pregnancy outcome in inflammatory bowel disease: prospective european case-control ecco-epicom...

Pregnancy outcome in inflammatory bowel disease: prospectiveEuropean case-control ECCO-EpiCom study, 2003–2006A. Bortoli*, N. Pedersen�, D. Duricova�, R. D¢Inca§, P. Gionchetti–, M. R. Panelli**, S. Ardizzone��, A. L. Sanroman��,J. P. Gisbert§§, I. Arena*, G. Riegler––, M. Marrollo***, D. Valpiani��, A. Corbellini��, S. Segato§§§, F. Castiglione––– &P. Munkholm� on behalf of the European Crohn-Colitis Organisation (ECCO) study group of EpidemiologicCommittee (EpiCom)

*Rho Hospital, Rho (MI), Italy.�Herlev University Hospital, Copenha-gen, Denmark.�IBD clinical and research centre,ISCARE a.s., Charles University, Pra-gue, Czech.§University of Padua, Padua, Italy.–Sant’Orsola Hospital, Bologna, Italy.**San Gerardo Hospital, Monza, Italy.��Sacco University Hospital, Milan,Italy.��Roman Y Cajal, Madrid, Spain.§§La Princesa University Hospital andIP, Madrid and Ciberehd, Spain.––II University Hospital, Naples, Italy.***A.O., San Camillo Forlanini, Rome,Italy.��Morgagni Hospital, Forli, Italy.��Melegnano Hospital, Melegnano(MI), Italy.§§§Macchi Hospital, Varese, Italy.–––University Federico II Hospital,Napoli, Italy.

Correspondence to:Dr P. Munkholm, Department of Gas-troenterology, University of Copenha-gen, Herlev Hospital, Herlev Ringvej75, 2730 Herlev, Denmark.E-mail: [email protected]

Publication dataSubmitted 10 December 2010First decision 7 January 2011Resubmitted 8 July 2011Accepted 11 July 2011EV Pub Online 4 August 2011

SUMMARY

BackgroundInflammatory bowel disease (IBD) frequently affects women during theirreproductive years. Pregnancy outcome in women with IBD is welldescribed, particularly in retrospective studies.

AimTo evaluate the pregnancy outcome in patients with IBD in a prospectiveEuropean multicentre case-control study.

MethodsInflammatory bowel disease pregnant women from 12 European countrieswere enrolled between January 2003 and December 2006 and matched (1:1)to non-IBD pregnant controls by age at conception and number of previouspregnancies. Data on pregnancy and newborn outcome, disease activity andtherapy were prospectively collected every third month using a standardquestionnaire. Logistic regression analysis with odds ratio was used for sta-tistical analyses. P value < 0.05 was considered significant.

ResultsA total of 332 pregnant women with IBD were included: 145 with Crohn’sdisease (CD) and 187 with ulcerative colitis (UC). Median age (range) atconception was 31 years (15–40) in CD and 31 (19–42) in UC patients. Nostatistically significant differences in frequency of abortions, preterm deliver-ies, caesarean sections, congenital abnormalities and birth weight wereobserved comparing CD and UC women with their non-IBD controls. InCD, older age was associated with congenital abnormalities and pretermdelivery; smoking increased the risk of preterm delivery. For UC, older ageand active disease were associated with low birth weight; while older ageand combination therapy were risk factors for preterm delivery.

ConclusionIn this prospective case-control study, women with either Crohn’s diseaseor ulcerative colitis have a similar pregnancy outcome when compared witha population of non-inflammatory bowel disease pregnant women.

Aliment Pharmacol Ther 2011; 34: 724–734

724 ª 2011 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2011.04794.x

Alimentary Pharmacology and Therapeutics

INTRODUCTIONCrohn’s disease (CD) and ulcerative colitis (UC) arechronic inflammatory diseases with an increasing inci-dence and prevalence, often affecting young women intheir reproductive years.1–4 It has been estimated thatafter a diagnosis of inflammatory bowel disease (IBD),approximately one quarter of female patients will con-ceive.5 Thus, these patients and their partners havemany concerns about the impact of IBD on preg-nancy.

Multiple studies have been published investigating theimpact of IBD on pregnancy outcome and foetal safetyof IBD-related therapy, with divergent results.6–22 Whilesome, mainly older retrospective studies, suggested nosignificant impact of IBD on pregnancy outcome,7, 23, 24

others found IBD to be associated with a poor pregnancyoutcome.12, 15, 16, 25

Two large population–based studies11, 25 reported anincreased risk of preterm delivery and low birth weight(LBW) in women with either CD or UC. The influenceof disease activity was not, however, assessed in thesetwo studies. Nevertheless, a recent large community-based study reported disease activity to be related to anincreased risk of preterm birth rate in CD femalepatients.19

The frequency of congenital abnormalities (CAs)does not appear to differ from healthy population bothin CD (OR 0.8; 95% CI: 0.2–3.8) and UC (OR 1.3;95% CI: 0.9–1.8) as reported in two population-basedstudies by Norgard et al.,18, 19 whereas an increased riskof CAs in newborns of UC mothers was found inanother population-based study (OR 3.8; 95% CI: 1.5–9.8)11 and also in a recent meta-analysis (OR 3.88; 95%CI: 1.47–3.82).5

Several studies have also investigated the impact ofIBD medications on pregnancy outcome, showing noassociation with poor pregnancy outcomes.6, 14, 17, 20

So far, the current knowledge regarding pregnancyoutcome in IBD is of limited quality, as the majority ofstudies are retrospective,9, 11, 15, 16 small, older ofdate,7, 21, 23, 24 with only a few being recent10, 14, 20, 26, 27

and not even one is prospective, as concluded by therecent European Crohn’s and Colitis Organization(ECCO) consensus on reproduction in IBD.28

As the natural history of pregnancy during IBD is soclinically important, a large multicentre, prospectivecase-control study seems to be an appropriate method toevaluate many of the parameters concerning IBD andpregnancy.

METHODS

Study designThis is a European, multicentre, prospective case-controlstudy on pregnancy and IBD in which pregnant IBDwomen were matched with pregnant non-IBD womenand nonpregnant IBD women 1:1:1. This study is thefirst part of the project dealing with outcome of preg-nancy in women with IBD. The study aim and protocolwere first proposed and discussed at the meeting of theECCO in Amsterdam in 2002. After approval by theECCO Scientific Committee, 68 centres from 12 Euro-pean countries participated in the study.

The Ethical Committee of the Coordinating Centre(Rho Hospital – Italy) approved the study protocol.

Study populationAll consecutive pregnancies which occurred in womenwith IBD, and followed by the participating centres fromJanuary 2003 to December 2006, were included. At thetime of enrolment (conception ⁄ first trimester until 12thgestational week), all IBD pregnant women wereintended to be matched (1:1) with non-IBD pregnantcontrols by age at conception ( � 5 years) and numberof previous pregnancies at the Obstetric and Gynaecol-ogy Department of each participating centre.

Data acquisitionEach participating centre received electronic case reportforms (CRFs, for index cases and controls) to record therequested data. The data were prospectively collected bytrained physicians at the participating centres at entry tothe study and then every 3 months until the end of preg-nancy by regular personal or telephone interviews as wellas a by review of patient’s medical records. All the com-pleted forms were sent electronically to the central data-base storage record, to allow data extraction andstatistical evaluation.

The following data were collected: (i) maternal vari-ables, (ii) treatment for IBD, (iii) disease activity, (iv)outcome of pregnancy and (v) mode of delivery.

Maternal variables included age at conception, numberof previous pregnancies, smoking status (current smokervs. nonsmoker), alcohol use (current alcohol use vs. noalcohol use) and details on underlying IBD. Medical andsurgical therapies, as well as disease activity, wererecorded at conception and then every third month. Dis-ease activity was assessed by Harvey & Bradshaw’s Activ-ity Index (HBI)29 for CD patients and Simple Clinical

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Aliment Pharmacol Ther 2011; 34: 724–734 725

ª 2011 Blackwell Publishing Ltd

Colitis Activity Index (SCCAI)30 for UC patients andclassified into two categories for each trimester as remis-sion (HBI £ 5; SCCAI £ 3) or active disease.

The outcomes of pregnancy recorded were: live births,spontaneous or therapeutic abortion, extra-uterine preg-nancy, infant death in utero, preterm delivery (<37 weeksof gestation) and at term delivery. Furthermore, mode ofdelivery (vaginal or caesarean), occurrence and type ofCAs and birth weight (LBW was defined as <2500 g)were registered.

Similarly, outcomes of pregnancy in non-IBD healthyfemales were followed prospectively and data on demo-graphics, smoking, alcohol use and pregnancy outcomewere recorded on CRFs in the same manner as in theIBD population.

Statistical analysisMatched logistic regression was used to compare casesand controls for the parameters of interest. The odds ratioand 95% CI for the parameter of interest were adjusted forthe following covariates measured for both cases and con-trols: age at conception, smoking, alcohol use. The impactof all covariates, including disease specific parameters onlymeasured for the cases, was analysed by a standard logisticregression model for the cases only. Due to sparse data forsome of the prognostic factors, the association betweenthe parameters of interest and all prognostic factors werealso investigated by Fisher’s Exact Test (for the cases

only). All tests were performed with a significance level of5%.

RESULTSA total of 520 IBD pregnant women: 244 with CD, 264with UC and 12 with indeterminate colitis (IC) wereenrolled. Nevertheless, only 373 of them were matchedto non-IBD pregnant controls and considered to be eligi-ble for the study. Further 32 IBD women had to be laterexcluded due to missing data on pregnancy outcome intheir controls. Women with IC were not included intodata analysis due to the small numbers. Hence, the finalpopulation comprised 332 IBD pregnant women, 145with CD and 187 with UC, who were matched (1:1) tonon-IBD pregnant controls (Figure 1). Two hundred andfifty-eight (78%) pregnant women were enrolled fromItalian centres and 74 (22%) from the other Europeancentres. No significant difference in pregnancy outcomebetween Italian and non-Italian patients was observed(data not shown). The pregnancy outcome of theexcluded population (98 women with CD, 78 with UCand 12 with IC) is outlined in Table S1 (on-line).

Crohn¢s diseaseThe demographic and disease characteristics of includedwomen are summarised in Table 1.

The majority of pregnant women with CD, 126(86.9%), were in remission at conception ⁄ first trimester,

IBD pregnant women enrolled

IBD pregnant women Included

n = 520

n = 9

n = 154 n = 187

n = 332

(CD 244; UC 264; IC 12)

IC women

CD women UC women

Excluded: n = 179

-Missing control data (n = 32)-No matching controls (n = 147)

Figure 1 | IBD pregnant women and non-IBD pregnant women (matched controls) enrolled in a prospective Europeancase-control study.

AA.. BBoorrttoollii eett aall..

726 Aliment Pharmacol Ther 2011; 34: 724–734


while 19 (13.1%) had active disease. Of those in remis-sion, 105 (85.8%) maintained remission during the entirepregnancy, whereas 38 (14.2%) women relapsed. As towomen with active disease, 14 (73.7%) obtained remis-sion later during the pregnancy, while five (26.3%)remained active until delivery.

At conception and ⁄ or during the first trimester, 28(19.3%) patients were without any medical treatment,while 117 (80%) women were under treatment withmono- or combined therapy. Sixty eight (46.9%) womenwere on 5-aminosalicylic acid (5-ASA) monotherapy, 20(13.8%) on immuno-monotherapy [azathioprine (AZA),6-mercaptopurine (6-MP), cyclosporine, biologics or cor-ticosteroids] and 28 (19.3%) on combination therapy

(two or more preparations). The median daily dose of 5-ASA preparations was 2400 mg (range 800–4800) with37 (46%) women taking a dosage of ‡ 3000 mg a day atconception, maintaining the same dose during the preg-nancy in majority of them. The pregnancy outcome ofthese women was favourable with 35 (95%) live births,33 at term and two preterm deliveries. Two (8%) preg-nancies ended in spontaneous abortion. No CAs in new-borns of women treated with high dose 5-ASA wereobserved. Four women required intervention duringpregnancy.

One woman with colonic disease and history ofperianal fistula underwent incision of a perianal abscessat gestational week 24. She had been in remission on

Table 1 | Demographic and clinical characteristics of pregnant women with inflammatory bowel disease (IBD) and non-IBD pregnant controls at conception

Pregnant CD (n = 145)Controls toCD (n = 145) UC (n = 187)

Controls toUC (n = 187)

Age* 31 (15–40) 31 (16–45) 31 (19–42) 32 (19–42)

Previous pregnancies

0–1 129 91 150 116

>1 16 54 37 71

Smoking (%) 21 (14.5) 15 (10.3) 15 (8. 0) 26 (13.9)

Alcohol (%) 3 (2.1) 9 (6.2) 8 (4.3) 13 (7.0)

Disease duration (months)* 84 (2–311) n.a. 66 (1–270) n.a.

Disease localisation ⁄ extension (%)

Small bowel 46 (32.0) n.a. n.a. n.a.

Colon 29 (20.0) n.a. n.a. n.a.

Small bowel + colon 69 (48.0) n.a. n.a. n.a.

Pancolitis n.a. n.a. 64 (34.0) n.a.

Left sided colitis n.a. n.a. 55 (30.0) n.a.

Proctosigmoiditis n.a. n.a. 67 (36.0) n.a.

Previous intestinal surgery (%) 47 (32.4) n.a. 6 (3.2) n.a.

Previous perianal ⁄ rectovaginal fistula (%) 18 (12.4) n.a. n.a. n.a.

Remission at conception ⁄ 1st trimester (%) 126 (86.9) n.a. 148 (79) n.a.

Onset during pregnancy (%) 1 (0.7) n.a. 2 (1.1) n.a.

Any therapy at conception ⁄ 1st trimester (%) 117 (80.7) n.a. 165 (88.2) n.a.

- Mesalazine 96 (66.2) n.a. 156 (83.4) n.a

- Corticosteroids 32 (22.1) n.a. 74 (39.6) n.a.

- Azathioprine ⁄6MP 32 (22.1) n.a. 19 (10.2) n.a.

- Infliximab 8 (5.5) n.a. 0 n.a.

- Cyclosporine 0 n.a. 1 (0.5) n.a.

n.a., not applicable; CD, Crohn¢s disease; UC, ulcerative colitis; n, number.

* Median (range).




azathioprine therapy since conception until the third tri-mester, when a perianal abscess occurred. She deliveredan at term 3300 g baby boy. A second patient with ileo-colonic CD was in remission and received no medicationuntil relapse at gestational week 14 and required drain-age of an intra-abdominal ileo-colonic abscess at gesta-tional week 19. This patient delivered a preterm living1040 g baby boy at week 26 by caesarean section. Thethird woman, with ileo-colonic and perianal involvement,was in remission on topical corticosteroids and systemicand topical 5-ASA therapy. A relapse at gestational week18 was complicated by intestinal perforation necessitatingsegmental ileo-colonic resection. This patient, however,went on to deliver a living at term 3350 g baby girl bycaesarean section. The fourth woman with colonic CDwas in remission on no medication at conception ⁄ firsttrimester and relapsed during the second trimester.Corticosteroids were initiated; nevertheless the diseaseremained active until the end of pregnancy. At gesta-tional week 39, an intra-abdominal abscess was foundand subsequently an ultrasonic drainage was performed.The patient delivered a 2800 g baby girl at term by cae-sarean section.

Ulcerative colitisDemographic and clinical characteristics of all womenincluded are summarised in Table 1.

The majority of pregnant women with UC, 148(79%), were in remission at conception ⁄ first trimester,while 39 (21%) had active disease. Of those in remission,109 (73.6%) maintained remission during the entirepregnancy and 39 (26.4%) relapsed. Regarding womenwith active disease, 26 (67%) went into remission laterduring the pregnancy, while 13 (33%) remained activeuntil delivery.

At conception and during the first trimester, 22(11.8%) were untreated, while 165 (88.2%) women wereunder treatment with mono- or combined therapy.Eighty eight (47.1%) women were on 5-ASA monothera-py, 14 (7.5%) on immuno-monotherapy (AZA, 6-MP,cyclosporine or corticosteroids) and 63 (33.7%) on com-bination therapy (two or more preparations). None ofthe UC patients received anti-TNF therapy. The mediandose of 5-ASA preparations was 2400 mg a day (range800–4800) with 37 (30%) women having a daily dosageof ‡ 3000 mg at conception, maintaining the same doseduring the pregnancy in majority of them. Similar toCD, the pregnancy outcome of women with UC on highdose 5-ASA therapy was favourable. There were 35(95%) live births, 31 at term and four preterm deliveries.One (3%) pregnancy ended in spontaneous abortion andone (3%) in therapeutic abortion. No CAs in newbornsof mothers receiving 5-ASA dose ‡ 3000 mg a day wasobserved.

Table 2 | Outcome of pregnancy in women with inflammatory bowel disease (IBD) and their controls (non-IBD preg-nant women in general population)

OutcomeCDn = 145

Controlsto CDn = 145 OR (95% CI) P

UCn = 187

Controlsto UCn = 187 OR (95% CI) P

Live births (%) 127 (88.2) 135 (93.1) 0.48 (0.19–1.24) 0.13 177 (94.7) 170 (91.4) 0.48 (0.19–1.24) 0.13

Spontaneousabortions (%)

9 (6.3) 8 (5.5) 1.30 (0.41–4.06) 0.66 9 (4.8) 15 (8.0) 0.62 (0.26–1.52) 0.30

Therapeuticabortions (%)

6 (4.2) 2 (1.4) 4.07 (0.45–36.85) 0.21 1 (0.5) 1 (0.5) 1.56 (0.09–28.12) 0.76

Infant deathin utero (%)

1 (0.7) 0 – 0 0 – –

Preterm delivery<37 weeks (%)

13 (9.1) 11 (7.6) 0.89 (0.38–2.08) 0.78 12 (6.5) 14 (7.5) 0.99 (0.41–2.39) 0.97

Caesarean section (%) 50 (40.3) 34 (26.2) 1.34 (0.74–2.43) 0.33 55 (31.3) 46 (27.7) 1.29 (0.74–2.24) 0.36

Congenitalabnormalities (%)

5 (3.5) 1 (0.7) 5.0 (0.58–42.79) 0.14 0 3 (1.7) – –

Birth weight (g)Mean � SD

3212 (431) 3269 (395) – 0.56 3190 (471) 3272 (448) – 0.07

CI, confidence interval; CD, Crohn‘s disease; UC, ulcerative colitis; n, number.

Odds ratio (OR) adjusted for age, smoking and alcohol use.




Table3|Factors

with

potentialim

pact

onpregna

ncyou

tcom

ein

wom

enwith

Crohn

¢sdisease

Factor

Live

birth

Spon

tane

ousab

ortio

nThe

rape

utic

abortio

nPreterm

delivery

Con

genitalab

norm

ality

Caesarean

section

Age

‡35

years

1.3(0.3

–6.0)

1.64

(0.2–11.2)

1.6(0.1–19.9)

9.8(1.7–55.6)

15.0

(1.4–163

.4)

1.1(0.4–3.2)

Smokingstatus

0.6

(0.1–2.5)

1.0(0

.1–10.3)

1.7(0.1–19.8)

5.6(1.1–28.9)

P=1.0

01.0

(0.3–3.2)

Alcoh

oluse

0.05(0

.003–0.6)

7.2(0.5–113.5)

P=0.12

P=1.0

0P=1.0

0P=1.0

0

Previous

surgery

1.4(0

.3–6

.2)

1.3(0.2–7.9)

P=0.18

0.4

(0.04–3.7)

–3.6(1.3–10.2)

Perianal

disease*

2.0(0.2–19.1)

P=0.60

3.2(0.2–57.9)

0.6

(0.05–7.2)

–2.0(0

.6–7.5)

Disease

activ

ity**

1.0(0.2–33.3)

0.34(0.06–

4.8)

3.9(0.2–76.3)

0.3

(0.04–1.9)

3.2(0.1–51.4)

0.9

(0.3–2.7)

Therapy**:

anytherapy

0.9

(0.2–4

.7)

0.6

(0.04–8

.1)19.3

(0.5–760

.8)

2.5(0.02–409.6)

P=0.053

P=0.66

5-ASA

mon

othe

rapy

2.4(0

.2–29.0)

5.0(0

.2–111.9)

P=0.23

0.4

(0.003–55

.3)

P=0.37

P=0.01

ISmon

othe

rapy

1.8(0

.1–30

.7)

9.4(0

.2–393

.3)

P=1.0

00.7

(0.003–134.4)

P=0.49

P=0.80

combinatio

ntherapy

2.1(0.1–33

.4)

11.0

(0.4–313.0)

P=0.64

2.7(0.02–417)

P=0.58

P=0.02

5-ASA

,mesalazine

⁄sulph

asalazine;

IS,immun

omod

ulator

therapy(azathioprine,

cyclospo

rine

,cortic

osteroids,infliximab).

Analyseswerepe

rformed

bymultiv

ariate

logistic

regression

(odd

sratio

;95%

confi

denceinterval)or

byFisher

¢sexact(P

value).

Highlighted

results

arestatistic

ally

sign

ificant.

*Atanytim

esincediagno

sis,**

Atanytim

edu

ring

pregnancy

⁄atconcep

tionor

first

trim

esterforcong

enita

labn

ormalities.




One woman, with extensive active UC since concep-tion, required subtotal colectomy at gestational week 12for steroid refractory UC. The patient delivered a healthy2850 g baby girl at term by caesarean section.

Pregnancy outcomeThere was no significant difference in live births, sponta-neous and therapeutic abortions, infant death in utero,preterm deliveries and caesarean sections, comparingboth CD and UC women with their non-IBD pregnantcontrols (Table 2). Likewise, no increased risk of CAs ininfants of CD or UC women vs. healthy controls wasseen (Table 2; Table S2 on-line).

Similarly, no significant difference in birth weight wasobserved between CD and UC women and their controls(Table 2).

Factors with impact on pregnancy outcomeIn CD, multivariate analysis identified older age( ‡ 35 years) to be associated with an increased risk ofCAs and preterm delivery. Alcohol intake was found todecrease the probability of live birth, whereas smokingincreased the risk of preterm delivery. Previous intestinalsurgery was associated with a higher rate of caesareansections. No impact of disease activity on pregnancy out-come was observed. Regarding IBD-related medication,women on 5-ASA monotherapy were less likely to havecaesarean sections (27% vs. 50%, P = 0.01), while those

on combination therapy were at increased risk of thismode of delivery (57% vs. 34%, P = 0.02) (Table 3).

In UC, women with older age were found to be atincreased risk of preterm delivery, whereas smokingwomen were found to have a higher rate of caesareansections. Older age and disease activity at any time dur-ing pregnancy were associated with a lower birth weight(mean 3146 g vs. 3343 g, P = 0.02 and 3110 g vs.3268 gP = 0.04, respectively). Regarding IBD-related medica-tion, women on 5-ASA monotherapy were less likely toget preterm delivery (1% vs. 10%, P = 0.01) whereaspatients on combination treatment were at increased riskof preterm delivery (13% vs. 1%, P = 0.03) (Table 4).

DISCUSSIONTo our knowledge this is the first prospective case-con-trol study on pregnancy outcome in women with IBD.In this study, IBD pregnant women were matched (1:1)at conception ⁄ during first trimester with non-IBD preg-nant healthy controls and follow-up was performed every3 months during the gestational period. Women withIBD, overall considered, were shown to have similarpregnancy outcomes as compared with healthy pregnantcontrols, with no difference in spontaneous and thera-peutic abortions, preterm delivery, congenital abnormali-ties and birth weight. Logistic regression analysisidentified prognostic factors with potential influence onpregnancy outcome: older age, smoking, disease activity,

Table 4 | Factors with potential impact on pregnancy outcome in women with ulcerative colitis

Factor Live birthSpontaneousabortion

Therapeuticabortion

Pretermdelivery

Caesareansection

Birthweight

Age ‡ 35 years 3.0 (0.3–25.9) 0.4 (0.05–3.5) P = 1.00 3.9 (1.1–14.2) 0.9 (0.4–1.9) P = 0.02

Smoking status 0.5 (0.05–5.4) 2.2 (0.2–23.1) P = 1.00 2.0 (0.3–13.0) 9.9 (2.4–40.0) P = 0.27

Alcohol use P = 1.00 P = 1.00 P = 1.00 P = 1.00 0.5 (0.06–4.89) P = 0.74

Previous surgery P = 1.00 P = 1.00 P = 1.00 P = 1.00 1.8 (0.2–13.2) P = 0.52

Disease activity* 5.6 (0.6–52.2) 0.2 (0.02–1.9) P = 1.00 0.5 (0.1–1.8) 0.7 (0.3–1.7) P = 0.04

Therapy for UC*:

any therapy P = 0.60 P = 0.56 P = 1.00 P = 0.60 P = 1.00 P = 0.11

5-ASA monotherapy P = 0.75 P = 1.00 P = 0.44 P = 0.01 P = 0.051 P = 0.83

IS monotherapy P = 1.00 P = 1.00 P = 1.00 P = 1.00 P = 0.40 P = 0.27

combination therapy P = 1.00 P = 1.00 P = 1.00 P = 0.004 P = 0.41 P = 0.94

5-ASA, mesalazine ⁄ sulphasalazine; IS, immunomodulator therapy (azathioprine, cyclosporine, corticosteroids, infliximab).

Analyses were performed by multivariate logistic regression (odds ratio; 95% confidence interval) or by Fisher¢s exact (P value).

Highlighted results are statistically significant.

* At any time during pregnancy.




alcohol and IBD-related medication. Smoking andage ‡ 35 years were found to be risk factors for pretermdelivery in CD, with the latter being associated with anincreased risk of congenital abnormalities in CD womenand preterm deliveries in UC patients. Disease activityduring pregnancy and older age were associated with alower birth weight in patients with UC. Women on 5-ASA monotherapy had lower probability of pretermdelivery in UC and caesarean section in CD while com-bination therapy increased the risk of these events.

The important strength of this study is the prospectivecharacter which allows standardised follow-up of bothpregnant women and matched healthy pregnant controls.This offers the high validity of the data and a solid levelof evidence regarding the outcome of pregnancy inwomen with IBD.28, 31

Previous case-control studies have shown an increasedrisk of adverse pregnancy outcome in women withIBD.7, 9 In the study of Baird et al.,7 IBD women whowere retrospectively matched by age, parity and smokingstatus, showed a two to threefold increased risk of pre-term birth compared with their healthy controls.Another retrospective case-control study9 comparingpregnancy outcome of IBD women in pre- and post-diagnosis period, revealed that prior to diagnosis of IBD,CD patients carried an increased risk of preterm delivery,whereas infants of UC patients had an increased risk ofLBW. After diagnosis, women with IBD were shown tohave higher incidence of CAs while patients with CDhad a higher risk of LBW infants.

Several other large population-based11, 15 and registry-based studies12, 25 also reported an increased risk of pre-term delivery and LBW in women with both CD andUC. However, neither disease activity nor therapies wereassessed in these studies.

Different results were found in women with UC in alarge nationwide Danish study25 involving 1531 infantsin which no differences were demonstrated in rates ofpreterm delivery overall considered, LBW and small forgestational age (SGA) compared with controls. Finally, ameta-analysis5 of 12 studies performed from 1980 to2006 including 3907 IBD patients and 320 531 controlsreported an increased risk of premature birth both inCD and UC patients, and higher rates of caesarean sec-tions and LBW in infants of CD women.

In our study, pregnancy outcome in women with CDand UC did not differ significantly from that of thehealthy background population. This favourable resultmight be attributed to the high remission rates of ourpatients, with 86% and 88% of CD and UC women,

respectively, having quiescent disease at conception ⁄ firsttrimester. This is also in agreement with findings of pre-vious studies showing a higher risk of premature birth,LBW, stillbirths and miscarriages when active disease ispresent at conception.7, 21, 23, 24

An increased risk of CAs in women with UC than inhealthy controls (7.9% vs. 1.7%; OR 3.8, 95% CI: 1.5–9.8) was shown in a study by Dominitz et al.11. Corre-spondingly, higher incidence rate of CAs in patients withUC vs. controls (OR 3.8; 95% CI 1.47–3.82) was foundin the recent meta-analysis by Cornish et al.5 In contrast,our study did not find an increased risk of CAs either inUC or in CD. Similarly, no significantly increased overallrisk of CAs was shown in infants born to women withUC in a large population-based case-control registrystudy by Norgard et al.18 (OR 1.3; 95% CI: 0.9–1.8).

When looking at separate factors with impact onpregnancy outcome, maternal age above 35 years andsmoking women with CD carry a risk of preterm deliv-ery in our study. Tobacco use in women with CD wasconsidered as a risk factor in study by Fonager et al.12

Another study,16 however, has shown that CD diagnosisand maternal age above 35 years, but not currenttobacco use, are predictive of adverse pregnancy out-come. Active disease during pregnancy and maternal ageabove 35 years were associated with a LBW in patientswith UC in our study. Our results are supported by thefindings in the other studies,19, 23 showing that if thepregnancy occurs while the disease is active; there is ahigh risk of premature birth or LBW in infant born towomen with UC.

More than 80% of CD and UC women were on medi-cation during pregnancy with the majority of themreceiving either 5-ASA preparations (66% and 83%), cor-ticosteroids (22% and 40%) or azathioprine ⁄ 6-mercap-topurine (22% and 10%). Eight women were treated withanti-TNFa medications. The finding of an associationbetween combination therapy and increased risk of pre-term delivery in UC and caesarean sections in CD, withan inverse result regarding 5-ASA monotherapy, mightbe just a reflection of a more or less complicated diseasecourse in such patients requiring more or less intensiveanti-inflammatory therapy. No impact of medication onoccurrence of CAs was observed in our study.

To date, there is an increasing evidence that themajority of the drugs used in IBD are safe during preg-nancy and that there is no need to withdraw the therapyprior to or after conception.32–34 Moreover, there isincreasing evidence that biological therapy is also feasibleand safe during pregnancy until week 32.35, 36 Discontin-




uation of the medication, may lead to disease activitywhich has been reported to be associated with an adversepregnancy outcome.23, 24 Thus it is recommended todayto sustain medical therapy, apart from methotrexate,during pregnancy to maintain IBD patients in remis-sion.32–34

It has to be emphasised that 46% of CD patients and30% of UC women on 5-ASA therapy in our studyreceived a dose which is higher than recommended(<3000 mg) in ECCO consensus.31 This may be clinicallyimportant, mainly regarding a recent concern aboutdibutyl phthalate (DBP) included in 5-ASA enteric-coat-ing preparations. High dose of DBP in animal studies37

has been shown to be associated with foetal malforma-tions. To date, there is limited evidence of potential sideeffects also in humans.20, 38, 39 Since until 2005 the sub-stantial proportion of 5-ASA preparations containedDBP, the majority of our women included and treatedwith 5-ASA were probably exposed to DBP. Neverthe-less, the pregnancy outcome in both CD and UC womenwas favourable and no CAs in newborns were observed.

The study has several limitations. Firstly, there wasthe big drop out of enrolled women due to a lack ofmatching and incomplete data record which influencedthe final sample size. This could have had an impact onstatistical significance of some rare pregnancy events,such as CAs, therapeutic and spontaneous abortions.Thus, further prospective studies are needed to confirmor disprove our results. Secondly, the number of ourwomen treated with immunomodulators or biologicalswas too low to make any firm conclusion about theimpact of the therapy on pregnancy outcome. On theother hand, our study population reflects to some extentthe everyday clinical practice when the majority ofwomen conceive while being in remission and do notrequire immunosuppressive or biological therapy.

In conclusion, this is the first prospective Europeancase-control study performed in pregnant women withIBD. The study found similar pregnancy outcomes inwomen with IBD as compared with their age and paritymatched non-IBD controls. We underline that themajority of pregnant IBD patients were in remission onmaintenance therapy. Regression analysis showed thatage < 35 years, inactive disease course and nonsmokerscarry the least risk of adverse pregnancy outcome. Tak-ing into consideration that the incidence of IBD has sub-stantially increased in the past decades and the naturaldisease course has also changed, there is still a need forprospective evaluations.

AUTHORS’ CONTRIBUTIONThe study was initiated by ECCO. The guarantors of themanuscript are AB, NP and PM. AB, NP and an ECCOcollaborative group performed the data collection. DD,NP, JKJ (Statistician) and PM performed the statisticalanalyses. AB and NP drafted the manuscript, which wascritically revised by all co-authors. All authors approvedthe final version of the manuscript.

ACKNOWLEDGEMENTSWe thank all collaborators from participating centreswho contributed with inclusion of patients and controls:Alberto Prada, Rho Hospital, Rho, Italy; Colm O’MorainDublin University, Ireland; Giovanni Casella, Desio Hos-pital, Italy; Giorgio Zoli, Cento Hospital, Italy; Licia Sni-der, Sant’Anna Hospital, Italy; Marco Daperno,Mauriziano Hospital, Torino, Italy; Pierenrico Lecis, SanMartino Hospital, Belluno, Italy; Christian Felley, Lau-sanne, Switzerland; Mario Gatti, Giussano Hospital, Italy;Giovanni Fornaciari, Reggio Emilia, Italy; Renzo Caprilli,La Sapienza University, Roma, Italy; Maddalena Terpin,Legnano Hospital, Italy; Fabrizio Bossa, San GiovanniRotondo, Italy; Giorgio Mortara, San Carlo Hospital, Mi-lano, Italy; Roberto de Franchis IRCCS Policlinico, Mi-lano, Italy; Maurizio Vecchi San Donato Hospital, SanDonato, Italy; Michele Comberlato, Bolzano Hospital,Italy; Christian Folwaczny, Poliklinik, Innerstadt Mun-chen, Germany; Enrico Colombo, Garbagnate Hospital,Italy; Carlo Maria Girelli, Busto Hospital, Italy; Paolo Ra-velli, Bolognini Hospital, Seriate, Italy; Walter Reinisch,University Hospital, Vienna, Austria; Luca Ferraris, Gall-arate Hospital, Italy; Guido Lupinacci, Crema Hospital,Italy; Daan Hommes, Leiden, The Netherlands; GerhardRogler, University Klinik of Regensburg, Germany; VitoAnnese, San Giovanni Rotondo, Italy; Maria Carla DiPaolo, S.Giovanni Addolorata Hospital, Rome, Italy; Epa-meinondas V. Tsianos, Joannina, Greece; Gerhard Ro-gler, University Klinik of Regensburg, Germany;Konstantinos Katsanov, Joannina, Greece; VenerinaImbezi, Policlinico San Matteo, Pavia, Italy; Anna Kohn,San Camillo Forlanini, Rome, Italy. Declaration ofpersonal interests: None. Declaration of funding interests:The authors have received funding from ECCO and froma research fund in the department of Pia Munkholm forthe present study.

SUPPORTING INFORMATIONAdditional Supporting Information may be found in theon-line version of this article:




Table S1. The pregnancy outcomes of excluded popu-lation of pregnant women with inflammatory bowel dis-ease (n = 188).

Table S2. Type of congenital abnormalities in new-borns of women with inflammatory bowel disease (IBD)vs. non-IBD pregnant controls.

Please note: Wiley-Blackwell are not responsible forthe content or functionality of any supporting materialssupplied by the authors. Any queries (other than missingmaterial) should be directed to the corresponding authorfor the article.

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