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Develop an Annotated Bibliography for Use in Your Research Paper
Include the following in your annotated bibliography:
about 3 peer reviewed references
· APA citations and annotations for three (3) sources you deem relevant to your problem statement (thesis).
For each source:
· Cite the source in proper APA format. The citations should be organized in alphabetical order by author as in an APA References page.
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Simon et al. Arthritis Research & Therapy (2015) 17:212
DOI 10.1186/s13075-015-0728-9
RESEARCH ARTICLE Open Access
Incidence of malignancy in adult patients
with rheumatoid arthritis: a meta-analysis
Teresa A. Simon1*, Adam Thompson1, Kunal K. Gandhi1, Marc C. Hochberg2 and Samy Suissa3
Abstract
Introduction: Patients with rheumatoid arthritis (RA) are at an increased risk of malignancies compared with the
general population. This has raised concerns regarding these patients, particularly with the widespread use of
immunomodulating therapies, including biologic disease-modifying antirheumatic drugs (DMARDs). We performed
a systematic literature review and analysis to quantify the incidence of malignancies in patients with RA and the
general population to update previously published data.
Methods: A literature search was conducted that was consistent with and similar to that in a meta-analysis
published in 2008. MEDLINE, BIOSIS Previews, Embase, Derwent Drug File and SciSearch databases were searched
using specified search terms. Predefined inclusion criteria identified the relevant observational studies published
between 2008 and 2014 that provided estimates of relative risk of malignancy in patients with RA compared with
the general population. Risk data on overall malignancy and site-specific malignancies (lymphoma, melanoma and
lung, colorectal, breast, cervical and prostate cancer) were extracted. The standardized incidence ratios (SIRs; a
measure of risk) relative to the general population were evaluated and compared with published rates.
Results: A total of nine publications met the inclusion criteria. Seven of these reported SIRs for overall malignancy;
eight for lymphoma, melanoma, and lung, colorectal and breast cancer; seven for prostate cancer; and four for
cervical cancer. Compared with those in the general population, the SIR estimates for patients with RA suggest a
modest increased risk in overall malignancy, as previously observed. Patients with RA continued to show an increased
risk of lymphoma and lung cancer compared with the general population. Overall, SIR estimates for colorectal and
breast cancers continued to show a decrease in risk, whereas cervical cancer, prostate cancer and melanoma appeared
to show no consistent trend in risk among patients with RA compared with the general population.
Conclusions: The additional data evaluated here are consistent with previously reported data. Patients with RA are at
an increased risk of lung and lymphoma malignancies compared with the general population. Quantifying differences
in malignancy rates between non-biologic and biologic DMARD-treated patients with RA may further highlight which
malignancies may be related to treatment rather than to the underlying disease.
Introduction
Rheumatoid arthritis (RA) is a polygenic, multifactorial
and chronic immune-mediated disease characterized by
chronic joint inflammation, a predilection for develop-
ment of joint damage and deformity, and extraarticular
involvement [1]. The management of RA includes the
use of biologic and non-biologic disease-modifying anti-
rheumatic drugs (DMARDs) [2, 3], which act by directly
modifying immunologic pathways involved in the patho-
genesis of RA. The risk of malignancy among patients
* Correspondence: teresa.simon@bms.com
1Bristol-Myers Squibb, Princeton, NJ, USA
Full list of author information is available at the end of the article
© 2015 Simon et al. Open Access This articl
International License (http://creativecommo
reproduction in any medium, provided you
link to the Creative Commons license, and
Dedication waiver (http://creativecommons
article, unless otherwise stated.
with RA has been of ongoing interest and research be-
cause of the autoimmune pathogenesis that underlies
RA, the common etiology between rheumatic disease
and malignancy, and the use of immunomodulatory
therapy, such as DMARDs, that may alter normal immu-
nosurveillance and elevate the risk of malignancy [4, 5].
Understanding this potential therapeutic risk has be-
come more relevant with the increasing use of biologic
DMARDs as a routine therapeutic approach to RA man-
agement [3]. With more biologic treatment options avail-
able and initiation of biologic treatments occurring earlier,
it is important to understand the baseline risk of malig-
nancies in patients with RA. Furthermore, continuous
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Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 2 of 10
updates on the incidence of malignancies published in the
literature are crucial to allow better understanding of the
background rates for malignancy in clinical trials and ob-
servational research evaluating real-world practice.
Smitten et al. [6] performed a meta-analysis on the
risk of overall malignancy and several site-specific can-
cers, including overall lymphoma, Hodgkin disease, non-
Hodgkin lymphoma, lung cancer, colorectal cancer and
breast cancer, using data published between 1990 and
2007. Their meta-analysis suggested a small overall in-
crease in risk of malignancy, which was elevated for
lymphoma, Hodgkin disease, non-Hodgkin lymphoma
and lung cancer, but they found a decreased risk of colo-
rectal and breast cancer in patients with RA compared
with the general population [6]. The malignancies in-
cluded were prespecified and based on the most fre-
quently reported malignancies in an RA population.
In this article, we review the data on the incidence of
malignancy reported since the Smitten et al. [6] meta-
analysis and additionally evaluate the risk of other im-
portant site-specific malignancies, namely, melanoma,
cervical cancer and prostate cancer, which have been a
topic of discussion in recent publications [7–9].
Methods
Literature search
We conducted a search of the MEDLINE, BIOSIS
Previews, Embase, Derwent Drug File and SciSearch
databases for literature published between 1 January 2008
and 30 November 2014, using the following specified
search terms: cancer or tumor, tumour, malign* and rheu-
matoid arthritis or RA, and epidemiolog* or inciden*,
population, observation, retrospective or occurren*.
Exclusion algorithm
Predefined inclusion criteria were used to identify rele-
vant observational studies that provided estimates of
relative risk of malignancy in patients with RA compared
with the general population. The same criteria as de-
tailed by Smitten et al. [6] were applied. Studies were eli-
gible for inclusion if they fulfilled the following criteria:
(1) observational study design (including prospective,
retrospective, epidemiologic, database, survey, registry,
cohort and case–control), (2) reported malignancy out-
comes in patients with RA and a general population, (3)
enrolled more than 100 patients, (4) included only
patients older than 18 years of age, (5) covered any
geographic region and (6) were reported in English as a
full-length publication. Citations meeting the inclusion
criteria were obtained and screened for the outcomes of
interest, which included the observed incidence rates of
total malignancy and lymphoma, lung, colorectal, breast,
melanoma, prostate and cervical cancers in patients with
RA compared with the expected incidence rates in the
general population. Lymphoma was reported as Hodgkin
or non-Hodgkin where available. The selection of studies
for inclusion was made without regard to evaluation of
specific RA management strategies. We attempted to
avoid overlap by excluding studies for which updated
publications were available. We also excluded studies
that compared specific RA biologic treatments with
other RA treatments, unless overall RA and general
population rates were reported.
Data presentation
Citations meeting the inclusion criteria were screened for
outcomes of interest. Risk data on overall malignancy and
site-specific malignancies (overall lymphoma, Hodgkin
disease, non-Hodgkin lymphoma, melanoma, and lung,
colorectal, breast, cervical and prostate cancers) were
extracted independently by two people and compared for
accuracy. Study-specific estimates of relative risk were
measured mostly by overall and age- and sex-adjusted
standardized incidence ratios (SIRs) relative to non-RA
patients or the general population. In one study using a
case–control approach, researchers reported an odds
ratio, which is an accurate estimator of the relative risk
[10]. Thus, all measures of relative risk and their res-
pective 95 % confidence intervals (CIs) were then com-
pared with previously published rates. Pooled relative risks
and 95 % CIs were then computed using the DerSimonian
and Laird technique [11], in which a random-effects
model takes into consideration both within-study and
between-studies variation by incorporating the hetero-
geneity of the effects in the overall analysis. Some studies
in which authors reported data separately for colon and
rectal cancer, or for men and women, were considered
separate studies when we pooled relative risks.
Results
A total of 136 articles were identified using the defined
search criteria (Fig. 1). Following identification, a total of
33 potential publications were further analyzed; of these, 9
studies met all the inclusion criteria (Fig. 1) [10, 12–19].
These studies included population- and community-based
RA cohorts, examined data from 458 to 84,475 patients
and had mean follow-up periods ranging from 4 to
25 years. The relative risk of overall malignancy was
reported in seven studies [12–15, 17–19]; lymphoma
(overall lymphoma, Hodgkin disease or non-Hodgkin
lymphoma), lung, colorectal and breast cancers and mel-
anoma in eight [10, 12–17, 19]; prostate cancer in seven
[10, 12–17]; and cervical cancer in four [12, 14, 16, 17].
Overall risk by malignancy type was reported in eight
studies [10, 12–17, 19], both overall risk and risk by sex
were reported in three [15, 17, 18] and risk stratified by
sex only was reported in one [16].
136 publicatio ns identified
129 unique publications
1
21 publications
–7 duplicate publications
61 publications
33 publications
21 publications
15 publications
11 publications
10 publications met inclusion criteria
(1 publication was previously cited in
Smitten et al. [6] as in press and
therefore was not included)
–8 non-English publications
–60 not full manuscript publication s (i.e. meeting abstracts)
–28 not observational-type studies (i.e. reviews, meta-analyses, case reports)
–12 did not compare data to general population
–6 did not report malignancy outcome s
–4 did not report incidence data
–1 reported malignancy not evaluated in this publication
Fig. 1 Literature search data
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 3 of 10
Overall malignancies
In general, SIRs for overall malignancy across the studies
were similar. Six of seven studies reported a significant in-
crease in overall risk of malignancy (Fig. 2) [12–15, 17–32].
The total pooled SIR (95 % CI) for studies analyzed by
Smitten et al. (1.05 [1.01–1.09]) [6] and those included
here was significant: 1.09 (1.06–1.13). With the addition of
the newer studies, there was no change in the overall sum-
mary statistic showing that patients with RA have a 10 %
increase in overall malignancy risk compared with the
general population.
Lymphoma
In eight studies, authors reported outcomes as either
overall lymphoma, Hodgkin disease or non-Hodgkin
lymphoma [10, 12–17, 19]. Two studies reported only
lymphoma, whereas the remaining six studies reported
overall lymphoma, Hodgkin disease and non-Hodgkin
lymphoma rates, with all of the new studies reporting a sig-
nificant increase in risk of lymphoma in patients with RA
compared with the general population (Figs. 3, 4 and 5).
This ranged from almost a doubling (SIR 1.75) (Fig. 3)
[10, 15, 17, 21, 23, 24, 29, 30, 33] to a 12-fold increase
(SIR 12.82) (Fig. 4) [12, 14–16, 19, 22, 24, 25, 27–29, 34, 35]
in the risk of developing lymphoma. The pooled SIR for
Hodgkin disease (Fig. 4) was higher than for non-Hodgkin
lymphoma (Fig. 5) [12–16, 19, 20, 22, 24, 25, 27–29, 34–36].
The total pooled SIR (95 % CI) for the studies reviewed
here and by Smitten et al. [6] was 2.46 (2.05–2.96) for ma-
lignant lymphoma, 3.21 (2.42–4.27) for Hodgkin disease
and 2.26 (1.82–2.81) for non-Hodgkin lymphoma. The
overall risk with the addition of the new studies is con-
sistent with previously reported SIRs (2.08 [1.80–2.39],
3.29 [2.56–4.22] and 1.95 [1.70–2.24], respectively) [6];
however, a slight increase in risk for non-Hodgkin disease
was noted.
Lung cancer
In eight studies, authors reported that patients with RA
had an increased risk of lung cancer compared with the
general population [10, 12–17, 19]. The SIRs (95 % CI) for
lung cancer ranged from 1.36 (1.34–1.38) to 2.9 (1.6–4.8)
(Fig. 6) [10, 12–17, 19–22, 24–28, 32, 36–38]. The total
pooled SIR (95 % CI) for the studies reviewed here and by
Smitten et al. [6] was 1.64 (1.51–1.79) for lung cancer.
The risk of lung cancer in patients with RA compared
Source n/N
SIR (95% CI)
Matteson 1991 (DMARDs) [32] 20/530 1.52 (0.90, 2.6)†
Gridley 1993 [24] 840/11,683 0.95 (0.9, 1.0)
Moritomo 1995 [26] 26/655 1.38 (0.90, 2.02)
Kauppi 1996 [31] 540/9469 1.16 (1.07, 1.26)
Mellemkjaer 1996 [25] 1832/20,699 1.08 (1.03, 1.13)§
Cibere1997 [22] 136/862 0.8 (0.67, 0.95)
Thomas 2000 [27] 2029/26,623 1.01 (1.0, 1.1)
Ekstrom 2003 [29] 8896/76,527 1.07 (1.05, 1.09)
Askling 2005 [21] 3379/53,067 1.05 (1.01, 1.08)
Askling 2005 (early RA) [21] 138/3703 1.1 (0.9, 1.3)‡
Askling 2005 (anti-TNF) [21] 67/4160 0.9 (0.7, 1.2)‡
Geborek 2005 [30] 69/800 1.4 (1.1, 1.8)‡
Geborek 2005 (anti-TNF) [30] 16/757 1.1 (0.6, 1.8)
Abasolo 2007 [20] 25/789 1.2 (0.8, 1.8)†
Franklin 2007 [23] 92/1237 1.1 (0.9, 1.3)†
Wolfe 2007 [28] 543/13,869 1.0 (1.0, 1.1)†
Buchbinder 2008 [19] 64/458 1.5 (1.2, 1.9)
Hemminki 2008 [14] 4366/42,262 1.23 (1.19, 1.27)
Chen 2011 [12] 935/23,644 1.12 (1.11, 1.13)
Yamada 2011 [17] 173/7566 1.18 (1.02, 1.37)
Female* 1.13 (0.94, 1.36)
Male* 1.29 (0.99, 1.67)
Kim 2012 [18] 30/1501 0.86 (0.58, 1.23)
Female* 0.99 (0.65, 1.42)
Male* 0.31 (0.04, 1.11)
Dreyer 2013 [13] 128/3812 1.25 (1.05, 1.48)
Mercer 2013 [15] 182/3771 1.28 (1.10, 1.48)
Female* 1.38 (1.15, 1.64)
Male* 1.11 (0.85, 1.44)
Total pooled SIR 23 1.09 (1.06, 1.13)
0.1 10.01.0
New studies
Fig. 2 Relative risk of overall malignancy in patients with rheumatoid arthritis (RA) compared with the general population. CI, confidence interval;
DMARD, disease-modifying antirheumatic drug; n, number of malignancies; N, population size; RR, relative risk; SIR, standardized incidence ratio;
TNF, tumor necrosis factor. *SIRs by sex are not included in the total pooled SIR. †Excluding non-melanoma skin cancer. ‡All solid tumors. §Excluding
lymphatic and hematopoietic
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 4 of 10
with the general population in the contemporary study
is consistent with what was previously observed (1.63
[1.43–1.87]) [6].
Colorectal cancer
In seven studies [12, 14–17, 19], authors reported that
patients with RA had a decreased risk of colon or
colorectal cancer, with SIRs (95 % CI) ranging from
0.49 (0.26–0.83) to 0.96 (0.56–1.54) (Fig. 7) [10, 12–17,
19–22, 24–28, 31, 36]. However, in some studies, authors
reported SIRs >1, with the highest being 1.53 (0.69–3.42)
Source n/N
Gridley 1993 [24] 48/11,683
Ekstrom 2003 [29] 535/76,527
Askling 2005 [21] 319/53,067
Askling (early RA) [21] 11/3703
Askling 2005 (anti-TNF) [21] 9/4160
Geborek 2005 [30] 2/800
Geborek 2005 (anti-TNF) [30] 5/757
Franklin 2007 [23] 9/1237
Wolfe 2007 [33] 95/19,591
Hellgren 2010† [10] 19/6745
Yamada 2011 [17] 20/7566
Female*
Male*
Mercer 2013 [15] 21/3771
Female*
Male*
Total pooled SIR 12
0
New studies
Fig. 3 Relative risk of malignant lymphoma in patients with rheumatoid ar
interval; n, number of malignancies; N, population size; OR, odds ratio; SIR,
are not included in the total pooled SIR. †Reported as odds ratio
for rectal cancer [10, 13]. For colorectal cancer, the total
pooled SIR (95 % CI) for the studies reviewed by Smitten
et al. (0.77 [0.65–0.90]) [6] plus those included here was
0.78 (0.71–0.86).
Breast cancer
For breast cancer, there was generally no increase in
risk; estimated risk varied from 0.63 to 1.21 in the new
studies [10, 12–17, 19] (Fig. 8) [10, 12–17, 19–22,
24–28, 36]. The total pooled SIR (95 % CI) for the
studies reviewed by Smitten et al. (0.84 [0.79–0.90]) [6]
SIR (95% CI)
1.75
1.98 (1.5, 2.6)
2.00 (1.83, 2.17)
1.9 (1.7, 2.1)
2.0 (1.1, 3.5)
2.9 (1.3, 5.5)
1.3 (0.2, 4.5)
11.5 (3.7, 26.9)
2.94 (1.34, 5.57)
1.8 (1.5, 2.2)
(1.04, 2.96)
6.07 (3.71, 9.37)
6.00 (3.28, 10.07)
6.22 (2.28, 13.54)
3.81 (2.36, 5.82)
3.73 (1.98, 6.37)
3.95 (1.71, 7.79)
2.46 (2.05, 2.96)
30.01.0
thritis (RA) compared with the general population. CI, confidence
standardized incidence ratio; TNF, tumor necrosis factor. *SIRs by sex
Parikh-Patel 2009 [16]
Source n/N SIR (95% CI)
Gridley 1993 [24] 12/11,683 2.34 (1.2, 4.1)
Mellemkjaer 1996 [25] 14/20,699 3.4 (1.8, 5.6)
Cibere 1997 [22] 0/862 0.0 (0.00, 8.53)
Kauppi 1997 [34] 4/9469 2.2 (0.6, 5.7)
Thomas 2000 [27] 17/26,623 3.85 (2.2, 6.2)
Mariette 2002 (MTX) [35] 7/30,000 7.4 (3.0, 15.3)
Ekstrom 2003 [29] 77/76,527 3.06 (2.42, 3.83)
Wolfe 2007 [28] 4/13,869 3.0 (1.3, 6.8)
Buchbinder 2008 [19] 1/458 8.9 (0.2, 49.8)
Hemminki 2008 [14] 35/42,262 4.05 (2.82, 5.63)
25/84,475
Female* 1.62 (0.91, 2.68)
Male* 2.76 (1.32, 5.08)
Chen 2011 [12] 1/23,644 1.76 (1.45, 2.17)
Mercer 2013 [15] 5/3771 12.82 (4.16, 29.92)
Total pooled SIR 14 3.21 (2.42, 4.27)
0 50.01.0
New studies
Fig. 4 Relative risk of Hodgkin disease in patients with rheumatoid arthritis (RA) compared with the general population. CI, confidence interval;
n, number of malignancies; N, population size; MTX, methotrexate; SIR, standardized incidence ratio. *SIRs by sex for Parikh-Patel et al. [16] are included
in the total pooled SIR, as overall SIR was not available in their study
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 5 of 10
plus those included here was found to be 0.86 (0.73–1.01)
for breast cancer.
Melanoma and cervical and prostate cancers
As previously noted, we included three additional malig-
nancies (melanoma and cervical and prostate cancer) in
our assessment that were not included in the Smitten
et al. meta-analysis [6]. Figs. 9, 10 and 11 highlight the ar-
ticles analyzed by Smitten et al. [6] and the newer studies
included in our assessment. For melanoma, we reviewed
17 studies (9 from Smitten et al. [20–22, 24–28, 36] and 8
new [10, 12–17, 19]). Of these, the overall range of SIRs
was 0.3–8.83, and five studies [12, 14, 19, 28, 36] showed a
significant increase in the risk of melanoma in the RA
population, ranging from 1.29 to 3.0 (Fig. 9) [10, 12–17,
19–22, 24–28, 36]. The total pooled SIR was 1.23 (1.01–
1.49).
For cervical cancer, SIRs were reported in a total of 13
studies (nine from Smitten et al. [20–22, 24–28, 36] and
Source n/N
Gridley 1993 [24] 36/11,683
Mellemkjaer 1996 [25] 85/20,699
Cibere 1997 [22] 3/862
Kauppi 1997 [34] 34/9469
Mariette 2002 [35] 18/30,000
Thomas 2000 [27] 101/26,623
Ekstrom 2003 [29] 458/76,527
Setoguchi 2006 (DMARDs) [36] 58/7830
Abasolo 2007 [20] 3/789
Wolfe 2007 [28] 42/13,869
Buchbinder 2008 [19] 8/458
Hemminki 2008 [14] 280/42,262
Parikh-Patel 2009 [16] 325/84,475
Female*
Male*
Chen 2011 [12] 59/23,644
Dreyer 2013 [13] 5/3812
Mercer 2013 [15] 16/3771
Female*
Male*
Total pooled SIR 17
0.1
New studies
Fig. 5 Relative risk of non-Hodgkin lymphoma in patients with rheumatoid
interval; DMARD, disease-modifying antirheumatic drug; n, number of malig
sex included in total pooled SIR only if overall SIR was not available
four new [12, 14, 16, 17]). Overall, the range of SIRs was
0.43–2.15, and all confidence intervals were overlapping
(Fig. 10) [12, 14, 16, 17, 20–22, 24–28, 36]. In three
studies, authors reported a significant decrease in risk
compared with the RA population [12, 16, 36]. The total
pooled SIR for cervical cancer was 0.87 (0.72–1.05). For
prostate cancer, SIRs were reported in a total of 15
studies (8 from Smitten et al. [20–22, 24, 25, 27, 28, 36]
and 7 new [10, 12–17]). Overall, the range of SIRs was
0.35–3.20, and the total pooled SIR was 1.15 (0.98–1.34)
(Fig. 11) [10, 12–17, 20–22, 24, 25, 27, 28, 36].
Discussion
Although individual studies can show considerable vari-
ation, the results of this updated meta-analysis of the
incidence of malignancy in adult patients with RA are
generally consistent with previously reported data for all
specific malignancies [6]. The updated data reported here
show that patients with RA have a modest increased risk
SIR (95% CI)
1.88 (1.3, 2.6)
2.4 (1.9, 2.9)
0.55 (0.11, 1.60)
2.2 (1.5, 3.1)
1.07 (0.6, 1.7)
2.13 (1.7, 2.6)
1.89 (1.72, 2.07)
2.2 (1.71, 2.87)
5.4 (1.1, 15.7)
1.7 (1.3, 2.2)
5.1 (2.2, 10.0)
2.34 (2.07, 2.63)
1.37 (1.19, 1.57)
2.07 (1.71, 2.48)
3.54 (3.45, 3.63)
2.27 (0.94, 5.45)
3.12 (1.79, 5.07)
3.39 (1.69, 6.07)
2.66 (0.86, 6.21)
2.26 (1.82, 2.81)
20.01.0
arthritis (RA) compared with the general population. CI, confidence
nancies; N, population size; SIR, standardized incidence ratio. *SIRs by
0.1 50.01.0
Source n/N SIR (95% CI)
Matteson 1991 (DMARDs) [32] 6/530 3.37 (1.58, 7.34)
McKendry 1993 (MTX) [37] 4/144 12.4 (3.38, 31.84)
Gridley 1993 [24] 68/11,683 1.31 (1.0, 1.7)
Mo ritomo 1995 [26] 0/655 0 (0, 1.82)
Kauppi 1996 [38] 73/8920 1.8 (1.4, 2.2)
Mellemkjaer 1996 [25] 308/20,699 1.5 (1.3, 1.7)
Cibere 1997 [22] 16/862 1.08 (0.61, 1.75)
Thomas 2000 [27] 472/26,623 1.39 (1.3, 1.5)
Askling 2005 [21] 330/53,067 1.48 (1.33, 1.65)
Askling 2005 (early RA) [21] 23/3703 2.4 (1.5, 3.6)
Askling 2005 (anti-TNF) [21] 10/4160 1.8 (0.9, 3.3)
Setoguchi 2006 [36] 169/7830 1.8 (1.52, 2.05)
Abasolo 2007 [20] 7/789 3.5 (1.4, 7.1)
Wolfe 2007 [28] 112/13,869 1.2 (1.0, 1.4)
Buchbinder 2008 [19] 14/458 2.9 (1.6, 4.8)
Hemminki 2008 [14] 448/42,262 1.73 (1.57, 1.89)
Parikh-Patel 2009 [16] 1178/84,475
Female* 1.28 (1.19, 1.38)
Male* 1.65 (1.49, 1.81)
Hellgren 2010† [10] 34/6745 2.24 (1.49, 3.36)
Chen 2011 [12] 123/23,644 1.36 (1.34, 1.38)
Ya mada 2011 [17] 34/7566 2.29 (1.57, 3.21)
Female* 1.66 (0.89, 2.85)
Male* 3.02 (1.85, 4.67)
Dreyer 2013 [13] 20/3812 1.67 (1.08, 2.59)
Mercer 2013 [15] 46/3771 2.39 (1.75, 3.19)
Female* 2.66 (1.79, 3.80)
Male* 2.01 (1.15, 2.36)
Total pooled SIR 23 1.64 (1.51, 1.79)
New studies
Fig. 6 Relative risk of lung cancer in patients with rheumatoid arthritis (RA) compared with the general population. CI, confidence interval;
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; n, number of malignancies; N, population size; SIR, standardized incidence
ratio; TNF, tumor necrosis factor. *SIRs by sex are included in total pooled SIR only if overall SIR was not available. †Reported as odds ratio
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 6 of 10
of overall malignancy as well as an increased risk of lung
cancer and lymphoma when compared with the general
population. Lymphoma was associated with the greatest
relative risk, especially Hodgkin disease, with a 12-fold in-
crease reported in one study [15] and an increase in
women versus men in another [16]. Lung cancer generally
showed a twofold increase in risk [10, 12–17, 19]. As
Fig. 7 Relative risk of colorectal cancer in patients with rheumatoid arthritis (R
DMARD, disease-modifying antirheumatic drug; n, number of malignancies; N
factor. *SIRs by sex are included in total pooled SIR only if overall SIR was not
previously noted, a decreased risk overall of colorectal
cancer in patients with RA compared with the general
population was found. For melanoma, the pooled SIR was
significantly greater than unity, although few of the indi-
vidual point estimates were statistically significant. Breast
and cervical cancers in general showed a decrease in risk
overall that failed to reach statistical significance.
A) compared with the general population. CI, confidence interval;
, population size; SIR, standardized incidence ratio; TNF, tumor necrosis
available. †Reported as odds ratio
Source n/N SIR (95% CI)
Gridley 1993 [24] 106/11,683 0.79 (0.6, 1.0)
Moritomo 1995 [26] 3/655 1.68 (0.34, 4.91)
Mellemkjaer 1996 [25] 186/20,699 0.8 (0.7, 0.9)
Cibere 1997 [22] 18/862 0.9 (0.46, 1.24)
Thomas 2000 [27] 249/26,623 0.95 (0.83, 1.07)
Askling 2005 [21] 471/53,067 0.83 (0.76, 0.91)
Askling 2005 (early RA) [21] 13/3703 0.6 (0.3, 1.0)
Askling 2005 (anti-TNF) [21] 8/4160 0.4 (0.2, 0.9)
Abasolo 2007 [20]2007 [20] 2/789 0.9 (0.1, 3.2)
Setoguchi 2006 (DMARDs) [36] 112/7830 0.9 (0.73, 1.06)
Wolfe 2007 [28] 102/13,869 0.8 (0.6, 0.9)
Buchbinder 2008 [19] 4/458 0.7 (0.2, 1.7)
Hemminki 2008 [14] 642/42,262 0.97 (0.90, 1.05)
Parikh-Patel 2009 [16] 842/84,475 0.63 (0.59, 0.67)
Hellgren 2010* [10] 42/6745 0.89 (0.64, 1.23)
Chen 2011 [12] 123/23,644 1.21 (1.19, 1.23)
Yamada 2011 [17] 20/7566 1.05 (0.64, 1.62)
Dreyer 2013 [13] 14/3812 0.89 (0.53, 1.51)
Mercer 2013 [15] 30/3771 1.07 (0.72, 1.52)
Total pooled SIR 19 0.86 (0.73, 1.01)
0.1 10.01.0
New studies
Fig. 8 Relative risk of breast cancer in patients with rheumatoid arthritis (RA) compared with the general population. CI, confidence interval;
DMARD, disease-modifying antirheumatic drug; n, number of malignancies; N, population size; SIR, standardized incidence ratio; TNF, tumor necrosis
factor. *Reported as odds ratio
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 7 of 10
Various explanations for the differences observed in
the risk of certain malignancies in patients with RA have
been proposed. It is thought that ongoing immunologic
stimulation over time may increase the risk of malignant
transformation of immune system cells and decrease the
number of T-suppressor lymphocytes, thus increasing
rates of lymphoma malignancy in patients with RA [4].
Chronic lung inflammation due to the disease in patients
with RA may explain the increased risk of lung cancer.
Smoking increases the risk of both RA and lung cancer;
however, the SIRs reported here were not adjusted for
smoking, so it is not possible to rule out the increase in
Askling 2005 (anti-TNF) [21]
Source n/N
Gridley 1993 [24] 12/11,683
Female*
Male*
Moritomo 1995 [26] 1/655
Female*
Mellemkjaer 1996 [25] 37/20,699
Female*
Male*
Cibere 1997 [22] 45/862
Thomas 2000 [27] 28/26,623
Female*
Male*
Askling 2005 [21] 120/53,067
Askling 2005 (early RA) [21] 4/3703
1/4160
Setoguchi 2006 (DMARDs) [36] 29/7830
Abasolo 2007 [20] 1/789
Male*
Wolfe 2007 [28] 32/13,869
Buchbinder 2008 [19] 7/458
Hemminki 2008 [14] 143/42,262
Parikh-Patel 2009 [16] 184/84,475
Female*
Male*
Hellgren 2010† [10] 11/6745
Chen 2011 [12] 3/23,644
Yamada 2011 [17] 4/7566
Female*
Male*
Dreyer 2013 [13] 3/3812
Mercer 2013 [15] 9/3771
Female*
Total pooled SIR 21
0
New studies
Fig. 9 Relative risk of melanoma in patients with rheumatoid arthritis (RA) co
disease-modifying antirheumatic drug; n, number of malignancies; N, populat
*SIRs by sex are included in total pooled SIR only if overall SIR was not availab
SIR being due to an indirect association. Thus, the risk
of both lymphoma and lung cancer has been hypothe-
sized to be dependent on the level of disease activity ex-
perienced by the patient [4, 6].
Patients with RA continued to show no increase in
overall risk of colorectal and breast cancers, in contrast
to their increased risk for lung cancer and lymphoma. In
patients with RA, any observed decreased risk in colo-
rectal malignancy may be due to the increased use of
non-steroidal anti-inflammatory drugs, which are known
to decrease this risk [4, 6]. Overall, the risk of malig-
nancy among patients with RA may be due in part to
SIR (95% CI)
0.93 (0.5, 1.16)
1.23 (0.6, 2.2)
0.25 (0, 1.4)
8.83 (0.12, 49.10)
13.3 (0.17, 74.0)
1.1 (0.8, 1.5)
1.1
1.3
0.83 (0.63, 1.16)
1.21 (0.79, 1.77)
0.34 (0.04, 1.22)
1.19 (0.99, 1.42)
0.9 (0.2, 2.2)
0.3 (0.0, 1.8)
2.3 (1.55, 3.22)
3.8 (0.1, 21.0)
17.1 (0.4, 95.2)
1.7 (1.3, 2.3)
3.0 (1.2, 6.2)
1.29 (1.09, 1.52)
0.63 (0.51, 0.76)
0.80 (0.63, 1.00)
1.04 (0.54, 1.99)
1.47 (1.31, 1.65)
2.34 (0.64, 6.00)
1.66 (0.20, 6.01)
3.96 (0.48, 14.30)
1.00 (0.32, 3.11)
2.05 (0.94, 3.90)
2.05 (0.75, 4.46)
1.23 (1.01, 1.49)
100.01.0
mpared with the general population. CI, confidence interval; DMARD,
ion size; SIR, standardized incidence ratio; TNF, tumor necrosis factor.
le. †Reported as odds ratio
Source n/N SIR (95% CI)
Gridley 1993 [24] 17/11,683 0.9 (0.5, 1.4)
Moritomo 1995 [26] 3/655 2.15 (0.43, 6.27)
Mellemkjaer 1996 [25] 40/20,699 1.1 (0.8, 1.5)
Cibere 1997 [22] 1/862 0.49 (0.06, 2.76)
Thomas 2000 [27] 26/26,623 0.89 (0.58, 1.31)
Askling 2005 [21] 33/53,067 1.03 (0.71, 1.45)
Askling 2005 (early RA) [21] 1/3703 0.8 (0.02, 4.3)
Askling 2005 (anti-TNF) [21] 1/4160 1.0 (0.0, 5.8)
Setoguchi 2006 (DMARDs) [36] 16/7830 0.5 (0.31, 0.82)
Abasolo 2007 [20] 1/789 1.0 (0.1, 22.7)
Wolfe 2007 [28] 4/13,869 0.8 (0.4, 1.9)
Hemminki 2008 [14] 58/42,262 1.26 (0.95, 1.62)
Parikh-Patel 2009 [16] 47/84,475 0.43 (0.31, 0.57)
Chen 2011 [12] 45/23,644 0.86 (0.84, 0.89)
Yamada 2011 [17] 4/7566 1.36 (0.37, 3.49)
Total pooled SIR 15 0.87 (0.72, 1.05)
0 30.0 1.0
New studies
Fig. 10 Relative risk of cervical cancer in patients with rheumatoid arthritis (RA) compared with the general population. CI, confidence interval;
DMARD, disease-modifying antirheumatic drug; n, number of malignancies; N, population size; SIR, standardized incidence ratio; TNF, tumor
necrosis factor
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 8 of 10
the autoimmune pathogenesis of RA and common
etiology between RA and malignancy, including genetic
factors, smoking-related tissue necrosis and viral infec-
tion [9]. The three other site-specific malignancies ex-
amined here but not studied previously by Smitten et al.
[6]—prostate cancer, cervical cancer and melanoma—are
all common cancers, with cervical cancer being attribut-
able to viral infection. In the present analysis, there did
not appear to be a consistent trend of increased or de-
creased risk of prostate cancer, cervical cancer or melan-
oma among patients with RA compared with the general
population. One review published in 2008 that did not
meet our criteria showed melanoma results that were con-
sistent with our present assessment. Some populations
showed an increase in risk, whereas others did not [8].
This review, like that of Smitten et al. [6], is based on
observational, real-world clinical data; however, these in-
dividual studies may have potential limitations. Although
most of the individual estimates were derived from simi-
lar database studies, their study designs (including popu-
lations, data sources, follow-up times, data analysis and
Fig. 11 Relative risk of prostate cancer in patients with rheumatoid arthritis
n, number of malignancies; N, population size; SIR, standardized incidence
procedures of reporting, particularly when linked to a
cancer registry) were a source of heterogeneity among
the studies and may be associated with bias of varying
magnitude. In addition, other potential sources of hetero-
geneity included geography and/or region, stage and se-
verity of RA, and treatment. Such heterogeneity should be
considered in any meta-analysis; the DerSimonian and
Laird technique used in this study [11] assumes hetero-
geneity across studies and incorporates it into the esti-
mation of the pooled SIRs and their confidence limits.
Therefore, although the variation observed among the in-
dividual SIRs reported should be treated with caution
when interpreting these data, it should be recognized that
this variation was accounted for in the analyses resulting
in the pooled SIRs.
For example, with regard to treatment, Dreyer et al. [13]
evaluated the effect of tumor necrosis factor (TNF) inhibi-
tor treatment on risk rate by examining the treated and
non-treated populations separately (only non-treated data
included in this analysis), whereas Mercer et al. [15]
evaluated biologic-naive patients. Buchbinder et al. [19]
(RA) compared with the general population. CI, confidence interval;
ratio. *Reported as odds ratio
Simon et al. Arthritis Research & Therapy (2015) 17:212 Page 9 of 10
examined malignancy risk only in patients with RA receiv-
ing methotrexate. However, the rest of the patients in
these studies are likely to have received treatments for
RA, therefore making it difficult to differentiate the effects
of treatment and disease. Nonetheless, to further under-
stand which malignancies may be related to treatment ver-
sus the underlying disease, it is important, where possible,
to quantify differences in malignancy rates between pa-
tients with RA treated with non-biologic DMARDs and
those treated with biologic DMARDs. Whether biologic
agents, predominantly TNF inhibitors, increase the risk of
malignancy has been debated [9]. Data have shown that
use of TNF inhibitors was not associated with a major
further increase in risk in the already elevated lymphoma
occurrence in patients with RA [39–44]. However, they do
appear to increase the risk of skin cancer, including
melanoma [39–43]. Furthermore, the data presented by
Simon et al. suggest that the observed incidence of total
malignancy and those for breast, colorectal and lung can-
cers and lymphoma in patients treated with abatacept was
largely consistent with that expected of patients with RA
treated with non-biologic DMARDs [45].
Conclusions
The additional data presented here are consistent with
previously reported data [6] for all specified malignancies.
For overall malignancy, the new studies analyzed here
show a similar increase in risk compared with that pre-
viously reported. In addition, patients with RA continue to
be at an increased risk of lung cancer and lymphoma when
compared with the general population. Further studies
examining specific aspects such as treatments, smoking or
other lifestyle factors are needed to investigate the under-
lying mechanisms for the increased or decreased risk of
specific cancers observed in patients with RA compared
with the general population. Also, it is important to quan-
tify any differences in malignancy risks between patients
with RA who are treated with non-biologic DMARDs and
those treated with biologic DMARDs, as understanding
which malignancies may be related to the treatment as
opposed to being related to underlying disease will allow
patients to be advised and monitored accordingly.
Abbreviations
CI: confidence interval; DMARD: disease-modifying anti-rheumatic drug;
MTX: methotrexate; NR: not reported; OR: odds ratio; RA: rheumatoid arthritis;
RR: relative risk; SIR: standardized incidence ratio; TNF: tumor necrosis factor.
Competing interests
TAS and KKG are employees and stockholders of Bristol-Myers Squibb. AT is
an intern at Bristol-Myers Squibb and a medical student at Rowan University
School of Osteopathic Medicine, Stratford, NJ, USA. MCH receives grant/
research support from the National Institutes of Health and is a consultant
for Bristol-Myers Squibb, Eli Lilly, EMD Serono, Genentech/Roche, Novartis
Pharma AG, Pfizer and UCB. SS is a consultant for Bristol-Myers Squibb and
Genentech/Roche. The authors declare that they have no non-financial
competing interests.
Authors’ contributions
TAS participated in the design and coordination of data collection,
contributed to analysis and interpretation of data and helped to draft the
manuscript. AT conducted the literature search and helped to draft the
manuscript. KKG contributed to the study design and data collection and
interpretation and helped to draft the manuscript. MCH contributed to the
study design and interpretation of the data and helped to draft the manuscript.
SS contributed to the study design, performed the meta-analysis, contributed
to data interpretation and helped to draft the manuscript. All authors read and
approved the final manuscript.
Acknowledgments
Bristol-Myers Squibb funded the study and reviewed and approved the
manuscript before its submission. The authors had ultimate control over the
decision to publish and the final version of the manuscript submitted for
publication. The authors thank Julia Chuang of Bristol-Myers Squibb for
providing research assistance. Professional medical writing and editorial
assistance was provided by Fiona Boswell at Caudex and was funded by
Bristol-Myers Squibb.
Author details
1Bristol-Myers Squibb, Princeton, NJ, USA. 2Departments of Medicine and
Epidemiology and Public Health, University of Maryland School of Medicine,
Baltimore, MD, USA. 3Division of Clinical Epidemiology, McGill University,
Montreal, QC, Canada.
Received: 13 May 2015 Accepted: 24 July 2015
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- c.ICABMDD_RRTH_20150101_B9B0CE553FC60B6A4530_893
Abstract
Introduction
Methods
Results
Conclusions
Introduction
Methods
Literature search
Exclusion algorithm
Data presentation
Results
Overall malignancies
Lymphoma
Lung cancer
Colorectal cancer
Breast cancer
Melanoma and cervical and prostate cancers
Discussion
Conclusions
Abbreviations
Competing interests
Authors’ contributions
Acknowledgments
Author details
References
REVIEW Open Access
Immunosuppressive drugs and fertility
Clara Leroy1,2, Jean-Marc Rigot2, Maryse Leroy3, Christine Decanter4, Kristell Le Mapihan1, Anne-Sophie Parent1,
Anne-Claire Le Guillou1, Ibrahim Yakoub-Agha5, Sébastien Dharancy6, Christian Noel7
and Marie-Christine Vantyghem1,8*
Abstract
Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in
transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on
fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side
effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to
provide recommendations on the management of patients who are seen prior to starting or who are already
receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations
for use are established with a rather low level of proof, which needs to be taken into account in the patient
management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are
contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the
case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since
experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as
cyclosporine and tacrolimus, ß-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing
in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-
fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible
consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and
the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively
in relation with the prescriber of the immunosuppressive drugs.
Keywords: Fertility, Pregnancy, Transplantation, Auto-immune diseases, Inflammatory diseases, Immunosuppressive
drugs: calcineurin inhibitor, Azathioprine, Corticosteroids, Mesalazine, Chloroquine, Cyclophosphamide, Methotrexate,
Mycophenolate, Leflunomide, Anti-TNF, mTOR inhibitors, Beta-interferon, Glatiramer, Natalizumab, Fingolimod,
Mitoxantrone, Dimethylfumarate
Disease name and definition
Immunosuppressive treatments, with their increasingly
varied mechanisms of action, are used in some inflam-
matory and autoimmune diseases, as well as in trans-
plantation. Frequently prescribed in young people, these
therapies can have deleterious effects on fertility, preg-
nancy outcomes and the unborn child. The aim of this
report is to summarise the main gonadal side effects of
immunosuppressive drugs, to detail the effects on fertil-
ity and pregnancy of each class of drug and to provide
practice guidelines on the management of patients who
are seen prior to starting or are already receiving im-
munosuppressive treatment.
Epidemiology
In Europe, close to 300,000 people have had transplant-
ation, with this number having risen by 45 % since 2000.
Autoimmune diseases have become the 3rd leading cause
of morbidity and mortality following cardiovascular dis-
ease and cancer.
The present review is based on a comprehensive PubMed
search between the dates of January 1, 1960, to October 1,
2014, using the search term fertility and pregnancy com-
bined with the different immunosuppressive drugs and
discussed according to the multidisciplinary clinical
* Correspondence: mc-vantyghem@chru-lille.fr
1Endocrinology and Metabolism, Hôpital Huriez, Lille University Hospital,
59037 Lille Cedex, France
8InsermU859 Biotherapies of Diabetes, Lille University Hospital, 59037 Lille
Cedex, France
Full list of author information is available at the end of the article
© 2015 Leroy et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136
DOI 10.1186/s13023-015-0332-8
http://crossmark.crossref.org/dialog/?doi=10.1186/s13023-015-0332-8&domain=pdf
mailto:mc-vantyghem@chru-lille.fr
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experience of the authors. Most of the published studies,
being retrospective, are observational studies without con-
trol groups, or are clinical case studies. Randomised, con-
trol studies are difficult to conduct for obvious ethical
reasons. There is very little data for some drugs, and they
are mainly based on animal studies.
Fertility after organ transplantation however has been
very well studied, but lacks the ability to distinguish the
roles played by immunosuppressive drugs from that
of improvement of general health after transplantation.
After liver or kidney transplantation, the rates of miscar-
riage range from 15 to 27 % [1–4], values that are
comparable to those of the general population, even if
considerably higher incidences (45 %) were observed
after kidney transplantation [5] between 1990 and 2003 in
the United States (US). The incidences of pre-eclampsia (5
to 15 %), intrauterine growth restriction (IUGR, 9 to
57 %), Caesarean sections (38 to 80 %), prematurity (4 to
50 %) and low-birth weight (32 %), heterogeneous accord-
ing to the studies and probably according to the under-
lying maternal condition, seem slightly higher than in the
general population [1, 2, 4]. Overall live birth rates, how-
ever, currently match that in the US population according
to the United States National Transplantation Pregnancy
and United Kingdom registries (80 %), as well as Desh-
pande’s meta-analysis (73.5 %) [4, 6]. The risk of foetal
anomalies is very depending on the type of drugs but this
risk can now be anticipated.
Clinical description of the consequences of
immunosuppressive drugs on fertility and
pregnancy
Most of the time, the intensity of immuno-suppression
decreases with time, especially after the first year in allo-
geneic organ transplantation. In addition, allogeneic
hematopoietic stem-cell transplant is preceded by the
eradication of diseased cells by chemotherapy, using drugs
such as cyclophosphamide, a cytotoxic and very gonado-
toxic immunosuppressive agent.
Immunosuppressive drugs and fertility
In transplanted male patients, there is a dose-dependent
decrease in plasma concentrations of testosterone, an in-
crease of gonadotrophins and an alteration of spermato-
genesis compared to the values of the general population.
These gonadal alterations however are less consider-
able than before the organ transplantation [7–9], as
in women [10, 11].
Immunosuppressive therapies and pregnancy
The efficacy of immuno-suppressive drugs in the treat-
ment of autoimmune diseases or transplants, the emer-
gence of new drugs, and a better knowledge of their side
effects, now make pregnancy possible where it was
contraindicated several years ago either because of the
teratogenic effect of the drugs or because of the under-
lying maternal condition. Steroids have been involved in
increased risk of premature membrane rupture, and ciclos-
porine in increased prematurity rates but the increased
risk of preterm birth in transplant recipient women is also
related to the maternal condition and not to immunosup-
pression. The risk of gestational diabetes and hypertension,
however, is amplified by immunosuppressive agents, par-
ticularly steroids and tacrolimus. Also, the risk of pre-
eclampsia is increased by creatininemia greater than
13 mg/L before pregnancy and/or the use of anticaci-
neurins. In addition, immunosuppressive drugs pose a
substantial maternal-foetal infectious risk (bacterial or
opportunistic infections especially cytomegalovirus or
BK reactivation). The risk of foetal transmission of hepa-
titis viruses, C in particular, is approximately 5 % and de-
pends on the mother’s viral load after liver transplantation.
Moreover, the risk of organ rejection or auto-immune/in-
flammatory disease reactivation related to the adjustment
of immunosuppressive drugs before or during pregnancy
is about 2 to 5 % [4]. Finally, breastfeeding should take into
account the passage of potential toxic metabolites into the
milk and therefore the neonate [12].
Most immunosuppressive agents cross the placental
barrier; some are permitted during pregnancy, others are
formally contraindicated due to the risk of foetal malfor-
mations. The risks of each of these therapeutic classes
are detailed in next section.
Diagnosis
The consequences of immunosuppressive drugs may be
anticipated or discovered at any time of a pregnancy in a
patient or even years after the birth in the child. The
diagnosis of these complications is made upon the med-
ical history (transplantation, rheumatoid arthritis, lupus,
bowel inflammatory diseases, multiple sclerosis…) and
the analysis of the previous treatment courses both in
mother and father before and during the pregnancy.
Diagnosis might be clinical by examination of a new-
born. Blood renal, haematological, infectious, hormonal
and immunologic investigations may me needed. Ultra-
sound examination is essential especially during preg-
nancy to screen for teratogenicity
Differential diagnosis
Immunosuppressive drugs are prescribed for a severe
disease and this underlying disease might be responsible
by itself for the anomaly. The genetic background may
also interfere. Recording all the cases of anomalies re-
corded with a given treatment may help to understand
the mechanisms and avoid further occurrence.
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 2 of 15
Aetiologies or effects of the different classes of
immunosuppressive agents on fertility and
pregnancy
The different drugs are grouped according to their deleteri-
ous effects on gametogenesis and on the hypothalamic–pi-
tuitary–gonadal axis, followed by potential teratogenic
effects of each drug (Table 1).
Contraindicated drugs when pregnancy is desired (Table 1)
Methotrexate
Study results differ regarding the deleterious effect of
methotrexate on spermatogenesis. If real, this effect seems
to be reversible after 3 months of treatment discontinu-
ation. Due to the mutagenic risk, men are advised to wait
3 months after stopping treatment to conceive. There is
no evidence of a teratogenic effect [13].
The repercussions of methotrexate treatment on female
fertility appear to be slight and may even be nonexistent.
Serum concentrations of the anti-Müllerian hormone
(AMH) were not lower in women treated with methotrex-
ate for rheumatoid arthritis than in controls [14]. The
evaluation was done however 6 months after the start of
treatment, and the pregnancy rates subsequently obtained
were not reported. A poorer response was observed to
ovarian stimulation in the 18 months following metho-
trexate treatment, though it improved thereafter [15].
In contrast, the folic acid antagonist methotrexate has
been documented to be teratogenic if administered dur-
ing the first trimester.of pregnancy, even at doses lower
than 30 mg/week. Over 30 cases of foetal malformation
involving the central nervous system and the limbs were
reported in association with IUGR and failure to thrive,
etc. [16, 17]. The embryolethal effect of methotrexate is
otherwise used in the medical treatment of ectopic preg-
nancies [16]. The miscarriage rate on treatment is ap-
proximately 40 %, considerably higher than that seen in
the general population or in those with autoimmune dis-
eases [18]. During the second and third trimester, metho-
trexate administration is unrelated to a teratogenic effect
but could increase the risk of IUGR and low birth weight.
Administration apart from conception does not increase
the risk of malformations or miscarriage [18]. However a
3-month treatment-free interval between discontinuation
of methotrexate and conception is recommended.
Mycophenolate (purine synthesis inhibitor)
Mycophenolate, being non-diabetogenic, is one of the
most commonly used immunosuppressive drugs in
transplantation.
There is no data on the effects of mycophenolate on
male fertility. The 205 pregnancies involving 152 trans-
planted fathers who had been treated with mycophenolate
were associated with a similar risk of prematurity (10 %)
and malformations (3 %) as in the general population [19].
The AMH levels of female patients treated with myco-
phenolate for lupus were not lower than in a control
population [20]. A very considerable amount of myco-
phenolate crosses the placental barrier. In rats, there is
a teratogenic and mutagenic effect. In women, mycopheno-
late poses an increased risk of miscarriage (32 % to 45 %)
and multiple craniofacial congenital malformations (MMF-
associated embryopathy (EMFO tetrada: Ear, Mouth,
Fingers, Ocular/Organ malformation) in 26 % of cases after
first trimester exposure to MMF according to The
European Network of Teratology Information Services
[21]. Foetal toxicity is present throughout the first trimester
and seems to be cumulative depending on the clinical cases
reported. For this reason, treatment must imperatively be
modified in the event that pregnancy occurs, and the pre-
scription of mycophenolate should be avoided in young,
transplanted women with a potential desire to become preg-
nant. There are few data on the exposure to mycopheno-
late during the second part of pregnancy, but the treatment
could result in blood count abnormalities in exposed new-
borns. The U.S. Food and Drug Administration (FDA)
launched a systematic information programme for pa-
tients on the teratogenic risk including the issuance of a
written information document, signature of informed con-
sent before the prescription, and incentive to participate
in a registry of pregnancies occurring on mycophenolate
or within 6 weeks of its discontinuation.
Leflunomide and teriflunomide
In animal models, teriflunomide, an inhibitor of de novo
synthesis of pyrimidine, active metabolite of leflunomide
does not have adverse effects on male or female fertility,
but both drugs are embryotoxic and teratogenic, promot-
ing the development of malformations of the axial skel-
eton and head (microphthalmia, hydrocephaly). There is
little data from pregnant women, but cases of complex
morphological-functional abnormalities (congenital blind-
ness and perceptive deafness) were reported in children
with parents exposed to leflunomide in the pre-conception
period or during pregnancy [22, 23]. These drugs are there-
fore contraindicated in the pre-conception period (the 3½
months before pregnancy) and during pregnancy. A
washout procedure may be proposed with cholestyramine
(8 g, 3 times daily) or activated charcoal (50 g, 4 times
daily) for 10 days in order to shorten the time period
needed between discontinuation of the treatment and
conception, since the total elimination of the drug may
take 8 to 24 months. A sperm cryopreservation is recom-
mended before treatment.
Cyclophosphamide
Cyclophosphamide, a cytotoxic alkylating agent widely
used in allogeneic bone marrow transplantation, per-
manently alters the ovarian reserve in a manner that is
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 3 of 15
Table 1 Consequences of the main immunosuppressor on fertility and pregnancy
Immunosuppressants Hypothalamic–pituitary–
gonadal axis
Gametogenesis Mutagenesis Teratogenesis Pregnancy NN Management
A: Contraindicated drugs when pregnancy is desired
Methotrexate M: alteration debated,
reversible after stopping for 3
months
M: mutagenic F: teratogenic
without dose
effect, especially
between 6 and 8
weeks
Increased frequency
MC 23%
CI during pregnancy,
especially during the
first trimester.
W: No effect: AMH the same
at 6 months between treated
or non-treated population
but less response to ovarian
stimulation the first 18
months post-MTX
>30 cases of
malformation of
the CNS, skull,
limbs, IUGR,
cardiopathy
Discontinuate at least 3
months before
pregnancy in both
genders
Mycophenolate In rats: no effect on fertility mutagenic in vivo in
rats
W: clasto-carcino-
teratogenic:
multiple
craniofacial
anomalie,…
crosses placenta +++ NN heamato
monitoring if data at
2nd or 3rd trimester
Switch to another drug
before pregnancy
M: No effect increased risk of MC
Le- and teri-
flunomide inhibitor
of de novo synthesis
of pyrimidine
Total elimination of the
drug may take 8 to 24
months.
No adverse effect on male or
female, even in animals at
high doses
neither mutagenic
nor clastogenic
Teratogenic in
animals: head
malformations
insufficient human
data
one case of congenital
blindness
Stop ≥ 3.5 months
before conception or
Wash-out with
cholestyramine (8gx3/
day) or charcoal
(50gx4/day) – 10 days
to obtain
concentration< 0.02
mg/L
no studies in
humans
Sperm
cryopreservation
recommended before
treatment in men
Cyclophosphamide
cytotoxic alkylating
agent
W: FSH/LH increased,
even with short
exposures
Lasting alteration of ovarian
reserve that is dose-,
duration- and age-
dependent: low AMH
mutagenic embryolethal and
teratogenic
without dose
effect, especially if
early exposure:
limbs, dysmorphia,
eye,
CI during pregnancy
and breastfeeding
IUGR
more late exposure,
more significant risk
NN haemato
Effective contraception
to be continued until
end of treatment
Wait for one ovulation
cycle after
discontinuation before
conception
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Table 1 Consequences of the main immunosuppressor on fertility and pregnancy (Continued)
Mitoxantrone anomalies of the
menstrual cycle or even
permanent amenorrhea
in 7 to 14% of treated
patients in correlation
with the cumulative
dose and the age of
exposure
deleterious effect on
spermatozoïds and ovocytes
leading to fertility alterations.
In association with other anti-
cancer drugs,
aneuploidism and
azoospermia
spontaneously
improved after 3 to 5
months of treatment
discontinuation
teratogenic in
animals and
humans
Contraindicated in
pregnancy .
A period of 6 months
is required after
treatment before
conception
Sperm
cryopreservation
recommended before
treatment in men and
contraception is
required in women.
Thalidomide teratogenic in
humans
B: Drugs to be used with caution if needed
mTOR inhibitors M: inhibitor M: oligoasthenosper mia,
reversible if stopped
(debated)
No mutagenic effect
in vitro/in vivo
embryo- and
foetotoxic in
animals
−16 reported
pregnancies
Substitute with other
drug and continue
contraception for 12
weeks after stopping
treatment
– sirolimus Testicular atrophy −3 MC and one child
with multiple
malformations
(+MMF)
No information on
breast feeding
– everolimus W: menstrual disorders 1st
year of graft, and 50-60%
ovarian cysts, diminishing
upon stopping or taking OP
in 80% of cases
temsirolimus
anti-TNFα M: no effect M: no effect non-mutagenic W: non-teratogenic
in animals and in
about 50
pregnancies
1st trimester: Few data
etanercept/
certolizumab ≠ inflixi/
adali:mumab NTR
Crosses placental
barrier ± (
infliximab
until 6 months in NN),
less for etanercept,
certolizumab
Not recommended to
discontinue therapy if
desire for pregnancy.
Anti-cytokine W: no studies FDA: increased risk
cardiac
malformations –
low level of proof
2nd3rd trim: 20 cases:
inflixim- adalim-
certoliz- umab-: NTR
CI live vaccines
etanercept
infliximab
adalimumab
certolizumab One child of mother
treated entire
pregnancy, died from
BCG (TB vaccine)
complications
Infections without
fever
golimumab
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Table 1 Consequences of the main immunosuppressor on fertility and pregnancy (Continued)
C: Authorised drugs
Anti-inflammatory M and W: synthetics and
high dose inhibit
hypothalamic–pituitary–
gonadal axis
promotes apoptosis of germ
cells
not more cleft lip-
palate
IUGR, premature,
eclampsia >
– case of NN ACI after
high doses
Possible breast feeding
glucocorticoids W: In practice, no major
impact on fertility
actual role of GC or
underlying disease?
– predisposes to
unfavourable adult
metabolic profile
Anti-inflammatory M: oligoasthenoteratospermia
reversible after 2 months of
stopping; 60% infertility. W:
no effect
no effect increased prematurity No information on
breast feeding
Prescribe folates
Sulfasalazine
Mesalazine
Prefer Mesalazine
Anti-metabolites M and W: no effect few deleterious effects mutagenic in vivo /in
vitro
M and W: Non-
teratogenic
increased prematurity Breastfeeding CI ±
failure to thrive +
reversible
haematological NN risk
– Avoid use in a male
patient wishing a
conception
Azathioprine carcinogenic and
teratogenic in animals
Mutagenic
– Discontinuation 3
months before
conception
Prodrug of 6
mercaptopurine
– US survey of
pregnancy if
conception by a
treated father
– Sperm
cryopreservation
recommended
– Use possible
regardless of
pregnancy term.
– Possible breast
feeding
Beta interferon increase of LH Alterations of ovarian reserve
high molecular
weight and should
not cross the
placenta.
no teratogenic
effect
numerous reported
pregnancies with
either the father or
the mother treated :
no problem
lower birth weight and
higher rate of
spontaneous abortions,
in the treated mother,
even if the treatment
is stopped as soon as
the pregnancy is
known
– Discontinuation not
necessary in case of
pregnancyNo sperm alterations
– No long term
deleterious effects
have been reported in
the offspring
Glatiramer acetate increase of LH Decrease of ovarian surface
and number of antral follicles
high molecular
weight and should
not cross the
placenta.
no teratogenic
effect
numerous reported
pregnancies with
either the father or
the mother treated :
no problem
– Discontinuation not
necessary in case of
pregnancy
– No long term
deleterious effects
reported in the
offspring
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Table 1 Consequences of the main immunosuppressor on fertility and pregnancy (Continued)
Chloroquine – No deleterious effects
on pregnancy or
breastfeeding
Calcineurin inhibitors W: no effect M: asthenoteratospermia if
dose > 2mg/kg/day
W: non-
teratogenic, limited
crossing to
placenta (5-20%)
increased infectious
risk (CMV)premature /
IUGR
passes into breast milk,
undetectable in
newborns
Use possible during
pregnancy; More
experience with
cyclosporine
Ciclosporine
Tacrolimus
non-teratogenic; 2
cases of congenital
malformations
30% premature/ low-
birth weight
no renal repercussions
in NN
Caution regarding
infections
Reversible involvement
of lymphocytes,
without clinical
repercussions.
Possible breast feeding
rare cases of transient
kidney failure in NN
D: Drugs with limited experience (biological therapies, inductors)
Tocilizumab Anti-IL-6
monoclonal Ab
poorly understood
effects on fertility
clearance: 2 weeks
Large molecule with limited
crossing to placenta and
breast milk
animal studies: no
lethal effect.
poorly understood
effects on both
fertility and
pregnancy
Very few pregnancies
reported.
Avoid pregnancy-
Limited experience-
Continue
contraception 3
months after stopping
(FDA).
Rituximab anti-CD20
monoclonal Ab, B
lymphocyte inhibitor
long half-life. Very limited transplacental
crossing (debated)
150 pregnancies,
some with early
exposure: NTR
Prematurity 15%
Haematological
anomalies, sometimes
infections up to 6–12
months after stopping
Avoid pregnancy less
than 12 months after
stopping
Abatacept (anti-
CD28 Ab or CTLA-4
fusion protein,
inhibiting the co-
stimulation pathway
of the T
lymphocytes (anti-T)
clearance: 2 ½ months
(half-life = 14 days)
-non-altered in animals large molecule: non-teratogenic in
animals
Several pregnancies
with early exposure:
NTR
Avoid
pregnancyLimited
experience- W: no studies
Anankira anti-IL-1
receptor
little teratogenicity
in the 1st trimester
since limited
crossing of
placenta ± end of
the 2nd trimester
when its crossing
increases.
<5 pregnancies reported: NTR
Administration in 3erd
trimester with
increased risk of NN
immunosuppression,
and CI live vaccines for
at least the first 6
months following
birth.
Avoid
pregnancyLimited
experience
Dimethyl fumarate inhibitor of immune
cells and an anti-oxidant
consequences on fertility not
known.
consequences on
pregnancy not
known.
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Table 1 Consequences of the main immunosuppressor on fertility and pregnancy (Continued)
Natalizumab Fertility alterations in female
but not male animals
No teratogenic
effects – effects not
fully known yet
Discontinuation of
treatment
recommended 2
months before
conception in men.
Fingolimod or FTY
720 or Sphingosine
1-phosphate
receptor modulator
Effects on fertility not well
known, − Would have a
protective effect on ovarian
function at least in vitro
teratogenic effects,
in animals
Recommended to stop
the treatment 2
months before the
conception in men
and women.
Induction Unknown effects on
both fertility and
pregnancy
Avoid pregnancy
within 12 months of
stopping- anti-human
thymocyte Ig
– IL-2 receptor
inhibitors
daclizumab
– belatacept fusion
protein (Fc fragment
of human IgG1
+extracellular CTLA-4
Note the significant impact of cyclophosphamide on fertility If emergency use needed, start the treatment if possible after the 1st trimester
The website of the French Teratogenic Agent Information Centre [Centre de Référence sur les Agents Tératogènes (CRAT)] (http://www.lecrat.org/) can provide more information
Ab antibodies, CI contraindicated, MC miscarriage, FDA Food and Drug administration, W women, M men, HAS French National Authority for Health [Haute Autorité de Santé], ACI adrenocortical insufficiency, Ig
immunoglobulin, IL-2 interleukin-2, MMF mycophenolate, MTX methotrexate, NN neonatal, OP oestrogen-progestin contraceptive pills, NTR nothing to report, IUGR intrauterine growth restriction), US United States
teratogen substance that causes malformations in the foetus when administered to the mother, mutagen substance that increases the number of mutations in the genome, mutations that are likely to promote
malformations or an increased carcinogenesis risk, clastogen substance likely to induce chromosomal breaks and thus aberrations
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dose-, duration- and age-dependent. This has been well
demonstrated through decreased plasma concentrations
of AMH and increases in gonadotrophins, with some
variations correlated to the cumulative dose of cyclo-
phosphamide, even for short exposures [19, 24].
Cyclophosphamide in animals is mutagenic, terato-
genic and embryolethal. In humans, it is a confirmed
teratogenic agent that promotes IUGR, malformation
of the extremities and the head (ocular involvement,
facial dysmorphia, craniostenosis, hydro- or micro-
cephaly). The reported cases are rare so that it is diffi-
cult to establish a dose–response relationship; some
malformations have been observed at low doses, while
newborns that had had high dosage exposures were
born healthy. The malformations seem to be secondary
to exposure during the 1st trimester. However, the
haematological side effects observed in the neonatal
period are all the more frequent the later the exposure
during the 2nd and 3rd trimesters of pregnancy. The
teratogenicity of cyclophosphamide absolutely contrain-
dicates its use in pregnancy. If its use is essential (e.g.,
breast cancer diagnosed during pregnancy), the treat-
ment will be prescribed after the 1st trimester if
possible. Conception is theoretically possible about two
days after the end of the treatment. In practice, effective
contraception must be continued until the end of treat-
ment, and a minimum of one ovulation cycle after the
end of treatment is recommended before considering
conception.
Mitoxantrone
Mitoxantrone (Table 1), sometimes used in multiple scler-
osis, also a chimiotherapy in leukemia and prostate cancer,
induces anomalies of the menstrual cycle or even perman-
ent amenorrhea in 7 to 14 % of treated patients The effects
are correlated with the cumulative dose and the age of ex-
posure [25, 26]. Mitoxantrone has a deleterious effect on
spermatozoïds and ovocytes leading to fertility alter-
ations. In association with other anti-cancer drugs,
mitoxanthrone may be responsible for aneuploidism
and azoospermia spontaneously improved after 3 to
5 months of treatment discontinuation [27, 28]. This
drug is teratogenic in animals and humans and is there-
fore contraindicated in pregnancy. Sperm cryopreservation
is recommended before treatment initiation in men and
contraception is recommended as well in women [29]. A
period of 6 months is required after treatment discontinu-
ation before conception.
In conclusion, these 5 immunosuppressive agents are
teratogens, and other immunosuppressive agents must
be used when pregnancy is desired. In addition, cyclo-
phosphamide alters the ovarian reserve, thus warranting
a consultation in a specialised centre for the purpose of
ovarian preservation before prescription of the drug.
Drugs to be used with caution (Table 1)
Anti-TNF-α (tumour necrosis factor alpha) (anti-cytokine)
The most commonly used anti-TNF alpha drugs are
first, etanercept, a TNF inhibitor acting as a soluble re-
ceptor, with a half-life of 72 h; and second, the anti-TNF
antibodies (infliximab, adalimumab, certolizumab, goli-
mumab), with a half-life up to 14 days.
Various andrological studies in men are not supportive
of spermatic alteration secondary to treatment with
TNF-alpha inhibitors. Therefore there are no recom-
mendations to stop treatment if conception is desired
[30]. Compared to case controls in spondyloarthritis, the
levels of inhibin B, testosterone and gonadotrophins are
unchanged by these drugs [30, 31], particularly etaner-
cept and adalimumab.
There have been no studies in women on the effects of
anti-TNF alpha agents on the hypothalamic–pituitary–
gonadal axis and the ovarian reserve.
Anti-TNF alpha agents are not teratogenic in animals,
nor mutagenic in pre-clinical tests.
These drugs cross the placenta − infliximab in particu-
lar, which has been detected up to 6 months after child-
birth in the child’s blood [32]. There are more reported
cases of exposure to infliximab and adalimumab in the
first trimester of pregnancy than to etanercept or certoli-
zumab. The reported cases of use of these drugs in the
second part of pregnancy are extremely rare. The data
however are reassuring and do not show malformations
in children born from these pregnancies [33]. A risk of
VACTERL association (anomalies of the vertebrae and/
or limbs, anal atresia, tracheoesophageal fistula, renal
malformation) and heart defects have been noted by the
Food and Drug Administration (FDA), but this report
has methodological biases [34].
The frequency of infections however, including reacti-
vation of tuberculosis in the mother, is higher, particularly
with certozilumab [35]. A case of severe tuberculosis that
resulted in death was reported after BCG vaccination in
one child.
In practical terms, considering the still limited experi-
ence available as to the use of these drugs, it is recom-
mended that contraception be continued in women
receiving TNF-alpha inhibitors, prolonged for 3 weeks
after stopping etanercept and 3 months after stopping
anti-TNF-alpha antibodies despite the lack of demon-
stration of teratogenic effects. In addition, infections may
not be accompanied by fever in patients using anti-TNF
alpha drugs. If the use of anti-TNF alpha treatment is
necessary, it is recommended that the last injection be
given at the start of the 3rd trimester of pregnancy due to
the long half-life of elimination. At birth, the child is
immunocompromised, and this may continue up until
6 months following the last maternal injection, making
the postponement of live vaccinations mandatory
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 9 of 15
(2013 HAS [French National Authority for Health]
Recommendations).
mTOR inhibitors: sirolimus, everolimus, temsirolimus
In addition to their immunosuppressive properties, the
mTOR inhibitors are also used as anti-tumour agents,
notably in pancreatic neuroendocrine tumours.
Sirolimus alters the functioning of the hypothalamic–
pituitary–gonadal axis [36, 37]. As a result, men with
kidney transplants who are treated with sirolimus have
lower serum testosterone levels and higher plasma con-
centrations of gonadotrophins than on other immuno-
suppressive drugs. These values nevertheless remain
within normal limits. These variations are positively cor-
related to the dose of sirolimus and are independent of
other variables, such as graft function, age of the patient,
body mass index, duration of dialysis, existence of post-
transplantation diabetes and use of steroids [38].
Similarly, high levels of everolimus (combined with
corticosteroids and calcineurin inhibitors) are the
cause of poorer recovery of testosterone, FSH and LH
levels after transplantation [39]. Sirolimus qualitatively
and quantitatively alters spermatogenesis in men, as
observed in 132 heart transplant patients [40–42].
This adverse effect is purportedly reversible upon
stopping the treatment [41, 43], although this revers-
ibility is controversial [42]. A testicular histological
study done in a patient treated with sirolimus who
needed surgical intervention for leydigioma showed
testicular atrophy and vacuolation of the seminiferous
epithelium [44], in agreement with the animal studies.
Young women treated with sirolimus and tacrolimus
have an increased risk of oligospanio- or amenorrhoea)
and ovarian cysts (50 to 62 % of cases) in the first year
of the transplant [45–47]. These cysts diminish in 80 %
of cases when sirolimus is stopped or with the use of
combined oestrogen plus progestin contraceptive pills.
Some cysts, such as mucinous cystadenomas or haemor-
rhagic cysts, require surgical cystectomy [47]. Their oc-
currence is allegedly promoted by insulin resistance
induced by immunosuppressive agents, but this hypoth-
esis has not been demonstrated.
In animal models (rats), treatment with tacrolimus, sir-
olimus or a combination of both lead to a decrease in
the ovarian surface, the number of ovulation cycles,
uterine size, and aromatase expression, although with
the corpora lutea present. Conversely, sirolimus treat-
ment allegedly protects the ovarian reserve and prevents
the transition of pre-antral follicles to antral follicles by
modulating the mTOR and signalling pathways [48].
In animals, sirolimus does not have an in vitro or in
vivo mutagenic effect, but it is embryo- and foetotoxic. In
the clinical setting, sixteen pregnancies were reported be-
tween 2004 and 2012 while using sirolimus or everolimus
[49]; of these, 3 resulted in miscarriage and one child had
many malformations but had received mycophenolate in
early pregnancy. Currently, experience with the use of this
treatment during pregnancy is insufficient. Even though the
published data seem to be reassuring, it is recommended
that another drug be used as a substitute for mTOR inhibi-
tors, and that contraception be continued for 12 weeks after
stopping treatment due to the clearance time.
Finally, these 2 therapeutic classes have little effect on
fertility and pregnancy, but the available experience of
use is still limited (about 10 years), and as a result their
prescription must be avoided when possible.
Treatments associated with a low risk of deleterious effects
on fertility and pregnancy (Table 1)
Glucocorticoids
The use of glucocorticoids has consequences on fertility
[50]. Therefore, synthetic (and even endogenous) corti-
costeroids have an inhibitor effect on the male hypothal-
amic–pituitary–gonadal axis: a) through direct and
indirect action on the level of transcription of the GnRH
receptor gene on the pituitary cells; b) by modulating
the expression of the LH receptor genes or of testoster-
one biosynthesis enzymes, whether through genomic ef-
fects or not; and c) through inhibition of the adrenal
synthesis of androgens. In the ovaries, low doses of corti-
costeroids play a positive role in steroidogenesis, the
maturation of oocytes, ovulation and maintenance of the
corpus luteum. However high-dose exogenous intake is
often deleterious.
In vitro, glucocorticoids exert a proapoptotic effect on
the germ cells of rat testes and ovaries of the female foetus
[51]. In practical terms however, there are no major conse-
quences on the fertilisation capacities in women receiving
corticosteroid treatment [52].
The incidence of IUGR, low-birth weight, pre-eclampsia,
hypertension, diabetes and prematurity is increased in
cases of exposure to corticosteroids during pregnancy
compared to the general population, regardless of the dos-
age and the type of corticosteroid use [53–55]. In addition,
high doses of glucocorticoids during intrauterine life risk
may cause neonatal adrenal insufficiency, but also dys-
function of the hypothalamic–pituitary–adrenal axis and
foetal “programming”, thus predisposing to an unfavour-
able metabolic profile as an adult [56].
Sulfasalazine
The use of sulfasalazine is the cause of oligo-astheno-
teratospermia and infertility in over 60 % of treated
men [57], although it is reversible after two months after
stopping treatment. However, the hypothalamic–pituit-
ary–gonadal axis changes little, as the plasma concentra-
tions of prolactin, testosterone and gonadotrophins are
normal [58]. In women, no effects of this treatment have
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 10 of 15
been reported on fertility parameters. There has been no
demonstration of congenital foetal anomalies on this ther-
apy [59], but the prescription of folate supplementation is
advised due to its mechanism of action.
Mesalazine
The hypothalamic–pituitary–gonadal axis and the sperm-
atic parameters are not altered with treatment using this
drug [60]. In fact, replacement of sulfasalazine by mesala-
zine improves the spermatic parameters [58]. There has
been no demonstration of congenital foetal anomalies
or maternal-foetal complications other than prematur-
ity, which was slightly increased with mesalazine [61].
Azathioprine (purine analog, precursor of 6- mercaptopurine)
Azathioprine is mutagenic. The rare andrological studies
are not supportive of alterations of fertility [62]. More
than 1000 pregnancies issued from men treated with
azathioprine or 6-mercaptopurine have been published
and no teratogenic effects have been reported. Neverthe-
less, chromosomal anomalies have been described on
spermatozoids of male subjects during the treatment
and the year following its discontinuation.
There is little published data in women, but azathio-
prine does not seem to have detrimental effects on fertility.
The AMH concentrations of patients treated with azathio-
prine, mycophenolate or calcineurin inhibitors for lupus
were not lower than in the control population [19].
Azathioprine is teratogenic in animals, as treated
pregnant females and their foetuses have presented
with chromosomal abnormalities on the circulating
lymphocytes.
Azathioprine is authorised during pregnancy. Although
it crosses the placental barrier, this agent cannot be con-
verted to an active metabolite, as the foetal liver lacks
the specific enzyme. No teratogenic risk has been dem-
onstrated in the many data, both in women and in men
[61, 63–65]. In contrast, prematurity [61], some cases of
immunosuppression that quickly resolve [66] and/or re-
versible involvement of the blood cell lineages have been
observed in newborns. Otherwise, breastfeeding is not
contraindicated, since the active metabolite, 6 mercapto-
purine, rarely passes, and if passes, remains at very low
level, into breast milk [67].
If azathioprine is required for control of the inflamma-
tory disease or the graft, it may be used during preg-
nancy, but an ultrasound monitoring should be proposed.
Amniocentesis may be discussed but can only discard
usual caryotypic alterations. A sperm cryopreservation is
recommended before instauration of the treatment in a
male subject because of the mutagenic effect. If a treated
male subject wishes a conception, the treatment should
be stopped if possible at least 3 months before conception
(a cycle of spermatogenesis).
Ciclosporine (calcineurin inhibitor)
No significant difference in the hormonal parameters
(FSH, LH, testosterone and prolactin) were observed be-
tween kidney transplants treated with ciclosporine and
those treated with tacrolimus [68]. However, rats treated
with ciclosporine had irreversible testicular damage [7].
In men, doses greater than 2 mg/kg/day [9] have been
implicated in asthenoteratospermia. No significant differ-
ence was seen in men receiving lower doses compared
to the control group. Therefore it is not recommended
that treatment be discontinued if pregnancy is desired.
Plasma concentrations of AMH in patients treated with
calcineurin inhibitors for lupus were not lower than in a
control population [20].
Limited amounts of ciclosporine cross the placenta
(5–20 %), and it does not result in teratogenic effects [69].
No renal repercussions attributable to ciclosporine were
observed during the follow-up of several hundred children
exposed in utero. Reversible involvement of B or T lympho-
cytes without clinical consequences, prematurity, and
IUGR have sometimes been reported. These neonatal ef-
fects may be attributed to ciclosporine but also to the dis-
ease and/or associated treatments.
Tacrolimus (calcineurin inhibitor)
There are a large number of published data on pregnant
women exposed to tacrolimus, and they show no evi-
dence of an increase in malformations [70]. The experi-
ence acquired over 13 years [71] in 37 women treated
with tacrolimus after liver transplantation and who gave
birth to 49 children resulted in:
– 30 % premature births [72]
– 32 % birth weight below the 50th percentile
– 5 to 6 % congenital malformations [70]
– rare cases of transient hyperkalaemia and kidney
failure in the child
Beta interferon and glatiramer acetate
Studies are scarce but significant alterations of ovarian
reserve have been reported both with beta interferon and
glatiramer acetate used in the treatment of multilocular
sclerosis [73]. These 2 molecules have a high molecular
weight and should not cross the placenta. Neither sperm-
atic alterations nor teratogenic effects have been observed
in the numerous reported pregnancies with either the
father or the mother treated with these 2 molecules
[74, 75]. Interferon is however associated with a lower
birth weight and a higher rate of spontaneous abortions, in
the treated mother, even if the treatment is stopped as soon
as the pregnancy is known [76, 77]. The discontinuation of
these treatments 3 months before conception is recom-
mended each time the disease is not a frequent relapsing
form. In other cases, the treatment might be stopped as
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 11 of 15
soon as the conception is proven. If necessary, the treat-
ment might be pursued during the whole pregnancy. No
long-term deleterious effects have been reported in the off-
spring [78–81].
Chloroquine
Chloroquine appears to have a deleterious effect on sperm
quality in vitro and in vivo in animal studies. Little data are
available in males, unlike in pregnant women in which
there is a large amount of reassuring data. The teratogenic
risk related to the use of hydroxychloroquine is very
low [82].
Chloroquine may be used at prophylactic doses for
malaria. In other situations, if continuation of the ther-
apy is required for good control of the treated disease, the
lowest possible dose should be used during pregnancy.
In conclusion, if these drugs are required for control
of the inflammatory disease or maintenance of the graft,
they may be used during pregnancy.
Recent drugs in which the effects are not fully known
(Table 1)
Biological therapies
Biological therapies (tocilizumab, rituximab, abatacept, ana-
nkira) seem to have few teratogenic effects in the first tri-
mester, since a very limited amount cross the placental
barrier. This is in contrast to the end of the 2nd trimester,
in which crossing is increased [83–85]. If administered in
the 3rd trimester, some of these drugs carry an increased
risk of neonatal immunosuppression, and their use contra-
indicates the use of live vaccines for at least the first
6 months after birth. Abatacept and anankira appear to be
associated to a lesser extent with side effects than the
anti-TNF alpha agents, infliximab in particular [34, 86].
Very few pregnancies have been reported. Due to this
scarcity of experience, the prescription of biological ther-
apies is discouraged if pregnancy is desired, both in women
and men due to the still poorly understood long-term side
effects [87]. Continued use of contraception is advised
for 3 months following discontinuation of these treat-
ments due to their long half-life.
Immunomodulators in multiple sclerosis
Besides beta interferon and glatiramer acetate use
(Table 1), and mitoxantrone (Table 1), dimethyl fu-
marate acts as an inhibitor of immune cells and an
anti-oxidant. Its consequences on fertility and preg-
nancy are not known.
Natalizumab alters fertility in female, but not male,
animals. No teratogenic effects have been observed in
women but the effects are not fully known yet [88, 89]. The
discontinuation of treatment is recommended 2 months
before conception in men.
The effects of fingolimod on fertility are not well known,
but fingolimod seems to have a protective effect on ovar-
ian function at least in vitro despite its teratogenic effects
in animals [90, 91]. Therefore, it is recommended to stop
the treatment 2 months before the conception in men as
well as in women [92].
Except for beta interferon and glatiramer acetate, which
might be prescribed if necessary, the other immunomodu-
lators used in multiple sclerosis should be stopped two
(natalizumab, fingolimod) to six months (mitoxanthrone)
before conception, with a possible wash-out procedure for
teriflunomide.
Induction immunosuppressive treatments
The effects of induction treatments (rabbit anti-human
thymocyte immunoglobulins; interleukin-2 receptor an-
tagonists such as daclizumab; belatacept) on fertility and
pregnancy have not been studied.
Management of patients using
immunosuppressive drugs
The management prior to the patient starting treatment
with an immunosuppressive agent, or when the patient is
already receiving this immunosuppressor treatment is sum-
marized in Tables 1 and 2 [93–95].
Pregnancy, when an option, must be planned under
conditions of strict monitoring, when the disease is not
in an acute phase. These findings prompt the recom-
mendation to delay pregnancy up to l to 2 years after
the transplant, when the immunosuppressive doses will
be lower and the menstrual cycles will have spontan-
eously re-established [14].
Most immunosuppressants cross the placental barrier
and, depending on the foetal malformation risk, some
are authorised during pregnancy (azathioprine, corti-
costeroids, anticalcineurins, ß interferon, glatiramer
acetate, chloroquine), and others are formally contra-
indicated (methotrexate, mycophenolate, le- and teri-
flunomide, cyclophosphamide, mitoxantrone). If the
latter treatments (cyclophosphamide in particular) need to
be prescribed for emergency purposes, it is preferable that
they be started after the 1st trimester of pregnancy. For
some drugs that have fewer data but seem reassuring, the
use may be continued during the pregnancy if needed
(anti-TNF alpha, mTOR inhibitors).
The preconception time period for stopping varies with
each drug and depends on its clearance time (5 half-lives):
12 weeks for the m-TOR inhibitors; 4 weeks to 2 years for
le- and teri-flunomide (according to whether or not the
wash-out protocol with charcoal and cholestyramine is
used); 12 weeks in men and in women for methotrexate;
one ovulation cycle for cyclophosphamide; and 6 weeks
for mycophenolate.
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 12 of 15
Prognosis and unresolved questions
In the 21st century, immunosuppressive drugs are indi-
cated in many different diseases due to their efficacy but
also due to a better understanding of their mechanisms of
action and their side effects. This efficacy has enabled im-
provement of underlying diseases, making parenthood an
option in some young patients who previously had defini-
tive life-threatening conditions. Nevertheless, these treat-
ments remain powerful therapies that require skilful
handling; therefore it should be borne in mind that
the long-term consequences are still not fully under-
stood. As an example, the marketing authorisation for
mTOR inhibitors only dates back 10–15 years. Although
childbirth is possible with these treatments, this undertak-
ing is never without risk to the mother and child. It must
be anticipated very far in advance, before the prescription
of the immunosuppressants, in order to preserve fertility,
and then before conception in order to adjust the immuno-
suppressive treatment. Close monitoring of the pregnancy
in conjunction with the prescriber of the immunosuppres-
sion and long-term follow-up of children from these
pregnancies is recommended. The potential conse-
quences of immunosuppressive drugs in children who
have received this exposure during pregnancy must still
be evaluated once they are adults. Recommendations
for use are established with a rather low level of proof,
which needs to be taken into account when informing
and monitoring patients. This multidisciplinary manage-
ment for planned parenthood must be discussed with the
couple so that they understand and accept the challenges
and obligations.
Abbreviations
Ab: Antibodies; CI: Contraindicated; MC: Miscarriage; FDA: Food and Drug
administration; HAS: French National Authority for Health [Haute Autorité de
Santé]; ACI: Adrenocortical insufficiency; Ig: Immunoglobulin; IL-2: Interleukin-
2; IUGR: Intrauterine growth restriction; MMF: Mycophenolate;
MTX: Methotrexate; NN: Neonatal; OP: Oestrogen-progestin
contraceptive pills; NTR: Nothing to report; W: Women; M: Men.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
CL, JMR, ML, CD, SD, MCV analyzed the literature data; KLM, ASP, ACLG, IYA,
CN discussed the litterature according to their experience; CL and MCV
wrote the manuscript. All authors gave final approval of the manuscript.
Acknowledgement
The authors thank Prof J. Orgiazzi for his attentive expertise.
Author details
1Endocrinology and Metabolism, Hôpital Huriez, Lille University Hospital,
59037 Lille Cedex, France. 2Andrology, Hôpital Calmette, Lille University
Hospital, 59037 Lille Cedex, France. 3Gynaecology –Obstetrics, Hôpital Jeanne
de Flandres, Lille University Hospital, 59037 Lille Cedex, France. 4Endocrine
Gynaecology, Hôpital Jeanne de Flandres, Lille University Hospital, 59037 Lille
Cedex, France. 5Hematology, Hôpital Huriez, Lille University Hospital, 59037
Lille Cedex, France. 6Liver Diseases and Gastroenterology, Hôpital Huriez, Lille
University Hospital, 59037 Lille Cedex, France. 7Nephrology Hôpital Huriez,
Lille University Hospital, 59037 Lille Cedex, France. 8InsermU859 Biotherapies
of Diabetes, Lille University Hospital, 59037 Lille Cedex, France.
Received: 9 May 2015 Accepted: 30 August 2015
Table 2 Management of patients prior to starting or already taking immunosuppressive drugs
A: Management prior to starting immunosuppressive treatment
1. Patient information to clarify the consequences of the planned treatment on future fertility and the couple desire for subsequent fertility
(”Bioethics Law of 2004 and 2011 France (Art. L. 2141-)11)
2. Verify the absence of pregnancy.
3. Send to a fertility preservation centre, particularly if cyclophosphamide (see Table 3).
4. Effective contraception until desire for pregnancy, even in case of supposedly already altered ovarian reserve if the treatment is teratogenic and/or
pregnancy would be at risk due to the underlying disorder. The metabolic effects of calcineurins and mTOR inhibitors as well as glucocorticoids will
require the prescription of a progestin-only rather than a combined oestrogen-progestin contraceptive.
5. Screening for potential gynaecological neoplasias (cervical-vaginal smear, mammography) that could be worsened by immunosuppressive
treatment
B Pre-conception management of a parent treated with immunosuppressive agent
1. Pre-conception consultation to discuss stopping/changing immunosuppressive drug with referring team.
2. Preconception consultation with the couple: an explanation will be offered concerning the possible strategies and obligations in order to minimise
the maternal-foetal risks if pregnancy is possible; these include the need for a stable disease, multidisciplinary management, a possible period of
weaning from the treatment or immuno-suppression switch, the risk of organ rejection and/ or reactivation of an underlying disease, the risk of
transmitting a genetic disorder causing organ failure (Wilson’s disease, polycystic kidney disease, etc.).
3. The pregnancy will need to be planned, and the treatment will need to be modified if necessary in a pre-conception time period adapted to its
half-life (See Table 1, last column).
4. If pregnancy inadvertently occurs while taking immunosuppressive treatment, reassure the patient, test for known complications (ultrasound fetal
examination) and consider stopping or replacing the treatment according to the context.
5. During a planned pregnancy while on authorised treatment, the dosages of immunosuppressive agents should be closely monitored in order to
avoid overdose situations that are shared with the foetus, but also to avoid underdosing, which would compromise the control of the disease or the
function of the graft. During pregnancy there are variations in absorption and metabolism of the drugs.
Leroy et al. Orphanet Journal of Rare Diseases (2015) 10:136 Page 13 of 15
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Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.
- c.ICABMDD_OJRD_20150101_32084110BF24CE40D324_10862
Abstract
Disease name and definition
Epidemiology
Clinical description of the consequences of immunosuppressive drugs on fertility and pregnancy
Immunosuppressive drugs and fertility
Immunosuppressive therapies and pregnancy
Diagnosis
Differential diagnosis
Aetiologies or effects of the different classes of immunosuppressive agents on fertility and pregnancy
Contraindicated drugs when pregnancy is desired (Table 1)
Methotrexate
Mycophenolate (purine synthesis inhibitor)
Leflunomide and teriflunomide
Cyclophosphamide
Mitoxantrone
Drugs to be used with caution (Table 1)
Anti-TNF-α (tumour necrosis factor alpha) (anti-cytokine)
mTOR inhibitors: sirolimus, everolimus, temsirolimus
Treatments associated with a low risk of deleterious effects on fertility and pregnancy (Table 1)
Glucocorticoids
Sulfasalazine
Mesalazine
Azathioprine (purine analog, precursor of 6- mercaptopurine)
Ciclosporine (calcineurin inhibitor)
Tacrolimus (calcineurin inhibitor)
Beta interferon and glatiramer acetate
Chloroquine
Recent drugs in which the effects are not fully known (Table 1)
Biological therapies
Immunomodulators in multiple sclerosis
Induction immunosuppressive treatments
Management of patients using immunosuppressive drugs
Prognosis and unresolved questions
Abbreviations
Competing interests
Authors’ contributions
Acknowledgement
Author details
References
ITALIAN JOURNAL
OF PEDIATRICS
Davanzo et al. Italian Journal of Pediatrics 2013, 39:50
http://www.ijponline.net/content/39/1/50
RESEARCH Open Access
Antiepileptic drugs and breastfeeding
Riccardo Davanzo, Sara Dal Bo, Jenny Bua, Marco Copertino, Elisa Zanelli and Lorenza Matarazzo*
Abstract
Introduction: This review provides a synopsis for clinicians on the use of antiepileptic drugs (AEDs) in the
breastfeeding mother.
Methods: For each AED, we collected all retrievable data from Hale’s “Medications and Mother Milk” (2012), from
the LactMed database (2013) of the National Library of Medicine, and from a MedLine Search of relevant studies in
the past 10 years.
Results: Older AEDs, such as carbamazepine, valproic acid, phenytoin, phenobarbital, primidone are considered to
have a good level of safety during lactation, due to the long term clinical experience and the consequent amount
of available data from the scientific literature. On the contrary, fewer data are available on the use of new AEDs.
Therefore, gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, pregabalin, leviracetam and topiramate are
compatible with breastfeeding with a less documented safety profile. Ethosuximide, zonisamide and the continue
use of clonazepam and diazepam are contraindicated during breastfeeding.
Conclusions: Although the current available advice on the use of AEDs during breastfeeding, given by different
accredited sources, present some contradictions, most AEDs can be considered safe according to our review.
Keywords: Antiepileptic drugs, Breastfeeding, Lactation risk
Introduction
Breastfeeding is known for its beneficial effects on both
mothers and infants [1,2]. Nevertheless, in mothers suf-
fering from epilepsy or bipolar disorders treated with
antiepileptic drugs (AEDs), some concerns on infant
health may raise. The decision to encourage breast-
feeding in those women should be taken after a careful
evaluation of the possible side-effects on the infant
caused by the indirect exposure to AEDs via breast milk.
Data on the use of AEDs by the nursing woman are
mainly represented by single pharmacologic or pharma-
cokinetic studies and/or by case reports or case series on
the side-effects attributed to their presence in breast
milk. Moreover, toxicological and clinical data on AEDs
during breastfeeding are dispersed in the scientific litera-
ture and consequently not easily accessible to health
professionals called to give an evidence-based clinical
advice. The present paper aims at providing the clinician
with an updated synopsis of the lactation risk of AEDs.
* Correspondence: lorenza.matarazzo@gmail.com
Division of Neonatology, Institute for Maternal and Child Health – IRCCS
“Burlo Garofolo”, Via dell’Istria 65/1, Trieste 34100, Italy
© 2013 Davanzo et al.; licensee BioMed Centr
Commons Attribution License (http://creativec
reproduction in any medium, provided the or
Methods
Drugs considered for the present review have been se-
lected as the most frequently used among those catego-
rized as major antiepileptic (Code N03) by the Anatomical
Therapeutic Chemical Classification System (ATC) [3]
together with the anxiolytic diazepam (N05BA01). Before
assessing the lactation risk of each AED, we have collected
information on their main pharmacokinetic parameters:
plasma protein binding, half-life, milk-to-plasma ratio,
oral bioavailability (see Table 1 for definitions). We de-
cided to present data on AEDS pharmacokinetic parame-
ters as they represent the theoretical basis on which the
lactation risk assessment should be developed. As an ex-
ample, we can assume that if a drug has a short half-life
(<3 hours), its level in the maternal plasma will be declin-
ing when the infant feeds again, considering a 3-hour
interval. Moreover, if the drug is highly protein bound, it
cannot enter the milk compartment easily. Milk/plasma
ratio has the primary use of quantifying the extent of drug
transfer into the milk; nevertheless, its use in assessing a
lactation risk is limited as the amount of drug transfer into
milk is mainly determined by the maternal plasma level.
Medications for the breastfeeding mother should have a
low oral bioavailability, as the result of either a poor gut
al Ltd. This is an Open Access article distributed under the terms of the Creative
ommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
iginal work is properly cited.
Table 1 Definitions and clinical relevance of the pharmacokinetic parameters used to assess the lactation risk
following maternal intake of medications
Pharmacokinetic parameter Definition
Half-life or “T ½” The half-life of a substance is the time it takes for its plasma concentration to halve. If the half-life is long (>12-24 hrs),
drugs may accumulate in maternal plasma and the time of drug transfer from plasma to breast milk is longer.
Maternal plasma protein
binding (PB)
This parameter is expressed in percentage. The higher the percentage of the drug bound to the maternal plasma
proteins, the less the drug passes into breast milk. An ideal drug to be taken during breastfeeding should have a
plasma protein binding > 80%.
Milk-to-plasma ratio (M/P) It denotes the ratio of the drug concentration in the mother’s milk (M) divided by its concentration in the mother’s
plasma (P). It is an indicator of drug transfer into breast milk. A M/P ratio greater than 1.0 suggests that the drug may
be present in breast milk in high concentrations.
Oral bioavailability It describes the fraction of one orally administered dose of a drug that reaches the systemic circulation. It is expressed
as a percentage of the administered dose. When the intestinal absorption of a drug is impaired, the risk of adverse
effects may be lower.
Davanzo et al. Italian Journal of Pediatrics 2013, 39:50 Page 2 of 11
http://www.ijponline.net/content/39/1/50
absorption, or the liver sequestration prior to entering the
plasma compartment. Table 2 summarises each AED main
pharmacokinetic characteristics.
Beyond presenting pharmacokinetic parameters on
AEDs, we chose to collect more relevant clinical param-
eters such as the theoretical infant dose (TID), the thera-
peutic dose in the neonatal period and the relative infant
dose (RID). All these parameters were reported in a table
(Table 3) together with the assessment of the lactation
Table 2 Main pharmacokinetic characteristics of antiepileptic
PB† Oral
Bioavailability ‡
(%) (%)
Carbamazepine 74 100
Clonazepam 50 – 86 100
Diazepam 99 100
Ethosuximide NA 100
Gabapentin < 3 50 – 60
Lamotrigine 55 98
Levetiracetam < 10 100
Oxcarbazepine 40 100
Phenobarbital 51 80 – 100
Phenytoin 89 70 – 100
Pregabalin NA 90
Primidone 25 90
Tiagabine 96 90
Topiramate 15 75
Valproate 94 100
Vigabatrin NA 50
Zonisamide 40 NA
† PB: maternal plasma protein binding expressed as percentage.
‡ Oral Bioavailability: intestinal absorption after oral administration expressed as pe
§ T ½: half-life of the drug.
¶ M/P: milk to plasma ratio of a drug concentration.
Data drawn from references 1–8 except where otherwise specified. NA: indicates th
risk (see below), in order to have a clinical overview of
each AED.
TID is the maximum estimated amount of ingested drug
with breast milk; in other words, it is the estimation in
milligrams per kilogram per day of the theoretical infant
dose (TID). We calculated it by using the formula by
Atkinson (TID = daily breast milk intake (150 ml/kg/day) ×
maximum breast milk concentration of medication). [4]
As AEDs may be used in the neonatal period as therapy,
drugs
T ½ § M/P¶
(hours)
18 – 54 0.69
18 – 50 0.33
43 0.2 – 2.7
30 – 60 0.94
5 – 7 0.7 – 1.3
29 0.057 – 1.47 [33]
6 – 8 0.76 – 1.55 [37,38]
9 (oxcarbazepine metabolyte) 0.5
20 – 133 0.4 – 0.6
(45–500 in newborns) [41]
6 – 24 0.18 – 0.45
(20–160 in preterm infants) [48]
6 NA
5 – 18 0.72
7 – 9 NA
18 – 24 0.86 – 1.1 [55]
14 0.42
7 < 1
63 0.93
rcentage of the administered dose.
at no data are available.
Table 3 Clinical relevant parameters for each antiepileptic drug and assessment of their lactation risk
Drug TID† Neonatal therapeutic
oral dose
RID‡ Assessment of the lactation risk according to:
(mg/kg/day) (%) Hale
2012§
LactMed 2013 Present study
(mg/kg/day)
(including adverse drug reactions)
Carbamazepine 0.7 10 - 20 3.8 - 5.9 L2 CBZ levels are relatively high in breast milk Safe
▪ Breastfed infants have serum levels that are
usually below the therapeutic range.
▪ Side effects were rarely reported as sedation,
decreased suckling, withdrawal reactions and 3
cases of liver dysfunction.
▪ Infant should be monitored for jaundice,
drowsiness, adequate weight gain, and
developmental milestones especially in premature
infants, exclusively breastfed and in combination
with other antipsychotics.
Clonazepam 0.002 0.1 - 0.2 2.8 L3 ▪ Monitor growth, sedation, developmental
milestones, especially in preterm neonates,
exclusively breastfed infants and if mother is
receiving psychotropic drugs.
Contraindicated
▪ Monitoring of serum concentration in breastfed
infant, if excessive sedation occurs.
Diazepam 0.05 IV dose available: 7.1 L3 ▪ Accumulates in maternal milk and serum of
breastfed infant. Other agents are preferred,
especially while nursing a newborn or preterm
infant.
Contraindicated
0.1- 0.3
Oral dose
▪ Single dose does not require delaying feeding.0.5 – 1 [76]
Ethosuximide 11.5 15 – 40 31.4-73.5 L4 ▪ Monitor infant for drowsiness, adequate weight
gain and psychomotor development.
Contraindicated
▪ Measurement of an infant serum level might help
rule out toxicity, if there is a concern.
Gabapentin 1.7 Only paediatric
dose available:
1.3 - 6.6 L2 ▪ Monitor the infant for drowsiness, adequate weight
gain, and developmental milestones, especially in
younger, exclusively breastfed infants and when
using combinations of anticonvulsant or
psychotropic drugs.
Moderately safe
10-15
Lamotrigine 0.7 1-6 with valproate, 5-
15
with enzyme
inducing AEDs
9.2 L3 ▪ It is not necessary to discontinue
breastfeeding, but any adverse effects such as
apnoea, rash, drowsiness, decreased sucking are
to be monitored and serum levels are to be
measured.
Moderately safe
(testo: 9.2-18.3)
▪ Monitoring of the platelet count may also be
advisable.
Levetiracetam 3.9 5 - 10 [78] 3.4 - 7.8 L3 ▪ Monitor infant for the appearance of sleepiness,
increase appropriate weight, normal psychomotor
development.
Moderately safe
Oxcarbazepine NA 27.7 – 50 1.5-1.7 L3 ▪ Monitor the infant for drowsiness and decreased
feeding, and developmental milestones especially
in the first 2 months of life.
Moderately safe
(<18 years) [72]
Phenobarbital 0.4 3-4 24 L3 ▪ The presence of phenobarbital in breast milk may
mitigate possible neonatal abstinence.
Safe
▪ Monitor the breastfed infant for the possible
onset of drowsiness, adequate weight gain and
developmental milestones, especially in younger,
exclusively breastfed infants and antiepileptic
polytherapy.
▪ Measurement of the infant’s serum drug
concentration might help rule out toxicity.
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Table 3 Clinical relevant parameters for each antiepileptic drug and assessment of their lactation risk (Continued)
Phenytoin 0.4 5-8 0.6-7.7 L2 ▪ The proportion ingested by infants is small and
generally brings about no problems except in
rare cases of idiosyncratic reactions.
Safe
Pregabalin NA 5-14 [79] NA L3 ▪ Compatible with breastfeeding. Moderately Safe
▪ An alternate drug may be preferred, especially
while nursing a newborn or preterm infant.
Primidone 0.9 12-20 8.4-8.6 L3 ▪ The presence of phenobarbital in breast milk may
mitigate possible neonatal abstinence.
▪ Monitor the breastfed infant for the possible
onset of drowsiness, adequate weight gain and
developmental milestones, especially in younger,
exclusively breastfed infants and antiepileptic
polytherapy.
Safe
▪ Measurement of the infant’s serum drug
concentration might help rule out toxicity.
Tiagabine NA <12 years: limited data
available.
NA L3 ▪ Monitor the infant for the onset of drowsiness,
for adequate weight gain and for developmental
milestones especially in younger, exclusively
breastfed infants and when using combinations
of anticonvulsant or psychotropic drugs.
Moderately safe
▪ Other drugs should be preferred especially while
nursing a newborn or preterm infant.
Topiramate 0.3 1 - 6 24.5 L3 ▪ Monitor the infant for the onset of diarrhea,
drowsiness, increase appropriate weight and
psychomotor development.
Moderately safe
(<2 years) [80]
Valproate 0.7 Limited data available
in the neonatal period.
1.4-1.7 L3 ▪ Breastfed infants are at risk for hepatotoxicity. Safe
▪ Monitor the infant for unusual bleeding
(a case of thrombocytopenia has been reported).
Vigabatrin 0.1 25-50 1.5 – 2.7 L3 ▪ Until more data are available, vigabatrin should
only be used with careful monitoring during
breastfeeding.
Moderately safe
S-enantiomer
Zonisamide 1.9 5 – 8 28.9 -36.8 L4 ▪ Monitor infant for drowsiness, adequate weight
gain and psychomotor development.
Contraindicated
▪ Measurement of an infant serum level might help
rule out toxicity if there is a concern.
† TID theoretical infant dose.
‡ RID relative infant dose.
§ Hale lactaction risk categories: L1: safe drugs at the highest level, L2: safe, L3: moderately safe; L4: possibly dangerous, L5: contraindicated. Present study risk categories: The
moderately safe category has a less documented safety profile due to a short clinical experience and lack of studies. The moderately safe AEDs can be used, but the lowest
dose of the drug should be chosen and the nursing infant should be clinically monitored and, when possible, his/her plasma level should be checked.
Data drawn from reference 1,41 except where otherwise specified. NA: indicates that no data are available.
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we presented their therapeutic dose, expressed in mg/kg/
day in order to have a direct comparison with the TID. A
therapeutic dose which is higher than the TID reassures of
the drug safety during breastfeeding. RID represents one
of the most useful parameters for assessing the lactation
risk. RID is calculated by dividing the infant dose via milk
in “mg/kg/day” by maternal dose in “mg/kg/day”, assum-
ing a 70 kg weight. [5] Many authors agree that anything
less than 10% of the maternal dose is considered probably
safe [5].
To review the lactation risk of AEDs, we consulted the
following two most accredited English sources: Medica-
tions and Mother’s Milk 2012, a Manual of Lactational
Pharmacology [1], and the 2013 Lactmed database (in
TOXNET) [6] of the National Library of Medicine. In
his textbook, updated every two years, Hale collects data
on many current medications and their use during
breastfeeding. After evaluating information on pharma-
cokinetics and what is currently published in the scien-
tific literature for each drug, including its reported side
effects, he makes a personal recommendation, using a 5
categories of lactation risk: L1: safe drugs at the highest
level, L2: safe drugs, L3: moderately safe drugs, L4: drugs
possibly dangerous, L5: contraindicated drugs. LactMed
database is part of the National Library of Medicine’s
Toxicology Data Network (TOXNET), and it includes
information on the levels of drugs and other chemicals
to which breastfeeding mothers may be exposed in
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breast milk and infant blood, together with the possible
adverse effects in the nursing infant. All data published
in LactMed are derived from the scientific literature and
fully referenced.
To complete our synopsis, we have also performed a
non-systematic Medline search of the literature with the
keywords “antiepileptic drugs” AND “breastfeeding”, re-
trieving studies from 2004 to April 9th 2013 , including
the most relevant and up-dated studies on lactation risk.
Data from the Committee on Drugs of the American
Academy of Pediatrics (AAP) [7], and the Goodman &
Gilman’s Textbook of Pharmacology [8] were also included
in our review.
For each AED we organized the relevant data into
small summaries.
As the result of our review we classified AEDs in 3
categories: safe, moderately safe and contraindicated
during breastfeeding. The moderately safe category has a
less documented safety profile due to a short clinical
experience and lack of studies. However, the moderately
safe AEDs can be used with caution. The lowest dose of
the drug should be chosen and the nursing infant should
be monitored and, when possible, his/her plasma level
should be checked.
Results
Benzodiazepines
Benzodiazepines (BDZ) are multiple-action psychoactive
compounds. Therefore, they may be used as anxiolytics,
antiepileptics, sedatives, hypnotics, muscle relaxants,
and as coadjuvants in anaesthesia induction. Simplifying,
we can state that all BDZ produce all these effects, albeit
with different expression of their principal effect (relative
selectivity).
In general, the first step to judge the safety of BDZ
during lactation is to know their half-life (short, inter-
mediate, long). Independently of other kinetic character-
istics, the longer is a drug half-life, the longer is its
passage into maternal milk, and the greater is the infant
metabolic effort to metabolize the drug. Both diazepam
and clonazepam have long half-life (diazepam 43 hours,
clonazepam 18–50 hours) [1]. Consequently, their pri-
mary risk to the infant is drug accumulation, which also
depends on the infant metabolism (i.e. slower in preterms)
and the therapy duration. Intermittent, short-term therapy
(24–72 h), carries a negligible risk of accumulation,
whereas prolonged use of a long half-life BDZ such as
diazepam and clonazepam, carries a greater risk. In the
meanwhile, there is no lactation risk after a single dose of
BZD, as no drug accumulation occurs.
Diazepam is highly protein bound and its transfer into
breast milk is variable. Concentrations of diazepam and
its metabolite desmethyldiazepam in maternal milk vary
between 7.7 and 87 ng/L and 19.2 and 77 ng/L, respectively
[9]. Its active metabolite tends to accumulate during
prolonged lactation. Lethargy and difficult feeding have
been attributed to diazepam during breastfeeding [10].
Maternal plasma peak usually occurs within 2 h. By
delaying feeding, the infant exposure to diazepam with
maternal milk can be reduced.
Despite its scarce transfer into maternal milk, clonaze-
pam was reported to cause irregular breathing, apnea and
cyanosis in the first 10 days of life in an infant whose
mother had been taking the drug also during pregnancy.
The child psychomotor development at 5 months was
normal [11]. On the contrary, in the study of Birnbaum,
no side effects on breastfed infants were reported by
mothers treated with benzodiazepines in association with
antidepressants [12]. Clonazepam has a later plasma peak
(2–6 hours) which limits the feasibility of delaying feeding
in order to reduce the infant exposure.
Carbamazepine
Carbamazepine (CBZ) is a broad-spectrum anticonvul-
sant, also used in psychiatric disorders (such as schizo-
phrenia) and in trigeminal neuralgia. If taken during
pregnancy, its concentration compared to the maternal
serum level ranges 60-76% in the umbilical cord and 32-
80% in breast milk [13]. Most available studies on carba-
mazepine in human milk usually refer to women under
anticonvulsant polytherapy with possible interference
between drugs.
The CBZ and its active epoxide metabolite (ECBZ) are
poorly excreted into breast milk (M/P: 0.69 and 0.79 re-
spectively), partly due to the good plasma protein bind-
ing. CBZ concentration in breast milk in the current
literature is widely variable (0.34-6 mg/L) [14–17]. Its
RID is low (3.8-5.9%) [1] and serum levels in babies are
usually low, while ECBZ is not detected at all [18–20].
LactMed Database suggests to monitor breastfed in-
fants for adequate growth and possible onset of sedation
and jaundice, given some case reports of liver dysfunc-
tion with cholestasis (increase in transaminases and
gammaGT) [21,22]. Nevertheless, the drug is considered
compatible with breastfeeding [7,22–25]. In fact, it is ad-
ministered, with a good safety profile, directly to patients
of pediatric age.
Ethosuximide
Ethosuximide is used in the treatment of absence sei-
zures. Protein binding of the drug is insignificant. Its
half-life is shorter in children (30–60 h) than in adults
(about 45 h) and the M/P ratio is 0.94 [1]. The amount
of ethosuximide excreted in breast milk leads to a rele-
vant RID (31.4-73.5%) [1], which explains the significant
serum concentrations in breastfed infants (15–40 mg/L)
[26]. Although the study of Rane reported some neuro-
logical symptoms in breastfed infants (hyperexcitability,
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sucking difficulty), this could have been due to the
antiepileptic polytherapy of their mothers and/or to the
combination with withdrawal symptoms [27]. Ethosu-
ximide is considered to be potentially dangerous during
lactation [1] and monitoring breastfed infant has been
suggested [26].
Gabapentin
Gabapentin is used in the treatment of partial epilepsy,
cluster headache [28], neuralgia, post-caesarean delivery
pain [2] and some psychosis. Gabapentin has a medium
half-life and is believed to accumulate in the fetus, while
it does not concentrate in breast milk (average M/P =
0.7-1.3) [1,29], leading to low serum levels and no side
effects in breastfed infants [29,30].
Lamotrigine
In fetuses exposed to lamotrigine, concentrations are
highest at birth and then gradually decline over time,
more quickly if the infant is not breastfed [31]. Some of
the pharmacokinetic characteristics of lamotrigine, such
as the long half life (29 hours) and the low protein bind-
ing (55%) [1] together with a recent reported case of
severe toxicity [32], warrant attention towards its use
during breastfeeding. The anecdotal case by Nordmo
refers to a 16 days-old-infant whose mother had shown
visual disturbances and dizziness, after taking a high
dose of lamotrigine (850 mg/day) [32]. Soon after, the
baby had a series of episodes of apnea followed by a
cyanotic crisis which requested resuscitation. Plasma
level of lamotrigine in that infant was consistently high
(4.87 μg/mL). After discontinuing the drug, the infant
recovered.
The excretion of lamotrigine in breast milk is largely
variable. A study on 30 breastfeeding women, treated for
more than 7 days with lamotrigine at doses 300–
450 mg/day, showed that breast milk samples collected
over 24 h contained 0.5-18.1 μg/mL of lamotrigine [33].
The M/P ratio ranged from 0.057 to 1.47. [1,33] The
dose that the breastfed infant would take has been calcu-
lated between 0.37 and 0.65 mg/kg/day, well below the
dose given to infants affected by epilepsy resistant to
common antiepileptic drugs [34,35]. The average RID is
9.2 (33).
Liporace reports that serum concentrations of lamotrigine
in breastfed children in some cases reach therapeutic ranges
[36]. These high levels may be explained by the genetic
variability in the neonatal glycuroconjugation responsible for
lamotrigine metabolism [36].
When maternal plasma levels are 4.5-13.4 μg/mL,
breastfed infant plasma levels are 0.6-1.8 μg/mL, with a
M/P ratio 0.413% on average [33]. Moreover laboratory
tests (electrolytes, hepatic function tests, complete blood
count) have been all normal, except from a modest
thrombocytosis (range: 329.000–652.000/mm3 PLT, in 7
out of 8 infants tested) [33]. Eventually, Newport et al.
reassure on lamotrigine use while breastfeeding, as no
adverse effects was reported in the nursing infants in
their study [33].
In conclusion, lamotrigine is considered moderately
safe during breastfeeding [1,30], and LactMed recom-
mends to check its plasma level and to carry out a platelet
count in infants whose mothers are on lamotrigine [6].
Levetiracetam
Levetiracetam is a new AED, and is usually added to
other drugs in case of inadequate control of seizures. It
significantly passes into breast milk (M/P: 0.76-1.55)
[5,37,38], it is completely absorbed orally and it has a
pediatric half-life of about 18 hours with a low RID (3.4-
7.8%) [1].
Serum levels of levetiracetam in breastfed infants are
low (<21 μmol/L) and no side-effects have been reported
when doses between 1.3 and 3 g/day are administered to
their mothers [37,38].
Consequently, levetiracetam is usually considered com-
patible with breastfeeding [1,37,38], even if associated to
other AEDs such as primidone and phenobarbital [39].
Oxcarbazepine
Oxcarbazepine (OXC) is a pro-drug which is converted
in its active metabolite (10-OH-carbazepine) (10-OH-CBZ)
in the liver. Reports of its use while breastfeeding are lim-
ited. Most information is obtained by the paper of Lutz:
oxcarbazepine has a long half-life (9 h), a low M/P ratio
(0.5) and a low concentration in human milk (<11 μg/mL)
with a low RID (1.5-1.7%) [40]. It lacks side effects in
breastfed infants. Blood levels in infants of OCX and 10-
OH-CBZ are negligible (both <0.2 μg/mL). Therefore, we
can consider OXC moderately safe in the breastfeeding
mother.
Phenobarbital
Phenobarbital is widely used in both adults and children.
Its metabolism is mainly hepatic. The extremely long
half-life in the pediatric age (20–133 hours in infants
and up to 500 hours in newborns) [41] and the lower
plasma protein binding in neonates compared to adults
(3-43% vs 51%) could explain why its blood levels may
be higher in newborns than in their mothers.
The main, yet rare, side-effect attributed to phenobar-
bital is sedation, holding true in adults as well as in
breastfed babies. This occurrence is reported more fre-
quently in infants whose mothers are in polytherapy,
because they are likely to be exposed to interactions be-
tween drugs with possible enhancement of both clinical
and side effects [39].
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Phenobarbital is commonly and safely used at a daily
dosage 5–7 mg/kg/day in newborns affected by seizures
or drug-abstinence syndrome. This dose is far higher
than the estimated dosage (2–4 mg/day) received by a
breastfed infant by a woman taking 150 mg (a high dose)
phenobarbital per day. Given these data, there is no need
to discontinue breastfeeding in mothers treated with
phenobarbital. However, AAP is more cautious and
recommends to monitor all breastfed infants whose
mothers are on phenobarbital [7]. In premature babies
or in infants with drowsiness, difficulty in sucking or
poor weight gain, it is recommended to monitor its
plasma levels [6,42–44].
Phenytoin
Despite the formerly reported methemoglobinemia in in-
fants [45], phenytoin is considered to be safe in lactation
[5,46,47], as it is highly bound to plasma proteins (89%)
[1], it scarcely passes into breast milk (M/P: 0.18-0.45)
[1,48,49] and has low concentration in human milk [49].
In fact, milk concentration of phenytoin has been
reported to be only 1.9 mg/L following maternal intakes
equal to 300–600 mg [50]. The amount ingested by
nursing infants is usually low (RID 0.6-7.7%) [1].
Pregabalin
Pregabalin is used to treat postoperative [51] and neuro-
pathic pain and some psychosis. There are no studies on
the passage of pregabalin into human milk. The absence
of binding to plasma proteins and its excellent oral bio-
availability [52] suggest that it can pass into the mother’s
milk and into the circulation of the nursing infants.
Numerous side effects such as dizziness, drowsiness,
impaired vision have been observed in adults. It is rated
as moderately safe during breastfeeding [1].
Primidone
Primidone is metabolized to phenobarbital and other
derivates. Serum levels of primidone and its metabolites
in breastfed infants could be close to the therapeutic
range values and cases of sedation and poor feeding are
reported in literature. It should be used with caution
during breastfeeding [14,42,43,53,54], also according to
the AAP [7]. The clinical assessment of its use during
breastfeeding is similar to phenobarbital.
Tiagabine
Tiagabine oral absorption is almost complete and it is
highly bound to plasma proteins [41]. There are no stud-
ies on its use during breastfeeding, leading to possibly
prefer other antiepileptic drugs. If taken by the nursing
mother, infant should be monitored [46].
Topiramate
Topiramate use is increasingly prescribed, being effective
and well-tolerated by epileptic patients. It is rapidly
absorbed, it has a low plasma protein binding, a rela-
tively long half-life and a significant excretion into breast
milk (M/P:0.86-1.1) [1,55] with a high RID (24.5%) [1].
Despite these characteristics may raise some concerns
on its use during breastfeeding, breastfed infants have
been found to have very low serum levels (<2.8 μmol/L)
in the first 3 months of life after maternal intakes of
150–200 mg/day of topiramate in association with CBZ
[55]. These low serum levels seem to depend on the in-
fant good capability to eliminate topiramate, possibly
facilitated by CBZ enzyme induction [55]. Moreover,
infants who were breastfed by mothers treated with
topiramate did not show side-effects. Notwithstanding,
they should be monitored [55,56].
Valproate
Patients taking valproate may develop hepatotoxicity,
thrombocytopenia and anemia. The limited passage of
valproate into breast milk (the drug is almost completely
bound to plasma proteins) make it safe in lactation.
[23,24,46,47] Serum levels in breastfed infants are low
[18]. However, some controversies exist on its safety
profile. The teratogenic effect of valproate exposure in
pregnancy [57], together with the decrease of methyla-
tion in the DNA extracted from the umbilical cord blood
[58] and a report of a breastfed infant with thrombocyto-
penia, purpura and anemia [59], induce a cautious use of
this AED during breastfeeding [1]. Although there is no
indication to perform routine laboratory investigations, in
case of late jaundice, it is reasonable to assess the
hepatobiliary function and to test its plasma levels in the
breastfed infant [23,46,57–62].
Vigabatrin
Vigabatrin is commonly used for multi-resistant epi-
lepsy. The maternal plasma concentration is 93 μmol/L
following an intake of 1.5 g vigabatrin. There are no pre-
cise data about its passage into breast milk. Since no
information is available about its use during lactation,
the nursing infants should be monitored [46].
Zonisamide
Zonisamide is a broad-spectrum anticonvulsant with a
half-life of nearly 63 hours [1], even if some authors re-
port a longer one (109 hours) [63]. It easily passes into
breast milk (M/P: 0.93) [6,64]. Although no studies
document side-effects in children of mothers receiving
zonisamide, due to a very high RID (28.9-36.8%), it has
been considered contraindicated by some authors [1].
Others authors simply recommend measurement of
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infant serum level to rule out toxicity, if there is a con-
cern [6].
Table 2 summarises each AED main pharmacokinetic
characteristics. Table 3 gives an overview of the clinical
relevant parameters for each antiepileptic drug (TID,
therapeutic dose, RID) and the assessment of their lacta-
tion risk according to the two main sources (Hale and
LactMed) and to our study group.
Discussion
The use of AEDs is often unavoidable for most mothers
with epilepsy. Moreover, the post partum period is a vul-
nerable time for women with epilepsy, owing to the
changes in the drug metabolism and possibly to sleep
deprivation. Both these conditions may trigger an epilep-
tic crisis [65].
As the newborn might be indirectly exposed to AEDs
via breast milk, pharmacologically treated epilepsy has
been and sometimes is still considered a contraindica-
tion to breastfeeding, irrespective of which AED is taken
by the mother [66]. On the contrary, health professionals
have currently become more aware of the need to weigh
the short and long-term risks for the nursing infant
against the well demonstrated nutritional, immuno-
logical, developmental, economic and ecological benefits
of breastfeeding [1,2,67]. When evaluating the safety
profile of an AED during lactation, the physician should
collect and process data which are often dispersed in the
scientific literature and difficult to retrieve [66]. We have
therefore completed the present review in order to facili-
tate the consultancy on the use of AEDs during breast-
feeding.
The comparison of advices from the main and most
recent accredited literature sources has highlighted the
existence of a certain degree of inconsistency [66], which
is probably the consequence of the combination of lim-
ited scientific evidence and of a certain degree of arbi-
trariness. This heterogeneity of advice is not specific of
AEDs. We have previously documented a metavariability
in the assessment of the lactation risk of other classes of
drugs, such as beta-blockers [68], corticosteroids [69]
and antidepressants [70].
Evaluating the lactation risk of any drug is complex
and should take into account several aspects. In our re-
view, we have shown that neither pharmacokinetic infor-
mation nor more clinical parameters (such as TID and
RID) are alone good predictors of the lactation risk. As
an example, a drug such as phenobarbital, which is
poorly bound to the mother plasma proteins and has a
relatively long half-life and an high RID, can still be con-
sidered compatible during breastfeeding [1].
When evaluating the lactation risk of a drug, we
should always check whether or not toxicity in breastfed
infants is reported. AEDs are expected to determine in
the nursing infant a series of symptoms related to their
pharmacological effects on the central nervous system,
such as altered sleep patterns, abnormal tone, poor feed-
ing and possibly poor growth secondary to inadequate
breast sucking. However, the clinical relevance of these
attributed side-effects vary widely. As an example, the
lactation risk of infant apnea after maternal use of clo-
nazepam [11] deserves a higher level of caution than the
risk of infant sedation after maternal use of CBZ.
Another variable to take into account when consider-
ing the infant tolerance to AEDs, is his/her ability to
metabolize the drug. This is much lower when the ma-
ternal treatment begins before or during pregnancy (as
the exposure of the baby through breast milk adds to
the one through the placenta), or in case of prematurity
and during the first 2 months of life [71]. Maternal
polytherapy is also expected to increase the lactation
risk, as the result of the possible synergistic interaction
of different medications [39].
We might also speculate that the alleged long-term nega-
tive effects on child psychomotor development resulting
from the passage of small amounts of the drug through
breast milk, though up to now not well-documented,
could be well-balanced by the benefits that breast-
feeding confers to the cognitive, social and relational
development. This hypothesis seems to be supported by
the results from a study conducted in the US on 199
children exposed in uterus to AEDs (phenytoin, carba-
mazepine, valproate and lamotrigine) and followed in
the first 3 years of life. In this cohort, there was no sig-
nificant difference regarding cognitive scores between
breastfed and not breastfed children [24].
Breastfeeding mothers should be provided sound and
clear information on the lactation risk of the prescribed
medications. Nevertheless, breastfeeding mothers taking
AEDs happen to receive inconsistent and sometimes
conflicting advices on whether or not to breastfeed from
different clinicians (general physician, neurologist, pedia-
trician, obstetrician, etc.). Unluckily, many such given ad-
vices are not evidence-based, but simply emphasize not
circumstantial assessments of the lactation risk.
We believe that mothers treated with AEDs should be
encouraged to start breastfeeding immediately after child-
birth, even if a definite and complete evidence-based in-
formation has yet not been collected. In fact, breast milk
should not be considered as a “presumed guilty”, because,
after a complete scrutiny, only very few AEDs resulted
contraindicated during breastfeeding [24,72,73].
The present study is not without limitations. First of
all, we did not conduct a systematic review of the pub-
lished literature, but we offered a synopsis of the two
most updated and authoritative clinical sources on the
lactation risk (namely: Hale and Toxnet). Secondly, the
existing reports on the lactation risks of medications in
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general [73], and particularly of AEDs [44] , are usually
anecdotal or based on case series and therefore of poor
methodological quality. However, we should remember
that any recorded side-effect, while biologically and
pharmacologically plausible in the nursing infant, is
rarely attributable with certainty to a particular drug
taken by her/his mother [74].
Conclusions
According to the present review, we grouped AEDs into
3 main classes of lactation risk:
1. AEDs safe to use during lactation. Carbamazepine,
valproic acid and phenytoin are compatible with
breastfeeding. Phenobarbital and primidone are also
compatible, although particular attention should be
paid on infant monitoring, possibly measuring the
infant plasma drug level.
2. AEDs with a less documented safety profile during
lactation (moderately safe). Gabapentin, lamotrigine,
levetiracetam, oxcarbazepine, pregabalin and vigabatrin
may be used during lactation, but their lowest dose
should be prescribed. The nursing infant should be
carefully monitored and, if required, the infant drug
plasma-level tested. When lamotrigine is taken by the
mother, it is advisable to check the presence of
thrombocytopenia in the nursing infant. Although
based on scarce available data, tiagabine and topiramate
can be considered compatible with breastfeeding.
3. AEDs contraindicated during lactation.
Ethosuximide should be used only when there are
no alternatives and after informed consent of the
mother. Lastly, zonisamide and the continuous use
of diazepam or clonazepam should be avoided.
Even if an AED can be safely taken by the breastfeeding
mother, it is a good clinical practice to call the mother
attention on the behavior, sleep, feeding patterns and
growth of the nursing infant, especially in the first
2 months of life [75]. When possible, we might advice to
monitor the infant plasma levels, especially for the moder-
ately safe AEDs. However, we are aware that there is no
clear agreement on when to test them. We believe that
after 4–8 weeks is a reasonable time window, as, if the
child is fully breastfed, breast milk would have reached its
highest production and the consequent intake by the
nursing infant would be at the maximum.
Competing interests
This study was performed without any funding or grants. All the authors
declare that they have no competing interest and do not have any financial
relationships with any biotechnology and/or pharmaceutical manufacturers.
Authors’ contributions
RD conception and design. LM, SDB, RD analysis and interpretation of the
data. LM, SDB RD drafting of the article. RD critical revision of the article for
important intellectual content. All authors listed here have seen and
approved the final version of the report. JB administrative, technical, or
logistic support. MC, EZ collection and assembly of data.
Acknowledgements
We thank Dr. Gian Paolo Chiaffoni (Pediatric Department, Conegliano, Italy)
and Prof. Giuliana Decorti (Institute of Pharmacology, University of Trieste, Italy)
for helpful advice.
Received: 23 April 2013 Accepted: 10 August 2013
Published: 28 August 2013
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Copertino, M., Bua, J., Zanelli, E., Davanzo, R., Dal Bo, S., & Matarazzo, L. (2013). Antiepileptic drugs and breastfeeding. Italian Journal of Pediatrics, 39(1), 1-11. doi:10.1186/1824-7288-39-50
Rigot, J., Le Mapihan, K., Parent, A., Leroy, C., Decanter, C., Yakoub-Agha, I., . . . Dharancy, S. (2015). Immunosuppressive drugs and fertility. Orphanet Journal of Rare Diseases, 10(1), 1-15. doi:10.1186/s13023-015-0332-8
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