Rheumatology 2016;55:16931697
RHEUMATOLOGY doi:10.1093/rheumatology/kev404
Advance Access publication 10 January 2016
Guidelines
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BSR and BHPR guideline on prescribing drugs in
pregnancy and breastfeeding—Part I: standard and
biologic disease modifying anti-rheumatic drugs and
corticosteroids
Julia Flint1, Sonia Panchal2, Alice Hurrell3, Maud van de Venne4, Mary Gayed5,
Karen Schreiber6,7, Subha Arthanari8, Joel Cunningham3, Lucy Flanders3,
Louise Moore9, Amy Crossley10, Neetha Purushotham3, Amisha Desai5,
Madeleine Piper11, Mohamed Nisar8, Munther Khamashta6, David Williams3,
Caroline Gordon12,13 and Ian Giles1,3 on behalf of the BSR and BHPR Standards,
Guidelines and Audit Working Group
Key words: rheumatic disease, pregnancy, breastfeeding, prescribing, corticosteroids, hydroxychloroquine,
DMARDs, biologics
GUID ELINES
Executive Summary avoided because active rheumatic disease is associated
with adverse pregnancy outcomes [1] and there is grow-
ing evidence of drug safety in pregnancy.
Scope and purpose of the guideline
Need for guidelines
The prescribing of many drugs in pregnancy is compli- 1
Centre for Rheumatology Research, UCL Division of Medicine,
cated by a lack of knowledge regarding their compatibility University College London, London, 2Department of Rheumatology,
leading to patient misinformation and withdrawal/denial of University Hospitals of Leicester, Leicester, 3Womens Health,
disease-ameliorating therapies. This situation should be University College London Hospital, London, 4Obstetrics and
Gynaecology, Frimley Park Hospital, Surrey, 5Department of
Rheumatology, University Hospital Birmingham NHS Foundation Trust,
Birmingham, 6Department of Rheumatology, Guy’s and St Thomas’
NHS Foundation Trust, London, UK, 7Department of Rheumatology,
Copenhagen University Hospital, Rigshospitalet, Denmark,
8
Department of Rheumatology, Burton Hospitals NHS Trust, Burton-
upon-Trent, 9Rheumatic and Musculoskeletal Disease Unit, Our Lady’s
Hospice and Care Services, Dublin, Ireland, 10Department of
Rheumatology, University College London Hospital, London,
11
Department of Rheumatology, Aneurin Bevan University Health
Board, Newport, UK, 12Department of Rheumatology, Sandwell and
West Birmingham Hospitals NHS Trust and 13Division of Immunity and
Infection, University of Birmingham, Birmingham, UK
NICE has accredited the process used by the BSR to produce its
guidance on prescribing drugs in pregnancy and breastfeeding. Submitted 17 June 2015; revised version accepted 4 November 2015
Accreditation is valid for 5 years from 10 June 2013. More information Correspondence to: Ian Giles, Centre for Rheumatology Research,
on accreditation can be viewed at www.nice.org.uk/accreditation. For UCL Division of Medicine, Room 411, Rayne Institute, 5 University
full details on our accreditation visit: www.nice.org.uk/accreditation. Street, London, UK. E-mail: i.giles@ucl.ac.uk
! The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Julia Flint et al.
Objectives of the guideline Recommendations for MTX in pregnancy
To provide evidence-based recommendations, which do and breastfeeding
not imply a legal obligation, for clinicians when prescribing (i) MTX at any dose should be avoided in pregnancy
anti-rheumatic drugs before/during pregnancy and and stopped 3 months in advance of conception
breastfeeding that update previous recommendations (LOE 2 , GOR D, SOA 100%).
[2, 3]. For recommendations on prescribing other drugs (ii) In women treated with low-dose MTX within 3
in pregnancy and breastfeeding see the British Society months prior to conception, folate supplementation
of Rheumatology (BSR) and British Health Professionals (5 mg/day) should be continued prior to and
in Rheumatology (BHPR) guidelines part II [4]. throughout pregnancy (LOE 1, GOR B, SOA
98.4%).
Target audience
(iii) In the case of accidental pregnancy on low-dose
Health professionals directly involved in managing pa-
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MTX, the drug should be stopped immediately,
tients with rheumatic disease in the UK who are (or plan- folate supplementation (5 mg/day) continued and a
ning to become) pregnant and/or breastfeeding, men careful evaluation of foetal risk carried out by local
planning to conceive and patients who have accidentally experts (LOE 4, GOR D, SOA 100%).
conceived while taking these medications. (iv) MTX cannot be recommended in breastfeeding be-
cause of theoretical risks and insufficient outcome
The areas the guideline does not cover
data (LOE 4, GOR D, SOA 100%).
This guideline does not cover the management of infertility (v) Based on limited evidence, low-dose MTX may be
or the indications for these drugs in specific rheumatic compatible with paternal exposure (LOE 2+, GOR
diseases in pregnancy. D, SOA 95.8%).
Key recommendations from the guidelines
Recommendations for SSZ in pregnancy
Specific questions were considered in relation to each drug.
Should it be stopped pre-conception? Is it compatible with
and breastfeeding
pregnancy? Is it compatible with breastfeeding? Where pos- (i) SSZ with folate supplementation (5 mg/day) is com-
sible, recommendations are made regarding compatibility patible throughout pregnancy (LOE 2+, GOR C,
with paternal exposure. These findings are summarized in SOA 100%).
Table 1. A description of evidence and full recommendations (ii) SSZ is compatible with breastfeeding in healthy,
are given in the full guideline provided as supplementary full-term infants (LOE 4, GOR D, SOA 100%).
data, available at Rheumatology Online. (iii) Men taking SSZ may have reduced fertility. There is
no evidence, however, that conception is enhanced
Recommendations for corticosteroids in by stopping SSZ for 3 months prior to conception
pregnancy and breastfeeding unless conception is delayed >12 months when
other causes of infertility should also be considered
(i) Prednisolone is compatible with each trimester of preg- (LOE 3, GOR D, SOA 97.4%).
nancy [level of evidence (LOE) 1 ++, grade of recommen-
dation (GOR) A, strength of agreement (SOA) 100%].
(ii) Prednisolone is compatible with breastfeeding Recommendations for LEF in pregnancy
(LOE 2 , GOR D, SOA 98.9%). and breastfeeding
(iii) Prednisolone is compatible with paternal exposure
(i) Based on limited evidence, LEF may not be a human
(LOE 2+, GOR D, SOA 98.9%).
teratogen but it is still not recommended in women
(iv) Methylprednisolone has rates of placental trans-
planning pregnancy (LOE 2+, GOR C, SOA 100%).
fer similar to prednisolone with equivalent anti-
(ii) Women on LEF considering pregnancy should stop
inflammatory effects at 80% of prednisolone dose
and undergo cholestyramine washout before
and would therefore be expected to be compatible
switching to alternative medication compatible
with pregnancy, breastfeeding and paternal expos-
with pregnancy (LOE 2+, GOR C, SOA 100%).
ure (LOE 4, GOR D, SOA 93.7%).
(iii) There is no human evidence of increased congeni-
tal abnormalities on LEF if washout is given.
Recommendations for HCQ in pregnancy Therefore, if accidental conception occurs on LEF,
and breastfeeding the drug should be stopped immediately and cho-
(i) HCQ remains the antimalarial of choice in women lestyramine washout given until plasma levels are
planning a pregnancy with rheumatic disease in undetectable (LOE 2+, GOR C, SOA 98.9%).
need of treatment and should be continued during (iv) No data exist on excretion into breast milk,
pregnancy (LOE 1 ++, GOR A, SOA 100%). therefore breastfeeding is not recommended (LOE
(ii) HCQ is compatible with breastfeeding (LOE 4, GOR 4, GOR D, SOA 100%).
D, SOA 98.9%). (v) Based on very limited evidence, LEF may be com-
(iii) Men should not be discouraged from taking HCQ while patible with paternal exposure (LOE 4, GOR D, SOA
trying to conceive (LOE 2 , GOR D, SOA 98.9%). 98.9%).
1694 www.rheumatology.oxfordjournals.org
BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding
TABLE 1 Summary of drug compatibility in pregnancy and breastfeeding
Compatible Compatible Compatible
Compatible with first Compatible with with with paternal
peri-conception trimester second/third trimester breastfeeding exposure
Corticosteroids
Prednisolone Yes Yes Yes Yes Yes
Methylprednisolone Yes Yes Yes Yes Yes
Antimalarials
HCQ Yes Yes Yes Yes Yesa
DMARDs
MTX <20 mg/week Stop 3 months No No No Yesa
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in advance
SSZ (with 5 mg folic acid) Yes Yes Yes Yesb Yesc
LEF Cholestyramine No No No data Yesa
washout, no
AZA <2 mg/kg/day Yes Yes Yes Yes yes
CSA Yes Yesd Yesd Yesa Yesa
Tacrolimus Yes Yesd Yesd Yesa Yesa
CYC No Noe Noe No No
MMF Stop 6 weeks No No No Yesa
in advance
IVIG Yes Yes Yes Yes Yesa
Anti-TNF
Infliximab Yes Yes Stop at 16 weeks Yesa Yesa
Etanercept Yes Yes Second but not third Yesa Yesa
Adalimumab Yes Yes Second but not third Yesa Yesa
Certolizumab Yes Yes Yesa Yesa No data
Golimumab No data No data No data No data No data
Other biologics
Rituximab Stop 6 months Nof No No data Yesa
in advance
Tocilizumab Stop 3 months Nof No No data No datag
in advance
Anakinra No Nof No No data No datag
Abatacept No Nof No No data No datag
Belimumab No Nof No No data No datag
For further information and caveats, see relevant recommendations and main text in executive summary and full guideline.
a
Data are limited. bIn healthy full-term infants only. cConception may be enhanced by stopping SSZ for 3 months prior to
conception. dSuggested monitoring of maternal blood pressure, renal function, blood glucose and drug levels. eOnly consider
in severe or life-/organ-threatening maternal disease. fUnintentional first trimester exposure is unlikely to be harmful. gUnlikely
to be harmful.
Recommendations for AZA in pregnancy Recommendations for tacrolimus in
and breastfeeding pregnancy and breastfeeding
(i) AZA is compatible throughout pregnancy at 42 mg/ (i) Tacrolimus is compatible throughout pregnancy at
kg/day (LOE 2 ++, GOR B, SOA 100%). the lowest effective dose (LOE 2 , GOR D, SOA
(ii) AZA is compatible with breastfeeding (LOE 2 , 99.5%).
GOR D, SOA 99.5%). (ii) Mothers on tacrolimus should not be discour-
(iii) AZA is compatible with paternal exposure (LOE 2+, aged from breastfeeding (LOE 3, GOR D, SOA
GOR D, SOA 100%). 99.5%).
(iii) Based on limited evidence, tacrolimus is compatible
with paternal exposure (LOE 2 , GOR D, SOA 98.4%).
Recommendations for CSA in pregnancy
and breastfeeding
(i) CSA is compatible throughout pregnancy at the
Recommendations for CYC in pregnancy
lowest effective dose (LOE 1, GOR B, SOA 100%). and breastfeeding
(ii) Mothers on CSA should not be discouraged from (i) CYC is teratogenic and gonadotoxic, therefore it
breastfeeding (LOE 3, GOR D, SOA 100%). should only be considered in pregnancy in life-/
(iii) Based on limited evidence, CSA is compatible with pa- organ-threatening maternal disease (LOE 2, GOR
ternal exposure (LOE 2 , GOR D, SOA 98.9%). C, SOA 100%).
www.rheumatology.oxfordjournals.org 1695
Julia Flint et al.
(ii) There is no evidence to recommend the use of CYC Recommendations for rituximab (RTX) in
in breastfeeding (LOE 4, GOR D, SOA 100%). pregnancy and breastfeeding
(iii) Paternal exposure to CYC is not recommended
(LOE 4, GOR D, SOA 98.4%). (i) RTX should be stopped 6 months before concep-
tion. Limited evidence has not shown RTX to be
teratogenic and only second-/third-trimester expos-
Recommendations for MMF in pregnancy ure is associated with neonatal B cell depletion.
and breastfeeding Therefore, unintentional RTX exposure early in the
first trimester is unlikely to be harmful (LOE 2 ,
(i) MMF remains contraindicated during pregnancy
GOR D, SOA 97.9%).
(LOE 2 , GOR D, SOA 100%).
(ii) There are no data on RTX use in breastfeeding
(ii) Treatment with MMF should be stopped at least 6
(SOA 100%).
weeks before a planned pregnancy (LOE 3, GOR D,
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(iii) Based on limited evidence, RTX is compatible with
SOR 100%).
paternal exposure (LOE 2 , GOR D, SOA 98.4%).
(iii) No data exist on excretion into breast milk, there-
fore breastfeeding is not recommended (LOE 4,
GOR D, SOA 99.5%). Recommendations for tocilizumab (TCZ)
(iv) Based on very limited evidence, MMF is compatible in pregnancy and breastfeeding
with paternal exposure (LOE 2 , GOR D, SOA
98.9%). (i) TCZ should be stopped at least 3 months before
conception, but unintentional exposure early in the
first trimester is unlikely to be harmful (LOE 3, GOR
Recommendations for IVIG in pregnancy D, SOA 96.8%).
(ii) There are no data on TCZ use in breastfeeding
and breastfeeding
(SOA 99.5%).
(i) IVIG is compatible with pregnancy (LOE 1 ++, GOR (iii) There are no data relating to paternal exposure to
A, SOA 100%). TCZ, but it is unlikely to be harmful (LOE 4, GOR D,
(ii) IVIG is compatible with breastfeeding (LOE 4, GOR SOA 97.9%).
D, SOA 98.9%).
(iii) Based on maternal compatibility, IVIG is unlikely to
be harmful (LOE 4, GOR D, SOA 98.9%). Recommendations for anakinra in preg-
nancy and breastfeeding
(i) There is limited evidence on which to base a rec-
Recommendations for anti-TNF ommendation for anakinra in pregnancy, but unin-
medications in pregnancy and tentional exposure in the first trimester is unlikely to
breastfeeding be harmful (LOE 2 , GOR D, SOA 96.8%).
(ii) There are no data on anakinra use in breastfeeding
(i) Infliximab (IFX) may be continued until 16 weeks
(SOA 100%).
and etanercept (ETA) and adalimumab (ADA) may
(iii) There are no data relating to paternal exposure to
be continued until the end of the second trimester
anakinra, but it is unlikely to be harmful (LOE 4,
(LOE 2 , GOR D, SOA 98.9%).
GOR D, SOA 98.9%).
(ii) To ensure low/no levels of drug in cord blood at
delivery, ETA and ADA should be avoided in the
third trimester and IFX stopped at 16 weeks. If Recommendations for abatacept (ABA) in
these drugs are continued later in pregnancy to
pregnancy and breastfeeding
treat active disease, then live vaccines should be
avoided in the infant until 7 months of age (LOE (i) There are insufficient data to recommend ABA in
3, GOR D, SOA 98.9%). pregnancy. Unintentional exposure early in the first
(iii) Certolizumab pegol is compatible with all three tri- trimester is unlikely to be harmful (LOE 3, GOR D,
mesters of pregnancy and has reduced placental SOA 98.9%).
transfer compared with other TNF inhibitors (ii) There are no data on ABA use in breastfeeding
(TNFis) (LOE 2 , GOR D, SOA 97.9%). (SOA 100%).
(iv) Golimumab is unlikely to be harmful in the first tri- (iii) There are no data relating to paternal exposure to
mester (LOE 4, GOR D, SOA 97.9%) ABA, but it is unlikely to be harmful (LOE 4, GOR D,
(v) Women should not be discouraged from breast- SOA 98.9%).
feeding on TNFis, but caution is recommended
until further information is available (LOE 3, GOR
Recommendations for belimumab (BEL)
D, SOA 98.4%).
(vi) Based on limited evidence IFX, ETA and ADA are in pregnancy and breastfeeding
compatible with paternal exposure (LOE 2 , GOR (i) There are insufficient data to recommend BEL in
D, SOA 98.9%). pregnancy. Unintentional exposure early in the first
1696 www.rheumatology.oxfordjournals.org
BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding
trimester is unlikely to be harmful (LOE 3, GOR D, support to attend meetings from GlaxoSmithKline, UCB
SOA 100%). and Astra-Zeneca, chairing fees from Bristol-Myers
(ii) There are no data on BEL use in breastfeeding Squibb and honoraria from GlaxoSmithKline/Human
(SOA 100%). Genome Sciences, Medimmune, INOVA Diagnostics and
(iii) There are no data relating to paternal exposure to Merck. M.G. has received individual support to attend a
BEL, but it is unlikely to be harmful (LOE 4, GOR D, meeting from Roche. All others have declared no
SOA 98.9%). conflicts of interest.
Funding: No specific funding was received from any fund-
ing bodies in the public, commercial or not-for-profit sec-
tors to carry out the work described in this article. Supplementary data
Disclosure statement: K.S. has received educational sup- The full guideline is available as supplementary data at
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port from Daiichi Sankyo. C.G. has undertaken consultan- Rheumatology Online.
cies and received honoraria from Bristol-Myers Squibb,
GlaxoSmithKline, MedImmune, Merck Serono and UCB,
has been a member of speakers’ bureau for
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