She continues IBD medications during pregnancy i

1
Pregnancy and the Inflammatory Bowel Disease
Patient
David G. Binion, M.D. Director, IBD
Center Associate Professor of Medicine Medical
College of Wisconsin Milwaukee, WI

2
Case 1 Pregnancy and IBDWhat we hope for ..

• 31 year old female with history of UC well
  controlled on oral mesalamine for 5 years becomes
  pregnant with second child.
• The patient states Ive never felt better than
  when I was pregnant.
• She continues IBD medications during pregnancy in
  combination with folic acid and prenatal vitamin
  and has vaginal delivery at term with healthy
  baby girl.
• The patient breast feeds for 3 months and remains
  in remission.

3
Case 2 Pregnancy and IBDWhat we hope to avoid
..

• 30 year old female with 4 yr history of CD
  colitis controlled on azathioprine 150 mg daily
  and 10 mg/kg infliximab every 6 weeks becomes
  pregnant with second child.
• The patient flares during first trimester.
  Prednisone 40 mg is started with gradual taper.
• At 22 weeks she is hospitalized with BRBPR,
  increasing diarrhea and abdominal pain. Partial
  response to IV hydrocortisone, but unable to
  decrease. C. difficile negative.
• IBD Surgery and high risk obstetric consults
  obtained. Both recommend medical treatment to
  control fulminant colitis if possible.
• Next therapeutic option?

4
Introduction Pregnancy and IBD

• Highest age adjusted incidence rates of IBD (15
  30) overlap peak reproductive years.
• Improved medical and surgical treatment of IBD
  has allowed patients with more significant
  illness to consider pregnancy and having
  children.
• Optimal treatment algorithms for IBD patients
  during pregnancy have not been defined, including
  issues regarding high risk pregnancy.
• Optimal management of reproductive heath in IBD
  patients is a challenge to gastroenterologists,
  obstetricians, IBD surgeons.

5
Goals Pregnancy and IBD

• Fertility becoming pregnant.
• Having an uneventful term pregnancy
• Avoiding preterm delivery
• Avoiding severe flare r- isk for preterm delivery
• Use of safe medications to maintain remission in
  mother during pregnancy.
• Use of safe medications during post-partum and
  breast feeding to help mother maintain remission.

6
Overview

• Fertility/Fecundity Rates
• Pregnancy Outcomes
• Effects of Medications on Pregnancy
• Special situations - IBD Surgery during pregnancy

7
Infertility UC
8
Pregnancy and ileoanal pouch - I

• 4 hospitals Sweden/Denmark
• All women age 18-40 UC/IPAA 1992-8
• Participation Rate
• 290/343 UC patients 661/1200 controls
• Fecundability rates
• Before diagnosis FR 1.46, p 0.002
• Before colectomy FR 1.01 p NS
• After IPAA FR 0.20, plt0.001

Olsen KO, et al. Gastroenterology 200212215-19
9
IPAA Cumulative Incidence of PregnancyWithin 5
Years
1.0
0.8
Before diagnosis
Reference
0.6
Before surgery
Cumulative Incidenceof Pregnancy
After surgery
0.4
0.2
0.0
60
24
48
12
36
0
Time to Pregnancy (months)
Reprinted from Olsen KØ, et al. Gastroenterology.
200212215-19 with permission from American
Gastroenterological Association.
10
Female Infertility After IPAA for UC
Success Rate in Becoming Pregnant ()
Infertility Rate(95 CI)
Before surgery
Before diagnosis
After surgery
After diagnosis
Plt.001
120
45
Plt.0001
38.6 (30.9-46.3)
40
97.5
96.9
95.8
100
35
30
80
25
56.1
60
20
13.3 (4.7-21.9)
15
40
10
20
5
0
0
UC Patients Managed Nonoperatively (N60)
IPAA Patients (N153)
IPAA Patients (N153)
UC Patients Managed Nonoperatively (N60)
Johnson P, et al. Dis Colon Rectum.
2004471119-1126.
11
Pregnancy and ileoanal pouch - II

• Effects of pelvic surgery adhesions involving
  Fallopian tubes? Tube factor
• Hudson (97) NE Scotland
• Medical 13 infertility, (7/15 resolved)
• Surgical 30 infertility, (7/16 resolved)
• FAP patients with IPAA also with decreased
  fecundability (54), but normal after IRA Olsen
  2003
• Perforated appendicitis does not lead to reduced
  rates of fecundability
• Important consideration for patients counseled
  for IPAA in UC. Rationale for biologic therapy in
  UC.

12
Infertility Crohns Disease


13
Summary Female Fertility

• Ulcerative Colitis
• Similar to the general population prior to
  colectomy
• Significantly decreased after IPAA
• Crohns Disease
• Studies vary
• Infertility partly voluntary
• (dyspareunia, illness, MD advise)
• Surgery decreased fertility

14
Pregnancy Outcomes in IBD
15
IBD pregnancy complications and outcomes MCW 1998
- 2004

• Pregnancies in 37 of 416 women (CD 316UC 110)
• 51 total pregnancies reviewed (CD 81UC 19)
• Mean pregnancy age 28 y/o
• Obstetric and IBD related complications in 57 of
  pregnancies
• 6 pregnancies required hospitalization (12)
• Spontaneous abortion in 11.8 (mean age 30.6
  years
• Term pregnancy in 70 CD and 80 UC (all children
  reported healthy)

Beaulieau DB, et al. Gastroenterology 128 A316,
2005.
16
MCW IBD Centers Pregnancies
Pregnancies in pts with
Crohn's Disease 81
Pregnancies in pts with
Ulcerative Colitis 19
51 pregnancies reviewed in 37 women
Beaulieau DB, et al. Gastroenterology 128 A316,
2005.
17
Timing of IBD flares during pregnancy
Numbers of IBD pregnancies
7
6
5
4
CD
UC
3
IBD
2
1
0
1st
2nd
3rd
pp
Pregnancy trimester
Beaulieau DB, et al. Gastroenterology 128 A316,
2005.
18
IBD Flares during pregnancy
Disease flare in 19 of CD pregnancies
Disease flare in 30 of UC pregnancies

• IBD flare occurred in 21.2 of the IBD
  pregnancies
• IBD flare occurred most commonly during the
  first trimester (63.6 of flares)
• IBD maintenance therapy had been discontinued in
  43 of patients experiencing first trimester
  flare.

19
IBD post-partum flares
13.7 of IBD patients post-partum flare

• 57 of post partum flares occurred within the
  1st month of delivery
• Post-partum flare was associated with drug
  cessation in 28.6 of patients

20
IBD obstetric complications

• Spontaneous abortions in 11.8 of IBD patients
• Pre-eclampsia in 7.8 of IBD patients
• Gestational diabetes in 2 of IBD patients

21
Effect of IBD on Birth Outcomes -Sweden, 1991-92

• IBD No IBD Adjusted OR
• n756 ngt239,000 (95 CI)
• Late fetal death 0.5 0.3 1.3 (0.6-2.6)
• Infant death 0.5 0.5
• LBW 1.2 0.6 2.2 (1.1-4.2)
• Very LBW 4.5 2.9 1.6 (1.1-2.2)
• Very Preterm 1.9 1.0 1.8 (1.1-3.1)
• Preterm 6.3 4.3 1.5 (1.1-2.0)
• SGA 4.0 2.9 1.4 (0.97-2.0)
• C-section 15 10 1.5 (1.2-1.8)
• Kornfeld et al, Am J Obstet Gynecol
  1997177942-6.

22
Birth Outcomes in IBD-State of Washington,
1987-96

• CUC CD Controls OR, CUC OR, CD
• n107 n155 n1308 (95 CI)
  (95 CI)
• LBW 7.6 16.8 5.3 1.1 (0.4-3.3) 3.6
  (2.2-5.9)
• Preterm 10.4 15.2 7.2 1.0 (0.4-2.5) 2.3
  (1.4-3.8)
• SGA 10.5 15.2 5.3 1.7 (0.8-3.8) 2.3
  (1.3-3.9)
• Congenital abnl 7.9 3.4 1.7 3.8
  (1.5-9.8) 2.0 (0.8-5.5)
• C-section 28.7 28.4 20.2 1.3 (0.8-2.2) 1.6
  (1.1-2.3)
• Dominitz et al, Am J Gastroenterol 200297641-8.

23
Outcomes Ulcerative Colitis

• Hungarian Case Control Surveillance of congenital
  anomalies (CA) 1980-1996
• UC 71 cases (0.3) 95 controls (0.2)
• OR 1.3 (95 CI0.9-1.8) Adjusted for parity,
  age, SAS/other drugs
• Limb deficiencies OR6.2 (2.9-13.1)
• Obstructive urinary CA OR3.3 (1.1-9.5)
• Multiple CA OR2.6 (1.3-5.4)

Norgard et al, Am J Gastroenterol
2003982006-10.
24
Outcomes Crohns Disease

• Fonager (1998) Danish pop. based study
• 510 births vs. 3018 controls, 1982-92
• Increased risk of LBW
• OR 2.4 (95 CI 1.6-3.7)
• Increased risk of preterm birth
• OR 1.6 (95 CI 1.1-2.3)

25
Pregnancy OutcomesPopulation Based Studies

• Kornfeld Am J Obstet Gynecol 1997 (n756 IBD)
• Fonager Am J Gastroenterol 1998 (n510 CD)
• Norgard Am J Gastroenterol 2000 (n1531 UC)
• Dominitz Am J Gastroenterol 2002 (n107 UC, 155
  CD)

26
Predictors of Poor Outcome

• Active Disease (UC and CD)
• 50 vs 21 (plt0.05) abnormal outcomes
• Activity at conception gt Fetal loss
• Activity during pregnancy gt LBW
• Independent of medication use
• Ileal Crohns Disease (p 0.035) Moser
• Not consistently found in other studies
• Previous bowel resection (p 0.065) Moser

27
Effect of Pregnancy on UC Disease Activity at
Conception
Miller JP. J R Soc Med. 198679221-5.
28
Effect of Pregnancy on CD Disease Activity at
Conception
Miller JP. J R Soc Med. 198679221-5.
29
Pregnancy outcomes in women with inflammatory
bowel disease population based cohort studyU
Mahdevan, WJ Sandborn, S Azmi, S Kane, DK Li,D
Corley

• Cohort study among members of the Northern
  California Kaiser Permanente population
• Identified 493 pregnant women with a pre-birth
  diagnosis of IBD and frequency matched 493
  non-pregnant women for age and hospital of
  pregnancy
• Univariate analyses included chi-square and
  t-test multivariate analyses used unconditional
  logistic regression. All analyses were two
  tailed.

30
Patient Characteristics

• N324 non-IBD vs 305 IBD (preliminary)
• Mean Age at Conception 30.1 vs 30.8
• Smokers 61 (19) vs 51 (17) p 0.46
• 203 UC and 96 CD
• IBD Duration 6.1 years
• Immunosuppressant Use 12 (4)
• Aminosalicylate Use 142 (47)
• Corticosteroid Use 57 (19)

31
IBD Pregnancy Outcomes
32
SummaryIBD Pregnancy Outcomes

• Preliminary Analysis
• IBD pts are more likely to have an adverse
  pregnancy outcome and complicated labor than
  women without IBD
• Adverse neonatal outcome not increased in IBD
• Impact of immunosuppressant medications is
  limited by a small sample size in available data

33
Medical Therapy in Conception and Pregnancy
34
Drugs in Pregnancy

• Limited data - Pharmaceutical trials almost never
  performed in pregnant women.
• PDRâ medicolegal disclaimer use in pregnancy is
  not recommended unless benefits justify risk to
  the fetus.
• Half of all pregnancies are unplanned.
• FDA classification (A, B, C, D, X)
• Ambiguous
• Difficult to interpret and use in counseling

Koren G et al. N Engl J Med. 19983381128.
35
FDA Teratogenicity Classification for Drugs
during Pregnancy

• Category A Controlled studies show no risk
• No IBD medications in Category A
• Category B No evidence of risk in humans
• Category C
• Animal reproduction studies show adverse effect
• No adequate studies in humans
• Drugs benefits in pregnant women may be
  acceptable despite its potential risk
• Category D Positive Evidence of Risk
• Category X Contraindicated in Pregnancy

36
Nutritional Therapy

• Elemental Diet
• Case reports of effectiveness in acute flares
  during pregnancy Teahon, Gut 1991
• Important to maintain nutrition to the fetus
• Total Parenteral Nutrition
• Less desirable, but case reports of effectiveness
  Gatenby, Human Nutrition 1987

37
Fish Oil

• Essential Fatty acids (EFA) and Docosahexaenoic
  acid (DHA)
• Potential antithrombotic effect
• Prolong gestation
• No evidence of prevention of proteinuric
  pregnancy
• Mild benefit in Crohns disease
• Concern regarding risk of metal toxicity USDA
  recommendation 8/03 to limit fish consumption
  during pregnancy

38
Pharmaceutical TherapyAminosalicylates - I

• Aminosalicylates Category B
• Only controlled trial (Diav-Citrin 1998
  Gastroenterology)
• 165 pts. Prospectively followed, controls with
  smoking/Etoh NOT IBD Mean daily dose 2 gm
• No teratogenicity
• Maternal weight gain significantly lower on 5ASA
• preterm delivery, LBW
• Ludvigson (2002) LBW if mother treated with
  mesalamine or steroids during pregnancy

39
Pharmaceutical TherapyAminosalicylates - II

• Sulfasalazine should be given with folic acid 1
  mg BID
• Folic acid neural tube defects, CV, urinary
  tract, cleft palate
• Case reports of congenital malformation
• Placental and Breast Milk Transfer Occurs
• Potential of allergic reaction in newborn with
  watery diarrhea
• SAS not associated with kernicterus or
  displacement of bilirubin form albumin

40
Corticosteroids

• No evidence of teratogenicity in humans
• Poorer outcomes likely due to worse disease
• Theoretical concern of adrenal suppression in
  newborn
• Cross placenta
• 10-12 of maternal concentration
• Safe in breast feeding

41
Antibiotics

• Metronidazol/Ciprofloxacin
• Low risk of teratogenicity
• Metronidazole case-control study and
  meta-analysis
• Ciprofloxacin prospective controlled study
• Growing cartilage may be a target for cipro
  toxicity
• Breast feeding is not advised
• Minimal benefit in Crohns and UC
• No data on long-term safety

42
Azathioprine/6-MP

• Purine analogues
• Interfere with synthesis of adenine and guanine
  ribonucleosides, precursors of DNA and RNA
• Act predominantly on rapidly dividing cells
• Incorporation of TGN nucleotides into cellular
  nucleic acids (cytotoxicity)
• Controversy - Class D label for pregnancy but
  commonly used in IBD, RA and transplant

43
Teratogenicity of 6MP/AZA

• Teratogenic in animals (mice, rabbits, rats)
• Given IV/IP at supratherapeutic doses (low oral
  bioavailability 47 AZA, 16 6MP)
• Increased cleft palate, ocular, skeletal,
  urogenital anomalies, hydrocephalus
• Poor oral bioavailability may produce levels too
  low to have substantial teratogenic effect
• No consistent increase in human teratogenicity
• Fetal liver in early pregnancy lacks inosinate
  pyrophosphorylase to convert AZA to active
  metabolites
• Polifka and Friedman (Teratology 65240-261.
  2002)

44
Human Studies 6MP/AZA

• Transplantation Experience
• Frequency of congenital anomalies in renal tx
  0.0-11.8 in 27 clinical series
• No recurrent pattern of anomalies seen
• No increase in anomalies in NTPR (Armenti 1994)
  in kidney transplant recipients on AZA
• Immunosuppression is never stopped in setting of
  organ tranplant
• No congenital anomalies in rheumatic disease, SLE

45
Norgard (Aliment Pharm Ther 2003)

• Population based prescription registry, Denmark
• 9 pregnancies (30d before concept/1st trimester)
• 10 pregnancies (exposed entire pregnancy)
• Outcomes vs (1) 19,418 pregnancies no drugs (2)
  any drug (3) 6MP/AZA gt3 mos before pregnancy
• 11 pts 55 IBD, 45 other disease
• Congenital malform OR 6.7 (95CI 1.4-32.4)
• Mortality OR 20 (2.5-161.4)
• Preterm Birth OR 6.6 (1.7-25.9)
• LBW OR 3.8 (0.4-33.3)
• After exclusion of most ill pt (AIH), no
  statistical significance in OR

46
AZA/6-MP

• Experience in IBD
• Alstead (1990) 14 pts 7 entire pregnancy
• No congenital anomalies
• Khan (2000) 8 preg/6 pt no complications
• Francella (2003) Retrospective
• 79F (24 UC), 76M (27 UC), 325 pregnancies
• No diff. b/w 6MP, no 6MP
• Breastfeeding not recommended

47
Outcomes of 6MP/AZA exposure
Francella A, et al. Gastroenterology 20031249
48
Cyclosporine

• Teratogenicity
• Not in animals, probably not in humans
• One case in humans, administered at 29 weeks.
• Healthy fetus at 34 weeks
• Used in fulminant colitis, better than emergent
  colectomy
• Breast feeding not advised
• Reserved for fulminant disease vs colectomy

49
Infliximab and pregnancy (Category B)

• Katz JA et al. (Am Journal Gastroenterol 2004)
• Infliximab Safety Database
• 146 identified pregnancies
• 82 CD, 1 UC, 10 RA, 3 unknown
• Outcome 96 pregnancies, n 100 births
• Live birth 64 (67)
• 1 preterm 24 wks (died), 1 tetrology Fallot, 1
  sepsis survived, 1 intestinal malrotation in twin
• Miscarriage 14(15) (1 stillbirth on MTX)
• Therapeutic termination 18 (19) (pts. choice)
• Data similar to expected for UC/CD note exposed
  to INF

50
Infliximab 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.
51
Intentional Infliximab in Pregnancy
10 Crohns disease patients intentionally
exposed to infliximab during pregnancy
8 women receivedmaintenance infusions
2 women receivedinitial infusions
10 Live Births
Congenitalmalformations (N0)
IUGR (N0)
SGA (N0)
Preterm (N3)
LBW (N1)
8 Caesarean sections 2 active luminal, 3
perianal disease, 1 preterm
Mahadevan U, et al. Aliment Pharmacol Ther.
200521733-738.
52
High serum infliximab levels in newborn of a
mother treated during pregnancy
Breast fed 7 wks
Breast feed resumed Wk 11
2
0
2
4
10
13
6
Time (weeks) from birth
Infliximab
infusions (10 mg/kg)

Birth 41 wks
Immune studies at 6 months T and B lymphocytes
normal IgG, IgM and IgA levels normal
Vasiliauskas E et al. DDW 2005, 148
53
Heparin and IBD pregnancy

• 20 of IBD patients have hypercoagulability risk
• Increased risk of hypercoagulability during
  pregnancy
• Heparin and low molecular weight heparin have
  established track record in maternal-fetal
  medicine
• Potential adjunctive role in IBD
• Case report heparin rescue therapy in
  hospitalized, refractory CD colitis
• Low mol wt heparin used as colitis rescue tx in
  Case 2 (60 mg subcutaneous injection b.i.d.)

DN Prajapati et al. Inflamm Bowel Dis. 2002
8192-5.
54
Parenteral iron therapy

• Oral iron may be poorly tolerated, abdominal pain
• Patients with obstructive symptoms may not
  tolerate prenatal vitamin. Consider for
  gastroduodenal CD.
• Hyperemesis gravidarum poor oral tolerance
• Intravenous iron sucrose 100 mg dosage
• FDA class B

55
Contraindicated Medications

• Methotrexate
• Known abortifacient
• Teratogenic (skeletal defects, cleft palate)
• 3 month washout in females and males prior to
  planned pregnancy
• Thalidomide
• 20-30 Rate of Birth defects or fetal death
• limb malformation (phocomelia)

56
Special Consideration

• Perianal Crohns Disease
• Fulminant Ulcerative Colitis
• Patients with IPAA

57
Perianal Crohns Disease

• Active perianal disease Caesarean section
  recommended
• No history (1/39) or inactive (0/11) perianal
  disease at birth, risk of relapse very low
  post-vaginal delivery
• 4/4 with active perianal disease worsened
  post-vaginal delivery Ilnycky 1999 AJG
  Manitoba database
• Episiotomy may predispose to perineal disease
  (17.9) without prior history of disease

58
Fulminant Ulcerative Colitis

• 2005 look for C. Difficile infection
• Nutrition
• Intravenous corticosteroids
• 75 successful
• Infliximab
• Heparin compounds
• Cyclosporine
• 1 case report. IV CSA 10 days, 34th wk delivery
• Colectomy
• 50-60 fetal mortality reported
• Rare to have fulminant colitis in pregnancy
• Surgery in 2nd trimester is preferable
• Tocolytic therapy high risk obstetrics in OR

59
Pouch Function and Pregnancy

• Reversible deterioration of pouch function during
  pregnancy
• No long-term detriment to pouch function
• Mode of delivery determined by obstetric
  indications
• Ravid Dis Col Rec 2002

60
Summary IBD and pregnancy

• Fertility
• IPAA Surgery clearly reduces fertility rates in
  women
• Role of medications in fertility unclear
• Pregnancy Outcomes
• Complicated pregnancies occur in majority of
  patients
• Increased rates Preterm birth, SGA LBW
• No increase in congenital anomalies
• Aggressive management of IBD flare during
  pregnancy with medications is warranted
• Medications
• Yes 5ASA, Steroids, 6MP/AZA, Infliximab
• No MTX, Thalidomide