Biologics and Pregnancy: Insights From the OTIS Study

PHILADELPHIA —Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than was a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

“Although outcomes were presented for these pregnancies, I always caution health care providers and patients that these are ongoing studies with a target sample size that is intended to have sufficient power to answer our research questions. For that reason, we have not performed any formal interim statistical analysis nor have we adjusted for differences between groups, such as maternal smoking or folic acid use, that may affect pregnancy outcomes,” said Dr. Chambers of the department of pediatrics and family and preventive medicine at the University of California, San Diego.

OTIS is a prospective observational cohort study with the purpose of evaluating the effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000 and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. Many participants are referred by their rheumatologists to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. Although the literature contains case reports, the OTIS project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls. The percentage of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%), and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls.

The defects included displaced stomach with epispa-dias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. No cases of the malformation patterns VATER or VACTERL were found.

“Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy (1%) cohorts. There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups, compared with healthy controls (4%). Mean birth weight was approximately 300 g less in term infants whose mothers had received adalimumab, compared with healthy controls, but similar to term infants in the disease-matched comparison group. Rates of major malformations were similar (4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis.

“It is important to recognize that many differences between medication-exposed and comparison groups can be accounted for by other maternal risk factors, and so until these are addressed in multivariate analysis, we are dealing with very preliminary results. We also will be evaluating minor anomalies, 1-year growth, and developmental screening data,” Dr. Chambers said.

'Firm conclusions await the accumulation of target sample size' needed for multivariate analysis.

Source DR. CHAMBERS

PHILADELPHIA —Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than was a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

“Although outcomes were presented for these pregnancies, I always caution health care providers and patients that these are ongoing studies with a target sample size that is intended to have sufficient power to answer our research questions. For that reason, we have not performed any formal interim statistical analysis nor have we adjusted for differences between groups, such as maternal smoking or folic acid use, that may affect pregnancy outcomes,” said Dr. Chambers of the department of pediatrics and family and preventive medicine at the University of California, San Diego.

OTIS is a prospective observational cohort study with the purpose of evaluating the effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000 and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. Many participants are referred by their rheumatologists to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. Although the literature contains case reports, the OTIS project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls. The percentage of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%), and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls.

The defects included displaced stomach with epispa-dias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. No cases of the malformation patterns VATER or VACTERL were found.

“Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy (1%) cohorts. There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups, compared with healthy controls (4%). Mean birth weight was approximately 300 g less in term infants whose mothers had received adalimumab, compared with healthy controls, but similar to term infants in the disease-matched comparison group. Rates of major malformations were similar (4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis.

“It is important to recognize that many differences between medication-exposed and comparison groups can be accounted for by other maternal risk factors, and so until these are addressed in multivariate analysis, we are dealing with very preliminary results. We also will be evaluating minor anomalies, 1-year growth, and developmental screening data,” Dr. Chambers said.

'Firm conclusions await the accumulation of target sample size' needed for multivariate analysis.

Source DR. CHAMBERS

PHILADELPHIA —Women with rheumatic disease who took etanercept during pregnancy were three times more likely to have a child with a major malformation than was a disease-matched comparison group, judging from interim results from a small sample.

Most of the malformations were isolated, and no patterns of birth defect were apparent, according to Christina Chambers, Ph.D., who presented the findings from the Autoimmune Diseases in Pregnancy Project being conducted by the Organization of Teratology Information Specialists (OTIS) at the annual meeting of the American College of Rheumatology.

“Although outcomes were presented for these pregnancies, I always caution health care providers and patients that these are ongoing studies with a target sample size that is intended to have sufficient power to answer our research questions. For that reason, we have not performed any formal interim statistical analysis nor have we adjusted for differences between groups, such as maternal smoking or folic acid use, that may affect pregnancy outcomes,” said Dr. Chambers of the department of pediatrics and family and preventive medicine at the University of California, San Diego.

OTIS is a prospective observational cohort study with the purpose of evaluating the effects of autoimmune diseases and their treatment on pregnancy outcomes and fetal development. Recruitment began in 2000 and is projected to continue through 2015. Current recruitment stands at 944, with a goal of 1,500.

Pregnant women are typically enrolled in the study before they reach 20 weeks of gestation. To be enrolled, the women must have current diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, or Crohn's disease. Many participants are referred by their rheumatologists to the OTIS coordinating center, where they undergo multiple interviews and review of their symptom management. After birth, the infants are followed for up to a year, during which time they are assessed by their pediatricians, undergo blinded dysmorphological examination by OTIS physicians, and are photographed.

“Evaluating pregnancy outcomes following medication exposure is a not a situation that lends itself to conducting a randomized controlled trial for obvious ethical reasons,” said Dr. Chambers. Although the literature contains case reports, the OTIS project is designed to give clinicians the evidence-based information they need to counsel patients who are pregnant or considering becoming pregnant.

At the time of this progress report, outcome was available for 115 women with RA who had been exposed to etanercept, compared with 55 disease-comparison controls. Outcome was available for 42 women with RA who were exposed to adalimumab, compared with 58 disease-matched women and 84 healthy controls. The percentage of live births was higher in those treated with etanercept, compared with those with similar rheumatic diseases (92% vs. 85%), and fewer spontaneous abortions occurred in the etanercept-treated group (4% vs. 11%). There were no ectopic pregnancies in either group. One stillbirth was reported in the etanercept cohort and none in the controls. Preterm deliveries were more common in women who were taking etanercept (23% vs. 13%).

Of the major malformations among all pregnancies enrolled in OTIS, 12% (14 of 114) were reported in the etanercept group, compared with 3.8% (2 of 53) in the disease-matched controls.

The defects included displaced stomach with epispa-dias and congenital eye defect; ventricular septal defect with peripheral pulmonic stenosis; pyloric stenosis; hypospadias; ventricular septal defect with patent foramen ovale and patent ductus arteriosus; volvulus; patent foramen ovale; atrial septal defect with patent ductus arteriosus; microcephaly; congenital hypothyroidism; and an unspecified heart defect. Three abnormalities—Noonan syndrome, Turner syndrome, and Down syndrome—were genetic or chromosomal. No cases of the malformation patterns VATER or VACTERL were found.

“Typically we would see a specific pattern of malformation with a medication that truly causes defects, but our results indicate that most of the defects were isolated with no apparent patterns,” Dr. Chambers said.

For those exposed to adalimumab, the percentage of live births was lower in those receiving the drug (88%) compared with those with similar autoimmune illnesses (93%) and healthy controls (92%). The rate of spontaneous abortions also was higher in the adalimumab-treated cohort (12%) compared with the disease-matched (5%) and healthy (1%) cohorts. There were no ectopic pregnancies or stillbirths in the drug-treated group.

Preterm delivery was higher in both the adalimumab-treated (14%) and disease-matched comparison (17%) groups, compared with healthy controls (4%). Mean birth weight was approximately 300 g less in term infants whose mothers had received adalimumab, compared with healthy controls, but similar to term infants in the disease-matched comparison group. Rates of major malformations were similar (4% to 5%) in all groups and within the range of expected numbers in the general population, said Dr. Chambers.

“Firm conclusions await the accumulation of target sample size for adalimumab and etanercept and multivariate analysis.

“It is important to recognize that many differences between medication-exposed and comparison groups can be accounted for by other maternal risk factors, and so until these are addressed in multivariate analysis, we are dealing with very preliminary results. We also will be evaluating minor anomalies, 1-year growth, and developmental screening data,” Dr. Chambers said.

'Firm conclusions await the accumulation of target sample size' needed for multivariate analysis.

Source DR. CHAMBERS