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 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.
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
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*
*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
1Stein

Most side effects linked to sulfapyridine moiety1
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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
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.
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 al1
Diav-Citrin et al2
n
123*
165
Mean
Mesalamine
Dosage
2.1 ± 0.8 g/d
2.0 ± 1.6 g/d
Incidence of Fetal
Malformations (%)
Patients
3.1
0.8
Controls
1.7-3.4†
3.8
*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.
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
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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 metaanalysis
– 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
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 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.
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.
2Francella
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 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.
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.
Infliximab (B) Safety Database in Pregnancy:
Outcomes of Women Exposed to Infliximab During Pregnancy
Proportion of Patients (%)
80
70
67
67
66
67
60
Live births
50
Miscarriages
40
Therapeutic
termination
30
20
17 16
20
19
17
15
13
All infliximab
patients
(N=96)
Infliximab
patients with
CD (N=82)
11
10
0
General
population
Crohn’s
disease
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.
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
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
Limited Data
Available
Azathioprine
6-Mercaptopurine
Infliximab
Contraindicated
Methotrexate
Cyclosporine
Metronidazole
Corticosteroids
Tacrolimus
Ciprofloxacin
Infliximab
Natalizumab
Adalimumab
Certolizumab
Physicians’ Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.
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