ANTI-RHEUMATIC MEDICATIONS IN LACTATION Jalilolghadr.Sh Associate Professor of Medical Sciences Pediatric Sleep Physician Member of Iranian Sleep Medicine Society (ISMS)and International Pediatric Sleep Association ( IPSA)

BENEFITS OF BREASTFEEDING  Ecological  For Society  To Families  Benefits to baby  Benefits to mother

Rheumatoid arthritis  A significant portion of women with rheumatoid arthritis will improve during pregnancy, most RA patients flare during the postpartum period.  Because of the physical demands of caring for a newborn and the associated sleep deprivation. For women with RA, these difficulties may be magnified especially if a woman develops worsening joint pain and swelling that make even relatively simple tasks such as changing a diaper difficult.

BREAST MILK  Breast milk is composed of lactose and oligosaccarides, fat, proteins including secretory immunoglobulin A (IgA), and minerals.  Breast milk components are secreted into the alveolar lumen by active transport mechanisms that include exocytosis, reverse pinocytosis, transcytosis, apical transport, and paracellular movement.  Drugs ingested by the mother are generally transferred to the milk via diffusion.

For discussions of drug safety:  Unbound fraction of a drug is transferred to breast milk.  Highly protein bound, high molecular weight, ionized, and nonlipid soluble medications are unlikely to cross into breast milk.  Drug kinetics; for example, drugs with long half-lives are more likely to accumulate in breast milk.  The milk-to plasma drug concentration  Avoiding nursing during hours with peak levels  Exclusive versus partial breastfeeding

For discussions of drug safety:  Infants themselves may differ in ability to absorb and metabolize medications.  Age : a premature or very young infant is more likely to suffer adverse effects from maternal drug exposure through lactation than an older infant.  Further specifics of the infant’s metabolism may be determined genetically and may affect serum level just as they do in the adult, for example, the impaired ability to metabolize TPMT deficient patients.

Main Rheumatic Disorders medications Anti- Inflammatory and analgesics Drugs Disease Modifying Anti-Rheumatic Drugs Biologic Drugs Other Drugs

Disease Modifying Anti-Rheumatic Drugs Hydroxychloroquine Sulphasalazine Methotrexate Leflunomide Azathioprine Cyclosporine Cyclophosphamide Mycophenolate Mofetile

Biologic Medications Anti-TNFs: Etanercept, Infliximab,Adalimumab Anti B-Cell: Rhituximab Anti- Interlukin Anakinra, Tocilizumab Abatacept Others

Rheumatic Disorders medications  1) Low, 2) High, and 3) Unknown risk for use

LOW-RISK MEDICATIONS NSAIDS, Prednisone and Prednisolone Antimalarial medications, Sulfasalazine, Cyclosporine, Azathioprine (AZA), TNFa,

NSAIDs  Less than 5%  Medications with shorter half-lives, such as ibuprofen, are preferred to those with longer half- lives, such as piroxicam, to help minimize potential transfer.  Analgesics;Paracetamol: Safe during lactation  In a series of women treated with 400mg ibuprofen every 6 h, no measurable ibuprofen was detected in the mothers’ breast milk.

NSAIDs  Lactating mothers should avoid medications with enterohepatic circulation, such as indomethacin, especially with premature or jaundiced infants, because of the potential to displace bilirubin.  Mothers nursing neonates who have thrombocytopenia should avoid NSAIDs because of their antiplatelet effect.  Aspirin at doses higher than 100mg daily should be avoided, as immature neonatal metabolism can lead to salicylate intoxication and bleeding.

Prednisone and Prednisolone  Less than 10%  Mothers taking 10–80 mg/day of prednisone, the milk:serum ratio ranged from 0.1 to Peak serum levels occur 1h after the dose,  Even at 80 mg/day, the amount of steroid added to the infant’s endogenous cortisol production is calculated at less than 10%.

Prednisone and Prednisolone  For women taking steroid doses greater than 20 mg/day, it is recommended that nursing be delayed for 4h after ingestion.  For women taking greater than 40mg of prednisone daily, it is prudent to monitor the infant for evidence of adrenal suppression.  Only trace amounts of hydrocortisone are excreted into human breast milk. No data are available for dexamethasone or betamethasone in lactating women.

Antimalarial drugs  limited distribution  For a SLE patient treated with 400mg hydroxychloroquine daily, the weight-adjusted infant dose was 2% of the maternal dose. No decrease in visual acuity, visual field or color vision, or alterations in electroretinogram and electro- oculogram or hearing impairment, or growth or developmental abnormalities were detected in children studied during the first year of life or up to 4 years of age. So, in patients with SLE, HCQ must continue during breastfeeding.

Sulfasalazine  metabolized to 5-aminosalicylic acid and sulfapyridine. Sulfapyridine is present at significant levels in breast milk, measured at 30–60% the levels in maternal serum.  There are reported of bloody diarrhea in infants exposed to sulfasalazine through lactation.  As a result, caution is recommended for use of sulfasalazine in healthy full-term infants, with careful follow-up for development of diarrhea in the infant.

 This medication should be avoided in:  Premature infants  Ill infants  Hyper bilirubinemia  Glucose-6-phosphate dehydrogenase deficiency, as sulfapyridine can displace bilirubin. Sulfasalazine

Cyclosporine  Relatively low risk during pregnancy make it a reasonable second-line agent during both pregnancy and lactation.  A series of post transplant mother: Maternal serum levels ;55 to 130 ng/ml, and breast milk levels ; 50 to 227 ng/ml. infant serum level ;less than 3 ng/ml  Blood levels in most infants have been undetectable. check infant drug level as well as infant serum creatinine.

Azathioprine  In past the AAP does not recommend breastfeeding because of the theoretical risk of :  Immunosuppression,  Carcinogenesis and  Growth restriction in the child

Azathioprine  6-MP ¬6-methylmercaptopurine and 6-thioguanine.  For IBD :appeared in the breast milk within the first 4h.The calculated average dose delivered through nursing : less than mg/kg/day  No study has reported detection of AZA or 6-MP metabolites in infant serum, and long-term follow- up of babies.

Azathioprine  No immunologic or developmental abnormalities  Low risk to BMF in term infants while may not be applicable to preterm infants or to infants with TPMT mutations.

Tissue Necrosis Factor a-inhibitors  Low-risk medications :  1) Little IgG1 is secreted in breast milk  2) High molecular weight proteins,  3) As these medications lack the secretory piece that protects maternal IgA in breast milk from enzymatic degradation, they are likely to be destroyed in the infant gastrointestinal system and not absorbed systemically.

Infliximab  Minimal transfer into human breast milk  Serum levels from Crohn’s disease patients treated with infliximab after delivery ranged from to mcg/ml, with undetectable levels in breast milk and infant serum. 

 Adalimumab In Crohn’s disease patient treated with adalimumab during lactation :less than 1/100 maternal serum level. Maximal milk level was measured at 6 days post injection.  Golimumab(IgG1 monoclonal antibody) There are currently no human reports of breastfeeding on golimumab,

Etanercept  in breast milk at low concentration with little passage to the infant during nursing. The highest concentration in RA patients, at 72 h post In ankylosing spondylitis patients :5 ng/ml despite maternal serum levels of 840–2000 ng/ml, and no was detected in the infant serum.

 Certolizumab pegol: There are no human reports of breastfeeding on this medication.  Tacrolimus: only 0.02% of the mother’s dose of is transmitted. Breastfeeding is possible.

IVIG  Normal percentages of T cells, B cells, NK cells and monocytes were found in infants born after maternal immunoglobulin treatment for fetal alloimmune thrombocytopenia.No data are available with regard to fertility or breastfeeding, but harmful effects seem unlikely.  Intravenous immunoglobulin can be used in pregnancy  Breastfeeding is allowed.

 Osteoporosis prevention  For women treated either with corticosteroids or with heparin throughout pregnancy, prevention of osteoporosis is important.  The routine use of oral calcium and vitamin D supplements is recommended in pregnancy and lactation.

HIGH-RISK MEDICATIONS  High-risk medications are generally avoided during breastfeeding, based on reported data and/or a high theoretical likelihood of adverse effects for the nursing infant.

Methotrexate  In breast milk with low concentration but with accumulation in neonatal tissues.  Detectable in breast milk and serum 2h after administration to woman treated with 22.5mg/day for choriocarcinoma: the peak milk level was reached between 4 and 10 h later at a concentration of 8% of the plasma concentration.  low once weekly doses used for RA may not pose a great risk to the infant (especially if milk were discarded for the first 24 h after the dose), it is recommended that breastfeeding be avoided because of lack of data and concern for accumulation in neonates.

Leflunomide  A pyrimidine synthesis inhibitor, leflunomide has a very long half-life (14 days). Given the lack of data and the very long half-life, this drug is best avoided during breastfeeding on theoretical grounds. Because the active metabolite of leflunomide is detectable in plasma until 2 years after discontinuation of the drug, cholestyramine must be given to enhance elimination from the body until plasma levels of leflunomide are undetectable.

UNKNOWN RISK MEDICATIONS  Although many of the medications are monoclonal antibodies or other macromolecules, they are not recommended for use during breastfeeding because of the lack of data.

Anakinra  An interleukin-1 receptor antagonist Short half-life of 4–6 h A woman with Still’s disease was treated with anakinra throughout pregnancy and lactation: her child displayed normal growth and development, although no assessments of milk or infant serum levels were performed.

Others:  Rituximab Eleven live born infants born to mothers who were treated with rituximab before or during pregnancy were reported to have neonatal hematological abnormalities;  Abatacept Abatacept has been detected in milk of lactatin animals, but there are no data on presence in human milk.  Tocilizumab No cases of breastfeeding on tolcilizumab Mycophenolate mofetil Breastfeeding is not recommended.

Tofacitinib  Tofacitinib is a Janus-associated kinase (Jak) 3 inhibitor. It is administered orally and has a low molecular weight of Da. As small molecules are known to diffuse into breast milk easily and there are no published data, it is recommended that breastfeeding should be avoided.

CONCLUSION  It may take many years to accumulate sufficient high- quality data to permit evidence based breastfeeding guidelines.  Rheumatologists consider for each patient to weigh the risks and benefits of breastfeeding while on a particular medication for herself and her child.  Any breastfed child of a mother on immunosuppressive medications, even those regarded as low risk, should be carefully monitored for infectious, Growth and development delay or other complications.