Management of IBD in Pregnancy

Transcript 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  Flexible sigmoidoscopy – low risk 2  Colonoscopy – should only be used for life-threatening colonic disease or when only alternative is laparotomy 2 ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein.

1 Hufton AP. Br J Radiol. 1979;52:735-740. 2 Cappell MS, et al. Dig Dis Sci. 1996;41:2353-2361.

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.

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.

Summary: Safety of IBD Medications During Pregnancy

Category B

Loperamide Mesalamine Balsalazide Corticosteroids Sulfasalazine Anti-TNF agents Metronidazole*

Category C

Ciprofloxacin Cyclosporine Diphenoxylate Olsalazine Tacrolimus Natalizumab

Category D

Azathioprine † 6-Mercaptopurine †

Category X

Methotrexate Thalidomide *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.

Sulfasalazine in Pregnancy

 Most side effects linked to sulfapyridine moiety 1  No increase in fetal malformations  Readily crosses placenta, but only minimal amounts in breast milk 2  Interferes with folic acid metabolism – Folate important for neural tube development 3 – Folic acid supplements (1 mg BID) advised prior to conception and throughout pregnancy 1 Stein RB, Hanauer SB. Gastroenterol Clin North Am. 1999;28:297-321. 2 Miller JP. J R Soc Med. 1986;79:221-225. 3 Czeizel AE, Dudas I. N Engl J Med. 1992;327:1832-1835.

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

Safety of Mesalamine in Pregnancy

Study

Marteau et al 1 Diav-Citrin et al 2

123* 165

Mean Mesalamine Dosage

2.1 ± 0.8 g/d 2.0 ± 1.6 g/d

Incidence of Fetal Malformations (%) Patients Controls

3.1

1.7-3.4

† 0.8

3.8

*96 taking mesalamine during first trimester. † General population in France.

1 Marteau P, et al. Aliment Pharmacol Ther. 1998;12:1101-1108. 2 Diav-Citrin O, et al. Gastroenterology. 1998;114:23-28.

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.

Antibiotics

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

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.

AZA/6-MP in Pregnancy

 Several studies in transplant recipients have reported safe use during pregnancy 1  Study of IBD patients showed no  in prematurity, spontaneous abortion, congenital abnormalities, or childhood neoplasia 2 – Study population included fathers treated with AZA/6-MP  In another study, AZA/6-MP did not reduce fertility in men 3  Risk of birth defects similar to that in general population 4 1 Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. 2 Francella A, et al. Gastroenterology. 2003;124:9-17. 3 Dejaco C, et al. Gastroenterology. 2001;121:1048-1053. 4 Library: IBD & Your Family. Available at www.ccfa.org/medcentral/library/family/drugpreg.htm. Accessed March 6, 2003.

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

Thiopurines and Nursing

 2 infants breast fed with mothers on 6MP – 6MP levels by HPLC < 0.09% maternal dose 1  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 offspring 2

Moretti M. Ann Pharmacother 2006; Dec (40); Gardiner S. Br J Clin Pharmacol 2006; 62:453-56.

Cyclosporine in Pregnancy

 Registry data on transplant recipients 1 – No specific congenital abnormalities or birth defects – Prematurity: 56% – Low birth weight: 49.5%  Study in 5 women with IBD 2 – 4 live births, 1 missed abortion – No congenital abnormalities  Should be given at experienced IBD centers 3 1 Armenti VT, et al. Transplantation. 1994;57;502-506. 2 Marion JF, et al. Am J Gastroenterol. 1996;91:1975. 3 Kornbluth A, Sachar DB. Am J Gastroenterol. 1997;92:204-211.

Infliximab (B) Safety Database in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy

80 70 60 67 66 67 67 50 40 30 20 17 16 17 15 19 20 11 13 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;21:1-59 Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.

Live births Miscarriages Therapeutic termination

Medications: Biologics

     Biologics – Category B: Infliximab, adalimumab, certolizumab – Category C: Natalizumab Infliximab: 102 pregnancies, 54 outcomes 1 – “Rescue” infliximab successful 2 – Infliximab not detected in breast milk (n=5) – Demonstrated to cross the placenta and detectable in cord blood for up to 6 months from birth 5 Adalimumab: 2 IBD pregnancies in published literature 3,4 – 47 reported in OTIS registry Certolizumab: no published data in humans Natalizumab: IgG4, placental transfer in 1 st trimester

1 Katz J. Am J Gastroenterol 2004; 99(12):2385-92. 2 Mahadevan U. APT 2005; 21(6):733-8. 3 Vesga L. Gut 2005; 54(6):890.

4 Mishkin DS. IBD 2006; 12(8):827-8.

5 Mahadevan Gastroenterology 2007;132:A-144

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.

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

Safety of IBD Medications in Breast-Feeding

Low risk to Use When Warranted

Oral mesalamine Topical mesalamine Sulfasalazine Corticosteroids Infliximab Adalimumab Certolizumab

Limited Data Available

Azathioprine 6-Mercaptopurine Infliximab Tacrolimus Natalizumab

Physicians’ Desk Reference

® . 57th ed. Montvale, NJ: Thompson PDR; 2003.

Contraindicated

Methotrexate Cyclosporine Metronidazole Ciprofloxacin