Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient.

BACKGROUND: Inflammatory bowel disease affects patients who are in their reproductive years. There are many questions regarding the management of IBD patients who are considering or who are already pregnant. These include the effect of the disease and the medications on fertility and on the pregnancy outcome. AIM: To create an evidence-based decision-making algorithm to help guide physicians through the management of pregnancy in the IBD patient. METHODS: A literature review using phrases that include: 'inflammatory bowel disease', 'Crohn's disease', 'ulcerative colitis', 'pregnancy', 'fertility', 'breast feeding', 'delivery', 'surgery', 'immunomodulators', 'azathioprine', 'mercaptopurine', 'biologics', 'infliximab', 'adalimumab', 'certolizumab'. CONCLUSIONS: The four decision-making nodes in the algorithm for the management of pregnancy in the IBD patient, and the key points for each one are as follows: (i) preconception counselling - pregnancy outcome is better if patients remain in remission during pregnancy, (ii) contemplating pregnancy or is already pregnant - drugs used to treat IBD appear to be safe during pregnancy, with the exception of methotrexate and thalidomide, (iii) delivery and (iv) breast feeding - drugs used to treat IBD appear to be safe during lactation, except for ciclosporin. Another key point is that biological agents may be continued up to 30 weeks gestation. The management of pregnancy in the IBD patient should be multi-disciplinary involving the patient and her partner, the family physician, the gastroenterologist and the obstetrician.

Safety of topical 5-aminosalicylic acid in pregnancy.

OBJECTIVE: To assess the safety and efficacy of topical 5-aminosalicylic acid preparations for therapy of distal colitis during pregnancy. METHODS: Nineteen pregnancies in sixteen consecutive patients with proven distal colitis were identified prospectively at a tertiary care center. All patients were given trials of weaning off medication and all failed. All subjects were on maintenance topical 5-aminosalicylic acid therapy at the time of conception. They were followed throughout their pregnancy and thereafter. Their children were also closely examined and followed by a pediatrician. RESULTS: The mean age at delivery was 25.8 yr, and the mean duration of illness was 4.6 yr. After taking topical therapy, there were no relapses during the pregnancy. There were 19 successful full-term pregnancies with no fetal abnormalities. The mothers and children were followed for more than 6 months. CONCLUSION: In this series, topical 5-aminosalicylic acid appears safe, effective, and well tolerated in the management of pregnant patients with distal colitis.

Comparison of amino acid v peptide based enteral diets in active Crohn's disease: clinical and nutritional outcome.

Elemental diets are considered an effective primary treatment for active Crohn's disease. This study examined the hypothesis that improvement occurs because of the presence of amino acids or the low fat content, or both. A randomised, controlled trial was undertaken in 40 patients with active Crohn's disease to evaluate clinical and nutritional outcomes after an amino acid based diet containing 3% fat was given by a feeding tube compared with a peptide based diet containing 33% fat. After three weeks' treatment, clinical remission occurred in 84% of patients who were given the amino acid diet and 75% of patients who received the peptide diet (p = 0.38). Plasma linoleic acid concentration was reduced after the amino acid but not the peptide diet. An increase in total body nitrogen was associated with the magnitude of nutritional depletion before treatment and at six months' follow up, only patients who showed gains in total body nitrogen after enteral nutrition had a sustained clinical remission. This study shows that peptide based high fat diets are as effective as amino acid low fat diets for achieving clinical remission in active Crohn's disease. Improved total body protein stores but not essential fatty acid depletion may be an important indicator of a sustained remission.

Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course.

BACKGROUND: Oral 5-aminosalicylic acid (5-ASA) has proven an effective maintenance therapy of ulcerative colitis and may also be useful in Crohn's disease, but its safety in pregnancy has not been established. The present study therefore examined the course and outcome of pregnancies in patients with inflammatory bowel disease who continued to take oral 5-ASA. METHODS: Ten patients with ulcerative colitis and 7 patients with Crohn's disease with a total of 19 pregnancies were studied while they were receiving 5-ASA. All patients were previously in remission on 5-ASA, at a mean dose of 1.7 g/day (range, 0.8-2.4 g/day). They continued taking the drug without a change in dose and were followed up throughout their pregnancies and postpartum. RESULTS: Eighteen pregnancies resulted in full-term delivery. No fetal abnormalities were found at delivery, and there were no clinical or biochemical abnormalities in the neonatal period. Four patients had a relapse. One patient required a colectomy but carried on to a full-term pregnancy. One patient had a miscarriage, but she had miscarried on four previous occasions before taking 5-ASA. She subsequently had a successful pregnancy on 5-ASA. CONCLUSIONS: Oral 5-ASA appears to be safe for the management of inflammatory bowel disease during pregnancy.

Treatment of ulcerative colitis with oral 5-aminosalicylic acid including patients with adverse reactions to sulfasalazine.

Sulfasalazine is an effective drug for maintaining remission in ulcerative colitis, but its use may be precluded by side effects. Eighty-five patients with active ulcerative colitis participated in a prospective open trial to examine the tolerance of the active constituent 5-aminosalicylic acid (5-ASA), coated with an acrylic resin, and its efficacy in inducing and subsequently maintaining a remission. Fifty-one of the patients had previously developed adverse reactions to sulfasalazine. After 4 wk of treatment with 3.2 g 5-ASA daily, a remission was achieved in 23 of 36 patients (64%) with mild or moderate disease, but in none of 43 patients with severe disease. Six patients were withdrawn because of side effects to 5-ASA, but only two of these patients had similar reactions on sulfasalazine. Supplementary corticosteroids for 6 wk or less induced a remission in 27 of the patients who had failed on 5-ASA alone. Fifty patients were therefore eligible for the maintenance phase of the trial, and 39 (78%) had a sustained clinical and endoscopic remission upon 1-yr follow-up. 5-ASA appears to be an effective drug for inducing remission in mild or moderate ulcerative colitis and for the maintenance of remission. It thus represents a valuable addition to the management of patients intolerant to sulfasalazine.

Cimetidine-resistant Zollinger-Ellison syndrome: successful management with ranitidine.

In a patient with the Zollinger-Ellison syndrome who had undergone vagotomy, pyloroplasty and, later, gastrojejunostomy, epigastric pain and stomal ulceration recurred despite the use of high doses (2700 mg/d) of cimetidine. Ranitidine, a new histamine H2-receptor antagonist, reversed all symptoms and healed the stomal ulcer without side effects, thus obviating the need for further surgery. Ranitidine may prove to be the drug of choice in the medical management of patients with the Zollinger-Ellison syndrome.

Rapid purification of human high molecular weight kininogen.

Human high molecular weight kininogen was isolated by a rapid procedure, using anion exchange chromatography on QAE-Sephadex, ammonium sulfate precipitation and cation exchange chromatography on CM-Sephadex. The poor recovery and relatively low specific activity observed in earlier experiments was found to be due to a contaminant, presumably enzymatic, capable of releasing kinin from the kininogen. The "spontaneous" kinin release was blocked by soy bean trypsin inhibitor and by C1-inactivator. The isolated kininogen was stable at different temperatures, did not contain free kinin and was a good substrate for plasma kallikrein and plasmin.

Generation of a vasoactive peptide by a neutral protease of human neutrophil leukocytes.

Neutrophil leukocyte lysosomes contain a neutral protease capable of cleaving a peptide from kininogen. The protease has a molecular weight of about 27,000-28,000, as determined by SDS-disc gel electrophoresis and gel filtration in the presence of guanidine-HCl. Its S-value is 2.7 and the pI 10.0-11.8. Although homogeneous by some criteria (sucrose density gradient ultracentrifugation, gel filtration in Sephadex G-75, SDS-disc gel electrophoresis, immunoelectrophoresis), the protease is heterogeneous by other criteria (cation exchange chromatography, cationic disc gel electrophoresis and isoelectric focusing). The heterogeneity is attributable to charge isomerism. The enzyme is inhibited by DFP and a number of chloromethyl ketone inhibitors. It is also inhibited by the plasma protease inhibitors alpha1-antitrypsin, alpha2-macroglobulin and antithrombin III. The generated peptide has chemical and pharmacological properties similar to the undecapeptide methionyl-lysyl-bradykinin, but probably contains one or two additional amino acids.

Neutral proteases of human PMN leukocytes with kininogenase activity.

A neutral protease with kininogenase activity was isolated from human polymorphonuclear (PMN) leukocytes by cation exchange chromatography and gel filtration. The protease appears heterogeneous by cation exchange chromatography, isoelectric focusing and cationic disc gel electrophoresis, but homogeneous by gel filtration, sucrose density gradient ultracentrifugation, SDS-disc gel electrophoresis and immunoelectrophoresis. By carrying out the electrophoresis of the protease in acrylamide gels of varying concentrations, it was shown that they represent charge isomers. The protease was stable at pH 4-10, but labile to heat, being almost completely inactivated when incubated for 30 min at 70 degrees C. It exhibited proteolytic activity between pH 5 and 9, being maximal at 7.5-8.5. The molecular weight of the PMN protease was estimated to be about 20,000 daltons by gel filtration in aqueous buffer and about 26,000-28,000 daltons by SDS-disc gel electrophoresis and gel filtration in Sepharose 6B in the presence of the dissociating agent guanidine HCl. Its sedimentation coefficient was about 2.7S. Corresponding to the charge heterogeneity, by isoelectric focusing, the kinin-generating and esterolytic activities of the PMN granule lysate focused between pH 6.0 and 11.5, whereas the isolated PMN protease focused between 10.0 and 11.8. With respect to kinin generation, caseinolysis, and alanine esterase activity, the protease was inhibited by DFP and certain chloromethyl ketone inhibitors, as well as the plasma protease inhibitory a1-antitrypsin, a2-macroglobulin and antithrombin III. Both bradykinin and a methionyl-lysyl-bradykinin-like peptide were generated from highly purified kininogens by a lysosomal lysate containing the PMN protease. However, this assay was done with a crude enzyme preparation which contains an aminopeptidase capable of converting lysyl-bradykinin or methionyl-lysyl-bradykinin to bradykinin. When injected intradermally, the protease induced hyperemia, hemorrhage, and moderate enhancement of vascular permeability, but the mixture of the protease and kininogen induced a marked enhancement of vascular permeability.