Families and healthcare professionals often ask pharmacists if a medicine is compatible with breastfeeding; however, despite considerable investment in pharmacovigilance and the capture of healthcare data in population databases, often the only information on medicines and breastfeeding emanates from small case series or pharmacokinetic studies, and is therefore a suboptimal evidence-base for advice.
Most maternal medicines do not adversely affect most breastfed infants. Some — such as paracetamol, when prescribed alone — are ‘generally regarded as safe’, while others are associated with self-limiting adverse effects, typically diarrhoea or oral thrush following antibiotic exposure[2,3]. However, adverse drug reactions (ADRs) of varying severity from breastmilk exposure are widely reported, some of which are life-threatening, including apnoea and meningeal haemorrhage[4–7]. Long-term sequelae are rarely reported.
Susceptibility to adverse drug reactions
Currently, there are insufficient data to predict which infants will be harmed, in the short or long term. The vulnerability of an infant depends on maturity, health status, genetics, timing of breastfeeding and co-exposures.
Most breastfed infants’ ADRs mirror adult ADRs and are dose-related, emanating from the combined effects of low clearance and high transfer into breastmilk.
The immature renal and hepatic function of preterm or sick infants leaves them vulnerable to drug accumulation, even when healthy term infants are able to clear the medicine effectively, but little information is available. Some enzymes do not function during the first months of life, such as those metabolising caffeine[6,8]. From 30 to 34 weeks’ gestational age, other enzymes, such as those metabolising morphine, display the same polymorphisms and activity range as adults[9,10]. Similarly, variations in codeine and oxycodone metabolism may explain why only ~20% infants experience drowsiness following breastmilk exposure[11,12].
Transfer from maternal plasma into breastmilk and infants’ circulation is highest in the first week postpartum and variable. For example, the milk–plasma ratio for venlafaxine ranges 0.85–4.85 (mean 2.59) and the lamotrigine and zonisamide infant–maternal blood concentrations range 0.6–90.3% (median 28.9%) and 35.2–125.3% (median 44.2%), respectively[13,14].
Some 25–30% of ADRs in breastfed infants are attributable to unpredictable hypersusceptibility or hypersensitivity responses. For example, neutropoenia has been reported in association with carbimazole, apnoea with opioids and agranulocytosis in one of four infants exposed to clozapine[7,15].
No long-term data
Variations in concentration of antidepressants appeared greater in hind milk than fore milk samples, possibly owing to the higher lipid content of hind milk. Case reports of infant harm are often associated with polypharmacy: for example, an infant exposed to olanzapine, clonazepam, droperidol, sertraline, thioridazine and valproic acid had impaired intellectual development.
In the absence of data from randomised controlled trials (RCTs) and whole-population prescribing databases, current practice recommendations rest on case series that suggest the potential for (at least) short-term ADRs in breastfed infants from: opioids, clozapine, amisulpride, combinations of central nervous system depressants, amiodarone, oral retinoids, radioiodine, topical and systemic free iodine, chemotherapy, all sedating medicines (including some antihistamines), quinolones, aspirin, gold salts, lithium, ergot derivatives, barbiturate derivatives, recreational drugs and alcohol in most doses[5,6,17–19].
However, variations in susceptibility indicate that quantifying the risk from rare but serious adverse events and identifying vulnerable subgroups will necessitate large studies to account for moderators, such as age at exposure, genotypes, comorbidities and time-varying confounders, such as co-prescribing and co-exposures. Without reassuring long-term data, anxieties over short-term or rare ADRs may deprive infants of the benefits of breastfeeding.
Breastfeeding benefited children’s development in an RCT and observational studies[20,21]. Short-term exposure to psychotropic medicines or opioids via breastmilk may cause sedation, irritability, restlessness, diarrhoea and suboptimal weight gain, but how these relate to childhood development is unknown[5,22].
Long-term data are scarce, with only five population databases in Europe holding data on breastfeeding plus medicines plus developmental outcomes — these will be explored in the ConcePTION study. Recruited cohorts of infants exposed to antiepileptics in utero plus via breastmilk report that the additional postnatal exposure from breastfeeding is not disadvantageous; however, data regarding phenytoin (n=36) are less reassuring[23,24].
Resolving the dilemma “should those prescribed long-term medicines breastfeed?” will require long-term research in whole populations. If the whole population is not studied, findings may be distorted by collider and volunteer selection bias and relate only to volunteer samples, which usually represent the more affluent sections of the population[1,25].
The complex physiology of lactation is also vulnerable to disruption by medicines that affect serotonergic pathways (including antidepressants); antagonise prolactin (amphetamines, oestrogens, ergot derivatives, aripiprazole, nicotine, antihistamines [promethazine, diphenhydramine, chlorpheniramine], injected corticosteroids, possibly diuretics, progesterone, tamoxifen); or reduce oxytocin release (alcohol, opioids, sympathomimetics [pseudoephedrine, phenylephrine, epinephrine], anticholinergics, antihistamines, antidepressants)[4,26–28]. Exposure to some medicines in late pregnancy, labour and postpartum affects breastfeeding rates: a dose–response effect is postulated[28–31].
Spontaneous reporting is important in signal generation but may only capture 5–10% of ADRs. Women may simply discontinue breastfeeding without reporting any suspicion of a link to a prescription medicine. Therefore, identifying associations between medicines and breastfeeding rates will need population-based approaches.
Data blind spot
Current data on medicines and breastfeeding are inconclusive. When marketed, most medicines have no data on breastfeeding: this is not obligatory. Consequently, for some medicines (including ciclosporin, mycophenolate mofetil, belatacept, fingolimod, and other immunosuppressants), formularies indicate “manufacturer advises avoid”, sometimes based on “no information available”.
Few medicines are licensed for use during lactation and there may be no reports of safe administration to neonates. The Cumberlege Report details how case reports of valproate teratogenicity from the 1980s were not actioned for decades — analyses of large population databases would militate against such oversights, but first, whole-population data on breastfeeding must be collected[1,35].
Support and monitoring
What should be done while we await more evidence? There are several approaches that could be beneficial in this area.
First, women prescribed long-term medicines are less likely to breastfeed and so the uncertainty and concern surrounding lack of information on infant ADRs, coupled with physiological difficulties, indicate that support may be needed to optimise breastfeeding[3,36]. Existing analyses offer sufficient evidence for using prescription records to trigger low-risk interventions, including additional breastfeeding support to the 15% of women prescribed antidepressants in the infant’s first year[29,30,37,38].
Second, people receiving long-term repeat prescriptions should be regularly monitored for their medicine’s adverse effects and effectiveness. This structured, formalised profiling approach should be extended to breastfed infants. Routine surveillance by midwives and health visitors is focused on immunisations, public health, emotional development and parenting concerns: the physical assessments at 72 hours and 6 weeks are not designed to monitor ADRs and are insufficient for noting sedation, irritability or other problems that may have developed in association with medicine administration.
Regular medicine-specific monitoring would detect problems early enough to pre-empt serious problems and offer parents reassurance regarding the safety of medicines during breastfeeding. This approach, with laboratory monitoring and genetic testing as indicated, is advocated by specialist teams caring for women prescribed lithium. Until more data are available, monitoring could be extended to other medicines known to affect breastfed infants, particularly opioids and psychotropics[40,41]. This would offer a response to the dilemma “do I take the medicine for my own needs or breastfeed my baby?”.
Funding and conflict of interest declaration
This work has been undertaken under the auspices of the ConcePTION project. The ConcePTION project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821520. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Funding was awarded to SJ, MA, CDM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have declared that no competing interests exist.
If you have specific questions about medications or treatments, please message the Drugs in Breastmilk information service Facebook page or email: email@example.com.
If you require breastfeeding support, please call the National Breastfeeding Helpline on 0300 100 0212.
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Healthcare professionals have a duty to protect and promote breastfeeding. There are many specialist resources available that provide information on the safety of medications when breastfeeding, most of which are open-access. e.g. LactMed, SPS Safety in Breastfeeding, e-Lactancia. Hale's Medication & Mother's Milk is subscriber-only. UKDILAS can be contacted by healthcare professionals, and the Drugs in Breastmilk Information Service [see contact info in the body of the article] have a team of volunteer pharmacists responding to parents, breastfeeding supporters and healthcare professionals 365 days a year. Wendy Jones, the founder of the DiBM service, can be contacted via her website [https://breastfeeding-and-medication.co.uk/contact-me]
Parents who choose to breastfeed should be supported with their feeding choice by selecting an appropriate treatment or procedure where possible. Most parents can be supported with medication use while breastfeeding so #dontsaystoplookitup or contact one of the services listed above for expert support.
Amanda Da Costa
The Breastfeeding Network's Drugs in Breastmilk Information Service Volunteer Pharmacist & Clinical Supervisor
With all the acknowledged advantages to mothers and babies of breastfeeding I have to say I have never read an article so negative about breastfeeding support for pharmacists. RCTs and large studies are not possible because of limited funding, even anecdotal reports suffer from publication bias as we never see the situations where the baby was not affected by the medication passing through breastmilk. There are several world wide expert sources of information based on the knowledge of the pharmacokinetics of medications passing through maternal milk - these have not even been acknowledged by the authors. UKDILAS is part of the UK Medicines Information Service and provides valuable individual data along with detailed factsheets. The Breastfeeding Newtork is run by volunteer pharmacists with a knowledge of drugs in breastmilk and breastfeeding in a service which has no funding. Women with complex medical conditions should be helped to make decisions based on evidence based information as supported by the MHRS consortium Safer Medicines in Breastfeeding and Medication. Outdated terms like fore milk and hind milk exemplify the concerns I have with this paper. I hope that fellow pharmacists will consult expert sources to enable them to support mothers who are breastfeeding and need medication. Dr Wendy Jones MBE Pharmacist with a special interest in breastfeeding and medication.
Whilst this article does raise the important issue of the data gap which exists for good quality published evidence for use of medicines during breastfeeding, we do not have to wait until this gap is filled before practical and evidence based advice can still be given.
Medication use is rarely a reason that breastfeeding cannot go ahead, and any risks can be managed. However, because of the data gap, advice and information sources can conflict with each other.
Nevertheless, my colleagues in their replies above, signpost to some very important information sources which are available to navigate this area, which includes the NHS UK Drugs in Lactation Advisory Service (part of the Specialist Pharmacy Service and the UK Medicines Information Network). The Specialist Pharmacy Service includes published advice from UKDILAS on their website and can be contacted regarding medicine use in breastfeeding (0300 770 8564). For more complex cases (including some of the scenarios mentioned in the article), UKDILAS can be contacted directly: https://www.sps.nhs.uk/breastfeeding-medicines-advice-service/
Clinical Lead Pharmacist, UK Drugs In Lactation Advisory Service
Thank you for adding these information sources: others are pasted below.
Our papers highlight that the ‘evidence base’ on medicines and breastfeeding is weak: however excellent the compilation of the evidence, there are too few large studies with long-term follow-up . Without these, we shall not know either how isolated the case reports of harm  are or which prescription medicines affect breastfeeding rates.
We argue that professionals should be proactive in supporting women prescribed long-term medicines to address the increased risk of ‘not breastfeeding’ and to check infants for any signs of sedation , irritability or poor feeding [4,5]. In some less affluent areas, many women simply stop breastfeeding, rather than engage with the excellent helplines available. Active monitoring should be tested in this context.
Sources of information include:
• The British National Formulary (BNF) has information on product licensing https://bnf.nice.org.uk/ as do the Summaries of Product Characteristics Home - electronic medicines compendium (emc)
• LACTMED: Drugs and lactation database (lactmed). In.: Bethesda (MD): National Library of Medicine (US); 2006.
• Specialist Pharmacy Services (SPS) ‘MEDICINES INFORMATION GUIDELINES’
• SPS breastfeeding information
• UK Medicines Information, requires registration https://future.nhs.uk/UKMedsInfoNetwk/grouphome
1. Jordan S, Bromley R, Damase-Michel C, et al. Breastfeeding, pregnancy, medicines, neurodevelopment, and population databases: the information desert. Int Breastfeed J. 2022;17. doi:10.1186/s13006-022-00494-5
2. Soussan C, Gouraud A, Portolan G, et al. Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database. Eur J Clin Pharmacol. 2014;70:1361–6. doi:10.1007/s00228-014-1738-2
3. Lam J, Kelly L, Ciszkowski C, et al. Central Nervous System Depression of Neonates Breastfed by Mothers Receiving Oxycodone for Postpartum Analgesia. The Journal of Pediatrics. 2012;160:33-37.e2. doi:10.1016/j.jpeds.2011.06.050
4. Anderson P, Sauberan J. Modeling drug passage into human milk. Clin. Pharmacol. Ther. 2016;100:42–52. doi:10.1002/cpt.377
5. Merlob P, Schaefer C. Psychotropic drugs. In: Schaefer C, Peters P, Miller R, eds. Drugs During Pregnancy and Lactation . Elsevier 2015. 743–774.