Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Evaluation and management of ileal pouch-anal anastamosis (IPAA) complications in pregnancy, and the impacts of an IPAA on fertility.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains the preferred surgical option for medically refractory ulcerative colitis. Management of individuals with an IPAA prior to and during pregnancy presents challenges that can have serious consequences. Infertility, mechanical obstructive and inflammatory pouch complications are frequently encountered in pregnant women with an IPAA. Mechanical obstructions occur due to a variety of underlying aetiologies, including stricturing disease, adhesions and pouch twists. Conservative management of such obstructions often results in resolution of symptoms without a need for endoscopic or surgical intervention, although endoscopic decompression may be attempted in isolation or as a bridge to definitive surgical intervention. Parenteral nutrition, and early delivery, may also be necessary. Faecal calprotectin and intestinal ultrasound, both of which are accurate in pregnancy, are useful in the setting of suspected inflammatory pouch complications, in some circumstances allowing for avoidance of pouchoscopy. Penicillin-based antimicrobials can be considered first line in pregnancy for the management of pouchitis and pre-pouch ileitis, and biologics can be safely instituted in the setting of refractory disease or suspected Crohn's disease-like inflammation of the pouch or pre-pouch ileum. Pragmatism, clear patient communication and multidisciplinary discussion are essential in approaching pregnant women with complications of an IPAA, particularly given the lack of definitive evidence to guide therapeutic decisions.

Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Strictures are the most common structural complication of Crohn's disease. Surgery and endoscopic balloon dilation are the main treatments; drug therapy has been considered contraindicated. Given that most strictures have an inflammatory component, we aimed to find out whether strictures are responsive to drug treatment and whether intensive drug therapy is more effective than standard drug therapy. METHODS: This open-label, single-centre, randomised controlled trial was performed in one specialist inflammatory bowel disease centre in Australia. Patients aged 18 years or older with Crohn's disease were included. Eligible patients had a de novo or postoperative anastomotic intestinal stricture on MRI or ileocolonoscopy, symptoms consistent with chronic or subacute intestinal obstruction (postprandial abdominal pain in the presence of a confirmed stricture), and evidence of active intestinal inflammation. Patients were randomly assigned (2:1) to receive intensive high-dose adalimumab (160 mg adalimumab once per week for 4 weeks followed by 40 mg every 2 weeks, with escalation of dose at 4 months and 8 months if assessment of disease activity indicated active inflammation) plus thiopurine (initial dose of azathioprine 2·5 mg/kg or mercaptopurine 1·5 mg/kg, with dose adjustment based on thiopurine metabolite testing) or standard adalimumab monotherapy (160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks) using stratified fixed block randomisation. Stratification factors were stricture dilation at study baseline colonoscopy and current biologic drug use. The primary endpoint was improvement (decrease) in the 14-day obstructive symptom score at 12 months by one or more points compared with baseline. This trial is registered with ClinicalTrials.gov, NCT03220841, and is completed. FINDINGS: Between Sept 10, 2017, and Sept 6, 2019, 123 patients were screened and 77 randomly assigned to intensive adalimumab plus thiopurine treatment (n=52) or standard adalimumab treatment (n=25). At 12 months, improvement in obstructive symptom score was noted in 41 (79%) of 52 patients in the intensive treatment group and 16 (64%) of 25 in the standard treatment group (odds ratio [OR] 2·10 [95% CI 0·73-6·01]; p=0·17). Treatment failure occurred in five (10%) patients in the intensive treatment group versus seven (28%) in the standard treatment group (OR 0·27 [95% CI 0·08-0·97]; p=0·045); four patients in each group required stricture surgery (0·44 [0·10-1·92]; p=0·27). Crohn's Disease Activity Index was less than 150 in 36 (69%) patients in the intensive treatment group versus 15 (60%) in the standard treatment group (1·50 [0·56-4·05]; p=0·42). MRI at 12 months showed improvement using the stricture MaRIA score (≥25%) in 31 (61%) of 51 versus seven (28%) of 25 patients (3·99 [1·41-11·26]; p=0·0091). MRI complete stricture resolution was seen in ten (20%) versus four (16%) patients (1·28 [0·36 to 4·57]; p=0·70). Intestinal ultrasound at 12 months showed improvement (>25%) in bowel wall thickness in 22 (51%) of 43 versus seven (33%) of 21 patients (2·10 [0·71 to 6·21]; p=0·18). Faecal calprotectin normalised in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Normalisation of CRP was seen in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Eight (15%) patients in the intensive treatment group and four (16%) in the standard treatment group reported serious adverse events. No deaths occurred during the study. INTERPRETATION: Crohn's disease strictures are responsive to drug treatment. Most patients had improved symptoms and stricture morphology. Treat-to-target therapy intensification resulted in less treatment failure, a reduction in stricture-associated inflammation, and greater improvement in stricture morphology, although these differences were not significantly different from standard therapy. FUNDING: Australian National Health and Medical Research Council, Gastroenterological Society of Australia Ferring IBD Clinician Establishment Award, Australasian Gastro Intestinal Research Foundation, AbbVie, and the Spotlight Foundation.

Ustekinumab levels in pregnant women with inflammatory bowel disease and infants exposed in utero.

BACKGROUND: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. METHODS: In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. RESULTS: 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26-3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r = -0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6-19) weeks (n = 9). CONCLUSION: Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20 weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.

A Single Educational Intervention Improves Pregnancy-Related Knowledge and Emotional Health Among Women With IBD Who Are Pregnant or Wish to Conceive.

BACKGROUND: There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD. METHODS: This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn's and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction. RESULTS: One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients' pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn's and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent. CONCLUSIONS: Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.

Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates.

BACKGROUND: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. AIMS: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. METHODS: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved. RESULTS: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 108 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 108 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 108 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved. CONCLUSIONS: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear.

Efficacy of drug and endoscopic treatment of Crohn's disease strictures: A systematic review.

BACKGROUND AND AIMS: Strictures are the commonest complication in Crohn's disease. Surgery and endoscopic dilation are the mainstays of treatment, while drug therapy has often been considered contraindicated. The benefit of nonsurgical treatments, particularly drug and endoscopic therapy, need to be defined. METHODS: Ovid MEDLINE, Embase, Emcare, PsycINFO, CINAHL and the Cochrane Library (inception until August 30, 2019) were searched. Studies with ≥ 10 patients with Crohn's disease strictures, reporting on outcomes following medication or endoscopic treatment, were included. RESULTS: Of 3480 records, 85 studies met inclusion criteria and formed the basis of this analysis. Twenty-five studies assessed drug therapy; none were randomized trials. Despite study heterogeneity anti-tumor necrosis factor (TNF) therapy appeared effective, with 50% of patients avoiding surgery after 4 years of follow up. No other drug therapy was of demonstrable benefit. Sixty studies assessed endoscopic therapy including 56 on endoscopic balloon dilation, two assessed needle knife stricturotomy, and two stent insertion. Dilation was equally effective for de novo and anastomotic strictures ≤ 5 cm in length, with most studies reporting a subsequent surgical rate of 30% to 50%. Repeat dilation was required in approximately half of all patients. CONCLUSIONS: Anti-TNF drug therapy and endoscopic balloon dilation are effective strategies for avoiding surgery in patients with stricturing Crohn's disease. Additional endoscopic therapies require further evaluation. Early data suggest that combining these therapies may provide greater benefit than individual therapies. Optimization of current drug and endoscopic therapy, and the incorporation of newer therapies, are needed for stricturing Crohn's disease.

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

BACKGROUND: The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown. AIMS: To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable. RESULTS: We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing. CONCLUSIONS: During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.

Monitoring Inflammatory Bowel Disease in Pregnancy Using Gastrointestinal Ultrasonography.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] affects women during their childbearing years. Gastrointestinal ultrasonography [GIUS] accurately identifies disease activity in non-pregnant patients with IBD. The utility of GIUS in pregnancy has not been established. We aimed to determine the feasibility and accuracy of GIUS in the assessment of IBD during pregnancy progression. METHODS: A multicentre observational study of women with IBD undergoing GIUS during pregnancy. Clinicians assessed the adequacy of bowel views and disease activity in four colonic segments and the terminal ileum. Location[s] in which views were impeded by the uterus were documented. GIUS disease activity [bowel wall thickness >3 mm] was compared with biochemical disease activity [faecal calprotectin >100 µg/g]. RESULTS: Ninety patients and 127 GIUS examinations were included [median gestation 19 weeks, range 4-33]. Adequate colonic views were obtained in 116/127 [91%] scans. Adequate ileal views were obtained in 62/67 [93%] scans <20 weeks and 30/51 [59%] scans at 20-26 weeks. There was a positive correlation between bowel wall thickness and calprotectin [r = 0.26, p = 0.03]. GIUS delivered a specificity of 83%, sensitivity of 74%, and negative predictive value of 90% compared with calprotectin. CONCLUSIONS: GIUS is a feasible and accurate modality for monitoring IBD in pregnancy. Adequate GIUS views of the colon and terminal ileum can be obtained in the majority of patients up to 20 weeks of gestation. Beyond 20 weeks, GIUS provides good views of the colon but the terminal ileum becomes difficult to assess.

Magnetic resonance enterography for predicting the clinical course of Crohn's disease strictures.

BACKGROUND AND AIMS: Strictures are the most common Crohn's disease complication, but their natural history is unknown. This study aimed to characterize inflammation, predict prognosis, and understand the impact of drug therapy using magnetic resonance enterography (MRE). METHODS: Patients with a stricture diagnosed on MRE over a 5-year period were reviewed for MRE disease extent and inflammation, clinical course, C-reactive protein, response to anti-TNF therapy, endoscopic dilatation, hospitalization, and surgery. RESULTS: 136 patients had 235 strictures (77, one and 59, ≥ 2 strictures). TREATMENT: 46% of patients underwent surgery after a median 6 months; median follow-up for those not requiring surgery was 41 months. Predictors of surgery: Hospitalization because of obstruction predicted subsequent surgery (OR 2.50; 95% CI 1.06-5.90) while anti-TNF therapy commenced at stricture diagnosis was associated with a reduced risk (OR 0.23; 95% CI 0.05-0.99). MRE characteristics associated with surgery were proximal bowel dilatation ≥ 30-mm diameter (OR 2.98; 95% CI 1.36-6.55), stricture bowel wall thickness ≥ 10-mm (OR 2.42; 95% CI 1.11-5.27), and stricture length > 5-cm (OR 2.56; 95% CI 1.21-5.43). 81% of patients with these three adverse MRE features required surgery versus 17% if none were present (P < 0.001). Accuracy for these three MRE variables predicting surgery was high (AUC 0.76). CONCLUSION: Magnetic resonance enterography findings in Crohn's disease strictures are highly predictive of the disease course and the need for future surgery. MRE may also identify who would benefit from treatment intensification. Anti-TNF therapy is associated with reduced risk of surgery and appears to alter the natural history of this complication.