Most women do not want to ingest any medications or products such as alcohol or tobacco when conceiving. With quiescent inflammatory bowel disease, many patients consider discontinuation of maintenance treatments. However meta-analysis data clearly supports maintenance medications such as sulfasalazine or mesalamine products. Relapsing inflammatory bowel disease symptoms during pregnancy should be aggressively managed with corticosteroids and perhaps antibiotics. As discussed earlier, most physicians feel that it is not advisable to initiate azathioprine (AZA) or 6-mercaptapurine (6-MP) during a pregnancy but maintenance use of AZA to continue remission during pregnancy is reasonable. Sachar (1998) has stated that “disease activity is more threatening to the pregnancy than most medical treatments”.
Sulfasalazine and Mesalamine
Sulfasalazine has been prescribed for decades in pregnant inflammatory bowel disease patients with no evidence of teratogenicity. Oral and topical mesalamine agents are not associated with congenital anomalies. However, as sulfasalazine interferes with folate metabolism, folic acid must be prescribed prior to conception to avoid neural tube defects. Again, education and planning are essential. High dose aminosalicylates should be avoided during pregnancy because of reported fetal nephrotoxicity
Metronidazole and ciprofloxacin after the first trimester, are considered to be safe in pregnancy. Metronidazole, though it crosses the placenta, has been used to treat vaginal trichomonas during the first trimester without evidence of congenital anomalies. Quinolones have been associated with fetal animal musculosketal problems but have not been associated with birth defects in humans. Penicillin’s and cephalosporins are pregnancy category B and maybe useful in perianal disease.
Prednisone has been used extensively in pregnancy without teratogenesis or fetal adrenocortical insufficiency. Corticosteroids cross the placental barrier and animal studies report an increase of cleft palate and stillbirth. These agents are used for moderate to severe disease in the pregnant patient.
AZA and Metabolites
Experience with immunomodulators in pregnant patients with renal transplants and systemic lupus erythematosis yields no teratogenecity or other adverse events. Physicians and patients should discuss the use of AZA and 6-MP for maintenance of remission during pregnancy especially if the disease activity was severe prior to beginning the medication. Controversy exists in the literature regarding the safety of AZA and 6-MP for childbearing female and male patients. In a recent publication, Francella, Present and colleagues reviewed the records of 155 inflammatory bowel disease patients who had conceived at least one pregnancy after developing inflammatory bowel disease. There were 325 pregnancies and 18 elective abortions. Seventy-nine of the patients were female and they had 171 pregnancies (median 2). There were 154 pregnancies from the 76 male patients. One involved 65 pregnancies with parents who had not been on 6-MP. There was no statistical difference in spontaneous abortions, abortions sec ondary to a birth defect, major congenital malformations, neoplasia, or increased infections among female or male patients taking 6-MP compared with controls.
TABLE. Safety of Inflammatory Bowel Disease Medications during Pregnancy
|Ciprofloxacin, metronidazole(after first trimester)||Infliximab||–|
The authors concluded that 6-MP use before (40 pregnancies), at conception (24 pregnancies) or during pregnancy (15 pregnancies) appears to be safe. They felt that discontinuation of 6-MP before and during pregnancy was not indicated. Personally, I believe disease activity to be far more detrimental than AZA/6-MP and I usually advise patients to continue this medication both before and during pregnancy if they need an immunomodulator to remain in remission.
Cyclosporine has been used again extensively during pregnancy in renal transplant patients and patients with systemic lupus erythematosus (SLE). The medical literature reports cyclosporine use to avoid colectomy in a few pregnant patients without fetal loss. However, nephrotoxicity, hypertension, and hepatoxicity are commonly reported in the pregnant patient and these are potential side effects of cyclosporine. One must therefore weigh the risk of medication toxicity versus urgent colectomy in the pregnant patient with severe colitis.
Methotrexate a folic acid antagonist is contraindicated before conception or during pregnancy. The drug is mutagenic and teratogenic with a high incidence of neural tube defects. In male patients, methotrexate can produce oligospermia and chromosomal damage. If a patient has received methotrexate prior to attemting conception, folic acid should be prescribed.
The Food and Drug Administration has classified infliximab as pregnancy category B; however, animal reproduction studies have not been conducted as infliximab does not cross react with tumor necrosis factor (TNF)-a in species other than humans and chimpanzees. Toxicity studies have been conducted in mice using an analogous antibody with no evidence of maternal toxicity or teratogenicity A safety database is maintained by Centocor (Malvern, PA). Outcomes data in direct exposure to infliximab report similar live births, miscarriage rates and therapeutic termination to the general population. Pharmacokinetics of this chimeric antibody to TNF-oc suggests a 3 to 6 month washout period to ensure infliximab is no longer present in circulation.