Watermeyer, G

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The South African Gastroenterology Review • March 2007 4IntroductionThe Inflammatory Bowel Diseases (IBD) Ulcerative colitis (UC)and Crohn’s disease (CD) demonstrate a bimodal agedistribution with a small secondary peak later in life but themajority diagnosed in adolescence and early adulthood,essentially the childbearing years. It is thus no surprise thatthe interface between IBD and pregnancy poses a commonchallenge. In order to adequately council and manage ourIBD patients when they consider starting a family there are 6issues with which we need to be familiar; the inheritance ofIBD, the impact of IBD on fertility, the effect of pregnancy onthe course of IBD and conversely the impact of IBD (and thesurgical and medical therapies thereof) on pregnancyoutcomes, the safest mode of delivery and the complexities ofbreastfeeding.The inheritance of IBDThe familial nature of IBD has long been recognized and thispredisposition is stronger for CD than for UC, as evidencedby higher concordance rates for CD than UC in monozygotictwins.1 There is also a high degree of concordance for IBDsubtype in affected members of IBD families, as well as somedegree of concordance for disease location and behavior. Ithas been shown that if one parent has CD or UC there is a 5and 1.6 % chance respectively of disease affecting offspring,with higher rates in individuals of Jewish descent.2 This risk isincreased substantially (to at least 36%) if both parents areaffected, regardless of IBD subtype.3 The inheritance of IBD ishowever complex and does not follow Mendelian principles.Numerous IBD susceptibility genes have been identified andthe strongest association to date is that of CD with 3polymorphisms of the NOD2 gene on chromosome 16.1 Arecent meta-analysis determined the odds ratios fordeveloping CD in carriers of 1 mutant allele, and found only asmall (2 to 4-fold) increased risk.4 Furthermore in the WesternCape these polymorphisms are infrequent in patients withIBD, as well as in population controls.5 Given the poorpredictive value for disease acquisition genetic testing in IBDis currently not recommended.IBD and fertilityInfertility is best defined as the inability to conceive within 12months of unprotected intercourse. Generally patients withIBD have infertility rates approaching that of the generalpopulation.6-9 Certainly IBD per se has little effect on malefertility, with the exception of several drugs used to treat thedisease. Infertility is reported in up to 60% of men takingsalazopyrine. This is due to a dose-dependent reduction insperm count. Sperm is also morphologically and functionallyabnormal. Fortunately this is reversible within 2 months ofdrug discontinuation and substituting an alternative 5-ASAagent restores sperm function to normal. Methotrexate mayalso induce oligospermia and while infliximab use in menmay affect semen quality, whether this alters fertility remainsto be established.7Woman with quiescent CD have normal fertility [6-9]. Incontrast active disease, in particular ileitis and colitis, appearsto reduce fertility which can be normalized by regainingdisease control. In contrast UC, whether active or quiescent,does not impact on female fertility.6-9 The notable exceptionhowever is women who have undergone ileal pouch anal-anastomosis (IPAA). A recent meta-analysis reports a threefold increase in infertility following this procedure.10Furthermore IPAA appears to impact on female fecundity,defined as the probability of pregnancy per menstrual cycleof unprotected intercourse. Before IPAA woman with UC havenormal fecundity ratios. Following IPAA however femalefecundity is reduced by an alarming 80%.11 This is largelyattributed to pelvic adhesions post surgery. Other factors suchas the type of pouch, patient age and smoking status have notbeen shown to impact significantly. As this is a majorcomplication of IPAA women need to be adequatelycounseled prior to surgery. A recent report suggests thatileorectal anastomosis may preserve fertility to a greaterextent than IPAA.12The impact of pregnancy on the course of IBDBoth UC and CD are governed by the “rule of thirds”; onethird improves, one third deteriorates and one third remainsunchanged during pregnancy. If patients flare it is usually inthe first trimester. The major factor influencing disease courseduring pregnancy is activity at the time of conception. 60% ofwomen with active disease will continue to flare duringgestation and 50% of these will deteriorate. As such everyeffort must be made to achieve quiescence beforeREVIEWPregnancy and inflammatorybowel diseaseGill WatermeyerGIT Clinic, Groote Schuur Hospital and University of Cape Town, South AfricaCorrespondence:Gill Watermeyeremail: gwmeyer@curie.uct.ac.zaThe South African Gastroenterology Review • March 2007 5considering pregnancy.6-9 A second factor affecting diseasecourse is HLA disparity between mother and foetus, and byinference disparity between maternal and paternal genes.The foetus is a foreign body and in order to prevent rejectionthe maternal immune system must aggressively down-regulate responses to foetal antigens. As such, pregnancy is astate of immunosuppression or immunotolerance. It has beenshown that if HLA disparity is present at 2 HLA alleles thecourse of IBD in pregnancy fares better than if a single locusis affected.13Previous pregnancies also impact on the future course ofIBD. Women with CD who have previously given birth havefewer resections and longer intervals between procedures,when compared to their nulliparous counterparts.Furthermore the course of future IBD is improved, with fewerrelapses in the years following pregnancy than before. Againthis may reflect pregnancy induced alterations in maternalimmunity [6-9].The impact of IBD on pregnancy outcomesFive endpoints are evaluated in clinical trials; the incidence ofcongenital malformations, stillbirths or spontaneous abortions,small for gestational age (SGA), preterm delivery (<37 weeksof gestation) and low birth weight (LBW) of less than 2.5kgs.Overall IBD fathers have normal outcomes. In contrast womanwith both CD and UC have an increased risk of adverseevents.6-9 This appears to relate to disease activity rather thanthe use of specific medications. A recent meta-analysis hasshown that overall both UC and CD are associated with asignificant incidence of prematurity (OR 1.87, 95% CI 1.5-2.3).CD but not UC is associated with LBW (OR 2.8, 95% CI 1.4-5.6) and UC (but not CD) has an increased incidence of birthdefects (OR 3.88, 95% CI 1.4-10.6). In contrast neitherdisorder appears to increase SGA or stillbirth/abortion rates.14IBD surgery and pregnancyIBD surgery in pregnancy should be restricted to majorcomplications such as haemorrhage, perforation, obstructionand fulminant colitis. Maternal and foetal risk, which issubstantial, correlates with the underlying disease severity,rather than the procedure itself. Emergency colectomy for UCcarries an abortion rate of 60% while emergency surgery forCD has an 18-40% foetal loss.6-9 The second trimester is thesafest time to operate. Given risk to mother and child activedisease in pregnancy must be aggressively treated withmedical therapy in attempt where ever possible to avoidsurgeryThe safety of IBD medications in pregnancy.The FDA stratifies drug safety in pregnancy into 5 categories(see Table 1).15Aminosalicylates are our mainstay of therapy for colonicdisease. Generally these drugs are safe in pregnancy andhave an FDA category B rating.15 A wealth of retrospective datahas not shown any significant association of these drugs withadverse outcomes (up to 3g/day). The use of salazopyrinerequires additional folic acid replacement (2g/day).6-9In contrast salazopyrine use in prospective fathers isassociated with an increased incidence of congenitalabnormalities in their offspring.16 This together with the wellrecognized effects on fertility suggest we should either stopthe drug or replace it with an alternative 5-ASA preparation atleast 3 months before attempting conception to allowspermatogenesis to return to normal.6-9Corticosteroids have an FDA category C rating.15 Overallthey pose a low risk to the developing foetus. Some but not allstudies have shown an association with oral clefts in thenewborn. There are also reports in the transplant literature ofpremature rupture of membranes, as well as a theoretical riskof adrenal insufficiency in the newborn, which fortunately israre in clinical practise. As in the non-pregnant IBD patient,steroids should only be used if truly indicated.6-9,15Antibiotics are often used to manage perianal andluminal CD. The usual suspects, ciprofloxacin andmetronidazole, are considered safe in pregnancy after the firsttrimester. However in the setting of IBD prolonged courses areusually required and furthermore evidence of true benefit islacking. As such chronic use should be avoided. Shortcourses if appropriate are acceptable.6-9,15Much of the controversy of prescribing in IBD pregnancyrevolves around the thiopurines, azathioprine and 6-mercaptopurine. These drugs have an unfortunate FDAcategory D rating, based largely on animal and early humanstudies that showed an increased risk of birth defects andspontaneous abortions with these agents. However extensiveretrospective evidence in the transplant, rheumatology andIBD literature suggests that these drugs are generally safe inpregnancy. Certainly no specific patterns of congenitalabnormalities have emerged and furthermore the foetus isrelatively protected during organogenesis by lowbioavailability, as well as inability of the immature foetal liverto convert azathioprine to active 6-MP. It certainly appears thatfoetal exposure to thiopurines is preferable to active anduncontrolled maternal disease. As such mostrecommendations in the literature suggest continuation inwoman effectively established on these drugs prior topregnancy.6-9,15 In contrast there is no place for commencingthese drugs after conception, given the category D rating, theprolonged time to efficacy and the dose adjustments inpregnancy reflecting fluctuations in BMI.There are conflicting reports that exposure of IBD fathersto thiopurines within 3 months of conception is associatedwith a risk of adverse outcomes. Evidence to date is howeverinsufficient to recommend discontinuation of azathioprine or6-MP for this indication.17Cyclosporine and tacrolimus both have FDA categoryC ratings. Evidence of safety and efficacy in IBD pregnancyhas been reported in several cases of fulminant or refractorycolitis. More extensive evidence from the transplant literaturesuggests little teratogenicity and certainly intrapartumcyclosporine exposure would be preferable to an emergencycolectomy.6-9,15REVIEWTable 1: FDA categories: safety of medication in pregnancy6-9,15Category InterpretationX ContraindicatedA Controlled studies show no risk (No category A IBD meds)B Generally safe in pregnancyC Risk cannot be ruled out (animal or human studies lacking)D Possible evidence of risk (can use if benefit outweighs risk)The South African Gastroenterology Review • March 2007 6Infliximab (IFX) has a category B FDA rating and isgenerally considered safe in pregnancy. Over the past 3 years,analysis of the TREAT registry as well as the Centocor IFX safetydatabase has identified numerous cases of unintentionalexposure to IFX in both IBD mothers and fathers. Birth defectsand adverse pregnancy outcomes have not been shown to differsignificantly from subjects not exposed to the drug.6-9,15 Morerecently 10 cases of intentional exposure to maintenance IFXduring pregnancy were described. All 10 pregnancies resultedin live births with no congenital abnormalities or SGA.18 As anIgG1 monoclonal antibody, IFX does not cross the placenta inany significant amounts during the first and second trimester,and thus exposure during organogenesis is minimal.Transplacental transfer of IFX does however occur in the thirdtrimester and as effects on neonatal immunity are currentlyunknown it may be prudent to discontinue IFX in the last 2months of pregnancy.Safety of adalimumab in pregnancy is limited to a few casereports.DeliveryEpidemiological studies have shown an increased caesareansection rate for both UC and CD. This likely reflects patient andpractitioner concern, rather than true evidence based medicine. Itis becoming increasingly apparent that the mode of deliveryshould be dictated by obstetric need only, and not the underlyingIBD.6-9 One exception is woman with active perianal disease whowill benefit from elective caesarean section.19 In contrast inactiveperianal disease does not appear to pose a risk of perianalcomplications following normal vaginal delivery (NVD). IAPP isalso not a contraindication to NVD.6-9 Several studies report goodpreservation of pouch function up to 4 years post NVD. Thishowever is somewhat controversial given the risk of occultsphincter damage with NVD, especially in primigravids, whichmay impact on future continence and pouch function. Long-termfollow up studies are required to address this question.Breastfeeding and IBDBreast feeding is obviously the preferred form of neonatalnutrition. Certain medications should however be avoided, due tohigh concentrations in breast milk and potential toxicity to thebaby.6-9,15 Table 2 summarises current recommendations on safetyof IBD medications in breast feeding.ConclusionPregnancy in IBD poses a common clinical challenge. In orderto optimise management of both mother and foetus, every effortshould be made to strive for remission before conception. Notonly will this improve fertility rates in women with CD, but is amajor factor influencing the course of IBD during gestation.Furthermore flares during pregnancy must be managedaggressively to prevent surgery and to improve pregnancyoutcomes. The true enemy of the IBD baby is active anduncontrolled disease, and not the medications used to treat it.With the notable exception of methotrexate and thalidomide,and salazopyrine in prospective fathers, the majority of IBDmedications pose little overt risk to the foetus.References1. Gaya DR, Russell RK, Nimmo E, et al. New genes in inflammatory boweldisease: lessons for complex diseases? Lancet 2006;367:1271-842. Yang H, McElree C, Roth M-P, et al. Familial empirical risks forinflammatory bowel disease: differences between Jews and non-Jews.Gut 1993;34:517-5243. Bennett RA, Rubin PH, Present DH. Frequency of inflammatory boweldisease in offspring of couples both presenting with inflammatorybowel disease. Gastroenterology 1991,1001638-43 4. Economou M, Trikalinos TA, Konstantinos TL, et al. Differential effects ofNOD2 variants on Crohn’s disease risk and phenotype in diversepopulations. Am J Gastroenterol 2004;99:2393-24045. Zaahl M, Winter T, Warnich L, Kotze M. Lack of association betweenCARD15/NOD2 main coding mutations (R702W, G908R, 1007fs) inSouth African inflammatory bowel disease patients. Mol Cell Probes2005;19:278-816. Kane S. Inflammatory Bowel Disease in Pregnancy. Gastroenterol ClinN Am 2003;32:323-407. Mahadevan U. Fertility and pregnancy in the patient with inflammatorybowel disease. Gut 2006;55:1198-12068. Steinlauf AF, Present DH. Medical management of the pregnant patientwith inflammatory bowel disease. Gastroenterol Clin n Am2004;33:361-3859. Katz J. Pregnancy and inflammatory bowel disease. Curr OpinGastroenterol 2004;29:328-33210. Waljee A, Waljee J, Morris AM, et al. Threefold increased risk ofinfertility after ileal pouch anal anastomosis in ulcerative colitis. Gut2006;55:1575-1580,11. Olsen KO, Juul S, Berndtsson I, et al. Ulcerative colitis: female fecunditybefore diagnosis, during disease and after surgery compared with apopulation sample.Gastroenterology 2002;122:15-19.12. Mortier P-E, Gambiez L, Karoui M, et al. Colectomy with ileorectalanastomosis preserves female fertility in ulcerative colitis.Gastroenterol Clin Biol 2006;30:594-59713. Kane S, Kisiel J, Shih S, et al HLA disparity determines disease activitythrough pregnancy in women with inflammatory bowel disease. Am JGastroenterol 2004;99:1523-614. Cornish J, Tan E, Teare J, et al. A meta-analysis on the influence ofinflammatory bowel disease on pregnancy. Gut 20060;1-8.doi:10.1136/gut.2006.10832415. Kane s, Mahadevan U.American Gastroenterological AssociationInstitute technical review on the use of gastrointestinal medications inpregnancy. Gastroenterology 2006;131:283-31116. Moody GA, Probert c, Jayanthi V, et al. The effects of chronic ill healthand treatment with sulphasalazine on fertility amongst men andwomen with inflammatory bowel disease in Leicestershire. Int JColorect Dis 1997;12:220-22417. Cohen RD. Sperm, sex and 6-MP: the perception on conception.Gastroenterology 2004;127:1263-127118. Mahadevan U, Kane S, Sandborne WJ, et al. Intentional Infliximab useduring pregnancy for induction and maintenance of remission inCrohn’s disease. Aliment Pharmacol Ther 2005;21:73319. Ilnyckyj A, Blanchard JF, Rawsthorne P, et al. Perianal Crohn’s diseaseand pregnancy: role of mode of delivery. Am J Gastroenterol1999;94:3274-3278REVIEWTable 2: Safety of IBD drugs in breast feeding6-9,15Safe Limited data Limited data ContraindicatedAppears safe Not advisedmesalazine IFX azathioprine thalidomidesalazopyrine 6-MP methotrexatecorticosteroids cyclosporinmetronidazoleciprofloxacin

Pregnancy and inflammatory bowel disease Gill

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