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

Background
The rationale behind this update of the 2016 BSR guidelines on prescribing anti-rheumatic drugs in pregnancy and breastfeeding (1, 2) was described in detail in the guideline scope (3). In brief, despite the existence of additional evidence-based guidelines on prescribing/managing rheumatic disease in pregnancy (4-7), the information contained within them requires continual review to include emerging information on the safety of new and existing drugs in pregnancy.

Chronic disease adversely affects pregnancy. Data from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK), reports regularly from a national programme of work conducting surveillance and investigating the causes of maternal deaths, stillbirths and infant deaths (8). Data from 2017-19, 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 (8). 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). As such, the potential benefit to the fetus from any drug changes in the mother must be balanced against the possible risks to the fetus from loss of disease control in the mother (9).

Need for guideline
There has been an appreciable increase in the number of published pregnancy exposures to biologic disease modifying anti-rheumatic drugs (bDMARDs), and two of these drugs are now licenced for use in pregnancy. In addition, therapeutic advances in management of various inflammatory rheumatic diseases (IRDs) have led to an expansion of bDMARDs and biosimilars with different modes of action, as well as a new class of targeted synthetic DMARDs (tsDMARDs).

The continuing expansion of existing and novel DMARDs means that uncertainty remains around use of many of these drugs in pregnancy. This uncertainty may still lead to withdrawal of treatment from pregnant women unnecessarily (10). Discontinuation of treatment in preparation for or during early pregnancy can increase the risk of disease activity and flares during pregnancy, and are reported following discontinuation of biologics in patients with IRDs (11). The compatibility of various immunosuppressive and disease-modifying medications relevant to rheumatic disease will be covered in this update. This updated information will provide advice for healthcare professionals and patients, to ensure more confident prescribing in these scenarios, and will highlight any 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 (MHRA) and the Faculty of Sexual and Reproductive Healthcare (12, 13).

Objectives of guideline
To update the previous BSR guidelines on prescribing in pregnancy in rheumatic disease of the following drug categories: antimalarials; corticosteroids; conventional synthetic (cs)DMARDs and immunosuppressive therapies; bDMARDs; and tsDMARDs. The full list of medications is shown in appendix 1. This revised guideline was produced by systematically reviewing all evidence published since the previous guideline, to answer specific questions in relation to each drug, as follows: Should it be stopped pre-conception? Is it compatible with pregnancy? Is it compatible with breastmilk exposure? Where possible, recommendations are made regarding compatibility with paternal exposure.

Target audience
The primary audience consists of health professionals in the UK directly 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 whilst 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).

The areas the guideline does not cover
This guideline does not cover the management of infertility or the indications for these drugs in specific rheumatic diseases in pregnancy. Other drug categories (pain management; non-steroidal anti-inflammatory drugs (NSAIDs) 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 (reference to be inserted once published). 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.

Stakeholder involvement
This guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair (IG), alongside representatives from relevant stakeholders shown in appendix 2. In accordance with BSR policy, all members of the GWG made declarations of interest, available on the BSR website.

Involvement and affiliations of stakeholder groups involved in guideline development
The GWG consisted of rheumatologists from a range of clinical backgrounds, various allied health professionals, other specialists in women’s health, lay members and representatives from the United Kingdom Tetralogy Information Service (UKTIS). All members of the working group contributed to the process for agreeing key questions, guideline content, recommendations and strength of agreement.