In view of the risk of preterm delivery and small babies with active IBD, the role of drugs in the maintenance of remission and the advisability of continuing them during pregnancy should be discussed at the earliest possible opportunity in all female patients. Most women's initial reaction is that they would not want to contemplate taking any sort of medication if they were planning conception or became pregnant. Therefore, an informed pre-pregnancy discussion, with the patient (and her partner if appropriate), facilitates a decision made in partnership with clinicians and the formulation of a management plan using the available data. The balance between continuing maintenance treatment and stopping it, which is likely to increase the chance of needing to treat an acute exacerbation, needs to be weighed up for each individual.
The drugs most commonly taken by patients with IBD who are pregnant are the 5-ASAs and sulphasalazine. The paper by Nørgård et al
in this issue of Gut19
provides the best available data on the use of 5-ASA preparations during pregnancy [see page 243]
. Over a 10 year period, using a population based prescription registry, the Danish birth registry, and a hospital discharge registry for North Jutland county, the authors were able to identify all prescriptions for 5-ASAs in the three months prior to or during pregnancy (148) and all pregnant patients who did not have prescriptions (19 418), including those patients with a diagnosis of IBD who did not have prescriptions.
Logistic regression analysis demonstrated no significant increase in congenital abnormalities. An increased risk of stillbirth and premature birth was found in women with a diagnosis of UC. The data were controlled for the effects of age, parity, and smoking but not disease activity. From this study, as from many previous studies, it is not possible to infer that the adverse effect on pregnancy is due to the drug. Despite the fact that it is generally advised that it is safe to take sulphasalazine or 5-ASA preparations in pregnancy, many women choose to stop all medication prior to conception and it is therefore likely that those who receive prescriptions for 5-ASAs prior to or during pregnancy have active disease. 5-ASA drugs are related to sulphasalazine, which is now less commonly used in Western Europe and the USA. The sulphapyridine moiety in sulphasalazine is a folic acid antagonist, theoretically likely to cause neural tube defects as well as cardiovascular and urinary tract abnormalities and oral clefts.20
In another large epidemiological study, published last year, Nørgård and colleagues21
shown that there was no evidence of increased incidence of congenital anomalies in Hungarian women taking sulphasalazine during pregnancy.
“The Nørgård study confirms an association between the use of steroids and stillbirth”
Some women who suffer an exacerbation of IBD in pregnancy may need to take steroids. An association between steroid use and low birth weight has previously been demonstrated.16
The Nørgård study confirms an association between the use of steroids and stillbirth. Steroids have not been associated with stillbirth when used for the treatment of other medical conditions and again, the adverse factor would appear to be disease activity. The only study looking specifically at the use of steroids to treat IBD in pregnancy did not find any association with complications of pregnancy.22
In women with more severe IBD, the use of second line agents during pregnancy may need to be considered. Generally, this will be continuation of azathioprine to maintain remission. Although there is extensive experience of the use of azathioprine in the treatment of transplant recipients and rheumatology patients, there have been only small retrospective studies in IBD of the use of azathioprine and 6-mercaptopurine during pregnancy.23,24
Cyclosporin is not teratogenic and has been suggested to be safer than surgery in a pregnant woman with fulminant UC.25
Starting cyclosporin in pregnancy is a different issue to that of continuing a drug such as azathioprine, upon which the patient is stabilised prior to pregnancy. As hypertension is a common side effect of cyclosporin therapy and fits have also been reported, the side effect profile of cyclosporin would suggest that it should be used with extreme caution, especially if started in late pregnancy.
In the post-marketing surveillance of infliximab used in the treatment of CD and rheumatoid arthritis, a number of pregnancies have been reported with no increase in adverse events.26
Unfractionated heparin has occasionally been used to treat refractory UC27
and has been extensively used in the treatment of thromboembolic disease in pregnancy. Antibiotics, especially metronidazole and ciprofloxacin, have been reported to be safe in short courses in pregnancy.28,29
“Female and male patients starting methotrexate must be using a reliable form of contraception and should avoid conceiving for six months after stopping the drug”
Methotrexate, a folic acid antagonist, like sulphasalazine, is however highly mutagenic and teratogenic, causing neural tube and other defects. Female and male patients starting methotrexate must be using a reliable form of contraception and should avoid conceiving for six months after stopping the drug. Should conception occur in a woman unable to consider a termination, high dose folic acid treatment for the remainder of the pregnancy may slightly reduce the risks to the fetus.30