Dr Ian Giles discusses how the BSR and BHPR guideline on anti-rheumatic drugs in pregnancy and breastfeeding will enable a more consistent approach to prescribing

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Read this article to learn more about:

  • evidence-based guidance on the safety of anti-rheumatic drugs taken by women and men who are planning to conceive, before and during pregnancy, and in breastfeeding
  • recommendations related to paternal exposure of anti-rheumatic drugs
  • recommendations about drugs most relevant to general practice.

Key points

GP commissioning messages

M any inflammatory rheumatic diseases affect women of childbearing age. Historically, inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), were considered to improve spontaneously in most patients during pregnancy. Modern prospective studies, however, have shown that less than one half of all patients with RA objectively improve during pregnancy and that there is a significant risk of disease flare post partum.1 In addition, adverse pregnancy outcomes have been linked with increased disease activity in conditions such as RA.2,3 The prescribing of standard and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) in women with rheumatic disease is, therefore, often required to control maternal disease activity adequately and to ensure satisfactory pregnancy outcomes.

Box 1: NICE Accreditation Mark

NICE accreditation logo

The BSR and BHPR guidelines on Prescribing for rheumatological conditions in pregnancy and breastfeeding has been awarded the NICE Accreditation Mark.

See evidence.nhs.uk/accreditation for further details. 

Background

The need for the BSR and BHPR guideline

The prescribing of many anti-rheumatic drugs in pregnancy is complicated by safety concerns. Although obvious risks have been identified with some anti-rheumatic drugs, a great deal of uncertainty exists about many others. In response to this uncertainty, the British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) published a two-part guideline in January 2016 on: Prescribing for rheumatological conditions in pregnancy and breastfeeding (see Box 1, above).4,5 It provides healthcare professionals in primary and secondary care with the necessary tools to facilitate optimum prescribing of anti-rheumatic drugs in patients who are pregnant or considering pregnancy. The guideline expands and updates previous consensus recommendations6,7 and systematically reviews all current evidence on the use of various anti-rheumatic drugs before/during pregnancy and breastfeeding in women with rheumatic disease. Some recommendations are also made regarding paternal exposure.

Drugs considered in the 2016 BSR and BHPR guideline—part I

Part I of the 2016 BSR and BHPR guideline4 covers:

  • corticosteroids
  • antimalarials
  • DMARDs
  • immunosuppressive therapies and biologics.

Summary recommendations of all drugs considered are shown in Table 1 (see below), although only key drugs (and recommendations) most relevant to general practice are discussed in this article.

Table 1: Rheumatic diseases and prescribing of drugs—compatibility in pregnancy and breastfeeding of corticosteroids, antimalarials, DMARDs, TNFα inhibitors, and biologics4
Drug Compatible with peri-conception Compatible with 1st trimester Compatible with 2nd/3rd 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*
TNFα inhibitors
Infliximab Yes Yes Stop at 16 weeks Yes* Yes*
Etanercept Yes Yes 2nd but not 3rd Yes* Yes*
Adalimumab Yes Yes 2nd but not 3rd 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**

DMARDs=disease-modifying anti-rheumatic drugs; TNF=tumour necrosis factor

* 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 1st trimester exposure is unlikely to be harmful.

** Unlikely to be harmful.

Adapted from 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; 55 (2); doi:10.1093/rheumatology/kev404 (Epub ahead of print)

Corticosteroids

Corticosteroids used to treat rheumatic disease (i.e. prednisolone, prednisone, and methylprednisolone) were considered to be compatible with pregnancy and breastfeeding in the previous consensus.6 Additional studies were identified in the 2016 BSR and BHPR guideline:4 47 on prednisolone (n=1503 pregnancies); 31 on dexamethasone (n=11,214 pregnancies); 27 on betamethasone (n=27,746 pregnancies); and 10 on general corticosteroid use (n=785 pregnancies). Despite these studies being confounded by multiple concomitant medications and use of steroids in high-risk pregnancies, no harmful effects on pregnancy and breastfeeding were found to be attributable to steroids.4

Therefore, the 2016 BSR and BHPR guideline recommends:4

  • prednisolone is compatible with each trimester of pregnancy and is the preferred corticosteroid in the treatment of maternal rheumatologic disease in 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.

Antimalarials

Hydroxychloroquine (HCQ) was previously recommended as the antimalarial of choice in women planning pregnancy and to be compatible with pregnancy and breastfeeding.6 The 2016 BSR and BHPR guideline identified an additional 23 studies on 810 HCQ pregnancy exposures. Many of these studies reported pregnancy outcomes in HCQ-exposed patients with systemic lupus erythematosus treated with other immunosuppressive agents, and/or anti-Ro/La-positive patients given HCQ to try to prevent recurrence of congenital heart block. No appreciable adverse effects, however, of HCQ on pregnancy outcomes, breastfeeding, or long-term follow up to 12 months postpartum were identified.4

Based on this evidence, the 2016 BSR and BHPR guideline recommends:4

  • HCQ remains the antimalarial of choice in women planning a pregnancy with rheumatic disease in need of treatment, and should be continued during pregnancy
  • HCQ is compatible with breastfeeding
  • based on maternal compatibility and limited paternal data, men should not be discouraged from taking HCQ while trying to conceive.

Methotrexate

Methotrexate (MTX) is contraindicated in pregnancy and should be stopped 3 months in advance of conception.6 Rheumatology uses low doses of MTX to treat inflammatory arthritis (<20 mg per week) and significantly less than the doses used in cancer chemotherapy. The largest studies of pregnancy outcomes studied exposure mostly to low-dose MTX from 3 months pre-conception to the end of the first trimester.8,9 A prospective cohort study of 324 pregnancies exposed to MTX found a cumulative incidence of spontaneous abortion (42.5%) and major congenital anomalies (6.6%) among 188 pregnancies exposed to a median dose of 10 mg/week MTX after a median of 4.3 weeks post conception.10 This difference was statistically significant compared with a cohort of women without autoimmune diseases but not when compared with a disease-matched cohort. In contrast, an increased risk of miscarriage and major congenital anomaly was not found in 136 pregnancies exposed to a median dose of 15 mg/week of MTX that was stopped within 3 months pre-conception.10

A study of 113 pregnancies after paternal exposure to low-dose MTX did not identify an increased risk of adverse fetal outcomes compared with 412 non-exposed pregnancies.11

Based on the available evidence, the 2016 BSR and BHPR guideline recommends:4

  • MTX at any dose should be avoided in pregnancy and stopped 3 months in advance of conception. Recent studies support a shorter drug-free interval of low-dose (<20 mg/week) MTX but further evidence is required to alter previous recommendations
  • in women treated with low-dose MTX within 3 months prior to conception, folate supplementation (5 mg/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
  • MTX cannot be recommended in breastfeeding because of theoretical risks and insufficient data on outcomes
  • based on limited evidence, low-dose MTX may be compatible with paternal exposure.

TNFα inhibitors

Five biologic agents that inhibit TNFα (TNFis) are currently licensed to treat rheumatic diseases: etanercept (ETA), infliximab (IFX), adalimumab (ADA), golimumab (GOL), and certolizumab pegol (CZP). Three of these drugs (IFX, ADA, and GOL) are monoclonal IgG1 directed against TNFα, one (ETA) is a fusion protein of the TNF receptor joined to the Fc region of IgG1, while CZP is an antigen-binding fragment (Fab´) of a monoclonal anti-TNFα antibody, which lacks the Fc region of IgG1 and has been conjugated with polyethylene glycol (PEG).4 The structure of these drugs is important because the Fc region of IgG1 is required for their active placental transfer, from the 16th week of pregnancy onwards. Therefore, these drugs have different half-lives, bioavailability, and rates of placental transfer, which are relevant to their potential use in pregnancy.4

Previous recommendations advised avoidance of ETA, IFX, and ADA in pregnancy and breastfeeding due to a lack of evidence.6,7 The 2016 BSR and BHPR guideline identified studies examining 706 TNF inhibitor-exposed pregnancies of patients with inflammatory bowel disease, rheumatic disease, and non-autoimmune-mediated recurrent spontaneous miscarriage compared with 399 disease and 170 healthy control pregnancies. Overall, no adverse effects on pregnancy duration, birth weight, maternal complications, miscarriages, and major malformations were attributed to these medications. A case of fatal tuberculosis-like disease, however, was reported post Bacillus Calmette–Guérin (BCG) vaccination in an infant who was not breastfed but was exposed to IFX throughout pregnancy.12

In one small study, CZP was found to have the lowest rates of placental transfer compared with other TNFis; this finding is consistent with its structure, which contains PEG and lacks the Fc region.13 In contrast, IFX has prolonged bioavailability and a high rate of placental transfer such that it should be stopped earlier in pregnancy for it to be undetectable in cord blood at delivery.

Limited breastfeeding studies on a small number of patients on ADA, ETA, and IFX detected low or no levels of these drugs in breast milk.14 -19 Certolizumab pegol was undetectable in longitudinal breast-milk samples taken from one patient.13 No adverse effects were found in any of these breastfed infants.

Paternal exposure to IFX, ETA, and ADA in 131 pregnancies did not identify an increased risk of adverse fetal outcomes.4 Therefore, the 2016 BSR and BHPR guideline recommends:4

  • IFX may be continued until 16 weeks and ETA and 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 IFX should be stopped at 16 weeks because of a theoretical increased infection risk in newborns. If these drugs are continued later in pregnancy to treat active disease, then live vaccines should be avoided in the infant until 7 months of age
  • limited evidence shows that CZP is compatible with all three trimesters of pregnancy and has reduced placental transfer compared with other TNFis
  • there is no evidence upon which to recommend GOL but it is unlikely to be harmful in the first trimester
  • based on limited but reassuring data, women should not be discouraged from breastfeeding while on TNFis, but caution is recommended until further information is available
  • based on limited evidence, IFX, ETA and ADA are compatible with paternal exposure.

Drugs considered in the 2016 BSR and BHPR guideline—part II

Part II of the 2016 BSR and BHPR guideline categorised drugs under:5

  • pain management
  • non-steroidal anti-inflammatory drugs (NSAIDs) and lowdose aspirin (LDA) in the management of multisystem rheumatic disease
  • anticoagulants
  • bisphosphonates
  • anti-hypertensive medication in the management of multisystem rheumatic disease
  • pulmonary vasodilators.

Summary recommendations of all drugs considered are shown in Table 2 (below).5 Only paracetamol, NSAIDs, and LDA are considered in this article.

Table 2: Rheumatic diseases and prescribing of drugs—compatibility in pregnancy and breastfeeding of conventional painkillers, other chronic pain treatments, NSAIDs, anticoagulants, biphosphonates, antihypertensives, and pulmonary vasodilators4
Drug Compatible with peri-conception Compatible with 1st trimester Compatible with 2nd/3rd trimester Compatible with breastfeeding Compatible with paternal exposure
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
Pregabilin 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
Sertaline 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
LMWH 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
Biphosphonates
Biphosphonates Stop 6 months in advance No No No data No data
Antihypertensives
ACEi Stop when pregnancy confirmed No Yes No data
Nifedipine Yes Yes <60 mg/day Yes <60 mg/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; LMWH=low-molecular-weight heparin; ACEi=angiotensin-converting enzyme inhibitor; MDT=multi-disciplinary team

* Intermittent use advised—see main text [of 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.

Adapted from 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; 55 (2); doi:10.1093/rheumatology/kev405 (Epub ahead of print)

Paracetamol

Paracetamol exposure in at least 59,940 exposed pregnancies compared with 238,199 healthy non-exposed controls was reviewed. Most studies did not identify an increased risk of malformations.5 A large Danish cohort study, however, reporting on 22,449 live births over a 6-year period, found that exposure to paracetamol (particularly for more than 4 weeks within gestational weeks 8–14) was associated with an increased incidence of cryptorchidism (hazard ratio of 1.38 [95% CI 1.1–1.8]).20 Another study (n=233) found an increased incidence of cryptorchidism with exposure to paracetamol for more than 2 weeks in pregnancy compared with controls (9.9% vs 7.0%, respectively; OR 2.8, 95% CI 1.1–6.8).21

There were conflicting results on the risk of developing wheeze in infants exposed to paracetamol during pregnancy. Several large studies found a small but significant increased risk of asthma in childhood following exposure to paracetamol during any time of pregnancy,22 -24 while others did not.25,26

Based on this evidence, the BSR and BHPR 2016 guideline recommends:5

  • paracetamol is compatible peri-conception and throughout pregnancy
  • if possible, intermittent use in pregnancy is advised because of a small increased risk of wheeze and childhood asthma reported with prolonged paracetamol use in pregnancy with some studies
  • avoid regular use of paracetamol during weeks 8–14 of pregnancy as a small risk of cryptorchidism has been reported
  • LactMed describes paracetamol as a good choice for analgesia and fever reduction in breastfeeding mothers
  • there are no data relating to paternal exposure to paracetamol, but due to maternal compatibility, it is unlikely to be harmful.

Non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors

The previous consensus recommended that non-selective cyclooxygenase (COX) inhibitors be continued during the first and second trimester.6 The 2016 BSR and BHPR guideline found additional data on 15,606 NSAID-exposed patients compared with 250,143 non-exposed controls.5

Data from a national pregnancy registry found the use of any type or dose of non-aspirin NSAID during pregnancy was significantly associated with an increased risk of spontaneous abortion (OR 2.43, 95% CI 2.12–2.79).27 A systematic review of articles from 1966–2008 concluded that exposure to aspirin or NSAIDs during the first trimester of pregnancy was associated with an increased risk of different congenital anomalies in some but not all studies.28 The reliability of these conclusions, however, has been questioned given their reliance upon observational studies and lack of quality assessment.29

One study of 5153 pregnancies exposed during the first trimester to non-selective COX inhibitors and 114 pregnancies exposed to COX-2 selective inhibitors (i.e. celecoxib, etoricoxib, rofecoxib) found an increased risk of musculoskeletal malformations with exposure to COX-2 selective inhibitors.30

Low-dose aspirin

A search for studies on use of LDA (60 to 150 mg/day) in pregnancy and breastfeeding identified 4254 pregnancies exposed to LDA compared with 16,221 healthy controls throughout pregnancy. Overall, there was no evidence of increased adverse pregnancy outcomes at any stage of pregnancy that were attributable to LDA.5

Two cohort studies31,32 reported on outcomes from 888 pregnancies after paternal exposure to NSAIDs. These studies were of low quality but they did not identify an increased risk of adverse fetal outcomes.

Therefore, the BSR and BHPR 2016 guideline recommends:5

  • 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 NSAIDs except LDA should be withdrawn at gestational week 32 to avoid premature closure of the ductus arteriosus
  • LDA may be continued throughout pregnancy and NICE guidelines (Aug 2010) for hypertension in pregnancy advise 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.

Conclusion

It is important to maintain control of inflammatory rheumatic diseases in pregnancy to ensure the best possible outcomes. The 2016 BSR and BHPR guideline provides medical practitioners with the necessary tools to facilitate optimum prescribing of anti-rheumatic drugs in patients considering pregnancy and during their pregnancy, thus avoiding the unnecessary withdrawal of potentially beneficial medication at this time.

The BSR and BHPR guideline recommends giving tailored prepregnancy counselling to patients with rheumatic disease. Patients should then be reviewed during pregnancy and the 4-month post-partum period. Arthritis Research UK and BSR are developing further resources for patients in line with the new guidance.

Key points

  • The 2016 BSR and BHPR guideline provides recommendations to ensure a consistent approach to the prescribing of anti-rheumatic drugs before/during pregnancy and breastfeeding in patients with rheumatic disease. The risks (if any) of paternal exposure to these drugs are also considered
  • Prednisolone is compatible with each trimester of pregnancy and is the preferred corticosteroid in the treatment of maternal rheumatic disease in pregnancy
  • Hydroxychloroquine remains the antimalarial of choice in women with rheumatic disease who are in need of treatment and who are planning a pregnancy, and it should be continued during pregnancy
  • Methotrexate at any dose should be avoided in pregnancy and stopped 3 months in advance of conception
  • 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 because of a theoretical increased infection risk in newborns. If these drugs are continued later in pregnancy to treat active disease, then live vaccines should be avoided in the infant until 7 months of age
  • Limited evidence shows CZP is compatible with all three trimesters of pregnancy and has reduced placental transfer compared with other TNFis
  • Paracetamol is compatible peri-conception and throughout pregnancy
  • Intermittent use of paracetamol is advised in pregnancy, because of a small increased risk of wheeze and childhood asthma reported with prolonged paracetamol use in pregnancy in some studies
  • 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 NSAIDs except LDA should be withdrawn at gestational week 32 to avoid premature closure of the ductus arteriosus; LDA may be continued throughout pregnancy.

ETA=etanercept; ADA=adalimumab; IFX=infliximab; CZP=certolizumab pegol; TNFis=TNFα-inhibitors; LDA=low-dose aspirin

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GP commissioning messages

written by Dr David Jenner, GP, Cullompton, Devon

  • Anti-rheumatic drugs (apart from NSAIDs and paracetamol) should only be initiated by specialist rheumatologists and patients should remain under their supervision
  • Commissioners should work with these specialist services to ensure that patients, at the start of their treatment, receive advice on the implications of anti-rheumatic drugs before and during pregnancy
  • Advice should also be given to prospective male parents about the potential effect anti-rheumatic drugs may have on their sperm, and any risk to children they conceive:
    • this advice should be available in leaflet form and also appear on local formulary websites, allowing easy reference to primary care clinicians where such drugs are prescribed under shared-care agreements
    • Guidance on the use of paracetamol and NSAIDS, which are available over the counter, should be included in pre-conceptual and early pregnancy counselling materials to all mothers.

NSAIDs=non-steroidal anti-inflammatory drugs

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Read the Guidelines summary of the BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding for more information on the correct prescribing of anti-rheumatic drugs

References

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  3. de Man Y, Hazes J, Heide H et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum 2009; 60 (11): 3196–3206.
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  5. 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; 55 (2): doi:10.1093/rheumatology/kev405 (Epub ahead of print).
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  29. Horbach D, Oort E, Donders R et al. Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Comparison between different assays for the detection of antiphospholipid antibodies. J Thromb Haemost 1996; 76 (6): 916–924.
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