Presentation on theme: "Management of IBD in Pregnancy"— Presentation transcript:
1 Management of IBD in Pregnancy A total management program for women with IBD includes assessment of disease activity and choice of medical as well as surgical options, with particular attention to issues such as fertility and pregnancy. This section reviews treatment in relation to those issues.
2 Assessment of Disease Activity in Pregnant IBD Patients Laboratory studies (ESR, Hgb, albumin, CRP)Ultrasound – low riskLow-dose X-rays pose minimal fetal risk1Endoscopy – low risk if used for appropriate indications2Flexible sigmoidoscopy – low risk2Colonoscopy – should only be used for life-threatening colonic disease or when only alternative is laparotomy2A range of diagnostic modalities may be used to assess disease activity in pregnant patients with IBD. Routine laboratory values for erythrocyte sedimentation rate, hemoglobin, albumin, and C-reactive protein are vital, especially in diseases such as IBD that have an immunologic component.Ultrasound, used to monitor the development of the fetus, is safe, and low-dose X-rays pose a minimal risk to the fetus.60Endoscopy is a valuable tool to assess the anatomic extent of UC.2 A study reported that 38 of 41 pregnant women who had flexible sigmoidoscopies during pregnancy had healthy babies. All reported poor fetal outcomes were in high-risk pregnancies and were not temporally related to the sigmoidoscopy, suggesting that this procedure, when performed in clinically stable pregnant patients, does not frequently cause complications. However, sigmoidoscopy should be performed during pregnancy for clinically significant overt lower-gastrointestinal bleeding; diarrhea or abdominal pain are weaker indications for this procedure. Colonoscopy in pregnancy should be considered only in life-threatening disease or when the alternative is surgery.61ESR = erythrocyte sedimentation rate; Hgb = hemoglobin; CRP = C-reactive protein.1Hufton AP. Br J Radiol. 1979;52: Cappell MS, et al. Dig Dis Sci. 1996;41:
3 Drugs in PregnancyPharmaceutical companies almost never test products in pregnant womenPDR® disclaimer: use in pregnancy is not recommended unless benefits justify risk to fetusFDA classifications (A, B, C, D, X)AmbiguousDifficult to interpret and use in counselingPharmaceutical companies rarely test drugs in pregnant women62 and, until recently, did not routinely include women in clinical trials on the grounds that even if a woman was not pregnant at the start of the trial, it was not possible to be sure that she might not become pregnant during the trial or while the trial drug was present in her body, and the drug might cause problems with current or future pregnancies. It was also thought that hormonal cycling or other factors might affect trial results.63As a consequence, even though pharmaceutical companies now include more women in trials leading to the approval of a drug, data about a drug’s effects in pregnant women and on pregnancy outcomes mostly come retrospectively after a drug has been in use for a considerable amount of time.The standard disclaimer in prescribing information is that use in pregnancy is not recommended unless benefits justify risk to the fetus.64PDR® = Physicians’ Desk Reference®; FDA = Food and Drug Administration.Koren G, et al. N Engl J Med. 1998;338:
4 Pregnancy-Risk Categories A: Controlled human studies do not show risk to fetus; chance of risk remoteB: No evidence of risk to fetus in human studies; chance of risk remote but possibleC: Inadequate studies in humans; risk cannot be ruled out, but benefits may outweigh risksD: Positive evidence of fetal risk; benefits might outweigh risks in life-threatening situations when safer drugs are ineffectiveX: Contraindicated in pregnancyThe FDA Use-in-Pregnancy ratings are as follows:A means that controlled human studies show no risk to the fetus in any trimesterB indicates no evidence of risk in humans; the chance of fetal harm is remote but possibleC means that risk cannot be ruled out; adequate human or animal studies are lacking; the chance of fetal harm exists, but the benefits may still outweigh the risksD represents positive evidence of risk, but the benefits may outweigh the risks in life-threatening situations where safer drugs are ineffectiveX indicates that a drug is contraindicated in pregnancy65These ratings are subjective to the clinician’s assessment of a therapy’s benefits outweighing its risks. Care must be used in discussing pregnancy drug classifications with patients, as the ratings leave room for interpretation that may confuse or frustrate patients.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 BCategory CCategory DCategory XLoperamideCiprofloxacinAzathioprine†MethotrexateMesalamineCyclosporine6-Mercaptopurine†ThalidomideBalsalazideDiphenoxylateCorticosteroidsOlsalazineSulfasalazineTacrolimusAnti-TNF agentsNatalizumabMetronidazole*This table groups drugs currently used to treat IBD in 4 categories: those that are safe to use in pregnancy within the indications stated in the prescribing information (Category B), those that are probably safe to use, but for which data are limited (Category C), those for which there is evidence of risk but whose benefits may outweigh risks in certain situations (Category D), and those that are totally contraindicated (Category X).When considering treatment with drugs in Category C or D, clinicians need to determine whether the benefits of drug therapy outweigh the potential risks to the mother or the fetus, bearing in mind that a disease flare due to nontreatment may also pose a risk to the mother or the fetus.*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; Physician’s Desk Reference®. 57th ed. Montvale, NJ: Thompson PDR; 2003.
6 Sulfasalazine in Pregnancy Most side effects linked to sulfapyridine moiety1No increase in fetal malformationsReadily crosses placenta, but only minimal amounts in breast milk2Interferes with folic acid metabolismFolate important for neural tube development3Folic acid supplements (1 mg BID) advised prior to conception and throughout pregnancySulfasalazine was the first therapeutic advance in the treatment of active UC and for the maintenance of remission in UC.66 The drug consists of sulfapyridine linked to 5-aminosalicylic acid, or 5-ASA. It was developed for use in rheumatoid arthritis, combining the antimicrobial action of sulfonamides with the anti-inflammatory action of salicylates. The 5-ASA moiety is responsible for the anti-inflammatory activity, and the sulfapyridine moiety acts as a carrier for 5-ASA, preventing absorption in the small intestine and facilitating delivery to the colon. Most of the side effects of sulfasalazine appear to be linked with the sulfapyridine moiety.1Sulfasalazine and sulfapyridine cross the placenta, but no firm evidence of harmful effects to the fetus has been found, and the consensus in the literature is that it can be used by pregnant women as it is by nonpregnant women. The concentrations of the 5-ASA moiety of the drug in cord and maternal serum are lower than those of sulfasalazine because of low absorption. Concentrations of sulfasalazine in breast milk are lower than in maternal or cord serum and are not thought likely to be harmful.55Sulfasalazine interferes with folic acid metabolism; therefore, folate supplementation is recommended to prevent neural tube malformations such as spina bifida.67The clinical utility of sulfasalazine is limited by a high incidence of adverse events (headache, dyspepsia, male infertility, skin rashes), which often necessitate discontinuation of treatment or dose reduction to subtherapeutic levels.681Stein RB, Hanauer SB. Gastroenterol Clin North Am. 1999;28: Miller JP. J R Soc Med. 1986;79: Czeizel AE, Dudas I. N Engl J Med. 1992;327:
7 Aminosalicylates (B,C) Meta-analysis 7 studies: 642 5ASA, no medCongenital 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 BIDFolic acid: neural tube defects, CV, GU, cleft palateCase reports of congenital malformationPlacental and Breast Transfer OccursPotential allergic reaction newborn: watery diarrheaSAS not associated with kernicterus or displacement of bilirubin from albuminOlsalazine: Pregnancy category C. All others, BRahimi Reprod Toxicol 2008
8 Safety of Mesalamine in Pregnancy StudynMean Mesalamine DosageIncidence of Fetal Malformations (%)PatientsControlsMarteau et al1123*2.1 ± 0.8 g/d3.1†Diav-Citrin et al21652.0 ± 1.6 g/d0.83.8This slide summarizes the results of 2 studies of mesalamine in pregnancy. The study by Marteau compares outcomes in women taking mesalamine with those in the general population in France73; the Diav-Citrin study is the Motherisk Study described previously. These studies confirm that the incidence of fetal malformations in infants born to women taking mesalamine during pregnancy is no higher than in the general population.*96 taking mesalamine during first trimester. †General population in France.1Marteau P, et al. Aliment Pharmacol Ther. 1998;12: Diav-Citrin O, et al. Gastroenterology. 1998;114:23-28.
9 Topical 5-ASA in Pregnancy Study of 19 pregnanciesMaintenance 5-ASA topical therapy at time of conception and throughout pregnancySuccessful full-term pregnancies for all patients, with no fetal abnormalitiesMinimal excretion of 5-ASA and metabolites in breast milkMany years of safe useThis was a small study of 19 pregnant women treated for UC with topical 5-ASA delivered by enema. All the women completed their pregnancies successfully, and there were no fetal abnormalities.745-ASA enemas have been shown to be safe and effective for maintaining remission, particularly in left-sided UC, the part of the colon to which the 5-ASA enema has access. The response rate to treatment is high, and the rate of complications is low. This is particularly important in UC, because of its high rate of spontaneous relapse,75 and equally important in pregnancy because of the threat to the fetus posed by active disease.Bell CM, Habal FM. Am J Gastroenterol. 1997;92:
10 Antibiotics Metronidazole (B) /Ciprofloxacin (C) Low risk of teratogenicityMetronidazole: prospective controlled study, 2 meta-analysisHowever, 2nd, 3rd T use, 1st T cleft lip, palateCiprofloxacin: prospective controlled study low risk of defectsAffinity for bones, arthropathy in childrenBreast feeding not advised on MNZL, probably compatible with ciprofloxacinMinimal benefit in CD and UC with longer use-avoidRifaximin: Pregnancy Cteratogenicity in animal studiesSafety 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 growthNo fetal adrenocortical insufficiencySafety uncertain with long-term use of high doses while breast-feedingActive-disease risks greater than drug risks to fetus, so use if neededAlthough there are risks associated with the use of corticosteroids in pregnancy, the risks of active disease exceed those to the fetus associated with corticosteroids. A reference guide to fetal and neonatal risk associated with drugs in pregnancy and lactation concludes that prednisone and prednisolone pose very small risks to the developing fetus and states that the American Academy of Pediatrics considers prednisone to be compatible with breast-feeding.80Although corticosteroids are known to be effective for induction of remission of moderate to severe CD, these agents have not been shown to be effective for long-term maintenance of remission. Corticosteroids also have important systemic side effects, some of which are irreversible. Thus, it is evident that these agents should be used with caution.1,81,82Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.
12 AZA/6-MP in PregnancySeveral studies in transplant recipients have reported safe use during pregnancy1Study of IBD patients showed no in prematurity, spontaneous abortion, congenital abnormalities, or childhood neoplasia2Study population included fathers treated with AZA/6-MPIn another study, AZA/6-MP did not reduce fertility in men3Risk of birth defects similar to that in general population4AZA and its active metabolite, 6-MP, are common choices for maintenance therapy in IBD after other agents have been used to induce remission or for patients who have not responded to systemic steroids.1,83 AZA is also used, often with prednisone, by transplant patients.84 A review of pregnancy in women with renal allografts reported no frequent or predominant developmental fetal abnormalities. Those that were reported were rare and often resolved.85 A small study of women with IBD taking AZA reported no congenital abnormalities and no perinatal problems. The authors concluded that AZA is safe in pregnancy for patients with IBD and that termination of pregnancy is not mandatory for patients who conceive while taking the drug.86A recent, large study assessed outcomes of infants born to 79 mothers with IBD who took AZA/6-MP either before conception, before conception and during pregnancy, or just during pregnancy or to 76 fathers who had been treated before conception.87 Results indicated no significant difference in rates of miscarriage, congenital abnormalities, premature birth, or neonatal and childhood infection between the treated cohort and untreated controls.In another study, semen quality and, thus, fertility in men with IBD was not reduced by treatment with AZA.13AZA has been found to be relatively safe in pregnancy. In a surveillance study of more than 225,000 pregnancies, no major malformations were observed in 6 categories – cardiovascular defects, oral cleft, spina bifida, polydactyl, limb reduction defect, and hypospadias.80 Fetal immunosuppression has been observed, including bone marrow suppression, leukopenia, and thrombocytopenia.86 Overall, the risk of a disease flare-up may strongly outweigh the risk of fetal damage, and this issue should be decided by patient and physician in each case.41Briggs GG, et al. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Francella A, et al. Gastroenterology. 2003;124: Dejaco C, et al. Gastroenterology. 2001;121: Library: IBD & Your Family. Available at Accessed March 6, 2003.
13 Azathioprine and Teratogenicity Largest Study to date189 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 treatmentsRate 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 weeks [p = .001]The AZA group had more prematurity21.4% vs. 5.2% [p < .001]The AZA group had more low birth weight23% vs. 6.0% [p < .001]Goldstein Birth Defects Res A Clin Mol Teratol Sep 10;79(10):
14 Thiopurines and Nursing 2 infants breast fed with mothers on 6MP6MP levels by HPLC < 0.09% maternal dose14 mother-infant pairs 3 months post-partum were tested for 6MP metabolitesAll infants were nursingMaternal levels within therapeutic rangeNo metabolites found in offspring2Moretti M. Ann Pharmacother 2006; Dec (40); Gardiner S. Br J Clin Pharmacol 2006; 62:
15 Cyclosporine in Pregnancy Registry data on transplant recipients1No specific congenital abnormalities or birth defectsPrematurity: 56%Low birth weight: 49.5%Study in 5 women with IBD24 live births, 1 missed abortionNo congenital abnormalitiesShould be given at experienced IBD centers3There are relatively little data on the safety of cyclosporine in pregnancy; however, based on the data available, it does not appear that cyclosporine poses a major risk to the fetus. The drug is not teratogenic in animals, and it is not likely to be teratogenic in humans. There is a fairly high incidence of fetal growth retardation and low-birth-weight infants.The National Transplantation Registry was established to study outcomes in all solid organ transplant recipients. The majority of the experience has been derived from female renal transplant recipients. Outcomes showed that no specific congenital abnormalities or birth defects were associated with cyclosporine use. Of the live-born infants, 56% were premature and 49.5% had low birth weight.88In a small report,89 the safety of cyclosporine was examined in 5 pregnant women who received the drug during their pregnancy. Four of 5 pregnancies resulted in live births and 1 had a missed abortion at 8 weeks. No congenital abnormalities or developmental defects were observed.A recent, small study found that patients given cyclosporine in combination with steroids for severe colitis tended to deliver lower-birth-weight, premature babies; overall, pregnancy outcomes were comparable to those for an untreated IBD control group.90If cyclosporine is used during pregnancy, it should be administered and monitored at experienced IBD centers.21Armenti VT, et al. Transplantation. 1994;57; Marion JF, et al. Am J Gastroenterol. 1996;91: Kornbluth A, Sachar DB. Am J Gastroenterol. 1997;92:
16 Proportion of Patients (%) Infliximab (B) Safety Database in Pregnancy: Outcomes of Women Exposed to Infliximab During Pregnancy80706766676760Live births50MiscarriagesProportion of Patients (%)40Therapeutic termination301920Infliximab Safety Database146 Identified pregnancies82 CD, 1 UC, 10 RA, 3 unknownOutcome 96 pregnancies, n=100 birthsLive birth 64 (67%)1 preterm 24 wks (died), 1 tetralogy Fallot, 1 sepsis survived, 1 intestinal malrotation in twinMiscarriage 14(15%) (1 stillbirth on MTX)Therapeutic termination 18 (19%) (pt. Choice)Five reports of infants who were born with complicationsOne infant born at 24-week gestation who did not surviveOne infant with a complicated neonatal course, but without apparent congenital anomaliesOne infant with Tetralogy of FallotOne infant born with intestinal malformationOne twin in a set reported as having delayed development and hypothyroidism2017161715131110General populationCrohn’s diseaseAll infliximab patients (N=96)Infliximab patients with CD (N=82)Katz JA, et al. Am J Gastroenterol. 2004;99:Ventura et al. National Center for Health Statistics Vital Health Stat 2000;21:1-59 Hudson et al. Int J Gynaecol Obstet 1997;58:
17 Medications: Biologics Category B: Infliximab, adalimumab, certolizumabCategory C: NatalizumabInfliximab: 102 pregnancies, 54 outcomes1“Rescue” infliximab successful2Infliximab not detected in breast milk (n=5)Demonstrated to cross the placenta and detectable in cord blood for up to 6 months from birth5Adalimumab: 2 IBD pregnancies in published literature3,447 reported in OTIS registryCertolizumab: no published data in humansNatalizumab: IgG4, placental transfer in 1st trimester1Katz J. Am J Gastroenterol 2004; 99(12): Mahadevan U. APT 2005; 21(6): Vesga L. Gut 2005; 54(6):890.4Mishkin DS. IBD 2006; 12(8): Mahadevan Gastroenterology 2007;132:A-144
18 Methotrexate in Pregnancy Contraindicated during pregnancyChromosomal damage, teratogenicAbortifacientOligospermia noted during treatment of menReturns to baseline posttreatmentLong-term effects unknownMethotrexate is contraindicated during pregnancy and for breast-feeding mothers. Forty-five women who became pregnant after discontinuing treatment with methotrexate (mean interval 2.7 years) had 31 live births, 7 spontaneous abortions, and 7 elective abortions.80In addition, of 10 pregnancies in women exposed to methotrexate, a folic acid antagonist, during the first trimester, 3 resulted in malformed infants. The pattern of methotrexate-related congenital abnormalities is similar to that caused by another folic acid antagonist, aminopterin.80In men, methotrexate appears to cause oligospermia, which resolves after the drug is discontinued; long-term effects are unknown.80Briggs 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-feedingImmunosuppressantsAZA/6-MP appear low risk during pregnancyMethotrexate contraindicatedAntibioticsAmpicillin and cephalosporins are low riskCiprofloxacin and metronidazole should be avoided for longterm useBiologics:Anti-TNF agents low risk. Infliximab and likely adalimumab cross placenta in third trimesterThe drugs most likely to be safe during pregnancy are sulfasalazine, mesalamine, and corticosteroids. Both sulfasalazine and corticosteroids have a fairly high rate of side effects, although these are not likely to affect fetuses.Among the immunosuppressive agents, AZA and 6-MP appear to be safe in pregnancy. Cyclosporine is contraindicated during breast-feeding, and methotrexate is contraindicated during both pregnancy and breast-feeding.80Of the antibiotics, ampicillin and the cephalosporins are safe. Ciprofloxacin and metronidazole are probably safe, although the data are far from unequivocal. Ciprofloxacin does not appear to be linked with an increased risk of major congenital malformations,78,80 but it is not recommended for women who are breast-feeding.80 Women who have been exposed to metronidazole during pregnancy should be reassured that the drug is probably safe and should not be counseled to terminate their pregnancies.79
20 Safety of IBD Medications in Breast-Feeding Low risk to Use When WarrantedLimited Data AvailableContraindicatedOral mesalamineAzathioprineMethotrexateTopical mesalamine6-MercaptopurineCyclosporineSulfasalazineInfliximabMetronidazoleCorticosteroidsAdalimumabCertolizumabTacrolimusNatalizumabCiprofloxacinThis slide groups IBD drugs into 3 categories: those that are safe during breast-feeding, those that are contraindicated, and those for which sufficient data are lacking.Those that are safe include both oral and topical mesalamine, sulfasalazine, and corticosteroids.Methotrexate, metronidazole, ciprofloxacin, and cyclosporine are contraindicated.For AZA/6-MP, infliximab, and tacrolimus, there are limited data available for a strong recommendation.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 conceptionMany IBD-specific therapies appear to be low risk in pregnancyMonitoring of fetal growth particularly importantMay need additional nutritional therapy because of malabsorptionOnce again, pregnancy outcomes are best when the patient is in remission at the time of conception. The most important factor in the course of the pregnancy is the health of the mother. Patients should be encouraged to remain adherent to their therapy through their pregnancies, since the risk of relapse is a greater threat to mother and infant than the risk from most drugs used to treat IBD.Many of the IBD drugs appear to be safe in pregnancy. Some drugs have an effect on fetal growth; therefore, monitoring fetal growth is particularly important. Some nutritional supplementation may be necessary.