Inflammatory bowel disease and pregnancy: patient education, assessment of disease activity and monitoring of drug therapies

© 2020 Emma Kate FlanaganInflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. The disease commonly impacts women during their reproductive years. IBD, particularly when active during pregnancy, is associated with worse maternofoetal outcomes. Pregnancy-related knowledge remains poor in many patients, with concerns regarding drug safety and a lack of understanding of the negative ramifications of active disease in pregnancy. Safe and effective monitoring of disease activity and drug therapies to control IBD throughout pregnancy are imperative. However, the utility and means of objective disease activity monitoring in pregnancy are unknown. The effect of pregnancy on the pharmacokinetics of immunosuppressant and biologic drugs in pregnancy remains undefined. This thesis presents a range of clinical research work as part of the prospective Pregnancy in Crohn’s and Colitis: Observations, Levels and Outcomes (PICCOLO) study. This study aimed to improve the pregnancy-related education and care of women with IBD; characterise the utility of objective disease activity monitoring including gastrointestinal ultrasonography in pregnancy; and examine the pharmacokinetics of thiopurine and biologic medications during pregnancy as well as infant outcomes following in utero medication exposure. I have explored the lived experience of IBD and pregnancy from the patient’s perspective using qualitative in-depth interviews. This research unearthed rich data relating to unique maternal fears and uncertainties around IBD medications and enduring a chronic illness throughout the pregnancy journey. I have demonstrated that a single individualised patient education intervention improves pregnancy-related knowledge among women with IBD. This novel intervention included a simple, accessible educational consultation for women with IBD who were pregnant or wishing to conceive. Pregnancy knowledge and quality of life scores were enhanced following the intervention and patient satisfaction levels were very high. This work has defined the role of gastrointestinal ultrasonography as a feasible and accurate modality for monitoring IBD in pregnancy. Adequate intestinal views were obtained in most patients to the end of the second trimester. Gastrointestinal ultrasound delivered a high specificity and sensitivity when compared with matched faecal calprotectin concentrations as an objective marker of disease activity. The research has contributed substantially to the understanding of the pharmacokinetics of thiopurines and biologic medications including infliximab, adalimumab and vedolizumab during pregnancy. Thiopurine metabolite concentrations were studied longitudinally in patients with IBD across pregnancy and in exposed neonates. Significant shunting of maternal thiopurine metabolites can occur during pregnancy. This work has established that complete clearance of thiopurine metabolites occurs in exposed infants by six weeks of age. Unlike a previous study, this work has shown that there is no association with neonatal anaemia following antenatal exposure to thiopurines. However, I identified the novel findings of thrombocytosis and abnormal liver function tests in exposed infants from six weeks of age, which gradually improved; possible mechanisms behind these infant haematological and biochemical findings are uncertain. Maternal drug levels of infliximab, adalimumab and vedolizumab in pregnancy were also prospectively assessed. This work has demonstrated that adalimumab levels remain stable and infliximab levels display a small increase in pregnancy. This study has described the first data regarding vedolizumab levels in pregnancy and clearance time in infants exposed to vedolizumab in utero. I have identified that maternal vedolizumab levels may show a small decrease in pregnancy, while infant vedolizumab cord blood levels are lower than maternal levels. All infants had undetectable vedolizumab levels by sixteen weeks of age. I have also presented preliminary data regarding another newer biologic agent, ustekinumab, including maternal levels in pregnancy and placental transfer. Infant cord blood levels of ustekinumab were found to be higher than maternal levels in the small cohort to date. This series of studies has the potential to change the paradigm of pregnancy-related education, objective disease activity monitoring and optimal use of IBD therapies for pregnant women with IBD globally