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Management of IBD in Pregnancy

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1 Management of IBD in Pregnancy
A total management program for women with IBD includes assessment of disease activity and choice of medical as well as surgical options, with particular attention to issues such as fertility and pregnancy. This section reviews treatment in relation to those issues.

2 Assessment of Disease Activity in Pregnant IBD Patients
Laboratory studies (ESR, Hgb, albumin, CRP) Ultrasound – low risk Low-dose X-rays pose minimal fetal risk1 Endoscopy – low risk if used for appropriate indications2 Flexible sigmoidoscopy – low risk2 Colonoscopy – should only be used for life-threatening colonic disease or when only alternative is laparotomy2 A range of diagnostic modalities may be used to assess disease activity in pregnant patients with IBD. Routine laboratory values for erythrocyte sedimentation rate, hemoglobin, albumin, and C-reactive protein are vital, especially in diseases such as IBD that have an immunologic component. Ultrasound, used to monitor the development of the fetus, is safe, and low-dose X-rays pose a minimal risk to the fetus.60 Endoscopy is a valuable tool to assess the anatomic extent of UC.2 A study reported that 38 of 41 pregnant women who had flexible sigmoidoscopies during pregnancy had healthy babies. All reported poor fetal outcomes were in high-risk pregnancies and were not temporally related to the sigmoidoscopy, suggesting that this procedure, when performed in clinically stable pregnant patients, does not frequently cause complications. However, sigmoidoscopy should be performed during pregnancy for clinically significant overt lower-gastrointestinal bleeding; diarrhea or abdominal pain are weaker indications for this procedure. Colonoscopy in pregnancy should be considered only in life-threatening disease or when the alternative is surgery.61 ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein. 1Hufton AP. Br J Radiol. 1979;52: Cappell MS, et al. Dig Dis Sci. 1996;41:

3 Drugs in Pregnancy Pharmaceutical companies almost never test products in pregnant women PDR® disclaimer: use in pregnancy is not recommended unless benefits justify risk to fetus FDA classifications (A, B, C, D, X) Ambiguous Difficult to interpret and use in counseling Pharmaceutical companies rarely test drugs in pregnant women62 and, until recently, did not routinely include women in clinical trials on the grounds that even if a woman was not pregnant at the start of the trial, it was not possible to be sure that she might not become pregnant during the trial or while the trial drug was present in her body, and the drug might cause problems with current or future pregnancies. It was also thought that hormonal cycling or other factors might affect trial results.63 As a consequence, even though pharmaceutical companies now include more women in trials leading to the approval of a drug, data about a drug’s effects in pregnant women and on pregnancy outcomes mostly come retrospectively after a drug has been in use for a considerable amount of time. The standard disclaimer in prescribing information is that use in pregnancy is not recommended unless benefits justify risk to the fetus.64 PDR® = Physicians’ Desk Reference®; FDA = Food and Drug Administration. Koren G, et al. N Engl J Med. 1998;338:

4 Pregnancy-Risk Categories
A: Controlled human studies do not show risk to fetus; chance of risk remote B: No evidence of risk to fetus in human studies; chance of risk remote but possible C: Inadequate studies in humans; risk cannot be ruled out, but benefits may outweigh risks D: Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are ineffective X: Contraindicated in pregnancy The FDA Use-in-Pregnancy ratings are as follows: A means that controlled human studies show no risk to the fetus in any trimester B indicates no evidence of risk in humans; the chance of fetal harm is remote but possible C means that risk cannot be ruled out; adequate human or animal studies are lacking; the chance of fetal harm exists, but the benefits may still outweigh the risks D represents positive evidence of risk, but the benefits may outweigh the risks in life-threatening situations where safer drugs are ineffective X indicates that a drug is contraindicated in pregnancy65 These ratings are subjective to the clinician’s assessment of a therapy’s benefits outweighing its risks. Care must be used in discussing pregnancy drug classifications with patients, as the ratings leave room for interpretation that may confuse or frustrate patients. Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.

5 Summary: Safety of IBD Medications During Pregnancy
Category B Category C Category D Category X Loperamide Ciprofloxacin Azathioprine† Methotrexate Mesalamine Cyclosporine 6-Mercaptopurine† Thalidomide Balsalazide Diphenoxylate Corticosteroids Olsalazine Sulfasalazine Tacrolimus Anti-TNF agents Natalizumab Metronidazole* This table groups drugs currently used to treat IBD in 4 categories: those that are safe to use in pregnancy within the indications stated in the prescribing information (Category B), those that are probably safe to use, but for which data are limited (Category C), those for which there is evidence of risk but whose benefits may outweigh risks in certain situations (Category D), and those that are totally contraindicated (Category X). When considering treatment with drugs in Category C or D, clinicians need to determine whether the benefits of drug therapy outweigh the potential risks to the mother or the fetus, bearing in mind that a disease flare due to nontreatment may also pose a risk to the mother or the fetus. *Safe for use after first trimester. †Increasing use in pregnancy. Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Physician’s Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.

6 Sulfasalazine in Pregnancy
Most side effects linked to sulfapyridine moiety1 No increase in fetal malformations Readily crosses placenta, but only minimal amounts in breast milk2 Interferes with folic acid metabolism Folate important for neural tube development3 Folic acid supplements (1 mg BID) advised prior to conception and throughout pregnancy Sulfasalazine was the first therapeutic advance in the treatment of active UC and for the maintenance of remission in UC.66 The drug consists of sulfapyridine linked to 5-aminosalicylic acid, or 5-ASA. It was developed for use in rheumatoid arthritis, combining the antimicrobial action of sulfonamides with the anti-inflammatory action of salicylates. The 5-ASA moiety is responsible for the anti-inflammatory activity, and the sulfapyridine moiety acts as a carrier for 5-ASA, preventing absorption in the small intestine and facilitating delivery to the colon. Most of the side effects of sulfasalazine appear to be linked with the sulfapyridine moiety.1 Sulfasalazine and sulfapyridine cross the placenta, but no firm evidence of harmful effects to the fetus has been found, and the consensus in the literature is that it can be used by pregnant women as it is by nonpregnant women. The concentrations of the 5-ASA moiety of the drug in cord and maternal serum are lower than those of sulfasalazine because of low absorption. Concentrations of sulfasalazine in breast milk are lower than in maternal or cord serum and are not thought likely to be harmful.55 Sulfasalazine interferes with folic acid metabolism; therefore, folate supplementation is recommended to prevent neural tube malformations such as spina bifida.67 The clinical utility of sulfasalazine is limited by a high incidence of adverse events (headache, dyspepsia, male infertility, skin rashes), which often necessitate discontinuation of treatment or dose reduction to subtherapeutic levels.68 1Stein RB, Hanauer SB. Gastroenterol Clin North Am. 1999;28: Miller JP. J R Soc Med. 1986;79: Czeizel AE, Dudas I. N Engl J Med. 1992;327:

7 Aminosalicylates (B,C)
Meta-analysis 7 studies: 642 5ASA, no med Congenital anomalies: OR 1.16 (0.76, 1.77) Stillbirth OR 2.38 (0.65, 8.72) SAB OR 1.14 (0.65, 2.01) Preterm delivery 1.35 (0.85, 2.13) LBW OR 0.93 (0.46, 1.85) Sulfasalazine given w/ folic acid 1 mg BID Folic acid: neural tube defects, CV, GU, cleft palate Case reports of congenital malformation Placental and Breast Transfer Occurs Potential allergic reaction newborn: watery diarrhea SAS not associated with kernicterus or displacement of bilirubin from albumin Olsalazine: Pregnancy category C. All others, B Rahimi Reprod Toxicol 2008

8 Safety of Mesalamine in Pregnancy
Study n Mean Mesalamine Dosage Incidence of Fetal Malformations (%) Patients Controls Marteau et al1 123* 2.1 ± 0.8 g/d 3.1 Diav-Citrin et al2 165 2.0 ± 1.6 g/d 0.8 3.8 This slide summarizes the results of 2 studies of mesalamine in pregnancy. The study by Marteau compares outcomes in women taking mesalamine with those in the general population in France73; the Diav-Citrin study is the Motherisk Study described previously. These studies confirm that the incidence of fetal malformations in infants born to women taking mesalamine during pregnancy is no higher than in the general population. *96 taking mesalamine during first trimester. †General population in France. 1Marteau P, et al. Aliment Pharmacol Ther. 1998;12: Diav-Citrin O, et al. Gastroenterology. 1998;114:23-28.

9 Topical 5-ASA in Pregnancy
Study of 19 pregnancies Maintenance 5-ASA topical therapy at time of conception and throughout pregnancy Successful full-term pregnancies for all patients, with no fetal abnormalities Minimal excretion of 5-ASA and metabolites in breast milk Many years of safe use This was a small study of 19 pregnant women treated for UC with topical 5-ASA delivered by enema. All the women completed their pregnancies successfully, and there were no fetal abnormalities.74 5-ASA enemas have been shown to be safe and effective for maintaining remission, particularly in left-sided UC, the part of the colon to which the 5-ASA enema has access. The response rate to treatment is high, and the rate of complications is low. This is particularly important in UC, because of its high rate of spontaneous relapse,75 and equally important in pregnancy because of the threat to the fetus posed by active disease. Bell CM, Habal FM. Am J Gastroenterol. 1997;92:

10 Antibiotics Metronidazole (B) /Ciprofloxacin (C)
Low risk of teratogenicity Metronidazole: prospective controlled study, 2 meta-analysis However, 2nd, 3rd T use, 1st T cleft lip, palate Ciprofloxacin: prospective controlled study low risk of defects Affinity for bones, arthropathy in children Breast feeding not advised on MNZL, probably compatible with ciprofloxacin Minimal benefit in CD and UC with longer use-avoid Rifaximin: Pregnancy C teratogenicity in animal studies Safety in humans in pregnancy/breastfeeding unknown

11 Corticosteroids in Pregnancy
Increased spontaneous abortions, cleft palate, stillbirths in mice; rare teratogenicity in humans (cleft palate) High doses associated with retardation of fetal growth No fetal adrenocortical insufficiency Safety uncertain with long-term use of high doses while breast-feeding Active-disease risks greater than drug risks to fetus, so use if needed Although there are risks associated with the use of corticosteroids in pregnancy, the risks of active disease exceed those to the fetus associated with corticosteroids. A reference guide to fetal and neonatal risk associated with drugs in pregnancy and lactation concludes that prednisone and prednisolone pose very small risks to the developing fetus and states that the American Academy of Pediatrics considers prednisone to be compatible with breast-feeding.80 Although corticosteroids are known to be effective for induction of remission of moderate to severe CD, these agents have not been shown to be effective for long-term maintenance of remission. Corticosteroids also have important systemic side effects, some of which are irreversible. Thus, it is evident that these agents should be used with caution.1,81,82 Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.

12 AZA/6-MP in Pregnancy Several studies in transplant recipients have reported safe use during pregnancy1 Study of IBD patients showed no  in prematurity, spontaneous abortion, congenital abnormalities, or childhood neoplasia2 Study population included fathers treated with AZA/6-MP In another study, AZA/6-MP did not reduce fertility in men3 Risk of birth defects similar to that in general population4 AZA and its active metabolite, 6-MP, are common choices for maintenance therapy in IBD after other agents have been used to induce remission or for patients who have not responded to systemic steroids.1,83 AZA is also used, often with prednisone, by transplant patients.84 A review of pregnancy in women with renal allografts reported no frequent or predominant developmental fetal abnormalities. Those that were reported were rare and often resolved.85 A small study of women with IBD taking AZA reported no congenital abnormalities and no perinatal problems. The authors concluded that AZA is safe in pregnancy for patients with IBD and that termination of pregnancy is not mandatory for patients who conceive while taking the drug.86 A recent, large study assessed outcomes of infants born to 79 mothers with IBD who took AZA/6-MP either before conception, before conception and during pregnancy, or just during pregnancy or to 76 fathers who had been treated before conception.87 Results indicated no significant difference in rates of miscarriage, congenital abnormalities, premature birth, or neonatal and childhood infection between the treated cohort and untreated controls. In another study, semen quality and, thus, fertility in men with IBD was not reduced by treatment with AZA.13 AZA has been found to be relatively safe in pregnancy. In a surveillance study of more than 225,000 pregnancies, no major malformations were observed in 6 categories – cardiovascular defects, oral cleft, spina bifida, polydactyl, limb reduction defect, and hypospadias.80 Fetal immunosuppression has been observed, including bone marrow suppression, leukopenia, and thrombocytopenia.86 Overall, the risk of a disease flare-up may strongly outweigh the risk of fetal damage, and this issue should be decided by patient and physician in each case.4 1Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Francella A, et al. Gastroenterology. 2003;124: Dejaco C, et al. Gastroenterology. 2001;121: Library: IBD & Your Family. Available at Accessed March 6, 2003.

13 Azathioprine and Teratogenicity
Largest Study to date 189 pregnant women on AZA who contacted one of seven teratogen information services were compared to a cohort of 230 pregnant women who took non-teratogenic treatments Rate of major malformations did not differ with six neonates each: AZA (3.5%) vs control ( 3.0%) (p = .775; OR 1.17; CI: 0.37, 3.69). Mean birth weight and gestational age were lower in AZA group: 2,995g vs. 3,252g [p = .001] 37.8 weeks vs weeks [p = .001] The AZA group had more prematurity 21.4% vs. 5.2% [p < .001] The AZA group had more low birth weight 23% vs. 6.0% [p < .001] Goldstein Birth Defects Res A Clin Mol Teratol Sep 10;79(10):

14 Thiopurines and Nursing
2 infants breast fed with mothers on 6MP 6MP levels by HPLC < 0.09% maternal dose1 4 mother-infant pairs 3 months post-partum were tested for 6MP metabolites All infants were nursing Maternal levels within therapeutic range No metabolites found in offspring2 Moretti M. Ann Pharmacother 2006; Dec (40); Gardiner S. Br J Clin Pharmacol 2006; 62:

15 Cyclosporine in Pregnancy
Registry data on transplant recipients1 No specific congenital abnormalities or birth defects Prematurity: 56% Low birth weight: 49.5% Study in 5 women with IBD2 4 live births, 1 missed abortion No congenital abnormalities Should be given at experienced IBD centers3 There are relatively little data on the safety of cyclosporine in pregnancy; however, based on the data available, it does not appear that cyclosporine poses a major risk to the fetus. The drug is not teratogenic in animals, and it is not likely to be teratogenic in humans. There is a fairly high incidence of fetal growth retardation and low-birth-weight infants. The National Transplantation Registry was established to study outcomes in all solid organ transplant recipients. The majority of the experience has been derived from female renal transplant recipients. Outcomes showed that no specific congenital abnormalities or birth defects were associated with cyclosporine use. Of the live-born infants, 56% were premature and 49.5% had low birth weight.88 In a small report,89 the safety of cyclosporine was examined in 5 pregnant women who received the drug during their pregnancy. Four of 5 pregnancies resulted in live births and 1 had a missed abortion at 8 weeks. No congenital abnormalities or developmental defects were observed. A recent, small study found that patients given cyclosporine in combination with steroids for severe colitis tended to deliver lower-birth-weight, premature babies; overall, pregnancy outcomes were comparable to those for an untreated IBD control group.90 If cyclosporine is used during pregnancy, it should be administered and monitored at experienced IBD centers.2 1Armenti VT, et al. Transplantation. 1994;57; Marion JF, et al. Am J Gastroenterol. 1996;91: Kornbluth A, Sachar DB. Am J Gastroenterol. 1997;92:

16 Proportion of Patients (%)
Infliximab (B) Safety Database in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy 80 70 67 66 67 67 60 Live births 50 Miscarriages Proportion of Patients (%) 40 Therapeutic termination 30 19 20 Infliximab Safety Database 146 Identified pregnancies 82 CD, 1 UC, 10 RA, 3 unknown Outcome 96 pregnancies, n=100 births Live birth 64 (67%) 1 preterm 24 wks (died), 1 tetralogy Fallot, 1 sepsis survived, 1 intestinal malrotation in twin Miscarriage 14(15%) (1 stillbirth on MTX) Therapeutic termination 18 (19%) (pt. Choice) Five reports of infants who were born with complications One infant born at 24-week gestation who did not survive One infant with a complicated neonatal course, but without apparent congenital anomalies One infant with Tetralogy of Fallot One infant born with intestinal malformation One twin in a set reported as having delayed development and hypothyroidism 20 17 16 17 15 13 11 10 General population Crohn’s disease All infliximab patients (N=96) Infliximab patients with CD (N=82) Katz JA, et al. Am J Gastroenterol. 2004;99: Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59 Hudson et al. Int J Gynaecol Obstet 1997;58:

17 Medications: Biologics
Category B: Infliximab, adalimumab, certolizumab Category C: Natalizumab Infliximab: 102 pregnancies, 54 outcomes1 “Rescue” infliximab successful2 Infliximab not detected in breast milk (n=5) Demonstrated to cross the placenta and detectable in cord blood for up to 6 months from birth5 Adalimumab: 2 IBD pregnancies in published literature3,4 47 reported in OTIS registry Certolizumab: no published data in humans Natalizumab: IgG4, placental transfer in 1st trimester 1Katz J. Am J Gastroenterol 2004; 99(12): Mahadevan U. APT 2005; 21(6): Vesga L. Gut 2005; 54(6):890.4Mishkin DS. IBD 2006; 12(8): Mahadevan Gastroenterology 2007;132:A-144

18 Methotrexate in Pregnancy
Contraindicated during pregnancy Chromosomal damage, teratogenic Abortifacient Oligospermia noted during treatment of men Returns to baseline posttreatment Long-term effects unknown Methotrexate is contraindicated during pregnancy and for breast-feeding mothers. Forty-five women who became pregnant after discontinuing treatment with methotrexate (mean interval 2.7 years) had 31 live births, 7 spontaneous abortions, and 7 elective abortions.80 In addition, of 10 pregnancies in women exposed to methotrexate, a folic acid antagonist, during the first trimester, 3 resulted in malformed infants. The pattern of methotrexate-related congenital abnormalities is similar to that caused by another folic acid antagonist, aminopterin.80 In men, methotrexate appears to cause oligospermia, which resolves after the drug is discontinued; long-term effects are unknown.80 Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.

19 Conclusions: IBD Drugs in Pregnancy
5-ASAs and corticosteroids low risk for use during pregnancy and breast-feeding Immunosuppressants AZA/6-MP appear low risk during pregnancy Methotrexate contraindicated Antibiotics Ampicillin and cephalosporins are low risk Ciprofloxacin and metronidazole should be avoided for longterm use Biologics: Anti-TNF agents low risk. Infliximab and likely adalimumab cross placenta in third trimester The drugs most likely to be safe during pregnancy are sulfasalazine, mesalamine, and corticosteroids. Both sulfasalazine and corticosteroids have a fairly high rate of side effects, although these are not likely to affect fetuses. Among the immunosuppressive agents, AZA and 6-MP appear to be safe in pregnancy. Cyclosporine is contraindicated during breast-feeding, and methotrexate is contraindicated during both pregnancy and breast-feeding.80 Of the antibiotics, ampicillin and the cephalosporins are safe. Ciprofloxacin and metronidazole are probably safe, although the data are far from unequivocal. Ciprofloxacin does not appear to be linked with an increased risk of major congenital malformations,78,80 but it is not recommended for women who are breast-feeding.80 Women who have been exposed to metronidazole during pregnancy should be reassured that the drug is probably safe and should not be counseled to terminate their pregnancies.79

20 Safety of IBD Medications in Breast-Feeding
Low risk to Use When Warranted Limited Data Available Contraindicated Oral mesalamine Azathioprine Methotrexate Topical mesalamine 6-Mercaptopurine Cyclosporine Sulfasalazine Infliximab Metronidazole Corticosteroids Adalimumab Certolizumab Tacrolimus Natalizumab Ciprofloxacin This slide groups IBD drugs into 3 categories: those that are safe during breast-feeding, those that are contraindicated, and those for which sufficient data are lacking. Those that are safe include both oral and topical mesalamine, sulfasalazine, and corticosteroids. Methotrexate, metronidazole, ciprofloxacin, and cyclosporine are contraindicated. For AZA/6-MP, infliximab, and tacrolimus, there are limited data available for a strong recommendation. Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.

21 Management of IBD in Pregnancy: Summary
Pregnancy outcomes best if patient in remission at time of conception Many IBD-specific therapies appear to be low risk in pregnancy Monitoring of fetal growth particularly important May need additional nutritional therapy because of malabsorption Once again, pregnancy outcomes are best when the patient is in remission at the time of conception. The most important factor in the course of the pregnancy is the health of the mother. Patients should be encouraged to remain adherent to their therapy through their pregnancies, since the risk of relapse is a greater threat to mother and infant than the risk from most drugs used to treat IBD. Many of the IBD drugs appear to be safe in pregnancy. Some drugs have an effect on fetal growth; therefore, monitoring fetal growth is particularly important. Some nutritional supplementation may be necessary.

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