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Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.
The data, culled from the British Society for Rheumatology Biologics Registry, is from the "largest detailed prospective collection of pregnancy outcomes in women with arthritis-related diseases exposed to anti-TNF therapy" to date, according to the authors.
Despite its relatively large size, however, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, as the authors readily admitted.
Nevertheless, "no firm conclusions can be drawn about the safety of anti-TNF therapy during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception must remain," recommended the authors.
The study was led by Dr. Suzanne M. M. Verstappen of the University of Manchester’s Arthritis Research UK Epidemiology Unit and was published online in Annals of the Rheumatic Diseases.
Dr. Verstappen and her colleagues looked at women in the registry who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception. A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a "known risk of adverse pregnancy outcomes," according to the authors.
A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use, but rather received nonbiological disease-modifying antirheumatic drugs (DMARDs), excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).
Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).
Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies. They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%) and 2 intrauterine deaths (occurring post-20 weeks).
There was also one neonatal death registered.
The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: the 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%). There were two intrauterine deaths, including the twin death.
Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were zero terminations and one spontaneous abortion (10%).
In all cohorts, the majority of patients had RA, and the majority took etanercept.
The baseline disease activity score-28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.
Dr. H. Michael Belmont, medical director of New York University’s Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, "The default choice would be to avoid these drugs during pregnancy. Certainly starting their use in a women contemplating conception should be delayed based on the data on hand."
Dr. Belmont, who was not affiliated with this study, joined the authors in pointing to a 2009 study by Carter et al., which found an increased observed: expected incidence of VACTERL defects (vertebral abnormalities, anal atresia, and/or cardiac, trachea, esophageal, renal, and limb abnormalities) in children born to women taking anti-TNFs (J. Rheumatol. 2009;36:635-41).
However, "The total observed number [of children born with VACTERL abnormalities] was small, 19 newborns, and the actual rate could not be calculated, as the authors relied on the [Food & Drug Administration] base of adverse events but did not know the [actual] number of exposed pregnancies, having to rely instead on historical controls to determine the expected ratio," he conceded.
On the other hand, Dr. Arthur Kavanaugh, a rheumatologist and director of the at the University of California San Diego’s Center for Innovative Therapy pointed to flaws in the current study’s analysis.
"The other explanation [for the finding of increased spontaneous abortion among anti-TNF users] is that it’s the disease more than the drug, so that people who have worse RA are going to have pregnancy outcomes that are not necessarily as good, and you just don’t know that from this because there’s only 10 people in the DMARD-only arm," he said in an interview.
"That’s just incredibly small. If you have one different outcome in that group, it would make a humongous difference in how you look at the data."
He added: "You can’t ignore the disease, and it’s the disease itself that’s going to affect the outcome as well."
Dr. Kavanaugh, like Dr. Belmont, was not affiliated with the study.
The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Wyeth Pharmaceuticals, and Roche. They added that they had no personal competing interests in relation to this study.
Dr. Kavanaugh disclosed that he has done research for the makers of TNF inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.
The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFs.
The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P. M. Symmons.
There are, however, a few problems with that strategy. "Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!" she joked.
"Beyond that, we have to wait for anecdotal evidence to accumulate."
In the meantime, she said, "We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment.
"There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug."
According to Dr. Symmons, when treating a female patient of child-bearing age, "I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.
"This study is reassuring for us to continue our current practice."
Dr. Symmons is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, in the UK. She had no financial interests to disclose.
The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P. M. Symmons.
There are, however, a few problems with that strategy. "Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!" she joked.
"Beyond that, we have to wait for anecdotal evidence to accumulate."
In the meantime, she said, "We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment.
"There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug."
According to Dr. Symmons, when treating a female patient of child-bearing age, "I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.
"This study is reassuring for us to continue our current practice."
Dr. Symmons is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, in the UK. She had no financial interests to disclose.
The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P. M. Symmons.
There are, however, a few problems with that strategy. "Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!" she joked.
"Beyond that, we have to wait for anecdotal evidence to accumulate."
In the meantime, she said, "We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment.
"There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug."
According to Dr. Symmons, when treating a female patient of child-bearing age, "I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.
"This study is reassuring for us to continue our current practice."
Dr. Symmons is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, in the UK. She had no financial interests to disclose.
Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.
The data, culled from the British Society for Rheumatology Biologics Registry, is from the "largest detailed prospective collection of pregnancy outcomes in women with arthritis-related diseases exposed to anti-TNF therapy" to date, according to the authors.
Despite its relatively large size, however, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, as the authors readily admitted.
Nevertheless, "no firm conclusions can be drawn about the safety of anti-TNF therapy during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception must remain," recommended the authors.
The study was led by Dr. Suzanne M. M. Verstappen of the University of Manchester’s Arthritis Research UK Epidemiology Unit and was published online in Annals of the Rheumatic Diseases.
Dr. Verstappen and her colleagues looked at women in the registry who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception. A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a "known risk of adverse pregnancy outcomes," according to the authors.
A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use, but rather received nonbiological disease-modifying antirheumatic drugs (DMARDs), excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).
Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).
Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies. They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%) and 2 intrauterine deaths (occurring post-20 weeks).
There was also one neonatal death registered.
The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: the 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%). There were two intrauterine deaths, including the twin death.
Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were zero terminations and one spontaneous abortion (10%).
In all cohorts, the majority of patients had RA, and the majority took etanercept.
The baseline disease activity score-28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.
Dr. H. Michael Belmont, medical director of New York University’s Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, "The default choice would be to avoid these drugs during pregnancy. Certainly starting their use in a women contemplating conception should be delayed based on the data on hand."
Dr. Belmont, who was not affiliated with this study, joined the authors in pointing to a 2009 study by Carter et al., which found an increased observed: expected incidence of VACTERL defects (vertebral abnormalities, anal atresia, and/or cardiac, trachea, esophageal, renal, and limb abnormalities) in children born to women taking anti-TNFs (J. Rheumatol. 2009;36:635-41).
However, "The total observed number [of children born with VACTERL abnormalities] was small, 19 newborns, and the actual rate could not be calculated, as the authors relied on the [Food & Drug Administration] base of adverse events but did not know the [actual] number of exposed pregnancies, having to rely instead on historical controls to determine the expected ratio," he conceded.
On the other hand, Dr. Arthur Kavanaugh, a rheumatologist and director of the at the University of California San Diego’s Center for Innovative Therapy pointed to flaws in the current study’s analysis.
"The other explanation [for the finding of increased spontaneous abortion among anti-TNF users] is that it’s the disease more than the drug, so that people who have worse RA are going to have pregnancy outcomes that are not necessarily as good, and you just don’t know that from this because there’s only 10 people in the DMARD-only arm," he said in an interview.
"That’s just incredibly small. If you have one different outcome in that group, it would make a humongous difference in how you look at the data."
He added: "You can’t ignore the disease, and it’s the disease itself that’s going to affect the outcome as well."
Dr. Kavanaugh, like Dr. Belmont, was not affiliated with the study.
The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Wyeth Pharmaceuticals, and Roche. They added that they had no personal competing interests in relation to this study.
Dr. Kavanaugh disclosed that he has done research for the makers of TNF inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.
The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFs.
Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.
The data, culled from the British Society for Rheumatology Biologics Registry, is from the "largest detailed prospective collection of pregnancy outcomes in women with arthritis-related diseases exposed to anti-TNF therapy" to date, according to the authors.
Despite its relatively large size, however, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, as the authors readily admitted.
Nevertheless, "no firm conclusions can be drawn about the safety of anti-TNF therapy during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception must remain," recommended the authors.
The study was led by Dr. Suzanne M. M. Verstappen of the University of Manchester’s Arthritis Research UK Epidemiology Unit and was published online in Annals of the Rheumatic Diseases.
Dr. Verstappen and her colleagues looked at women in the registry who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception. A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a "known risk of adverse pregnancy outcomes," according to the authors.
A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use, but rather received nonbiological disease-modifying antirheumatic drugs (DMARDs), excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).
Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).
Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies. They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%) and 2 intrauterine deaths (occurring post-20 weeks).
There was also one neonatal death registered.
The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: the 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%). There were two intrauterine deaths, including the twin death.
Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were zero terminations and one spontaneous abortion (10%).
In all cohorts, the majority of patients had RA, and the majority took etanercept.
The baseline disease activity score-28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.
Dr. H. Michael Belmont, medical director of New York University’s Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, "The default choice would be to avoid these drugs during pregnancy. Certainly starting their use in a women contemplating conception should be delayed based on the data on hand."
Dr. Belmont, who was not affiliated with this study, joined the authors in pointing to a 2009 study by Carter et al., which found an increased observed: expected incidence of VACTERL defects (vertebral abnormalities, anal atresia, and/or cardiac, trachea, esophageal, renal, and limb abnormalities) in children born to women taking anti-TNFs (J. Rheumatol. 2009;36:635-41).
However, "The total observed number [of children born with VACTERL abnormalities] was small, 19 newborns, and the actual rate could not be calculated, as the authors relied on the [Food & Drug Administration] base of adverse events but did not know the [actual] number of exposed pregnancies, having to rely instead on historical controls to determine the expected ratio," he conceded.
On the other hand, Dr. Arthur Kavanaugh, a rheumatologist and director of the at the University of California San Diego’s Center for Innovative Therapy pointed to flaws in the current study’s analysis.
"The other explanation [for the finding of increased spontaneous abortion among anti-TNF users] is that it’s the disease more than the drug, so that people who have worse RA are going to have pregnancy outcomes that are not necessarily as good, and you just don’t know that from this because there’s only 10 people in the DMARD-only arm," he said in an interview.
"That’s just incredibly small. If you have one different outcome in that group, it would make a humongous difference in how you look at the data."
He added: "You can’t ignore the disease, and it’s the disease itself that’s going to affect the outcome as well."
Dr. Kavanaugh, like Dr. Belmont, was not affiliated with the study.
The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Wyeth Pharmaceuticals, and Roche. They added that they had no personal competing interests in relation to this study.
Dr. Kavanaugh disclosed that he has done research for the makers of TNF inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.
The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFs.
FROM ANNALS OF THE RHEUMATIC DISEASES
Major Finding: Among women who took anti–tumor necrosis factor drugs at the time of conception, 24% of pregnancies ended in spontaneous abortion vs. 17% among women who took the drugs in the past but not at conception and 10% among women with no history of exposure.
Data Source: The British Society for Rheumatology Biologics Registry.
Disclosures: The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Shering-Plough, Roche, and Wyeth Pharmaceuticals. They added that they had no personal competing interests in relation to this study.
Dr. Kavanaugh disclosed that he has done research for the makers of TNF-inhibitors, including Abbot Laboratories, Amgen, Centocor, and UCB. Dr. Belmont did not make any disclosures relevant to this study.
The British Society for Rheumatology receives funding from several pharmaceutical companies, including the makers of anti-TNFS.