," according to Dr. Fletcher, he is concerned that food addiction proponents have neglected to see these data in a larger context. "The literature is hugely inconsistent, and ignoring this fact may be inconvenient ... but if we continue to do so, it will come back to slap us in the face."
Because neuroimages "are often ambiguous, unless they are constrained by a specific hypothesis, it becomes more like reading tarot cards than interpreting scientific data," he said. "There is a dangerous tendency for people to have a particular perspective and then, no matter what the fMRI data show, to interpret them according to the perspective with which they started out."
And while this free hand with data interpretation happens generally, Dr. Fletcher said he has been "particularly struck" by its occurrence in the food addiction field. "There seem to be very few constraints on interpretation of the regional activation," he said, noting that whether researchers are looking at obesity, binge-eating, or anyone assumed to have a food addition. "Inevitably, [the researchers] find differences in neural activation in such groups but the interpretations of those activations are often post hoc and heavily biased by what the researchers believed in the first place."
As an example, he cited how activity in the anterior cingulate cortex in overweight people given food cues may be interpreted as a sign of craving. "But this is an unjustified inference because we do not know what the anterior cingulate cortex does and it far more frequently related to other processes than to craving."
Dr. Fletcher and his colleagues’ alarm over this "oversimplification of data" prompted a polite, but impassioned, back and forth with Dr. Gearhardt and her associates, published in Nature Reviews Neuroscience (2012;13:279-86 [doi:10.1038/nrn3212]); (2012;13:514 [doi:10.1038/nrn3212-c1]); (2012;13:514 [doi:10.1038/nrn3212-c2]).
In the first of these editorials, Dr. Fletcher and his coauthors wrote that "the messages now emerging from the neuroscientific research community may therefore have an unprecedented impact on policy development," and in another, urged the adoption of "a more detailed consideration" of how to explore food addiction, particularly since cognitive neuroscience is already moving the field beyond ideas based "purely on clinical overlap" and the model of addiction as delineated in the DSM-IV-TR.
Obesity subsets
"Dr. Fletcher and I agree that the concept of ‘food addiction’ is still an open question," Dr. Gearhardt said in an interview. "My group believes that there is evidence building that suggests it is plausible that an addictive process contributes to problematic eating in some circumstances, especially for eaters who exhibit behavioral phenotypes."
Binge eating, emotional eating, and other pathologies surrounding attitudes toward food also were noted in participants with high YFAS scores in Dr. Gearhardt’s study. "We see evidence of addictive-like processes contributing to problematic eating even for individuals who do not meet the criteria for BED," she said.
Dr. Fletcher noted that "there is a clear degree of clinical overlap between obesity and binge eating, particularly binge eating disorder and drug addiction." Specifically, tolerance, withdrawal, persistent desire for food, eating more than intended, and the diminishment of social engagement in exchange for more time spent acquiring and ingesting food all parallel drug addiction. "However, we don’t know what the overlap is," said Dr. Fletcher. "Is it sugar? Is it fat? Is it a combination? We really don’t know yet."
Populations vs. individuals
"If certain foods are addictive, this may partially explain the difficulty people experience in achieving sustainable weight loss," according to Dr. Gearhardt in commenting on the fMRI study results. "Ubiquitous food advertising and the availability of inexpensive palatable foods may make it extremely difficult to adhere to healthier food choices because the omnipresent food cues trigger the reward system."
Dr. Gearhardt speculated that a focus on specific food ingredients being at the root of addiction-linked obesity may spur activism by manufacturers. "The food industry will likely use any inconsistency in the food addiction literature to plant doubt, attack scientists’ credibility, or fund negative studies," they wrote.
By focusing on how detrimental the food environment has become as a result of "heavily marketed foods that interact with the brain in harmful ways," the public may be more likely to support restrictive policies such as "taxing addictive foods, limiting marketing of these foods to children, and enacting zoning laws that limit the number of vendors selling such foods" among other measures, she wrote.
Dr. Fletcher acknowledged that there is likely a legitimate "battle to be joined" against marketers of junk food and other agents contributing to a deleterious food environment, but attacking the problem at the societal level without consideration of the potential impact on the individual will ultimately backfire. "We must be very careful about how we line up our troops," he said.
"Changing behavior at a population level, which indubitably is required, is not going to be easy," said Dr. Ziauddeen. "As well as the resistance of those with vested interests, such changes will be considered widely unacceptable if they are perceived to entail a loss of liberty."
Although Dr. Fletcher and Dr. Ziauddeen agree a lack of willpower and moral frailty are antiquated notions of why people become obese, assuming that diagnosing people as food addicts will protect them, either from stigmatization or any unforeseen effects of policy changes, is short-sighted.
"Based on our experience with drug addictions over the centuries, it is hard to think that food addiction will not come with some stigma and the consequences thereof," he said.
And Dr. Ziauddeen agreed that, "If the science is shaky and hard to defend, it will be ripped apart." Beyond it possibly being "indefensible" in the face of the opposition from processed food manufacturers, thus setting the field back on its heels, there is the danger of a loss of personal liberty that results, not for the sake of the greater good, but solely from policies based on shoddy science.
"The removal of choice is less threatening if it is done to protect against a situation in which the individual has no real choice anyway, as is the case with addictive substances," said Dr. Ziauddeen. "In short, if there is an addictive agent in some foods, then policy change and legislation can be seen as protective rather than restrictive." This is only possible however, he said, if there is "clear, consistent evidence that there is indeed an addictive substance in food."
And yet, regarding a connection between obesity and food addiction, "the most striking finding is complete inconsistency," said Dr. Fletcher. "I would like to see the same sorts of changes that those supporting food addiction would like, but I do not think that we are going to succeed by using a poorly specified concept with little real evidence to back it up."
Dopamine response not reliable measure
"Food addiction may well exist, [but] even then, it may only explain a tiny fraction of obesity and overeating," according to Dr. Fletcher. "Perhaps the major problem is our general limitations in our often dopaminergically centered views of what constitutes addiction."
A full understanding of the brain’s pathophysiology is still under development, he said. But in addition to classic behavioral manifestations, such as persistent use of a substance, accepted components of addiction include reduced dopamine-receptor density in the ventral striatum and a flip in the neurocircuitry for decision making from the ventral to the dorsal striatum.
Otherwise, he said, conclusive statements about the neurobiology of addiction are suspect. "When we run a functional neuroimaging experiment, we are looking at many different brain regions and, for pretty much all of these, there is a fairly dense ambiguity about what processes they carry out."
In addition, said Dr. Fletcher, although several researchers have tried to replicate one particular study showing that that showed those with severe obesity had reduced raclopride, an indication their dopamine reception was suppressed, the various findings have been inconsistent, thus, said Dr. Fletcher, "there is no proof that there is reduced dopamine in obesity" (Lancet 2001;357:354-7).
As the field of addiction research advances, there will be a shift in the viewpoint that dopamine is the "end all and be all," in part because there will be a deeper understanding of individual variability to different substances that lead to different forms of eating pathologies, he said. "We need to entertain the notion that no single characteristic will define the nature of reward-processing in obesity and that there may be many routes to positive calorie balance."
Longitudinal studies of individual variability to certain foods also could help better determine the impact of certain foods on the brain, he said.
Winners and ‘losers’
"In terms of those who stand to gain from the acceptance of food addiction," said Dr. Fletcher, "At first glance, this would seem to be the people who offer treatments for food addiction and the people who might make some money by suing [processed food] companies."
Yet, for Dr. Gearhardt, if food addiction is proved, and a direct line can be drawn between the food industry’s intentional manipulation of ingredients to profit from this "brain hijacking," Dr. Gearhardt said, "This brings up the question of industry culpability and the ethics of aggressively marketing it to children."
Dr. Gearhardt also believes the possibility of a clinical food addiction diagnosis for those who struggle with pathological eating might "encourage more people ... to receive professional help rather than beat themselves up for not being able to stick to diet after diet on their own."
Conversely, Dr. Ziauddeen noted what while a food addiction diagnosis may offer someone consolation and motivation to seek help, "What if the person is subject to restrictions or treatments based on the diagnosis?" Specifically, he cited ineligibility for bariatric surgery or less clout in the eyes of the court for child custody. "This does not require a stretch of the imagination," he said. "If you have a diagnosis of alcohol dependence, it influences your chances of receiving a liver transplant. If you have a diagnosis of drug or alcohol addiction, it impacts social care decisions made about your children."
Accepting food addiction as real will affect not only those given the diagnosis, but also the so-called "unaffected" public, said Dr. Fletcher. "If food ‘X’ is addictive, to what extent should it be controlled?" He also suggested that health care provision would experience overhaul: "What will be the effect of diverting funding to food addiction treatment from other obesity-related treatments?"
Food addiction "may help us think of novel and hopefully more effective strategies for treating eating-related concerns," said Dr. Gearhardt.
Regardless, Dr. Fletcher warned that because obesity is multifactorial, and includes molecular, metabolic, behavioral, societal and environmental elements, we should not rush to accept "simplistic" answers, or force things to fit where they actually might not. "The thing I think we need to stop right now is this selective citing because we like the narrative."
Dr. Fletcher, Dr. Ziauddeen, and Dr. Gearhardt had no relevant disclosures.
EXPERT ANALYSIS FROM OBESITY WEEK
Immunosuppressive therapy ups risk for skin cancers
HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.
Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."
Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.
In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).
"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.
To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."
Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).
Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."
The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).
Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).
A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).
In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).
Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.
Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.
The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.
HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.
Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."
Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.
In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).
"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.
To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."
Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).
Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."
The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).
Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).
A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).
In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).
Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.
Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.
The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.
HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.
Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."
Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.
In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).
"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.
To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."
Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).
Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."
The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).
Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).
A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).
In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).
Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.
Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.
The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.
EXPERT ANALYSIS FROM 2013 ADVANCES IN IBD
Misdiagnosis, noncompliance often culprits in refractory celiac disease
HOLLYWOOD, FLA. – Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn.
"When faced with such a patient, it’s important to reconfirm the original diagnosis," said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel.
In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray.
When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with "true" celiac disease, not just family members who have chosen to stop eating gluten, "I will always ask for the original biopsies," said Dr. Murray.
In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. "Gliadin antibodies are not celiac specific," said Dr. Murray. "You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless." Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America.
Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, "That’s pathognomonic for celiac disease," said Dr. Murray.
For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. "She wasn’t exactly happy about her 10 years of living gluten free," he said.
Dangers of noncompliance
As for patients who claim to follow a gluten-free diet, "That’s not true most of the time," said Dr. Murray. "A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten." It can either be advertent or inadvertently, he said.
However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray.
If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. "Eliminating the gluten may take time. Often we have to use behavioral counselors to help," said Dr. Murray.
Also key is to stay in touch with the patient. "Follow-up in patients with celiac disease is abysmal," Dr. Murray said, "It’s almost like once the disease is diagnosed, it’s forgotten about medically."
"The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together," said Dr. Murray. "Complications of celiac disease also can occur in multiples."
Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease.
Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. "Often, that will work, so I don’t even test for lactose intolerance initially," he said.
Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while "true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients," said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50).
Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, "but rarely affect the ileum," according to Dr. Murray.
Possible lymphomas
"The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’" said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said.
Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. "A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma," he said.
True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. "By definition, there should be no lymphoma," said Dr. Murray.
Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells.
Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. "Type 2 refractory disease is not a trivial disease," he said.
Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]).
"We really don’t know what we should do about those asymptomatic patients," said Dr. Murray. He noted that, "Failure to heal is not entirely benign, but it’s not refractory celiac disease," said Dr. Murray.
Dr. Murray stated that he had no disclosures.
HOLLYWOOD, FLA. – Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn.
"When faced with such a patient, it’s important to reconfirm the original diagnosis," said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel.
In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray.
When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with "true" celiac disease, not just family members who have chosen to stop eating gluten, "I will always ask for the original biopsies," said Dr. Murray.
In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. "Gliadin antibodies are not celiac specific," said Dr. Murray. "You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless." Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America.
Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, "That’s pathognomonic for celiac disease," said Dr. Murray.
For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. "She wasn’t exactly happy about her 10 years of living gluten free," he said.
Dangers of noncompliance
As for patients who claim to follow a gluten-free diet, "That’s not true most of the time," said Dr. Murray. "A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten." It can either be advertent or inadvertently, he said.
However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray.
If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. "Eliminating the gluten may take time. Often we have to use behavioral counselors to help," said Dr. Murray.
Also key is to stay in touch with the patient. "Follow-up in patients with celiac disease is abysmal," Dr. Murray said, "It’s almost like once the disease is diagnosed, it’s forgotten about medically."
"The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together," said Dr. Murray. "Complications of celiac disease also can occur in multiples."
Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease.
Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. "Often, that will work, so I don’t even test for lactose intolerance initially," he said.
Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while "true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients," said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50).
Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, "but rarely affect the ileum," according to Dr. Murray.
Possible lymphomas
"The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’" said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said.
Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. "A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma," he said.
True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. "By definition, there should be no lymphoma," said Dr. Murray.
Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells.
Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. "Type 2 refractory disease is not a trivial disease," he said.
Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]).
"We really don’t know what we should do about those asymptomatic patients," said Dr. Murray. He noted that, "Failure to heal is not entirely benign, but it’s not refractory celiac disease," said Dr. Murray.
Dr. Murray stated that he had no disclosures.
HOLLYWOOD, FLA. – Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn.
"When faced with such a patient, it’s important to reconfirm the original diagnosis," said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel.
In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray.
When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with "true" celiac disease, not just family members who have chosen to stop eating gluten, "I will always ask for the original biopsies," said Dr. Murray.
In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. "Gliadin antibodies are not celiac specific," said Dr. Murray. "You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless." Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America.
Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, "That’s pathognomonic for celiac disease," said Dr. Murray.
For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. "She wasn’t exactly happy about her 10 years of living gluten free," he said.
Dangers of noncompliance
As for patients who claim to follow a gluten-free diet, "That’s not true most of the time," said Dr. Murray. "A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten." It can either be advertent or inadvertently, he said.
However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray.
If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. "Eliminating the gluten may take time. Often we have to use behavioral counselors to help," said Dr. Murray.
Also key is to stay in touch with the patient. "Follow-up in patients with celiac disease is abysmal," Dr. Murray said, "It’s almost like once the disease is diagnosed, it’s forgotten about medically."
"The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together," said Dr. Murray. "Complications of celiac disease also can occur in multiples."
Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease.
Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. "Often, that will work, so I don’t even test for lactose intolerance initially," he said.
Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while "true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients," said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50).
Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, "but rarely affect the ileum," according to Dr. Murray.
Possible lymphomas
"The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’" said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said.
Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. "A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma," he said.
True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. "By definition, there should be no lymphoma," said Dr. Murray.
Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells.
Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. "Type 2 refractory disease is not a trivial disease," he said.
Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]).
"We really don’t know what we should do about those asymptomatic patients," said Dr. Murray. He noted that, "Failure to heal is not entirely benign, but it’s not refractory celiac disease," said Dr. Murray.
Dr. Murray stated that he had no disclosures.
EXPERT ANALYSIS FROM 2013 ADVANCES IN IBD
