BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding

British Society for Rheumatology


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Introduction

  • The prescribing of many drugs in pregnancy is complicated by a lack of knowledge regarding their compatibility, leading to patient misinformation and withdrawal/denial of disease-ameliorating therapies. This situation should be avoided because active rheumatic disease is associated with adverse pregnancy outcomes and there is growing evidence of drug safety in pregnancy
  • These guidelines are for healthcare professionals directly involved in managing patients with rheumatic disease in the UK who are (or planning to become) pregnant and/or breastfeeding, men planning to conceive and patients who have accidentally conceived while taking these medications. The guideline will also be useful to obstetricians, obstetric physicians, renal physicians, and general practitioners who prescribe these medications in pregnancy

Corticosteroids

  • Prednisolone is compatible with each trimester of pregnancy
  • Prednisolone is compatible with breastfeeding
  • Prednisolone is compatible with paternal exposure
  • Methylprednisolone has similar rates of placental transfer to prednisolone with equivalent anti-inflammatory effects at 80% of prednisolone dose and would therefore be expected to be compatible with pregnancy, breastfeeding and paternal exposure

Hydroxychloroquine

  • Hydroxychloroquine (HCQ) remains the antimalarial of choice in women planning a pregnancy with rheumatic disease in need of treatment and should be continued during pregnancy
  • Hydroxychloroquine is compatible with breastfeeding
  • Men should not be discouraged from taking HCQ whilst trying to conceive

Methotrexate

  • Methotrexate (MTX) at any dose should be avoided in pregnancy and stopped three months in advance of conception
  • In women treated with low dose MTX within 3 months prior to conception, folate supplementation (5mg/day) should be continued prior to and throughout pregnancy
  • In the case of accidental pregnancy on low dose MTX, the drug should be stopped immediately, folate supplementation (5 mg/day) continued and a careful evaluation of fetal risk carried out by local experts
  • Methotrexate cannot be recommended in breastfeeding because of theoretical risks and insufficient outcome data
  • Based on limited evidence, low dose MTX may be compatible with paternal exposure

Sulfasalazine

  • Sulfasalazine (SSZ) with folate supplementation (5 mg/day) is compatible throughout pregnancy
  • Sulfasalazine is compatible with breastfeeding in the healthy, full-term infant
  • Men taking SSZ may have reduced fertility. There is no evidence, however, that conception is enhanced by stopping SSZ for 3 months prior to conception unless conception is delayed more >12 months when other causes of infertility should also be considered

Leflunomide

  • Based on limited evidence leflunomide (LEF) may not be a human teratogen but it is still not recommended in women planning pregnancy
  • Women on LEF considering pregnancy should stop and undergo cholestyramine washout before switching to alternative medication compatible with pregnancy
  • There is no human evidence of increased congenital abnormalities on LEF if washout is given. Therefore, if accidental conception occurs on LEF the drug should be stopped immediately and cholestyramine washout given until plasma levels are undetectable
  • No data exist on excretion into breast milk. Therefore, breastfeeding is not recommended
  • Based on very limited evidence LEF may be compatible with paternal exposure

Azathioprine

  • Azathioprine (AZA) is compatible throughout pregnancy at 2 mg/kg per day or less
  • Azathioprine is compatible with breastfeeding
  • Azathioprine is compatible with paternal exposure

Ciclosporin

  • Ciclosporin (CSA) is compatible throughout pregnancy at the lowest effective dose
  • Mothers on CSA should not be discouraged from breastfeeding
  • Based on limited evidence CSA is compatible with paternal exposure

Tacrolimus

  • Tacrolimus is compatible throughout pregnancy at the lowest effective dose
  • Mothers on tacrolimus should not be discouraged from breastfeeding
  • Based on limited evidence tacrolimus is compatible with paternal exposure

Cyclophosphamide

  • Cyclophosphamide (CYC) is teratogenic and gonadotoxic, therefore should only be considered in pregnancy in life/organ-threatening maternal disease
  • There is no evidence to recommend use of CYC in breastfeeding
  • Paternal exposure to CYC is not recommended

Mycophenolate mofetil

  • Mycophenolate mofetil (MMF) remains contraindicated during pregnancy
  • Treatment with MMF should be stopped at least 6 weeks before a planned pregnancy
  • No data exist on excretion into breast milk; breastfeeding is therefore not recommended
  • Based on very limited evidence MMF is compatible with paternal exposure

Intravenous immunoglobulin

  • Intravenous immunoglobulin (IVIG) is compatible with pregnancy
  • Intravenous immunoglobulin is compatible with breastfeeding
  • Based on maternal compatibility, IVIG is unlikely to be harmful

Anti-TNF medications

  • Infliximab (INF) may be continued until 16 weeks, and etanercept (ETA) and adalimumab (ADA) may be continued until the end of the second trimester
  • To ensure low/no levels of drug in cord blood at delivery ETA and ADA should be avoided in the third trimester and INF stopped at 16 weeks. If these drugs are continued later in pregnancy to treat active disease then live vaccines should be avoided in the infant until seven months of age
  • Certolizumab pegol is compatible with all three trimesters of pregnancy and has reduced placental transfer compared with other TNFi
  • Golimumab (GOL) is unlikely to be harmful in the first trimester
  • Women should not be discouraged from breastfeeding on TNFi, but caution is recommended until further information is available
  • Based on limited evidence INF, ETA and ADA are compatible with paternal exposure

Rituximab

  • Rituximab (RTX) should be stopped six months before conception. Limited evidence however, has not shown RTX to be teratogenic and only second-/third-trimester exposure is associated with neonatal B cell depletion. Therefore, unintentional RTX exposure early in the first trimester is unlikely to be harmful
  • There are no data upon RTX use in breastfeeding
  • Based on limited evidence RTX is compatible with paternal exposure

Tocilizumab

  • Tocilizumab (TCZ) should be stopped at least 3 months before conception, but unintentional exposure early in the first trimester is unlikely to be harmful
  • There are no data upon TCZ use in breastfeeding
  • There are no data relating to paternal exposure to TCZ, but it is unlikely to be harmful

Anakinra

  • There is limited evidence on which to base a recommendation for anakinra in pregnancy but unintentional exposure in the first trimester is unlikely to be harmful
  • There are no data upon anakinra use in breastfeeding
  • There are no data relating to paternal exposure to anakinra, but it is unlikely to be harmful

Abatacept

  • There are insufficient data to recommend abatacept (ABA) in pregnancy. Unintentional exposure early in the first trimester is unlikely to be harmful
  • There are no data upon ABA use in breastfeeding
  • There are no data relating to paternal exposure to ABA, but it is unlikely to be harmful

Belimumab

  • There are insufficient data to recommend belimumab (BEL) in pregnancy. Unintentional exposure early in the first trimester is unlikely to be harmful
  • There are no data upon BEL use in breastfeeding
  • There are no data relating to paternal exposure to BEL, but it is unlikely to be harmful

Paracetamol

  • Paracetamol is compatible peri-conception and throughout pregnancy
  • Intermittent use is advised because of a small risk of wheeze and childhood asthma with prolonged paracetamol use in pregnancy
  • Avoid regular use during weeks 8–14 of pregnancy due to small reported risk of cryptorchidism
  • LactMed describes paracetamol as a good choice for analgesia and fever reduction in breastfeeding mothers
  • There are no data on paternal exposure to paracetamol, but due to maternal compatibility, it is unlikely to be harmful

Codeine

  • Codeine is compatible peri-conception and throughout pregnancy. 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 CNS depression resulting from unpredictable metabolism of codeine to morphine
  • There are no data relating to paternal exposure to codeine, but due to maternal compatibility, it is unlikely to be harmful

Tramadol

  • Tramadol is compatible with pregnancy, although there have been no high quality studies published which investigate the safety of tramadol in pregnancy
  • Based on limited data tramadol may be compatible with short-term use in breastfeeding
  • There are no data relating to paternal exposure to tramadol, but due to maternal compatibility, it is unlikely to be harmful

Amitriptyline

  • Amitriptyline is compatible with pregnancy
  • Low dose amitriptyline for chronic pain is unlikely to cause adverse effects in breastfed infants
  • There are no data relating to paternal exposure to amitriptyline, but due to maternal compatibility, it is unlikely to be harmful

Gabapentin

  • There is insufficient evidence to recommend gabapentin for treatment of chronic pain in pregnancy or breastfeeding
  • There are no data to recommend pregabalin in pregnancy or breastfeeding
  • There are no data on which to base a recommendation regarding paternal exposure to gabapentin or pregabalin

Serotonin-norepinephrine reuptake inhibitors

  • 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
  • There is insufficient evidence to recommend venlafaxine for treatment of chronic pain in breastfeeding women
  • There are no data relating to paternal exposure to SNRIs, but due to maternal compatibility, they are unlikely to be harmful

Selective serotonin reuptake inhibitors

  • Fluoxetine, paroxetine and sertraline are compatible with pregnancy
  • Cessation of anti-depressant therapy in the post-natal period is not recommended, due to the risk of relapsing depression
  • Based on limited data, women should not be discouraged from breastfeeding on serotonin-norepinephrine reuptake inhibitors (SSRIs)
  • There are no data relating to paternal exposure to SSRIs, but based on maternal compatibility, they are unlikely to be harmful

NSAIDs, COX-1 inhibitors and low dose aspirin

  • Discordant findings from retrospective, large studies with population controls on the use of non-selective NSAIDs in the first trimester of pregnancy raise the possibility of a low risk of miscarriage and malformation. Therefore, these drugs should be used with caution in the first trimester of pregnancy
  • All non-selective NSAID except low dose aspirin (LDA) should be withdrawn at gestational week 32 to avoid premature closure of the ductus arteriosus
  • Low dose aspirin may be continued throughout pregnancy and NICE guidelines for hypertension in pregnancy (NICE CG107) advises treatment with LDA (for pre-eclampsia) until delivery
  • At present there are limited data on selective COX-2 inhibitors; they should therefore be avoided during pregnancy
  • Non-selective NSAIDs are excreted into breast milk but there is no published evidence of harm
  • Non-selective NSAIDs are compatible with paternal exposure
  • There are no data relating to the use of LDA during breastfeeding or paternal exposure to LDA but there are no theoretical concerns

Anticoagulants

  • Low molecular weight heparin is compatible throughout pregnancy
  • Although no additional data on heparin use during breastfeeding were found, there are no theoretical concerns
  • The use of warfarin in pregnancy is associated with increased fetal risk throughout pregnancy and should only be considered in exceptional circumstances
  • Warfarin is compatible with breastfeeding
  • There are no data regarding paternal exposure to warfarin or heparin, but there are no theoretical concerns
  • Rivaroxaban and dabigatran cannot be recommended in pregnancy or breastfeeding due to lack to human data and concerns from animal studies

Bisphosphonates

  • There are 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 before pregnancy
  • There are no data on which to base a recommendation for the use of bisphosphonates during breastfeeding
  • There are no data on which to base a recommendation for paternal exposure to bisphosphonates

ACE inhibitors

  • Angiotensin converting enzyme inhibitors (ACEI) 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
  • Angiotensin converting enzyme inhibitors should be avoided in the second and third trimester
  • There is limited evidence on use of ACEI in breastfeeding. The human breast may selectively restrict the passage of captopril and/or enalapril from blood into breast milk so it is unlikely to cause adverse effects in breastfed infants
  • There are insufficient data on which to base a recommendation regarding paternal exposure to ACEI, but there are no theoretical concerns

Calcium channel blockers

  • Nifedipine is compatible with pregnancy with no direct evidence of harm at doses up to 60mg/day
  • Nifedipine is compatible with breastfeeding
  • There are insufficient data to recommend amlodipine in pregnancy but there is no evidence of harm during pregnancy and an absence of evidence during breastfeeding
  • There are no data relating to paternal exposure to calcium channel blockers, but they are unlikely to cause harm

Pulmonary vasodilators

  • 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 or paternal exposure to pulmonary vasodilators on which to base a recommendation
Summary of drug compatibility in pregnancy and breastfeeding
  Compatible peri-conception Compatible with first trimester Compatible with second/third trimester Compatible with breastfeeding Compatible with paternal exposure
CORTICOSTEROIDS
Prednisolone Yes Yes Yes Yes Yes
Methylprednisolone Yes Yes Yes Yes Yes
ANTIMALARIALS
Hydroxychloroquine Yes Yes Yes Yes Yes*
DMARDS
Methotrexate <20 mg/week Stop 3 months in advance No No No Yes*
Sulfasalazine (with 5 mg folic acid) Yes Yes Yes Yes Yes
Leflunomide Cholestyramine washout, no No No No data Yes*
Azathioprine <2 mg/kg/day Yes Yes Yes Yes Yes
Ciclosporin Yes Yes§ Yes§ Yes* Yes*
Tacrolimus Yes Yes§ Yes§ Yes* Yes*
Cyclophosphamide No No| No| No No
Mycophenolate mofetil Stop 6 weeks in advance No No No Yes*
Intravenous immunoglobulin Yes Yes Yes Yes Yes*
ANTI-TNF
Infliximab Yes Yes Stop at 16 weeks Yes* Yes*
Etanercept Yes Yes Second but not third Yes* Yes*
Adalimumab Yes Yes Second but not third Yes* Yes*
Certolizumab Yes Yes Yes* Yes* No data
Golimumab No data No data No data No data No data
OTHER BIOLOGICS
Rituximab Stop 6 months in advance No No No data Yes*
Tocilizumab Stop 3 months in advance No No No data No data**
Anakinra No No No No data No data**
Abatacept No No No No data No data**
Belimumab No No No No data No data**
CONVENTIONAL PAINKILLERS
Paracetamol Yes Yes†† Yes†† Yes Yes‡‡
Codeine Yes Yes Yes Caution Yes‡‡
Tramadol Yes Yes Yes Yes§§ Yes‡‡
OTHER CHRONIC PAIN TREATMENTS
Amitriptyline Yes Yes Yes Yes Yes‡‡
Gabapentin No Insufficient data|| Insufficient data|| Insufficient data No data
Pregabalin No data No data No data No data No data
Venlafaxine Yes Yes Yes Insufficient data|| Yes‡‡
Fluoxetine Yes Yes Yes Caution|| Yes‡‡
Paroxetine Yes Yes Yes Caution|| Yes‡‡
Sertraline Yes Yes Yes Caution|| Yes‡‡
NSAIDS
NSAIDs Yes Caution¶¶ Stop by week 32 Yes Yes
COX-2 inhibitors No No No No No data
Low-dose aspirin Yes Yes Yes Yes*** Yes‡‡
ANTICOAGULANTS
Warfarin No No No Yes No data
Low-molecular-weight heparin Yes Yes Yes Yes*** Yes‡‡
Rivaroxaban No data No data No data No data No data
Dabigatran No data No data No data No data No data
BISPHOSPHONATES
Bisphosphonates Stop 6 months in advance No No No data No data
ANTIHYPERTENSIVES
Angiotensin-converting-enzyme inhibitor Stop when pregnancy confirmed No Yes§§ No data
Nifedipine Yes Yes <60mg/day Yes <60mg/day Yes Yes‡‡
Amlodipine No data No data No data No data Yes***
PULMONARY VASODILATORS
Sildenafil MDT assessment No data No data
Bosentan MDT assessment No data No data
Prostacyclines MDT assessment No data No data
NSAIDS=non-steroidal anti-inflammatory drugs; COX-2=cyclooxygenase-2; MDT=multidisciplinary team.
* Data are limited
In healthy full-term infants only
Conception may be enhanced by stopping sulfasalazine for 3 months prior to conception
§ Suggested monitoring of maternal blood pressure, renal function, blood glucose and drug levels
| Only consider in severe or life-/organ-threatening maternal disease
Unintentional first trimester exposure is unlikely to be harmful
** Unlikely to be harmful
†† Intermittent use advised, see full guideline for details
‡‡ No studies identified, but unlikely to be harmful due to maternal compatibility
§§ Limited evidence, but unlikely to be harmful
|| Insufficient evidence regarding use for treatment of chronic pain in pregnancy
¶¶ Possible association with miscarriage and malformation
*** No studies identified, but unlikely to be harmful.

References

full guideline available from...
www.rheumatology.org.uk

Flint J, Panchal S, Hurrell A et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology 2016 (Epub ahead of print).

Flint J, Panchal S, Hurrell A et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—Part II: analgesics and other drugs used in rheumatology practice. Rheumatology 2016 (Epub ahead of print).


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