Management of IBD in Pregnancy

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. 197952735-740. 2Cappell MS, et
al. Dig Dis Sci. 1996412353-2361.
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. 19983381128-1137.
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
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.
Physicians 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. 199928297-321. 2Miller JP. J R Soc Med.
198679221-225. 3Czeizel AE, Dudas I. N Engl J
Med. 19923271832-1835.
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
Study n Mean Mesalamine Dosage Incidence of Fetal Malformations () Incidence of Fetal Malformations ()
Study n Mean Mesalamine Dosage Patients Controls
Marteau et al1 123 2.1 0.8 g/d 3.1 1.7-3.4
Diav-Citrin et al2 165 2.0 1.6 g/d 0.8 3.8
96 taking mesalamine during first trimester.
General population in France. 1Marteau P, et al.
Aliment Pharmacol Ther. 1998121101-1108.
2Diav-Citrin O, et al. Gastroenterology.
199811423-28.
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.
1997922201-2202.
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. 20031249-17. 3Dejaco C, et
al. Gastroenterology. 20011211048-1053.
4Library IBD Your Family. Available at
www.ccfa.org/medcentral/library/family/drugpreg.ht
m. 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 lt .001
• The AZA group had more low birth weight
• 23 vs. 6.0 p lt .001

Goldstein Birth Defects Res A Clin Mol Teratol.
2007 Sep 1079(10)696-701
14
Thiopurines and Nursing

• 2 infants breast fed with mothers on 6MP
• 6MP levels by HPLC lt 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 62453-56.
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.
199457502-506. 2Marion JF, et al. Am J
Gastroenterol. 1996911975. 3Kornbluth A,
Sachar DB. Am J Gastroenterol. 199792204-211.
16
Infliximab (B) Safety Database in Pregnancy
Outcomes of Women Exposed to Infliximab During
Pregnancy
80
70
67
67
67
66
60
Live births
50
Miscarriages
Proportion of Patients ()
40
Therapeutictermination
30
20
19
20
17
17
16
15
13
11
10
0
General population
Crohns disease
All infliximab patients(N96)
Infliximab patients with CD (N82)
Katz JA, et al. Am J Gastroenterol.
2004992385-2392. Ventura et al. National
Center for Health Statistics Vital Health Stat
2000211-59Hudson et al. Int J Gynaecol Obstet
199758229-237.
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 (n5)
• 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
2007132A-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
Low risk to Use When Warranted Limited Data Available Contraindicated
Oral mesalamine Azathioprine Methotrexate
Topical mesalamine 6-Mercaptopurine Cyclosporine
Sulfasalazine Infliximab Metronidazole
Corticosteroids Infliximab Adalimumab Certolizumab Tacrolimus Natalizumab Ciprofloxacin
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