Last update: Aug. 15, 2019
Moderately safe. Probably compatible.
Mild risk possible. Follow up recommended.
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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 (AEMPS 2018, EMA 2017) and, off-label, in inflammatory bowel disease, 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).
Administration is generally oral (also subcutaneous or intramuscular) once a week, except in carcinomas where there are 5-day cycles every 12-14 days. In obstetrics, single or 3-day intramuscular doses of 50 mg/m2 of body surface area (mg/m2 BS) are administered for expulsion purposes.
Excretion in breastmilk is very limited (Brown 2017, Østensen 2006), perhaps due to 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 (1,12 mg/kg) 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).
No problems have been recorded or observed in infants whose mothers were taking it (Thorne 2014).
The recommendations of experts and the practical attitude among clinicians about maintaining treatment during breastfeedingn are divided (Huang 2016, Götestam 2016, Martínez 2009, Weber 2008, Østensen 2007).
Several authors consider isolated or weekly use in low doses during breastfeeding to be safe (Anderson 2019, Delaney 2017, Noviani 2016, Thorne 2014, Koren 2013, Østensen 2009, Tanaka 2009, Weber 2008, Moretti 2000, Goldsmith 1989, Johns 1972).
Other authors and expert consensus discourage it (Flint 2016, Nguyen 2016, Götestam 2016, Kavanaugh 2015, van der Woude 2015, Mahadevan 2015, Grunewald 2015, Samaritano 2014, Mervic 2014, Mottet 2007, Temprano 2005, WHO 2002, AAP 2001, Janssen 2001).
In these cases, exposure can be reduced by almost half by interrupting breastfeeding 24 hours after taking the drug, expressing and discarding the milk in the meantime (Delaney 2017, Hale 2017 p628, Noviani 2016), which in practice means not breastfeeding the day MTX is taken and breastfeeding the rest of the week.
Some recommend clinical or hematologic monitoring or of MTX levels in the infant (Rademaker 2017, Almas 2016, Østensen 2009) and administering folic acid to the infant (Almas 2016).
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 (17 hours), these 5 T½ would correspond to 3.5 days and 7 T½ would be almost 5 days, which is what expert authors recommend waiting after the last dose to restart breastfeeding. (Hale 2017 p628). 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).
We do not have alternatives for MTX.
Suggestions made at e-lactancia are done by APILAM´s pediatricians and pharmacists, and are based on updated scientific publications.
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