Rheumatoid Arthritis Medications and Lactation
Rheumatoid Arthritis Medications and Lactation
Low-risk medications for lactating mothers have generally included NSAIDs, prednisone and prednisolone, antimalarial medications, and sulfasalzine. Recent data suggest that maternal intake of cyclosporine, azathioprine (AZA), and tissue necrosis factorα (TNFα)-inhibitors may also confer a low risk of side-effects to the nursing infant.
NSAIDs are weak acids and are highly protein bound; thus, little if any drug is transferred into breast milk. In general, less than 5% of the therapeutic infant dose reaches the breast milk. Medications with shorter half-lives, such as ibuprofen, are preferred to those with longer half-lives, such as piroxicam, to help minimize potential transfer. In a series of 12 women treated with 400 mg ibuprofen every 6 h, no measurable ibuprofen was detected in the mothers' breast milk. 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 100 mg daily should also be avoided, as immature neonatal metabolism can lead to salicylate intoxication and bleeding.
On average, less than 10% of a prednisone or prednisolone dose is excreted into breast milk. In one study of six lactating women taking 10–80 mg/day of prednisone, the milk:serum ratio ranged from 0.1 to 0.25. Peak serum levels occur 1 h after the dose, and decline rapidly afterwards. Even at 80 mg/day, the amount of steroid added to the infant's endogenous cortisol production is calculated at less than 10%. Nonetheless, for women taking steroid doses greater than 20 mg/day, it is recommended that nursing be delayed for 4 h after ingestion. For women taking greater than 40 mg of prednisone daily, it is prudent to monitor the infant for evidence of adrenal suppression.
Antimalarial drugs are weak bases with limited distribution into breast milk. In one study of six women given chloroquine, 0.268–0.462 of the serum concentration was found in the breast milk. For a systemic lupus erythematosus patient treated with 400 mg hydroxychloroquine daily, the weight-adjusted infant dose was 2% of the maternal dose. Clinical follow-up of infants of mothers treated through pregnancy and lactation with hydroxychloroquine has not shown retinal, motor, or growth abnormalities.
Sulfasalazine is metabolized in vivo 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 is a single reported case of bloody diarrhea in an infant 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 or ill infants and infants with hyperbilirubinemia or glucose-6-phosphate dehydrogenase deficiency, as sulfapyridine can displace bilirubin.
Data from treated patients that suggest cyclosporine may be relatively low risk during pregnancy make it a reasonable second-line agent during both pregnancy and lactation. However, cyclosporine clearly can pass into breast milk. A series of seven posttransplant mother–infant pairs reported cyclosporine levels in both mothers' and babies' blood and in breast milk. Maternal serum levels ranged from 55 to 130 ng/ml, and breast milk levels were similar, from 50 to 227 ng/ml. Breast milk cyclosporine concentrations in a renal transplant mother averaged 596 ng/ml, but despite the significant level found in breast milk, the infant serum level was measured at less than 3 ng/ml. Blood levels in most infants have been undetectable. Despite these reassuring reports, it is potentially disconcerting that one full-term infant was found to have a therapeutic cyclosporine blood concentration (131 mcg/l) despite a low level measured in the mother's breast milk. The National Transplantation Pregnancy Registry and other reports found no abnormalities on clinical follow-up of infants breastfed by mothers taking cyclosporine. However, if a mother chooses to breastfeed on cyclosporine, it may be reasonable to check infant drug level as well as infant serum creatinine to monitor for adverse effects.
Evaluation of AZA level is not useful in assessing breast milk levels: AZA is inactive but undergoes hepatic metabolism to its active metabolite 6-mercaptopurine (6-MP) in vivo. AZA and 6-MP are further metabolized to 6-methylmercaptopurine and 6-thioguanine.
Mothers on AZA therapy have long been discouraged from breastfeeding; however, several case series suggest that this medication may present a low risk to the nursing infant. Eight lactating women on AZA for inflammatory bowel disease were evaluated with milk and plasma levels of 6-MP measured 30 and 60 min after administration of medication, and hourly thereafter for 5 h. The majority of the 6-MP appeared in the breast milk within the first 4 h of drug administration and breast milk levels varied from 2 to 50 mcg/l. The calculated average dose delivered through nursing was less than 0.008 mg/kg/day. Other reports find low or no measurable 6-MP in breast milk from lactating mothers on AZA. The largest reported series, of 10 nursing women on AZA, found no detectable 6-MP in 29 of 31 milk samples; two samples had low 6-MP concentrations, 1.2 and 7.6 ng/ml, in contrast to maternal plasma concentrations of 50 ng/ml.
No study has reported detection of AZA or 6-MP metabolites in infant serum, and long-term follow-up of babies breastfed by mothers on AZA has not revealed immunologic or developmental abnormalities. Despite theoretical concerns regarding immunosuppression in breastfeeding mothers on AZA, data show little to no drug transfer to term newborns. This suggests a low risk for breastfeeding in term infants while on AZA which may not, however, be applicable to preterm infants or to infants with TPMT mutations. If parents are known to have a low or intermediate TPMT levels, it may be reasonable to check the infant's status before nursing.
In theory, TNFα-inhibitors, by nature of their structure, should be low-risk medications for breastfeeding patients. Little IgG1 is secreted in breast milk, and most available TNFα-inhibitors are based on or contain parts of IgG1 constructs. In addition to the low likelihood of active transport, all TNFα-inhibitors are high molecular weight proteins, and would be expected to have poor diffusion into breast milk. Finally, 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.
Despite significant levels of infliximab in cord blood when administered throughout pregnancy, case reports show minimal transfer of infliximab into human breast milk when the drug is continued through lactation. For one patient treated with infliximab throughout her pregnancy and lactation, infant serum level at 6 weeks postpartum was 39.5 mcg/ml, followed by a slow decline to zero over the next 6 months despite continued nursing. No infliximab was detected in breast milk samples. Serum levels from three Crohn's disease patients treated with infliximab after delivery ranged from 59.97 to 74.27 mcg/ml, with undetectable levels in breast milk and infant serum.
One 26-year-old Crohn's disease patient treated with adalimumab during lactation has been reported. Adalimumab was excreted at a low level in the breast milk, less than 1/100 maternal serum level. Maximal milk level was measured at 6 days postinjection.
There are currently no human reports of breastfeeding on golimumab, another IgG1 monoclonal antibody. There were no adverse effects noted in infants of breastfeeding macaques treated with golimumab in a single animal study.
Etanercept has been detected in breast milk at low concentration with little passage to the infant during nursing. The highest measured concentration in six breast milk samples from an RA patient, at 72 h postetanercept, was negligible at 7.5 ng/ml. Breast milk concentration in an ankylosing spondylitis patient was 5 ng/ml despite maternal serum levels of 840–2000 ng/ml, and no etanercept was detected in the infant serum. Another etanercept-treated RA patient had maternal serum levels during nursing from 2306 to 3512 ng/ml; levels in the infant serum decreased from 81 ng/ml immediately postpartum to zero at 12 weeks despite continued nursing.
There are no human reports of breastfeeding on this medication. Levels in rat breast milk and pup serum were lower if mothers received the Fab fragment of this medication rather than whole antibody.
Low-risk Medications
Low-risk medications for lactating mothers have generally included NSAIDs, prednisone and prednisolone, antimalarial medications, and sulfasalzine. Recent data suggest that maternal intake of cyclosporine, azathioprine (AZA), and tissue necrosis factorα (TNFα)-inhibitors may also confer a low risk of side-effects to the nursing infant.
NSAIDs and Aspirin
NSAIDs are weak acids and are highly protein bound; thus, little if any drug is transferred into breast milk. In general, less than 5% of the therapeutic infant dose reaches the breast milk. Medications with shorter half-lives, such as ibuprofen, are preferred to those with longer half-lives, such as piroxicam, to help minimize potential transfer. In a series of 12 women treated with 400 mg ibuprofen every 6 h, no measurable ibuprofen was detected in the mothers' breast milk. 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 100 mg daily should also be avoided, as immature neonatal metabolism can lead to salicylate intoxication and bleeding.
Prednisone and Prednisolone
On average, less than 10% of a prednisone or prednisolone dose is excreted into breast milk. In one study of six lactating women taking 10–80 mg/day of prednisone, the milk:serum ratio ranged from 0.1 to 0.25. Peak serum levels occur 1 h after the dose, and decline rapidly afterwards. Even at 80 mg/day, the amount of steroid added to the infant's endogenous cortisol production is calculated at less than 10%. Nonetheless, for women taking steroid doses greater than 20 mg/day, it is recommended that nursing be delayed for 4 h after ingestion. For women taking greater than 40 mg of prednisone daily, it is prudent to monitor the infant for evidence of adrenal suppression.
Hydroxychloroquine and Chloroquine
Antimalarial drugs are weak bases with limited distribution into breast milk. In one study of six women given chloroquine, 0.268–0.462 of the serum concentration was found in the breast milk. For a systemic lupus erythematosus patient treated with 400 mg hydroxychloroquine daily, the weight-adjusted infant dose was 2% of the maternal dose. Clinical follow-up of infants of mothers treated through pregnancy and lactation with hydroxychloroquine has not shown retinal, motor, or growth abnormalities.
Sulfasalazine
Sulfasalazine is metabolized in vivo 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 is a single reported case of bloody diarrhea in an infant 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 or ill infants and infants with hyperbilirubinemia or glucose-6-phosphate dehydrogenase deficiency, as sulfapyridine can displace bilirubin.
Cyclosporine
Data from treated patients that suggest cyclosporine may be relatively low risk during pregnancy make it a reasonable second-line agent during both pregnancy and lactation. However, cyclosporine clearly can pass into breast milk. A series of seven posttransplant mother–infant pairs reported cyclosporine levels in both mothers' and babies' blood and in breast milk. Maternal serum levels ranged from 55 to 130 ng/ml, and breast milk levels were similar, from 50 to 227 ng/ml. Breast milk cyclosporine concentrations in a renal transplant mother averaged 596 ng/ml, but despite the significant level found in breast milk, the infant serum level was measured at less than 3 ng/ml. Blood levels in most infants have been undetectable. Despite these reassuring reports, it is potentially disconcerting that one full-term infant was found to have a therapeutic cyclosporine blood concentration (131 mcg/l) despite a low level measured in the mother's breast milk. The National Transplantation Pregnancy Registry and other reports found no abnormalities on clinical follow-up of infants breastfed by mothers taking cyclosporine. However, if a mother chooses to breastfeed on cyclosporine, it may be reasonable to check infant drug level as well as infant serum creatinine to monitor for adverse effects.
Azathioprine
Evaluation of AZA level is not useful in assessing breast milk levels: AZA is inactive but undergoes hepatic metabolism to its active metabolite 6-mercaptopurine (6-MP) in vivo. AZA and 6-MP are further metabolized to 6-methylmercaptopurine and 6-thioguanine.
Mothers on AZA therapy have long been discouraged from breastfeeding; however, several case series suggest that this medication may present a low risk to the nursing infant. Eight lactating women on AZA for inflammatory bowel disease were evaluated with milk and plasma levels of 6-MP measured 30 and 60 min after administration of medication, and hourly thereafter for 5 h. The majority of the 6-MP appeared in the breast milk within the first 4 h of drug administration and breast milk levels varied from 2 to 50 mcg/l. The calculated average dose delivered through nursing was less than 0.008 mg/kg/day. Other reports find low or no measurable 6-MP in breast milk from lactating mothers on AZA. The largest reported series, of 10 nursing women on AZA, found no detectable 6-MP in 29 of 31 milk samples; two samples had low 6-MP concentrations, 1.2 and 7.6 ng/ml, in contrast to maternal plasma concentrations of 50 ng/ml.
No study has reported detection of AZA or 6-MP metabolites in infant serum, and long-term follow-up of babies breastfed by mothers on AZA has not revealed immunologic or developmental abnormalities. Despite theoretical concerns regarding immunosuppression in breastfeeding mothers on AZA, data show little to no drug transfer to term newborns. This suggests a low risk for breastfeeding in term infants while on AZA which may not, however, be applicable to preterm infants or to infants with TPMT mutations. If parents are known to have a low or intermediate TPMT levels, it may be reasonable to check the infant's status before nursing.
Tissue Necrosis Factorα-inhibitors
In theory, TNFα-inhibitors, by nature of their structure, should be low-risk medications for breastfeeding patients. Little IgG1 is secreted in breast milk, and most available TNFα-inhibitors are based on or contain parts of IgG1 constructs. In addition to the low likelihood of active transport, all TNFα-inhibitors are high molecular weight proteins, and would be expected to have poor diffusion into breast milk. Finally, 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
Despite significant levels of infliximab in cord blood when administered throughout pregnancy, case reports show minimal transfer of infliximab into human breast milk when the drug is continued through lactation. For one patient treated with infliximab throughout her pregnancy and lactation, infant serum level at 6 weeks postpartum was 39.5 mcg/ml, followed by a slow decline to zero over the next 6 months despite continued nursing. No infliximab was detected in breast milk samples. Serum levels from three Crohn's disease patients treated with infliximab after delivery ranged from 59.97 to 74.27 mcg/ml, with undetectable levels in breast milk and infant serum.
Adalimumab
One 26-year-old Crohn's disease patient treated with adalimumab during lactation has been reported. Adalimumab was excreted at a low level in the breast milk, less than 1/100 maternal serum level. Maximal milk level was measured at 6 days postinjection.
Golimumab
There are currently no human reports of breastfeeding on golimumab, another IgG1 monoclonal antibody. There were no adverse effects noted in infants of breastfeeding macaques treated with golimumab in a single animal study.
Etanercept
Etanercept has been detected in breast milk at low concentration with little passage to the infant during nursing. The highest measured concentration in six breast milk samples from an RA patient, at 72 h postetanercept, was negligible at 7.5 ng/ml. Breast milk concentration in an ankylosing spondylitis patient was 5 ng/ml despite maternal serum levels of 840–2000 ng/ml, and no etanercept was detected in the infant serum. Another etanercept-treated RA patient had maternal serum levels during nursing from 2306 to 3512 ng/ml; levels in the infant serum decreased from 81 ng/ml immediately postpartum to zero at 12 weeks despite continued nursing.
Certolizumab Pegol
There are no human reports of breastfeeding on this medication. Levels in rat breast milk and pup serum were lower if mothers received the Fab fragment of this medication rather than whole antibody.
Source...