Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.

The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.

©SilverV/Thinkstock.com

Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.

The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.

The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).

Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.

“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.

The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.

Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.

The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.

©SilverV/Thinkstock.com

Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.

The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.

The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).

Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.

“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.

The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.

Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.

The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.

©SilverV/Thinkstock.com

Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.

The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.

The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).

Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.

“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.

The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.

A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.

Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.

The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.

Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).

The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.

To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).

This survival benefit was independent of many known risk factors, including tumor grade, they noted.

These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.

This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.

A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.

Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.

The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.

Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).

The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.

To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).

This survival benefit was independent of many known risk factors, including tumor grade, they noted.

These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.

This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.

A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.

Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.

The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.

Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).

The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.

To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).

This survival benefit was independent of many known risk factors, including tumor grade, they noted.

These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.

This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

SNOWMASS, COLO. – It’s time to eliminate the practice of prescribing aspirin for stroke prevention in patients with atrial fibrillation and a CHA₂DS₂-VASc score of 1, two eminent cardiologists agreed at the Annual Cardiovascular Conference at Snowmass.

“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current U.S. guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” predicted Dr. Bernard J. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

“It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation,” he declared.

Dr. N.A. Mark Estes III agreed the aspirin evidence is seriously flawed.

“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” according to Dr. Estes, a past president of the Heart Rhythm Society who is professor of medicine and director of the New England Cardiac Arrhythmia Center at Tufts University, Boston.

The sole positive clinical trial of aspirin versus placebo, the 25-year-old Stroke Prevention in Atrial Fibrillation (SPAF) study (Circulation. 1991 Aug;84[2]:527-39), found an unrealistically high stroke protection benefit for aspirin, a result made implausible by multiple other randomized trials showing no benefit, the cardiologists agreed.

“In our current guidelines for atrial fibrillation (Circulation. 2014 Dec 2;130[23]:2071-104), aspirin can be considered as a Class IIb level of evidence C recommendation in patients with a CHA₂DS₂-VASc of 1. But I would just take it off of your clinical armamentarium because the best available data indicates that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA₂DS₂-VASc of 1, I’m discussing the risks and benefits of a NOAC [novel oral anticoagulant],” Dr. Estes said.

Dr. Gersh was also critical of another common practice in stroke prevention in atrial fibrillation: concomitant use of aspirin with an oral anticoagulant.

“We use too much aspirin in patients on oral anticoagulation. Aspirin is perhaps the major cause of bleeding in patients on an oral anticoagulant. Other than in people with a drug-eluting stent, there’s no role at all for aspirin in stroke prevention,” he asserted.

He was coauthor of an analysis of 7,347 participants in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) who were on an oral anticoagulant. Fully 35% of them were also on aspirin. In a multivariate analysis, concomitant aspirin and oral anticoagulation was independently associated with a 53% increased risk of major bleeding and a 52% increase in hospitalization for bleeding, compared with atrial fibrillation patients on an oral anticoagulant alone (Circulation. 2013 Aug 13;128[7]:721-8).

Moreover, the widespread use of dual therapy in this real-world registry didn’t appear to be rational. Thirty-nine percent of those on aspirin plus an oral anticoagulant had no history of atherosclerotic disease, the presence of which would be an indication for considering aspirin. And 17% of dual therapy patients had an elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score of 5 or more, making dual therapy particularly risky.

This clinically important interaction between aspirin and oral anticoagulation was recently underscored in an analysis of rivaroxaban-treated patients in the ROCKET AF trial, Dr. Gersh observed. Long-term use of aspirin at entry into this pivotal randomized trial of rivaroxaban (Xarelto) versus warfarin in patients with atrial fibrillation proved to be an independent predictor of a 47% increase in the risk of gastrointestinal bleeding, compared with patients on rivaroxaban alone (J Am Coll Cardiol. 2015 Dec 1;66[21]:2271-81).

He added that there is no evidence that combining aspirin and oral anticoagulation enhances stroke prevention beyond the marked benefit achieved with oral anticoagulation alone.

Dr. Gersh reported serving on the leadership of the ORBIT-AF Registry, which was sponsored by Janssen Pharmaceuticals. Dr. Estes reported having no financial conflicts relevant to this discussion.

[email protected]

SNOWMASS, COLO. – It’s time to eliminate the practice of prescribing aspirin for stroke prevention in patients with atrial fibrillation and a CHA₂DS₂-VASc score of 1, two eminent cardiologists agreed at the Annual Cardiovascular Conference at Snowmass.

“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current U.S. guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” predicted Dr. Bernard J. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

“It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation,” he declared.

Dr. N.A. Mark Estes III agreed the aspirin evidence is seriously flawed.

“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” according to Dr. Estes, a past president of the Heart Rhythm Society who is professor of medicine and director of the New England Cardiac Arrhythmia Center at Tufts University, Boston.

The sole positive clinical trial of aspirin versus placebo, the 25-year-old Stroke Prevention in Atrial Fibrillation (SPAF) study (Circulation. 1991 Aug;84[2]:527-39), found an unrealistically high stroke protection benefit for aspirin, a result made implausible by multiple other randomized trials showing no benefit, the cardiologists agreed.

“In our current guidelines for atrial fibrillation (Circulation. 2014 Dec 2;130[23]:2071-104), aspirin can be considered as a Class IIb level of evidence C recommendation in patients with a CHA₂DS₂-VASc of 1. But I would just take it off of your clinical armamentarium because the best available data indicates that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA₂DS₂-VASc of 1, I’m discussing the risks and benefits of a NOAC [novel oral anticoagulant],” Dr. Estes said.

Dr. Gersh was also critical of another common practice in stroke prevention in atrial fibrillation: concomitant use of aspirin with an oral anticoagulant.

“We use too much aspirin in patients on oral anticoagulation. Aspirin is perhaps the major cause of bleeding in patients on an oral anticoagulant. Other than in people with a drug-eluting stent, there’s no role at all for aspirin in stroke prevention,” he asserted.

He was coauthor of an analysis of 7,347 participants in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) who were on an oral anticoagulant. Fully 35% of them were also on aspirin. In a multivariate analysis, concomitant aspirin and oral anticoagulation was independently associated with a 53% increased risk of major bleeding and a 52% increase in hospitalization for bleeding, compared with atrial fibrillation patients on an oral anticoagulant alone (Circulation. 2013 Aug 13;128[7]:721-8).

Moreover, the widespread use of dual therapy in this real-world registry didn’t appear to be rational. Thirty-nine percent of those on aspirin plus an oral anticoagulant had no history of atherosclerotic disease, the presence of which would be an indication for considering aspirin. And 17% of dual therapy patients had an elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score of 5 or more, making dual therapy particularly risky.

This clinically important interaction between aspirin and oral anticoagulation was recently underscored in an analysis of rivaroxaban-treated patients in the ROCKET AF trial, Dr. Gersh observed. Long-term use of aspirin at entry into this pivotal randomized trial of rivaroxaban (Xarelto) versus warfarin in patients with atrial fibrillation proved to be an independent predictor of a 47% increase in the risk of gastrointestinal bleeding, compared with patients on rivaroxaban alone (J Am Coll Cardiol. 2015 Dec 1;66[21]:2271-81).

He added that there is no evidence that combining aspirin and oral anticoagulation enhances stroke prevention beyond the marked benefit achieved with oral anticoagulation alone.

Dr. Gersh reported serving on the leadership of the ORBIT-AF Registry, which was sponsored by Janssen Pharmaceuticals. Dr. Estes reported having no financial conflicts relevant to this discussion.

[email protected]

SNOWMASS, COLO. – It’s time to eliminate the practice of prescribing aspirin for stroke prevention in patients with atrial fibrillation and a CHA₂DS₂-VASc score of 1, two eminent cardiologists agreed at the Annual Cardiovascular Conference at Snowmass.

“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current U.S. guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” predicted Dr. Bernard J. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

“It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation,” he declared.

Dr. N.A. Mark Estes III agreed the aspirin evidence is seriously flawed.

“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” according to Dr. Estes, a past president of the Heart Rhythm Society who is professor of medicine and director of the New England Cardiac Arrhythmia Center at Tufts University, Boston.

The sole positive clinical trial of aspirin versus placebo, the 25-year-old Stroke Prevention in Atrial Fibrillation (SPAF) study (Circulation. 1991 Aug;84[2]:527-39), found an unrealistically high stroke protection benefit for aspirin, a result made implausible by multiple other randomized trials showing no benefit, the cardiologists agreed.

“In our current guidelines for atrial fibrillation (Circulation. 2014 Dec 2;130[23]:2071-104), aspirin can be considered as a Class IIb level of evidence C recommendation in patients with a CHA₂DS₂-VASc of 1. But I would just take it off of your clinical armamentarium because the best available data indicates that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA₂DS₂-VASc of 1, I’m discussing the risks and benefits of a NOAC [novel oral anticoagulant],” Dr. Estes said.

Dr. Gersh was also critical of another common practice in stroke prevention in atrial fibrillation: concomitant use of aspirin with an oral anticoagulant.

“We use too much aspirin in patients on oral anticoagulation. Aspirin is perhaps the major cause of bleeding in patients on an oral anticoagulant. Other than in people with a drug-eluting stent, there’s no role at all for aspirin in stroke prevention,” he asserted.

He was coauthor of an analysis of 7,347 participants in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) who were on an oral anticoagulant. Fully 35% of them were also on aspirin. In a multivariate analysis, concomitant aspirin and oral anticoagulation was independently associated with a 53% increased risk of major bleeding and a 52% increase in hospitalization for bleeding, compared with atrial fibrillation patients on an oral anticoagulant alone (Circulation. 2013 Aug 13;128[7]:721-8).

Moreover, the widespread use of dual therapy in this real-world registry didn’t appear to be rational. Thirty-nine percent of those on aspirin plus an oral anticoagulant had no history of atherosclerotic disease, the presence of which would be an indication for considering aspirin. And 17% of dual therapy patients had an elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score of 5 or more, making dual therapy particularly risky.

This clinically important interaction between aspirin and oral anticoagulation was recently underscored in an analysis of rivaroxaban-treated patients in the ROCKET AF trial, Dr. Gersh observed. Long-term use of aspirin at entry into this pivotal randomized trial of rivaroxaban (Xarelto) versus warfarin in patients with atrial fibrillation proved to be an independent predictor of a 47% increase in the risk of gastrointestinal bleeding, compared with patients on rivaroxaban alone (J Am Coll Cardiol. 2015 Dec 1;66[21]:2271-81).

He added that there is no evidence that combining aspirin and oral anticoagulation enhances stroke prevention beyond the marked benefit achieved with oral anticoagulation alone.

Dr. Gersh reported serving on the leadership of the ORBIT-AF Registry, which was sponsored by Janssen Pharmaceuticals. Dr. Estes reported having no financial conflicts relevant to this discussion.

[email protected]

When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.

In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.

In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.

For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.

When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.

In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.

In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.

For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.

When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.

In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.

In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.

For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.

Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).

Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.

What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.

Risks and causes

Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.

Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.

Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.

As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).

The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).

A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).

In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).

A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).

Work-up and prevention

Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.

Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.

In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.

Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).

When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.

Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.

In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).

A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.

Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.

In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.

For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).

Current research

One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).

Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).

In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.

Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.

Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).

The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.

Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.

Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).

Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.

What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.

Risks and causes

Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.

Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.

Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.

As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).

The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).

A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).

In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).

A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).

Work-up and prevention

Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.

Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.

In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.

Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).

When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.

Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.

In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).

A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.

Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.

In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.

For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).

Current research

One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).

Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).

In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.

Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.

Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).

The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.

Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.

Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).

Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.

What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.

Risks and causes

Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.

Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.

Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.

As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).

The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).

A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).

In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).

A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).

Work-up and prevention

Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.

Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.

In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.

Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).

When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.

Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.

In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).

A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.

Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.

In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.

For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).

Current research

One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).

Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).

In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.

Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.

Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).

The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.

Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.

Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study conducted in acute care settings.

The findings could have important implications for combating inappropriate antibiotic use and emerging antibiotic resistance, Dr. Ephraim L. Tsalik of the department of medicine at Duke University, Durham, N.C., and his colleagues reported online Jan. 20 in Science Translational Medicine.

©Kativ/iStockphoto

The investigators analyzed peripheral whole-blood gene expression from 273 subjects with community-onset viral ARI (115 subjects), bacterial ARI (70 subjects), or noninfectious illness (88 subjects) who were seen in an emergency department, and from 44 healthy control subjects. Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were developed, and were 87% accurate overall (Sci Transl Med. 2016;8[322]:322ra11. doi/ 10.1126/scitranslmed.aad6873).

“Bacterial ARI was identified in 83% of patients and excluded in 94% without bacterial infection. Viral ARI was identified in 90% and excluded in 92% of cases. Using the noninfectious illness classifier, infection was excluded in 86% of cases,” they wrote.

The classifiers were more accurate than procalcitonin – a widely used biomarker with some specificity for bacterial infection (86% vs. 78% accuracy in 238 available samples), and three published classifiers of bacterial vs. viral infection, and were validated in five publicly available data sets, they noted.

The gene signature patterns identified in the course of this study mark an important step toward development of a rapid blood test that could be used in clinics to guide appropriate treatment for ARIs, the investigators said.

Precision treatment of viruses

More precise ways to distinguish infections could reduce unnecessary antibiotic use and lead to more precise treatment of viruses, senior author Dr. Geoffrey S. Ginsburg, director of Duke’s Center for Applied Genomics & Precision Medicine, said in a press statement.

“Right now, we can give patients [oseltamivir] Tamiflu to help them recover from an influenza infection, but for most viral infections, the treatment is fluids and rest until it resolves. In the next 5-10 years, we will likely see new antiviral medications for common bugs like respiratory syncytial virus and even rhinovirus, and guiding treatment choices will be even more important,” he added.

Senior author Dr. Christopher W. Woods, also of Duke University, further explained in an interview that the findings are particularly exciting because “there isn’t much out there that accomplishes what we’ve done. So just about any level of accuracy is an improvement.” Further, he said the test is “a tool to aid in diagnosis, used in conjunction with the patient’s symptoms, examination, and other testing. So an imperfect test is okay, because it does not stand alone.”

Next steps include putting the assay on a testing platform that can be used at the point of care, and validating the findings in all populations, including infants, the elderly, and across ethnic groups, he said.

“The work is ongoing, and we expect to have results available within the course of an outpatient visit in the near future,” Dr. Woods, also a professor of medicine and global health, added, noting that efforts also are underway to “expand the repertoire of this approach to many different types of viral and bacterial infections and also to fungal infections, and to address the challenges of critically ill patients in intensive care units.”

This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests.

[email protected]

Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study conducted in acute care settings.

The findings could have important implications for combating inappropriate antibiotic use and emerging antibiotic resistance, Dr. Ephraim L. Tsalik of the department of medicine at Duke University, Durham, N.C., and his colleagues reported online Jan. 20 in Science Translational Medicine.

©Kativ/iStockphoto

The investigators analyzed peripheral whole-blood gene expression from 273 subjects with community-onset viral ARI (115 subjects), bacterial ARI (70 subjects), or noninfectious illness (88 subjects) who were seen in an emergency department, and from 44 healthy control subjects. Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were developed, and were 87% accurate overall (Sci Transl Med. 2016;8[322]:322ra11. doi/ 10.1126/scitranslmed.aad6873).

“Bacterial ARI was identified in 83% of patients and excluded in 94% without bacterial infection. Viral ARI was identified in 90% and excluded in 92% of cases. Using the noninfectious illness classifier, infection was excluded in 86% of cases,” they wrote.

The classifiers were more accurate than procalcitonin – a widely used biomarker with some specificity for bacterial infection (86% vs. 78% accuracy in 238 available samples), and three published classifiers of bacterial vs. viral infection, and were validated in five publicly available data sets, they noted.

The gene signature patterns identified in the course of this study mark an important step toward development of a rapid blood test that could be used in clinics to guide appropriate treatment for ARIs, the investigators said.

Precision treatment of viruses

More precise ways to distinguish infections could reduce unnecessary antibiotic use and lead to more precise treatment of viruses, senior author Dr. Geoffrey S. Ginsburg, director of Duke’s Center for Applied Genomics & Precision Medicine, said in a press statement.

“Right now, we can give patients [oseltamivir] Tamiflu to help them recover from an influenza infection, but for most viral infections, the treatment is fluids and rest until it resolves. In the next 5-10 years, we will likely see new antiviral medications for common bugs like respiratory syncytial virus and even rhinovirus, and guiding treatment choices will be even more important,” he added.

Senior author Dr. Christopher W. Woods, also of Duke University, further explained in an interview that the findings are particularly exciting because “there isn’t much out there that accomplishes what we’ve done. So just about any level of accuracy is an improvement.” Further, he said the test is “a tool to aid in diagnosis, used in conjunction with the patient’s symptoms, examination, and other testing. So an imperfect test is okay, because it does not stand alone.”

Next steps include putting the assay on a testing platform that can be used at the point of care, and validating the findings in all populations, including infants, the elderly, and across ethnic groups, he said.

“The work is ongoing, and we expect to have results available within the course of an outpatient visit in the near future,” Dr. Woods, also a professor of medicine and global health, added, noting that efforts also are underway to “expand the repertoire of this approach to many different types of viral and bacterial infections and also to fungal infections, and to address the challenges of critically ill patients in intensive care units.”

This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests.

[email protected]

Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study conducted in acute care settings.

The findings could have important implications for combating inappropriate antibiotic use and emerging antibiotic resistance, Dr. Ephraim L. Tsalik of the department of medicine at Duke University, Durham, N.C., and his colleagues reported online Jan. 20 in Science Translational Medicine.

©Kativ/iStockphoto

The investigators analyzed peripheral whole-blood gene expression from 273 subjects with community-onset viral ARI (115 subjects), bacterial ARI (70 subjects), or noninfectious illness (88 subjects) who were seen in an emergency department, and from 44 healthy control subjects. Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were developed, and were 87% accurate overall (Sci Transl Med. 2016;8[322]:322ra11. doi/ 10.1126/scitranslmed.aad6873).

“Bacterial ARI was identified in 83% of patients and excluded in 94% without bacterial infection. Viral ARI was identified in 90% and excluded in 92% of cases. Using the noninfectious illness classifier, infection was excluded in 86% of cases,” they wrote.

The classifiers were more accurate than procalcitonin – a widely used biomarker with some specificity for bacterial infection (86% vs. 78% accuracy in 238 available samples), and three published classifiers of bacterial vs. viral infection, and were validated in five publicly available data sets, they noted.

The gene signature patterns identified in the course of this study mark an important step toward development of a rapid blood test that could be used in clinics to guide appropriate treatment for ARIs, the investigators said.

Precision treatment of viruses

More precise ways to distinguish infections could reduce unnecessary antibiotic use and lead to more precise treatment of viruses, senior author Dr. Geoffrey S. Ginsburg, director of Duke’s Center for Applied Genomics & Precision Medicine, said in a press statement.

“Right now, we can give patients [oseltamivir] Tamiflu to help them recover from an influenza infection, but for most viral infections, the treatment is fluids and rest until it resolves. In the next 5-10 years, we will likely see new antiviral medications for common bugs like respiratory syncytial virus and even rhinovirus, and guiding treatment choices will be even more important,” he added.

Senior author Dr. Christopher W. Woods, also of Duke University, further explained in an interview that the findings are particularly exciting because “there isn’t much out there that accomplishes what we’ve done. So just about any level of accuracy is an improvement.” Further, he said the test is “a tool to aid in diagnosis, used in conjunction with the patient’s symptoms, examination, and other testing. So an imperfect test is okay, because it does not stand alone.”

Next steps include putting the assay on a testing platform that can be used at the point of care, and validating the findings in all populations, including infants, the elderly, and across ethnic groups, he said.

“The work is ongoing, and we expect to have results available within the course of an outpatient visit in the near future,” Dr. Woods, also a professor of medicine and global health, added, noting that efforts also are underway to “expand the repertoire of this approach to many different types of viral and bacterial infections and also to fungal infections, and to address the challenges of critically ill patients in intensive care units.”

This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests.

[email protected]

Everolimus improves outcomes in patients with advanced, progressive neuroendocrine tumors of gastrointestinal (GI) or unknown origin regardless of primary location and prior therapy, according to new subgroup analyses of the RADIANT-4 trial.

The phase III trial is the largest of its type in patients with nonfunctioning GI tract or lung neuroendocrine tumors. The subgroup findings for those whose tumors originated in the GI tract or an unknown site (but suspected to be GI) were presented in a presscast held in advance of the Gastrointestinal Cancers Symposium.

Compared with placebo, everolimus prolonged progression-free survival by 6-9 months, corresponding to a 46%-48% relative reduction in the risk of progression or death, reported lead study author Dr. Simron Singh of Sunnybrook’s Odette Cancer Centre in Toronto. Benefit was similar regardless of whether patients had midgut or non-midgut tumors, and whether they had previously received a somatostatin analog or not.

“In my opinion, this study in advanced, progressive neuroendocrine patients [shows] an effective, new and exciting treatment option in a disease where we’ve had very few treatments to date,” Dr. Singh said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, agreed, saying that everolimus could help address an unmet need in this disease.

“Patients with GI neuroendocrine tumors have had very few treatment options. Once they have progressed on somatostatin analogues, there really are no good systemic treatments,” she said. “So this finding is very important, that the mTOR inhibitor everolimus has demonstrated an improvement in risk of progression by over 40% and with very little severe toxicity. This is a welcome finding for these patients who have limited systemic treatment options.”

Patients enrolled in RADIANT-4 had lung, GI, or unknown-origin neuroendocrine tumors that had progressed on other therapies, including somatostatin analogs, surgery, or chemotherapy.

They were randomly assigned in 2:1 ratio to receive everolimus (Afinitor) or placebo, each in addition to best supportive care. Everolimus is currently approved by the Food and Drug Administration for the treatment of pancreatic neuroendocrine tumors, as well as breast and kidney cancer, and subependymal giant cell astrocytoma.

Results for the entire trial population have been previously reported and showed that everolimus prolonged progression-free survival by 7.1 months, reducing the risk of events by 52% (Lancet. 2015 Dec 15. doi.org/10.1016/S0140-6736[15]01234-9).

The new subgroup analyses were restricted to the patients with tumors originating in the GI tract (n =175) or an unknown site generally thought to be the GI tract (n = 36).

Among the group with GI tumors, median progression-free survival was 13.1 months with everolimus versus 5.4 months with placebo, Dr. Singh reported. Among the group with tumors of unknown origin, it was 13.6 and 7.5 months, respectively.

Relative to placebo, everolimus prolonged progression-free survival by 6.41 months, reducing the risk of events by 29%, in patients whose tumors originated in the midgut (duodenum, ileum, jejunum, cecum, or appendix). The relative benefit was 6.17 months, with a reduction in the risk of events of 73%, in patients whose tumors originated in non-midgut sites (stomach, colon, and rectum).

In addition, everolimus prolonged progression-free survival by 6.73 months, reducing the risk of events by 46%, in patients who had previously received somatostatin analogues, and by 9.07 months, reducing the risk by 48%, in patients who had not received these agents.

The safety profile of everolimus was consistent with that expected based on the use of this agent in other patient populations, according to Dr. Singh. The most common adverse events were stomatitis, infections, diarrhea, peripheral edema, and fatigue. No new safety signals were seen.

Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.

Everolimus improves outcomes in patients with advanced, progressive neuroendocrine tumors of gastrointestinal (GI) or unknown origin regardless of primary location and prior therapy, according to new subgroup analyses of the RADIANT-4 trial.

The phase III trial is the largest of its type in patients with nonfunctioning GI tract or lung neuroendocrine tumors. The subgroup findings for those whose tumors originated in the GI tract or an unknown site (but suspected to be GI) were presented in a presscast held in advance of the Gastrointestinal Cancers Symposium.

Compared with placebo, everolimus prolonged progression-free survival by 6-9 months, corresponding to a 46%-48% relative reduction in the risk of progression or death, reported lead study author Dr. Simron Singh of Sunnybrook’s Odette Cancer Centre in Toronto. Benefit was similar regardless of whether patients had midgut or non-midgut tumors, and whether they had previously received a somatostatin analog or not.

“In my opinion, this study in advanced, progressive neuroendocrine patients [shows] an effective, new and exciting treatment option in a disease where we’ve had very few treatments to date,” Dr. Singh said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, agreed, saying that everolimus could help address an unmet need in this disease.

“Patients with GI neuroendocrine tumors have had very few treatment options. Once they have progressed on somatostatin analogues, there really are no good systemic treatments,” she said. “So this finding is very important, that the mTOR inhibitor everolimus has demonstrated an improvement in risk of progression by over 40% and with very little severe toxicity. This is a welcome finding for these patients who have limited systemic treatment options.”

Patients enrolled in RADIANT-4 had lung, GI, or unknown-origin neuroendocrine tumors that had progressed on other therapies, including somatostatin analogs, surgery, or chemotherapy.

They were randomly assigned in 2:1 ratio to receive everolimus (Afinitor) or placebo, each in addition to best supportive care. Everolimus is currently approved by the Food and Drug Administration for the treatment of pancreatic neuroendocrine tumors, as well as breast and kidney cancer, and subependymal giant cell astrocytoma.

Results for the entire trial population have been previously reported and showed that everolimus prolonged progression-free survival by 7.1 months, reducing the risk of events by 52% (Lancet. 2015 Dec 15. doi.org/10.1016/S0140-6736[15]01234-9).

The new subgroup analyses were restricted to the patients with tumors originating in the GI tract (n =175) or an unknown site generally thought to be the GI tract (n = 36).

Among the group with GI tumors, median progression-free survival was 13.1 months with everolimus versus 5.4 months with placebo, Dr. Singh reported. Among the group with tumors of unknown origin, it was 13.6 and 7.5 months, respectively.

Relative to placebo, everolimus prolonged progression-free survival by 6.41 months, reducing the risk of events by 29%, in patients whose tumors originated in the midgut (duodenum, ileum, jejunum, cecum, or appendix). The relative benefit was 6.17 months, with a reduction in the risk of events of 73%, in patients whose tumors originated in non-midgut sites (stomach, colon, and rectum).

In addition, everolimus prolonged progression-free survival by 6.73 months, reducing the risk of events by 46%, in patients who had previously received somatostatin analogues, and by 9.07 months, reducing the risk by 48%, in patients who had not received these agents.

The safety profile of everolimus was consistent with that expected based on the use of this agent in other patient populations, according to Dr. Singh. The most common adverse events were stomatitis, infections, diarrhea, peripheral edema, and fatigue. No new safety signals were seen.

Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.

Everolimus improves outcomes in patients with advanced, progressive neuroendocrine tumors of gastrointestinal (GI) or unknown origin regardless of primary location and prior therapy, according to new subgroup analyses of the RADIANT-4 trial.

The phase III trial is the largest of its type in patients with nonfunctioning GI tract or lung neuroendocrine tumors. The subgroup findings for those whose tumors originated in the GI tract or an unknown site (but suspected to be GI) were presented in a presscast held in advance of the Gastrointestinal Cancers Symposium.

Compared with placebo, everolimus prolonged progression-free survival by 6-9 months, corresponding to a 46%-48% relative reduction in the risk of progression or death, reported lead study author Dr. Simron Singh of Sunnybrook’s Odette Cancer Centre in Toronto. Benefit was similar regardless of whether patients had midgut or non-midgut tumors, and whether they had previously received a somatostatin analog or not.

“In my opinion, this study in advanced, progressive neuroendocrine patients [shows] an effective, new and exciting treatment option in a disease where we’ve had very few treatments to date,” Dr. Singh said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, agreed, saying that everolimus could help address an unmet need in this disease.

“Patients with GI neuroendocrine tumors have had very few treatment options. Once they have progressed on somatostatin analogues, there really are no good systemic treatments,” she said. “So this finding is very important, that the mTOR inhibitor everolimus has demonstrated an improvement in risk of progression by over 40% and with very little severe toxicity. This is a welcome finding for these patients who have limited systemic treatment options.”

Patients enrolled in RADIANT-4 had lung, GI, or unknown-origin neuroendocrine tumors that had progressed on other therapies, including somatostatin analogs, surgery, or chemotherapy.

They were randomly assigned in 2:1 ratio to receive everolimus (Afinitor) or placebo, each in addition to best supportive care. Everolimus is currently approved by the Food and Drug Administration for the treatment of pancreatic neuroendocrine tumors, as well as breast and kidney cancer, and subependymal giant cell astrocytoma.

Results for the entire trial population have been previously reported and showed that everolimus prolonged progression-free survival by 7.1 months, reducing the risk of events by 52% (Lancet. 2015 Dec 15. doi.org/10.1016/S0140-6736[15]01234-9).

The new subgroup analyses were restricted to the patients with tumors originating in the GI tract (n =175) or an unknown site generally thought to be the GI tract (n = 36).

Among the group with GI tumors, median progression-free survival was 13.1 months with everolimus versus 5.4 months with placebo, Dr. Singh reported. Among the group with tumors of unknown origin, it was 13.6 and 7.5 months, respectively.

Relative to placebo, everolimus prolonged progression-free survival by 6.41 months, reducing the risk of events by 29%, in patients whose tumors originated in the midgut (duodenum, ileum, jejunum, cecum, or appendix). The relative benefit was 6.17 months, with a reduction in the risk of events of 73%, in patients whose tumors originated in non-midgut sites (stomach, colon, and rectum).

In addition, everolimus prolonged progression-free survival by 6.73 months, reducing the risk of events by 46%, in patients who had previously received somatostatin analogues, and by 9.07 months, reducing the risk by 48%, in patients who had not received these agents.

The safety profile of everolimus was consistent with that expected based on the use of this agent in other patient populations, according to Dr. Singh. The most common adverse events were stomatitis, infections, diarrhea, peripheral edema, and fatigue. No new safety signals were seen.

Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.

Over the past 3 decades, total knee arthroplasty (TKA) has been considered a safe and effective treatment for end-stage knee arthritis.¹ However, as the population, the incidence of obesity, and life expectancy continue to increase, the number of TKAs will rise as well.^2,3 It is expected that over the next 16 years, the number of TKAs performed annually will exceed 3 million in the United States alone.⁴ This projection represents an over 600% increase from 2005 figures.⁵ Given the demographic shift expected over the next 2 decades, patients are anticipated to undergo these procedures at younger ages compared with previous generations, such that those age 65 years or younger will account for more than 55% of primary TKAs.⁶ More important, given this exponential growth in primary TKAs, there will be a concordant rise in revision procedures. It is expected that, the annual number has roughly doubled from that recorded for 2005.⁴

Compared with primary TKAs, however, revision TKAs have had less promising results, with survivorship as low as 60% over shorter periods.^7,8 In addition, recent studies have found an even higher degree of dissatisfaction and functional limitations among revision TKA patients than among primary TKA patients, 15% to 30% of whom are unhappy with their procedures.^9-11 These shortcomings of revision TKAs are thought to result from several factors, including poor bone quality, insufficient bone stock, ligamentous instability, soft-tissue incompetence, infection, malalignment, problems with extensor mechanisms, and substantial pain of uncertain etiology.

Despite there being several complex factors that can lead to worse outcomes with revision TKAs, surgeons are expected to produce results equivalent to those of primary TKAs. It is therefore imperative to delineate the objective and subjective outcomes of revision techniques to identify areas in need of improvement. In this article, we provide a concise overview of revision TKA outcomes in order to stimulate manufacturers, surgeons, and hospitals to improve on implant designs, surgical techniques, and care guidelines for revision TKA. We review the evidence on 5 points: aseptic survivorship, functional outcomes, patient satisfaction, quality of life (QOL), and economic impact. In addition, we compare available outcome data for revision and primary TKAs.

1. Aseptic survivorship

Fehring and colleagues¹² in 2001 and Sharkey and colleagues¹³ in 2002 evaluated mechanisms of failure for revision TKA and reported many failures resulted from infection or were associated with the implant, and occurred within 2 years after the primary procedure. More recently, Dy and colleagues¹⁴ found the most common reason for revision was aseptic loosening, followed by infection. The present review focuses on aseptic femoral and tibial revision.

The failure rate for revision TKA is substantially higher than for primary TKA with the same type of prosthesis because of the complexity of the revision procedure, the increasing constraint of the implant design, and the higher degree of bone loss. (Appendix 1 lists risk factors for revision surgery. Appendix 2 is a complete list of survivorship outcomes of revision TKA.)

Sheng and colleagues¹⁵ in 2006 and Koskinen and colleagues¹⁶ in 2008 analyzed Finnish Arthroplasty Register data to determine failure rates for revision and primary TKA. Sheng and colleagues¹⁵ examined survivorship of 2637 revision TKAs (performed between 1990 and 2002) for all-cause endpoints after first revision procedure. Survivorship rates were 89% (5 years) and 79% (10 years), while Koskinen and colleagues¹⁶ noted all-cause survival rates of 80% at 15 years. More recently, in 2013, the New Zealand Orthopaedic Association¹⁷ analyzed New Zealand Joint Registry data for revision and re-revision rates (rates of revision per 100 component years) for 64,556 primary TKAs performed between 1999 and 2012. During the period studied, 1684 revisions were performed, reflecting a 2.6% revision rate, a 0.50% rate of revision per 100 component years, and a 13-year Kaplan-Meier survivorship of 94.5%. The most common reasons for revision were pain, deep infection, and tibial component loosening (Table 1).

Posterior stabilized implants

Laskin and Ohnsorge¹⁸ retrospectively reviewed the cases of 58 patients who underwent unilateral revision TKA (with a posterior stabilized implant), of which 42% were for coronal instability and 44% for a loose tibial component. At minimum 4-year follow-up, 52 of the 58 patients had anteroposterior instability of less than 5 mm. In addition, 5 years after surgery, aseptic survivorship was 96%. Meijer and colleagues¹⁹ conducted a retrospective comparative study of 69 revision TKAs (65 patients) in which 9 knees received a primary implant and 60 received a revision implant with stems and augmentation (60 = 37 posterior stabilized, 20 constrained, 3 rotating hinge). Survival rates for the primary implants were 100% (1 year), 73% (2 years), and 44% (5 years), and survival rates for the revision implants were significantly better: 95% (1 year), 92% (2 years), and 92% (5 years) (hazard ratio, 5.87; P = .008). The authors therefore indicated that it was unclear whether using a primary implant should still be an option in revision TKA and, if it is used, whether it should be limited to less complex situations in which bone loss and ligament damage are minimal (Table 2).

Constrained and semiconstrained implants

In a study of 234 knees (209 patients) with soft-tissue deficiency, Wilke and colleagues²⁰ evaluated the long-term survivorship of revision TKA with use of a semiconstrained modular fixed-bearing implant system. Overall Kaplan-Meier survival rates were 91% (5 years) and 81% (10 years) at a mean follow-up of 9 years. When aseptic revision was evaluated, however, the survival rates increased to 95% (5 years) and 90% (10 years). The authors noted that male sex was the only variable that significantly increased the risk for re-revision (hazard ratio, 2.07; P = .02), which they attributed to potentially higher activity levels. In 2006 and 2011, Lachiewicz and Soileau^21,22 evaluated the survival of first- and second-generation constrained condylar prostheses in primary TKA cases with severe valgus deformities, incompetent collateral ligaments, or severe flexion contractures. Of the 54 knees (44 patients) with first-generation prostheses, 42 (34 patients) had a mean follow-up of 9 years (range, 5-16 years). Ten-year survival with failure, defined as component revision for loosening, was 96%. The 27 TKAs using second-generation prostheses had a mean follow-up of about 5 years (range, 2-12 years). At final follow-up, there were no revisions for loosening or patellar problems, but 6 knees (22%) required lateral retinacular release of the patella (Table 3).

Rotating hinge implants

Neumann and colleagues²³ evaluated the clinical and radiographic outcomes of 24 rotating hinge prostheses used for aseptic loosening with substantial bone loss and collateral ligament instability. At a mean follow-up of 56 months (range, 3-5 years), there was no evidence of loosening of any implants, and nonprogressive radiolucent lines were found in only 2 tibial components. Kowalczewski and colleagues²⁴ evaluated the clinical and radiologic outcomes of 12 primary TKAs using a rotating hinge knee prosthesis at a minimum follow-up of 10 years. By most recent follow-up, no implants had been revised for loosening, and only 3 had nonprogressive radiolucent lines (Table 4).

Endoprostheses (modular segmental implants)

In a systematic review of 9 studies, Korim and colleagues²⁵ evaluated 241 endoprostheses used for limb salvage under nononcologic conditions. Mean follow-up was about 3 years (range, 1-5 years). The devices were used to treat various conditions, including periprosthetic fracture, bone loss with aseptic loosening, and ligament insufficiency. The overall reoperation rate was 17% (41/241 cases). Mechanical failures were less frequent (6%-19%) (Table 5).

2. Functional outcomes

The goal in both primary and revision TKA is to restore the function and mobility of the knee and to alleviate pain. Whereas primary TKAs are realistically predictable and reproducible in their outcomes, revision TKAs are vastly more complicated, which can result in worse postoperative outcomes and function. In addition, revision TKAs may require extensive surgical exposure, which causes more tissue and muscle damage, prolonging rehabilitation. (Appendix 3 is a complete list of studies of functional outcomes of revision TKA.)

This discrepancy in functional outcomes between primary and revision TKA begins as early as the postoperative inpatient rehabilitation period. Using the functional independence measurement (FIM), which estimates performance of activities of daily living, mobility, and cognition, Vincent and colleagues²⁶ evaluated the functional improvement produced by revision versus primary TKA during inpatient rehabilitation. They compared 424 consecutive primary TKAs with 138 revision TKAs. For both groups, FIM scores increased significantly (P = .015) between admission and discharge. On discharge, however, FIM scores were significantly (P = .01) higher for the primary group than the revision group (29 and 27 points, respectively). Furthermore, in the evaluation of mechanisms of failure, patients who had revision TKA for mechanical or pain-related problems did markedly better than those who had revision TKA for infection.

Compared with primary knee implants, revision implants require increasing constraint. We assume increasing constraint affects knee biomechanics, leading to worsening functional outcomes. In a study of 60 revision TKAs (57 patients) using posterior stabilized, condylar constrained, or rotating hinge prostheses, Vasso and colleagues²⁷ examined functional outcomes at a median follow-up of 9 years (range, 4-12 years). At most recent follow-up, mean International Knee Society (IKS) Knee and Function scores were 81 (range, 48-97) and 79 (range, 56-92), mean Hospital for Special Surgery (HSS) score was 84 (range, 62-98), and mean range of motion (ROM) was 121° (range, 98°-132°) (P < .001). Although there were no significant differences in IKS and HSS scores between prosthesis types, ROM was significantly (P < .01) wider in the posterior stabilized group than in the condylar constrained and rotating hinge groups (127° vs 112° and 108°), suggesting increasing constraint resulted in decreased ROM. Several studies have found increasing constraint might lead to reduced function.^28-30

However, Hwang and colleagues³¹ evaluated functional outcomes in 36 revision TKAs and noted that the cemented posterior stabilized (n = 8), condylar constrained (n = 25), and rotating hinge (n = 13) prostheses used did not differ in their mean Knee Society scores (78, 81, and 83, respectively).

There remains a marked disparity in patient limitations seen after revision versus primary TKA. Given the positive results being obtained with newer implants, studies might suggest recent generations of prostheses have allowed designs to be comparable. As design development continues, we may come closer to achieving outcomes comparable to those of primary TKA.

3. Patient satisfaction

Several recent reports have shown that 10% to 25% of patients who underwent primary TKA were dissatisfied with their surgery^30,32; other studies have found patient satisfaction often correlating to function and pain.^33-35 Given the worse outcomes for revision TKA (outlined in the preceding section), the substantial pain accompanying a second, more complex procedure, and the extensive rehabilitation expected, we suspect patients who undergo revision TKA are even less satisfied with their surgery than their primary counterparts are. (See Appendix 4 for a complete list of studies of patient satisfaction after revision TKA.)

Barrack and colleagues³² evaluated a consecutive series of 238 patients followed up for at least 1 year after revision TKA. Patients were asked to rate their degree of satisfaction with both their primary procedure and the revision and to indicate their expectations regarding their revision prosthesis. Mean satisfaction score was 7.4 (maximum = 10), with 13% of patients dissatisfied, 18% somewhat satisfied, and 69% satisfied. Seventy-four percent of patients expected their revision prosthesis to last longer than the primary prosthesis.

Greidanus and colleagues³⁶ evaluated patient satisfaction in 60 revision TKA cases and 199 primary TKA cases at 2-year follow-up. The primary TKA group had significantly (P < .01) higher satisfaction scores in a comparison with the revision TKA group: Global (86 vs 73), Pain Relief (88 vs 70), Function (83 vs 67), and Recreation (77 vs 62). These findings support the satisfaction rates reported by Dahm and colleagues^33,34: 91% for primary TKA patients and 77% for revision TKA patients.

4. Quality of life

Procedure complexity leads to reduced survivorship, function, and mobility, longer rehabilitation, and decreased QOL for revision TKA patients relative to primary TKA patients.³⁷ (See Appendix 5 for a complete list of studies of QOL outcomes of revision TKA.)

Greidanus and colleagues³⁶ evaluated joint-specific QOL (using the 12-item Oxford Knee Score; OKS) and generic QOL (using the 12-Item Short Form Health Survey; SF-12) in 60 revision TKA cases and 199 primary TKA cases at a mean follow-up of 2 years. (The OKS survey is used to evaluate patient perspectives on TKA outcomes,³⁸ and the multipurpose SF-12 questionnaire is used to assess mental and physical function and general health-related QOL.³⁹) Compared with the revision TKA group, the primary TKA group had significantly higher OKS after surgery (78 vs 68; P = .01) as well as significantly higher SF-12 scores: Global (84 vs 72; P = .01), Mental (54 vs 50; P = .03), and Physical (43 vs 37; P = .01). Similarly, Ghomrawi and colleagues⁴⁰ evaluated patterns of improvement in 308 patients (318 knees) who had revision TKA. At 24-month follow-up, mean SF-36 Physical and Mental scores were 35 and 52, respectively.

Deehan and colleagues⁴¹ used the Nottingham Health Profile (NHP) to compare 94 patients’ health-related QOL scores before revision TKA with their scores 3 months, 1 year, and 5 years after revision. NHP Pain subscale scores were significantly lower 3 and 12 months after surgery than before surgery, but this difference was no longer seen at the 5-year follow-up. There was no significant improvement in scores on the other 5 NHP subscales (Sleep, Energy, Emotion, Mobility, Social Isolation) at any time points.

As shown in the literature, patients’ QOL outcomes improve after revision TKA, but these gains are not at the level of patients who undergo primary TKA.^36,41 Given that revision surgery is more extensive, and that perhaps revision patients have poorer muscle function, they usually do not return to the level they attained after their index procedure.

5. Economic impact

Consistent with the outcomes already described, the economic impact of revision TKAs is excess expenditures and costs to patients and health care institutions.⁴² The sources of this impact are higher implant costs, extra operative trays and times, longer hospital stays, more rehabilitation, and increased medication use.⁴³ Revision TKA costs range from $49,000 to more than $100,000—a tremendous increase over primary TKA costs ($25,000-$30,000).^43-45 Furthermore, the annual economic burden associated with revision TKA, now $2.7 billion, is expected to exceed $13 billion by 2030.⁴⁶ In the United States, about $23.2 billion will be spent on 926,527 primary TKAs in 2015; significantly, the costs associated with revising just 10% of these cases account for almost 50% of the total cost of the primary procedures.⁴⁶

In a retrospective cost-identification multicenter cohort study, Bozic and colleagues⁴⁷ found that both-component and single-component revisions, compared with primary procedures, were associated with significantly increased operative time (~265 and 221 minutes vs 200 minutes), use of allograft bone (23% and 14% vs 1%), length of stay (5.4 and 5.7 days vs 5.0 days), and percentage of patients discharged to extended-care facilities (26% and 26% vs 25%) (P < .0001). Hospital costs for both- and single-component revisions were 138% and 114% higher than costs for primary procedures (P < .0001). More recently, Kallala and colleagues⁴⁴ analyzed UK National Health Service data and compared the costs of revision for infection with revision for other causes (pain, instability, aseptic loosening, fracture). Mean length of stay associated with revision for infection (21.5 days) was more than double that associated with revision for aseptic loosening (9.5 days; P < .0001), and mean cost of revision for septic causes (£30,011) was more than 3 times that of revision for other causes (£9655; P < .0001). The authors concluded that the higher costs of revision knee surgery have a considerable economic impact, especially in infection cases.

With more extensive procedures, long-stem or more constrained prostheses are often needed to obtain adequate fixation and stability. The resulting increased, substantial economic burden is felt by patients and the health care system. Given that health care reimbursements are declining, hospitals that perform revision TKAs can sustain marked financial losses. Some centers are asking whether it is cost-effective to continue to perform these types of procedures. We must find new ways to provide revision procedures using less costly implants and tools so that centers will continue to make these procedures available to patients.

Conclusion

Given the exponential growth in primary TKAs, there will be a concordant increase in revision TKAs in the decades to come. This review provides a concise overview of revision TKA outcomes. Given the low level of evidence regarding revision TKAs, we need further higher quality studies of their prostheses and outcomes. Specifically, we need systematic reviews and meta-analyses to provide higher quality evidence regarding outcomes of using individual prosthetic designs.

Over the past 3 decades, total knee arthroplasty (TKA) has been considered a safe and effective treatment for end-stage knee arthritis.¹ However, as the population, the incidence of obesity, and life expectancy continue to increase, the number of TKAs will rise as well.^2,3 It is expected that over the next 16 years, the number of TKAs performed annually will exceed 3 million in the United States alone.⁴ This projection represents an over 600% increase from 2005 figures.⁵ Given the demographic shift expected over the next 2 decades, patients are anticipated to undergo these procedures at younger ages compared with previous generations, such that those age 65 years or younger will account for more than 55% of primary TKAs.⁶ More important, given this exponential growth in primary TKAs, there will be a concordant rise in revision procedures. It is expected that, the annual number has roughly doubled from that recorded for 2005.⁴

Compared with primary TKAs, however, revision TKAs have had less promising results, with survivorship as low as 60% over shorter periods.^7,8 In addition, recent studies have found an even higher degree of dissatisfaction and functional limitations among revision TKA patients than among primary TKA patients, 15% to 30% of whom are unhappy with their procedures.^9-11 These shortcomings of revision TKAs are thought to result from several factors, including poor bone quality, insufficient bone stock, ligamentous instability, soft-tissue incompetence, infection, malalignment, problems with extensor mechanisms, and substantial pain of uncertain etiology.

Despite there being several complex factors that can lead to worse outcomes with revision TKAs, surgeons are expected to produce results equivalent to those of primary TKAs. It is therefore imperative to delineate the objective and subjective outcomes of revision techniques to identify areas in need of improvement. In this article, we provide a concise overview of revision TKA outcomes in order to stimulate manufacturers, surgeons, and hospitals to improve on implant designs, surgical techniques, and care guidelines for revision TKA. We review the evidence on 5 points: aseptic survivorship, functional outcomes, patient satisfaction, quality of life (QOL), and economic impact. In addition, we compare available outcome data for revision and primary TKAs.

1. Aseptic survivorship

Fehring and colleagues¹² in 2001 and Sharkey and colleagues¹³ in 2002 evaluated mechanisms of failure for revision TKA and reported many failures resulted from infection or were associated with the implant, and occurred within 2 years after the primary procedure. More recently, Dy and colleagues¹⁴ found the most common reason for revision was aseptic loosening, followed by infection. The present review focuses on aseptic femoral and tibial revision.

The failure rate for revision TKA is substantially higher than for primary TKA with the same type of prosthesis because of the complexity of the revision procedure, the increasing constraint of the implant design, and the higher degree of bone loss. (Appendix 1 lists risk factors for revision surgery. Appendix 2 is a complete list of survivorship outcomes of revision TKA.)

Sheng and colleagues¹⁵ in 2006 and Koskinen and colleagues¹⁶ in 2008 analyzed Finnish Arthroplasty Register data to determine failure rates for revision and primary TKA. Sheng and colleagues¹⁵ examined survivorship of 2637 revision TKAs (performed between 1990 and 2002) for all-cause endpoints after first revision procedure. Survivorship rates were 89% (5 years) and 79% (10 years), while Koskinen and colleagues¹⁶ noted all-cause survival rates of 80% at 15 years. More recently, in 2013, the New Zealand Orthopaedic Association¹⁷ analyzed New Zealand Joint Registry data for revision and re-revision rates (rates of revision per 100 component years) for 64,556 primary TKAs performed between 1999 and 2012. During the period studied, 1684 revisions were performed, reflecting a 2.6% revision rate, a 0.50% rate of revision per 100 component years, and a 13-year Kaplan-Meier survivorship of 94.5%. The most common reasons for revision were pain, deep infection, and tibial component loosening (Table 1).

Posterior stabilized implants

Laskin and Ohnsorge¹⁸ retrospectively reviewed the cases of 58 patients who underwent unilateral revision TKA (with a posterior stabilized implant), of which 42% were for coronal instability and 44% for a loose tibial component. At minimum 4-year follow-up, 52 of the 58 patients had anteroposterior instability of less than 5 mm. In addition, 5 years after surgery, aseptic survivorship was 96%. Meijer and colleagues¹⁹ conducted a retrospective comparative study of 69 revision TKAs (65 patients) in which 9 knees received a primary implant and 60 received a revision implant with stems and augmentation (60 = 37 posterior stabilized, 20 constrained, 3 rotating hinge). Survival rates for the primary implants were 100% (1 year), 73% (2 years), and 44% (5 years), and survival rates for the revision implants were significantly better: 95% (1 year), 92% (2 years), and 92% (5 years) (hazard ratio, 5.87; P = .008). The authors therefore indicated that it was unclear whether using a primary implant should still be an option in revision TKA and, if it is used, whether it should be limited to less complex situations in which bone loss and ligament damage are minimal (Table 2).

Constrained and semiconstrained implants

In a study of 234 knees (209 patients) with soft-tissue deficiency, Wilke and colleagues²⁰ evaluated the long-term survivorship of revision TKA with use of a semiconstrained modular fixed-bearing implant system. Overall Kaplan-Meier survival rates were 91% (5 years) and 81% (10 years) at a mean follow-up of 9 years. When aseptic revision was evaluated, however, the survival rates increased to 95% (5 years) and 90% (10 years). The authors noted that male sex was the only variable that significantly increased the risk for re-revision (hazard ratio, 2.07; P = .02), which they attributed to potentially higher activity levels. In 2006 and 2011, Lachiewicz and Soileau^21,22 evaluated the survival of first- and second-generation constrained condylar prostheses in primary TKA cases with severe valgus deformities, incompetent collateral ligaments, or severe flexion contractures. Of the 54 knees (44 patients) with first-generation prostheses, 42 (34 patients) had a mean follow-up of 9 years (range, 5-16 years). Ten-year survival with failure, defined as component revision for loosening, was 96%. The 27 TKAs using second-generation prostheses had a mean follow-up of about 5 years (range, 2-12 years). At final follow-up, there were no revisions for loosening or patellar problems, but 6 knees (22%) required lateral retinacular release of the patella (Table 3).

Rotating hinge implants

Neumann and colleagues²³ evaluated the clinical and radiographic outcomes of 24 rotating hinge prostheses used for aseptic loosening with substantial bone loss and collateral ligament instability. At a mean follow-up of 56 months (range, 3-5 years), there was no evidence of loosening of any implants, and nonprogressive radiolucent lines were found in only 2 tibial components. Kowalczewski and colleagues²⁴ evaluated the clinical and radiologic outcomes of 12 primary TKAs using a rotating hinge knee prosthesis at a minimum follow-up of 10 years. By most recent follow-up, no implants had been revised for loosening, and only 3 had nonprogressive radiolucent lines (Table 4).

Endoprostheses (modular segmental implants)

In a systematic review of 9 studies, Korim and colleagues²⁵ evaluated 241 endoprostheses used for limb salvage under nononcologic conditions. Mean follow-up was about 3 years (range, 1-5 years). The devices were used to treat various conditions, including periprosthetic fracture, bone loss with aseptic loosening, and ligament insufficiency. The overall reoperation rate was 17% (41/241 cases). Mechanical failures were less frequent (6%-19%) (Table 5).

2. Functional outcomes

The goal in both primary and revision TKA is to restore the function and mobility of the knee and to alleviate pain. Whereas primary TKAs are realistically predictable and reproducible in their outcomes, revision TKAs are vastly more complicated, which can result in worse postoperative outcomes and function. In addition, revision TKAs may require extensive surgical exposure, which causes more tissue and muscle damage, prolonging rehabilitation. (Appendix 3 is a complete list of studies of functional outcomes of revision TKA.)

This discrepancy in functional outcomes between primary and revision TKA begins as early as the postoperative inpatient rehabilitation period. Using the functional independence measurement (FIM), which estimates performance of activities of daily living, mobility, and cognition, Vincent and colleagues²⁶ evaluated the functional improvement produced by revision versus primary TKA during inpatient rehabilitation. They compared 424 consecutive primary TKAs with 138 revision TKAs. For both groups, FIM scores increased significantly (P = .015) between admission and discharge. On discharge, however, FIM scores were significantly (P = .01) higher for the primary group than the revision group (29 and 27 points, respectively). Furthermore, in the evaluation of mechanisms of failure, patients who had revision TKA for mechanical or pain-related problems did markedly better than those who had revision TKA for infection.

Compared with primary knee implants, revision implants require increasing constraint. We assume increasing constraint affects knee biomechanics, leading to worsening functional outcomes. In a study of 60 revision TKAs (57 patients) using posterior stabilized, condylar constrained, or rotating hinge prostheses, Vasso and colleagues²⁷ examined functional outcomes at a median follow-up of 9 years (range, 4-12 years). At most recent follow-up, mean International Knee Society (IKS) Knee and Function scores were 81 (range, 48-97) and 79 (range, 56-92), mean Hospital for Special Surgery (HSS) score was 84 (range, 62-98), and mean range of motion (ROM) was 121° (range, 98°-132°) (P < .001). Although there were no significant differences in IKS and HSS scores between prosthesis types, ROM was significantly (P < .01) wider in the posterior stabilized group than in the condylar constrained and rotating hinge groups (127° vs 112° and 108°), suggesting increasing constraint resulted in decreased ROM. Several studies have found increasing constraint might lead to reduced function.^28-30

However, Hwang and colleagues³¹ evaluated functional outcomes in 36 revision TKAs and noted that the cemented posterior stabilized (n = 8), condylar constrained (n = 25), and rotating hinge (n = 13) prostheses used did not differ in their mean Knee Society scores (78, 81, and 83, respectively).

There remains a marked disparity in patient limitations seen after revision versus primary TKA. Given the positive results being obtained with newer implants, studies might suggest recent generations of prostheses have allowed designs to be comparable. As design development continues, we may come closer to achieving outcomes comparable to those of primary TKA.

3. Patient satisfaction

Several recent reports have shown that 10% to 25% of patients who underwent primary TKA were dissatisfied with their surgery^30,32; other studies have found patient satisfaction often correlating to function and pain.^33-35 Given the worse outcomes for revision TKA (outlined in the preceding section), the substantial pain accompanying a second, more complex procedure, and the extensive rehabilitation expected, we suspect patients who undergo revision TKA are even less satisfied with their surgery than their primary counterparts are. (See Appendix 4 for a complete list of studies of patient satisfaction after revision TKA.)

Barrack and colleagues³² evaluated a consecutive series of 238 patients followed up for at least 1 year after revision TKA. Patients were asked to rate their degree of satisfaction with both their primary procedure and the revision and to indicate their expectations regarding their revision prosthesis. Mean satisfaction score was 7.4 (maximum = 10), with 13% of patients dissatisfied, 18% somewhat satisfied, and 69% satisfied. Seventy-four percent of patients expected their revision prosthesis to last longer than the primary prosthesis.

Greidanus and colleagues³⁶ evaluated patient satisfaction in 60 revision TKA cases and 199 primary TKA cases at 2-year follow-up. The primary TKA group had significantly (P < .01) higher satisfaction scores in a comparison with the revision TKA group: Global (86 vs 73), Pain Relief (88 vs 70), Function (83 vs 67), and Recreation (77 vs 62). These findings support the satisfaction rates reported by Dahm and colleagues^33,34: 91% for primary TKA patients and 77% for revision TKA patients.

4. Quality of life

Procedure complexity leads to reduced survivorship, function, and mobility, longer rehabilitation, and decreased QOL for revision TKA patients relative to primary TKA patients.³⁷ (See Appendix 5 for a complete list of studies of QOL outcomes of revision TKA.)

Greidanus and colleagues³⁶ evaluated joint-specific QOL (using the 12-item Oxford Knee Score; OKS) and generic QOL (using the 12-Item Short Form Health Survey; SF-12) in 60 revision TKA cases and 199 primary TKA cases at a mean follow-up of 2 years. (The OKS survey is used to evaluate patient perspectives on TKA outcomes,³⁸ and the multipurpose SF-12 questionnaire is used to assess mental and physical function and general health-related QOL.³⁹) Compared with the revision TKA group, the primary TKA group had significantly higher OKS after surgery (78 vs 68; P = .01) as well as significantly higher SF-12 scores: Global (84 vs 72; P = .01), Mental (54 vs 50; P = .03), and Physical (43 vs 37; P = .01). Similarly, Ghomrawi and colleagues⁴⁰ evaluated patterns of improvement in 308 patients (318 knees) who had revision TKA. At 24-month follow-up, mean SF-36 Physical and Mental scores were 35 and 52, respectively.

Deehan and colleagues⁴¹ used the Nottingham Health Profile (NHP) to compare 94 patients’ health-related QOL scores before revision TKA with their scores 3 months, 1 year, and 5 years after revision. NHP Pain subscale scores were significantly lower 3 and 12 months after surgery than before surgery, but this difference was no longer seen at the 5-year follow-up. There was no significant improvement in scores on the other 5 NHP subscales (Sleep, Energy, Emotion, Mobility, Social Isolation) at any time points.

As shown in the literature, patients’ QOL outcomes improve after revision TKA, but these gains are not at the level of patients who undergo primary TKA.^36,41 Given that revision surgery is more extensive, and that perhaps revision patients have poorer muscle function, they usually do not return to the level they attained after their index procedure.

5. Economic impact

Consistent with the outcomes already described, the economic impact of revision TKAs is excess expenditures and costs to patients and health care institutions.⁴² The sources of this impact are higher implant costs, extra operative trays and times, longer hospital stays, more rehabilitation, and increased medication use.⁴³ Revision TKA costs range from $49,000 to more than $100,000—a tremendous increase over primary TKA costs ($25,000-$30,000).^43-45 Furthermore, the annual economic burden associated with revision TKA, now $2.7 billion, is expected to exceed $13 billion by 2030.⁴⁶ In the United States, about $23.2 billion will be spent on 926,527 primary TKAs in 2015; significantly, the costs associated with revising just 10% of these cases account for almost 50% of the total cost of the primary procedures.⁴⁶

In a retrospective cost-identification multicenter cohort study, Bozic and colleagues⁴⁷ found that both-component and single-component revisions, compared with primary procedures, were associated with significantly increased operative time (~265 and 221 minutes vs 200 minutes), use of allograft bone (23% and 14% vs 1%), length of stay (5.4 and 5.7 days vs 5.0 days), and percentage of patients discharged to extended-care facilities (26% and 26% vs 25%) (P < .0001). Hospital costs for both- and single-component revisions were 138% and 114% higher than costs for primary procedures (P < .0001). More recently, Kallala and colleagues⁴⁴ analyzed UK National Health Service data and compared the costs of revision for infection with revision for other causes (pain, instability, aseptic loosening, fracture). Mean length of stay associated with revision for infection (21.5 days) was more than double that associated with revision for aseptic loosening (9.5 days; P < .0001), and mean cost of revision for septic causes (£30,011) was more than 3 times that of revision for other causes (£9655; P < .0001). The authors concluded that the higher costs of revision knee surgery have a considerable economic impact, especially in infection cases.

With more extensive procedures, long-stem or more constrained prostheses are often needed to obtain adequate fixation and stability. The resulting increased, substantial economic burden is felt by patients and the health care system. Given that health care reimbursements are declining, hospitals that perform revision TKAs can sustain marked financial losses. Some centers are asking whether it is cost-effective to continue to perform these types of procedures. We must find new ways to provide revision procedures using less costly implants and tools so that centers will continue to make these procedures available to patients.

Conclusion

Given the exponential growth in primary TKAs, there will be a concordant increase in revision TKAs in the decades to come. This review provides a concise overview of revision TKA outcomes. Given the low level of evidence regarding revision TKAs, we need further higher quality studies of their prostheses and outcomes. Specifically, we need systematic reviews and meta-analyses to provide higher quality evidence regarding outcomes of using individual prosthetic designs.

Over the past 3 decades, total knee arthroplasty (TKA) has been considered a safe and effective treatment for end-stage knee arthritis.¹ However, as the population, the incidence of obesity, and life expectancy continue to increase, the number of TKAs will rise as well.^2,3 It is expected that over the next 16 years, the number of TKAs performed annually will exceed 3 million in the United States alone.⁴ This projection represents an over 600% increase from 2005 figures.⁵ Given the demographic shift expected over the next 2 decades, patients are anticipated to undergo these procedures at younger ages compared with previous generations, such that those age 65 years or younger will account for more than 55% of primary TKAs.⁶ More important, given this exponential growth in primary TKAs, there will be a concordant rise in revision procedures. It is expected that, the annual number has roughly doubled from that recorded for 2005.⁴

Compared with primary TKAs, however, revision TKAs have had less promising results, with survivorship as low as 60% over shorter periods.^7,8 In addition, recent studies have found an even higher degree of dissatisfaction and functional limitations among revision TKA patients than among primary TKA patients, 15% to 30% of whom are unhappy with their procedures.^9-11 These shortcomings of revision TKAs are thought to result from several factors, including poor bone quality, insufficient bone stock, ligamentous instability, soft-tissue incompetence, infection, malalignment, problems with extensor mechanisms, and substantial pain of uncertain etiology.

Despite there being several complex factors that can lead to worse outcomes with revision TKAs, surgeons are expected to produce results equivalent to those of primary TKAs. It is therefore imperative to delineate the objective and subjective outcomes of revision techniques to identify areas in need of improvement. In this article, we provide a concise overview of revision TKA outcomes in order to stimulate manufacturers, surgeons, and hospitals to improve on implant designs, surgical techniques, and care guidelines for revision TKA. We review the evidence on 5 points: aseptic survivorship, functional outcomes, patient satisfaction, quality of life (QOL), and economic impact. In addition, we compare available outcome data for revision and primary TKAs.

1. Aseptic survivorship

Fehring and colleagues¹² in 2001 and Sharkey and colleagues¹³ in 2002 evaluated mechanisms of failure for revision TKA and reported many failures resulted from infection or were associated with the implant, and occurred within 2 years after the primary procedure. More recently, Dy and colleagues¹⁴ found the most common reason for revision was aseptic loosening, followed by infection. The present review focuses on aseptic femoral and tibial revision.

The failure rate for revision TKA is substantially higher than for primary TKA with the same type of prosthesis because of the complexity of the revision procedure, the increasing constraint of the implant design, and the higher degree of bone loss. (Appendix 1 lists risk factors for revision surgery. Appendix 2 is a complete list of survivorship outcomes of revision TKA.)

Sheng and colleagues¹⁵ in 2006 and Koskinen and colleagues¹⁶ in 2008 analyzed Finnish Arthroplasty Register data to determine failure rates for revision and primary TKA. Sheng and colleagues¹⁵ examined survivorship of 2637 revision TKAs (performed between 1990 and 2002) for all-cause endpoints after first revision procedure. Survivorship rates were 89% (5 years) and 79% (10 years), while Koskinen and colleagues¹⁶ noted all-cause survival rates of 80% at 15 years. More recently, in 2013, the New Zealand Orthopaedic Association¹⁷ analyzed New Zealand Joint Registry data for revision and re-revision rates (rates of revision per 100 component years) for 64,556 primary TKAs performed between 1999 and 2012. During the period studied, 1684 revisions were performed, reflecting a 2.6% revision rate, a 0.50% rate of revision per 100 component years, and a 13-year Kaplan-Meier survivorship of 94.5%. The most common reasons for revision were pain, deep infection, and tibial component loosening (Table 1).

Posterior stabilized implants

Laskin and Ohnsorge¹⁸ retrospectively reviewed the cases of 58 patients who underwent unilateral revision TKA (with a posterior stabilized implant), of which 42% were for coronal instability and 44% for a loose tibial component. At minimum 4-year follow-up, 52 of the 58 patients had anteroposterior instability of less than 5 mm. In addition, 5 years after surgery, aseptic survivorship was 96%. Meijer and colleagues¹⁹ conducted a retrospective comparative study of 69 revision TKAs (65 patients) in which 9 knees received a primary implant and 60 received a revision implant with stems and augmentation (60 = 37 posterior stabilized, 20 constrained, 3 rotating hinge). Survival rates for the primary implants were 100% (1 year), 73% (2 years), and 44% (5 years), and survival rates for the revision implants were significantly better: 95% (1 year), 92% (2 years), and 92% (5 years) (hazard ratio, 5.87; P = .008). The authors therefore indicated that it was unclear whether using a primary implant should still be an option in revision TKA and, if it is used, whether it should be limited to less complex situations in which bone loss and ligament damage are minimal (Table 2).

Constrained and semiconstrained implants

In a study of 234 knees (209 patients) with soft-tissue deficiency, Wilke and colleagues²⁰ evaluated the long-term survivorship of revision TKA with use of a semiconstrained modular fixed-bearing implant system. Overall Kaplan-Meier survival rates were 91% (5 years) and 81% (10 years) at a mean follow-up of 9 years. When aseptic revision was evaluated, however, the survival rates increased to 95% (5 years) and 90% (10 years). The authors noted that male sex was the only variable that significantly increased the risk for re-revision (hazard ratio, 2.07; P = .02), which they attributed to potentially higher activity levels. In 2006 and 2011, Lachiewicz and Soileau^21,22 evaluated the survival of first- and second-generation constrained condylar prostheses in primary TKA cases with severe valgus deformities, incompetent collateral ligaments, or severe flexion contractures. Of the 54 knees (44 patients) with first-generation prostheses, 42 (34 patients) had a mean follow-up of 9 years (range, 5-16 years). Ten-year survival with failure, defined as component revision for loosening, was 96%. The 27 TKAs using second-generation prostheses had a mean follow-up of about 5 years (range, 2-12 years). At final follow-up, there were no revisions for loosening or patellar problems, but 6 knees (22%) required lateral retinacular release of the patella (Table 3).

Rotating hinge implants

Neumann and colleagues²³ evaluated the clinical and radiographic outcomes of 24 rotating hinge prostheses used for aseptic loosening with substantial bone loss and collateral ligament instability. At a mean follow-up of 56 months (range, 3-5 years), there was no evidence of loosening of any implants, and nonprogressive radiolucent lines were found in only 2 tibial components. Kowalczewski and colleagues²⁴ evaluated the clinical and radiologic outcomes of 12 primary TKAs using a rotating hinge knee prosthesis at a minimum follow-up of 10 years. By most recent follow-up, no implants had been revised for loosening, and only 3 had nonprogressive radiolucent lines (Table 4).

Endoprostheses (modular segmental implants)

In a systematic review of 9 studies, Korim and colleagues²⁵ evaluated 241 endoprostheses used for limb salvage under nononcologic conditions. Mean follow-up was about 3 years (range, 1-5 years). The devices were used to treat various conditions, including periprosthetic fracture, bone loss with aseptic loosening, and ligament insufficiency. The overall reoperation rate was 17% (41/241 cases). Mechanical failures were less frequent (6%-19%) (Table 5).

2. Functional outcomes

The goal in both primary and revision TKA is to restore the function and mobility of the knee and to alleviate pain. Whereas primary TKAs are realistically predictable and reproducible in their outcomes, revision TKAs are vastly more complicated, which can result in worse postoperative outcomes and function. In addition, revision TKAs may require extensive surgical exposure, which causes more tissue and muscle damage, prolonging rehabilitation. (Appendix 3 is a complete list of studies of functional outcomes of revision TKA.)

This discrepancy in functional outcomes between primary and revision TKA begins as early as the postoperative inpatient rehabilitation period. Using the functional independence measurement (FIM), which estimates performance of activities of daily living, mobility, and cognition, Vincent and colleagues²⁶ evaluated the functional improvement produced by revision versus primary TKA during inpatient rehabilitation. They compared 424 consecutive primary TKAs with 138 revision TKAs. For both groups, FIM scores increased significantly (P = .015) between admission and discharge. On discharge, however, FIM scores were significantly (P = .01) higher for the primary group than the revision group (29 and 27 points, respectively). Furthermore, in the evaluation of mechanisms of failure, patients who had revision TKA for mechanical or pain-related problems did markedly better than those who had revision TKA for infection.

Compared with primary knee implants, revision implants require increasing constraint. We assume increasing constraint affects knee biomechanics, leading to worsening functional outcomes. In a study of 60 revision TKAs (57 patients) using posterior stabilized, condylar constrained, or rotating hinge prostheses, Vasso and colleagues²⁷ examined functional outcomes at a median follow-up of 9 years (range, 4-12 years). At most recent follow-up, mean International Knee Society (IKS) Knee and Function scores were 81 (range, 48-97) and 79 (range, 56-92), mean Hospital for Special Surgery (HSS) score was 84 (range, 62-98), and mean range of motion (ROM) was 121° (range, 98°-132°) (P < .001). Although there were no significant differences in IKS and HSS scores between prosthesis types, ROM was significantly (P < .01) wider in the posterior stabilized group than in the condylar constrained and rotating hinge groups (127° vs 112° and 108°), suggesting increasing constraint resulted in decreased ROM. Several studies have found increasing constraint might lead to reduced function.^28-30

However, Hwang and colleagues³¹ evaluated functional outcomes in 36 revision TKAs and noted that the cemented posterior stabilized (n = 8), condylar constrained (n = 25), and rotating hinge (n = 13) prostheses used did not differ in their mean Knee Society scores (78, 81, and 83, respectively).

There remains a marked disparity in patient limitations seen after revision versus primary TKA. Given the positive results being obtained with newer implants, studies might suggest recent generations of prostheses have allowed designs to be comparable. As design development continues, we may come closer to achieving outcomes comparable to those of primary TKA.

3. Patient satisfaction

Several recent reports have shown that 10% to 25% of patients who underwent primary TKA were dissatisfied with their surgery^30,32; other studies have found patient satisfaction often correlating to function and pain.^33-35 Given the worse outcomes for revision TKA (outlined in the preceding section), the substantial pain accompanying a second, more complex procedure, and the extensive rehabilitation expected, we suspect patients who undergo revision TKA are even less satisfied with their surgery than their primary counterparts are. (See Appendix 4 for a complete list of studies of patient satisfaction after revision TKA.)

Barrack and colleagues³² evaluated a consecutive series of 238 patients followed up for at least 1 year after revision TKA. Patients were asked to rate their degree of satisfaction with both their primary procedure and the revision and to indicate their expectations regarding their revision prosthesis. Mean satisfaction score was 7.4 (maximum = 10), with 13% of patients dissatisfied, 18% somewhat satisfied, and 69% satisfied. Seventy-four percent of patients expected their revision prosthesis to last longer than the primary prosthesis.

Greidanus and colleagues³⁶ evaluated patient satisfaction in 60 revision TKA cases and 199 primary TKA cases at 2-year follow-up. The primary TKA group had significantly (P < .01) higher satisfaction scores in a comparison with the revision TKA group: Global (86 vs 73), Pain Relief (88 vs 70), Function (83 vs 67), and Recreation (77 vs 62). These findings support the satisfaction rates reported by Dahm and colleagues^33,34: 91% for primary TKA patients and 77% for revision TKA patients.

4. Quality of life

Procedure complexity leads to reduced survivorship, function, and mobility, longer rehabilitation, and decreased QOL for revision TKA patients relative to primary TKA patients.³⁷ (See Appendix 5 for a complete list of studies of QOL outcomes of revision TKA.)

Greidanus and colleagues³⁶ evaluated joint-specific QOL (using the 12-item Oxford Knee Score; OKS) and generic QOL (using the 12-Item Short Form Health Survey; SF-12) in 60 revision TKA cases and 199 primary TKA cases at a mean follow-up of 2 years. (The OKS survey is used to evaluate patient perspectives on TKA outcomes,³⁸ and the multipurpose SF-12 questionnaire is used to assess mental and physical function and general health-related QOL.³⁹) Compared with the revision TKA group, the primary TKA group had significantly higher OKS after surgery (78 vs 68; P = .01) as well as significantly higher SF-12 scores: Global (84 vs 72; P = .01), Mental (54 vs 50; P = .03), and Physical (43 vs 37; P = .01). Similarly, Ghomrawi and colleagues⁴⁰ evaluated patterns of improvement in 308 patients (318 knees) who had revision TKA. At 24-month follow-up, mean SF-36 Physical and Mental scores were 35 and 52, respectively.

Deehan and colleagues⁴¹ used the Nottingham Health Profile (NHP) to compare 94 patients’ health-related QOL scores before revision TKA with their scores 3 months, 1 year, and 5 years after revision. NHP Pain subscale scores were significantly lower 3 and 12 months after surgery than before surgery, but this difference was no longer seen at the 5-year follow-up. There was no significant improvement in scores on the other 5 NHP subscales (Sleep, Energy, Emotion, Mobility, Social Isolation) at any time points.

As shown in the literature, patients’ QOL outcomes improve after revision TKA, but these gains are not at the level of patients who undergo primary TKA.^36,41 Given that revision surgery is more extensive, and that perhaps revision patients have poorer muscle function, they usually do not return to the level they attained after their index procedure.

5. Economic impact

Consistent with the outcomes already described, the economic impact of revision TKAs is excess expenditures and costs to patients and health care institutions.⁴² The sources of this impact are higher implant costs, extra operative trays and times, longer hospital stays, more rehabilitation, and increased medication use.⁴³ Revision TKA costs range from $49,000 to more than $100,000—a tremendous increase over primary TKA costs ($25,000-$30,000).^43-45 Furthermore, the annual economic burden associated with revision TKA, now $2.7 billion, is expected to exceed $13 billion by 2030.⁴⁶ In the United States, about $23.2 billion will be spent on 926,527 primary TKAs in 2015; significantly, the costs associated with revising just 10% of these cases account for almost 50% of the total cost of the primary procedures.⁴⁶

In a retrospective cost-identification multicenter cohort study, Bozic and colleagues⁴⁷ found that both-component and single-component revisions, compared with primary procedures, were associated with significantly increased operative time (~265 and 221 minutes vs 200 minutes), use of allograft bone (23% and 14% vs 1%), length of stay (5.4 and 5.7 days vs 5.0 days), and percentage of patients discharged to extended-care facilities (26% and 26% vs 25%) (P < .0001). Hospital costs for both- and single-component revisions were 138% and 114% higher than costs for primary procedures (P < .0001). More recently, Kallala and colleagues⁴⁴ analyzed UK National Health Service data and compared the costs of revision for infection with revision for other causes (pain, instability, aseptic loosening, fracture). Mean length of stay associated with revision for infection (21.5 days) was more than double that associated with revision for aseptic loosening (9.5 days; P < .0001), and mean cost of revision for septic causes (£30,011) was more than 3 times that of revision for other causes (£9655; P < .0001). The authors concluded that the higher costs of revision knee surgery have a considerable economic impact, especially in infection cases.

With more extensive procedures, long-stem or more constrained prostheses are often needed to obtain adequate fixation and stability. The resulting increased, substantial economic burden is felt by patients and the health care system. Given that health care reimbursements are declining, hospitals that perform revision TKAs can sustain marked financial losses. Some centers are asking whether it is cost-effective to continue to perform these types of procedures. We must find new ways to provide revision procedures using less costly implants and tools so that centers will continue to make these procedures available to patients.

Conclusion

Given the exponential growth in primary TKAs, there will be a concordant increase in revision TKAs in the decades to come. This review provides a concise overview of revision TKA outcomes. Given the low level of evidence regarding revision TKAs, we need further higher quality studies of their prostheses and outcomes. Specifically, we need systematic reviews and meta-analyses to provide higher quality evidence regarding outcomes of using individual prosthetic designs.

The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.

While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.

For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.

Crossing the placenta

Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.

Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.

Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.

Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.

Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.

Infection risk

Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.

Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.

There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.

Impact on vaccination

Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.

Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.

Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.

So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.

Future directions

Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.

The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].

The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.

While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.

For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.

Crossing the placenta

Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.

Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.

Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.

Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.

Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.

Infection risk

Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.

Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.

There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.

Impact on vaccination

Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.

Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.

Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.

So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.

Future directions

Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.

The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].

The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.

While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.

For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.

Crossing the placenta

Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.

Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.

Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.

Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.

Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.

Infection risk

Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.

Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.

There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.

Impact on vaccination

Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.

Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.

Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.

So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.

Future directions

Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.

The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].