Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.

BACKGROUND & AIMS: Little is known about in utero exposure to and postnatal clearance of anti-tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P = .02). CONCLUSIONS: In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

Casein glycomacropeptide for active distal ulcerative colitis: a randomized pilot study.

BACKGROUND: In ulcerative colitis (UC), dietary supplements may have anti-inflammatory properties and improve disease course. We investigated the effects of casein glycomacropeptide (CGMP), a fraction of bovine whey protein, in active UC. MATERIALS AND METHODS: In a randomized open-label intervention study, 24 patients with active UC involving 10-40 cm of the distal colon were randomized in a 2 : 1 ratio into two groups. The first group was administered their usual treatment plus a daily supplement of CGMP 30 g, and the second group was administered a dose escalation to 4800 mg oral mesalamine daily (standard treatment) for 4 weeks. Clinical, endoscopic, mucosal and circulating disease activity markers were monitored. Acceptance of and adherence to CGMP up to 8 weeks were documented. RESULTS: After 4 weeks of treatment, 10 of 16 (63%) patients who received CGMP had an unchanged or decreased Simple Clinical Colitis Activity Index (SCCAI), which was similar to the four of eight (50%) (P = 0·67) patients on the standard treatment. The number of patients in which SCCAI decreased by three or more did not differ between the two groups: nine of 16 (56%) in the CGMP group vs. four of eight (50%) in the standard treatment group (P = 0·77). Changes in disease extent and severity were similar between the two groups. CGMP was well tolerated and accepted by the patients. CONCLUSIONS: The addition of CGMP as a nutritional therapy to standard treatment was safe and accepted by patients with active distal UC. The disease-modifying effect of CGMP was similar to that of the mesalamine dose escalation.

Symptoms and findings in adult-onset celiac disease in a historical Danish patient cohort.

OBJECTIVE: The presentation of celiac disease (CD) has changed over the past decades. We aimed to describe the incidence of CD and its complications at diagnosis in a historical cohort in a well-defined population in Denmark. METHODS: We included all patients aged 15+ years, who lived in Aarhus County, Denmark, and who were diagnosed with CD between January 2008 and August 2013. Data regarding gastrointestinal symptoms, anthropometrics, biochemistry, and bone mineral density were retrieved from patient records. RESULTS: A total of 93 patients with a valid CD diagnosis were identified, corresponding to an incidence rate of 6.4 per 100,000 person-years. At diagnosis, diarrhea and weight loss occurred in 54% and 47% patients, respectively. In total, 30% had anemia; 40%, iron deficiency; 20%, folate deficiency; and 17%, vitamin B12 deficiency. Vitamin D deficiency was present in 34%. In 28%, bone mineral density was determined during the first year after diagnosis. Of these, 54% had osteopenia and 12% osteoporosis. After introduction of a gluten-free diet, 28% had normalized transglutaminase antibody levels after 6 months, and 56% did after 12 months. Diabetes mellitus type 1 was present in 7%; dermatitis herpetiformis, in 3%; and thyroid dysfunction, in 5%. CONCLUSIONS: Only half of newly diagnosed CD patients presented with classic gastrointestinal symptoms. Anemia and vitamin deficiencies were common. Bone mineral density was determined in less than a third of the patients, and osteoporosis occurred in 12% of these. Serologic markers of CD normalized in approximately half of patients during the first year after the diagnosis.

Individualized Therapy Is a Long-Term Cost-Effective Method Compared to Dose Intensification in Crohn's Disease Patients Failing Infliximab.

BACKGROUND: In Crohn's disease patients failing infliximab therapy, interventions defined by an algorithm based on infliximab and anti-infliximab antibody measurements have proven more cost-effective than intensifying the infliximab regimen. AIM: This study investigated long-term economic outcomes at the week 20 follow-up study visit and after 1 year. Clinical outcomes were assessed at week 20. METHODS: Follow-up from a 12-week, single-blind, clinical trial where patients with infliximab treatment failure were randomized to infliximab intensification (5 mg/kg every 4 weeks) (n = 36), or algorithm-defined interventions (n = 33). Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry. RESULTS: At the scheduled week 20 follow-up study visit, response and remission rates were similar in all study subpopulations between patients treated by the algorithm or by infliximab intensification. However, the sum of healthcare costs related to Crohn's disease was substantially lower (31 %) for patients randomized to algorithm-based interventions than infliximab intensification in the intention-to-treat population: $11,940 versus $17,236; p = 0.005. For per-protocol patients (n = 55), costs at the week 20 follow-up visit were even lower (49 %) in the algorithm group: $8,742 versus $17,236; p = 0.002. Figures were similar for patients having completed the 12-week trial as per protocol (50 % reduction in costs) (n = 45). Among patients continuing the allocated study intervention throughout the entire 20-week follow-up period (n = 29), costs were reduced by 60 % in algorithm-treated patients: $7,056 versus $17,776; p < 0.001. Cost-reduction percentages remained stable throughout one year. CONCLUSION: Economic benefit of algorithm-based interventions at infliximab failure is maintained throughout 1 year.

Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system.

BACKGROUND: Tracking an ingested magnet by the Magnet Tracking System MTS-1 (Motilis, Lausanne, Switzerland) is an easy and minimally-invasive method to assess gastrointestinal transit. The aim was to test the validity of MTS-1 for assessment of gastric transit time and small intestinal transit time, and to illustrate transit patterns detected by the system. METHODS: A small magnet was ingested and tracked by an external matrix of 16 magnetic field sensors (4 × 4) giving a position defined by 5 coordinates (position: x, y, z, and angle: θ, φ). Eight healthy subjects were each investigated three times: (1) with a small magnet mounted on a capsule endoscope (PillCam); (2) with the magnet alone and the small intestine in the fasting state; and (3) with the magnet alone and the small intestine in the postprandial state. RESULTS: Experiment (1) showed good agreement and no systematic differences between MTS-1 and capsule endoscopy when assessing gastric transit (median difference 1 min; range: 0-6 min) and small intestinal transit time (median difference 0.5 min; range: 0-52 min). Comparing experiments (1) and (2) there were no systematic differences in gastric transit or small intestinal transit when using the magnet-PillCam unit and the much smaller magnetic pill. In experiments (2) and (3), short bursts of very fast movements lasting less than 5% of the time accounted for more than half the distance covered during the first two hours in the small intestine, irrespective of whether the small intestine was in the fasting or postprandial state. The mean contraction frequency in the small intestine was significantly lower in the fasting state than in the postprandial state (9.90 min-1 vs. 10.53 min-1) (p = 0.03). CONCLUSION: MTS-1 is reliable for determination of gastric transit and small intestinal transit time. It is possible to distinguish between the mean contraction frequency of small intestine in the fasting state and in the postprandial state.

Anti-TNF Therapy in Pregnant Women With Inflammatory Bowel Disease: Effects of Therapeutic Strategies on Disease Behavior and Birth Outcomes.

BACKGROUND: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling. METHODS: Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression. RESULTS: Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided. CONCLUSIONS: To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.

Development of a Sexual Dysfunction Scale for Women With Inflammatory Bowel Disease.

Background: Women with inflammatory bowel disease (IBD) may have decreased sexual function. To understand how common this condition is in our female patients, we developed a new IBD-specific Female Sexual Dysfunction Scale (the IBD-FSDS). Methods: We performed a prospective cross-sectional study of 454 female IBD patients ≥18 years of age attending 1 of 3 IBD clinics in the United States or Denmark. We gathered information on sexual function via a de novo 23-item scale. General sexual functioning was measured with the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R). Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9). Medical history and sociodemographic data were collected via chart review. Exploratory factor analyses (EFAs) of the English language version of IBD-FSDS assessed unidimensionality, factor structure, reliability, criterion validity, and construct validity. Results: EFAs suggested retaining 15-items creating a unidimensional scale with strong internal consistency reliability (α = 0.93). Validity of the English language IBD-FSDS was measured using Spearman's coefficient, demonstrating significant criterion validity with the FSDS-R (P < 0.05) and the FSFI (P < 0.05) and significant construct validity with the composite for cases of active IBD (P < 0.05) and PHQ-9 (P < 0.05). Sexual dysfunction in women with IBD was significantly associated with depression (P = 0.042), active IBD (P = 0.002), and no history of surgery (P = 0.044). Conclusions: We have developed and validated an IBD-specific scale to assess the psychosexual impact of IBD in women. This novel screening questionnaire may help health care providers recognize factors contributing to impaired sexual function in their female patients.

Faecal microbiota transplantation for recurring Clostridium difficile infection in a patient with Crohn's disease and ileorectal anastomosis.

Faecal microbiota transplantation (FMT) is increasingly being used to treat refractory and recurring Clostridium difficile infection (CDI). Although FMT appears to be safe and highly effective in patients with a preserved colon and immunocompetence, its use in patients with inflammatory bowel disease (IBD) who are on immunomodulating therapies is controversial. In particular, patients who have undergone colectomy may have different treatment responses to FMT. In this case report, we describe the successful use of FMT in a female patient aged 19 years with Crohn's disease who underwent ileorectal anastomosis following colectomy. She had recurrent CDIs that were refractory to metronidazole, pulse-tapered vancomycin and fidaxomicin treatments. She underwent 2 FMTs, which were performed via sigmoidoscopy; her mother served as a donor. Follow-up was conducted for 12 months and indicated sustained remission of CDI.

Diagnosis of Helicobacter Pylori Infection is Associated with Lower Prevalence and Subsequent Incidence of Crohn's Disease.

BACKGROUND AND AIMS: Helicobacter pylori infection may protect against some chronic inflammatory diseases. This study examined H. pylori infection and its association with the prevalence of the gastrointestinal diseases Crohn's disease [CD], ulcerative colitis [UC], and coeliac disease [CeD]. Incident cases in a follow-up period after H. pylori testing were recorded to investigate if protective effects of H. pylori persisted after probable eradication. METHODS: This was a historical cohort study performed in the Central Denmark Region. Patients were enrolled consecutively from primary health care centres after a urea breath test [UBT] for H. pylori and were then followed for a median of 6 years. The patient's diseases, country of birth, and gender were acquired from nationwide administrative registries. We used logistic regression to compare the prevalences of CD, UC, and CeD and Cox regression to compare the incidences of CD, UC, and CeD between H. pylori-positive and H. pylori-negative patients, adjusting for confounding variables. RESULTS: We found a lower prevalence of CD in H. pylori-positive than in H. pylori-negative patients (odds ratio = 0.36 [0.17-0.75]). There were fewer incident cases of CD in H. pylori-positive than H. pylori-negative patients in the follow-up period (hazard ratio = 0.59 [0.36-0.96]). Similar trends were found for CeD but not for UC. CONCLUSIONS: H. pylori infection may be a protective factor against the development of CD. However, the incidence of CD is still reduced after UBT and probable H. pylori eradication; thus, H. pylori status may be a marker for other factors that protect against CD.

Implications of Infliximab Treatment Failure and Influence of Personalized Treatment on Patient-reported Health-related Quality of Life and Productivity Outcomes in Crohn's Disease.

BACKGROUND: This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation. METHODS: Sixty-nine Crohn's disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health-related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks. RESULTS: Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non-responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX. CONCLUSION: Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease-related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes.

Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.

BACKGROUND AND AIMS: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. RESULTS: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 µg/mL, p = 0.035; HMSA, 9.9 versus 4.7 µg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 µg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. CONCLUSION: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.

Prednisolone but not infliximab aggravates the upregulated hepatic nitrogen elimination in patients with active inflammatory bowel disease.

BACKGROUND: Catabolism and weight loss are serious problems in patients with active inflammatory bowel disease (IBD). The body nitrogen (N) depletion is partly related to increased hepatic capacity for the elimination of N through urea synthesis. This is probably caused by the inflammation per se, and the treatment with prednisolone may aggravate the problem, whereas the effect of biological therapy is unknown. Therefore, we examined the effects of prednisolone or infliximab on the regulation of urea synthesis in patients with active IBD. METHODS: Urea synthesis was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the urea nitrogen synthesis rate and the blood α-amino nitrogen concentration during alanine infusion. Thirty-seven patients with active IBD treated with either prednisolone or infliximab were examined before and after 7 days of treatment. RESULTS: At baseline, the FHNC was similar in the 2 treatment groups (36 L/h). After 7 days, prednisolone increased the FHNC by 40% (55 L/h) (P = 0.03), whereas infliximab tended to reduce the FHNC by 15% (30 L/h) (P = 0.09). The changes in the FHNC differed significantly between the 2 treatment groups (P < 0.01). CONCLUSIONS: Prednisolone treatment further upregulated urea synthesis, which increases the hepatic loss of nitrogen and promotes body catabolism. In contrast, infliximab treatment caused no such aggravation and likely reduced the N loss. These results may argue in favor of infliximab therapy for IBD and add to the pathophysiological understanding of the interplay between inflammation, catabolism, and anti-inflammatory treatment.

Bile acid malabsorption investigated by selenium-75-homocholic acid taurine ((75)SeHCAT) scans: causes and treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea.

BACKGROUND: The liver produces and secretes bile acids into the small intestine. In the small intestine, most of the bile acids are absorbed in the distal ileum with portal vein transportation back to the liver and resecretion (enterohepatic recycling). Increased spillover of bile acids from the small intestine into the colon (bile acid malabsorption) may affect the secretion of colonic water and electrolytes and result in watery diarrhoea. The aim of this study was to investigate the frequency of bile acid malabsorption and treatment responses to cholestyramine with (75)SeHCAT scanning among patients suffering from chronic watery diarrhoea. METHODS: This was a retrospective study that included all patients who received a (75)SeHCAT scan over a five-year period (2004-2009). RESULTS: In total, 298 patients (198 females, 100 men) with a median age of 42 years (range 16-82 years) were investigated. Bile acid malabsorption ((75)SeHCAT retention<15% after seven days) was identified in 201 patients (68%, 95% confidence interval (CI): 62%-73%). Bile acid malabsorption due to ileal dysfunction (Type I) was found in 77 patients, idiopathic bile acid malabsorption (Type II) was found in 68 patients and 56 patients with other conditions had bile acid malabsorption (Type III). Of the 150 patients who were able to take cholestyramine continuously, 108 patients (71%, CI: 63%-78%) reported a positive effect on their bowel habits. CONCLUSIONS: Bile acid malabsorption is a frequent problem in patients with chronic watery diarrhoea. Treatment with bile acid binders was effective regardless of type and severity.

Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?

BACKGROUND: Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. METHODOLOGY/PRINCIPAL FINDINGS: We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. CONCLUSION/SIGNIFICANCE: CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents.

Therapeutic drug use in women with Crohn's disease and birth outcomes: a Danish nationwide cohort study.

BACKGROUND: Crohn's disease (CD) is associated with increased risk of adverse birth outcomes. However, existing studies have not taken into account the impact of drug treatment. We examined the impact of drug treatment on birth outcomes--low birth weight (LBW), preterm birth, LBW at term, and congenital abnormalities (CAs)--among CD women. METHODS: A nationwide Danish cohort study of 900 children born to CD women between 1996 and 2004, based on the National Registry of Patients, the Birth Registry, and the nationwide prescription database. Pregnancies were classified according to receipt of prescriptions for CD medication: no drugs (reference group), 5-aminosalicylic acid (5-ASA)/sulfasalazine, steroids, and azathioprine (AZA)/6-mercaptopurine (6-MP). We used logistic regression analyses to estimate the relative risk of birth outcomes with 95% confidence intervals. We used a proxy measure for disease activity. RESULTS: Preterm births were more prevalent among steroid- and AZA/6-MP-exposed women (12.3% and 25%, respectively) compared with the reference group (6.5%). CAs were more prevalent among AZA/6-MP-exposed compared with reference group (15.4%vs 5.7%). Among steroid exposed, the risk of preterm birth was 1.4 (95% CI 0.6-3.3). Among AZA/6-MP exposed, the risk of preterm birth and CAs was 4.2 (95% CI 1.4-12.5) and 2.9 (95% CI 0.9-8.9), respectively. CONCLUSIONS: The relative risk of adverse birth outcomes among CD women varied by type of drugs prescribed during pregnancy. The risk of preterm birth and CAs was greater when AZA/6-MP was prescribed, even after adjusting for confounders. However, further information is needed to determine whether the associations are causal.