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Management of IBD in Pregnancy. Assessment of Disease Activity in Pregnant IBD Patients Laboratory studies (ESR, Hgb, albumin, CRP) Laboratory studies.

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Presentation on theme: "Management of IBD in Pregnancy. Assessment of Disease Activity in Pregnant IBD Patients Laboratory studies (ESR, Hgb, albumin, CRP) Laboratory studies."— Presentation transcript:

1 Management of IBD in Pregnancy

2 Assessment of Disease Activity in Pregnant IBD Patients Laboratory studies (ESR, Hgb, albumin, CRP) Laboratory studies (ESR, Hgb, albumin, CRP) Ultrasound – low risk Ultrasound – low risk Low-dose X-rays pose minimal fetal risk 1 Low-dose X-rays pose minimal fetal risk 1 Endoscopy – low risk if used for appropriate indications 2 Endoscopy – low risk if used for appropriate indications 2 Flexible sigmoidoscopy – low risk 2 Flexible sigmoidoscopy – low risk 2 Colonoscopy – should only be used for life-threatening colonic disease or when only alternative is laparotomy 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: Cappell MS, et al. Dig Dis Sci. 1996;41:

3 Drugs in Pregnancy Pharmaceutical companies almost never test products in pregnant women Pharmaceutical companies almost never test products in pregnant women PDR ® disclaimer: use in pregnancy is not recommended unless benefits justify risk to fetus PDR ® disclaimer: use in pregnancy is not recommended unless benefits justify risk to fetus FDA classifications (A, B, C, D, X) 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:

4 Pregnancy-Risk Categories A:Controlled human studies do not show risk to fetus; chance of risk remote 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 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 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 D:Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are ineffective X:Contraindicated in pregnancy X:Contraindicated in pregnancy Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.

5 *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; Physicians Desk Reference ®. 57th ed. Montvale, NJ: Thompson PDR; Summary: Safety of IBD Medications During Pregnancy Category B Category C Category C Category D Category X LoperamideCiprofloxacin Azathioprine Azathioprine Methotrexate MesalamineCyclosporine 6-Mercaptopurine 6-Mercaptopurine Thalidomide BalsalazideDiphenoxylate CorticosteroidsOlsalazine SulfasalazineTacrolimus Anti-TNF agents Natalizumab Metronidazole*

6 Sulfasalazine in Pregnancy Most side effects linked to sulfapyridine moiety 1 Most side effects linked to sulfapyridine moiety 1 No increase in fetal malformations No increase in fetal malformations Readily crosses placenta, but only minimal amounts in breast milk 2 Readily crosses placenta, but only minimal amounts in breast milk 2 Interferes with folic acid metabolism 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: 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, 1158 no med 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 Sulfasalazine given w/ folic acid 1 mg BID Folic acid: neural tube defects, CV, GU, cleft palateFolic acid: neural tube defects, CV, GU, cleft palate Case reports of congenital malformationCase reports of congenital malformation Placental and Breast Transfer Occurs Placental and Breast Transfer Occurs Potential allergic reaction newborn: watery diarrheaPotential allergic reaction newborn: watery diarrhea SAS not associated with kernicterus or displacement of bilirubin from albuminSAS not associated with kernicterus or displacement of bilirubin from albumin Olsalazine: Pregnancy category C. All others, B 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. 1 Marteau P, et al. Aliment Pharmacol Ther. 1998;12: Diav-Citrin O, et al. Gastroenterology. 1998;114: Studyn Mean Mesalamine Dosage Incidence of Fetal Malformations (%) PatientsControls Marteau et al 1 123* 2.1 ± 0.8 g/d Diav-Citrin et al ± 1.6 g/d

9 Topical 5-ASA in Pregnancy Study of 19 pregnancies 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 Minimal excretion of 5-ASA and metabolites in breast milk Many years of safe use Many years of safe use Bell CM, Habal FM. Am J Gastroenterol. 1997;92:

10 Antibiotics Metronidazole (B) /Ciprofloxacin (C) Metronidazole (B) /Ciprofloxacin (C) –Low risk of teratogenicity Metronidazole: prospective controlled study, 2 meta- analysisMetronidazole: prospective controlled study, 2 meta- analysis –However, 2 nd, 3 rd T use, 1 st T cleft lip, palate Ciprofloxacin: prospective controlled study low risk of defectsCiprofloxacin: 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 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) Increased spontaneous abortions, cleft palate, stillbirths in mice; rare teratogenicity in humans (cleft palate) High doses associated with retardation of fetal growth High doses associated with retardation of fetal growth No fetal adrenocortical insufficiency No fetal adrenocortical insufficiency Safety uncertain with long-term use of high doses while breast-feeding 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 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 pregnancy 1 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 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 In another study, AZA/6-MP did not reduce fertility in men 3 Risk of birth defects similar to that in general population 4 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; 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 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 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 : 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: 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 The AZA group had more prematurity –21.4% vs. 5.2% [p <.001] The AZA group had more low birth weight 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 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 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:

15 Cyclosporine in Pregnancy Registry data on transplant recipients 1 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 Study in 5 women with IBD 2 –4 live births, 1 missed abortion –No congenital abnormalities Should be given at experienced IBD centers 3 Should be given at experienced IBD centers 3 1 Armenti 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 Infliximab (B) Safety Database in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy 0 Proportion of Patients (%) 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: General population Crohns disease All infliximab patients (N=96) Infliximab patients with CD (N=82) Live births Therapeutic termination Miscarriages

17 Medications: Biologics Biologics Biologics –Category B: Infliximab, adalimumab, certolizumab –Category C: Natalizumab Infliximab: 102 pregnancies, 54 outcomes 1 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 Adalimumab: 2 IBD pregnancies in published literature 3,4 –47 reported in OTIS registry Certolizumab: no published data in humans Certolizumab: no published data in humans Natalizumab: IgG4, placental transfer in 1 st trimester Natalizumab: IgG4, placental transfer in 1 st trimester 1 Katz J. Am J Gastroenterol 2004; 99(12): Mahadevan U. APT 2005; 21(6): Vesga L. Gut 2005; 54(6): Mishkin DS. IBD 2006; 12(8): Mahadevan Gastroenterology 2007;132:A-144

18 Methotrexate in Pregnancy Contraindicated during pregnancy Contraindicated during pregnancy –Chromosomal damage, teratogenic –Abortifacient Oligospermia noted during treatment of men 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 5-ASAs and corticosteroids low risk for use during pregnancy and breast-feeding Immunosuppressants Immunosuppressants –AZA/6-MP appear low risk during pregnancy –Methotrexate contraindicated Antibiotics Antibiotics –Ampicillin and cephalosporins are low risk –Ciprofloxacin and metronidazole should be avoided for longterm use Biologics: Biologics: –Anti-TNF agents low risk. Infliximab and likely adalimumab cross placenta in third trimester

20 Safety of IBD Medications in Breast-Feeding Low risk to Use When Warranted Limited Data Available Contraindicated Oral mesalamine AzathioprineMethotrexate Topical mesalamine 6-MercaptopurineCyclosporine SulfasalazineInfliximabMetronidazole CorticosteroidsInfliximabAdalimumabCertolizumabTacrolimusNatalizumabCiprofloxacin 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 Pregnancy outcomes best if patient in remission at time of conception Many IBD-specific therapies appear to be low risk in pregnancy Many IBD-specific therapies appear to be low risk in pregnancy Monitoring of fetal growth particularly important Monitoring of fetal growth particularly important May need additional nutritional therapy because of malabsorption May need additional nutritional therapy because of malabsorption


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