Management of IBD Management of IBD in Pregnancyin Pregnancy

Assessment of Assessment of Disease Activity in Disease Activity in

Pregnant IBD PatientsPregnant IBD Patients

Laboratory studies (ESR, Hgb, albumin, CRP)Laboratory studies (ESR, Hgb, albumin, CRP)

Ultrasound – low riskUltrasound – low risk

Low-dose X-rays pose minimal fetal riskLow-dose X-rays pose minimal fetal risk11

Endoscopy – low risk if used for appropriate Endoscopy – low risk if used for appropriate indicationsindications22

Flexible sigmoidoscopy – low riskFlexible sigmoidoscopy – low risk22

Colonoscopy – should only be used for life-threatening Colonoscopy – should only be used for life-threatening colonic disease or when only alternative is laparotomycolonic disease or when only alternative is laparotomy22

ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein.ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein.

11Hufton AP. Hufton AP. Br J Radiol.Br J Radiol. 1979;52:735-740. 1979;52:735-740. 22Cappell MS, et al. Cappell MS, et al. Dig Dis Sci.Dig Dis Sci. 1996;41:2353-2361. 1996;41:2353-2361.

Drugs in PregnancyDrugs in Pregnancy

Pharmaceutical companies almost never test Pharmaceutical companies almost never test products in pregnant women products in pregnant women

PDRPDR®® disclaimer: use in pregnancy is not disclaimer: use in pregnancy is not recommended unless benefits justify risk to fetusrecommended unless benefits justify risk to fetus

FDA classifications (A, B, C, D, X) FDA classifications (A, B, C, D, X) – Ambiguous Ambiguous – Difficult to interpret and use in counselingDifficult to interpret and use in counseling

PDRPDR® ® = = Physicians’ Desk ReferencePhysicians’ Desk Reference®®; FDA = Food and Drug Administration.; FDA = Food and Drug Administration.

Koren G, et al. Koren G, et al. N Engl J Med.N Engl J Med. 1998;338:1128-1137. 1998;338:1128-1137.

Pregnancy-Risk CategoriesPregnancy-Risk Categories

A:A: Controlled human studies do not show risk to fetus; Controlled human studies do not show risk to fetus; chance of risk remotechance of risk remote

B:B: No evidence of risk to fetus in human studies; chance No evidence of risk to fetus in human studies; chance of risk remote but possibleof risk remote but possible

C:C: Inadequate studies in humans; risk cannot be ruled Inadequate studies in humans; risk cannot be ruled out, but benefits may outweigh risksout, but benefits may outweigh risks

D:D: Positive evidence of fetal risk; benefits might outweigh Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are risks in life-threatening situations when safer drugs are

ineffectiveineffective

X:X: Contraindicated in pregnancyContraindicated in pregnancy

Briggs GG, et al. Briggs GG, et al. Drugs in Pregnancy and Lactation.Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.1998.

*Safe for use after first trimester. *Safe for use after first trimester. ††Increasing use in pregnancy.Increasing use in pregnancy.

Briggs GG, et al. Briggs GG, et al. Drugs in Pregnancy and Lactation.Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. 1998. Physician’s Desk ReferencePhysician’s Desk Reference®®. 57th ed. Montvale, NJ: Thompson PDR; 2003.. 57th ed. Montvale, NJ: Thompson PDR; 2003.

Summary: Safety of IBD Summary: Safety of IBD Medications During PregnancyMedications During Pregnancy

Category BCategory B Category CCategory C Category D Category D Category XCategory X

LoperamideLoperamide CiprofloxacinCiprofloxacin AzathioprineAzathioprine†† MethotrexateMethotrexate

MesalamineMesalamine CyclosporineCyclosporine 6-Mercaptopurine6-Mercaptopurine†† ThalidomideThalidomide

BalsalazideBalsalazide DiphenoxylateDiphenoxylate

CorticosteroidCorticosteroidss

OlsalazineOlsalazine

SulfasalazineSulfasalazine TacrolimusTacrolimus

Anti-TNF Anti-TNF agentsagents

NatalizumabNatalizumab

MetronidazoleMetronidazole**

Sulfasalazine in PregnancySulfasalazine in Pregnancy

Most side effects linked to sulfapyridine moietyMost side effects linked to sulfapyridine moiety11

No increase in fetal malformationsNo increase in fetal malformations

Readily crosses placenta, but only minimal amounts Readily crosses placenta, but only minimal amounts in breast milkin breast milk22

Interferes with folic acid metabolismInterferes with folic acid metabolism– Folate important for neural tube developmentFolate important for neural tube development33

– Folic acid supplements (1 mg BID) advised prior Folic acid supplements (1 mg BID) advised prior to conception and throughout pregnancyto conception and throughout pregnancy

11Stein RB, Hanauer SB. Stein RB, Hanauer SB. Gastroenterol Clin North Am.Gastroenterol Clin North Am. 1999;28:297-321. 1999;28:297-321. 22Miller JP. Miller JP. J R Soc Med.J R Soc Med. 1986;79:221-225. 1986;79:221-225. 33Czeizel AE, Dudas I. Czeizel AE, Dudas I. N Engl J Med.N Engl J Med. 1992;327:1832-1835. 1992;327:1832-1835.

Aminosalicylates (B,C)Aminosalicylates (B,C)

Meta-analysis 7 studies: 642 5ASA, 1158 no medMeta-analysis 7 studies: 642 5ASA, 1158 no med

– Congenital anomalies: OR 1.16 (0.76, 1.77)Congenital anomalies: OR 1.16 (0.76, 1.77)– Stillbirth OR 2.38 (0.65, 8.72)Stillbirth OR 2.38 (0.65, 8.72)– SAB OR 1.14 (0.65, 2.01)SAB OR 1.14 (0.65, 2.01)– Preterm delivery 1.35 (0.85, 2.13)Preterm delivery 1.35 (0.85, 2.13)– LBW OR 0.93 (0.46, 1.85)LBW OR 0.93 (0.46, 1.85)

Sulfasalazine given w/ folic acid 1 mg BIDSulfasalazine 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 OccursPlacental and Breast Transfer Occurs• Potential allergic reaction newborn: watery diarrheaPotential allergic reaction newborn: watery diarrhea• SAS not associated with kernicterus or displacement of SAS not associated with kernicterus or displacement of

bilirubin from albuminbilirubin from albumin Olsalazine: Pregnancy category C. All others, BOlsalazine: Pregnancy category C. All others, B

Rahimi Reprod Toxicol 2008Rahimi Reprod Toxicol 2008

Safety of Mesalamine Safety of Mesalamine in Pregnancyin Pregnancy

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

11Marteau P, et al. Marteau P, et al. Aliment Pharmacol Ther.Aliment Pharmacol Ther. 1998;12:1101-1108. 1998;12:1101-1108. 22Diav-Citrin O, et al. Diav-Citrin O, et al. Gastroenterology.Gastroenterology. 1998;114:23-28.1998;114:23-28.

StudyStudy nn

Mean Mean Mesalamine Mesalamine

DosageDosage

Incidence of Incidence of Fetal Fetal

Malformations Malformations (%)(%)

PatienPatientsts

ControlControlss

Marteau et alMarteau et al11 123123**

2.1 ± 0.8 g/d2.1 ± 0.8 g/d 3.13.1 1.7-3.41.7-3.4††

Diav-Citrin et alDiav-Citrin et al22 165165 2.0 ± 1.6 g/d2.0 ± 1.6 g/d 0.80.8 3.83.8

Topical 5-ASA in PregnancyTopical 5-ASA in Pregnancy

Study of 19 pregnanciesStudy of 19 pregnancies– Maintenance 5-ASA topical therapy at time Maintenance 5-ASA topical therapy at time

of conception and throughout pregnancyof conception and throughout pregnancy– Successful full-term pregnancies for all patients, Successful full-term pregnancies for all patients,

with no fetal abnormalitieswith no fetal abnormalities

Minimal excretion of 5-ASA and metabolites in Minimal excretion of 5-ASA and metabolites in breast milkbreast milk

Many years of safe useMany years of safe use

Bell CM, Habal FM. Bell CM, Habal FM. Am J Gastroenterol.Am J Gastroenterol. 1997;92:2201-2202. 1997;92:2201-2202.

AntibioticsAntibiotics

Metronidazole (B) /Ciprofloxacin (C)Metronidazole (B) /Ciprofloxacin (C)– Low risk of teratogenicityLow risk of teratogenicity

• Metronidazole: prospective controlled study, 2 meta-Metronidazole: prospective controlled study, 2 meta-analysisanalysis

– However, 2However, 2ndnd, 3, 3rdrd T use, 1 T use, 1stst T cleft lip, palate T cleft lip, palate• Ciprofloxacin: prospective controlled study low risk of Ciprofloxacin: prospective controlled study low risk of

defectsdefects– Affinity for bones, arthropathy in childrenAffinity for bones, arthropathy in children

– Breast feeding not advised on MNZL, probably compatible Breast feeding not advised on MNZL, probably compatible with ciprofloxacinwith ciprofloxacin

– Minimal benefit in CD and UC with longer use-avoidMinimal benefit in CD and UC with longer use-avoid

Rifaximin: Pregnancy C Rifaximin: Pregnancy C – teratogenicity in animal studiesteratogenicity in animal studies– Safety in humans in pregnancy/breastfeeding unknownSafety in humans in pregnancy/breastfeeding unknown

Corticosteroids in PregnancyCorticosteroids in Pregnancy

Increased spontaneous abortions, cleft palate, Increased spontaneous abortions, cleft palate, stillbirths in mice; rare teratogenicity in humans (cleft stillbirths in mice; rare teratogenicity in humans (cleft palate)palate)

High doses associated with retardation of fetal growth High doses associated with retardation of fetal growth

No fetal adrenocortical insufficiencyNo fetal adrenocortical insufficiency

Safety uncertain with long-term use of high doses Safety uncertain with long-term use of high doses while breast-feedingwhile breast-feeding

Active-disease risks greater than drug risks to fetus, so Active-disease risks greater than drug risks to fetus, so use if neededuse if needed

Briggs GG, et al. Briggs GG, et al. Drugs in Pregnancy and Lactation.Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.1998.

AZA/6-MP in Pregnancy AZA/6-MP in Pregnancy

Several studies in transplant recipients have reported safe Several studies in transplant recipients have reported safe use during pregnancyuse during pregnancy11

Study of IBD patients showed no Study of IBD patients showed no in prematurity, in prematurity, spontaneous abortion, congenital abnormalities, or spontaneous abortion, congenital abnormalities, or childhood neoplasiachildhood neoplasia22

– Study population included fathers treated with Study population included fathers treated with AZA/6-MPAZA/6-MP

In another study, AZA/6-MP did not reduce fertility in menIn another study, AZA/6-MP did not reduce fertility in men33

Risk of birth defects similar to that in general populationRisk of birth defects similar to that in general population44

11Briggs GG, et al. Briggs GG, et al. Drugs in Pregnancy and Lactation.Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998. 1998. 22Francella A, et al. Francella A, et al. Gastroenterology.Gastroenterology. 2003;124:9-17. 2003;124:9-17. 33Dejaco C, et al. Dejaco C, et al. Gastroenterology.Gastroenterology. 2001;121:1048-1053. 2001;121:1048-1053. 44Library: IBD & Your Family. Available at Library: IBD & Your Family. Available at www.ccfa.org/medcentral/library/family/drugpreg.htm. Accessed March 6, 2003. www.ccfa.org/medcentral/library/family/drugpreg.htm. Accessed March 6, 2003.

Azathioprine and TeratogenicityAzathioprine and Teratogenicity

Largest Study to dateLargest Study to date

189 pregnant women on AZA who contacted one of seven 189 pregnant women on AZA who contacted one of seven teratogen information services were compared to a cohort of teratogen information services were compared to a cohort of 230 pregnant women who took non-teratogenic treatments 230 pregnant women who took non-teratogenic treatments

Rate of major malformations did not differ with six neonates Rate of major malformations did not differ with six neonates eacheach::– AZA (3.5%) vs control ( 3.0%) (p = .775; OR 1.17; CI: 0.37, 3.69). 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] 2,995g vs. 3,252g [p = .001] – 37.8 weeks vs. 39.1 weeks [p = .001] 37.8 weeks vs. 39.1 weeks [p = .001]

The AZA group had more prematurity The AZA group had more prematurity – 21.4% vs. 5.2% [p < .001]21.4% vs. 5.2% [p < .001]

The AZA group had more low birth weightThe AZA group had more low birth weight – 23% vs. 6.0% [p < .001]23% vs. 6.0% [p < .001]

Goldstein Birth Defects Res A Clin Mol Teratol. 2007 Sep 10;79(10):696-701 Goldstein Birth Defects Res A Clin Mol Teratol. 2007 Sep 10;79(10):696-701

Thiopurines and NursingThiopurines and Nursing

2 infants breast fed with mothers on 6MP2 infants breast fed with mothers on 6MP– 6MP levels by HPLC < 0.09% maternal dose6MP levels by HPLC < 0.09% maternal dose11

4 mother-infant pairs 3 months post-partum were 4 mother-infant pairs 3 months post-partum were tested for 6MP metabolitestested for 6MP metabolites– All infants were nursingAll infants were nursing– Maternal levels within therapeutic rangeMaternal levels within therapeutic range– No metabolites found in offspringNo metabolites found in offspring22

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

Cyclosporine in PregnancyCyclosporine in Pregnancy

Registry data on transplant recipientsRegistry data on transplant recipients11

– No specific congenital abnormalities or birth defectsNo specific congenital abnormalities or birth defects– Prematurity: 56%Prematurity: 56%– Low birth weight: 49.5%Low birth weight: 49.5%

Study in 5 women with IBDStudy in 5 women with IBD22

– 4 live births, 1 missed abortion4 live births, 1 missed abortion– No congenital abnormalitiesNo congenital abnormalities

Should be given at experienced IBD centersShould be given at experienced IBD centers33

11Armenti VT, et al. Armenti VT, et al. Transplantation.Transplantation. 1994;57;502-506. 1994;57;502-506. 22Marion JF, et al. Marion JF, et al. Am J Gastroenterol.Am J Gastroenterol. 1996;91:1975. 1996;91:1975. 33Kornbluth A, Sachar DB. Kornbluth A, Sachar DB. Am J Gastroenterol.Am J Gastroenterol. 1997;92:204-211. 1997;92:204-211.

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

PregnancyPregnancy

0

Pro

po

rtio

n o

f P

atie

nts

(%

)

Katz JA, et al. Katz JA, et al. Am J Gastroenterol.Am J Gastroenterol. 2004;99:2385-2392. 2004;99:2385-2392. Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59Hudson et al. Int J Gynaecol Obstet 1997;58:229-237. Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.

General population

Crohn’s disease

All infliximab patients(N=96)

Infliximab patients with CD (N=82)

10

20

30

40

50

60

70

80

67 66 67 67

17 16 17

1115

19 20

13

Live births

Therapeutictermination

Miscarriages

Medications: BiologicsMedications: Biologics

Biologics Biologics – Category B: Infliximab, adalimumab, certolizumabCategory B: Infliximab, adalimumab, certolizumab– Category C: NatalizumabCategory C: Natalizumab

Infliximab: 102 pregnancies, 54 outcomesInfliximab: 102 pregnancies, 54 outcomes11

– ““Rescue” infliximab successfulRescue” infliximab successful22

– Infliximab not detected in breast milk (n=5)Infliximab not detected in breast milk (n=5)– Demonstrated to cross the placenta and detectable in Demonstrated to cross the placenta and detectable in

cord blood for up to 6 months from birthcord blood for up to 6 months from birth55

Adalimumab: 2 IBD pregnancies in published literatureAdalimumab: 2 IBD pregnancies in published literature3,43,4

– 47 reported in OTIS registry47 reported in OTIS registry Certolizumab: no published data in humansCertolizumab: no published data in humans Natalizumab: IgG4, placental transfer in 1Natalizumab: IgG4, placental transfer in 1stst trimester trimester

11Katz J. Am J Gastroenterol 2004; 99(12):2385-92. Katz J. Am J Gastroenterol 2004; 99(12):2385-92. 22Mahadevan U. APT 2005; 21(6):733-8. Mahadevan U. APT 2005; 21(6):733-8. 33Vesga L. Gut 2005; Vesga L. Gut 2005;

54(6):890.54(6):890.44Mishkin DS. IBD 2006; 12(8):827-8.Mishkin DS. IBD 2006; 12(8):827-8.5 5 Mahadevan Mahadevan Gastroenterology 2007;132:A-144Gastroenterology 2007;132:A-144

Methotrexate in PregnancyMethotrexate in Pregnancy

Contraindicated during pregnancyContraindicated during pregnancy– Chromosomal damage, teratogenicChromosomal damage, teratogenic– AbortifacientAbortifacient

Oligospermia noted during treatment of menOligospermia noted during treatment of men– Returns to baseline posttreatmentReturns to baseline posttreatment– Long-term effects unknownLong-term effects unknown

Briggs GG, et al. Briggs GG, et al. Drugs in Pregnancy and Lactation.Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.1998.

Conclusions: Conclusions: IBD Drugs in Pregnancy IBD Drugs in Pregnancy

5-ASAs and corticosteroids low risk for use during 5-ASAs and corticosteroids low risk for use during pregnancy and breast-feedingpregnancy and breast-feeding

ImmunosuppressantsImmunosuppressants– AZA/6-MP appear low risk during pregnancyAZA/6-MP appear low risk during pregnancy– Methotrexate contraindicatedMethotrexate contraindicated

AntibioticsAntibiotics– Ampicillin and cephalosporins are low riskAmpicillin and cephalosporins are low risk– Ciprofloxacin and metronidazole should be avoided Ciprofloxacin and metronidazole should be avoided

for longterm usefor longterm use Biologics: Biologics:

– Anti-TNF agents low risk. Infliximab and likely Anti-TNF agents low risk. Infliximab and likely adalimumab cross placenta in third trimesteradalimumab cross placenta in third trimester

Safety of IBD Medications in Safety of IBD Medications in Breast-FeedingBreast-Feeding

Low risk to Use Low risk to Use When WarrantedWhen Warranted

Limited Data Limited Data AvailableAvailable

ContraindicateContraindicatedd

Oral mesalamineOral mesalamine AzathioprineAzathioprine MethotrexateMethotrexate

Topical mesalamineTopical mesalamine 6-Mercaptopurine6-Mercaptopurine CyclosporineCyclosporine

SulfasalazineSulfasalazine InfliximabInfliximab MetronidazoleMetronidazole

CorticosteroidsCorticosteroids

InfliximabInfliximab

AdalimumabAdalimumab

CertolizumabCertolizumab

TacrolimusTacrolimus

NatalizumabNatalizumab

CiprofloxacinCiprofloxacin

Physicians’ Desk ReferencePhysicians’ Desk Reference®®. 57th ed. Montvale, NJ: Thompson PDR; 2003.. 57th ed. Montvale, NJ: Thompson PDR; 2003.

Management of IBD in Management of IBD in Pregnancy: SummaryPregnancy: Summary

Pregnancy outcomes best if patient in remission at Pregnancy outcomes best if patient in remission at time of conceptiontime of conception

Many IBD-specific therapies appear to be low risk in Many IBD-specific therapies appear to be low risk in pregnancypregnancy

Monitoring of fetal growth particularly importantMonitoring of fetal growth particularly important

May need additional nutritional therapy because May need additional nutritional therapy because of malabsorptionof malabsorption