Treatment of Inflammatory Bowel

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v. 47 no.2 abr./jun. 2010 Arq Gastroenterol 197

REVISO

/REVIEW

ARQGA/1489

TREATMENT OF INFLAMMATORY BOWEL

DISEASE AND PREGNANCY:

a review of the literature

Lucianna Motta CORREIA, Danielle Queiroz BONILHA, Juliana Dantas RAMOS,

Orlando AMBROGINI and Sender Jankiel MISZPUTEN

ABSTRACTContext- The inammatory bowel disease is diagnosed requently among woman o childbearing capacity. The management

must be careully because there are potential risks or the mother and etus. Results and conclusions - We review literature about the

management o inammatory bowel disease in pregnancy. Some studies are needed to ensure the best approach to inammatory

bowel disease in pregnant women.

HEADINGS - Inammatory bowel disease. Pregnancy complications, inectious. Iniximab.

INTRODUCTION

Inammatory bowel disease (IBD) requently aectswomen in childbearing age. During pregnancy, clinicalexacerbations not treated adequately may have seriousconsequences to the pregnant woman and to the etus.The teratogenicity o the drugs used in treatment oIBD is rarely described but the unknowledgment aboutthis by physicians and patients leads to inadvertentdiscontinuation o treatment. However, the controlling

the activity o the disease is the main determinant othe good prognosis o pregnancy.

Clinical manifestations during the pregnancyThe maniestations o IBD during the pregnancy

are the same o that in non-pregnancy. The majority opregnancies in patients with IBD, although classifedas high risk, courses without several complications(26,27). Reports o clinical exacerbation, especially in thefrst trimester, occurs in up to one third o pregnantwomen with IBD(24, 27). Bortoli et al.(8) ound recurrencerates o disease in 17.3% o women that were inremission, being more requent in patients withidiopathic ulcerative rectocolitis (IUR) compared

to those with Crohns disease (CD), but withoutstatistical dierence (P = 0.38). Nineteen percento births occurred during clinical exacerbationsand 8.7% during remission, all carriers o IUR (8).Riis et al.(49) analyzing cohort study in 508 womendiagnosed with IBD beore or ater pregnancy, havenot observed dierences in the pattern o diseaseor need or surgery or their adequate control, but

identifed reduction in the number o episodes oclinical exacerbation, ater pregnancy. However, therisk o clinical exacerbations is no greater than anyother period in lie(1).

Furthermore, the adequate control o diseaseactivity seems to be the main prognostic actor inpregnancy(1, 4, 24, 28). Disease activity is associated withincreased number o spontaneous abortions, prematuredeliveries, babies born with low weight and/or smallor gestational age and increased demand or surgical

deliveries(11, 18, 28, 35)

. However, the DII does not increasethe risk o maternal complications such as hypertensionor proteinuria(11).

Regarding IUR, about 70%-80% o patients remainin remission during pregnancy and rates o relapse aresimilar to non pregnant(28). Up to 7% present the frstepisode o colitis during pregnancy or puerperal period(58).Carriers o ileum-anal anastomosis tolerate pregnancybetter and exacerbations have more light and transient,resolving completely up in the post-partum period(28).The rates o cesarean sections are higher in carriers othe disease, although IUR by itsel represents no ormalindication or this route o delivery(28).

The behavior o CD pattern is similar to the IUR

during pregnancy. I the design is done in time toclinical remission, this is kept up to 70% o patients.Relapses occur most oten during the frst trimesterand puerperium. Nor is there consensus on the routeo delivery indicated, should be considered obstetricindications(28).

Women with IBD have a risk twice higher thanthe general population to have premature births

Universidade Federal de So Paulo, Escola Paulista de Medicina, So Paulo, SP, Brazil.

The authors have no interest to disclosure. There is no fnancial support to this paper.Correspondence: Dr. Lucianna Motta Correia - Rua Aonso Celso, 1102 apt. 101 - Vila Clementino - 04119-061 - So Paulo, SP, Brazil. E-mail: [email protected]


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Arq Gastroenterol198 v. 47 no.2 abr./jun. 2010

or children considered o low birth weight and greaterlikelihood o surgical deliveries, which seems more relatedto activity o disease than the side eects o medications (18,44, 51). Otherwise, the pregnancy can be quite normal in this

group o patients(4, 51)

. The best obstetric prognostic actoris the control o disease(1, 4).

Diagnosis during the pregnancyPeculiarities in the diagnosis in this situation should

be remembered. The evidence o inammatory activityare commonly altered in pregnancy without necessarilyreecting activity o disease, but the levels o C-reactiveprotein (CRP) tends to be elevated in this period and may beuseul as markers. Because o hemodilution, the hemoglobinand albumin are little reliable parameters or evaluation oactivity and it decreases with the progression o pregnancy.Iron defciency is common in this situation and should not beused as a marker o blood loss(54). Regarding the endoscopicexaminations, the retossigmoidoscopy is relatively sae and mayhelp in the diagnosis o active colitis. In addition, the saetyo colonoscopy is still questionable during pregnancy(9, 12, 52).

Radiologic investigation should be avoided, unlessperoration, toxic megacolon or obstruction are suspected(26).Ultrasound and magnetic resonance are sae or use in thissituation(26).

Furthermore, pregnancy does not appear to inuence thecourse o the disease or the need or surgical treatment, butappears to be associated with reduced number o relapsesover the next years(4, 49).

Treatment of IBD during pregnancy and breastfeeding

Nutritional supportAcid olic supplementation is recommended or all

pregnant woman, especially in use o sulasalazine or indisease activity(26). The recommended doses are 5 mg/day.In pregnant women in use o steroids, the supplement ovitamin D should be administered(26). Precoce nutritionalsupplementation is recommended to pregnant women withno weight gain during disease activity(26). Total parenteralnutrition should be initied in very sick patients(26).

Drug therapyThe drug in this context is perhaps the biggest source o

doubt regarding the clinical management o IBD in pregnancy.We describe the medical treatment more requent used inthis condition.

a) AminossalicilatesThe use o aminossalicilates has been relatively sae,

included during breasteeding(26). The sulasalazine (SSZ),considered as Class B by the Food and Drugs Administration(FDA), crosses the placental barrier and reaches the etus inconcentrations similar to maternal, not related to increasedmorbidity or etal abortions(28, 32, 34, 40). However, some previousreports have described potential teratogenicity or this drug(19,30, 42). There are some studies that describe neonatal jaundice

with SZA(17, 58). The replacement o olic acid is recommendedbecause o the antagonistic eects o SSZ, interacting withthe cell membrane transporters.

The mesalazine (MZA) in conventional doses is sae

during pregnancy(21)

and in higher doses (above 3 g/d) at risko developing interstitial nephritis in newborn(17) but withoutteratogenicity (17, 21, 38). It is also considered Class B drug or useduring the pregnancy. It is excreted in breast milk, withoutsignifcant risk to newborn(15).

b) CorticosteroidsSteroids seem to be sae during pregnancy, with no

convincing evidence o teratogenicity(40). They are indicatedin moderately to severe cases(1). Findings o low birth weightand newborns small or gestational age during the use oprednisolone during pregnancy have not been confrmed inmore recent studies(25, 41, 48). It is classifed as Class C or useduring pregnancy. The prednisolone should be the choicebecause o the etal exposure is lower when compared withbetamethasone and dexamethasone(7, 20).

In a metanalysis, prednisone increases to 3.4-old the risko oral clet, but without major complications in therapeuticdoses(45). However, oral budesonide seems to be sae, in doses6 to 9 mg/d, without reports o maternal adrenal suppression,glucose intolerance, ocular side eects, hypertension or etalcongenital abnormalities(3). There seems to be no signifcantplacental transer o topical corticosteroids, but there is asmall number o researches(28). Its use seems to be sae inthe frst trimester and the benefts outweighed the risks oactivity disease uncontrolled(26). The administration rote, oral,parenteral or topic, depends to severity o disease activity

and tolerability o patient.

c) Immunosuppressive drugsThere is no evidence so ar o adverse eects o azathioprine

(AZA) when the adequate doses(50). Despite apparentcertainty as to the use is not recommended the initiationo therapy during pregnancy or its potential myelotoxicity,but or those who already are in therapy to maintain thesuspension is not necessary. The 6-mercaptopurine (6 MP)increases the risk o miscarriage and premature birthsin humans and its use is inadvisable during gestation(24).Drugs are considered by the FDA or use class D duringpregnancy. The 6-MP excretion in the breast milk occurswithin the frst 4 hours ater intake, with low concentrationto the newborn(15). The use during breasteeding shouldbe recommended(5).

The use o cyclosporine (class C) should be consideredonly in severe cases not responsive to steroids, to avoidedemergency colectomy that presents elevated mortality(23).Its use has been related to prematurity and etal growthretardation, in addition to the potential risk o renal andhepatic toxicity in pregnancy use(24). In doses that aimed orblood levels 200 ng/mL seems to be sae in inducing remissionin patients with several activity o IUR(47).

Methotrexate (MTX) is an alternative to AZA in patientswith steroid reractoriness. Is contraindicated in pregnancy


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or its mutagenic and teratogenic eects, because intereresin acid olic metabolism and purine syntheses (26). It is beingassociated with cranio-acial malormations, central nervoussystem abnormalities, including anencephaly, and deects

in members(39, 46)

. I a pregnancy occurs during its use, thedrug should be suspended immediately and pregnant womenshould receive high doses o olic acid(22).

Tacrolimus is an immunosuppressant with action similarto cyclosporine. It is contraindicated to breasteeding(26) andis associated to perinatal hyperkalemia and prematurity(31).

Thalidomide is an option to reractory CD but is an drugclass X or FDA and contraindicated to pregnant womenand breasteeding(26).

d) AntibioticsThe use o antibiotics may be necessary at times during

the treatment o patients with IBD, especially Crohns disease.The drug metronidazole is teratogenic in animals, but does notappear to be associated with deleterious eects on humans(10).However, there are ew data available with respect to theireects at higher doses and or longer periods, as is usuallynecessary in patients with IBD. Potential toxicity is relatedwith long-term use while breasteeding(37).

Ciprooxacin and other quinolones have been usedin pregnant women without evidence o congenital ormusculoskeletal abnormalities in children and should beavoided its use in the frst trimester(26). However, morestudies are needed to confrm(6). Its use seems to be saein breasteeding(26). Tetracycline and sulonamides arecontraindicated in pregnancy(13). Amoxicilin with or noclavulinic acid is compatible with breasteeding and does

not increase the risks or congenital anomalies(6)

.

e) Biological therapyThe biological therapy with iniximab has changed the

course o IBD considered reractory. So ar, no evidence oadverse eects (maternal toxicity, embryotoxicity, teratogenicity)with its use during pregnancy in isolated models animals(24).Report described complications such as premature birth,tetralogy o Fallot and neonatal death in intracerebralhemorrhage and/or the lung in humans(53).

Iniximab is a chimeric monoclonal antibody against tumornecrosis actor alpha (TNF-), considered eective or bothinduction and or maintenance o clinical remission o theCD(36). The initial dose, administered intravenously, is 5 mg/kg

at week 0, 2 and 6 or induction o response and maintainedthis dose every 8 weeks or maintenance o remission. It isclassifed as FDA class B drugs or use during pregnancy.There are ew isolated reports o associated malormations(53),but most studies have been avorable to its use in period(43).What is known, however, is that eorts should be made tocontrol the IBD during pregnancy, as activities with greaterintensity may put at risk both the mother and the etus. Theoutcomes in pregnant women seems not dierent that in thegeneral population(33).

Serum levels o iniximab can be ound in newbornso mothers who used this medication during pregnancy (56).What can explain this act is the transplacental transer omaternal antibodies in the frst quarter, as it is an antibodyo Class IgG(36). In some reports ound, this transer doesnot seem to be harmul to the etus (Table 1) and, similar toother maternal antibodies, iniximab has a hal-lie prolongedin the newly born(36). There is no evidence o excretion thisdrug in the mothers milk(54, 56).

Adalimumab is classifed as class B drugs or use duringpregnancy. In a case report with the use o adalimumab oundno morbidity related to this medication(55). There is no dateon its saety on breasteeding until the moment(29).

Aussalah at al.(2) report a case o a pregnant woman thatwas successully treated with certulizumab but the saety ocertulizumab is unknown.

CONCLUSIONS

Fear o congenital malormations and/or severe sideeects or birth deects related to medications is the mainresponsible or the difculty in obtaining eective treatmentduring pregnancy. However, the prognostic actor o majorimportance in pregnant women suering rom inammatorybowel disease is adequate control o disease activity in thisperiod. Clarifcation o the patients and physicians to thisact may reduce complications.

TABLE 1. Case reports

Reference n Disease Drug Infusion Results

Roux et al.(51) 3 RA Etanercept, adalimumab Maintenance Prematurity, neonatal jaundice, neonatal urinal inection,

hereditary congenital adrenal hyperplasia

Vasiliauskas et al.(56) 1 Crohn Iniximab

(10 mg/kg)

Maintenance Normal birth without comorbidities

Mahadevan et al.(37) 10 Crohn Iniximab 2 induction

8 maintenance

3 premature births and 1 low birth weight

Katz et al.(33) 96 Crohn, RA Iniximab Maintenance Spontaneous abortions in 15% and therapeutic abortions in

19%. Results did not dier rom those o other patients with

Crohns disease, who did not receive iniximab

Chakravarty et al.(14) 2 RA Iniximab Maintenance Without fndings o teratogenicity or maternal morbidities

Palmer et al.(44) 1 RCUI Iniximab Induction Fetal obit


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Correia LM, Bonilha DQ, Ramos JD, Ambrogini O, Miszputen SJ. Tratamento da doena inamatria intestinal durante a gravidez: reviso da literatura.

Arq Gastroenterol. 2010;47(2):197-201.

RESUMO Contexto - A doena inamatria intestinal acomete mulheres em idade rtil com relativa requncia. A conduta exige maior ateno

durante esta condio clnica em virtude dos riscos potenciais de complicaes materno-etais.Resultados e concluses

- Esta uma reviso sobre asmaniestaes clnicas das doenas inamatrias intestinais durante a gravidez e seu tratamento durante este perodo. Ainda so necessrios estudos

sobre o tema para melhor abordagem das doenas inamatrias intestinais em gestantes.

DESCRITORES Enteropatias inamatrias. Complicaes inecciosas na gravidez. Iniximab.

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Received 22/4/2009.

Accepted 3/9/2009.

Treatment of Inflammatory Bowel

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