Tox and Hound – Breastfeeding on Bup

A very special welcome to our newest hound, Dr. Christine Murphy! You can learn more about her here . . .

by Christine Murphy

Several months ago, I was taking care of an infant whose mother was terrified she would cause opioid withdrawal if she stopped breastfeeding. The mother was on medication assisted therapy (MAT) with buprenorphine, and was told in the hospital she could either breastfeed her newborn, as buprenorphine in her breast milk would prevent her newborn from going into withdrawal, or the newborn would need opioid therapy for neonatal abstinence syndrome (NAS). When speaking with several pediatricians, emergency medicine physicians, and a few toxicology colleagues about this case, I realized there is a lot of confusion regarding the safety of and reasons for recommending breastfeeding to mothers on buprenorphine.

Why is this confusing?

I think there are two primary reasons providers struggle with this. The first reason stems from not fully understanding the science in the literature. Both methadone and buprenorphine are excreted into the breast milk, breastfeeding decreases NAS symptoms, as well as the duration and amount of pharmacologic treatment for infants with NAS, and many providers infer that it is the drug in the breast milk that provides treatment for the infant. However, methadone and buprenorphine are each unique opioids, and what we know about methadone with regard to pregnancy and breastfeeding shouldn’t be extracted and applied to buprenorphine. Second, there are continued concerns that breastfeeding while on MAT isn’t safe for the infant. These concerns likely originate from the American Association of Pediatrics’ (AAP) original position on breastfeeding for mothers on methadone and a few published case reports.

In 1983, the AAP published a report on the “Transfer of Drugs and Other Chemicals into Human Breast Milk.”^​1​ Methadone was included as “usually compatible with breastfeeding” if mothers were on a dose of methadone <20 mg/day.^​1​ Many providers interpreted this to mean it wasn’t safe for infants to be breastfed if mom was on a higher dose of methadone. Interestingly, the reference cited as the rationale for this recommendation does not note any negative effects of breastfeeding from mothers on methadone maintenance (average 80-120 mg/day), and the last line of the article states “the pragmatic approach has been that when a woman is motivated to breastfeed she is permitted to do so, and, so far, no deleterious effects have been noted.”^​2,3​ The AAP changed their policy in 2001 to encourage breastfeeding, regardless of mom’s methadone dose as more data became available describing the low concentrations of methadone in breast milk. Unfortunately, I think the damage was already done and despite increasing literature supporting it, the safety of breastfeeding on any MAT remains a concern for many providers.

The publication of three case reports associating both toxicity resulting in an infant’s death, and development of withdrawal on discontinuation of breastfeeding in two infants of mothers on methadone likely added to the safety concerns.^​4,5​ Now don’t get me wrong, I’m a toxicologist, so I love a good case report, but these cases provide very little data to actually support true causality. However, they are the basis for a lot of fear and concern about breastfeeding while on MAT, and these articles continue to be cited as evidence of adverse effects of breastfeeding on methadone.

Given how confusing this is for providers, imagine the messages mothers receive from their doctors, family, friends, and the internet on breastfeeding while on MAT. So let’s try to clear up those misconceptions.

Some Background Info

The use of buprenorphine in pregnant women with opioid use disorder (OUD) is a well-known practice supported by the American Association of Pediatrics, the American College of Obstetricians and Gynecologists, and the American Society of Addiction Medicine.^​6–8​ Evidence supporting this recommendation comes from multiple studies, however, the MOTHER study, which compared the effects of buprenorphine and methadone on maternal and fetal outcomes, is one of the most frequently cited studies.^​9​ In this study, infants of mothers treated during their pregnancy with buprenorphine required less morphine for NAS. Furthermore, these infants had decreased length of hospitalization and decreased duration of NAS treatment.

What is NAS and how do you treat it?

Neonatal abstinence syndrome is the constellation of symptoms experienced by a neonate as they withdraw from in utero exposure to substances used or abused by their mother. This syndrome is associated with many illicit and prescription drugs, but the term was initially used to describe withdrawal from opioids. Neonates experience autonomic and central nervous system regulatory dysfunction manifested by symptoms like vomiting, hypertonicity, irritability, tachypnea, and weight loss. There are several different scores available to assess the severity of NAS, however the modified Finnegan Neonatal Abstinence Score is the most widely used and referenced scale in the United States.^​10​

When a neonate shows any signs of withdrawal, nonpharmacologic treatment options are first-line regardless of the initial symptoms. Breastfeeding, rooming-in (the practice of allowing the neonate to stay in the mother’s room postpartum), swaddling, and skin-to-skin contact are the best-supported modalities.^​11,12​ Morphine and methadone are typically used to treat opioid-related NAS when nonpharmacologic treatments fail. Other agents used include clonidine and phenobarbital. There are a few recent studies describing the successful use of buprenorphine for the treatment of NAS.^{​13–16​}

Why is Breastfeeding Good for NAS?

Breastfeeding helps build strong mother-infant bonds, and can be very empowering for mothers. Breastfed infants have delayed onset of NAS, decreased severity of NAS, require less pharmacotherapy for NAS, and have decreased length of stay.^{​17–22​} It is believed that the act of breastfeeding itself eases neonatal withdrawal from opioids – not because of the amount of drug excreted into the breast milk, but rather because breastfeeding decreases pain and stress responses.^​23​ The small amount of buprenorphine excreted in breast milk is not thought to impact NAS – more on this shortly.

The World Health Organization recommends exclusively breastfeeding infants for the first six months of life. Breastfeeding by all mothers, including those receiving MAT with methadone or buprenorphine, is supported by multiple professional medical organizations in North America.^{​7,8,24–26​} Contraindications to breastfeeding vary depending on the source but include maternal HIV, cracked nipples or bleeding from the skin around the nipple with concurrent hepatitis B or C infection, and illicit drug use. Despite the support among professional medical societies organizations, the rate of initiation of breastfeeding among women on any opioid therapy is low. One recent study reported 71% of mothers on methadone and 82% of mothers on buprenorphine initiated breastfeeding. However, only 19% and 31% of these mothers were breastfeeding on discharge compared to hospital averages of 90% initiation and 84% continuation of breastfeeding on discharge.^​27​

Is it the act of breastfeeding, or the breast milk itself, that helps with NAS?

This is a bit difficult to answer, but most evidence supports breastfeeding. Gray et al. found breastfeeding of healthy infants decreased markers of pain and stress (i.e., grimace, crying, and heart rate) during heel sticks.^​23​ This suggests the act of breastfeeding itself might attenuate symptoms of withdrawal. Most studies evaluate the effect of breastfeeding on NAS compared to those that are not breastfed without discerning if non-breastfed infants are receiving expressed breast milk.^{​18,20–22​} Overall, breastfed infants had lower NAS scores, had decreased need for pharmacologic treatment, decreased duration of pharmacologic treatment, and decreased length of stay. One group did identify whether infants were strictly breastfed or if they received expressed breast milk.^​19​ In this study, 58 breastfed infants and 27 infants receiving expressed breast milk were grouped together and compared to 105 infants receiving formula. Infants fed breast milk had decreased treatment duration for NAS, decreased length of stay, decreased mean NAS scores, delayed onset of withdrawal, and decreased need for pharmacologic treatment, compared to formula fed. In a separate analysis of the breastfed vs expressed breast milk, there was no difference in the Finnegan scores. The authors felt breast milk independently was associated with a decreased need for pharmacologic NAS treatment. Additionally, for infants exposed to multiple substances in utero, the breast milk fed infants had lower Finnegan scores than the formula fed infants.

Interestingly, when the type of maternal MAT was identified, the majority of mothers were on methadone in these studies. Both Welle-Strand, et al. and Pritham, et al. tried to evaluate breastfeeding mothers on buprenorphine, but the subgroups were so small that they were likely not powered appropriately.^​18,20​ While these studies suggest breastfeeding of infants with NAS by mothers on buprenorphine decreases the length of stay and duration of treatment, none of these are statistically significant when compared to non-breastfed infants. The only study I found where all the mothers were on buprenorphine for maintenance therapy was by O’Connor, et al.^​17​ In this study there were lots of suggestions that breastfeeding may attenuate withdrawal but none of the markers were statistically significant. However, none of the infants in the study were readmitted for withdrawal, which is encouraging.

Buprenorphine in Breast Milk

How do you estimate infant drug exposure from breast milk?

Before we get into the details of the studies that examine the amount of buprenorphine in breast milk, let’s take a moment to review some terms commonly used to describe drug concentrations in breast milk and infant exposures to drugs in breast milk.

• The absolute infant dose (AID) is the product of the average concentration (C_avg) of the drug in the breast milk over 24-hours.
• A relative infant dose (RID) should be weight adjusted for the maternal daily dose of the medication. An RID <10% is often considered the threshold reference point for risk assessment for the amount of drug transferred to the infant. The RID only takes into account maternal dosing and transmission into the breast milk. It is not a measure of toxicity, and does not take into account the infant bioavailability, metabolism, or excretion of the drug.
• The milk-to-plasma (M/P) ratio is one of the most frequently used methods to estimate infant exposure to a drug, but does not take into account drug absorption or clearance by the infant. This is important to understand because while most drugs report an M/P ratio of around 1, a ratio of greater than 1 does not necessarily mean the drug is dangerous to the infant, or estimate the amount of the drug the infant will actually absorb.

How much buprenorphine is actually in breast milk?

There are several studies evaluating the concentration of buprenorphine in breast milk.^{​28–31​} Women in these studies were on standard doses of buprenorphine.^{​29–31​} All of these studies measured concentrations of both buprenorphine and norbuprenorphine (the main metabolite) in breast milk. The median M/P ratios for buprenorphine were 1.7-2 and 0.7 for norbuprenorphine.^​30,31​ The median C_avg of buprenorphine and norbuprenorphine in breast milk was 2.76-5 μg/L (range 0.83-10.8 μg/L) and 1.59-4.16 μg/L (range 0.45-6.25 μg/L), respectively, with collection occurring between five and 21 days depending on the study.^{​29–31​} Two studies looked at breast milk at 7 months and 9 months of lactation and found similar results.^​28,31​ Lindelmalm, et al. also evaluated the plasma and urine of a 9-month-old and found low concentrations of buprenorphine in the plasma (0.23 μg/L), undetectable buprenorphine in the urine (< 0.23 μg/L), and low levels of norbuprenorphine in the urine (0.45 μg/L).^​31​ The median RID of buprenorphine and norbuprenorphine was calculated in both the Ilet and Lindelmalm studies, and found to be less than 1% (0.2-0.38% and 0.12-0.18%, respectively).^​29,31​ Ilet, et al. also calculated the AID of buprenorphine at 0.55 μg/kg/day and norbuprenorphine at 0.29 μg/kg/day.^​29​ That’s a really small dose!

There were correlations between maternal buprenorphine dose and concentrations of buprenorphine in maternal plasma and breast milk in one study, but the authors did not find a correlation between maternal dose and infant plasma concentration of buprenorphine.^​30​ In several of the infants evaluated at 14 days of age in the Jansson study, buprenorphine (limit of detection 0.1 μg/L) was not detected in the plasma, and none of the infants had quantifiable plasma norbuprenorphine (limit of detection 2 μg/L).^​30​

What Does all this Mean?

These studies demonstrate there are negligible amounts of buprenorphine and norbuprenorphine in breast milk, and infants absorb even less than they are exposed to. Infant absorption is low because buprenorphine undergoes significant first-pass hepatic metabolism, leading to very low oral bioavailability, approximately 15%.^​18,32​ Sublingual buprenorphine bioavailability is a bit higher with the majority of studies supporting a bioavailability of 30-55%.^{​33–37​}

So, when you look at the amount of buprenorphine used to treat NAS (13.2-60 μg/kg/day), the amount infants are exposed to (let alone absorb) from breast milk isn’t near enough to treat NAS.^{​14–16​} Additionally, there have been no reports to date documenting withdrawal after acute discontinuation of breastfeeding, even with abrupt cessation at 8 weeks.^​38​

The Bottom Line

There are many benefits to breastfeeding infants with in utero opioid exposures. Buprenorphine exposure from breast milk is minuscule and likely has no pharmacological effect on the infant. Mothers on buprenorphine maintenance therapy who are interested in breastfeeding should be encouraged to do so without fear of harming their child should they need to discontinue breastfeeding.

Based on all of this information, I felt very comfortable recommending that the mother in the case above continue breastfeeding if she was interested in doing so, and I was able to reassure her that if she wanted to stop breastfeeding she would not cause withdrawal in her child.

Take Home Points

• Breastfeeding is safe and should continue to be encouraged in interested mothers receiving buprenorphine MAT.
• Breastfeeding, and possibly the breast milk itself, delayed onset of NAS, decrease the need for and duration of pharmacologic treatment and decrease pain and stress responses
• Buprenorphine (and norbuprenorphine) in breast milk is negligible; the amount absorbed by the infant even less
• There is likely no pharmacologic effect from buprenorphine breast milk exposure
• There are no published reports of the development of NAS with the discontinuation of breastfeeding by mothers on buprenorphine
• Mothers face enough obstacles when breastfeeding, fear of inadvertent harm from buprenorphine shouldn’t be one of them