ميثوتريكسات

Methotrexate (MTX) is an antineoplastic antimetabolite and folic acid analogue and antagonist with antineoplastic and immunosuppressive properties from interfering with the synthesis and cellular replication of DNA. Indicated in the treatment of certain neoplasms, rheumatic problems: arthritis, severe psoriasis, Reiter’s syndrome, inflammatory bowel disease ^{(Pfizer 2019 & 2008, AEMPS 2018, EMA 2017)} and, off-label, in multiple sclerosis and in some obstetric procedures: abortion, ectopic pregnancy, placenta accreta. ^{(Practice Committee of the American Society for Reproductive Medicine 2013, Kulier 2011).}

ONCOLOGIC USE:

Administration can be intramuscular, intravenous or intrathecal and the dose can vary from 15 mg to 3 g per day, with highly variable duration and cycles depending on the type of cancer. ^{(Pfizer 2019 & 2008)}

Excretion in breastmilk is very low ^{(Brown 2017, Østensen 2006, Johns 1972)}, perhaps due to a high volume of distribution and a very low pKa that makes it very insoluble in liquids at physiological pH ^{(Götestam 2016)}. After isolated doses of 50 mg/m² BS for obstetric purposes, even after doses of 92 mg daily for 4 days, undetectable or negligible levels have been found in breastmilk ^{(Baker 2018, Tanaka 2009)}. Zero or negligible transfer to milk has also been found when used in low weekly doses (25 mg) during the maintenance treatment of rheumatoid arthritis and other autoimmune diseases. ^{(Delaney 2017, Thorne 2014)}

Although the levels found in breastmilk are very low ^{(Johns 1972)}, during cancer treatment it is recommended to stop breastfeeding due to potentially serious side effects for the infant. ^{(Rademaker 2017, Moretti 2000)}

Chemotherapy does not affect milk production during or after treatment. Abrupt weaning can be psychologically traumatic for both the mother and the infant. ^{(Pistilli 2013)}

If the mother wishes, the production of milk can be maintained by regular expressing from the breast, being able to return to breastfeeding in the periods in which no significant traces of the drug remain in the milk (Anderson 2016) or at the end of the treatment. ^{(Pistilli 2013)}

It is known from pharmacokinetics that after 3 elimination half-lives (T½) 87.5% of the drug is eliminated from the body; after 4 T½ it is 94%, after 5 T½, 96.9%, after 6 T½, 98.4% and after 7 T½ it is 99%. From 7 T½ the plasma concentrations of the drug in the body are negligible. In general, a period of at least five half-lives can be considered a safe waiting period before breastfeeding again.^{(Anderson 2016)}

Taking as reference the longest published T½ (15 hours), these 5 T½ would correspond to 3 days and 7 T½ would be 4 days, which is what expert authors recommend waiting after the last dose to restart breastfeeding ^(Hale). Meanwhile, express and discard milk from the breast regularly.

When it is possible to do so, detections in the breastmilk of each patient to determine the total elimination of the drug would be the best indicator of resuming breastfeeding between two cycles of chemotherapy.

Some chemotherapeutic agents with antibiotic effects can alter the composition of the microbiota (bacterial cluster or bacterial flora) of the milk and the concentration of some of its components ^{(Urbaniak 2014)}. This possibly occurs temporarily with subsequent recovery, although no harmful effects are expected nor have been reported in breastfed infants.

Women undergoing chemotherapy during pregnancy have lower rates of breastfeeding due to experiencing difficulties with breastfeeding ^{(Stopenski 2017)}, needing more support to achieve it.

Given the strong evidence that exists regarding the benefits of breastfeeding for the development of babies and the health of mothers, it is advisable to evaluate the risk-benefit of any maternal treatment, including chemotherapy, individually advising each mother who wishes to continue with breastfeeding.^{(Koren 2013)}

See below the information of this related product:

• Methotrexate (obstetric and immunosuppressive use) (Fairly safe. Mild or unlikely adverse effects. Compatible under certain circumstances. Follow-up recommended. Read Commentary.)