Prescribing Drugs in Pregnancy and Breastfeeding: Comorbidity Medications Used in Rheumatology Practice

Overview

Many patients with inflammatory rheumatic disease (IRD) have an additional burden of pain and comorbid illness that require treatment with medications other than disease-modifying antirheumatic drugs. This new Guidelines summary of the British Society for Rheumatology’s guideline covers the various comorbidity medications relevant to rheumatic disease, giving advice for healthcare professionals on prescribing these medications in pregnancy and during breastfeeding.

This guideline does not cover the management of infertility or acute pain relief during labour. For recommendations on antimalarials, corticosteroids, disease-modifying antirheumatic and immunosuppressive therapies, and biologic drugs, refer to the Guidelines summary, Guideline on Prescribing Drugs in Pregnancy and Breastfeeding: Immunomodulatory Antirheumatic drugs and Corticosteroids.

Reflecting on your Learnings

Reflection is important for continuous learning and development, and a critical part of the revalidation process for UK healthcare professionals. Click here to access the Guidelines Reflection Record.

Generic Recommendations on Prescribing in Rheumatic Disease in Pregnancy

• Pre-conception counselling should be addressed by all healthcare professionals, with referral to professionals with relevant experience as appropriate to optimise all therapy, including non-pharmacological options for chronic pain management during pregnancy
• The risks and benefits of drug treatment to mother and fetus should be discussed and clearly documented by all healthcare professionals involved in the patient’s care
• The cause of pain and other symptoms should be assessed and managed appropriately
• The requirement for analgesia should be assessed and minimum effective dose should be prescribed and titrated according to response
• Tricyclic antidepressants are preferred over other antidepressant medications to manage chronic pain
• Cessation of antidepressant therapy that is being used as chronic pain medication in the postnatal period is not recommended, due to the risk of adverse impact on mood
• Low-dose aspirin (LDA) (≤150 mg/day) is recommended in all patients at high risk for pre-eclampsia
• Low molecular-weight heparin (LMWH) is the preferred anticoagulant
• Nifedipine is the preferred vasodilator
• Paternal drug exposure may reduce male fertility but has not been associated with adverse fetal development or pregnancy outcome. Although evidence is weak, it is recommended that men are reassured about the safety of fathering a pregnancy whilst taking medicines to manage comorbidities as described in the full guideline.

Key Standards of Care

• Patients with rheumatic disease should receive tailored pre-pregnancy counselling and then be reviewed during pregnancy and the 4-month postpartum period by clinical practitioners with expertise in the management of rheumatic disease in pregnancy, in addition to their routine obstetric care
• Patients with rheumatic disease should have access to written information on relevant medications in pregnancy and breastfeeding that is accurate and allows them to make informed decisions regarding compatibility of certain drugs in pregnancy.

Pain Management: Conventional Analgesics

Paracetamol in Pregnancy and Breastfeeding

• Paracetamol is the analgesic of choice and compatible peri-conception and throughout pregnancy
• LactMed describes paracetamol as a good choice for analgesia and fever reduction in breastfeeding mothers.

Codeine in Pregnancy and Breastfeeding

• Codeine is compatible peri-conception and throughout pregnancy, although long-term use should be avoided. There is no consistent evidence to recommend a dose reduction pre-delivery, but neonatologists should be aware of maternal use
• Caution is advised with use of codeine in breastfeeding, due to the risk of central nervous system depression resulting from unpredictable metabolism of codeine to morphine.

Tramadol in Pregnancy and Breastfeeding

• Avoid tramadol peri-conception and in first trimester and only consider in second/third trimester if no alternative analgesia
• Based on limited data, tramadol may be compatible with short-term use in breastfeeding.

Other Treatments for Chronic Pain

Amitriptyline in Pregnancy and Breastfeeding

• Amitriptyline is compatible with pregnancy. There is no evidence of adverse effect on IQ or developmental outcomes
• Since very little amitriptyline is found in breast milk with antidepressant doses and it is used at lower doses for chronic pain, it is unlikely to cause adverse effects in breastfed infants.

Gabapentin and Pregabalin in Pregnancy and Breastfeeding

• Gabapentin at lowest effective dose may be considered in pregnancy with folic acid supplementation if no alternative analgesic suitable
• Gabapentin may be considered in breastfeeding if no alternative analgesic is suitable
• Pregabalin may be considered in pregnancy (with folic acid supplementation) and during breastfeeding.

Serotonin–Norepinephrine Reuptake Inhibitors in Pregnancy and Breastfeeding

• Venlafaxine is compatible at conception and throughout pregnancy. There may be an increased risk of neonatal abstinence syndrome/short-term behavioural effects, but larger studies are needed to evaluate this finding
• Duloxetine may be considered in pregnancy and breastfeeding but there are fewer data than for venlafaxine
• Venlafaxine and duloxetine may be considered in breastfeeding if there is no alternative chronic pain medication.

Selective Serotonin Reuptake Inhibitors in Pregnancy and Breastfeeding

• Fluoxetine, paroxetine, and sertraline are compatible with pregnancy
• Based on limited evidence, selective serotonin reuptake inhibitors are compatible with breastfeeding.

Anti-inflammatory, Antiplatelet, and Anticoagulant Medications

Non-steroidal Anti-inflammatory Drugs and Cyclo-oxygenase-2 Inhibitors in Pregnancy and Breastfeeding

• Discordant findings from retrospective, large studies with population controls on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the first trimester of pregnancy raise the possibility of a low risk of miscarriage and malformation. Therefore, these drugs should only be used intermittently in the first trimester of pregnancy
• Intermittent rather than regular use of all non-selective NSAID except LDA is recommended throughout pregnancy and weaned from end of second trimester (26 weeks) to stop by gestational week 30 to avoid premature closure of the ductus
• At present there are limited data on selective cyclo-oxygenase-2 inhibitors; they should therefore be avoided during pregnancy
• Non-selective NSAIDs (especially ibuprofen) are compatible with breastfeeding.

Low-dose Aspirin and Clopidogrel in Pregnancy and Breastfeeding

• LDA of ≤150 mg/day may be continued throughout pregnancy and NICE guidelines (2019) for hypertension in pregnancy advise treatment with LDA (for prophylaxis of pre-eclampsia) until delivery
• LDA is compatible with breastfeeding
• There are limited data on clopidogrel, but it may be considered where alternative drugs are not suitable in pregnancy and breastfeeding.

Colchicine and Dapsone in Pregnancy and Breastfeeding

• Colchicine therapy may be considered during pregnancy
• Dapsone may be used in pregnancy
• Colchicine may be used in breastfeeding
• Dapsone may be used in breastfeeding and due to the risk of haemolytic anaemia it is advised to monitor the infant for signs of haemolysis, especially in newborn or premature breastfed infants.

Anticoagulants in Pregnancy and Breastfeeding

• LMWH is compatible throughout pregnancy
• LMWH is compatible with breastfeeding
• The use of warfarin in pregnancy is associated with increased fetal risk throughout pregnancy and has limited indications, therefore should only be considered in exceptional circumstances
• Warfarin is compatible with breastfeeding
• Direct oral anticoagulants (DOACs) cannot be recommended in pregnancy
• Rivaroxaban may be considered in breastfeeding
• Other DOACs are not recommended in breastfeeding due to lack of human data and concerns from animal studies
• Fondaparinux may be considered in pregnancy and breastfeeding if there is an allergy or adverse response to LMWH.

Other Treatments for Comorbid Conditions

Bisphosphonates in Pregnancy and Breastfeeding

• There is insufficient data upon which to recommend bisphosphonates in pregnancy or to advise a specific time for them to be stopped pre-conception. Given their biological half-life in bone of up to 10 years and no evidence of harm from limited reports of their use in pregnancy, a pragmatic recommendation is that they should be stopped 3 months in advance of pregnancy
• There are no data on which to base a recommendation for the use of bisphosphonates during breastfeeding.

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Pregnancy and Breastfeeding

• Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) should be stopped as soon as possible when pregnancy is confirmed in the first trimester and if necessary an alternative antihypertensive compatible with pregnancy given
• ACEi/ARB should be avoided in the second and third trimester, but may be considered under specialist advice in certain circumstances
• Based on limited evidence, enalapril is compatible with breastfeeding.

Calcium Channel Blockers in Pregnancy and Breastfeeding

• Nifedipine is compatible with pregnancy with no direct evidence of harm at doses up to 90 mg/day
• Nifedipine is compatible with breastfeeding
• Amlodipine can be considered in pregnancy and breastfeeding as there is no evidence of harm.

Pulmonary Vasodilators in Pregnancy and Breastfeeding

• Established moderate-to-severe pulmonary hypertension (PHT) remains a contraindication to pregnancy. If pregnancy occurs, the use of these pulmonary vasodilator drugs in pregnancy should be considered only as part of a multidisciplinary team assessment
• Limited evidence supports the use of prostacyclines to treat PHT during pregnancy
• Limited evidence supports the use of sildenafil to treat PHT during pregnancy
• Bosentan is teratogenic in animals and although there is no evidence of harm from human pregnancy, the evidence is insufficient to recommend in pregnancy
• There are no data relating to breastfeeding exposure to pulmonary vasodilators on which to base a recommendation.

Paternal Exposures

• Paracetamol is compatible with paternal exposure
• Amitriptyline, serotonin–norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors are compatible with paternal exposure
• Non-selective NSAIDs are compatible with paternal exposure
• Based on limited or no data and no association with adverse fetal development or pregnancy outcome, paternal exposure to all other drugs described in this guideline are unlikely to be harmful.