Metformin therapy and diabetes in pregnancy

To the Editor: We wish to commend the Australasian Diabetes in Pregnancy Society (ADIPS) ad hoc working party for providing an update on the safety of metformin in pregnancy.1 However, we would like to comment on the information they provided on the safety of this drug in breastfeeding.

Metformin can be regarded as a well studied drug with respect to its distribution into human breastmilk;2,3 most drugs are not as well served in this regard. As Simmons et al indicated,1 the infant “dose” in breastmilk is small at less than 0.4% of the maternal dose, corrected for body weight. This is substantially lower than the arbitrary cut-off of 10% used to guide drug use during lactation and thus implies safety.4 Further evidence for the safety of this drug in breastfeeding arises from failure to detect metformin in blood sampled from four of six infants exposed via breastmilk (limit of detection, 5–10 μg/L) and lack of adverse effects noted in nine exposed infants.2,3

Simmons et al stated that infant exposure to metformin could be reduced by breastfeeding immediately before maternal dose ingestion and then avoiding feeding for at least 2–3 hours after the dose. For drugs with a short elimination half-life, this recommendation — avoiding feeding at peak drug concentrations in the milk — may reduce infant exposure. However, this is not the case for metformin.

Two studies investigating metformin in breastfeeding have shown that the metformin peak plasma concentration occurs about 2–4 hours after the dose, while milk concentrations are “flat” across the entire dosing interval. This is distinctly different from most drugs, in which the drug concentrations in milk mimic the rise and fall of plasma concentrations, consistent with passive diffusion.2,3 The flat profile observed with metformin raises the possibility that the distribution of metformin into or out of breastmilk may involve an active process such as organic cation transporter(s), in addition to passive diffusion

Given this unusual concentration profile in breastmilk, infant exposure (albeit small) will not be reduced by the practice of avoiding breastfeeding for a few hours after maternal dose ingestion, as suggested by Simmons et al. In other words, mothers may feed their infants at any time during the dosing interval and this will not affect infant exposure to metformin.

We believe that there is sufficient evidence for metformin to be considered a safe therapeutic option in the treatment of diabetes or polycystic ovary syndrome in breastfeeding mothers, with the usual caveat of weighing up the risk–benefit ratio in each case.