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Pregnancy and the Inflammatory Bowel Disease Patient

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. Case 1: Pregnancy and IBD What we hope for ……….

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Pregnancy and the Inflammatory Bowel Disease Patient

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  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 “I’ve 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, p<0.001 Olsen KO, et al. Gastroenterology 2002;122:15-19

  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 0 12 24 36 48 60 Time to Pregnancy (months) Reprinted from Olsen KØ, et al. Gastroenterology. 2002;122:15-19 with permission from American Gastroenterological Association.

  10. Female Infertility After IPAA for UC Infertility Rate(95% CI) Success Rate in Becoming Pregnant (%) Before surgery Before diagnosis After surgery After diagnosis P<.001 45 120 P<.0001 38.6% (30.9-46.3) 40 97.5% 96.9% 95.8% 100 35 80 30 25 56.1% 60 20 13.3% (4.7-21.9) 40 15 10 20 5 0 0 IPAA Patients (N=153) UC Patients Managed Nonoperatively (N=60) IPAA Patients (N=153) UC Patients Managed Nonoperatively (N=60) Johnson P, et al. Dis Colon Rectum. 2004;47:1119-1126.

  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: Crohn’s Disease

  13. Summary: Female Fertility • Ulcerative Colitis • Similar to the general population prior to colectomy • Significantly decreased after IPAA • Crohn’s 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 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.

  16. MCW IBD Center’s Pregnancies Pregnancies in pts with Crohn's Disease 81% Pregnancies in pts with UlcerativeColitis 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 n=756 n>239,000 (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 1997;177:942-6.

  22. Birth Outcomes in IBD-State of Washington, 1987-96 CUC CD Controls OR, CUC OR, CD n=107 n=155 n=1308 (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 2002;97:641-8.

  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% CI=0.9-1.8) [Adjusted for parity, age, SAS/other drugs] • Limb deficiencies: OR=6.2 (2.9-13.1) • Obstructive urinary CA: OR=3.3 (1.1-9.5) • Multiple CA: OR=2.6 (1.3-5.4) Norgard et al, Am J Gastroenterol 2003;98:2006-10.

  24. Outcomes: Crohn’s 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 Outcomes:Population Based Studies • Kornfeld: Am J Obstet Gynecol 1997 (n=756 IBD) • Fonager: Am J Gastroenterol 1998 (n=510 CD) • Norgard: Am J Gastroenterol 2000 (n=1531 UC) • Dominitz: Am J Gastroenterol 2002 (n=107 UC, 155 CD)

  26. Predictors of Poor Outcome • Active Disease (UC and CD) • 50% vs 21% (p<0.05) abnormal outcomes • Activity at conception => Fetal loss • Activity during pregnancy => LBW • Independent of medication use • Ileal Crohn’s Disease (p = 0.035) Moser • Not consistently found in other studies • Previous bowel resection (p = 0.065) Moser

  27. n=528 n=227 66% 45% 34% 27% 24% NoRelapse Relapse WorsenedActivity Continued Activity DecreasedActivity Inactive Active Effect of Pregnancy on UC: Disease Activity at Conception Miller JP. J R Soc Med. 1986;79:221-5.

  28. 73% n=186 n=93 34% 33% 32% 27% NoRelapse Relapse WorsenedActivity Continued Activity DecreasedActivity Inactive Active Effect of Pregnancy on CD: Disease Activity at Conception Miller JP. J R Soc Med. 1986;79:221-5.

  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 • 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 • 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. 1998;338:1128.

  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 • Drug’s 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 Crohn’s 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 Crohn’s 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 65:240-261. 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 >3 mos before pregnancy • 11 pts: 55% IBD, 45% other disease • Congenital malform OR = 6.7 (95%CI 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 2003;124:9

  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 67 67 67 70 66 60 Live births 50 Miscarriages Proportion of Patients (%) 40 Therapeutictermination 30 20 19 17 17 20 16 15 13 11 10 0 General population Crohn’s disease All infliximab patients(N=96) Infliximab patients with CD (N=82) Katz JA, et al. Am J Gastroenterol. 2004;99:2385-2392. Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59Hudson et al. Int J Gynaecol Obstet 1997;58:229-237.

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