Guest guest Posted October 21, 2004 Report Share Posted October 21, 2004 To view the article with Web enhancements, go to:http://www.medscape.com/viewarticle/487082 Gastroenterology Expert Column IBD and Pregnancy Audrey H. Calderwood, MD; Sunanda V. Kane, MD Medscape General Medicine 6(4), 2004. © 2004 Medscape Posted 10/08/2004 Introduction Inflammatory bowel disease (IBD) refers to ulcerative colitis and Crohn's disease, 2 chronic conditions of unknown etiology that can affect women in their childbearing years. There are many issues of clinical consideration that arise for the female patient with IBD who is pregnant or contemplating pregnancy, including: inheritance in the offspring; fertility; the effect of the gestational period on IBD and, conversely, the effect of IBD on the pregnancy; and the safety of drugs on the developing fetus and nursing newborn. Issues regarding fertility and potential teratogenicity from medications used to control the disease also concern couples when the male partner is afflicted with IBD. This article reviews some of the knowledge regarding the effects of IBD and its treatment on fertility and pregnancy, and summarizes the literature regarding treatment options and outcomes in adults with IBD who wish to have children or who are pregnant or lactating. Onset and Diagnosis During Pregnancy An early clinical series suggested that the prognosis was poor for women with ulcerative colitis diagnosed during pregnancy.[1] Since that time, epidemiologic data have failed to show that disease course is worsened during pregnancy.[2] To date, there has been no large study involving de novo diagnosis of Crohn's disease during pregnancy; therefore, no conclusion about its severity under these physiologic conditions can be drawn. Fertility Overall, fertility rates for women with IBD are comparable to rates in the normal population. Epidemiologic studies performed in the 1980s suggested lower fertility rates,[3] but more recent research has demonstrated an increased voluntary childless rate in IBD patients.[4,5] Some women remain childless for fear of disease transmission to their offspring. It is important to remember that the inheritance of IBD does not occur in a true Mendelian fashion -- other factors are necessary to produce expression of disease. Current data suggest that disease transmission is low: 7% if one parent has Crohn's disease, and even less if one parent has ulcerative colitis.[6] The risk of IBD increases up to 37% if both parents have the disease. The risk of inheriting IBD is higher in Jewish (7.8%) than in non-Jewish (5.8%) families.[6] Active Crohn's disease can reduce fertility in several ways. Voluntary childlessness can result from fear of intimacy and dyspareunia. Active inflammation in the colon as well as any inflammation or scarring directly involving the fallopian tubes or ovaries has been shown to decrease fertility.[5] Women who have had any surgical resection are at risk for adhesions, which can also impair tubal function.[7] In women with a history of ulcerative colitis, restorative proctocolectomy with ileoanal anastomosis has been shown to increase dyspareunia and significantly reduce fertility.[8-11] None of the medications used to treat IBD has a direct effect on female fertility, but it is important to remember that in men, sulfasalazine therapy causes a reversible reduction in sperm count and motility.[12-15] Although there is no minimum required time period for quiescent disease prior to a planned conception, at least 3 months is recommended. Effect of IBD on Pregnancy Open discussion between patient and physician is the best way to ensure the best outcome of a pregnancy. If a woman is doing well and in remission, there is every reason to expect the pregnancy to proceed smoothly. Women with IBD appear no more likely to experience spontaneous abortion or stillbirth, or to have children with congenital abnormalities. If active disease is present, it is likely to continue through pregnancy and will place the pregnancy at greater risk for complications.[16] This risk appears to be higher in Crohn's disease than in ulcerative colitis. Therefore, the main priority is to establish and maintain remission prior to conception. Miscarriage can be seen more frequently in women with active disease (up to 35% of conceptions).[17-19] A short series suggested that active Crohn's disease at the time of conception increased the natural risk of fetal loss after 16 weeks.[20] Despite progress in the treatment of IBD, an increased risk of premature and low-birth-weight babies is still observed.[3-5, 17,18, 20-24] As in all pregnancies, cessation of smoking is extremely important. With respect to congenital malformations, all reports published to date, except for 1 abstract,[25] show no increased risk above that seen in the general population (1%-4.8%).[16-19,21-24,26] The presence of IBD does not appear to have an impact on maternal complications of pregnancy, including hypertension and proteinuria. Effect of Pregnancy on IBD For women with quiescent ulcerative colitis, the rate of relapse is approximately the same in pregnant vs nonpregnant patients. This is in contrast to the presence of active disease at the time of conception, which is associated with continued or worsening disease activity in approximately 70% of women.[27] Comparable observations are seen in Crohn's disease. Although it has been generally accepted that pregnancy does not significantly influence the clinical course of IBD, 2 interesting studies suggest that pregnancy may actually decrease the activity of IBD.[28,29] In one study of parous women with Crohn's disease, the need for surgical resection was inversely correlated with increasing parity.[28] Another study showed that in parous women, the relapse rate was lower in the 3 years following pregnancy than in the 3 preceding years.[29] One possible explanation for pregnancy causing a decrease in Crohn's disease activity is that relaxin, a hormone produced exclusively in pregnancy, inhibits macrophage function, which may result in less fibrosis and stricture formation. Other investigators suggest that downregulation of the immune system may occur with maternal-fetal HLA disparity.[30] Disease Assessment During pregnancy, hemoglobin and albumin levels decrease and the sedimentation rate increases. Because of these normal physiologic changes, disease assessment during pregnancy should rely more on clinical symptoms rather than laboratory parameters. If radiologic imaging is contemplated, ultrasound exams are safe, as is magnetic resonance imaging,[31] but these modalities are rarely used for clinical assessment. It is best to avoid exposure of the fetus to radiation from abdominal x-rays, especially early in the pregnancy. However, the absolute risk of abdominal radiography to the fetus is minimal, and clinical necessity should guide decision making.[32] There is no evidence that sigmoidoscopy will induce premature labor.[33,34] Most patients can be evaluated with sigmoidoscopy without full colonoscopy. However, if colonoscopy is necessary for diagnosis or determination of extent and severity of disease, close fetal monitoring is indicated. Treatment Corticosteroids have not been associated with teratogenicity in humans, and can be used as necessary to control disease activity.[3,35,36] Prednisone crosses the placenta less efficiently than betamethasone or dexamethasone; after metabolization, only 10% of the maternal dose is exposed to the fetus. Budesonide has not yet been studied in this clinical setting. One of the mainstays of treatment for maintenance of remission in IBD is 5-aminosalicylic acid (5-ASA) and its derivatives, sulfasalazine and mesalamine. Only small amounts of either agent are detected in maternal and cord plasma.[37] Sulfasalazine and 5-ASA at doses of < 3 g/day have not been associated with any increased birth defects or kernicterus.[37-39] Given the risk of sulfasalazine-induced folate deficiency, together with the heightened folate requirements in pregnancy and data showing a decrease in neural tube defects with folate supplementation, daily folic acid supplementation should be taken by any woman on sulfasalazine who is considering pregnancy. Mesalamine preparations at doses of < 2.4 g/day are considered safe and do not affect the rate of live births, miscarriages, or adverse events.[23, 37-40] However, a prospective study following women on mesalamine showed a significant increase in the rate of preterm deliveries (13% vs 5%), less mean maternal weight gain (13.1 vs 15.6 kg), and lower mean birth weight (3.2 vs 3.4 kg) when compared with the normal population.[40] The safety of larger doses of 5-ASA has not been studied to the same extent as the lower-dose regimens. Use of topical 5-ASA agents during pregnancy has not been shown to increase adverse birth outcomes. Limited data are available on the safety of antibiotics in Crohn's disease. Ampicillin, cephalosporin, erythromycin, and short courses (7-10 days) of metronidazole are believed to be safe.[41] The quinolones are contraindicated in pregnancy given the arthropathogenicity of these medications in immature animals.[42] There are no large prospective or population-based studies on the use of immunomodulators (azathioprine, 6-mercaptopurine) during pregnancy in IBD. Up until recently, most of our information has come from the transplantation literature and small retrospective series in IBD.[43-45] The most experienced IBD clinicians generally suggest that 6-mercaptopurine, azathioprine, and cyclosporine can be used safely during pregnancy if the mother's health mandates therapy. Of note, a small retrospective study found that the use of 6-mercaptopurine in fathers within 3 months of conception resulted in an increase in pregnancy-related complications,[46] but subsequent data have failed to corroborate these findings. Methotrexate, another immunomodulator, is associated with severe fetal malformations in the first trimester and is contraindicated in pregnancy. Women should stop methotrexate therapy at least 1 month before conception, and men, at least 3 months before conception (time required for spermatogenesis). Anti-tumor necrosis factor antibody therapy appears safe in pregnancy, although data are limited. Antidiarrheals are used for symptom relief in IBD. Loperamide is not teratogenic in animals, but human data are limited. Loperamide use has not been associated with an increased rate of first-trimester fetal malformations, spontaneous abortion, or premature delivery. It may, however, be associated with lower-than-normal birth weights, and use in late pregnancy has been implicated in neonatal intestinal obstructions.[47] Therefore, it is best to avoid large doses of this agent during pregnancy. Long-term diphenoxylate use during pregnancy is not recommended.[48] Table 1 details the safety of medications used in IBD. Postpartum Issues Nearly all drugs used to treat IBD are secreted in breast milk. The advantages of breastfeeding for the mother and newborn are well known. General recommendations (which reflect consensus of expert opinion but that have not been established in clinical series) are shown in Table 2. Corticosteroids can be used in breastfeeding mothers because the dose ingested by the infant is < 0.1% of the mother's dose.[35] Some physicians recommend that mothers on corticosteroid doses of > 20 mg/day wait at least 4 hours before nursing. As of the time of this writing, immunomodulator use during breastfeeding is not recommended because of the theoretical risk of immune suppression, but emerging data suggest that metabolite levels are miniscule and that no increased risk is imparted on nursing infants. Surgery and Pregnancy The indications for surgery during pregnancy are identical to those for nonpregnant patients, including obstruction, perforation, abscess, and hemorrhage. Although the obstetric indications for caesarean section do not differ in women with IBD, women with IBD undergo elective caesarean sections more frequently than do women in the normal population. In Crohn's disease, vaginal delivery can trigger or worsen existing perineal disease. Caesarean section may prevent aggravation of perineal disease and/or anal incontinence. Pregnancy has not been shown to complicate stoma function.[49] Summary Points Fertility is affected in postsurgical ulcerative colitis and active Crohn's disease. There are no increases in adverse outcomes with quiescent IBD. Active disease at conception increases the risk for adverse outcomes. The majority of medications for IBD are safe in pregnancy and breastfeeding. While the weight of retrospective data is encouraging, the advent of newer therapies and biologics make decision-making about childbearing more difficult. There is currently a large insurance database study under way to assess both maternal and fetal health issues in women with IBD. Only with these kinds of large studies with access to comprehensive amounts of medical information will we truly understand the roles that disease activity and therapy (medical as well as surgical) play in disease course and outcomes. Tables Table 1. Safety of IBD Medications During Pregnancy Category B Medications Category C, D Medications Contraindicated Oral, topical mesalamine Corticosteroids Methotrexate Sulfasalazine, olsalazine, balsalazide Azathioprine Thalidomide Infliximab 6- mercaptopurine Ciprofloxacin, metronidazole(after first trimester) Cyclosporine Loperamide Diphenoxylate + atropine Table 2. Safety of IBD Medications During Breastfeeding Safe to Use When Indicated Limited No Data Contraindicated Oral, topical mesalamine Infliximab Methotrexate Sulfasalazine, olsalazine, balsalazide Azathioprine Thalidomide Low doses of steroids (< 20 mg) 6- mercaptopurine Cyclosporine References Banks B, Korelitz BI, Zetzel L. The course of non-specific ulcerative colitis: A review of twenty years of experience and late results. Gastroenterology. 1957;32:983-1012. Abstract Woolfson K, Cohen Z, McLeod RS. Crohn's disease and pregnancy. Dis Colon Rectum. 1990;33:869-873. Abstract Korelitz BI. Inflammatory bowel disease and pregnancy. In Pregnancy and Gastro-intestinal disorders. Gastroenterol Clin North Am. 1998;27:213-224. Abstract Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm birth for women with inflammatory bowel disease. Gastroenterology. 1990;9:987-994. Mayberry JF, Weterman IT. 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