Evaluating the Effect of a 14-Day Course of Domperidone on Breast Milk Production: A Per-Protocol Analysis from the EMPOWER Trial

Abstract

Background:

Galactogogues are often considered when mothers of very preterm infants experience challenges in producing adequate amounts of breast milk. We conducted a per-protocol analysis of those mothers who completed a 14-day course of domperidone during the EMPOWER trial. Our primary aim was to evaluate the response to a completed course of domperidone and whether the response was affected by the timing of the initiation of intervention.

Methods:

For this analysis, 83 mothers of infants ≤29 weeks gestation were included: 45 mothers who received domperidone from days 1 to 14 of the trial study treatment period and 38 mothers who received domperidone from days 15 to 28. Domperidone was given at a dose of 10 mg thrice daily for 14 days. The primary outcome was the proportion of mothers who achieved a modest 50% increase in breast milk volume from the volume at the end of the 2-week period of treatment of domperidone.

Results:

When adjusted for the initiation of domperidone treatment, the proportion of mothers in the days 1–14 group (77.8%) was similar compared to those in the days 15–28 group (65.8%), OR 1.96 (95% CI 0.72–5.32; p = 0.19).

Conclusion:

Taking into consideration potential limitations in power, this secondary analysis was able to show that the mothers in the EMPOWER study who were identified as actually completing a 14-day treatment course responded irrespective of the timing of their initiation of domperidone and demonstrated a modest increase in breast milk volume.

Background

With an increasing demand for mother's own milk as a primary source of nutritional support in the care of very small and preterm infants, mothers of these infants can be at risk of expressing inadequate amounts of milk.^1,2 Many mothers of very preterm infants, for a variety of reasons such as illness, stress, and other factors related to preterm birth, are unable to exclusively feed their infants.^3–5 While pumping on a regular schedule remains the mainstay of breast milk production in these mothers, nonpharmacologic support techniques are often used to variable success.⁶ When these are not helpful, the use of galactogogues is often added to an increased pumping regime to augment breast milk volume. Domperidone is one of the most widely studied galactogogues in mothers of preterm infants.^7–12 Domperidone studies showed a modest increase in breast milk production but the approaches in dosing, timing, and duration of treatment vary considerably.¹³ Clearer information on the more specific response of a treatment approach may be helpful.

A recent trial, EMPOWER, sought to determine whether administration of domperidone, initiated within the first 21 days after delivery, would lead to a higher proportion of mothers having a modest 50% increase in the volume of expressed breast milk at the end of 14 days of treatment compared to mothers receiving a placebo.^11,12 More mothers achieved a 50% increase in milk volume after 14 days of receiving domperidone (77.8%) compared to those who received a placebo (57.8%); odds ratio [OR] 2.56 (95% confidence interval [CI]1.02–6.25; p = 0.04).¹²

The analysis for EMPOWER was an intention-to-treat analysis. However, the intention-to-treat analysis included all mothers who were randomized and allocated to one of the two treatment arms and avoided the effects of protocol deviations, withdrawal, and anything else that happened after randomization. It did not allow a more direct evaluation of domperidone in those mothers who completed a total 14-day course especially as mothers allocated to the placebo group went on to start domperidone for a 14-day course in the second part of the 28-day study treatment period.

To evaluate the effect of completing a 14-day course of domperidone on increasing breast milk volume in either allocated groups in the EMPOWER trial, we conducted an analysis of the response to domperidone of those mothers who were known to have received domperidone and completed the 14-day study treatment as per-protocol. One group of mothers initiated domperidone immediately upon enrollment into the study, whereas the other group of mothers started domperidone 14 days later. For this analysis, we sought to determine if there was a difference in the proportion of mothers from either group who achieved a 50% increase in breast milk volume from the volume at the start of their respective study period to the end of the 2-week period of treatment with domperidone and whether this was affected by the timing of the initiation of intervention.

Methods

EMPOWER trial design

The trial design of EMPOWER has been previously described in detail.^11,12 The goal of EMPOWER was to determine domperidone's ability to increase breast milk volume to a clinically significant amount which required the use of a modified placebo arm. Mothers were randomly assigned to one of two groups as follows: domperidone 10 mg orally thrice daily for 28 days or equivalent placebo orally thrice daily for 14 days followed by domperidone 10 mg orally thrice daily for 14 days. The primary outcome for the trial was based on the first 14 days of the study period for both groups.

Mothers were eligible if their preterm infants were born ≤29 completed weeks gestation (23^0/7–29^6/7 weeks); were 8–21 days postdelivery; were pumping a minimum of six times a day in the 4 days before study entry; and experiencing a milk volume that was <150 mL/kg/d (based on their infant's birth weight) during the previous 72-hour period before study entry or a maternal report of milk volume reduction by more than 1/3 from a peak volume of the previous 72 hours. One year into the study, the inclusion criteria were felt to be too restrictive and were modified to 250 mL/kg/d or experiencing a milk volume reduction of 20% or more from a peak volume during the previous 72-hour period before study entry.

The trial was conducted in eight level III Neonatal Intensive Care units across Canada. The research ethics committee of each center approved the study protocol. All the mothers who participated provided a written informed consent before enrollment. Because the study was utilizing an off-label indication for domperidone, the study was conducted under the Food and Drug Act of Health Canada.

Because of its pragmatic nature, the centers were encouraged to maintain their standard approach in supporting mothers as it related to the types of pumps used in each center. However, for the purpose of the trial, mothers were encouraged to pump a minimum of six to eight times in a given 24-hour period. A diary was provided to the mothers to log their doses taken, record their pumping times, volumes pumped, and any side effects they may experience from the study treatment. Mothers were encouraged to report any adverse events immediately to the study personnel. Nonpharmacologic interventions were encouraged but not specified. The trial did not collect serum prolactin.

Study participants

For the purpose of this analysis, the study participants were those mothers who were identified as having completed all of the 14 assigned days of domperidone from day 1 to 14 in the active treatment arm and from day 15 to 28 in initial placebo arm. The study logs were verified as to the compliance of taking domperidone, documenting pumping during the 24-hour period for each of the 14-day period, and had a recorded volume on the 14th day of treatment.

Outcome measures

For this analysis, the primary outcome measure was the proportion of mothers who achieved a 50% increase in breast milk volume from the volume at the start of their respective study period to the end of the 2-week period of treatment of domperidone.

Additional outcome measures were as follows: (i) median expressed breast milk volume at the end of the 14-day domperidone treatment; (ii) the mean total breast milk volume at the end of the 14-day domperidone treatment; and, (iii) the mean percent volume change at the end of the 14-day domperidone treatment.

Analysis

The analysis was carried out using SAS Version 9.3 (SAS Institute, Cary, NC). Descriptive statistics was calculated for all variables of interest. Continuous measures were summarized using means and standard deviations, whereas categorical measures were summarized using counts and percentages. Where applicable, nonparametric statistics (Wilcoxon rank sum test) was used.

The primary outcome was assessed between groups using a bivariate logistic regression model and adjusted for the timing of initiation of domperidone during the trial. Specifically generalized estimating equations with a logit link function were used to account for correlation among observations taken at the same site, as well as multiple births by the same mother. Odds ratios were presented along with their associated 95% confidence intervals and p-values. Secondary outcomes were assessed between groups using Wilcoxon rank sum tests.

Results

Between June 1, 2012 and June 30, 2015, 90 mothers were enrolled and equally allocated, 45 to each of the trial study arms in EMPOWER. Of these 90 mothers, there were 45 mothers who completed the 14-day treatment of domperidone from day 1–14 (Group A) and 38 mothers who completed the 14-day treatment from day 15–28 (Group B). The timing of entry into the trial was similar between both groups of mothers being studied, a median of 14 days for Group A and 15 days for Group B. The baseline characteristics of the two groups of mothers are outlined in Table 1. The mean maternal age for Group A was 31.3 years and for Group B was 32.8 years. The mean gestational age at delivery was 29.9 weeks for Group A and 27.5 weeks for Group B. The two groups of mothers were similar in other characteristics except that the mothers in Group A had a higher rate of being delivered by cesarean section and also more comorbidities in pregnancy. The mean milk volume before the start of their respective 14-day course of domperidone was 121 ± 96 mL for the mothers in Group A and 217 ± 168 mL for the mothers in Group B.

Table 1.

Baseline Characteristics of Mothers

Characteristic	Group A (N = 45), n (%)	Group B (N = 38), n (%)	p-Value^a
Married/Common Law	38 (84.4)	33 (86.6)	0.99
Self-declared ethnicity
Caucasian	29 (64.4)	26 (68.4)	0.75
Black	6 (13.3)	3 (7. 9)
Other	10 (22.3)	9 (23.7)
Smoking before pregnancy	14 (31.8)	9 (23.7)	0.47
Nulliparous	28 (62.2)	28 (73.7)	0.27
Comorbidities during pregnancy	28 (62.2)	13 (34.2)	0.01
Hypertension (Gestational/chronic)	2 (15.38)	1 (33.33)
Diabetes (Gestational/Type I and II)	3 (23.08)	0 (0)
Preterm Labor	3 (23.08)	0 (0)
Chorioamnionitis	9 (32.14)	3 (23.08)
Antepartum hemorrhage	5 (17.86)	3 (23.08)
Other	8 (28.57)	4 (30.77)
Antenatal corticosteroids	41 (91.1)	31 (81.6)	0.33
Cesarean Delivery	31 (68.9)	15 (39.5)	0.01
Singleton Pregnancy	38 (84.4)	33 (86.8)	0.99

p-Values based on chi-square test or Fisher exact test.

Table 2 shows the proportion of mothers in both groups who achieved a 50% increase in expressed milk volume after the 14-day treatment course of domperidone. After considering the timing of the initiation of the domperidone between the two groups, there was no significant difference in the proportion of mothers in group A (77.8%) compared to those in Group B (65.8%), OR 1.96 (95% CI 0.72–5.32; p = 0.19). Because mode of delivery and maternal comorbidities between the groups of mothers were viewed as potential confounders, an additional logistic regression was performed after controlling for these two variables with the OR being 1.73 (95% CI 0.61–4.94; p = 0.31).

Table 2.

Primary Outcome

	Group A (N = 45), n (%)	Group B (N = 38), n (%)	Odds ratio (95% confidence interval) unadjusted	Odds ratio (95% confidence interval) adjusted
Number of mothers who achieved a 50% increase in milk volume after 14-day treatment of domperidone	35 (77.8%)	25 (65.8%)	1.82 (0.69–4.81)	1.96 (0.72–5.32)
			p = 0.23^a	p = 0.19^a

p-Values were based on logistic regression controlling for time of initiation of domperidone treatment.

Table 3 outlines the secondary outcomes for the study. There was no significant difference in the median expressed breast milk volume at the end of the 14-day treatment of domperidone. Both groups of mothers expressed similar daily milk volumes after the 14-day treatment, 269 mL versus 302 mL. Although not statistically significant, the mothers in Group A had a higher mean percent volume change from the start to the end of treatment compared to those in Group B, 146% compared to 103% (Table 4).

Table 3.

Secondary Outcomes: Milk Volumes at End of 14-Day Treatment

	Group A (N = 45)	Group B (N = 38)	p-Value
Median daily expressed breast milk volume (mL) at end of the 14-day domperidone treatment (range in mL)	241 (1–757)	302 (0–960)	0.99^a
Mean expressed daily breast milk volume (mL) at end of the 14-day domperidone treatment (standard deviation)	294 (209)	302 (228)	0.99^a
Mean % volume change at end of the 14-day domperidone treatment (%) (standard deviation)	146 (129)	103 (161)	0.09^a

Wilcoxon rank sum test.

Table 4.

Secondary Outcomes: Milk Volumes Change at End of Treatment

	Group A (N = 45)	Group B (N = 38)	p-Value
Mean % volume change at end of the 14-day domperidone treatment (%) (standard deviation)	146 (129)	103 (161)	0.09^a

Wilcoxon rank sum test.

Discussion

In this secondary analysis, we were able to show that the two groups of mothers in the EMPOWER study who were identified as actually completing a 14-day treatment course responded similarly. In both groups, mothers were able to demonstrate a similar 50% increase in breast milk volume at the end of their respective 14-day treatment. Although the overall daily volume achieved did not differ between the two groups, there seemed to be a trend of improved volume as demonstrated by the % volume change with earlier introduction of domperidone, although this was not statistically significant. However, this may be clinically important as it may suggest that starting domperidone as early as 8 days postdelivery may help mothers start increasing their breast milk supply, which may provide an incentive to those mothers to keep pumping and hopefully achieve a supply that will be sustained through all the stages of their infants' hospital stay.

Absolute breast milk volumes can be quite variable among mothers of very preterm infants and can be affected by varying supportive techniques; most importantly, a consistent pumping schedule as was encouraged in the trial. The mothers in Group B did have a higher starting volume compared to Group A, and this could have been secondary to the pumping support in the 2 weeks before initiation of their domperidone treatment. However, our goal for this analysis was to see if a 14-day treatment would lead to a higher proportion of mothers, in either group, achieve a modest gain in breast milk volume, in this case 50%. Having more mothers achieve a gain in breast milk volume regardless of the starting volumes can mean that more of mother's own milk will be available to a preterm infant for nutritional support. The mothers who were included in this analysis were expressing significantly low values and well below the target often cited necessary to meet the needs of an infant at discharge.¹⁴ What may be more critical for the clinician is ensuring that if a treatment option is provided, there is a reasonable assurance of success in increasing volumes regardless of the starting volume. This was seen here; however, despite when the domperidone treatment was initiated, the volumes achieved still fell below the target volume of 500 mL/day.¹⁴ This is important from a clinical perspective as these mothers require ongoing support to maintain whatever gains they achieve with galactogogue support.

Over the past several years there has been an abundance of literature related to the cardiac side effects of domperidone which has led to ongoing debates about the safety of its use for whatever indication but most specifically in women wishing to augment breast milk volumes for nutritional support of their infants.^15–22 Despite these warnings, the use of domperidone for lactation support remains widespread with various authors reporting on the positive aspects of the use of domperidone with no serious side effects to report.^12,13,23

Because of this, it is important to report on how best to achieve a balance in the use of domperidone in the best interest of patient safety as a galactogogue while supporting mothers in all of the other techniques to enhance breast milk production. There continues to remain, unfortunately, a paucity of literature on how best to use domperidone. The current study shows that when a full 14-day course is given, more mothers will achieve a gain in expressed breast milk and that this can be achieved starting as early as 8 days postdelivery or later at 35 days postdelivery.

There are strengths and limitations to this study. The findings of this study are based on a population of mothers who were recruited for the purposes of an already published randomized controlled trial.¹² The results of this study may be seen as having limited statistical power and prone to bias as the original sample size was based on achieving a difference in the primary outcome based on an intention-to-treat analysis. This is always a concern with a per-protocol analysis. The confidence intervals of 0.72 and 5.36 are wide which would suggest that the sample size may have been too small to adequately evaluate the primary objective and may require additional studies to evaluate the question. In this case, a sample of 109 mothers would be needed to detect the odds ratio of 1.82 to be statistically significant with a power of 0.8. However, the aim of this study was to determine if the effects of domperidone were similar with different initiation approaches when known to be completing a full 14-day treatment unlike the intention-to-treat approach undertaken in the trial. We were reassured that our findings were not overly biased as the two groups of mothers in the analysis were similar in most of the baseline characteristics and adjustments were made in the analysis to account for two of the potential confounders identified.

Conclusion

Domperidone will continue to be a primary galactogogue prescribed by clinicians caring for mothers and their preterm infants. As with any medication, it is important to investigate how best to use domperidone to ensure that it is being used in the most appropriate settings. The approach in EMPOWER was very conservative due to the climate regarding domperidone's use and safety. Yet, more research needs to be completed to determine the most appropriate clinical settings, as well as further examination of dosing approaches.

This secondary analysis was able to show that the mothers in the EMPOWER study who were identified as actually completing a 14-day treatment course responded similarly regardless of the timing of their initiation of domperidone and demonstrated a modest increase in breast milk volume.

Lactation support should continue to focus on the nonpharmacologic approaches, in particular pumping, to assist these mothers; mothers need to maintain consistent pumping to facilitate the autocrine regulatory mechanism involved with breast milk production.^24–27 However, if these measures appear inadequate or unsuccessful, then a 14-day treatment of domperidone can be considered to provide added support in increasing breast milk production.

Research Ethics Board

The Research Ethics Board at the Sunnybrook Health Sciences Centre approved the EMPOWER trial on December 14, 2011 (REB ID #232-2011).

Availability of Data

Data are available at the Sunnybrook Research Institute.

Contribution to Authorship

All authors reviewed and approved the final copy of the article: Concept and design: E.V.A., A.K., O.D.; drafting of the article: E.V.A., A.K.; statistical analysis: A.K.; critical revision of article for important intellectual design: E.V.A., A.K., O.D., M.C.Y., D.K., S.I.

Footnotes

Acknowledgments

The authors thank Xingshan Cao for his ongoing assistance in analytic support for this article.

EMPOWER was funded by the Canadian Institutes of Health Research (CIHR) grant MOP# 114980. CIHR had no role in the design, management, data collection, analysis, or interpretation of the data. CIHR had no role in the writing of the article or in the decision to submit for publication.

Trial registration: EMPOWER has been registered at (identifier NCT 01512225).

EMPOWER Study Collaborative Group: Christoph Fusch, McMaster University, Hamilton, Ontario, Canada; Lajos Kovacs, Jewish General Hospital, Montreal, PQ, Canada; Annie Janvier, Sainte-Justine Hospital, Montreal, PQ, Canada; Georges Cauotte, Centre Hospitalier Universitaire de Quebec, PQ, Canada; Abhay Lodha, Foothills Medical Centre, Calgary, AB, Canada; Barbara Bulleid, Everett Chalmers Regional Hospital, Fredericton NB, Canada; Doug McMilllan, Balpreet Singh, Izaak Walton Killam Health Centre, Halifax, NS, Canada.

Disclosure Statement

No potential conflicts of interest relevant to this study is present among the authors listed.

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