Ann Rheum Dis 2011;70:823–826. doi:10.1136/ard.2010.140822 823
Accepted 15 November 2010
Published Online First
28 February 2011
Objective The British Society for Rheumatology
Biologics Register (BSRBR) has collected data on adverse
events including pregnancies in patients with rheumatoid
arthritis treated with anti-tumour necrosis factor (anti-
TNF) therapy. The purpose of this report is to summarise
the pregnancy outcomes in women treated with anti-TNF
in the BSRBR.
Methods Patients were categorised according to
anti-TNF exposure as follows: (1) exposure to anti-TNF
and to methotrexate (MTX) and/or lefl unomide (LEF) at
conception (n=21 pregnancies); (2) exposure to anti-TNF
at conception (n=50); (3) exposure to anti-TNF prior to
conception (n=59); (4) no exposure to anti-TNF (control
Results Eighty-eight live births in a total of 130
pregnancies were reported in patients who received anti-
TNF before or during pregnancy. The rate of spontaneous
abortion was highest among patients exposed to
anti-TNF at the time of conception (with MTX/LEF 33%
and without MTX/LEF 24%). This compared with 17%
spontaneous abortions in those with prior exposure to
anti-TNF and 10% spontaneous abortions in the control
group. Ten terminations were performed.
Conclusion Although the results to date have been
promising, no fi rm conclusions can be drawn about the
safety of anti-TNF during pregnancy and, without further
evidence, guidelines which suggest these drugs should
be avoided at the time of conception cannot yet be
Anti-tumour necrosis factor (anti-TNF) therapies
have been available for the management of arthri-
tis-related diseases for over a decade. The US FDA
categorises anti-TNF agents as category ‘B’ drugs
because animal reproduction studies have failed to
demonstrate a risk to the fetus but adequate and
well-controlled studies of pregnant women have
not been conducted. 1
To date, information on pregnancies in patients
exposed to anti-TNF agents has been reassuring,
with few reports of adverse pregnancy outcomes.
One exception has been the report by Carter et al 2
which listed 61 congenital anomalies reported to
the FDA in 41 women exposed to anti-TNF agents
including one child with the VACTERL syndrome
(a syndrome seen in embryos and fetuses charac-
terised by abnormalities of the vertebrae (V), anus
(A), cardiovascular tree (C), trachea (T), oesophagus
(E), renal system (R) and limb buds (L)). However,
this study lacked a denominator of exposure.
National registries such as the British Society for
Rheumatology Biologics Register (BSRBR), which
collects data on adverse events and pregnancy out-
comes in patients treated with anti-TNF therapy,
provide a more realistic representation of the effect
of anti-TNF therapy on pregnancy outcome. Using
data from the BSRBR, we previously reported on
32 pregnancies with known outcome in women
exposed to anti-TNF agents. 3 Since this publica-
tion, the number of pregnancies reported to the
BSRBR has increased to 130 and the outcome of
these pregnancies is reviewed in this paper.
Study design and patient population
The patients for this study were participants regis-
tered in the BSRBR starting treatment with one of
the three available anti-TNF therapies (adalimumab
(ADA), etanercept (ETA) and infl iximab (INF)). In
addition to the anti-TNF cohort, a parallel cohort of
patients with active rheumatoid arthritis (RA) receiv-
ing non-biological disease- modifying antirheumatic
drugs (nb-DMARD) has been recruited (guide dis-
ease activity score in 28 joints (DAS28) >4.2).
Follow-up information is collected from medical
records every 6 months for the fi rst 3 years and annu-
ally thereafter. Data at follow-up include any changes
to antirheumatic treatment, reasons for changes, and
the onset of any adverse event including pregnan-
cies. In addition, for the fi rst 3 years of the study,
patients are asked directly if they have received new
treatments and about new referrals to (hospital) doc-
tors. Data on pregnancies and pregnancy outcomes
are also extracted from these patient reports.
All reports of pregnancies are followed up with
an additional questionnaire which includes infor-
mation on exposure to biological agents at the
time of conception, details of pregnancy outcome
including live births, spontaneous abortions and
terminations. Details of pregnancy complications
are collected as well as any details of congenital
malformations. For the purpose of this analysis,
pregnancies were divided into three groups: group I
(exposure to anti-TNF at conception); group II (past
exposure to anti-TNF); group III (never exposed to
anti-TNF). Given the known risk of adverse preg-
nancy outcomes associated with the DMARDs
methotrexate (MTX) and lefl unomide (LEF), group
I was further categorised into (a) those exposed to
MTX and/ or LEF at conception and (b) those not
▶ Additional data are published
online only. To view these fi les
please visit the journal online at
Arthritis Research UK
Epidemiology Unit, The
University of Manchester,
Manchester Academic Health
Science Centre, Manchester,
Dr Kimme Hyrich, Arthritis
Research UK Epidemiology
Unit, Manchester Academic
Health Centre, University of
Manchester, Stopford Building,
Oxford Road, Manchester M13
Anti-TNF therapies and pregnancy: outcome of
130 pregnancies in the British Society for
Rheumatology Biologics Register
Suzanne M M Verstappen, Yvonne King, Kath D Watson, Deborah P M Symmons,
Kimme L Hyrich; BSRBR Control Centre Consortium, BSR Biologics Register
Ann Rheum Dis 2011;70:823–826. doi:10.1136/ard.2010.140822824
anti-TNF agents were reported. At registration, baseline DAS28
and Health Assessment Questionnaire (HAQ) scores were sig-
nifi cantly higher in the anti-TNF therapy groups than in the nb-
DMARD group ( table 1 ). For both baseline DAS28 and HAQ
score, a signifi cant difference was observed between groups Ia
and Ib. Patients in group Ia also had a higher HAQ score com-
pared with patients in group II.
Eighty-eight live births in a total of 130 pregnancies (including
three pregnancies with twin gestation) in patients exposed to
anti-TNF therapy were reported: 42/71 (59%) in group I and
exposed to MTX and/or LEF at conception. Women could have
been included more than once in the analysis if more than one
pregnancy had been recorded during the follow-up time and
each pregnancy was allocated to the appropriate exposure group.
For descriptive data, the denominator represents the number of
pregnancies per group, and, therefore, the sum of the percent-
ages presented within each group can be more than 100%.
A total of 130 pregnancies in 118 women ever exposed to anti-
TNF agents and 10 pregnancies in 10 women never exposed to
Table 1 Overview of pregnancy outcomes in the BSRBR
Number of women with pregnancy
Number of pregnancies
Age, mean (SD)
Baseline DAS28 score, n/N*
Baseline HAQ score, n/N†
Adult-onset Still’s disease
Anti-TNF therapy at conception
Anti-TNF therapy prior to conception
Infl iximab (INF)
>1 anti-TNF agent
Conventional DMARD use at conception
MTX or LEF at time
but no MTX or LEF at
time of conception
prior to conception
never exposed to
13 0 0 0
Lefl unomide (LEF)
Combination of DMARDs
3 (MTX/HCQ) and
Steroid use at conception
Premature delivery (≤36 weeks)
*DAS28 score signifi cantly higher in the anti-TNF groups compared with the nb-DMARD group. DAS28 signifi cantly higher in group Ia compared with group II (p=0.0213, unpaired t test).
**Since the number of outcomes is divided by the number of pregnancies, the total sum of percentages can be more than 100%
†HAQ score signifi cantly higher in the anti-TNF groups compared with the nb-DMARD group. HAQ score signifi cantly higher in group Ia compared with group Ib (p=0.0353) and
signifi cantly higher in group Ia compared with group II (p<001).
‡Including one of twins.
¶One because of Down’s syndrome.
DAS28, disease activity score in 28 joints; HAQ, Health Assessment Questionnaire; n/N, number of patients with available data/number of women with pregnancy; RA = rheumatoid
arthritis; PsA = psoriatic arthritis ; JIA = juvenile idiopathic arthritis ; AS = ankylosing spondylitis; SLE = Systemic Lupus Erythematosus.
Ann Rheum Dis 2011;70:823–826. doi:10.1136/ard.2010.140822 825
or neonatal illnesses. 9 10 14 15 Data from OTIS, published only
in abstract form, show that the spontaneous abortion rate was
7.4% in patients exposed to ADA during the fi rst trimester
and 6.1% in the RA comparison group. These percentages are
lower than we found in our study population, but no informa-
tion regarding DMARD intake at conception and general disease
activity was provided for the OTIS population. 16
Both MTX and LEF are ‘X’ category drugs. There is a rec-
ognised association between high-dose MTX and spontane-
ous abortion. A recent systematic review found that 23% of
pregnancies exposed to MTX in the fi rst trimester resulted
in spontaneous abortion and 5% of pregnancies resulted in
reported minor neonatal malformations. 17 In our study, 20
patients became pregnant while receiving ‘X’ class drugs. It
is not known whether they were informed about the detri-
mental effects of these drugs, although we do know that a
few patients became pregnant while using oral contracep-
tives which suggests that these were unplanned pregnancies.
However, it cannot be concluded that the concurrent use of
MTX and/or LEF is the only explanation for this increased rate
of spontaneous abortion, as the rate of spontaneous abortion
in women exposed to anti-TNF therapy at conception without
these drugs was also higher than in those previously or never
exposed to anti-TNF agents. There are data to suggest that
women with severe RA may have an unfavourable pregnancy
outcome, and those patients unable to discontinue anti-TNF
therapies may be those with the most severe disease. 18 19 We
did not collect data on disease activity at time of conception.
It is thus important to weigh the impact of disease severity
on pregnancy outcome and the results found in our study
with regard to the somewhat increased risk of spontaneous
abortions in patients receiving anti-TNF agents at conception.
Despite the exposure of anti-TNF therapy at conception, few
patients opted for termination. Compared with the termina-
tion rate of 12.9% in women aged 30–34 years in the gen-
eral population of England and Wales (ie, the percentage of
pregnancies resulting in one or more live births or a stillbirth
or legal abortion that were terminated by abortion), 20 the ter-
mination rate was higher in those exposed to anti-TNF ther-
apy plus MTX or LEF at conception (19%) but lower in those
exposed to anti-TNF agents alone (8%).
Data on drug safety during pregnancy are largely restricted
to the cumulative experience of patients and physicians and
often limited to case reports. One of the biggest challenges in
obtaining safety data is ensuring that outcomes in all exposed
patients are recorded, not just those with particularly good or
bad outcomes. The BSRBR, through the systematic follow-up
of patients, has captured all pregnancy outcomes as they have
occurred since the study started in 2001, including information
on terminations, spontaneous abortions as well as pregnancy
complications. This may also in part explain the higher rate of
spontaneous abortion observed in this study compared with
previous reports. We were also able to compare the pregnancy
outcomes of patients exposed to anti-TNF therapy before or at
conception with a control group of patients with RA who were
never exposed to anti-TNF therapy. However, the number of
recorded pregnancies in this control group was small.
The results of this current study, one of the largest detailed pro-
spective studies to date, suggest that treatment with anti-TNF
therapy at the time of conception may be associated with an
increased risk of spontaneous abortion, but the role of disease
46/59 (78%) in group II; 10/10 (100%) live births were reported
in the nb-DMARD group. In two of the three twin pregnan-
cies (one in group I and one in group II), one of the fetuses died
in utero and one was delivered at/near term ( table 1 ). The rate
of spontaneous abortion was highest among patients exposed
to anti-TNF at the time of conception (group I): overall 19/71
(27%); with MTX/LEF 7/21 (33%); without MTX/LEF 12/50
(24%). This compared with 10/59 spontaneous abortions (17%
of pregnancies) in those with prior exposure to anti-TNF agents
(group II) and 1/10 spontaneous abortion (10% of pregnancies) of
those never exposed to anti-TNF (group III). In total there were
10 terminations (4 in group Ia, 4 in group Ib and 2 in group II).
Of the 42 live births or 22 spontaneous abortions/intrauterine
or neonatal deaths in women who were receiving anti-TNF
therapy at the time of conception (group I), 33/42 (79%) and
18/22 (82%), respectively, discontinued anti-TNF therapy dur-
ing the fi rst trimester, 5/42 (12%) and 0 (0%) during the sec-
ond trimester and 4/42 (9%) and 1/22 (5%) received anti-TNF
therapy throughout their pregnancy. No data on anti-TNF expo-
sure during pregnancy was available for 0 and 3 pregnancies,
respectively. In those patients with prior exposure to anti-TNF,
the length of time since the last dose of anti-TNF therapy did not
differ between those with a live birth and those who miscarried
(median 7.1 months (IQR 4.4–13.2) vs median 5.7 months (IQR
Of 88 live births in the anti-TNF groups, 19 babies (22%) were
born prematurely (11/42 (26%) in group I and 8/46 (17%) in
group II) compared with 2/10 (20%) in the nb-DMARD group.
One full-term baby had a low birth weight. Four fetuses died in
utero (two in group Ib and two in group II), including two single
fetuses in two twin pregnancies. One neonatal death 27 h after
delivery was reported in a patient who received ETA during the
fi rst trimester. The cause of death was perinatal hypoxia. There
were four reports of congenital malformations, two in group
Ib (congenital dislocation of the hip and pyloric stenosis) and
two in group II (winking jaw syndrome and strawberry birth
Our study presents the results of the largest detailed prospec-
tive collection of pregnancy outcomes in women with arthri-
tis-related diseases exposed to anti-TNF therapy. In our study
population a potential signal of an increased spontaneous abor-
tion rate was observed in women exposed to anti-TNF thera-
pies at conception, although this was most evident in those also
receiving MTX or LEF (33%). Two general population-based
studies found a clinical spontaneous abortion rate of around
12%, 4 5 although the actual rate may be higher (~25%) if clini-
cally undetectable pregnancies are also included. 6
To put these results into context with the evidence currently
available, it is important to compare our fi ndings with those pub-
lished in previous reports (see table in online supplement). 7 – 15 Of
the known outcomes in pregnancies in cohort studies including
any patients exposed to anti-TNF agents before or during preg-
nancy, the spontaneous abortion rate ranged from 0% to 14%. 15
In one study, including data from a survey of US rheumatolo-
gists 8 , one spontaneous abortion occurred in a patient using ETA
in combination with MTX at the time of conception. Across all
studies, 31 terminations were reported. 7 – 9 12 14 15 One pregnancy
was terminated because of concomitant MTX use at the time
of conception. 7 Eleven babies were born with complications
Ann Rheum Dis 2011;70:823–826. doi:10.1136/ard.2010.140822826
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severity and other antirheumatic treatment cannot be excluded.
Although the collected results to date have been promising with
few reports of congenital malformations, no fi rm conclusions
can be drawn about the safety of anti-TNF therapy during preg-
nancy and, without further evidence, guidelines which suggest
these drugs should be avoided at the time of conception must
Acknowledgements The authors acknowledge the enthusiastic collaboration
of all consultant rheumatologists and their specialist nurses in the UK in providing
the data. In addition, we acknowledge the support from Dr Ian Griffi ths (Past) and
Professor David Isenberg (Current), Chairs of the BSRBR Management Committee,
Professor Gabriel Panayi, Professor David G I Scott, Dr Andrew Bamji and Dr Deborah
Bax, Presidents of the BSR during the period of data collection, for their active role in
enabling the Register to undertake its tasks and Samantha Peters (CEO of the BSR),
Mervyn Hogg, Nia Taylor and members of the BSRBR Scientifi c Steering Committee.
We also acknowledge the seminal role of the BSR Clinical Affairs Committee for
establishing national biologic guidelines and recommendations for such a Register.
Finally we would like to acknowledge the substantial contribution of Andy Tracey,
Katie McGrother and Dr Mark Lunt to database design and manipulation and Professor
Alan Silman in his prior role as principal investigator of the BSRBR.
Funding Funding for this project was provided by the British Society for
Rheumatology (BSR). The BSR commissioned the Biologics Register (BSRBR) as
a UK-wide national project to investigate the safety of biologic agents in routine
medical practice. DPMS and KH are principal investigators on the BSRBR. BSR
receives restricted income from UK pharmaceutical companies, presently Abbott
Laboratories, Biovitrum, Shering Plough, Wyeth Pharmaceuticals and Roche. This
income fi nances a wholly separate contract between the BSR and the University of
Manchester. The principal investigators and their team have full academic freedom
and are able to work independently of the pharmaceutical industry. All decisions
regarding analyses, interpretation and publication are made autonomously of any
Competing interests Members of the Manchester team, BSR trustees, committee
members and staff complete an annual declaration in relation to confl icts of interest.
The authors declare no other confl ict of interest.
Patient consent Obtained.
Ethics approval The study received ethical approval from the UK North West
Research Ethics Committee (MREC 00/8/53).
Provenance and peer review Not commissioned; externally peer reviewed.
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2. Carter JD, Ladhani A, Ricca LR, et al. A safety assessment of tumor necrosis
factor antagonists during pregnancy: a review of the Food and Drug Administration
database. J Rheumatol 2009 ; 36 : 635 – 41 .