By Thomas W. Hale, RPh, PhD, and Pamela D. Berens, MD, FACOG, IBCLC
Excerpt from Preface:
The number of women who leave the hospital breastfeeding has risen to an all-time high. Virtually all of these women will at one time or another use a medication. Many will require treatment for severe and complicated syndromes. Thus, one of the most common questions we get is, “What medications can we use in this patient with this syndrome?” In the ensuing decade, much more data have been published on the various medications, and we can now provide good evidence of safety for many medications.
The purpose of this work is to provide the clinician a guide not only into the best types of medications in breastfeeding mothers, but also a guide in the current therapy of various syndromes as well. The data on treatment and choice of medications for various syndromes have been thoroughly reviewed in the literature and should be accurate with present treatment protocols. It is by no means our intent to guide therapy with these suggestions, but only to provide safety data on the medications commonly found to be useful for various syndromes and conditions.
We fully understand that certain conditions require the use of very specific medications, and they may not be suitable for a breastfeeding mother. This is the domain of the clinician who is treating the patient. We simply hope to provide some suitable alternative medications available that have published data on their transmission into human milk. Why not choose a medication fully effective for the syndrome, and one that is safe for a breastfeeding infant?
In medicine we sometimes have a tendency to use the newest and most advertised medication. Unfortunately, these are the exact medications for which we have limited or no data on their use in breastfeeding mothers. Science is a slow process. It takes a lot of time before we know the complications and levels of these same medications in human milk. We, therefore, respectfully suggest that if an older, better, studied medication will work and we know it is safe for breastfed infants, then it should be the clinician’s first choice in this situation.
Because we have limited data on the many thousands of medications available, if it is not included in this text, then we probably do not have any breastfeeding data available, otherwise we would have included it. This does not mean that the drug cannot be used safely in breastfeeding mothers, only that we could not find any data to support its entry in this work.
Everyone now knows that breastfed infants are infinitely more healthy. Numerous research trials in the last decade confirm this. We urge that the reader always opt to assist the breastfeeding mother in choosing medications that are compatible with breastfeeding. Even brief interruptions of breastfeeding for unfounded reasons may predispose the mother to losing her milk supply.
THE AUTHORS MAKE NO RECOMMENDATIONS AS TO THE SAFETY OF THESE MEDICATIONS DURING LACTATION, BUT ONLY REVIEWS WHAT IS CURRENTLY KNOWN IN THE SCIENTIFIC LITERATURE.
The references enclosed are primarily review articles that summarize the current standard of care for the various syndromes or conditions. For exact references concerning drug levels in milk, please consult Medications and Mothers’ Milk where each medication is thoroughly referenced.
Insufficient Milk Supply
Principles of Therapy
While insufficient milk production is one of the most commonly perceived dysfunctions in breastfeeding, it occurs rarely. Because new mothers often worry that the infant is receiving insufficient volumes of milk, this is almost universally the main reason that many new mothers give for early weaning and for supplementation with formulas. The vast majority of women who wean due to suspected poor supply are incorrect in their perception. Objective evidence for insufficient milk supply should be sought prior to beginning pharmacologic therapy. Further support for the social component regarding milk production is that other cultures often complain more of oversupply, rather than undersupply. Because it is difficult to ascertain how much volume the infant is receiving, even in infants that are gaining and thriving, the mother frequently worries that her supply is insufficient. Prior to assuming insufficient milk production, the clinician must assess a number of critical indicators, such as: 1) the number of stools per day (normally five to ten by the end of the first week), but this varies depending on age of the child, 2) the number of wet diapers per day (at least six to eight), 3) the baby should show no signs of dehydration or hyperbilirubinemia, and 4) the infant is gaining weight along an acceptable growth curve. An insufficient milk supply may predispose to hyperbilirubinemia. The definitive indicator of sufficiency in the early neonatal period is infant weight gain. Specialized infant scales are available to allow pre and post feeding weights in an attempt to quantify the amount of milk received at a nursing.
- Objective evidence of insufficient supply should be sought as most mother’s perceiving insufficient supply are incorrect in their belief.
- The definitive indicator of sufficiency is infant weight gain.
- Specialized infant scales are available to allow pre and post feeding weights in an attempt to quantify the amount of milk received at a nursing.
- An insufficient milk supply may predispose to hyperbilirubinemia.
DOMPERIDONE (Motilium, Motilidone)
- AAP = Maternal Medication Usually Compatible with Breastfeeding
- LRC = L1
- RID = 0.01-0.04%
- Pregnancy = C
- Comment: Domperidone (Motilium) is a peripheral dopamine antagonist (similar to Reglan)generally used for controlling nausea and vomiting, dyspepsia, and gastric reflux. It blocks peripheral dopamine receptors in the GI wall and in the CRTZ (nausea center) in the brain stem and is currently used in Canada as an antiemetic. Unlike metoclopramide (Reglan), it does not enter the brain compartment, and it has few CNS effects, such as depression.
It is also known to produce significant increases in prolactin levels and has proven useful as a galactagogue. Serum prolactin levels have been found to increase from 8.1 ng/mL to 124.1 ng/mL in non-lactating women after one 20 mg dose. Concentrations of domperidone reported in milk vary according to dose. But following a dose of 10 mg three times daily, the average concentration in milk was only 2.6 μg/L.
In a study by da Silva, 16 mothers with premature infants and low milk production (mean = 112.8 mL/d in domperidone group; 48.2 mL/d in placebo group) were randomly chosen to receive placebo (n= 9) or domperidone (10 mg TID) (n= 7) for seven days. Milk volume increased from 112.8 to 162.2 mL/d in the domperidone group and 48.2 to 56.1 mL/d in the placebo group. Prolactin levels increased from 12.9 to 119.3 μg/L in the domperidone group and 15.6 to 18.1 μg/L in the placebo group. On day five, the mean domperidone concentration was 6.6 ng/mL in plasma and 1.2 μg/L in breastmilk of the treated group (n= 6). No adverse effects were reported in infants or mothers.
In a new study just released, a group of six breastfeeding women were placed in a double blind randomized crossover trial to compare doses of domperidone. In this trial, mothers were studied in a run-in phase (no drug treatment), 30 mg, or 60 mg domperidone daily doses (10 or 20 mg every eight hours). Milk volume created per hour and plasma prolactin levels were monitored. With milk production, two mothers did not respond to domperidone treatment. Four other mothers showed a significant increase from 8.7 g/hour in the run-in phase to 23.6 g/h for the 30 mg/d dose, to 29.4 g/h for the 60 mg dose. While plasma prolactin levels were increased by domperidone treatment, there was no significant difference between levels at 30 mg and 60 mg doses. Median domperidone concentrations in milk were 0.28 μg/L and 0.49 μg/L for the 30 mg and 60 mg doses, respectively. The mean Relative Infant Dose was 0.012% at 30 mg daily and 0.009% at the 60 mg/day dose.
The usual oral dose for controlling GI distress is 10-20 mg three to four times daily, although for nausea and vomiting the dose can be higher (up to 40 mg). The galactagogue dose is suggested to be 10-20 mg orally three to four times daily. The prior studies clearly suggest that doses of 10-20 mg three to four times daily elevate prolactin levels to levels more than adequate to produce milk. Doses higher than this should be avoided in breastfeeding mothers.
Recently the US FDA issued a warning on this product stating that it could induce arrhythmias in patients. These claims were derived from data many years old where domperidone was used intravenously as an antiemetic during cancer chemotherapy (20 mg stat followed by 10 mg/kg/24 h). Many of these patients were undergoing extensive chemotherapy, were extremely ill, and hypokalemic to begin with. In addition, intravenous domperidone produces plasma levels many times higher than oral use. Thus far, we do not have any recent published data suggesting that domperidone used orally in breastfeeding mothers is arrhythmogenic, although its use in women who are already arrhythmic is not recommended.
- AAP = Drugs whose effect on nursing infants is unknown but may be of concern
- LRC = L2
- RID = 4.7-14.3%
- Pregnancy = B
- Comment: Metoclopramide has multiple functions, but is primarily used for increasing the lower esophageal sphincter tone in gastroesophageal reflux in patients with reduced gastric tone. In breastfeeding, it is sometimes used in lactating women to stimulate prolactin release from the pituitary and enhance breastmilk production. Since 1981, a number of publications have documented major increases in breastmilk production following the use of metoclopramide, domperidone, or sulpiride. With metoclopramide, the increase in serum prolactin and breastmilk production appears dose related up to a dose of 15 mg three times daily. Many studies show 66 to 100% increases in milk production depending on the degree of breastmilk supply in the mother prior to therapy and maybe her initial prolactin levels. Doses of 15 mg/day were found ineffective, whereas doses of 30-45 mg/day were most effective. In most studies, major increases in prolactin were observed, such as from 125 ng/mL to 172 ng/mL in one patient.
In Kauppila’s study, the concentration of metoclopramide in milk was consistently higher than the maternal serum levels. The peak occurred at two to three hours after administration of the medication. During the late puerperium, the concentration of metoclopramide in the milk varied from 20 to 125 μg/L, which was less than the 28 to 157 μg/L noted during the early puerperium.
The authors estimated the daily dose to infant to vary from 6 to 24 μg/kg/day during the early puerperium and from 1 to 13 μg/kg/day during the late phase. These doses are minimal compared to those used for therapy of reflux in pediatric patients (0.1 to 0.5 mg/kg/day). In these studies, only one of five infants studied had detectable blood levels of metoclopramide; hence, no accumulation or side effects were observed. While plasma prolactin levels in the newborns were comparable to those in the mothers prior to treatment, Kauppila found slight increases in prolactin levels in four of seven newborns following treatment with metoclopramide, although a more recent study did not find such changes. However, prolactin levels are highly variable and subject to diurnal rhythm, thus timing is essential in measuring prolactin levels and could account for this inconsistency.
In another study of 23 women with premature infants, milk production increased from 93 mL/day to 197 mL/day between the first and seventh day of therapy with 30 mg/day. Prolactin levels, although varied, increased from 18.1 to 121.8 ng/mL. While basal prolactin levels were elevated significantly, metoclopramide seems to blunt the rapid rise of prolactin when milk was expressed. Nevertheless, milk production was still elevated.
Gupta studied 32 mothers with inadequate milk supply. Following a dose of 10 mg three times daily, a 66-100% increase in milk supply was noted. Of twelve cases of complete lactation failure, eight responded to treatment in an average of three to four days after starting therapy. In this study, 87.5% of the total 32 cases responded to metoclopramide therapy with greater milk production. No untoward effects were noted in the infants.
In a study of five breastfeeding women who were receiving 30 mg/day, daily milk production increased significantly from 150.9 mL/day to 276.4 mL/day in this group. Infant plasma prolactin levels in breastfed infants were determined as well on the fifth postnatal day and no changes were noted; thus the amount of metoclopramide transferred in milk was not enough to change the infants’ prolactin levels.
In a study by Lewis in ten patients who received a single oral dose of 10 mg, the mean maternal plasma and milk levels at two hours was 68.5 ng/mL and 125.7 μg/L, respectively. Hansen’s study showed that 28 women receiving 30 mg/day had no significant increase in milk production as compared to the placebo group. However, this study was initiated within 96 hours of delivery, a time when virtually all mothers would have had exceedingly high plasma prolactin levels anyway. Metoclopramide should not be expected to work as a galactagogue when plasma prolactin levels are high.
It is well recognized that metoclopramide increases a mother’s milk supply, but it is exceedingly dose dependent, and yet some mothers simply do not respond. In those mothers who do not respond, Kauppila’s work suggests that such patients may already have elevated prolactin levels. In his study, three of the five mothers who did not respond with increased milk production had the highest basal prolactin levels (300-400 ng/mL). Thus it may be advisable to do plasma prolactin levels on under-producing mothers prior to instituting metoclopramide therapy to assess the response prior to treating.
Side effects, such as gastric cramping and diarrhea, limit the compliance of some patients, but are rare. Further, it is often found that upon rapid discontinuation of the medication, the supply of milk may in some instances reduce significantly. Tapering of the dose is generally recommended, and one possible regimen is to decrease the dose by 10 mg per week. Long-term use of this medication (>4 weeks) may be accompanied by increased side effects, such as depression in the mother, although some patients have used it successfully for months. Another dopamine antagonist, Domperidone, due to minimal side effects, is a preferred choice, but is unfortunately not available in the USA other than in compounding pharmacies.
Two recent cases of serotonin-like reactions (agitation, dysarthria, diaphoresis, and extrapyramidal movement disorder) have been reported when metoclopramide was used in patients receiving sertraline or venlafaxine. The FDA has recently warned of symptoms of tardive dyskinesia after three months of exposure.
SULPIRIDE (Dolmatil, Sulparex, Sulpitil)
- AAP = Not reviewed
- LRC = L2
- RID = 2.7-20.7%
- Pregnancy =
- Comment: Sulpiride is a selective dopamine antagonist used as an antidepressant and antipsychotic. Sulpiride is a strong neuroleptic antipsychotic drug; however, several studies using smaller doses have found it to significantly increase prolactin levels and breastmilk production in smaller doses that do not produce overt neuroleptic effects on the mother. In a study with 14 women who received sulpiride (50 mg three times daily), and in a subsequent study with 36 breastfeeding women, Ylikorkala found major increases in prolactin levels and significant, but only moderate, increases in breastmilk production. In a group of 20 women who received 50 mg twice daily, breastmilk samples were drawn two hours after the dose. The concentration of sulpiride in breastmilk ranged from 0.26 to 1.97 mg/L. No effects on breastfed infants were noted. The authors concluded that sulpiride, when administered early in the postpartum period, is useful in promoting initiation of lactation.
In a study by McMurdo, sulpiride was found to be a potent stimulant of maternal plasma prolactin levels. Interestingly, it appears that the prolactin response to sulpiride is not dose-related and reached a maximum at 3-10 mg. Thereafter, further increased doses did not further increase prolactin levels. Sulpiride is not available in the USA.
While extremely rare, some women fail to produce sufficient milk for their infant. This may be due to a myriad of problems, including insufficient glandular tissue, breast surgery or reduction, mammoplasty with severing of the ductal tissues near the nipple, anemia, shock, retained placental fragments, or postpartum hemorrhage. Sub-optimal early lactation management is a leading potentially preventable etiology for insufficient milk supply.
Regardless of the cause for low milk supply, continued frequent breastfeeding and, if needed, use of supplemental feeding for the infant until supply increases is indicated. Alternative feeding methods, such as supplemental feeding devices, cup feeding, or finger feeding, instead of the use of a bottle are advocated by some experts. Regardless of feeding method, breast stimulation with manual expression or a pump should be used to stimulate milk supply in these cases. Warm compresses applied to the breasts and relaxation techniques may be of benefit.
Metoclopramide has multiple effects, but is primarily used for increasing the lower esophageal sphincter tone in gastroesophageal reflux in patients with reduced gastric tone. It is sometimes used in lactating women to stimulate prolactin release from the pituitary and enhance breastmilk production. Since 1981, a number of publications have documented major increases in breastmilk production following the use of metoclopramide, domperidone, or sulpiride. All are peripheral dopamine antagonists. With metoclopramide, the increase in serum prolactin and breastmilk production appears dose-related, up to a dose of 15 mg three times daily. Many studies show 66 to 100% increases in milk production, depending on the degree of breastmilk supply in the mother prior to therapy. In another study of 23 women with premature infants, milk production increased from 93 mL/day to 197 mL/day between the first and seventh day of therapy with 30 mg/day. Prolactin levels, although varied, increased from 18.1 to 121.8 ng/mL. Gupta studied 32 mothers with inadequate milk supply. Following a dose of 10 mg three times daily, a 66-100% increase in milk supply was noted. No untoward effects were noted in the infants. Doses of 15 mg/day were found ineffective, whereas doses of 30-45 mg/day were most effective. In most studies, major increases in prolactin were observed, such as 18.1 ng/mL to 121.8 ng/mL after therapy in one study. While it is well recognized that metoclopramide increases milk supply, it is very dose-dependent, and some mothers simply do not respond. Side effects, such as depression, gastric cramping, and diarrhea, limit the compliance of some patients. Further, it is often found that upon discontinuing the medication, the supply of milk reduces rapidly. A slow tapering of the dose over several weeks is generally recommended in those women who respond. Long-term use of this medication (>4 weeks) is not generally recommended, as the incidence of depression and tardive dyskinesia increases. A FDA black box warning regarding this medication was issued in 2007 due to the incidence of tardive dyskinesia. Tardive dyskinesia was reported in 20% of patients taking the medication > three months, and the effect may be permanent in some cases. As postpartum depression carries a high likelihood of recurrence, use of metoclopramide in a mother with prior history of depression provides a relative contraindication. If metoclopramide fails to work within seven days, it is unlikely that longer therapy will be effective.
Domperidone is considered a “peripheral” dopamine antagonist and fails to pass the blood-brain barrier. Due to minimal side effects and superior efficacy, it is considered a better choice, but it is not available in the USA. The usual oral dose for controlling GI distress is 10-20 mg three to four times daily. Recent studies have suggested that doses higher than 10-20 mg three times daily do not increase prolactin levels above the lower dose. The FDA has issued a warning to healthcare providers and breastfeeding women not to use this unapproved drug to increase milk production, as they are concerned about potential health risks.
Sulpiride is a selective dopamine antagonist used as an antidepressant and antipsychotic. Several studies using smaller doses have found it to significantly increase prolactin levels and breastmilk production in smaller doses that do not produce overt neuroleptic effects on the mother. This drug is also not available in the US.
Multiple herbal therapies are touted as benefiting poor milk supply. Scientific evidence supporting the effectiveness of many of these compounds is limited. Concern also exists regarding the relative potency and quality control of herbal products in the United States. Fenugreek in doses of three 600 mg tablets three times daily has been suggested to improve milk supply. In a case-control study of ten exclusively breast pumping women, the increase in milk production was > 20% in five of ten mothers and >100% in three of these. Further study is needed regarding the safety and effectiveness of herbal galactogogues.
Clinicians may consider drawing plasma prolactin levels surrounding breastfeeding to assess response.
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