Download Document

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 halflives, 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 0.25. 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 electrooculogram 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.

Sulfasalazine





This medication should be avoided in:
Premature infants
Ill infants
Hyper bilirubinemia
Glucose-6-phosphate dehydrogenase deficiency, as
sulfapyridine can displace bilirubin.
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 0.008 mg/kg/day
No study has reported detection of AZA or 6-MP
metabolites in infant serum , and long-term followup 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 59.97 to
74.27 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 504.5 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 highquality 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.