title: Birth outcome in women with ulcerative colitis and Crohn's disease, and pharmacoepidemiological aspects of anti-inflammatory drug therapy.
abstract: The clinical epidemiological studies included in this thesis fall into three parts. The first part includes studies on birth outcome in women with ulcerative colitis. The second part includes pharmacoepidemiological studies on birth outcome after anti-inflammatory drug therapy in pregnancy, including patients with ulcerative colitis and Crohn's disease. The third part (and the latest publications) includes birth outcome in women with Crohn's disease; and the methods of cohort establishment in these studies are developed and improved due to the knowledge gathered from conducting the earlier studies.  The birth outcomes in women with ulcerative colitis are examined in a nationwide, Danish, cohort of women based on data from the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry, and within a Hungarian case-control data set. Our data suggest:   1) Significantly increased risk of preterm birth when women give birth 0-6 months after establishment of the diagnosis. It is considered whether the increased risk may be influenced by disease activity around the time of establishing the diagnosis.  2) No increased risk of giving birth to children with low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall).  3) Significantly increased risk of some selected congenital abnormalities (limb deficiencies, obstructive urinary and multiple congenital abnormalities). No other studies have examined the risk of selected congenital abnormalities in children born by women with ulcerative colitis.  The pharmacoepidemiological studies on birth outcomes after use of anti-inflammatory drug therapy in pregnancy, including women with ulcerative colitis and Crohn's disease, are based on data from the Hungarian case-control data set, a countywide Danish prescription Database, the Danish National Hospital Discharge Registry, the Danish Medical Birth Registry, and review of selected medical records. After exposure to sulfasalazine during pregnancy our data suggest.  No significantly increased overall relative risk of congenital abnormalities and no significantly increased risks of selected congenital abnormalities.  After exposure to 5-aminosalicylic acid during pregnancy our data suggest. No significantly increased relative risk of low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall).   A significantly increased relative risk of preterm birth and stillbirth in ulcerative colitis women, compared to women with no prescription of reimbursed medicine in pregnancy - and also after comparing with women with chronic inflammatory bowel disease not taking 5-aminosalicylic acid during pregnancy. It is not clear whether these associations are causal or influenced by confounding by disease activity in particular. After maternal exposure to azathioprine/6-mercaptopurine during pregnancy our data suggest. An increased relative risk of preterm birth, congenital abnormalities, and perinatal mortality - also after using controls with similar underlying diseases.  It is difficult to rule out an influence of uncontrolled confounding. These were the first published data from a controlled observational study on exposed women with chronic inflammatory bowel disease.  After preconceptional paternal use of azathioprine/6-mercaptopurine our data suggest  An increased risk of congenital abnormalities, although not significantly increased.  The birth outcomes in women with Crohn's disease are examined in nationwide sub-cohorts classified according to type of anti-inflammatory drug exposure during pregnancy, and based on data from the Danish National Hospital Discharge Registry, the nationwide Danish Prescription Database and the Danish Medical Birth Registry. Furthermore, birth outcomes are examined in Crohn's disease women with disease activity during pregnancy, based on data from review of hospital records, the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry. Our data suggest: 1) The risk of adverse birth outcomes in women with Crohn's disease varies according to the type of anti-inflammatory drug therapy in pregnancy. 2) Reassuring results according to low birth weight, intrauterine growth retardation, preterm birth and congenital abnormalities after use of sulfasalazine/5-aminosalicylic acid or steroids. 3) Worrisome findings of a significantly increased risk of preterm birth and an increased risk of congenital abnormalities (not significantly increased) after prescription of azathioprine/6-mercaptopurine during pregnancy. Some residual confounding by disease activity may have been left in the analyses of preterm birth.   In Crohn's disease women with disease activity during pregnancy our data suggest: 1) A significantly increased relative risk of preterm birth in women with the highest degree of disease activity during pregnancy. 2) Disease activity does not seem to increase the risk of low birth weight, intrauterine growth retardation or congenital abnormalities.  This study is the first epidemiological study of the risk of adverse birth outcomes in Crohn's disease women with disease activity during pregnancy, compared to women with no activity during pregnancy, and in which confounders have been taken into consideration.  Exceeding the studies included in my previous PhD thesis, this thesis provides new evidence on the following subjects: i) the risk of selected congenital abnormalities in children of women with ulcerative colitis, ii) pharmacoepidemiological studies on the risk of adverse birth outcome after maternal azathioprine/6-mercaptopurine exposure in pregnancy, and the risk of congenital abnormalities in children fathered by men treated with azathioprine/6-mercaptopurine before conception, iii) the risk of adverse birth outcome in women with Crohn's disease according to type of anti-inflammatory drug treatment in pregnancy (sulfasalazine/5-aminosalicylic acid, steroids or azathioprine/6-mercaptopurine), and iv) the impact of disease activity in women with Crohn's disease on adverse birth outcome.  We learned from the studies in this thesis that the traditional way of reporting birth outcome in women with chronic inflammatory bowel disease, i.e. without having valid information on the type of underlying disease, concurrent therapeutic drug treatment and disease activity, is of limited value. The studies show that the risk of specific adverse birth outcome in women with ulcerative colitis and Crohn's disease depends on several factors including the time of birth in relation the début of disease, the type of underlying disease (ulcerative colitis or Crohn's disease), the type of anti-inflammatory drug treatment during pregnancy, and the degree of disease activity during pregnancy. At the same time one also has to realize that the existing evidence is still limited, especially in the field of reproductive safety after therapeutic drug treatment during pregnancy and possible effects of preconceptional therapeutic drug exposure.
authors.affiliation: Centre for National Clinical Databases, South, The Danish Clinical Quality Improvement Programme, OUH, Odense University Hospital, Entrance 101, Sdr. Boulevard 29, 5000 Odense C, Denmark. bente.noergaard@ouh.regionsyddanmark.dk
authors.forename: Bente Mertz
authors.initials: BM
authors.lastname: Nørgård
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D010131:Aminosalicylic Acid / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001379:Azathioprine / Q000627:therapeutic use; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000473:pathology; D016001:Confidence Intervals; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology; D003718:Denmark; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015122:Mercaptopurine / Q000627:therapeutic use; D016017:Odds Ratio; D018743:Perinatal Care; D017891:Pharmacoepidemiology / Q000379:methods; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000473:pathology; D011256:Pregnancy Outcome; D012042:Registries; D012460:Sulfasalazine / Q000627:therapeutic use; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D012460:Sulfasalazine; D010131:Aminosalicylic Acid; D015122:Mercaptopurine; D001379:Azathioprine