ORIGINAL ARTICLE

Systematic Review and Meta-analysis on the Effects of

Thiopurines on Birth Outcomes from Female and Male
Patients with Inflammatory Bowel Disease
Mona Akbari, MD, MPH,* Sveta Shah, MD,* Fernando S. Velayos, MD, MPH,† Uma Mahadevan, MD,†
and Adam S. Cheifetz, MD‡

Background: Inflammatory bowel disease (IBD) affects people during their prime reproductive years. The thiopurines (6-mercaptopurine and
azathioprine), commonly used for induction and maintenance of remission, are U.S. Food and Drug Administration (FDA) pregnancy category
D, raising concern for fetal risk. We performed a systematic review and meta-analysis to evaluate the effects of thiopurine exposure during preg-
nancy or at the time of conception on three measures of fetal risk in women and men with IBD.
Methods: A systematic search of PubMed and Web of Science using a combination of Mesh and text terms was performed to identify studies
reporting birth outcomes from IBD women and men exposed to thiopurines within 3 months of conception and/or during pregnancy. A meta-
analysis was performed using the random effects model to pool estimates and report odds ratio (OR) for three outcomes in women: low birth
weight (LBW), preterm birth, and congenital abnormalities and one in men: congenital abnormalities.
Results: In women with IBD exposed to thiopurines, the pooled ORs for LBW, preterm birth, and congenital abnormalities were 1.01 (95%
confidence interval [CI] 0.96, 1.06), 1.67 (95% CI 1.26, 2.20), and 1.45 (95% CI 0.99, 2.13), respectively. In men, the pooled OR for congenital
abnormality was 1.87 (95% CI 0.67, 5.25).
Conclusions: Thiopurine exposure in women with IBD was not associated with LBW or congenital abnormalities, but was associated with pre-
term birth. Exposure in men at the time of conception was not associated with congenital abnormalities.
(Inflamm Bowel Dis 2012;000:000–000)
Key Words: thiopurines, mercaptopurine, birth outcomes, congenital abnormalities, inflammatory bowel disease

I nflammatory bowel disease (IBD) most commonly

presents in young adults, during the childbearing years.
Thiopurines, 6-mercaptopurine (6-MP) and its prodrug, aza-
The U.S. Food and Drug Administration (FDA) clas-
sifies 6-MP and AZA as category D medications, indicating
that that while there may be fetal risk, the benefits from
thioprine (AZA), are commonly used to treat both Crohn’s use in pregnancy may be acceptable. Patients and physi-
disease (CD) and ulcerative colitis (UC). 6-MP and AZA cians struggle with the question of whether to continue thi-
are effective steroid-sparing agents and have been demon- opurines during this time period. Patients report fear of
strated to induce and maintain remission in patients with continuing medical therapy of their IBD during pregnancy,
IBD.1–9 in part due to fear of harm to the fetus.10,11 Physicians
struggle to balance potential reported risks to the fetus12–18
with the known benefits of therapy.
Additional Supporting Information may be found in the online version of this The risks to the fetus associated with thiopurine use
article. around the time of conception and during pregnancy are
Received for publication February 20, 2012; Accepted February 22, 2012.
From the *Department of Internal Medicine, Beth Israel Deaconess Medical not well characterized, and the literature is sparse. Studies
Center, Boston, Massachusetts, †Division of Gastroenterology, Center for Colitis are often small and outcomes rare, suggesting larger studies
and Crohn’s Disease, University of California, San Francisco, California,
‡
with sufficient sample size are needed and a systematic
Division of Gastroenterology, Center for Inflammatory Bowel Disease, Beth
review of available studies may help to identify consistent
Israel Deaconess Medical Center, Boston, Massachusetts.
Reprints: Adam S. Cheifetz, Center for IBD, Beth Israel Deaconess Medical trends. Prior meta-analysis has reported on birth outcomes
Center, 330 Brookline Ave., Rabb 425, Boston, MA 02215 (e-mail: acheifet@ for women with IBD compared to the general population.19
bidmc.harvard.edu). To our knowledge, there are no meta-analyses to date that
Copyright VC 2012 Crohn’s & Colitis Foundation of America, Inc.
compare birth outcomes for IBD patients exposed and not
DOI 10.1002/ibd.22948
Published online in Wiley Online Library (wileyonlinelibrary. exposed to thiopurines at conception and/or during preg-
com). nancy. Moreover, there is no pooled analysis that has

Inflamm Bowel Dis 1

Akbari et al Inflamm Bowel Dis

looked at thiopurine effects on men with IBD. The objective determination of exposure (case–control studies) or outcome
of this study was to conduct a systematic review and meta- (cohort studies). Studies are assigned points for various ques-
analysis to determine whether thiopurine exposure in women tions in each category and can have a maximum of nine points.
or men with IBD at the time of conception and/or during We considered greater than seven points as high quality.19
pregnancy is associated with adverse birth outcomes.
Statistical Analysis
MATERIALS AND METHODS In conducting and reporting our analysis, we followed
the consensus guidelines by the Meta-analysis of Observatio-
Search Strategy
nal Studies in Epidemiology group22 and the Preferred Report-
Two independent reviewers (M.A., S.S.) completed an
ing Items for Systematic Reviews and Meta-Analyses.23 Birth
online systematic search, from the institutional library, using
outcomes were reported as odds ratios (ORs), which represent
PubMed (National Center for Biotechnology Information) and
the odds of adverse outcomes for births exposed to thiopurines
Web of Science (Web of Knowledge), to identify all articles
compared to controls. Pooled ORs were calculated using the
published between 1960 and 2011 and written in English on
random effects model. The random effects model was used to
thiopurine use and birth outcomes in patients with CD or UC.
account for variations between studies and give a more con-
The following combination of Mesh and text terms was used
servative pooled estimate.24
in the search: Inflammatory Bowel Disease; Ulcerative Colitis;
When possible, maximally adjusted ORs for pregnancy
Crohn’s Disease; thiopurine; azathioprine; 6 mercaptopurine;
outcomes of individual studies were pooled. For studies that
premature birth; infant, low birth weight; congenital abnormal-
did not report ORs, 2
2 contingency tables were constructed
ities; and pregnancy. Studies that were not available online
based on reported outcomes and unadjusted ORs were calcu-
were retrieved by hand searches at the institutional library and
lated using Woolf’s method.25
references from the bibliographies of related articles were
The Q test was used to assess for heterogeneity and I2
crosschecked to find additional articles. All searches were
statistic to quantify the percentage of heterogeneity due to
completed by September 20 2011.
between-study variation.26 Funnel plots and the Egger’s test
were used to evaluate for publication bias.27 Given the limita-
Inclusion and Exclusion Criteria tions of pooling too few studies, we performed sensitivity
Studies had to meet the following inclusion criteria: 1) analyses only when three or more studies were available.
study population included patients with a diagnosis of IBD, Therefore, if only two studies provided results of interest, these
CD, and/or UC; 2) outcomes for thiopurine-exposed patients results were reported descriptively rather than a pooled analysis.
were compared to a reference group unexposed to thiopurines We sought to characterize effects of disease activity as well as
around the time of pregnancy; 3) exposed patients received study quality. Moreover, we performed two sensitivity analyses
AZA or 6-MP at the time of conception (defined as within 3 to test the robustness of our results. The first sensitivity analysis
months of conception or last menstrual period) and/or for any removed one study at a time to see if any one study was driv-
duration during pregnancy; and 4) studies reporting birth out- ing the results. The second sensitivity analysis included only
comes for either low birth weight (LBW), preterm birth, and/ larger studies with sample size (n) greater than 100 participants.
or congenital abnormalities. Significance levels were set at a P < 0.05. All statistical analy-
Studies that did not report outcomes for an IBD-only ses were performed using Stata (College Station, TX).
population or in which it was not possible to extract outcome
data from published results were excluded. Case reports,
series, review articles, and letters were also excluded. RESULTS
Studies Retrieved
Data Extraction Electronic and manual searches yielded 314 citations,
Information retrieved independently from each study, by of which 285 were eliminated on review of titles, abstracts,
two authors (M.A., S.S.), included: first author’s name, publi- and studies (Fig. 1). Of the remaining 29 citations, 22 stud-
cation date, study design, covariates used for matching or mul- ies were excluded because they did not distinguish between
tivariate analysis, method of IBD diagnosis, characteristics thiopurines and other immunomodulators, such as antitumor
and number of the thiopurine exposed and unexposed patients, necrosis factor a, there was incomplete information on birth
exposure assessment, and birth outcomes (LBW, preterm birth, outcomes reported, such that ORs for LBW, preterm birth,
and congenital abnormalities). and congenital abnormalities could not be calculated,10,28–36
there was inadequate control group,37–42 IBD-specific birth
Quality Assessment outcomes could not be determined,43,44 or they evaluated
We assessed study quality using the Newcastle Ottawa thiopurine use during breastfeeding45 or prior to 3 months of
Scale (NOS).20,21 The NOS assesses studies on three broad cat- conception.46 Three studies had overlapping popula-
egories: selection of study groups, comparability of groups, and tions12,47,48; thus, the most recent study was used.47 A total

2
Inflamm Bowel Dis Effects of Thiopurines on Birth Outcomes

Confounding was accounted for by matching52 and/or

multivariate analysis.47,51,52 Two of the five studies in
women attempted to control for disease activity using hospi-
talization as a surrogate marker.47,52 One of the three studies
in men excluded those with female partners who were
treated with immunomodulators for any indication,53 and
another study indicated that no female partners reported ill-
nesses or exposures to toxins during pregnancy.54 In estimat-
ing a pooled OR, we calculated unadjusted ORs from two
studies that reported events in cases and controls.49,50

Low Birth Weight

Five studies reported on the incidence of LBW for
pregnancies from mothers with IBD. LBW was defined as
less than 2500 g. Pooled analysis for the association
between thiopurine use and LBW was not statistically sig-
nificant (Fig. 2; OR 1.01, 95% confidence interval [CI]
0.96, 1.06; P ¼ 0.831). In the two studies that accounted
for disease activity, the association for LBW was not statis-
tically significant.47,52

Preterm Birth
Five studies reported on the incidence of preterm
birth, defined as gestational age less than 37 weeks, for
pregnancies from mothers with IBD. A statistically signifi-
cant difference was observed in pooled analysis for women
taking thiopurines (Fig. 3; OR 1.67; 95% CI 1.26, 2.20;
P < 0.001). In the two studies that accounted for disease
activity, the association between thiopurines and preterm
birth was not statistically significant in one, OR 2.28 (95%
FIGURE 1. Search and study selection process.
CI 0.67, 7.73),52 but was significant in the other, OR 4.2
(95% CI 1.4, 12.5).47
of seven studies met inclusion criteria; five measured thio-
Congenital Abnormalities
purine exposure in women47,49–52 and three in men.49,53,54
Pooled analysis for five studies that reported on
maternal thiopurine exposure and congenital defects was
Study Quality and Characteristics not statistically significant (Fig. 4; OR 1.45; 95% CI 0.99,
A total of 3045 women and 217 men with IBD were 2.13; P ¼ 0.055). The reported congenital defects for
identified as having eligible pregnancies. A detailed list of infants born to mothers on thiopurines were: hyperplastic
study quality and characteristics is shown in Table 1. Four heart (n ¼ 1),52 ventricular septal defect (n ¼ 2),51 atrial
studies described pregnancy outcomes in a population of CD septal defect (n ¼ 2),51 hydrocephalus (n ¼ 1),49 cataract
and UC females49–52 and one in a CD-only female popula- (n ¼ 2),47,50 cervical angioma (n ¼ 1),50 encephalocele
tion.47 Three studies were performed in a population of men (n ¼ 1),47 sternocleidomastoid malformation (n ¼ 1),47
with CD and UC.49,53,54 Studies identified IBD patients congenitae aliae cutis (n ¼ 1),47 and others (n ¼ 16). The
and treatment exposure through medical records,49,52–54 association between thiopurines and congenital defects
national registries,47,51 nationwide prescription databases,47 were not significant in the two studies that accounted for
interviews,49,51,53 and questionnaires.50,53 Birth outcomes disease activity.47,52
were identified by medical records,52,53 international classifi- Three studies reported on congenital defects in
cation of disease codes from national registries,47,51 inter- infants born to fathers on thiopurines. Pooled analysis for
views,49,53,54 and questionnaires.50,53 The exposure included: congenital anomalies was not statistically significant
AZA or 6-MP,47,52,53 AZA only,51 6-MP only,49,54 and ‘‘thi- (Fig. 5; OR 1.87; 95% CI 0.67, 5.25; P ¼ 0.236). The con-
opurines.’’50 All but one study50 were retrospective case– genital abnormalities reported for infants born to fathers
control studies by design. taking thiopurines were: interauricular communication with

3
Akbari et al Inflamm Bowel Dis

TABLE 1. Study Characteristics

Maternal Exposure to Thiopurines
Pregnancies Covariates for
Publication Study Patients with UC CD Exposed to Multivariate Analysis Study
First Author Year Design IBD (n) Patients (n) Patients (n) AZA/6-MP (n) or Matching Quality

Francella 2003 R 79 24 55 39 1, 2a ***

Norgard 2007 R 648b — 648 20 2-5 *******
Cleary 2009 R 2051 NS NS 324 2, 5-8 *****
Coelho 2010 P, R 204d 44 155 86 None ****
Shim 2011 R 63 NS NS 19 2, 4, 5, 7, 9-16a *****
Paternal Exposure to Thiopurines
Francella 2003 R 76 27 49 37 1, 2a ***
Rajapakse 2000 R 57 23 34 13 None ****
Teruel 2010 R 84 NS NS 46 7, 11, 17-18a ****
a
Studies do not provide adjusted ORs for outcomes: LBW, preterm, and/or congenital anomalies.
b
Total number of births.
c
Number of women with IBD exposed to thiopurines only.
d
Five patients were ‘‘IBD unclassified.’’
NS: Not specified; R: Retrospective; P: Prospective.
Study quality is derived from the Newcastle Ottawa scale and takes on values of one star (lowest quality) to nine stars (highest quality).
Covariates for matching or multivariate analysis: 1, Gender of affected parent; 2, Mother’s age; 3 Disease activity; 4, Gestational age; 5, Parity; 6, Body
mass index; 7, Smoking; 8, Year of birth; 9, Mode of delivery; 10, Corticosteroids; 11, 5-ASA; 12, Hospitalization; 13, Low birth weight; 14, Preterm
birth; 15, Neonatal adverse outcomes; 16, Congenital anomalies; 17, Father’s age; 18, Sulfasalazine.

persistent ductus arteriosus (n ¼ 1),53 missing thumb (n ¼ driving the pooled ORs for LBW, preterm birth, and con-
1),54 multiple anomalies (n ¼ 1),54 and meningomyelocele genital abnormalities (results not shown). The second sensi-
(n ¼ 1).49 tivity analysis, which analyzed three studies with greater
than 100 female patients with IBD, showed results that
Sensitivity Analysis were consistent with the overall pooled results. Thiopurine
The first sensitivity analysis, in which one study was exposure was not associated with LBW (OR 1.29, 95% CI
removed at a time, did not suggest that any one study was 0.93, 1.79; P ¼ 0.129) or congenital abnormalities (OR

FIGURE 2. Forest plot for maternal thiopurine use and LBW, includ- FIGURE 3. Forest plot for maternal thiopurine use and preterm
ing all studies. The OR for LBW and maternal thiopurine use, 95% birth, including all studies. The OR for LBW and maternal thiopur-
CIs for each study, and pooled analysis from a random-effects ine use, 95% CIs for each study, and pooled analysis from a ran-
model are depicted on a logarithmic scale. The lateral points of dom-effects model are depicted on a logarithmic scale. The lateral
the diamond provide the confidence interval for the combined points of the diamond provide the confidence interval for the com-
estimate. bined estimate.

4
Inflamm Bowel Dis Effects of Thiopurines on Birth Outcomes

unclear. Disease activity has been associated with negative

fetal outcomes in a number of reports.55–59 One study dem-
onstrated that 27% of births from IBD females with disease
flares were preterm, compared to 8% of births from women
without flares, P ¼ 0.02.55 Similarly, in another study pre-
term birth occurred more frequently in IBD women hospi-
talized for disease flare (70%) compared to those not hospi-
talized (7.3%), P < 0.0001.59
It is likely that mothers treated with thiopurines lead-
ing up to and at the time of conception had more severe or
active IBD than the patients from control groups. In the
study by Shim et al,52 31.6% thiopurine-exposed births and
12.2% unexposed births were from women hospitalized for
IBD flare (P < 0.001), indicating to a degree that patients
on thiopurines had more flares. In this study, 50% of
FIGURE 4. Forest plot for maternal thiopurine use and congenital
anomalies, including all studies. The OR for LBW and maternal thio-
patients on thiopurines were treated with adjunctive corti-
purine use, 95% CIs for each study, and pooled analysis from a ran- costeroids, but only a third of them were hospitalized for
dom-effects model are depicted on a logarithmic scale. The lateral flares. Therefore, it is possible that mild to moderate dis-
points of the diamond provide the confidence interval for the com-
bined estimate.
ease flares managed in an outpatient setting would not be
captured by the use of ‘‘hospitalization’’ as a surrogate for
disease activity and thus underestimate disease activity. In
1.48, 95% CI 0.85, 2.60, P ¼ 0.170), but was associated
our meta-analysis, only two studies accounted for disease
with preterm birth (OR 1.72, 95% CI 1.04, 2.84, P ¼
activity and did so using hospital admissions during preg-
0.035). Sensitivity analyses on studies accounting for dis-
nancy as a surrogate. Since only two studies accounted for
ease activity as well as study quality were not performed,
disease activity, we did not provide pooled results.
as there were too few studies in each group.
Although one study still demonstrated that thiopurine expo-
sure increased the risk of preterm birth,47 the other did not
Publication Bias and Heterogeneity find a significant effect.52 Both studies still may be under-
Funnel plots are shown for overall analyses in Sup- estimating disease activity.
porting Figures 1–3. Studies remained within the 95% CI Meta-analyses can improve the precision of effect
limits. While there was some potential asymmetry for LBW estimate and increase the power to see a difference that is
graphically visualized the Egger’s test for asymmetry was not readily identified by small studies.60 Of the seven
not significant (P ¼ 0.929). The funnel plots for preterm
birth (P ¼ 0.326) and congenital anomalies (P ¼ 0.933) did
not show evidence of asymmetry and publication bias. There
was no evidence of heterogeneity amongst studies.

DISCUSSION
This study provides a unique review of the literature,
as well as estimates across studies to assess birth outcomes
from women and men with IBD on AZA or 6-MP. Our
results suggest thiopurine exposure at the time of conception
and/or during pregnancy in women and men with IBD are
not associated with increased infant congenital anomalies.
Maternal thiopurine exposure was not associated with LBW,
but was associated with increased odds of preterm births.
Thiopurine use in women was associated with approximately
a 70% increased odds of preterm births. Our findings
remained consistent in subsequent sensitivity analyses.
In our analysis, preterm birth was the only outcome FIGURE 5. Forest plot for paternal thiopurine use and congenital
that was significantly associated with thiopurines. Whether anomalies. The OR for LBW and maternal thiopurine use, 95% CIs
for each study, and pooled analysis from a random-effects model
this association is secondary to the use of thiopurines or are depicted on a logarithmic scale. The lateral points of the dia-
that thiopurines are a marker for more severe disease is mond provide the confidence interval for the combined estimate.

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Akbari et al Inflamm Bowel Dis

studies included in this analysis, only three had more than Although multivariate analysis can be difficult when small
100 subjects with IBD. As such, we selected meta-analysis numbers exist in each category, confounders such as con-
as the approach to study the question of birth outcomes current medication therapy and IBD disease activity are
and thiopurine use. We included studies in which the important to consider when evaluating birth outcomes.
exposed and comparison groups comprised of births from Moreover, none of the studies provided adequate informa-
only an IBD population, since IBD itself can increase the tion on medication duration or dose per day to determine a
risk of adverse birth outcomes, including LBW and preterm dose–response relationship between thiopurines and birth
birth.19,61–68 We chose to analyze only IBD cases since the outcomes. Studies also did not provide outcomes for thio-
question of interest is whether to stop or continue the thio- purine exposure by trimester, to assess risks to fetus during
purine, not whether having IBD confers a higher risk of different stages of fetal development. Future, larger pro-
adverse birth outcomes. spective studies that adjust for confounders such as disease
Based on two sensitivity analyses, our results are not activity are needed to evaluate these questions.
changed by undue influence of any one study alone or by
larger studies (n > 100). It is important to highlight the rel- CONCLUSIONS
atively small number of pregnancies exposed to thiopurines In summary, we found that thiopurine use at the time
in each study. The study by Cleary and Kallen51 reported a of conception and/or during pregnancy in women with IBD
disproportionately larger number of pregnancies that were is not associated with LBW or congenital abnormalities,
exposed to thiopurines. However, our sensitivity analysis but is associated with preterm birth. Men with IBD
does not suggest that the findings from the Cleary and exposed to thiopurines at the time of conception are not at
Kallen study significantly changed the results. Moreover, in increased risk for infants with congenital abnormalities.
an effort to detect publication bias the Egger’s test did not Larger, prospective studies that adequately identify expo-
demonstrate significance. We also did not find significant sure and outcomes as well as appropriately adjust for
heterogeneity that would limit interpretation of a pooled potential confounders, such as disease activity, are needed
analysis. to confirm these findings.
6-MP and AZA are classified as category D, medica-
tions that have potential fetal risk but benefits from use in ACKNOWLEDGMENTS
pregnancy may be acceptable. Under consideration is a Authors contributions: M.A.: study design, drafting
proposal to remove the general global letter grading system of the article, analysis and interpretation of data; critical re-
that summarizes risk vs. benefit in favor of a more trans- vision of the article for important intellectual content of
parent narrative that includes a risk summary, clinical con- the article; S.S.: analysis and interpretation of data; critical
siderations, and a data section. We have provided an over- revision of the article for important intellectual content of
all pooled estimate of risk for the three outcomes of the article; U.M.: interpretation of data; critical revision of
interest as well as detailed information on congenital the article for important intellectual content of the article;
anomalies that could prove helpful in discussing the use of F.S.V.: interpretation of data; critical revision of the article
6-MP and AZA during pregnancy. for important intellectual content of the article; A.S.C.:
Known limitations of meta-analyses include quality study concept and design, acquisition of data, analysis and
of the original studies. A number of studies relied on inter- interpretation of data; critical revision of the article for
views, questionnaires, and/or self-report for pregnancy out- important intellectual content of the article.
comes49,50 and thiopurine exposure50,54 without mention of
reference to primary records. These may not be the most
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