Mary Ann Moon

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

"Critical access" hospitals show higher patient mortality and worse performance on standard measures of health care quality, compared with other hospitals, according to a July 6 report in JAMA.

Critical access hospitals are so designated because they provide close-to-home basic inpatient and emergency care for people who otherwise would have no such access – chiefly the 20% of Americans who live in rural areas. The designation was created in 1997 by the federal government to provide extra reimbursement for small, geographically isolated hospitals that were struggling with financial insolvency, and it has succeeded in allowing them to remain open. At present, more than one-fourth of the acute-care hospitals in the United States are critical access hospitals.

However, little is known about the quality of care provided at these facilities, largely because they are exempt from reporting to the Joint Commission performance measure program and the Hospital Quality Alliance national public reporting program, said Dr. Karen E. Joynt of the department of health policy and management, Harvard School of Public Health, Boston, and her associates.

"We sought to examine critical access hospitals’ clinical and personnel resources, the quality of care they deliver, and their patients’ outcomes. We focused on three common conditions – congestive heart failure, acute myocardial infarction, and pneumonia," the researchers said.

To do so, they assessed Medicare data on acute care services and data from the American Hospital Association on hospital characteristics, and linked this with county-level data on household incomes and the poverty rate in all 50 states. They identified 2,351,701 index admissions to 4,738 hospitals nationwide for these three conditions during a recent 1-year period, including 149,989 admissions to 1,268 critical access hospitals (JAMA 2011;306: 45-52).

For all three conditions, patients admitted to critical access hospitals had higher risk-adjusted 30-day mortality than did those admitted to other hospitals. Thirty-day mortality was 7.3% higher for patients with acute MI (23.5% vs. 16.2%), 2.5% higher for patients with CHF (13.4% vs 10.9%), and 2% higher for patients with pneumonia (14.1% vs 12.1%).

Similarly, for all three conditions, critical access hospitals had poorer performances on measures of health care quality. For 14 of the 17 individual measures, critical access hospitals were consistently outperformed by other hospitals even after the data were adjusted to account for differences in case mix and hospital characteristics.

"These findings suggest that efforts to date have been insufficient in improving the quality of inpatient care in rural communities – and indicate a need for greater policy attention to the challenges [critical access] hospitals face," Dr. Joynt and her colleagues said.

"More than a decade after major federal and state efforts to save U.S. rural hospitals, these findings should be seen as a call to focus on helping these hospitals improve the quality of care they provide so that all individuals in the United States have access to high-quality inpatient care regardless of where they live," they added.

Differences in personnel and technical capabilities explain some of the discrepancy in patient mortality between critical access hospitals and other hospitals. For example, in this study, critical access hospitals were located in counties that had sevenfold fewer cardiologists and pulmonologists per 100,000 population, compared with other hospitals.

Rural hospitals are known to have difficulty in recruiting clinicians, particularly specialists. Strategies that may address this problem include promoting partnerships with large health care systems, allowing on-site rotations by specialists, increasing the use of telemedicine, and establishing formal referral and transfer agreements that allow patients to stay close to home while still facilitating access to specialty care.

"The use of technology, particularly telemedicine and clinical data exchange, has important applications in underserved areas. [But currently,] critical access hospitals lack financial capital and access to the personnel needed to install and effectively maintain these systems," the researchers said.

One of Dr. Joynt’s associates reported ties to UpToDate and Humedica. No other financial conflicts of interest were disclosed.

A Challenge to Improve Rural Health Care

"The report by Joynt et al. is likely to be disappointing to those committed to rural health care," Dr. Martin S. Lipsky and Michael Glasser, Ph.D., wrote in an editorial (JAMA 2011;306:96-7).

"Although the differences in critical access hospitals’ outcomes may be accounted for by cultural, economic, and other environmental issues, this study should also serve as a challenge to improve the health care experienced by rural residents.

"All residents of the United States should have access to safe, high-quality health care and should have confidence in the health care system regardless of where they live," Dr. Lipsky and Dr. Glasser said.

Dr. Lipsky and Dr. Glasser are in the department of community and family medicine at the University of Illinois, Rockford. Dr. Glasser is also at the National Center for Rural Health Professions, Rockford. Dr. Lipsky was formerly on the board of the Midwest Medical Center, Galena, Ill. Dr. Glasser reported ties to the Illinois Critical Access Hospital Network.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Environmental factors appear to play a larger role than hereditary factors in the development of autism, according to the California Autism Twin Study, published online July 4 in Archives of General Psychiatry.

In the study of 404 children (202 twin pairs), environmental factors accounted for about 55% of susceptibility to autism. "Although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism," said Dr. Joachim Hallmayer of Stanford (Calif.) University and his associates (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.76]).

Potential environmental influences may include parental age, low birth weight, multiple births, and maternal infections during pregnancy, the researchers noted.

The study included identical (monozygotic) and fraternal (dizygotic) twins. Despite the genetic diversity between fraternal twins, the probability that a child would have autism or autism spectrum disorder (ASD) if his/her fraternal twin did was greater than that found in previous studies – thus suggesting that shared environment may play a greater causative role than previously suspected.

"Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes," the investigators noted. "Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies, and the influence of genetic factors on the susceptibility to develop autism overestimated.

"The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research," they added.

Dr. Hallmayer and his colleagues performed what they described as "the largest population-based twin study of autism that used contemporary standards [of] diagnosis." They identified twin pairs born in 1987-2004 in which one or both children were affected. To do so, they used a California database for the 21 regional centers that coordinate services for people with autism, mental retardation, and other developmental disabilities.

All the study subjects were rigorously assessed between 2005 and 2009 using the Autism Diagnostic Interview-Revised, a structured parent interview, and the Autism Diagnostic Observation Schedule, a standardized play and interview scale.

Of the 404 twins, 242 met criteria for autism spectrum disorder, including 171 who met the stricter criteria for autism. A subset of 192 twin pairs was included in the final analysis: 54 monozygotic and 138 dizygotic pairs.

For autism, probandwise concordance rates for monozygotic twins were similar for 40 male pairs (58%) and 7 female pairs (60%), and were comparable with rates reported previously.

However, probandwise concordance rates for dizygotic pairs were higher than previously reported, at 21% for 31 male pairs and 27% for 10 female pairs.

For ASD, probandwise concordance for monozygotic twins was 77% for 45 male pairs and 50% for 9 female pairs; however, concordance rates for dizygotic twins were 31% for 45 male pairs and 36% for 13 female pairs.

Among the female dizygotic twins of 76 boys with ASD, the probandwise concordance rate was 5.3%. But the rate for the male dizygotic twins of six girls with ASD was nearly 10 times greater, at 50%.

"These dizygotic concordance rates are higher than previously reported and have a significant impact on the heritability analysis," the investigators said.

For autism, genetic factors accounted for an estimated 37% and a shared environment accounted for an estimated 55% of susceptibility to autism. For ASD, genetic factors accounted for an estimated 38% and a shared environment accounted for 58%.

Dr. Hallmayer and his associates noted that their study population was highly diverse in ethnicity, socioeconomic status, and other demographic factors. That means that the results should be readily generalizable to other populations.

That diversity also may explain some of the differences between the findings of the latest study and those of previous twin studies, "which were based exclusively on individuals from Northern Europe," they added.

The National Institute of Mental Health and Autism Speaks supported the study. No financial conflicts of interest were reported.

Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.

"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.

"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.

"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.

The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.

After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).

Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.

The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).

The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.

However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."

There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.

"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.

This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.

Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.

"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.

"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.

"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.

The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.

After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).

Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.

The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).

The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.

However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."

There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.

"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.

This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.

Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.

"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.

"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.

"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.

The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.

After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).

Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.

The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).

The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.

However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."

There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.

"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.

This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.

Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.

"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.

"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.

"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.

The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.

After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).

Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.

The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).

The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.

However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."

There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.

"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.

This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.

Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.

"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.

"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.

"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.

The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.

After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).

Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.

The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).

The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.

However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."

There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.

"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.

This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.

Prenatal exposure to selective serotonin reuptake inhibitors, particularly during the first trimester, may "modestly" raise the risk of autism spectrum disorders, according to a preliminary study published online July 4 in Archives of General Psychiatry.

"The fraction of cases of [autism spectrum disorders] that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD," said Lisa A. Croen, Ph.D., of Kaiser Permanente Northern California, Oakland, and her associates.

"Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or the fetus of untreated mental health disorders," they noted.

"We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies designed to address the very complex question of whether prenatal exposure to SSRIs may be etiologically linked to later diagnoses of ASD in offspring," the investigators added.

The study was a population-based case-control assessment of mothers’ antidepressant use during pregnancy and the later diagnosis of ASD in their children. The sample was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1,507 unaffected controls matched for age, sex, and area of residence within Northern California.

Twenty case mothers (6.7%) and 50 control mothers (3.3%) had at least one prescription for an antidepressant during the year before the birth of the child. Most of these prescriptions – for 5% of the case mothers and 2.3% of the control mothers – were for SSRIs.

After the data were adjusted to account for maternal age, race/ethnicity, and education level and for the child\'s birth weight and sex, "we found an approximately twofold increased risk of ASD associated with treatment with SSRIs ... and an approximately threefold increased risk associated with treatment during the first trimester," Dr. Croen and her colleagues said (Arch. Gen. Psychiatry 2011 July 4 [doi:10.1001/archgenpsychiatry.2011.73]).

Mothers of children later diagnosed as having ASD were twice as likely as other mothers to have had at least one antidepressant prescription during the year preceding the birth. In addition, mothers with a prescription for an antidepressant were more than twice as likely as other mothers to have a child who was later diagnosed as having ASD. No such associations were seen among women prescribed any non-SSRI antidepressants, but the number of women in that group was quite small.

The link between SSRIs and ASD risk remained robust in several further statistical analyses. It remained strong when the analysis was restricted to only term births, as well as when it was restricted to only cases in which only one child in the family was affected with ASD ("simplex" cases).

The correlation also remained strong regardless of the indication for which the mother took the drugs. Moreover, ASD risk did not correlate with a history of mental health disorders. These two findings indicate that the SSRIs themselves, not the underlying indications for taking the medications, were the relevant contributing factor, Dr. Croen and her associates said.

However, they cautioned that "despite the significant association, the number of women in this [study] population exposed to SSRIs was modest, and the proportion of children with ASD in this population that can be statistically attributed to SSRI exposure is quite low: 2.1% for exposure during the year before delivery, and 2.3% for exposure during the first trimester."

There are several biologically plausible explanations for this link between SSRI exposure and ASD. Many studies have implicated serotonin abnormalities and anomalies in serotoninergic pathways in autism. And several animal studies "suggest the possibility that prenatal exposure to SSRIs may operate directly on the developing brain, perhaps selectively in fetuses with abnormalities in serotonin-related genes," they said.

"To our knowledge, our study is the first to directly examine antidepressant use during pregnancy as a potential risk factor for childhood ASD. A substantial strength of our study is our reliance on data documented in medical records and thus recorded at the time of diagnosis or treatment, avoiding potential biases associated with the mothers’ recall after diagnosis of ASD in the children," the investigators wrote.

This study was supported by the Kaiser Permanente Community Benefit Clinician Research Fund, and the Centers for Disease Control and Prevention. No relevant financial disclosures were reported.

Major Finding: The hazard ratios for diabetes were 0.62 for patients taking TNF inhibitors and 0.54 for patients taking hydroxychloroquine, compared with patients taking nonbiologic DMARDs to treat their rheumatoid arthritis or psoriasis.

Data Source: A retrospective observational study involving 13,905 adults who had either RA or psoriasis, received a DMARD, and were followed for approximately 6 months for the development of diabetes. Participants were enrolled in one of two health care systems.

Disclosures: This study was supported by Amgen. Dr. Solomon reported ties to Abbott, Amgen, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to numerous industry sources.

Some disease-modifying antirheumatic drugs that are taken for rheumatoid arthritis or psoriasis appear to reduce the rate of incident diabetes.

In a retrospective cohort study of patients who had RA or psoriasis, the use of a tumor necrosis factor (TNF) inhibitor or hydroxychloroquine to treat the systemic inflammatory disorder was associated with a reduced risk of developing diabetes, compared with the use of methotrexate or nonbiologic DMARDs, said Dr. Daniel H. Solomon of the divisions of phamacoepidemiology and rheumatology at Brigham and Women's Hospital, Boston, and his associates.

“Considering these results, in light of prior findings regarding improved insulin and glucose metabolism and reduced diabetes risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in diabetes prevention,” they noted.

The investigators assessed the relation between DMARDs and the risk of new-onset diabetes because previous studies have shown that inflammatory conditions such as RA and psoriasis predispose patients to insulin resistance, and that some of these anti-inflammatory medications appear to improve insulin resistance and prevent the onset of diabetes. They analyzed information from the databases of a Canadian health care system and a commercial U.S. health plan to identify 13,905 adults with RA or psoriasis who had filled at least one prescription for a DMARD and could be followed for 6 months.

The DMARDs were divided into four mutually exclusive groups: TNF inhibitors such as adalimumab, etanercept, or infliximab; methotrexate; hydroxychloroquine; and other nonbiologic DMARDs such as sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, 6-thioguanine, and the following gold preparations: auranofin, myochrysine, or solganol.

A total of 267 study subjects developed incident diabetes. The incidence was highest among patients who were taking nonbiologic DMARDs.

Patients taking a TNF inhibitor or hydroxychloroquine showed a reduced risk of diabetes, compared with patients taking any other agents. After accounting for the effects of potentially confounding factors such as patient age, sex, and several clinical variables, investigators found that the hazard ratios for diabetes were 0.62 for TNF inhibitors and 0.54 for hydroxychloroquine, compared with the nonbiologic DMARDs, Dr. Solomon and his colleagues said (JAMA 2011;305:2525-31).

“These findings held up across a variety of sensitivity analyses,” they added.

“Taken in the context of prior research, [our] study supports the potential role for systemic immunosuppression in prevention and control of diabetes. If future studies show this convincingly, systemic immunosuppression in such situations would be predicated on a favorable risk-benefit profile.”

For example, the benefit of immunosuppression may outweigh the risk in a patient with a systemic rheumatic disease for which a DMARD is already indicated. But immunosuppression may not outweigh the risk in a patient who already has diabetes and is prone to infection.

The investigators emphasized that this was an observational epidemiologic study, so causation cannot be inferred. “It is possible that patients receiving a TNF inhibitor or hydroxychloroquine were different from the reference group of other nonbiologic DMARD users in ways that went unmeasured, such as body mass index, exercise participation, family history, or disease severity,” they noted.

They added that the findings warrant study in a randomized, controlled trial to test “the ability of these agents to prevent diabetes among participants with systemic inflammatory disorders.”

Major Finding: The hazard ratios for diabetes were 0.62 for patients taking TNF inhibitors and 0.54 for patients taking hydroxychloroquine, compared with patients taking nonbiologic DMARDs to treat their rheumatoid arthritis or psoriasis.

Data Source: A retrospective observational study involving 13,905 adults who had either RA or psoriasis, received a DMARD, and were followed for approximately 6 months for the development of diabetes. Participants were enrolled in one of two health care systems.

Disclosures: This study was supported by Amgen. Dr. Solomon reported ties to Abbott, Amgen, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to numerous industry sources.

Some disease-modifying antirheumatic drugs that are taken for rheumatoid arthritis or psoriasis appear to reduce the rate of incident diabetes.

In a retrospective cohort study of patients who had RA or psoriasis, the use of a tumor necrosis factor (TNF) inhibitor or hydroxychloroquine to treat the systemic inflammatory disorder was associated with a reduced risk of developing diabetes, compared with the use of methotrexate or nonbiologic DMARDs, said Dr. Daniel H. Solomon of the divisions of phamacoepidemiology and rheumatology at Brigham and Women's Hospital, Boston, and his associates.

“Considering these results, in light of prior findings regarding improved insulin and glucose metabolism and reduced diabetes risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in diabetes prevention,” they noted.

The investigators assessed the relation between DMARDs and the risk of new-onset diabetes because previous studies have shown that inflammatory conditions such as RA and psoriasis predispose patients to insulin resistance, and that some of these anti-inflammatory medications appear to improve insulin resistance and prevent the onset of diabetes. They analyzed information from the databases of a Canadian health care system and a commercial U.S. health plan to identify 13,905 adults with RA or psoriasis who had filled at least one prescription for a DMARD and could be followed for 6 months.

The DMARDs were divided into four mutually exclusive groups: TNF inhibitors such as adalimumab, etanercept, or infliximab; methotrexate; hydroxychloroquine; and other nonbiologic DMARDs such as sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, 6-thioguanine, and the following gold preparations: auranofin, myochrysine, or solganol.

A total of 267 study subjects developed incident diabetes. The incidence was highest among patients who were taking nonbiologic DMARDs.

Patients taking a TNF inhibitor or hydroxychloroquine showed a reduced risk of diabetes, compared with patients taking any other agents. After accounting for the effects of potentially confounding factors such as patient age, sex, and several clinical variables, investigators found that the hazard ratios for diabetes were 0.62 for TNF inhibitors and 0.54 for hydroxychloroquine, compared with the nonbiologic DMARDs, Dr. Solomon and his colleagues said (JAMA 2011;305:2525-31).

“These findings held up across a variety of sensitivity analyses,” they added.

“Taken in the context of prior research, [our] study supports the potential role for systemic immunosuppression in prevention and control of diabetes. If future studies show this convincingly, systemic immunosuppression in such situations would be predicated on a favorable risk-benefit profile.”

For example, the benefit of immunosuppression may outweigh the risk in a patient with a systemic rheumatic disease for which a DMARD is already indicated. But immunosuppression may not outweigh the risk in a patient who already has diabetes and is prone to infection.

The investigators emphasized that this was an observational epidemiologic study, so causation cannot be inferred. “It is possible that patients receiving a TNF inhibitor or hydroxychloroquine were different from the reference group of other nonbiologic DMARD users in ways that went unmeasured, such as body mass index, exercise participation, family history, or disease severity,” they noted.

They added that the findings warrant study in a randomized, controlled trial to test “the ability of these agents to prevent diabetes among participants with systemic inflammatory disorders.”

Major Finding: The hazard ratios for diabetes were 0.62 for patients taking TNF inhibitors and 0.54 for patients taking hydroxychloroquine, compared with patients taking nonbiologic DMARDs to treat their rheumatoid arthritis or psoriasis.

Data Source: A retrospective observational study involving 13,905 adults who had either RA or psoriasis, received a DMARD, and were followed for approximately 6 months for the development of diabetes. Participants were enrolled in one of two health care systems.

Disclosures: This study was supported by Amgen. Dr. Solomon reported ties to Abbott, Amgen, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to numerous industry sources.

Some disease-modifying antirheumatic drugs that are taken for rheumatoid arthritis or psoriasis appear to reduce the rate of incident diabetes.

In a retrospective cohort study of patients who had RA or psoriasis, the use of a tumor necrosis factor (TNF) inhibitor or hydroxychloroquine to treat the systemic inflammatory disorder was associated with a reduced risk of developing diabetes, compared with the use of methotrexate or nonbiologic DMARDs, said Dr. Daniel H. Solomon of the divisions of phamacoepidemiology and rheumatology at Brigham and Women's Hospital, Boston, and his associates.

“Considering these results, in light of prior findings regarding improved insulin and glucose metabolism and reduced diabetes risk with hydroxychloroquine and TNF inhibitors, there is evidence suggesting a possible role for DMARDs and immunosuppression in diabetes prevention,” they noted.

The investigators assessed the relation between DMARDs and the risk of new-onset diabetes because previous studies have shown that inflammatory conditions such as RA and psoriasis predispose patients to insulin resistance, and that some of these anti-inflammatory medications appear to improve insulin resistance and prevent the onset of diabetes. They analyzed information from the databases of a Canadian health care system and a commercial U.S. health plan to identify 13,905 adults with RA or psoriasis who had filled at least one prescription for a DMARD and could be followed for 6 months.

The DMARDs were divided into four mutually exclusive groups: TNF inhibitors such as adalimumab, etanercept, or infliximab; methotrexate; hydroxychloroquine; and other nonbiologic DMARDs such as sulfasalazine, leflunomide, cyclosporine, azathioprine, cyclophosphamide, mycophenolate mofetil, 6-thioguanine, and the following gold preparations: auranofin, myochrysine, or solganol.

A total of 267 study subjects developed incident diabetes. The incidence was highest among patients who were taking nonbiologic DMARDs.

Patients taking a TNF inhibitor or hydroxychloroquine showed a reduced risk of diabetes, compared with patients taking any other agents. After accounting for the effects of potentially confounding factors such as patient age, sex, and several clinical variables, investigators found that the hazard ratios for diabetes were 0.62 for TNF inhibitors and 0.54 for hydroxychloroquine, compared with the nonbiologic DMARDs, Dr. Solomon and his colleagues said (JAMA 2011;305:2525-31).

“These findings held up across a variety of sensitivity analyses,” they added.

“Taken in the context of prior research, [our] study supports the potential role for systemic immunosuppression in prevention and control of diabetes. If future studies show this convincingly, systemic immunosuppression in such situations would be predicated on a favorable risk-benefit profile.”

For example, the benefit of immunosuppression may outweigh the risk in a patient with a systemic rheumatic disease for which a DMARD is already indicated. But immunosuppression may not outweigh the risk in a patient who already has diabetes and is prone to infection.

The investigators emphasized that this was an observational epidemiologic study, so causation cannot be inferred. “It is possible that patients receiving a TNF inhibitor or hydroxychloroquine were different from the reference group of other nonbiologic DMARD users in ways that went unmeasured, such as body mass index, exercise participation, family history, or disease severity,” they noted.

They added that the findings warrant study in a randomized, controlled trial to test “the ability of these agents to prevent diabetes among participants with systemic inflammatory disorders.”

Major Finding: Two additional cases of incident diabetes per 1,000 patient-years developed in subjects taking intensive statin therapy, compared with those taking moderate statin therapy.

Data Source: A meta-analysis of five large randomized controlled trials comparing intensive with moderate statin therapy in 32,752 participants who were followed for a mean of 5 years.

Disclosures: Dr. Preiss' associates reported ties to numerous industry sources.

The risk of developing type 2 diabetes rises with increasing doses of statin therapy, according to the findings of a large meta-analysis.

“Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy,” said Dr. David Preiss of the BHF Glasgow (Scotland) Cardiovascular Research Centre at the University of Glasgow, and his associates.

Several recent studies have suggested that statin therapy may raise the risk of diabetes, and some have indicated that the risk is higher at higher doses of the drugs.

Dr. Preiss and his colleagues conducted a meta-analysis of five large (at least 1,000 subjects each) randomized clinical trials that compared moderate-dose with intensive-dose statin therapy and followed patients for a minimum of 1 year. These trials were intended to compare cardiovascular outcomes, but they also tracked adverse events, blood glucose levels, and the use of diabetes medications, so cases of new-onset diabetes could be identified.

Overall, 32,752 subjects who did not have diabetes at baseline were followed for a mean of 5 years. During that time 2,749 subjects (8%) developed diabetes.

There were 149 more cases of diabetes among subjects taking intensive statin therapy than in those taking moderate statin therapy, for an odds ratio of 1.1.

“In absolute terms, there were two additional cases of diabetes per 1,000 patient-years among those receiving intensive-dose therapy (mean 18.9 cases per 1,000 patient-years with high-dose statin treatment vs. 16.9 cases per 1,000 patient-years with moderate-dose therapy), corresponding to a number needed to harm of 498 per year,” the investigators said.

This dose-response relation persisted across several subgroups of patients, regardless of age, HDL cholesterol level, body mass index, or fasting plasma glucose level at baseline. The dose-response relation also was comparable between subjects receiving simvastatin and those receiving atorvastatin, Dr. Preiss and his associates said (JAMA 2011;305:2556-64).

However, more intensive statin therapy also provided clear cardiovascular benefits compared with less intensive statin therapy. “When expressed in absolute terms, there was one additional case of diabetes for every 498 patients treated for 1 year, compared with one fewer patient experiencing a cardiovascular event for every 155 patients treated for 1 year,” they noted.

“We hypothesize that given that cardiovascular risk from diabetes is modest in the first decade after diagnosis, and as the benefit of statin therapy increases over time and in absolute terms with increasing age, net cardiovascular benefit in high-risk individuals will still strongly favor statin therapy,” the investigators said.

The mechanism by which statins raise diabetes risk is not known. The data on subgroups in this meta-analysis do not shed light on the issue since all subgroups were at comparable risk.

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Benefits Eclipse Rare Events

Over the many years of placebo-controlled statin trials, physicians have encountered inconsistent reports on the risk of new-onset diabetes with statins.

A recent meta-analysis of statin/placebo trials with 91,140 participants found a 9% increased risk of diabetes with number needed to harm, or cause one case of new-onset diabetes per year, as 1,020.

This new meta-analysis examining the dose-response association, giving the number needed to harm with intensive versus moderate dose statin therapy as 498 per year, with both high-dose simvastatin and atorvastatin associated with this effect.

What is clear from this meta-analysis is that the number needed to treat with higher-versus lower-dose statin to prevent cardiovascular events is 155 per year, which in subanalyses is significant for the more frequent nonfatal MI and coronary revascularizations but not for the fewer cardiovascular deaths and nonfatal strokes. This cardiovascular preventive effect of intensive versus moderate statin dosing was significant for atorvastatin but not for simvastatin. This plus the recent Food and Drug Administration recommendation to no longer increase simvastatin from 40 to 80 mg in those not attaining LDL cholesterol goals but to switch to another statin (see article on p. 11), suggests that use of 80-mg dose simvastatin for intensive statin-lowering therapy will decrease.

Although a mechanism for possible myocyte insensitivity to carbohydrate oxidation with the use of simvastatin has recently been shown (J. Physiol. 2009;587:219-30), thus increasing the probability of this association as causal, nonetheless, the absolute low frequency of new-onset diabetes of 1/500 to 1/1,000 per year, can be used to reassure worried patients that the greater cardiovascular preventive effects of statin therapy significantly outweigh the possible but much smaller risk of diabetes.

DONALD A. SMITH, M.D., M.P.H., is associate professor of medicine at Mount Sinai Medical Center, New York. He has no relevant disclosures.

Vitals

Major Finding: Two additional cases of incident diabetes per 1,000 patient-years developed in subjects taking intensive statin therapy, compared with those taking moderate statin therapy.

Data Source: A meta-analysis of five large randomized controlled trials comparing intensive with moderate statin therapy in 32,752 participants who were followed for a mean of 5 years.

Disclosures: Dr. Preiss' associates reported ties to numerous industry sources.

The risk of developing type 2 diabetes rises with increasing doses of statin therapy, according to the findings of a large meta-analysis.

“Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy,” said Dr. David Preiss of the BHF Glasgow (Scotland) Cardiovascular Research Centre at the University of Glasgow, and his associates.

Several recent studies have suggested that statin therapy may raise the risk of diabetes, and some have indicated that the risk is higher at higher doses of the drugs.

Dr. Preiss and his colleagues conducted a meta-analysis of five large (at least 1,000 subjects each) randomized clinical trials that compared moderate-dose with intensive-dose statin therapy and followed patients for a minimum of 1 year. These trials were intended to compare cardiovascular outcomes, but they also tracked adverse events, blood glucose levels, and the use of diabetes medications, so cases of new-onset diabetes could be identified.

Overall, 32,752 subjects who did not have diabetes at baseline were followed for a mean of 5 years. During that time 2,749 subjects (8%) developed diabetes.

There were 149 more cases of diabetes among subjects taking intensive statin therapy than in those taking moderate statin therapy, for an odds ratio of 1.1.

“In absolute terms, there were two additional cases of diabetes per 1,000 patient-years among those receiving intensive-dose therapy (mean 18.9 cases per 1,000 patient-years with high-dose statin treatment vs. 16.9 cases per 1,000 patient-years with moderate-dose therapy), corresponding to a number needed to harm of 498 per year,” the investigators said.

This dose-response relation persisted across several subgroups of patients, regardless of age, HDL cholesterol level, body mass index, or fasting plasma glucose level at baseline. The dose-response relation also was comparable between subjects receiving simvastatin and those receiving atorvastatin, Dr. Preiss and his associates said (JAMA 2011;305:2556-64).

However, more intensive statin therapy also provided clear cardiovascular benefits compared with less intensive statin therapy. “When expressed in absolute terms, there was one additional case of diabetes for every 498 patients treated for 1 year, compared with one fewer patient experiencing a cardiovascular event for every 155 patients treated for 1 year,” they noted.

“We hypothesize that given that cardiovascular risk from diabetes is modest in the first decade after diagnosis, and as the benefit of statin therapy increases over time and in absolute terms with increasing age, net cardiovascular benefit in high-risk individuals will still strongly favor statin therapy,” the investigators said.

The mechanism by which statins raise diabetes risk is not known. The data on subgroups in this meta-analysis do not shed light on the issue since all subgroups were at comparable risk.

View on The News

Benefits Eclipse Rare Events

Over the many years of placebo-controlled statin trials, physicians have encountered inconsistent reports on the risk of new-onset diabetes with statins.

A recent meta-analysis of statin/placebo trials with 91,140 participants found a 9% increased risk of diabetes with number needed to harm, or cause one case of new-onset diabetes per year, as 1,020.

This new meta-analysis examining the dose-response association, giving the number needed to harm with intensive versus moderate dose statin therapy as 498 per year, with both high-dose simvastatin and atorvastatin associated with this effect.

What is clear from this meta-analysis is that the number needed to treat with higher-versus lower-dose statin to prevent cardiovascular events is 155 per year, which in subanalyses is significant for the more frequent nonfatal MI and coronary revascularizations but not for the fewer cardiovascular deaths and nonfatal strokes. This cardiovascular preventive effect of intensive versus moderate statin dosing was significant for atorvastatin but not for simvastatin. This plus the recent Food and Drug Administration recommendation to no longer increase simvastatin from 40 to 80 mg in those not attaining LDL cholesterol goals but to switch to another statin (see article on p. 11), suggests that use of 80-mg dose simvastatin for intensive statin-lowering therapy will decrease.

Although a mechanism for possible myocyte insensitivity to carbohydrate oxidation with the use of simvastatin has recently been shown (J. Physiol. 2009;587:219-30), thus increasing the probability of this association as causal, nonetheless, the absolute low frequency of new-onset diabetes of 1/500 to 1/1,000 per year, can be used to reassure worried patients that the greater cardiovascular preventive effects of statin therapy significantly outweigh the possible but much smaller risk of diabetes.

DONALD A. SMITH, M.D., M.P.H., is associate professor of medicine at Mount Sinai Medical Center, New York. He has no relevant disclosures.

Vitals

Major Finding: Two additional cases of incident diabetes per 1,000 patient-years developed in subjects taking intensive statin therapy, compared with those taking moderate statin therapy.

Data Source: A meta-analysis of five large randomized controlled trials comparing intensive with moderate statin therapy in 32,752 participants who were followed for a mean of 5 years.

Disclosures: Dr. Preiss' associates reported ties to numerous industry sources.

The risk of developing type 2 diabetes rises with increasing doses of statin therapy, according to the findings of a large meta-analysis.

“Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy,” said Dr. David Preiss of the BHF Glasgow (Scotland) Cardiovascular Research Centre at the University of Glasgow, and his associates.

Several recent studies have suggested that statin therapy may raise the risk of diabetes, and some have indicated that the risk is higher at higher doses of the drugs.

Dr. Preiss and his colleagues conducted a meta-analysis of five large (at least 1,000 subjects each) randomized clinical trials that compared moderate-dose with intensive-dose statin therapy and followed patients for a minimum of 1 year. These trials were intended to compare cardiovascular outcomes, but they also tracked adverse events, blood glucose levels, and the use of diabetes medications, so cases of new-onset diabetes could be identified.

Overall, 32,752 subjects who did not have diabetes at baseline were followed for a mean of 5 years. During that time 2,749 subjects (8%) developed diabetes.

There were 149 more cases of diabetes among subjects taking intensive statin therapy than in those taking moderate statin therapy, for an odds ratio of 1.1.

“In absolute terms, there were two additional cases of diabetes per 1,000 patient-years among those receiving intensive-dose therapy (mean 18.9 cases per 1,000 patient-years with high-dose statin treatment vs. 16.9 cases per 1,000 patient-years with moderate-dose therapy), corresponding to a number needed to harm of 498 per year,” the investigators said.

This dose-response relation persisted across several subgroups of patients, regardless of age, HDL cholesterol level, body mass index, or fasting plasma glucose level at baseline. The dose-response relation also was comparable between subjects receiving simvastatin and those receiving atorvastatin, Dr. Preiss and his associates said (JAMA 2011;305:2556-64).

However, more intensive statin therapy also provided clear cardiovascular benefits compared with less intensive statin therapy. “When expressed in absolute terms, there was one additional case of diabetes for every 498 patients treated for 1 year, compared with one fewer patient experiencing a cardiovascular event for every 155 patients treated for 1 year,” they noted.

“We hypothesize that given that cardiovascular risk from diabetes is modest in the first decade after diagnosis, and as the benefit of statin therapy increases over time and in absolute terms with increasing age, net cardiovascular benefit in high-risk individuals will still strongly favor statin therapy,” the investigators said.

The mechanism by which statins raise diabetes risk is not known. The data on subgroups in this meta-analysis do not shed light on the issue since all subgroups were at comparable risk.

View on The News

Benefits Eclipse Rare Events

Over the many years of placebo-controlled statin trials, physicians have encountered inconsistent reports on the risk of new-onset diabetes with statins.

A recent meta-analysis of statin/placebo trials with 91,140 participants found a 9% increased risk of diabetes with number needed to harm, or cause one case of new-onset diabetes per year, as 1,020.

This new meta-analysis examining the dose-response association, giving the number needed to harm with intensive versus moderate dose statin therapy as 498 per year, with both high-dose simvastatin and atorvastatin associated with this effect.

What is clear from this meta-analysis is that the number needed to treat with higher-versus lower-dose statin to prevent cardiovascular events is 155 per year, which in subanalyses is significant for the more frequent nonfatal MI and coronary revascularizations but not for the fewer cardiovascular deaths and nonfatal strokes. This cardiovascular preventive effect of intensive versus moderate statin dosing was significant for atorvastatin but not for simvastatin. This plus the recent Food and Drug Administration recommendation to no longer increase simvastatin from 40 to 80 mg in those not attaining LDL cholesterol goals but to switch to another statin (see article on p. 11), suggests that use of 80-mg dose simvastatin for intensive statin-lowering therapy will decrease.

Although a mechanism for possible myocyte insensitivity to carbohydrate oxidation with the use of simvastatin has recently been shown (J. Physiol. 2009;587:219-30), thus increasing the probability of this association as causal, nonetheless, the absolute low frequency of new-onset diabetes of 1/500 to 1/1,000 per year, can be used to reassure worried patients that the greater cardiovascular preventive effects of statin therapy significantly outweigh the possible but much smaller risk of diabetes.

DONALD A. SMITH, M.D., M.P.H., is associate professor of medicine at Mount Sinai Medical Center, New York. He has no relevant disclosures.

Vitals

IUD insertion immediately after first-trimester induced or spontaneous abortion rather than at a later visit decreases the likelihood of unintended pregnancy 6 months later, without raising the risk of complications such as IUD expulsion, pelvic infection, or uterine perforation, according to a recent report.

“Mathematical modeling suggests that a switch from delayed IUD insertion to immediate insertion could prevent more than 70,000 unintended pregnancies annually in the United States. However, the availability of immediate IUD insertion is restricted by federal funding for contraceptive use … because the provision of contraceptive services on the day of an abortion in the same facility is prohibited.

“Such policies that require health care providers to separate contraception provision from abortion provision reduce the likelihood that women will obtain the contraception needed to prevent unintended pregnancy,” said Dr. Paula H. Bednarek of Oregon Health and Science University, Portland, and her associates.

The investigators compared outcomes between immediate and delayed IUD insertion following first-trimester uterine aspiration in a study of 575 women who were treated at four academic medical centers across the United States. All the women requested an IUD, and selected either a levonorgestrel-releasing IUD (Mirena) or a copper device (ParaGard T380A) before undergoing uterine aspiration for induced or spontaneous abortion at 5–12 weeks' gestation.

Before the procedure commenced, the study subjects were randomly assigned to either immediate IUD insertion (258 women) within 15 minutes after completion of the procedure, or delayed insertion (317 women) at a separate visit 2–6 weeks later. Women were excluded from the study “in cases of failure to confirm completion of the aspiration, hemorrhage, perforation, or any other condition that, in the opinion of the surgeon, precluded safe IUD insertion,” the researchers noted.

All the study subjects maintained daily diaries of bleeding; cramping or pain; and medication use from the day of the aspiration until 1 month after IUD insertion. They were followed at 1, 3, and 6 months after the procedure with review of the diary; completion of a questionnaire; physical examination; ultrasound verification of the location of the IUD; and assessment for infection, pain, bleeding, pregnancy, and other medical concerns.

IUDs were inserted in 100% of the immediate-insertion group, compared with only 71% of the delayed-insertion group. This was because 29% of the women in the delayed-insertion group never returned for their scheduled insertion visit.

“Our results confirm previously published data showing that 25%–68% of women who make an appointment for an IUD placement after an abortion do not return,” Dr. Bednarek and her colleagues said.

After 6 months, the rate of IUD use was significantly higher in the immediate-insertion group (92%) than in the delayed-insertion group (77%). Women in the delayed-insertion group who never received an IUD frequently reported that they were instead using much-less-effective forms of contraception such as condoms (32%), or no method at all (25%).

During follow-up, no pregnancies occurred in the immediate-insertion group, while five pregnancies occurred in the delayed-insertion group. All five occurred in women who were not using IUDs. “Although this difference was not statistically significant, our study was not powered for this outcome and involved only 6 months of follow-up. A greater cumulative effect would be expected over a longer period,” they noted (N. Engl. J. Med. 2011;364:2208–17).

Rates of IUD expulsions were low in both groups and not significantly different between the two groups, with a 5% rate in the immediate-insertion group and a 2.7% rate in the delayed-insertion group. Thus, immediate IUD insertion carried a slightly higher but statistically noninferior rate of expulsion than delayed IUD insertion.

Rates of other adverse events also were no different between the two groups. Rates of incomplete abortion requiring a repeat uterine aspiration were 0.8% with immediate insertion and 0.9% with delayed insertion. Rates of pelvic infection were 1.9% and 1.6%, respectively, and there were no cases of uterine perforation.

Pelvic infections were uncommon, even among women with a history of pelvic inflammatory disease and women who tested positive for chlamydia at the time of the procedure. “These findings support the expansion of access to IUDs after first-trimester uterine aspiration, including elimination of an additional visit to test for sexually transmitted infection when no infection is clinically evident.

“In addition, these data add to the growing body of evidence supporting the safety and effectiveness of IUD use among a wider range of women who previously may not have been considered good candidates for an IUD,” Dr. Bednarek and her associates said.

This study was limited in that there was substantial loss to follow-up in both groups of patients, with 27% of women in the immediate-insertion group and 25% of those in the delayed-insertion group dropping out of the study. “Ongoing contact with women who have undergone an abortion is difficult,” as many of them “have to travel a great distance to obtain an abortion and many wish to maintain their privacy,” they said.

This study was supported by grants from the Susan Thompson Buffett Foundation. Duramed Pharmaceuticals (now Teva Pharmaceuticals) donated the copper IUDs for this study. Dr. Bednarek reported ties to Bayer HealthCare Pharmaceuticals (maker of Mirena IUDs), Schering Plough (now merged with Merck), and Medicines 360 (a not-for-profit pharmaceutical company); her associates reported ties to Merck, Medicines 360, Duramed, Teva Women's Health Research, and others.

IUD insertion immediately after first-trimester induced or spontaneous abortion rather than at a later visit decreases the likelihood of unintended pregnancy 6 months later, without raising the risk of complications such as IUD expulsion, pelvic infection, or uterine perforation, according to a recent report.

“Mathematical modeling suggests that a switch from delayed IUD insertion to immediate insertion could prevent more than 70,000 unintended pregnancies annually in the United States. However, the availability of immediate IUD insertion is restricted by federal funding for contraceptive use … because the provision of contraceptive services on the day of an abortion in the same facility is prohibited.

“Such policies that require health care providers to separate contraception provision from abortion provision reduce the likelihood that women will obtain the contraception needed to prevent unintended pregnancy,” said Dr. Paula H. Bednarek of Oregon Health and Science University, Portland, and her associates.

The investigators compared outcomes between immediate and delayed IUD insertion following first-trimester uterine aspiration in a study of 575 women who were treated at four academic medical centers across the United States. All the women requested an IUD, and selected either a levonorgestrel-releasing IUD (Mirena) or a copper device (ParaGard T380A) before undergoing uterine aspiration for induced or spontaneous abortion at 5–12 weeks' gestation.

Before the procedure commenced, the study subjects were randomly assigned to either immediate IUD insertion (258 women) within 15 minutes after completion of the procedure, or delayed insertion (317 women) at a separate visit 2–6 weeks later. Women were excluded from the study “in cases of failure to confirm completion of the aspiration, hemorrhage, perforation, or any other condition that, in the opinion of the surgeon, precluded safe IUD insertion,” the researchers noted.

All the study subjects maintained daily diaries of bleeding; cramping or pain; and medication use from the day of the aspiration until 1 month after IUD insertion. They were followed at 1, 3, and 6 months after the procedure with review of the diary; completion of a questionnaire; physical examination; ultrasound verification of the location of the IUD; and assessment for infection, pain, bleeding, pregnancy, and other medical concerns.

IUDs were inserted in 100% of the immediate-insertion group, compared with only 71% of the delayed-insertion group. This was because 29% of the women in the delayed-insertion group never returned for their scheduled insertion visit.

“Our results confirm previously published data showing that 25%–68% of women who make an appointment for an IUD placement after an abortion do not return,” Dr. Bednarek and her colleagues said.

After 6 months, the rate of IUD use was significantly higher in the immediate-insertion group (92%) than in the delayed-insertion group (77%). Women in the delayed-insertion group who never received an IUD frequently reported that they were instead using much-less-effective forms of contraception such as condoms (32%), or no method at all (25%).

During follow-up, no pregnancies occurred in the immediate-insertion group, while five pregnancies occurred in the delayed-insertion group. All five occurred in women who were not using IUDs. “Although this difference was not statistically significant, our study was not powered for this outcome and involved only 6 months of follow-up. A greater cumulative effect would be expected over a longer period,” they noted (N. Engl. J. Med. 2011;364:2208–17).

Rates of IUD expulsions were low in both groups and not significantly different between the two groups, with a 5% rate in the immediate-insertion group and a 2.7% rate in the delayed-insertion group. Thus, immediate IUD insertion carried a slightly higher but statistically noninferior rate of expulsion than delayed IUD insertion.

Rates of other adverse events also were no different between the two groups. Rates of incomplete abortion requiring a repeat uterine aspiration were 0.8% with immediate insertion and 0.9% with delayed insertion. Rates of pelvic infection were 1.9% and 1.6%, respectively, and there were no cases of uterine perforation.

Pelvic infections were uncommon, even among women with a history of pelvic inflammatory disease and women who tested positive for chlamydia at the time of the procedure. “These findings support the expansion of access to IUDs after first-trimester uterine aspiration, including elimination of an additional visit to test for sexually transmitted infection when no infection is clinically evident.

“In addition, these data add to the growing body of evidence supporting the safety and effectiveness of IUD use among a wider range of women who previously may not have been considered good candidates for an IUD,” Dr. Bednarek and her associates said.

This study was limited in that there was substantial loss to follow-up in both groups of patients, with 27% of women in the immediate-insertion group and 25% of those in the delayed-insertion group dropping out of the study. “Ongoing contact with women who have undergone an abortion is difficult,” as many of them “have to travel a great distance to obtain an abortion and many wish to maintain their privacy,” they said.

This study was supported by grants from the Susan Thompson Buffett Foundation. Duramed Pharmaceuticals (now Teva Pharmaceuticals) donated the copper IUDs for this study. Dr. Bednarek reported ties to Bayer HealthCare Pharmaceuticals (maker of Mirena IUDs), Schering Plough (now merged with Merck), and Medicines 360 (a not-for-profit pharmaceutical company); her associates reported ties to Merck, Medicines 360, Duramed, Teva Women's Health Research, and others.

IUD insertion immediately after first-trimester induced or spontaneous abortion rather than at a later visit decreases the likelihood of unintended pregnancy 6 months later, without raising the risk of complications such as IUD expulsion, pelvic infection, or uterine perforation, according to a recent report.

“Mathematical modeling suggests that a switch from delayed IUD insertion to immediate insertion could prevent more than 70,000 unintended pregnancies annually in the United States. However, the availability of immediate IUD insertion is restricted by federal funding for contraceptive use … because the provision of contraceptive services on the day of an abortion in the same facility is prohibited.

“Such policies that require health care providers to separate contraception provision from abortion provision reduce the likelihood that women will obtain the contraception needed to prevent unintended pregnancy,” said Dr. Paula H. Bednarek of Oregon Health and Science University, Portland, and her associates.

The investigators compared outcomes between immediate and delayed IUD insertion following first-trimester uterine aspiration in a study of 575 women who were treated at four academic medical centers across the United States. All the women requested an IUD, and selected either a levonorgestrel-releasing IUD (Mirena) or a copper device (ParaGard T380A) before undergoing uterine aspiration for induced or spontaneous abortion at 5–12 weeks' gestation.

Before the procedure commenced, the study subjects were randomly assigned to either immediate IUD insertion (258 women) within 15 minutes after completion of the procedure, or delayed insertion (317 women) at a separate visit 2–6 weeks later. Women were excluded from the study “in cases of failure to confirm completion of the aspiration, hemorrhage, perforation, or any other condition that, in the opinion of the surgeon, precluded safe IUD insertion,” the researchers noted.

All the study subjects maintained daily diaries of bleeding; cramping or pain; and medication use from the day of the aspiration until 1 month after IUD insertion. They were followed at 1, 3, and 6 months after the procedure with review of the diary; completion of a questionnaire; physical examination; ultrasound verification of the location of the IUD; and assessment for infection, pain, bleeding, pregnancy, and other medical concerns.

IUDs were inserted in 100% of the immediate-insertion group, compared with only 71% of the delayed-insertion group. This was because 29% of the women in the delayed-insertion group never returned for their scheduled insertion visit.

“Our results confirm previously published data showing that 25%–68% of women who make an appointment for an IUD placement after an abortion do not return,” Dr. Bednarek and her colleagues said.

After 6 months, the rate of IUD use was significantly higher in the immediate-insertion group (92%) than in the delayed-insertion group (77%). Women in the delayed-insertion group who never received an IUD frequently reported that they were instead using much-less-effective forms of contraception such as condoms (32%), or no method at all (25%).

During follow-up, no pregnancies occurred in the immediate-insertion group, while five pregnancies occurred in the delayed-insertion group. All five occurred in women who were not using IUDs. “Although this difference was not statistically significant, our study was not powered for this outcome and involved only 6 months of follow-up. A greater cumulative effect would be expected over a longer period,” they noted (N. Engl. J. Med. 2011;364:2208–17).

Rates of IUD expulsions were low in both groups and not significantly different between the two groups, with a 5% rate in the immediate-insertion group and a 2.7% rate in the delayed-insertion group. Thus, immediate IUD insertion carried a slightly higher but statistically noninferior rate of expulsion than delayed IUD insertion.

Rates of other adverse events also were no different between the two groups. Rates of incomplete abortion requiring a repeat uterine aspiration were 0.8% with immediate insertion and 0.9% with delayed insertion. Rates of pelvic infection were 1.9% and 1.6%, respectively, and there were no cases of uterine perforation.

Pelvic infections were uncommon, even among women with a history of pelvic inflammatory disease and women who tested positive for chlamydia at the time of the procedure. “These findings support the expansion of access to IUDs after first-trimester uterine aspiration, including elimination of an additional visit to test for sexually transmitted infection when no infection is clinically evident.

“In addition, these data add to the growing body of evidence supporting the safety and effectiveness of IUD use among a wider range of women who previously may not have been considered good candidates for an IUD,” Dr. Bednarek and her associates said.

This study was limited in that there was substantial loss to follow-up in both groups of patients, with 27% of women in the immediate-insertion group and 25% of those in the delayed-insertion group dropping out of the study. “Ongoing contact with women who have undergone an abortion is difficult,” as many of them “have to travel a great distance to obtain an abortion and many wish to maintain their privacy,” they said.

This study was supported by grants from the Susan Thompson Buffett Foundation. Duramed Pharmaceuticals (now Teva Pharmaceuticals) donated the copper IUDs for this study. Dr. Bednarek reported ties to Bayer HealthCare Pharmaceuticals (maker of Mirena IUDs), Schering Plough (now merged with Merck), and Medicines 360 (a not-for-profit pharmaceutical company); her associates reported ties to Merck, Medicines 360, Duramed, Teva Women's Health Research, and others.