BREASTFEEDING MEDICINE

Volume XX, Number XX, 2019

ª Mary Ann Liebert, Inc.
DOI: 10.1089/bfm.2019.0111

Effects of Domperidone in Increasing Milk Production

in Mothers with Insufficient Lactation for Infants
in the Neonatal Intensive Care Unit

Yuka Wada,1 Fumio Suyama,1 Aiko Sasaki,2 Jumpei Saito,3 Yuika Shimizu,4
Shoichiro Amari,1 Yushi Ito,1 and Haruhiko Sago2
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 09/07/19. For personal use only.

Abstract

Breast milk is the optimum for all infants, but hospitalization in the neonatal intensive care unit can cause
separation of mothers and infants, which often interferes with milk secretion. Some reports show that dom-
peridone is effective in promoting milk secretion. However, the Food and Drug Administration in the United
States cautioned to not use domperidone for increasing milk volume because domperidone carries some risk of
cardiac events, including QT prolongation, cardiac arrest, and sudden death. In contrast, it is used in Canada,
Australia, and the United Kingdom with safety. The pharmacodynamics and pharmacokinetics of drugs may
vary by race or ethnic origin, and it is not known whether domperidone is effective or safe for Japanese. In this
study we report the effects of domperidone for Japanese mothers with insufficient lactation. Ten mothers were
enrolled in a pilot study. After confirming that there were no abnormal findings on the electrocardiogram, the
mothers were administered domperidone. Seven of 10 who took domperidone increased their milking volume.
Prolactin was increased in 9 of 10 mothers. Adverse events were observed in two mothers, one headache and
one abdominal pain; all symptoms were mild and improved promptly; and there were no adverse cardiac events.
These results are consistent with reports from other countries. Domperidone may tentatively be considered
effective for increasing milk secretion in Japanese mothers as in other populations. Our preliminary study of 10
cases indicates the need for further studies with larger sample sizes to assess the efficacy and safety of
domperidone.

Keywords: domperidone, prolactin, insufficient lactation, breast milk, milk secretion

Introduction mide easily passes through the blood–brain barrier and can
cause extrapyramidal symptoms, but domperidone rarely

B reast milk is the optimum for all infants. Particularly

for infants who are hospitalized in the neonatal intensive
care unit (NICU), the benefits of breast milk are great for
many reasons, such as prevention of infection and necrotizing
enterocolitis and improvement of neurological development.
However, hospitalization in the NICU can cause separation
of mothers and infants, which often interferes with breast-
feeding. In addition, milking volume may not be sufficient
even if milking efforts are made, especially when direct
lactation is not possible.
Although technical and emotional breastfeeding support is
important, medical support using domperidone or metoclo-
pramide may help to promote milk secretion. Metoclopra-
does so and is, therefore, preferable to use for the purpose of
increasing milk secretion. Domperidone is a potent dopamine
D2 receptor antagonist and stimulates the release of prolactin.
Increased prolactin promotes milk production.
However, domperidone has not been available in the
United States since 2004 when the Food and Drug Admin-
istration (FDA) reported adverse events of arrhythmia, car-
diac arrest, and sudden death. In contrast, it is used at the dose
of 30 mg for 7, 14, or 28 days in Canada,1–3 at 30 or 60 mg for
7–14 days in Australia,4 and at 30 mg for 10 days in the
United Kingdom.5 The most common dose of domperidone is
30 mg for a duration of 7–14 days. Reports from these
countries also described its safety. The pharmacodynamics

Divisions of 1Neonatology and 2Obstetrics, Center for Maternal-Fetal, Neonatal, and Reproductive Medicine, National Center for Child
Health and Development, Setagaya-ku, Japan.
Departments of 3Pharmaceuticals and 4Nursing, National Center for Child Health and Development, Setagaya-ku, Japan.

1
 2 WADA ET AL.
and pharmacokinetic effects of drugs may vary by race or
ethnic origin, and it is not known whether domperidone is
effective or safe for Japanese mothers. In this study we report
the effects of domperidone for Japanese mothers with in-
sufficient lactation.
Materials and Methods
The subjects were Japanese mothers who had insufficient
lactation despite adequate breastfeeding support and effort
and whose infants were hospitalized in the NICU. Insufficient
lactation is defined after 2 weeks postpartum as a milking
volume of <300 mL/day or the required amount for the infant,
that is, 160 mL/kg per day. Adequate breastfeeding support
and effort are determined by confirming the milking proce-
dure and adequate milking frequency, which is at least six
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 09/07/19. For personal use only.
times per day. Mothers with allergy to domperidone, already
taking domperidone, and those with prior breast surgery were
excluded. Entry began in November 2015 and 10 cases were
examined for a pilot study. After confirming that there were no
abnormal findings, including QT prolongation on the elec-
trocardiogram (ECG), the mothers were administered dom-
peridone 10 mg three times daily for 14 days. ECG was not
repeated after domperidone administration if there were no
symptoms because, in Japan, the same dose of domperidone is
usually administered for nausea or vomiting without routine
follow-ups of ECG. A milking diary was given to the mothers
and milking volume was recorded by them for 14 days. Blood
tests (prolactin concentration before milking, complete blood
count, aspartate aminotransferase (AST), alanine aminotrans-
ferase, blood urea nitrogen, and creatinine levels) were per-
formed before administration, at the 7th day, and at the 14th day
after administration. For infants, oxygen saturation, heart rate,
and blood pressure were measured and a general examination
was performed. An effective case of domperidone was regarded
as a milking volume of 1.5 times or more compared with that
before administration. This study was approved by the Ethics
Committee of the National Center for Child Health and De-
velopment. We obtained written consent from all participants.
Results
The median maternal age was 36 years (range 21–43).
Three women were multiparous and seven were primiparous.
In two cases, infants were delivered vaginally, and in eight
cases by cesarean section. There was one mother who had
systemic lupus erythematosus (SLE). The infants were born
at a median weight of 1,689 g (range 623–2,722 g) and a
median of 34.3 weeks (range 23.4–38.9) of gestation. There
were five premature infants. Seven of them had congenital
malformations or chromosomal abnormalities.
The median milking volume per day before administration
of domperidone was 60 mL (range 2–310 mL) and that of the
14th day after administration was 176 mL (range 11–400 mL).
Seven of 10 mothers had an increase in milking volume of
>1.5 times on the 14th day of administration compared
with that before administration (median 2.8 times, range 1.8–
5.4 times). There was no change for three mothers (Fig. 1).
The median serum prolactin concentration was 46 ng/mL
(range 4–128) before administration and 167 ng/mL (range
59–356) on the 14th day after administration. In nine moth-
ers, prolactin level increased to more than twice that before
administration, but in one case it decreased from 118 ng/mL
before domperidone administration to 68 ng/mL on day 14
after administration (Fig. 1). However, this mother was an ef-
fective case in whom the milking volume was 1.5 times or more,
that is, 100 mL/day before administration and 400 mL/day on
day 14 after administration. Of the nine mothers with ele-
vated prolactin, domperidone was ineffective for three
mothers. There was no apparent correlation between blood
prolactin concentration and milking volume.
Adverse events observed in two mothers during domper-
idone administration were headache in one case and ab-
dominal pain in another case, but all symptoms were mild and
improved promptly. One mother showed elevated AST at
80 U/mL before administration and 100 U/mL on day 14 after
administration. This mother had SLE and her AST had been
fluctuating between 65 and 110 before the administration of
domperidone; there was no exacerbation. No adverse events
were observed in infants.
Discussion
Effects of milk secretion
Seven of 10 Japanese mothers who took domperidone in-
creased their milking volume. From Canada, da Silva et al.
reported in 2001 that domperidone was effective for all of
FIG. 1. Milking volume and se-
rum prolactin concentration. Seven
of 10 Japanese mothers who took
domperidone increased their milk-
ing volume. Prolactin was increased
in 9 of 10 Japanese mothers.
 EFFECTS OF DOMPERIDONE IN JAPANESE MOTHERS
seven mothers who took 10 mg three times daily for 7 days
and Campbell-Yeo et al. reported in 2009 that it was effective
for 17 of 19 mothers who took 10 mg three times daily for 14
days.1,2 There are other reports from Australia and the United
Kingdom stating that domperidone was effective.4,5 In a
systematic review, in which domperidone was administered
to mothers who gave birth to preterm infants, five trials of 194
mothers were examined and reported that milking volume
was increased.6 Our results are consistent with these studies,
and it is suggested that domperidone is also effective in
Japanese mothers. In contrast, nonresponders exist in all
populations. There may be other physiological processes for
milk secretion that do not involve prolactin, but they are not
clearly known.
Serum prolactin concentration
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 09/07/19. For personal use only.
Prolactin levels were increased in 9 of 10 Japanese mothers.
This result is consistent with reports from other countries such
as Canada and Australia.1–4 In one mother whose prolactin did
not increase, but whose breast milk secretion increased, pro-
lactin was sufficiently high at 118 ng/mL before administra-
tion and 68 ng/mL on day 14 after administration. It is
suspected that the level of prolactin did not increase with
domperidone administration because the level of prolactin
was already sufficiently high. It might also be possible that
domperidone acted in a nonprolactin-mediated pathway, or
that it was placebo effective.
Adverse events
Headache and abdominal pain were observed separately in
two mothers, but both symptoms were mild and the etiologies
were unknown. The FDA surveyed the adverse events asso-
ciated with domperidone from 50 years of FDA Adverse
Event Reporting System data in 2004; they determined the
likelihood of drug causality in four categories (probable,
possible, unlikely, or not assessable) and assessed three
probable cases and three possible cases. From this informa-
tion, the FDA is cautioning not to use domperidone for in-
creasing milk secretion because domperidone carries a risk
for cardiac events, including QT prolongation. However,
domperidone is being used in many countries other than the
United States. From Canada, da Silva et al. reported no ad-
verse events in 20 mothers who took domperidone 10 mg
three times daily for 7 days, and Campbell-Yeo et al. also
reported no adverse events in 46 mothers who took 10 mg
three times daily for 14 days.1,2 From Australia, Wan et al.
reported that three of eight mothers who took domperidone
30 mg daily for 1–2 weeks had adverse events, including
abdominal cramping in one case, dry mouth in three cases,
and headache in one case.4 From the United Kingdom, In-
gram et al. reported that 3 of 24 mothers who took domper-
idone 30 mg daily for 10 days had adverse events, including
headache in one case, diarrhea in one case, mood swings in
one case, and dizziness in one case.5 None were serious and
there were no reports of cardiac arrhythmia or sudden death.
A systematic review in 2016 analyzed cardiac adverse events
in people who received domperidone not only for increasing
milk secretion but also for treatment of nausea or vomiting; it
concluded that domperidone increases the risk for cardiac
adverse events, but also stated that there was a population
bias because most participants were male and elderly.7 In
3
addition, another study in 2019 reports that 30 to 80 mg daily
of domperidone was administered to 246 patients with gas-
troparesis and that the QTc interval was assessed.8 Dom-
peridone was associated with QTc prolongation in only 6% of
patients, with no QT interval reaching the point considered to
be clinically significant. They suggest that domperidone can
be safely used for the treatment of gastroparesis.
Regarding the safety for the breastfed infant, our previous
study revealed very low concentrations of domperidone in
breast milk, yielding a relative infant dose of domperidone at
0.01%.9 This is apparently not a serious issue. Although there
are only 10 cases in this study, it can be inferred that there
were no serious adverse events and that domperidone can be
safely used in Japanese mothers. Safety can be monitored by
performing electrocardiography before administration, con-
firming that QT prolongation does not exist. In contrast, a
2015 systematic review suggests that it is more effective and
safe to improve breastfeeding practices rather than adminis-
ter domperidone because the risk of using domperidone
cannot be ruled out.10 It is important to consider the risk–
benefit ratio.
The reasons why 7 of 10 infants had congenital mal-
formations or chromosomal abnormalities were speculated to
be that their mothers had not been able to breastfeed directly
for a long time and milking volume had decreased; there
might have been a strong wish that they would like to give
their own breast milk for their infants. Most of the mothers
were able to continue breastfeeding after administration of
domperidone.
The major limitations of our study are the very small
sample size and the fact that the appropriate domperidone
dose for insufficient lactation could not be determined be-
cause we did not compare different doses. Future larger
studies would be required to clarify the efficacy and safety of
domperidone for lactating mothers.
Conclusions
Domperidone was considered to be effective for increasing
milk secretion in Japanese mothers in our study sample, as in
other study populations. In our study, we considered that it
could be safely used after checking QTc intervals by ECG.
Based on our study, larger randomized controlled trials about
efficacy and safety of domperidone should be conducted in
countries like Japan where domperidone is often used for
gastroenteritis.
Acknowledgments
The authors thank the mothers and their infants for their
time and participation.
Disclosure Statement
No competing financial interests exist.
Funding Information
This work was supported by the National Center for Child
Health and Development, Research and Development, Grant
No. 27–28.
 4 WADA ET AL.

References systematic review and meta-analysis. Clin Drug Investig

2016;36:97–107.
1. da Silva OP, Knoppert DC, Angelini MM, et al. Effect of
8. Field J, Wasilewski M, Bhuta R, et al. Effect of chronic
domperidone on milk production in mothers of premature
domperidone use on QT interval: A large single center
newborns: A randomized, double-blind, placebo-controlled
study. J Clin Gastroenterol 2019 [Epub ahead of print];
trial. CMAJ 2001;164:17–21.
DOI: 10.1097/MCG.0000000000001183.
2. Campbell-Yeo ML, Allen AC, Joseph KS, et al. Effect of
9. Saito J, Yakuwa N, Suyama F, et al. Transfer of domper-
domperidone on the composition of preterm human breast
idone into breast milk, calculation of infant drug dose, and
milk. Pediatrics 2010;125:e107–e114.
effect on breast-fed infants. Japanese J Dev Pharmacol
3. Knoppert DC, Page A, Warren J, et al. The effect of two
Ther 2018;31;1 (In press).
different domperidone doses on maternal milk production.
10. Paul C, Zénut M, Dorut A, et al. Use of domperidone as a
J Hum Lact 2013;29:38–44.
galactagogue drug: A systematic review of the benefit-risk
4. Wan EW, Davey K, Page-Sharp M, et al. Dose-effect study
ratio. J Hum Lact 2015;31:57–63.
of domperidone as a galactagogue in preterm mothers with
insufficient milk supply, and its transfer into milk. Br J Clin
Pharmacol 2008;66:283–289.
5. Ingram J, Taylor H, Churchill C, et al. Metoclopramide or Address correspondence to:
Yuka Wada, MD, PhD
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 09/07/19. For personal use only.

domperidone for increasing maternal breast milk output: A

randomised controlled trial. Arch Dis Child Fetal Neonatal Division of Neonatology
Ed 2012;97:F241–F245. Center for Maternal-Fetal, Neonatal,
6. Grzeskowiak LE, Smithers LG, Amir LH, et al. Domper- and Reproductive Medicine
idone for increasing breast milk volume in mothers ex- National Center for Child Health and Development
pressing breast milk for their preterm infants: A systematic Setagaya-ku 1578535
review and meta-analysis. BJOG 2018;125:1371–1378. Japan
7. Leelakanok N, Holcombe A, Schweizer ML. Domperidone
and risk of ventricular arrhythmia and cardiac death: A E-mail: wada-y@ncchd.go.jp