EULAR Guidelines on Reproductive Health Save

Rheumatology patients considering or actually having babies can safely take most of the medications currently used to treat their conditions, according to an updated guideline from the European Alliance of Associations for Rheumatology (EULAR).

Mainstays of treatment such as azathioprine, hydroxychloroquine, and the most common biologic drugs were okayed for use during pregnancy and breastfeeding, determined a committee led by Frauke Förger, MD, of HOCH Cantonal Hospital St. Gallen in Switzerland.

Still, a number of familiar medications are best avoided, including methotrexate, mycophenolate mofetil, and many Janus kinase (JAK) inhibitors. In some cases, these drugs are known teratogens or definitely enter breast milk at significant levels; in others, the panel's caution stemmed from lack of evidence one way or the other.

The update was published in Annals of the Rheumatic Diseases. The last version came out in 2016; meanwhile, numerous new medications, as well as studies on older ones, have emerged.

Förger and colleagues first set out five "overarching principles" to guide their recommendations:

• All patients (including men) should be counselled on reproductive health and how their plans for childbearing may mean changes to their treatment regimens
• Whether during preconception, pregnancy, or lactation, therapeutic goals should remain disease remission or low activity
• Risks to the fetus or infant from medical therapy should be balanced against those from un- or undertreated disease in the mother
• Women should not be discouraged from breastfeeding; medications compatible with lactation should be given
• Treatment decisions should be made jointly with the patient

The panel then followed with specific recommendations for medications to use, not use, or minimize before and during pregnancy, during breastfeeding, and -- addressing a concern omitted in the 2016 version -- in male patients.

Preconception and Pregnancy

Other than methotrexate, mycophenolate, and cyclophosphamide, all standard conventional disease-modifying anti-rheumatic drugs (DMARDs) can be taken by pregnant women or those hoping to conceive. However, Förger and colleagues urged caution about nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy. "NSAIDs should only be used intermittently and stopped after 28 wk of gestation," they recommended. When NSAIDs are needed, they added, ibuprofen and others with a short half-life are preferred. As well, patients having trouble conceiving should consider stopping any NSAIDs.

Corticosteroids also are best minimized or stopped, the panel said. If such drugs would otherwise be given for "severe refractory" disease activity, acceptable substitutes include intravenous immunoglobulin (IVIG), "pregnancy-compatible" conventional DMARDS, or most biologics. In severe disease occurring after the first trimester, mycophenolate or cyclophosphamide can also be used

Tumor necrosis factor (TNF) inhibitors got the OK for most uses. Other biologics require more caution, the committee indicated: the potential for "transplacental transfer" should be taken into account, along with their need in controlling disease symptoms. Newer agents with non-TNF targets including guselkumab (Tremfya), risankizumab (Skyrizi), and anifrolumab (Saphnelo) should be avoided unless no effective alternatives can be found.

Finally, a substantial number of medications, mostly newer oral products, have "insufficient safety data on use in pregnancy" and therefore should be avoided. These include now-common JAK inhibitors such as tofacitinib (Xeljanz) and upadacitinib (Rinvoq) as well as apremilast (Otezla), avacopan (Tavneos), and bosentan (Tracleer). The old-line DMARD leflunomide also made this list.

Lactation

Most of the drugs on that latter list should also be avoided during breastfeeding, along with mycophenolate and cyclophosphamide, also because safety data are largely missing. Permissible medications include nearly all biologic products and most conventional DMARDs and corticosteroids. Even methotrexate is OK if doses don't exceed 25 mg/week.

Male Patients

Förger and colleagues listed only one drug as having a clear impact on male fertility: cyclophosphamide, which "is associated with a dose-related potential risk for irreversible infertility. Male patients should be counselled about options for fertility preservation before starting treatment" with this agent, the panel wrote.

Otherwise, most standard antirheumatic drugs, including biologics, should not affect pregnancy outcomes when taken by men. But the same list of medications for which the panel had reservations when considering female patients, primarily for lack of safety data, such as with JAK inhibitors, also appeared with a cautionary note in this category. While the authors did not recommend firmly against these products for men trying to conceive, "an alternative antirheumatic medication" may be preferable, they suggested.

The committee concluded with recommendations for future research, pressing for focused studies on medication safety during conception, pregnancy, and lactation. Pregnant women should be included in clinical trials, for example, "especially if preclinical reproductive toxicity studies did not show any signals for increased risk of miscarriage/malformations." Similarly, research should evaluate DMARD concentrations in breast milk and infant blood.

Specific recommendations

I. Antirheumatic drugs before and during pregnancy 

1. csDMARDs and other drugs used in rheumatology practice that are compatible with pregnancy include azathioprine or mercaptopurine, chloroquine, colchicine, cyclosporine, hydroxychloroquine, sulfasalazine, and tacrolimus.    
2. Cyclophosphamide, methotrexate, and mycophenolate are teratogenic and should be discontinued before pregnancy. 
3. NSAIDs, prednisone, and prednisolone can be considered during pregnancy if needed to control disease activity. Adding or switching pregnancy-compatible csDMARDs or bDMARDs should be considered if needed to control active disease.
   1. In pregnancy, NSAIDs should only be used intermittently and stopped after 28 wk of gestation. Due to limited evidence on selective COX-2 inhibitors, nonselective NSAIDs with a short half-life (eg, ibuprofen) are preferred. Discontinuation of NSAIDs should be considered if there is difficulty in conceiving.  
   2. In pregnancy, prednisone and prednisolone should be tapered where possible to a maintenance dose of ≤5 mg/d and, when possible, withdrawn. The use of higher dosages should be weighed against the risk of maternal-foetal complications. 
4. In severe, refractory maternal disease during pregnancy, IV methylprednisolone pulses, IVIG, sildenafil, pregnancy-compatible csDMARDs and/or bDMARDs, or, in the second and third trimesters, cyclophosphamide, or mycophenolate can be considered.
5. For bDMARD use in pregnancy, individual drug effectiveness and transplacental transfer should be taken into consideration. 
   1. All TNFi bDMARDs can be used throughout pregnancy.
   2. The following non-TNFi bDMARDs may be used if needed to effectively control maternal disease: abatacept, anakinra, belimumab, canakinumab, ixekizumab, rituximab, sarilumab, secukinumab, tocilizumab, and ustekinumab.
   3. Very limited or no data are available on safe use in pregnancy for anifrolumab, eculizumab, guselkumab, mepolizumab, and risankizumab. These drugs should only be used during pregnancy if no other pregnancy-compatible medication can effectively control maternal disease. 
   4. Nonlive vaccines can be administered to all infants after exposure to any bDMARD during pregnancy. Administration of live-attenuated vaccines during the first 6 mo after delivery is dependent upon timing of maternal exposure to bDMARDs during pregnancy, transplacental passage of the bDMARD and type of the vaccine.
6. Drugs for which there are insufficient safety data on use in pregnancy should be avoided until further evidence is available. This applies to apremilast, avacopan, baricitinib, bosentan, filgotinib, leflunomide, mepacrine, tofacitinib, upadacitinib, and voclosporin.

II. Antirheumatic drugs during lactation

1. csDMARDs and other drugs used in rheumatology practice that are compatible with breastfeeding include azathioprine or mercaptopurine, celecoxib, chloroquine, colchicine, cyclosporine, hydroxychloroquine, IVIG, IV methylprednisolone pulses, nonselective NSAIDs (eg, ibuprofen), prednisone and prednisolone, sulfasalazine, and tacrolimus.    
2. Minimal transfer into breast milk and limited systemic absorption by the breastfed child has been shown for bDMARDs due to their physicochemical and pharmacokinetic properties. Continuation of TNFi bDMARDs and non-TNFi bDMARDs should be considered compatible with breastfeeding. 
3. Drugs with limited or no data on breastfeeding 
   1. Since the following drugs have very low levels in breast milk and show no evidence of harm in breastfed infants, they may be considered during breastfeeding if no alternative drug compatible with breastfeeding can be used: bosentan, sildenafil, and methotrexate ≤25 mg weekly.
   2. The following drugs should be avoided in breastfeeding women and alternative drugs should be considered: apremilast, avacopan, baricitinib, cyclophosphamide, etoricoxib, filgotinib, iloprost, leflunomide, mycophenolate, tofacitinib, upadacitinib, and voclosporin.

III. Antirheumatic drugs in male patients

1. Treatment with the following drugs has not demonstrated a clinically relevant impact on offspring outcome and can be continued in male patients trying to conceive. This applies to azathioprine or mercaptopurine, colchicine, cyclosporine, hydroxychloroquine and chloroquine, IVIG, leflunomide, methotrexate ≤25 mg/week, mycophenolate, NSAIDs, prednisone and prednisolone, sildenafil, sulfasalazine, tacrolimus, TNFi bDMARDs, and non-TNFi bDMARDsc. 
2. Cyclophosphamide is associated with a dose-related potential risk for irreversible infertility. Male patients should be counselled about options for fertility preservation before starting treatment. 
3. Limited or no data are available on the impact of male treatment with the following drugs: anifrolumab, apremilast, avacopan, baricitinib, bosentan, eculizumab, filgotinib, guselkumab, mepolizumab, risankizumab, tofacitinib, upadacitinib, and voclosporin. Consider switching to an alternative antirheumatic medication in male patients trying to conceive.