Monoclonal Antibody Drugs in Breastfeeding Moms

Monoclonal antibodies are molecules created in a lab to function like antibodies of the immune system and are important in the treatment of organ transplant, chronic inflammatory diseases like rheumatoid arthritis and inflammatory bowel disease, neurological diseases like multiple sclerosis, and certain cancers. These antibodies are made by immune cells that are identical clones of a starting parent cell (hence the “clonal” part of monoclonal) and are designed to bind to a specific antigen. For example, a monoclonal antibody created to treat an inflammatory condition could bind to a signaling molecule to prevent the activation of an autoimmune response. Generic drug names for monoclonal antibodies end in –mab.

Women with chronic inflammatory conditions often experience flares after pregnancy, which can leave breastfeeding mothers feeling like they have to choose between treating their symptoms and feeding their baby.  Passage of molecules into breastmilk requires a few conditions to be met. After delivery when milk production begins in earnest, open spaces between mammary epithelial cells begin to close and are fully closed two weeks postpartum1. Without these open spaces, molecules have to either be small enough to go through aqueous channels or fit criteria based on charge, molecular weight, how the molecule interacts with the pH, and on protein-binding. The drug most likely to pass into breastmilk would be small, uncharged or minimally charged, and not protein-bound. The accepted size cutoff for passage into breastmilk is 800 Da. Since monoclonal antibodies are 140,000 Da and charged, we would not expect to see any in breastmilk.

However, some studies have found monoclonal antibodies in breastmilk. While these drugs are assumed to have poor oral absorption due to large size and breakdown in the digestive system, their use during lactation falls under “use with caution”. If case studies have found evidence of monoclonal antibodies in breastmilk, a manufacturer warning label will read “manufacturer recommends breast feeding be discontinued during therapy”1. Experts agree that monoclonal antibodies designed for treatment of rheumatoid arthritis and inflammatory bowel disease are compatible breastfeeding. In fact, breastfeeding may have a protective effect on flare ups2. No similar recommendations have been made for medications that treat multiple sclerosis. Specific monoclonal antibodies will be discussed below.

Rituximab is a monoclonal antibody that targets CD20 on B cells and is used to treat rheumatoid arthritis, vasculitis, and certain kinds of cancer like Non-Hodgkin’s Lymphoma and Chronic Lymphoid Leukemia. A case report of a 34-year-old mother with granulomatosis with polyangiitis found minimal excretion of the drug into breast milk, <240 times the amount in maternal serum3. More data are required to prove safety, and experts have not reached consensus. Manufacturer recommends discontinuing breastfeeding until 6 months after treatment, while some experts a cessation only if less than 2 weeks postpartum or after receiving a dose. The minimal excretion combined with poor oral bioavailability suggests breast feeding should probably not be discouraged in women who need treatment.

Infliximab targets TNF-alpha and is used to treat autoimmune diseases. A few reports found peak excretion is 1 to 4 days post infusion and has been found at low levels in breastmilk, 0.5% maternal serum concentration which is below the arbitrary acceptable cutoff level of 10%3. Experts consider Infliximab compatible with breastfeeding while exercising caution.

Certolizumab pegol is another monoclonal antibody directed against TNF-alpha and is used to treat Crohn's disease, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This monoclonal antibody is the only PEGylated anti-TNF without Fc region, the part of the antibody thought to be involved in intestinal uptake4. The prospective, multicenter, pharmacokentic study CRADLE found minimal passage of certolizumab into breastmilk with a relative infant dose 0.04% to 0.35%, which is below the 10% cutoff, and no passage of PEG4. During the study, nasopharyngitis was reported in one breastfed infant. Combined with poor bioavailability, the findings supported continuing treatment during breast feeding while exercising caution. 

Vedolizumab is designed to bind to an integrin protein in the digestive tract and is used to treat inflammatory bowel diseases.  A prospective observational study found it present at low levels in breastmilk, peaking at 3 to 4 days post infusion5.  Vedolizumab is detectable in breastmilk at any given time in between infusions, but its peak concentration is less than 1% maternal serum concentration, below the 10% cutoff6. Experts consider Vedolizumab compatible with breastfeeding while exercising caution.

 

 Medication Breast milk drug concentration and potential safety concerns Breastfeeding recommendations

Infliximab

≤ 0.5% of mother's plasma concentration
Peak excretion 1-4 d post infusion

Compatible
Adalimumab

Low levels in milk
< 1% of mother's plasma concentration
Peak excretion 1-6 d post injection

Compatible
Certolizumab Pegol Undetectable or very low levels in milk
Peak excretion 0.5-2 d post injection
Compatible
Golimumab Low or undetectable Compatible
Natalizumab Low or undetectable Compatible
Vedolizumab Unknown Compatible
Ustekinumab Low or undetectable
Peak excretion 1 post injection
Compatible

Table 1: Biologic Medications for Inflammatory Bowel Disease During Lactation, based on limited data
Source: Mahadevan et al. Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease. Gastroenterology. 2017 Jan; 152(1):451–462

In conclusion

  • A general rule: use with caution as a blanket statement and continue when being treated for inflammatory conditions.
  • Most monoclonal antibodies used in the treatment of inflammatory bowel diseases are compatible with breastfeeding.  
  • Studies for certolizumab pegol support continued use during breast feeding term infants and with caution in preterm infants.
  • More data is needed

TNF-alpha Inhibitors

 

 

 

 

Infliximab

IgG1

Ankylosing spondylitis, Crohn disease, Plaque psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Ulcerative colitis

Off label: Pustular psoriasis; Pyoderma gangrenosum

 

Present in breastmilk

 

Low levels, 0.5% maternal serum concentration (below 10% cutoff)

Experts consider Infliximab compatible with breastfeeding

Adalimumab

IgG1

Ankylosing spondylitis, Crohn disease, Plaque psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Ulcerative colitis, Hidradenitis suppurativa, Juvenile idiopathic arthritis, Uveitis

 

Off label: Pyoderma gangrenosum

 

Present in breastmilk

 

Low levels, 0.1% maternal serum concentration (below 10% cutoff)

Experts consider Adalimumab compatible with breastfeeding

Certolizumab

 pegol

IgG1 Fab fragment without Fc

Ankylosing spondylitis, Crohn disease, Plaque psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Axial spondyloarthritis

Present in breastmilk

Relative infant dose 0.04 - 0.35%, (below the 10% cutoff)

 

No passage of PEG

 

Experts consider Certolizumab pegol compatible with breastfeeding

Golimumab

IgG1-kappa

Ankylosing spondylitis, , Psoriatic arthritis, Rheumatoid arthritis, Ulcerative colitis

 

Off label: Axial spondyloarthritis

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

 

 

 

 

IL-1 Inhibition

 

 

 

 

Canakinumab

IgG1-kappa

Periodic fever syndromes and Systemic juvenile idiopathic arthritis

 

Off label: Gout

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

 

 

 

 

IL-6 Inhibition

 

 

 

 

Tocilizumab

IgG1

Cytokine release syndrome, Giant cell arteritis, Polyarticular juvenile idiopathic arthritis, Rheumatoid arthritis, Systemic juvenile idiopathic arthritis

 

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

Sarilumab

IgG1

Rheumatoid arthritis

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

 

 

 

 

IL-17 Inhibition

 

 

 

 

Secukinumab

IgG1-kappa

Ankylosing spondylitis, Plaque psoriasis, Psoriatic arthritis

No studies available, passage is unknown

 

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

Ixekizumab

IgG4

Ankylosing spondylitis, Plaque psoriasis, Psoriatic arthritis

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

 

 

 

 

IL-12/23 Inhibition

 

 

 

 

Ustekinumab

IgG1-kappa

Crohn disease, Plaque psoriasis, Psoriatic arthritis

 

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

Guselkumab

IgG1-lambda

Plaque psoriasis

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

 

 

 

 

Integrin Inhibition

 

 

 

 

Vedolizumab

IgG1

Crohn Disease, Ulcerative Colitis

Present in breastmilk

 

Peak concentration is less than 1% maternal serum concentration (below the 10% cutoff)

Experts consider Vedolizumab compatible with breastfeeding

Natalizumab

IgG4

Multiple sclerosis with Crohn disease

Present in breastmilk

 

Relative Infant Dose is 1.7% on average  and 5.3% at peak, below the 10% cutoff but still quite high

Experts have not reached consensus:

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

 

 

 

 

B-cell depletion and inhibition

 

 

 

 

Rituximab

IgG1

Chronic lymphocytic leukemia, Granulomatosis with polyangiitis, Microscopic polyangiitis, Non-Hodgkin lymphomas, Pemphigus vulgaris, Rheumatoid arthritis

 

Off label: Antibody-mediated rejection in cardiac transplantation, Autoimmune hemolytic anemia, Burkitt lymphoma, CNS lymphoma, Graft-versus-host disease, Hodgkin lymphoma, Lupus nephritis, MALT, Myasthenia gravis, ITP, TTP

 

Present in breastmilk

 

Minimal excretion, <240 times the amount in maternal serum

Experts have not reached consensus but are presently using this in MS patients.

 

Manufacturer recommends discontinuing breastfeeding until 6 months after treatment

 

 

Belimumab

IgG1-lambda

Systemic lupus erythematosus

No studies available, passage is unknown

Use with caution, weigh risks of infant exposure and benefits of breastfeeding and maternal treatment

 

1. Anderson P. Monoclonal Antibodies. Breastfeeding Medicine. 2016; 11(3):100-101.

2. Mahadevan U, McConnell R, Chambers C. Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease. Gastroenterology. 2017 Jan; 152(1):451–462.

3. Bragnes Y, Boshuizen R, de Vries A, Lexberg Å, Østensen M. Low level of Rituximab in human breast milk in a patient treated during lactation. Rheumatology (Oxford). 2017 Jun 1;56(6):1047-1048.

4. Clowse ME, Förger F, Hwang C, Thorp J, Dolhain RJ, van Tubergen A, Shaughnessy L, Simpson J, Teil M, Toublanc N, Wang M, Hale TW. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017

Nov;76(11):1890-1896.

5. Lahat A, Shitrit AB, Naftali T, Milgrom Y, Elyakim R, Goldin E, Levhar N, Selinger L, Zuker T, Fudim E, Picard O, Yavzori M, Ben-Horin S. Vedolizumab Levels in Breast Milk of Nursing Mothers With Inflammatory Bowel Disease. J Crohns Colitis. 2018 Jan 5;12(1):120-123.

6. Julsgaard M, Kjeldsen J, Bibby BM, Brock B, Baumgart DC. Vedolizumab Concentrations in the Breast Milk of Nursing Mothers With Inflammatory Bowel Disease. Gastroenterology. 2018 Feb;154(3):752-754.

 

Kendall Marshall, MS4
Thomas W. Hale Ph.D.

InfantRisk Center

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