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Management of IBD in Pregnancy

Management of IBD in Pregnancy. Assessment of Disease Activity in Pregnant IBD Patients. Laboratory studies (ESR, Hgb, albumin, CRP) Ultrasound – low risk Low-dose X-rays pose minimal fetal risk 1 Endoscopy – low risk if used for appropriate indications 2

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Management of IBD in Pregnancy

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  1. Management of IBD in Pregnancy

  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 ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein. 1Hufton AP. Br J Radiol. 1979;52:735-740. 2Cappell MS, et al. Dig Dis Sci. 1996;41:2353-2361.

  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 PDR® = Physicians’ Desk Reference®; FDA = Food and Drug Administration. Koren G, et al. N Engl J Med. 1998;338:1128-1137.

  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 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 *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; 1998. 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 1Stein RB, Hanauer SB. Gastroenterol Clin North Am. 1999;28:297-321. 2Miller JP. J R Soc Med. 1986;79:221-225. 3Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835.

  7. Aminosalicylates (B,C) • Meta-analysis 7 studies: 642 5ASA, 1158 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 *96 taking mesalamine during first trimester. †General population in France. 1Marteau P, et al. Aliment Pharmacol Ther. 1998;12:1101-1108. 2Diav-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 Bell CM, Habal FM. Am J Gastroenterol. 1997;92:2201-2202.

  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 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 1Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. 2Francella A, et al. Gastroenterology. 2003;124:9-17. 3Dejaco C, et al. Gastroenterology. 2001;121:1048-1053. 4Library: IBD & Your Family. Available at www.ccfa.org/medcentral/library/family/drugpreg.htm. 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. 39.1 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. 2007 Sep 10;79(10):696-701

  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; 62:453-56.

  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 1Armenti VT, et al. Transplantation. 1994;57;502-506. 2Marion JF, et al. Am J Gastroenterol. 1996;91:1975. 3Kornbluth A, Sachar DB. Am J Gastroenterol. 1997;92:204-211.

  16. Infliximab (B) Safety Database in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy 80 67 67 67 70 66 60 Live births 50 Miscarriages Proportion of Patients (%) 40 Therapeutictermination 30 20 19 17 17 20 16 15 13 11 10 0 General population Crohn’s disease All infliximab patients(N=96) Infliximab patients with CD (N=82) Katz JA, et al. Am J Gastroenterol. 2004;99:2385-2392. Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.

  17. Medications: Biologics • 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):2385-92. 2Mahadevan U. APT 2005; 21(6):733-8. 3Vesga L. Gut 2005; 54(6):890.4Mishkin DS. IBD 2006; 12(8):827-8.5 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 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

  20. Safety of IBD Medications in Breast-Feeding 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

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