Pregnancy and the Inflammatory Bowel Disease

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

Case 1: Pregnancy and IBD
Case 2: Pregnancy and IBD

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.

Goals: Pregnancy and IBD

* Fertility – becoming pregnant.
* Having an uneventful term pregnancy:
o Avoiding preterm delivery
o 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.

Overview

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

Infertility: UC

Pregnancy and ileoanal pouch - I
Olsen KO, et al. Gastroenterology 2002;122:15-19

IPAA: Cumulative Incidence of Pregnancy

Cumulative Incidence of Pregnancy

Time to Pregnancy (months)

After surgery

Before diagnosis

Reference

Before surgery

Female Infertility After IPAA for UC

Johnson P, et al. Dis Colon Rectum. 2004;47:1119-1126.

Success Rate in Becoming Pregnant (%)

Infertility Rate

UC Patients Managed
Nonoperatively
IPAA Patients
After surgery
After diagnosis
IPAA Patients
UC Patients Managed
Nonoperatively
Before surgery
Before diagnosis
Pregnancy and ileoanal pouch - II
Infertility: Crohn’s Disease
Summary: Female Fertility

* Ulcerative Colitis
o Similar to the general population prior to colectomy
o Significantly decreased after IPAA

* Crohn’s Disease
o Studies vary
o Infertility partly voluntary
+ (dyspareunia, illness, MD advise)
o Surgery: decreased fertility

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

* Pregnancies in 37 of 416 women (CD 316;UC 110)
* 51 total pregnancies reviewed (CD 81%;UC 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.

MCW IBD Center’s Pregnancies
Numbers of IBD pregnancies
Pregnancy trimester
Beaulieau DB, et al. Gastroenterology 128: A316, 2005.
Norgard et al, Am J Gastroenterol 2003;98:2006-10.

Outcomes: Crohn’s Disease
Predictors of Poor Outcome

Pregnancy outcomes in women with inflammatory bowel disease: population based cohort study
U 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.

Patient Characteristics

* N=324 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
o IBD Duration: 6.1 years
o Immunosuppressant Use: 12 (4%)
o Aminosalicylate Use: 142 (47%)
o Corticosteroid Use: 57 (19%)
IBD Pregnancy Outcomes
IBD
Non-IBD
Summary
IBD 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

Medical Therapy in Conception and Pregnancy
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)
o Ambiguous
o Difficult to interpret and use in counseling

Koren G et al. N Engl J Med. 1998;338:1128.
FDA Teratogenicity Classification for Drugs during Pregnancy

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

Nutritional Therapy

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

Fish Oil

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

Pharmaceutical Therapy
Aminosalicylates - I

* Aminosalicylates – Category B
o 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
o Ludvigson (2002) LBW if mother treated with mesalamine or steroids during pregnancy

o 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
o 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


Pharmaceutical Therapy
Aminosalicylates - II

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

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

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

Teratogenicity of 6MP/AZA
* Teratogenic in animals (mice, rabbits, rats)
o Given IV/IP at supratherapeutic doses (low oral bioavailability: 47% AZA, 16% 6MP)
o Increased cleft palate, ocular, skeletal, urogenital anomalies, hydrocephalus
o 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

o Polifka and Friedman (Teratology 65:240-261. 2002)

Human Studies: 6MP/AZA
* Transplantation Experience
o Frequency of congenital anomalies in renal tx 0.0-11.8% in 27 clinical series
o No recurrent pattern of anomalies seen
o No increase in anomalies in NTPR (Armenti 1994) in kidney transplant recipients on AZA
o Immunosuppression is never stopped in setting of organ tranplant
* No congenital anomalies in rheumatic disease, SLE

Norgard (Aliment Pharm Ther 2003)

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

AZA/6-MP

* Experience in IBD

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

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

Infliximab in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy

Therapeutic termination

Miscarriages
Intentional Infliximab in Pregnancy
10 Crohn’s disease patients intentionally exposed to
infliximab during pregnancy
Mahadevan U, et al. Aliment Pharmacol Ther. 2005;21:733-738.
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

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

Special Consideration
* Perianal Crohn’s Disease
* Fulminant Ulcerative Colitis
* Patients with IPAA

Perianal Crohn’s Disease

* Active perianal disease: Caesarean section recommended
o No history (1/39) or inactive (0/11) perianal disease at birth, risk of relapse very low post-vaginal delivery
o 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

Fulminant Ulcerative Colitis

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

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

Summary: IBD and pregnancy

* Fertility
o IPAA Surgery clearly reduces fertility rates in women
o Role of medications in fertility unclear
* Pregnancy Outcomes
o Complicated pregnancies occur in majority of patients
o Increased rates Preterm birth, SGA LBW
o No increase in congenital anomalies
o Aggressive management of IBD flare during pregnancy with medications is warranted
* Medications

Pregnancy and the Inflammatory Bowel Disease