Disease-matched Group Research Articles

S751 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update

Introduction: Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab in human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational pregnancy cohort study planned to enroll and analyze the outcomes of 100 vedolizumab-exposed (Vedo) participants compared to 100 disease-matched (DM) and 100 healthy comparison (HC) participants. Methods: Pregnant women treated with vedolizumab for UC or CD with at least one dose in the first trimester were enrolled in the Vedo group. Pregnant women with UC or CD but no exposure to vedolizumab were enrolled in the DM group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an auto-inflammatory or other exclusionary disease were enrolled in the HC group. Data were collected from telephone interviews and maternal and pediatric medical records; live-born children were followed to one year of age with a dysmorphological examination and developmental screening. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC. Results: Between December 2015 and March 2022, outcomes were collected for 301 women, 98 in the Vedo group, 104 in the DM group, and 99 in the HC group. SIBDQ mean scores were similar in the Vedo group, 5.8 (SD 1.0) and the DM group, 5.9 (SD 1.0). Preliminary descriptive outcome data are shown in Table. In the Vedo group 7.3% of pregnancies resulted in a fetus or infant with a major birth defect, compared to 7.8% in the DM group, and 4.7% in the HC group. No pattern of major birth defects was identified in the Vedo group. Conclusion: The proportion of pregnancies with vedolizumab exposure resulting in a major birth defect are similar to proportions in the disease comparison group, and did not represent a specific pattern. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis planned once the study is completed in 2023. Table 1. - Pregnancy Outcomes in the Study Cohort Vedo-Total(N=98) DM-Total(N=104) HC-Total(N=99) Pregnancies ending with live born infant - n/N (%) 93/98 (94.9) 99/104 (95.2) 85/99 (85.9) Spontaneous abortion – N (Left Truncation Accounted Rate a ) 3 (8.7%) 3 (6.1%) 1 (6.4%) Termination - n/N (%) 0/98 (0.0) 0/104 (0.0) 0/99 (0.0) Stillbirth - n/N (%) 0/98 (0.0) 1/104 (1.0) 0/99 (0.0) Lost to follow-up (LTFU) - n/N (%) 2/98 (2.0) 1/104 (1.0) 13/99 (13.1) Preterm delivery – N (Rate b ) 13 (14.5%) 6 (6.1%) 6 (7.2%) Birth weight full term infants – mean g (SD) 3410.4 (436.7) 3428.8 (454.0) 3308.1 (432.3) Number of pregnancies with major birth defects among all pregnancies excluding LTFU – n/N’ (%) 7/96 (7.3) 8/103 (7.8) 4/86 (4.7) Serious infections in live born infants up to 1 year of age – n/N’(%) c 3/97 (3.1) 2/99 (2.0) 1/88 (1.1) Ages and Stages Screening at 1 year of age with concern – n/N’ (%) c 10/66 (15.2) 20/87 (23.0) 11/59 (18.6) aSpontaneous abortion rate computed using Fleming-Harrington estimate at 20 weeks' gestation, accounting for left truncation because women can enroll at various times in gestation;bComputed using Fleming-Harrington estimate at 37 weeks' gestation;cIncludes twins; % = (n/N') * 100. N' at each category: Number of pregnancies meeting the criteria specified in the row title.

Normative vs. patient-specific brain connectivity in deep brain stimulation

Brain connectivity profiles seeding from deep brain stimulation (DBS) electrodes have emerged as informative tools to estimate outcome variability across DBS patients. Given the limitations of acquiring and processing patient-specific diffusion-weighted imaging data, a number of studies have employed normative atlases of the human connectome. To date, it remains unclear whether patient-specific connectivity information would strengthen the accuracy of such analyses. Here, we compared similarities and differences between patient-specific, disease-matched and normative structural connectivity data and their ability to predict clinical improvement.Data from 33 patients suffering from Parkinson's Disease who underwent surgery at three different centers were retrospectively collected. Stimulation-dependent connectivity profiles seeding from active contacts were estimated using three modalities, namely patient-specific diffusion-MRI data, age- and disease-matched or normative group connectome data (acquired in healthy young subjects). Based on these profiles, models of optimal connectivity were calculated and used to estimate clinical improvement in out of sample data.All three modalities resulted in highly similar optimal connectivity profiles that could largely reproduce findings from prior research based on this present novel multi-center cohort. In a data-driven approach that estimated optimal whole-brain connectivity profiles, out-of-sample predictions of clinical improvements were calculated. Using either patient-specific connectivity (R = 0.43 at p = 0.001), an age- and disease-matched group connectome (R = 0.25, p = 0.048) and a normative connectome based on healthy/young subjects (R = 0.31 at p = 0.028), significant predictions could be made.Our results of patient-specific connectivity and normative connectomes lead to similar main conclusions about which brain areas are associated with clinical improvement. Still, although results were not significantly different, they hint at the fact that patient-specific connectivity may bear the potential of explaining slightly more variance than group connectomes. Furthermore, use of normative connectomes involves datasets with high signal-to-noise acquired on specialized MRI hardware, while clinical datasets as the ones used here may not exactly match their quality. Our findings support the role of DBS electrode connectivity profiles as a promising method to investigate DBS effects and to potentially guide DBS programming.

717 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update

INTRODUCTION: Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab during human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational cohort study intends to enroll and analyze the outcomes of 100 vedolizumab-exposed participants compared to 100 disease-matched (DM) comparison and 100 healthy comparison (HC) participants. This abstract describes progress of the study through March 1, 2019. METHODS: Pregnant women treated with vedolizumab for UC or CD for at least some part of the first trimester were enrolled in the vedolizumab-exposed group. Pregnant women with no exposure to vedolizumab were enrolled in a DM comparison group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an autoimmune disease or any other disease as defined by the OTIS Research Center were enrolled in a HC group. Pregnancy exposure and outcome data were collected from telephone interviews and medical records. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC at enrollment and 32 weeks' gestation. Follow-up of live born children included a dysmorphological exam, pediatric records review and developmental screening at one year of age. RESULTS: Between December 2015 and March 2019, outcomes were collected for 223 women, 53 in the vedolizumab group, 88 in the DM group, and 82 in the HC group. Preliminary descriptive data are shown in Table 1. No major structural birth defects were reported in the vedolizumab group, compared to 5 (5.7%) in the DM group, and 4 (5.3%) in the HC group. There was no evidence of a pattern of minor structural defects in the vedolizumab group. CONCLUSION: Updated data indicate pregnant women treated with vedolizumab in at least the 1st trimester have similar birth outcomes to disease-matched and healthy comparison women. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis to be performed when the study is completed.

Pregnancy Outcome in Women Treated With Adalimumab for the Treatment of Rheumatoid Arthritis: An Update on the OTIS Autoimmune Diseases in Pregnancy Project

Introduction: To investigate pregnancy outcomes in women who received adalimumab (ADA) to treat rheumatoid arthritis (RA) during pregnancy. Methods: The OTIS collaborative research group conducted a prospective cohort study in the U.S. and Canada, 2004-2013, comparing pregnancy outcomes in women with RA treated with ADA to women with RA not treated with ADA. Participants may have been treated with another disease-modifying antirheumatic drug or steroid but not methotrexate. An additional comparison group included women without any autoimmune disease. Participants enrolled <19 weeks gestation and were followed by telephone interviews and medical record review. A subset of infants received a dysmorphological examination by a study physician. Outcomes were compared using regression or survival methods with adjustment for confounders. Results: Seventy-four ADA-exposed, 80 disease-matched and 218 non-diseased women were enrolled. Women in the ADA group had at least 1 dose in the first trimester; ˜43% used ADA in all trimesters. Disease severity was similar between the two diseased groups. The rates of major defects in the exposed, disease-matched, and non-diseased comparison groups were 5.6%, 7.8%, and 5.5% respectively. There was no significant difference in the rate of major malformations among live births in the ADA vs. disease-matched group (adjusted relative risk 1.14, 95% confidence interval [CI] 0.26, 4.93). Among those who received the dysmorphological examination, there were no differences in number with ≥3 minor malformations, and no specific pattern was identified. There was no significant difference in the risk of spontaneous abortion in the ADA vs. disease-matched groups (adjusted hazard ratio 1.96, 95% CI 0.47, 8.26); the rate was elevated in comparison to the non-diseased group (adjusted hazard ratio 3.79, 95% CI 1.01, 14.23), although the number of events was small. Rates of preterm delivery and small for gestational age were similar across groups. Conclusion: Pregnant women with RA treated with ADA in the first trimester compared to women with the same condition do not appear to be at increased risk of the adverse pregnancy outcomes evaluated. Although the sample size is small, these results are reassuring to pregnant women with RA who require treatment with ADA. AbbVie provided funding for this study and participated in the study design. AbbVie did not participate in study conduct, analysis, and interpretation of data. AbbVie had the opportunity to review and comment on the publication. All authors independently analyzed and interpreted the data, and authors maintained full control over the content of the publication. Disclosure - Research Grant Funding: Bristol Myers Squibb, La Roche, Genentech, CSL, Novartis, Amgen, Celgene, GSK, UCB, Eli, Protein Sciences, Abbott, TIS, Norvartis, Janseen, Sanofi Aventis, Pfizer. This research was supported by an industry grant from This research was supported by a grant from AbbVie Inc.

Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study

Background: Safety data on first-trimester natalizumab exposure are scarce, as natalizumab is usually withdrawn three months before pregnancy. Objective: The objective of this paper is to investigate the fetal safety of exposure to natalizumab (Tysabri®) during the first trimester of pregnancy using disease-matched (DM) and healthy control (HC) comparison groups. Methods: A total of 101 German women with RRMS exposed to natalizumab during the first trimester of pregnancy were identified. Birth outcomes in the exposed group were compared to a DM group (N = 78) with or without exposure to other disease-modifying drugs, and an HC group (N = 97). Results: A total of 77, 69 and 92 live births occurred in the Exposed, DM and HC groups, respectively. The rates of major malformations (p = 0.67), low birth weight (<2500 grams) (p = 1.0) and premature birth (p = 0.37) did not differ among groups. Higher miscarriage rates (p = 0.002) and lower birth weights (p = 0.001) occurred among the Exposed and DM groups, as compared to the HC; however, there was no significant difference between the Exposed and DM groups. Conclusion: Exposure to natalizumab in early pregnancy does not appear to increase the risk of adverse pregnancy outcomes in comparison to a DM group not exposed to natalizumab.

Pregnancy Outcomes in Women Exposed to Adalimumab

Purpose: The fully human, anti-tumor necrosis factor monoclonal antibody adalimumab is approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis in the United States, Europe, and elsewhere, as well as for juvenile idiopathic arthritis in the United States. Methods: This report describes preliminary outcomes from an ongoing study of the safety of adalimumab in RA patients during pregnancy conducted by the Organization of Teratology Information Specialists (OTIS). Through a prospective cohort design, women with RA treated with adalimumab during the first trimester of pregnancy were followed for 1-year postpartum. Pregnancy outcomes were compared with those from a disease-matched group of pregnant women with RA who had not been treated with adalimumab during their pregnancies, and a non-diseased group of women who neither had RA nor had been treated with adalimumab. In addition to conducting the cohort study, the OTIS investigators also collected information on adalimumab-exposed pregnancies that did not meet the cohort criteria, but were followed as a case series. The case-series pregnancies are presented separately as they have no comparison group. They include patients treated for diseases other than RA, as well as retrospectively reported outcomes. Results: As of May 15, 2008 (4 years of the study), pregnancy outcomes were available for 126 women in the cohort (Table). Two major structural defects (6.6%) had been reported for 30 women with adalimumab exposure during their first trimesters for whom pregnancy outcomes were known: 1 with undescended testicle and 1 with microcephaly. For 51 pregnancies in the disease-matched comparison group for which pregnancy outcomes were known, 1 fetus (2.0%) was diagnosed with chromosomal abnormalities. Two major structural defects (5.1%) have been reported via 39 pregnancies with known outcomes in the healthy comparison group. In the case-series group (data not included in the Table), of the 66 known outcomes, 7 (10.6%) resulted in major congenital defects — 3 chromosomal anomalies, 1 spina bifida with hydrocephalus, 1 ventricular septal defect, 1 congenital hip dysplasia with inguinal hernia, and 1 congenital hypothyroidism. Of these 66 known outcomes in the case series, 23 had a diagnosis of Crohn's disease.Table: Pregnancy Outcomes in the OTIS Cohort StudyConclusion: Based on these preliminary data, no concerns have been raised regarding increased risks for adverse pregnancy outcomes associated with early pregnancy exposure to adalimumab in the treatment of RA. Firm conclusions await accumulation of sufficient sample size in this prospective cohort study. In Fall 2008, the OTIS cohort study will expand enrollment to include patients with Crohn's disease.

Citalopram use in pregnancy: Prospective comparative evaluation of pregnancy and fetal outcome

Citalopram is a selective serotonin reuptake inhibitor indicated for depression. The safety of this medication in pregnancy has not been fully established. The purpose of this study was to investigate whether citalopram is associated with an increased incidence of adverse pregnancy outcomes. Pregnant women who contacted the Motherisk Program, a Teratogen Information Center in Toronto, Ontario, with regard to the safety of citalopram in pregnancy were enrolled in the study. The exposed women were matched to a disease-matched group of women and a nonteratogenic group. All women were matched for age (+/- 2 years) and gestational age at time of first call to the Motherisk (+/- 2 weeks). A structured telephone follow-up interview was conducted following the expected date of confinement. The total number of pregnant women enrolled in this study was 396 (132 women in each group). A total of 125 women took citalopram at least in the first trimester. Seventy-one (54%) women continued to take the drug throughout pregnancy. One hundred fourteen women (86%) had live births, 14 (11%) had spontaneous abortions, 2 (1.5%) had elective terminations, and 2 (1.5%) experienced stillbirths. Fetal survival rates, mean birth weights, and duration of pregnancy were not statistically different among the 3 groups. Of 108 live-born infants whose mothers were exposed to citalopram in the first trimester, there was 1 (0.9%) male infant born with a major malformation. There was a relative risk of 4.2 (95% confidence interval 1.71-10.26) in neonates exposed to citalopram close to term to be admitted to special-care nurseries as compared with the unexposed infants. Citalopram use during the period of embryogenesis in pregnancy is not associated with an apparent major teratogenic risk. Late pregnancy use of citalopram is associated with increased risk of poor neonatal adaptation syndrome, recently described with other selective serotonin reuptake inhibitors.

Pregnancy outcome following gestational exposure to montelukast: A prospective cotrolled study

Background Asthma is the most common respiratory crisis complicating pregnancy. Montelukast is prescribed orally for chronic treatment of asthma. Although animal reproductive studies show no evidence of teratogenic effects, there are no human studies assessing possible effects on the developing fetus with in utero exposure. Despite known risks associated with poorly controlled asthma, lack of safety data prevents women from using montelukast in pregnancy. Our aim is to evaluate pregnancy outcomes following gestational exposure to montelukast. Methods This prospective controlled study enrolls pregnant women who contact Motherisk about exposure to montelukast. These women are followed up using standardized data collection forms. Montelukast-exposed women are compared to a disease-matched group using inhalers for similar indications and a group of women exposed to known non-teratogens. Rates of major anomalies and other adverse outcomes are compared between groups. Results To date, 64 women exposed to montelukast during 1st trimester have been enrolled, of which 24 have used it throughout pregnancy. Outcomes of this group include: 62 (96.9%) live births, 2 (3.1%) SA and 2 (3.1%) major malformations. Upon comparison to controls, no statistical differences are apparent in these or any other endpoints of interest. Conclusions Data collected thus far in this ongoing study appear to suggest no increased risk for major malformations above baseline of 1–3%, following use of montelukast in pregnancy. Clinical Pharmacology & Therapeutics (2005) 77, P30–P30; doi: 10.1016/j.clpt.2004.12.005

The Ross Procedure: Shorter Hospital Stay, Decreased Morbidity, and Cost Effective

Background. The Ross procedure has become an accepted and sometimes preferred alternative to mechanical aortic valve replacement. One criticism of the Ross procedure is that it may have a higher operative mortality, morbidity, and cost. Several groups have shown that this operation can be performed safely with less than 3% mortality. The issue of higher cost has not been resolved. In this retrospective study we compared a consecutive group of patients undergoing the Ross procedure with an age- and disease-matched group of patients who underwent mechanical aortic valve replacement. Methods. From 1993 to 1996, 22 consecutive adult patients (age range, 20 to 57 years; mean, 38 ± 14 years) underwent the Ross procedure. Twenty-seven patients (age range, 17 to 57 years; mean, 41 ± 10 years) underwent mechanical aortic valve replacement between 1991 and 1996. The hospital cost (in 1996 dollars) and postoperative length of stay were calculated for each patient using Transition I, a hospital-wide cost accounting system. Results. There was no hospital mortality in either group. The incidence of significant valve-related complication was 5% (1/22 patients) in the Ross procedure group and 22% (6/27 patients) in the mechanical valve group. There were two late deaths in the group with mechanical aortic valve replacement. The length of stay for the Ross procedure group was 5.9 ± 2.1 days, versus 8 ± 1.85 days for the mechanical valve group ( p < 0.01). The mean hospital costs were not significantly different, $23,140 ± $7,825 for the mechanical valve group and $23,226 ± $6,960 for the group having the Ross procedure. Conclusions. The data from this review demonstrate that the Ross procedure can be done safely, with short hospital stays, decreased morbidity, and costs comparable with those of standard mechanical aortic valve replacement in patients with isolated aortic valve disease.

New postmarketing surveillance data supports a lack of association between quinolone use in pregnancy and fetal and neonatal complications

Citalopram is a selective serotonin reuptake inhibitor indicated for depression. The safety of this medication in pregnancy has not been fully established. The purpose of this study was to investigate whether citalopram is associated with an increased incidence of adverse pregnancy outcomes.Pregnant women who contacted the Motherisk Program, a Teratogen Information Center in Toronto, Ontario, with regard to the safety of citalopram in pregnancy were enrolled in the study. The exposed women were matched to a disease-matched group of women and a nonteratogenic group. All women were matched for age (± 2 years) and gestational age at time of first call to the Motherisk (± 2 weeks). A structured telephone follow-up interview was conducted following the expected date of confinement.The total number of pregnant women enrolled in this study was 396 (132 women in each group). A total of 125 women took citalopram at least in the first trimester. Seventy-one (54%) women continued to take the drug throughout pregnancy. One hundred fourteen women (86%) had live births, 14 (11%) had spontaneous abortions, 2 (1.5%) had elective terminations, and 2 (1.5%) experienced stillbirths. Fetal survival rates, mean birth weights, and duration of pregnancy were not statistically different among the 3 groups. Of 108 live-born infants whose mothers were exposed to citalopram in the first trimester, there was 1 (0.9%) male infant born with a major malformation. There was a relative risk of 4.2 (95% confidence interval 1.71-10.26) in neonates exposed to citalopram close to term to be admitted to special-care nurseries as compared with the unexposed infants.Citalopram use during the period of embryogenesis in pregnancy is not associated with an apparent major teratogenic risk. Late pregnancy use of citalopram is associated with increased risk of poor neonatal adaptation syndrome, recently described with other selective serotonin reuptake inhibitors.