Executive Summary: British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids

NICE has accredited the process used by BSR to create its clinical guidelines. The term began on 27 February 2012 and the current renewed accreditation is valid until 31 December 2023. More information on accreditation can be viewed at www.nice.org.uk/accreditation. The rationale behind this update of the 2016 British Society for Rheumatology (BSR) guidelines on prescribing anti-rheumatic drugs in pregnancy and breastfeeding [1, 2] was previously described [3]. Additional evidence-based guidelines on managing rheumatic disease in pregnancy now exist [4–7]. However, emerging information on pregnancy exposures to biologic DMARDs, biosimilars and targeted synthetic DMARDs requires regular review to assess their safety in pregnancy. Uncertainty around use of these drugs in pregnancy may lead to withdrawal of treatment from women with inflammatory rheumatic diseases (IRDs) unnecessarily [8], which can increase the risk of poor disease control during pregnancy [9]. Data from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK) between 2017 and 2019 found that 8.8 women per 100 000 died during pregnancy or up to six weeks after childbirth or the end of pregnancy, and most women who died had multiple health problems or other vulnerabilities [10]. In all decisions regarding medication choices and changes, it is important to consider the potential for deterioration in the mother's wellbeing through side effects or reduced disease control (and its adverse impact on the baby) [10]. As such, the potential benefit to the foetus from any drug changes in the mother must be balanced against the possible risks to the foetus from loss of disease control in the mother [11]. To update the previous BSR guidelines on prescribing in pregnancy in rheumatic disease of corticosteroids and immunomodulatory drugs (Supplementary Data S1, available at Rheumatology online) by systematically reviewing all evidence published since the previous guideline. This guideline will highlight medications that should be stopped and/or avoided in the reproductive age group unless highly effective contraception is used, in line with guidance issued by the Medicines and Healthcare Products Regulatory Agency and the Faculty of Sexual and Reproductive Healthcare [12, 13]. This guideline is directed at healthcare professionals in the UK involved in managing patients with rheumatic disease who are (or are planning to become) pregnant and/or breastfeeding, men with rheumatic disease who are planning to conceive, and patients with rheumatic disease who have unintentionally conceived while taking these medications. This audience includes rheumatologists, rheumatology nurses/allied health professionals, rheumatology speciality trainees and pharmacists, as well as the patients themselves. The guideline will also be useful to obstetricians, obstetric physicians, midwives, renal physicians, dermatologists, gastroenterologists, respiratory physicians and general practitioners who prescribe these medications in pregnancy. This guideline uses the terms ‘woman’, ‘maternal’ or ‘mother’ throughout. These should be taken to include people who do not identify as women but are pregnant or have given birth [14]. Where the term ‘breastfeeding’ is used in this guideline it also refers to infant breastmilk exposure via other methods (e.g. expressed breastmilk, administered via a bottle). This guideline does not cover the management of infertility or the indications for these drugs in rheumatic diseases in pregnancy. Other drug categories (pain management; non-steroidal anti-inflammatory drugs and low dose aspirin; anticoagulants; bisphosphonates; anti-hypertensives; and pulmonary vasodilators) are considered in the BSR guideline on prescribing drugs in pregnancy and breastfeeding: comorbidity medications used in rheumatology practice [15]. All recommendations in this guideline were formulated by the working group on the basis of published evidence at the time of the systematic literature search, and do not necessarily refer to licencing information or Summary of Product Characteristics for individual medications. A guideline working group (GWG), chaired by I.G., consisted of rheumatologists from a range of clinical backgrounds, allied health professionals, other specialists in women’s health, lay members, and representatives from the United Kingdom Teratology Information Service (UKTIS), this is shown in Supplementary Table S1, available at Rheumatology online. Evidence used to develop these guidelines was compiled from a systematic literature search conducted according to guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [16]. Studies were identified by searching MEDLINE and Embase databases from 1 January 2014 to 31 December 2020, with additional studies identified through the Cochrane, LactMed and UKTIS databases (Supplementary Data S2, available at Rheumatology online). The searches were conducted in January 2021. Limits were placed for English language studies. The searches were not limited by disease indication; studies in non-rheumatic diseases were considered, if relevant. Evidence from the current searches (referred to as ‘recent studies’ in the text) was combined with data from the previous guideline (referred to as ‘previous studies’) [1], to inform recommendations. Relevant pharmaceutical companies were also contacted for additional data. Two independent reviewers screened the titles and abstracts of articles, reviewed the full texts of studies that met inclusion criteria (Supplementary Data S2, available at Rheumatology online), and performed data extraction. Any disagreements were resolved by group discussion. This guideline was developed in line with BSR’s Guidelines Protocol using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology, to determine quality of evidence and strength of recommendation. Accompanying each recommendation, in brackets, is the strength of recommendation, quality of evidence and strength of agreement (SOA). were as the the risks (or or the were balanced with the risks or The quality of evidence was as or low the in the of or The of each was by all and to a for on a of to The guideline will be in A of is shown in The for all drug information from the previous BSR guideline [1], are in the guideline. of the of each drug during pregnancy, with breastmilk and with exposure is shown in Table each information is in and while information is in Table The data for is shown in Supplementary Data available at Rheumatology online. The of the evidence is shown in Supplementary Data also available at Rheumatology online. of studies for inclusion Summary of drug in pregnancy and breastmilk exposure information and recommendations and in the and full guideline. In the infant is by consider of other of of renal and drug in of or low risk of disease and stopped by full term infant can have a low risk of disease and stopped by full term infant can have a low risk of disease and stopped by full term infant can have a be considered to disease if other drugs are used in in infant until of Summary of drug in pregnancy and breastmilk exposure information and recommendations and in the and full guideline. In the infant is by consider of other of of renal and drug in of or low risk of disease and stopped by full term infant can have a low risk of disease and stopped by full term infant can have a low risk of disease and stopped by full term infant can have a be considered to disease if other drugs are used in in infant until of Summary of exposure to synthetic DMARDs, and corticosteroids 31 1 1 increase in of to drug the of in women planning a pregnancy with rheumatic disease in of and should be during pregnancy at dose of is with breastmilk exposure 1 1 increase in of to drug is with pregnancy and is the in the treatment of disease in pregnancy and requires with obstetric to and Where the dose of should be and to the effective dose to control in with drugs with pregnancy is with breastmilk exposure has of to and be to be with pregnancy and breastmilk exposure 1 of but studies limited of of at any dose should be avoided in pregnancy and stopped at in of it should be to drug to of disease In women with to should be up to weeks of pregnancy In pregnancy on is risk to the the drug should be stopped and a of risk with to a considered of are be in breastfeeding of risks and data on 1 not in the of increase in of to drug is pregnancy, with in the and during the is with breastmilk exposure in increase in of to but most stopped in and may not be a but evidence to use at the time of or during pregnancy on pregnancy should and a and to medication with pregnancy on the drug should be stopped and a with to a considered is not breastfeeding 1 increase in of to drug is pregnancy is with breastmilk exposure Data by exposure is pregnancy with of renal and drug is with breastmilk exposure 1 1 in is pregnancy with of renal and drug is with breastmilk exposure 1 1 from individual or available is a and and should be considered in pregnancy in of disease is risk of and and this is not breastfeeding Data from of reduced and birth during pregnancy, and should be avoided in women planning pregnancy or to a at weeks to In of to a and refer to for and risk is not breastfeeding 1 1 1 increase in of to limited data available is with pregnancy is with breastmilk exposure 31 1 1 increase in of to drug the of in women planning a pregnancy with rheumatic disease in of and should be during pregnancy at dose of is with breastmilk exposure 1 1 increase in of to drug is with pregnancy and is the in the treatment of disease in pregnancy and requires with obstetric to and Where the dose of should be and to the effective dose to control in with drugs with pregnancy is with breastmilk exposure has of to and be to be with pregnancy and breastmilk exposure 1 of but studies limited of of at any dose should be avoided in pregnancy and stopped at in of it should be to drug to of disease In women with to should be up to weeks of pregnancy In pregnancy on is risk to the the drug should be stopped and a of risk with to a considered of are be in breastfeeding of risks and data on 1 not in the of increase in of to drug is pregnancy, with in the and during the is with breastmilk exposure in increase in of to but most stopped in and may not be a but evidence to use at the time of or during pregnancy on pregnancy should and a and to medication with pregnancy on the drug should be stopped and a with to a considered is not breastfeeding 1 increase in of to drug is pregnancy is with breastmilk exposure Data by exposure is pregnancy with of renal and drug is with breastmilk exposure 1 1 in is pregnancy with of renal and drug is with breastmilk exposure 1 1 from individual or available is a and and should be considered in pregnancy in of disease is risk of and and this is not breastfeeding Data from of reduced and birth during pregnancy, and should be avoided in women planning pregnancy or to a at weeks to In of to a and refer to for and risk is not breastfeeding 1 1 1 increase in of to limited data available is with pregnancy is with breastmilk exposure All studies that and/or information on the safety of the drug in pregnancy were data be from the was of data in this were are shown in Supplementary Data available at Rheumatology online. shown in the are Supplementary Data available at Rheumatology online. not strength of systematic Summary of exposure to synthetic DMARDs, and corticosteroids 31 1 1 increase in of to drug the of in women planning a pregnancy with rheumatic disease in of and should be during pregnancy at dose of is with breastmilk exposure 1 1 increase in of to drug is with pregnancy and is the in the treatment of disease in pregnancy and requires with obstetric to and Where the dose of should be and to the effective dose to control in with drugs with pregnancy is with breastmilk exposure has of to and be to be with pregnancy and breastmilk exposure 1 of but studies limited of of at any dose should be avoided in pregnancy and stopped at in of it should be to drug to of disease In women with to should be up to weeks of pregnancy In pregnancy on is risk to the the drug should be stopped and a of risk with to a considered of are be in breastfeeding of risks and data on 1 not in the of increase in of to drug is pregnancy, with in the and during the is with breastmilk exposure in increase in of to but most stopped in and may not be a but evidence to use at the time of or during pregnancy on pregnancy should and a and to medication with pregnancy on the drug should be stopped and a with to a considered is not breastfeeding 1 increase in of to drug is pregnancy is with breastmilk exposure Data by exposure is pregnancy with of renal and drug is with breastmilk exposure 1 1 in is pregnancy with of renal and drug is with breastmilk exposure 1 1 from individual or available is a and and should be considered in pregnancy in of disease is risk of and and this is not breastfeeding Data from of reduced and birth during pregnancy, and should be avoided in women planning pregnancy or to a at weeks to In of to a and refer to for and risk is not breastfeeding 1 1 1 increase in of to limited data available is with pregnancy is with breastmilk exposure 31 1 1 increase in of to drug the of in women planning a pregnancy with rheumatic disease in of and should be during pregnancy at dose of is with breastmilk exposure 1 1 increase in of to drug is with pregnancy and is the in the treatment of disease in pregnancy and requires with obstetric to and Where the dose of should be and to the effective dose to control in with drugs with pregnancy is with breastmilk exposure has of to and be to be with pregnancy and breastmilk exposure 1 of but studies limited of of at any dose should be avoided in pregnancy and stopped at in of it should be to drug to of disease In women with to should be up to weeks of pregnancy In pregnancy on is risk to the the drug should be stopped and a of risk with to a considered of are be in breastfeeding of risks and data on 1 not in the of increase in of to drug is pregnancy, with in the and during the is with breastmilk exposure in increase in of to but most stopped in and may not be a but evidence to use at the time of or during pregnancy on pregnancy should and a and to medication with pregnancy on the drug should be stopped and a with to a considered is not breastfeeding 1 increase in of to drug is pregnancy is with breastmilk exposure Data by exposure is pregnancy with of renal and drug is with breastmilk exposure 1 1 in is pregnancy with of renal and drug is with breastmilk exposure 1 1 from individual or available is a and and should be considered in pregnancy in of disease is risk of and and this is not breastfeeding Data from of reduced and birth during pregnancy, and should be avoided in women planning pregnancy or to a at weeks to In of to a and refer to for and risk is not breastfeeding 1 1 1 increase in of to limited data available is with pregnancy is with breastmilk exposure All studies that and/or information on the safety of the drug in pregnancy were data be from the was of data in this were are shown in Supplementary Data available at Rheumatology online. shown in the are Supplementary Data available at Rheumatology online. not strength of systematic Summary of exposure to DMARDs and targeted synthetic DMARDs individual drugs 1 increase in of to drug with disease on a with do not to be to with or during pregnancy is with all of pregnancy, has to with other and does not any to the infant considered to have low risk of disease on withdrawal of in pregnancy at and at and at weeks that a infant can have a with at weeks as per the UK or may be pregnancy to disease in these should be avoided in until are of age a is stopped in pregnancy, it can be as as in the of or of breastfeeding to control of disease are with breastmilk exposure 1 increase in of to drug 1 increase in of to drug 1 increase in of to drug increase in of to drug increase in of to drug increase in of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure increase in of to drug evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure 1 in at evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure 1 1 of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug 1 of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug are data to a on use during pregnancy and should be stopped at weeks are data to in breastfeeding given are to should be avoided individual drugs 1 increase in of to drug with disease on a with do not to be to with or during pregnancy is with all of pregnancy, has to with other and does not any to the infant considered to have low risk of disease on withdrawal of in pregnancy at and at and at weeks that a infant can have a with at weeks as per the UK or may be pregnancy to disease in these should be avoided in until are of age a is stopped in pregnancy, it can be as as in the of or of breastfeeding to control of disease are with breastmilk exposure 1 increase in of to drug 1 increase in of to drug 1 increase in of to drug increase in of to drug increase in of to drug increase in of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure increase in of to drug evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure 1 in at evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure 1 1 of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug 1 of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug are data to a on use during pregnancy and should be stopped at weeks are data to in breastfeeding given are to should be avoided All studies that and/or information on the safety of the drug in pregnancy were data be from the was of data in this were are shown in Supplementary Data available at Rheumatology online. shown in the are Supplementary Data available at Rheumatology online. not strength of Summary of exposure to DMARDs and targeted synthetic DMARDs individual drugs 1 increase in of to drug with disease on a with do not to be to with or during pregnancy is with all of pregnancy, has to with other and does not any to the infant considered to have low risk of disease on withdrawal of in pregnancy at and at and at weeks that a infant can have a with at weeks as per the UK or may be pregnancy to disease in these should be avoided in until are of age a is stopped in pregnancy, it can be as as in the of or of breastfeeding to control of disease are with breastmilk exposure 1 increase in of to drug 1 increase in of to drug 1 increase in of to drug increase in of to drug increase in of to drug increase in of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure increase in of to drug evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure 1 in at evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure 1 1 of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug evidence has not shown to be evidence to be that are with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are are used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug 1 of to drug evidence has not shown to be evidence to be that it is with pregnancy. the drug at Any during pregnancy is to be may be considered to disease in pregnancy if other drugs are is used to disease in the it is to all in the infant until of age on limited treatment with is with breastmilk exposure of to drug are data to a on use during pregnancy and should be stopped at weeks are data to in breastfeeding given are to should be avoided individual drugs 1 increase in of to drug with disease on a with