Is domperidone safe for lactating mothers and does it work as a galactogogue?

It is a truth universally acknowledged that breastfeeding provides babies with the best start in life and is a major determinant of infant and maternal health. In Australia, the National Health and Medical Research Council (NHMRC) recommends exclusive breastfeeding until six months of age, with the introduction of solid foods at around six months and continued breastfeeding until at least the age of 12 months. In 2010, the Australian National Infant Feeding Survey reported the encouraging statistic that 96 per cent of newborn babies were fully breastfed; however, by four months this figure had dropped to 39 per cent and by six months to only 15 per cent.¹

Around four to six weeks is a common time for mothers to have doubts about their milk supply, as many babies will experience fussy periods. The most widely reported reason for discontinuing breastfeeding is a perceived lack of supply.^2,3

Information and support

Before considering any pharmacological treatment, it is important to assess whether low supply actually exists in a particular breastfeeding woman. In reality, at least 95 per cent of mothers are able to produce sufficient milk for their babies without pharmacological or other intervention, especially when adequately supported and appropriately advised.³ Maternal medical reasons for low milk supply should be considered (such as primary mammary glandular insufficiency, hypothyroidism or polycystic ovarian syndrome) and women with little knowledge of the basics of breastfeeding should be given some education on how breastmilk is produced. Referral to a lactation consultant can clarify whether there is an actual or a perceived low supply. The website of the Australian Breastfeeding Association (ABA) has user-friendly information on increasing supply, and trained breastfeeding counsellors are available on the ABA national helpline. Frequent stimulation of the breast and complete milk removal at regular intervals coupled with emotional support and encouragement will help to ensure supply is promoted and maintained.

Galactogogues

Various pharmaceutical and herbal products have been tried by women in attempts to increase milk supply. The use of metoclopramide as a galactogogue was first reported 40 years ago⁴ and of domperidone more than 30 years ago.⁵ However, good evidence for the use of pharmaceutical galactogogues is still lacking.⁶ If a galactogogue is deemed appropriate to increase supply, the mother should be counselled that it will only be useful if frequent breastfeeding and breastfeeding support continues. Human lactogenesis is complex and, despite prolactin being required for lactation, there is no evidence that serum prolactin levels directly correlate with the volume of milk produced in lactating women.^6,7

Domperidone in lactation

Currently, domperidone is the preferred pharmaceutical galactogogue, owing to its favourable side effect profile (dry mouth and headache being the most commonly reported adverse effects). It passes poorly into breastmilk, with no adverse effects reported in breastfed babies. Domperidone is a dopamine antagonist with antiemetic properties. It is licensed in Australia for short-term (less than or equal to six months) treatment of symptoms associated with idiopathic diabetic gastroparesis and intractable nausea or vomiting from any cause. Its use as a galactogogue is off-label.

The Australian Medicines Handbook (AMH) states domperidone is ‘safe to use’ in lactation and ‘does not readily cross the blood-brain barrier so extrapyramidal side effects are rare’. Conversely, it states that ‘lactation stimulation is no longer listed as an accepted indication in AMH due to safety concerns and limited evidence of efficacy’. Instead, conservative, non-pharmacological measures for lactation stimulation are advised, such as ‘breastfeeding more frequently and ensuring correct positioning and attachment’.

Very low levels of domperidone are detectable in milk as the molecule is poorly lipid soluble and highly protein bound in maternal plasma. It is also poorly orally bioavailable.⁷ Thus infants are expected to be exposed to less than 0.01 per cent of the maternal weight-adjusted dose. The American Academy of Paediatrics classifies domperidone as compatible with breastfeeding⁸ and Thomas Hale, a lactation expert and pharmacist, rates it an L1 (safest category) in his risk categorisation of medications in lactation L1-L5.⁹

Domperidone safety

Several warnings about domperidone have been issued by the US Food and Drug Administration (FDA)(2004), Health Canada (2012) and the European Medicines Agency (2014).^10-12 These warnings describe a small increased risk of serious cardiac side effects in patients over 60 years of age, those on long-term high-dose therapy (greater than 30mg/day for longer than a week) and those with pre-existing cardiac conditions, such as congestive heart failure. Prolongation of the QT interval, torsade de pointes, arrhythmias and sudden cardiac death have been reported. Often cited in the literature are reports of cardiac arrhythmia and sudden death in cancer patients treated with intravenous domperidone.^13-16 Among these patients, the majority had co-morbid serious illnesses, were being treated with chemotherapy, and/or were severely hypokalaemic. Risk is greater in those taking other QT-prolonging medicines or CYP3A4 inhibitors concomitantly. Commonly prescribed examples include the azole antifungals (fluconazole, ketoconazole and itraconazole) and macrolide antibiotics (clarithromycin and erythromycin).

Breastfeeding mothers using domperidone do not, generally speaking, fall into the same demographics as the patients involved in the studies from which the warnings have been generated.¹⁷ Generally, breastfeeding women are young and healthy, but with the average age of mothers increasing, prescribers are reminded that domperidone should be prescribed with caution and awareness of possible drug interactions.¹⁸

While intravenous domperidone has been withdrawn from the market worldwide, the FDA took the extreme step of removing ALL forms from the US market in 2004, and warned breastfeeding mothers specifically not to use it.¹⁰ Despite this, US mothers continue to be prescribed domperidone, obtaining it from compounding pharmacies and ordering online or from overseas. In September 2011, the FDA granted orphan drug status to domperidone specifically for ‘treatment of hypoprolactinaemia in breastfeeding mothers’. This is only the first step in a long regulatory process that aims to eventually secure FDA approval.

Domperidone efficacy

It appears the real controversy lies not in the safety of domperidone in this population, but rather in its efficacy. Studies have tended to show a pattern of increased milk production, but they have generally been of poor quality; lacking randomisation, controls or blinding; comprising small sample sizes; recording high dropout rates and not optimising; or omitting non-pharmacological measures.²⁰

One well-designed study in mothers of babies less than 31 weeks gestation in a neonatal intensive care unit (NICU) found domperidone (10mg three times a day for two weeks) to be an effective galactogogue, increasing serum prolactin levels and breastmilk volume without altering milk composition.²¹ The majority of mothers initiated treatment within 21–28 days of delivery.

The ongoing EMPOWER study aims to evaluate the safety and efficacy of domperidone in mothers identified as having difficulty producing milk to meet the nutritional needs of their infant in the NICU setting. It is a multi-centre (Canada, Israel, Qatar and Chile), double-blinded, randomised controlled trial conducted over a two-week period.²² It also aims to determine optimal time to initiate therapy, dose and duration of treatment. Enrolment began in June 2012, with expected completion mid- to late-2015.

Summary

Overall, we conclude that although good-quality evidence is lacking for its use as a galactogogue, if domperidone is prescribed at recommended doses, for a defined time period, and only after non-pharmacological methods have failed, it is not expected to cause harm to mother or baby.

If a prescriber feels that a breastfeeding mother may benefit from use of domperidone as a galactogogue, the following recommendations should be followed:
confirm a supply ‘problem’ really exists and trial nonpharmacologic lactation support before prescribing;

• screen for co-morbid medical conditions;
• discuss risks and benefits of the medication, and of breastfeeding itself;
• prescribe lowest effective dose and titrate up according to response;
• ensure regular follow-up to monitor for efficacy and side effects; and
• ensure the treatment is for a limited time only.