厚生労働省:「授乳・離乳の支援ガイド」改定に関する研究会. 授乳・離乳の支援ガイド [Internet]. 2019. Available from: https://www.mhlw.go.jp/content/11908000/000496257.pdf
Ruud H J Verstegen, Shinya Ito
Drugs in lactation.
J Obstet Gynaecol Res. 2019 Mar;45(3):522-531. doi: 10.1111/jog.13899. Epub 2019 Jan 20.
Abstract/Text
Although most medications can be taken safely during breastfeeding, potential risks of infant toxicity do exist because all medications will be excreted into the breast milk to some extent. The amount of medication excreted in the milk depends mainly on (i) within-drug variation, such as dosing; (ii) between-drug variation including chemical characteristics of the medication; and (iii) host factors, such as maternal pharmacokinetics (PK), including variations of pregnancy-associated changes and their post-partum recovery. Neonatal drug exposure is usually assessed by calculating an expected total infant daily dose through breast milk and comparing it to the normal therapeutic dose. However, clinical PK studies in this population are challenging to conduct. Recently, research methods using population PK analyses and physiologically-based PK modeling and simulation techniques have been recognized as a complementary approach to the conventional PK studies in this field. These efforts are important for rational risk assessment balancing the toxicity risk against the benefits of human milk. Health benefits of lactation for both mother and child are significant and a decision to withhold from this should not be taken lightly. In case limited information is present, additional expertise from pharmacists or clinical pharmacologist with expertise in this area should be sought.
© 2019 Japan Society of Obstetrics and Gynecology.
Section on Breastfeeding
Breastfeeding and the use of human milk.
Pediatrics. 2012 Mar;129(3):e827-41. doi: 10.1542/peds.2011-3552. Epub 2012 Feb 27.
Abstract/Text
Breastfeeding and human milk are the normative standards for infant feeding and nutrition. Given the documented short- and long-term medical and neurodevelopmental advantages of breastfeeding, infant nutrition should be considered a public health issue and not only a lifestyle choice. The American Academy of Pediatrics reaffirms its recommendation of exclusive breastfeeding for about 6 months, followed by continued breastfeeding as complementary foods are introduced, with continuation of breastfeeding for 1 year or longer as mutually desired by mother and infant. Medical contraindications to breastfeeding are rare. Infant growth should be monitored with the World Health Organization (WHO) Growth Curve Standards to avoid mislabeling infants as underweight or failing to thrive. Hospital routines to encourage and support the initiation and sustaining of exclusive breastfeeding should be based on the American Academy of Pediatrics-endorsed WHO/UNICEF "Ten Steps to Successful Breastfeeding." National strategies supported by the US Surgeon General's Call to Action, the Centers for Disease Control and Prevention, and The Joint Commission are involved to facilitate breastfeeding practices in US hospitals and communities. Pediatricians play a critical role in their practices and communities as advocates of breastfeeding and thus should be knowledgeable about the health risks of not breastfeeding, the economic benefits to society of breastfeeding, and the techniques for managing and supporting the breastfeeding dyad. The "Business Case for Breastfeeding" details how mothers can maintain lactation in the workplace and the benefits to employers who facilitate this practice.
Shinya Ito, Jane Alcorn
Xenobiotic transporter expression and function in the human mammary gland.
Adv Drug Deliv Rev. 2003 Apr 29;55(5):653-65.
Abstract/Text
Xenobiotic transport in the mammary gland has tremendous clinical, toxicological and nutritional implications. Mechanisms such as passive diffusion, carrier-mediated transport, and transcytosis mediate xenobiotic transfer into milk. In vivo animal and human studies suggest the functional expression of both xenobiotic and nutrient transporters in the lactating mammary gland and the potential involvement of such systems in the significant accumulation of certain compounds in milk. In vitro cell culture systems provide further evidence for carrier-mediated transport across the lactating mammary epithelium. Additionally, molecular characterization studies indicate the expression of various members of the organic cation transporter, organic anion transporter, organic anion polypeptide transporter, oligopeptide transporter, nucleoside and nucleobase transporter, multidrug resistant transporter, and multidrug resistant-like protein transporter families at the lactating mammary epithelium. The in vivo relevance of the expression of such xenobiotic and nutrient transporters and their involvement in drug disposition at the mammary gland requires investigation.
Johan W Jonker, Gracia Merino, Sandra Musters, Antonius E van Herwaarden, Ellen Bolscher, Els Wagenaar, Elly Mesman, Trevor C Dale, Alfred H Schinkel
The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk.
Nat Med. 2005 Feb;11(2):127-9. doi: 10.1038/nm1186. Epub 2005 Jan 30.
Abstract/Text
Contamination of milk with drugs, pesticides and other xenotoxins can pose a major health risk to breast-fed infants and dairy consumers. Here we show that the multidrug transporter BCRP (encoded by ABCG2) is strongly induced in the mammary gland of mice, cows and humans during lactation and that it is responsible for the active secretion of clinically and toxicologically important substrates such as the dietary carcinogen PhIP, the anticancer drug topotecan and the antiulcerative cimetidine into mouse milk.
J Alcorn, X Lu, J A Moscow, P J McNamara
Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction.
J Pharmacol Exp Ther. 2002 Nov;303(2):487-96. doi: 10.1124/jpet.102.038315.
Abstract/Text
Transporter-mediated processes in the lactating mammary gland may explain the significant accumulation of certain drugs in breast milk. The purpose of this study was to identify potential candidate drug transport proteins involved in drug accumulation in milk. Quantitative reverse transcription-polymerase chain reaction methods were developed to determine the relative RNA levels of 30 different drug transporter genes. Transporter gene RNA levels in lactating mammary epithelial cells (MEC) purified from pooled fresh breast milk samples were compared with levels in nonlactating MEC, liver, and kidney tissue. Transcripts were detected in lactating MEC for OCT1, OCT3, OCTN1, OCTN2, OATP-A, OATP-B, OATP-D, OATP-E, MRP1, MRP2, MRP5, MDR1, CNT1, CNT3, ENT1, ENT3, NCBT1, PEPT1, and PEPT2. No transcripts were detected for OCT2, OAT1, OAT2, OAT3, OAT4, OATP-C, MRP3, MRP4, CNT2, ENT2, and NCBT2. Lactating MEC demonstrated more than 4-fold higher RNA levels of OCT1, OCTN1, PEPT2, CNT1, CNT3, and ENT3, and more than 4-fold lower RNA levels of MDR1 and OCTN2 relative to nonlactating MEC. Lactating MEC showed significantly higher RNA levels of CNT3 relative to liver and kidney, increased PEPT2 RNA levels relative to liver, and increased OATP-A RNA levels relative to kidney. These data imply CNT3 may play a specialized role in nucleoside accumulation in milk and may identify an important role for PEPT2 and OATP-A transporters at the lactating mammary epithelium. Furthermore, transporters expressed in lactating MEC identify a potential role for these transporters in drug disposition at the mammary gland.
Alba M García-Lino, Indira Álvarez-Fernández, Esther Blanco-Paniagua, Gracia Merino, Ana I Álvarez
Transporters in the Mammary Gland-Contribution to Presence of Nutrients and Drugs into Milk.
Nutrients. 2019 Oct 5;11(10). doi: 10.3390/nu11102372. Epub 2019 Oct 5.
Abstract/Text
A large number of nutrients and bioactive ingredients found in milk play an important role in the nourishment of breast-fed infants and dairy consumers. Some of these ingredients include physiologically relevant compounds such as vitamins, peptides, neuroactive compounds and hormones. Conversely, milk may contain substances-drugs, pesticides, carcinogens, environmental pollutants-which have undesirable effects on health. The transfer of these compounds into milk is unavoidably linked to the function of transport proteins. Expression of transporters belonging to the ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies varies with the lactation stages of the mammary gland. In particular, Organic Anion Transporting Polypeptides 1A2 (OATP1A2) and 2B1 (OATP2B1), Organic Cation Transporter 1 (OCT1), Novel Organic Cation Transporter 1 (OCTN1), Concentrative Nucleoside Transporters 1, 2 and 3 (CNT1, CNT2 and CNT3), Peptide Transporter 2 (PEPT2), Sodium-dependent Vitamin C Transporter 2 (SVCT2), Multidrug Resistance-associated Protein 5 (ABCC5) and Breast Cancer Resistance Protein (ABCG2) are highly induced during lactation. This review will focus on these transporters overexpressed during lactation and their role in the transfer of products into the milk, including both beneficial and harmful compounds. Furthermore, additional factors, such as regulation, polymorphisms or drug-drug interactions will be described.
S Ito
Drug therapy for breast-feeding women.
N Engl J Med. 2000 Jul 13;343(2):118-26. doi: 10.1056/NEJM200007133430208.
Abstract/Text
Ruud H J Verstegen, Philip O Anderson, Shinya Ito
Infant drug exposure via breast milk.
Br J Clin Pharmacol. 2022 Oct;88(10):4311-4327. doi: 10.1111/bcp.14538. Epub 2020 Sep 13.
Abstract/Text
More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.
© 2020 The British Pharmacological Society.
American Academy of Pediatrics Committee on Drugs
Transfer of drugs and other chemicals into human milk.
Pediatrics. 2001 Sep;108(3):776-89.
Abstract/Text
The American Academy of Pediatrics places emphasis on increasing breastfeeding in the United States. A common reason for the cessation of breastfeeding is the use of medication by the nursing mother and advice by her physician to stop nursing. Such advice may not be warranted. This statement is intended to supply the pediatrician, obstetrician, and family physician with data, if known, concerning the excretion of drugs into human milk. Most drugs likely to be prescribed to the nursing mother should have no effect on milk supply or on infant well-being. This information is important not only to protect nursing infants from untoward effects of maternal medication but also to allow effective pharmacologic treatment of breastfeeding mothers. Nicotine, psychotropic drugs, and silicone implants are 3 important topics reviewed in this statement.
Line Alleslev Larsen, Shinya Ito, Gideon Koren
Prediction of milk/plasma concentration ratio of drugs.
Ann Pharmacother. 2003 Sep;37(9):1299-306. doi: 10.1345/aph.1C379.
Abstract/Text
OBJECTIVE: The milk to plasma (m/p) concentration ratio of drugs is used to estimate the amount of drug offered to the suckling infant. Published literature was reviewed to identify drugs for which sufficient data exist for calculation of m/p ratio and to examine whether the existing empiric data agree with the published method of Atkinson for mathematical prediction of m/p ratios based on physiochemical characteristics.
METHODS: Using a comprehensive reference text, we identified studies reporting sufficient data to calculate m/p ratio based on the AUC for milk and plasma. Subsequently, we calculated the m/p ratio with Atkinson's formula based on pKa, lipophilicity, and protein binding. We then correlated the empiric versus predicted (calculated) m/p ratios.
RESULTS: Of 192 drugs of which at least some data on milk accumulation have been published, there were sufficient data to quantify m/p ratios for only 69 medications (78 studies). There was no significant correlation between the empiric m/p ratios and the predicted values using the Atkinson's model.
CONCLUSIONS: Reliable data on m/p concentration ratios exist for few medications. Presently, there is no appropriate model to predict milk concentrations of drugs in humans.
Hari Cheryl Sachs, Committee On Drugs
The transfer of drugs and therapeutics into human breast milk: an update on selected topics.
Pediatrics. 2013 Sep;132(3):e796-809. doi: 10.1542/peds.2013-1985. Epub 2013 Aug 26.
Abstract/Text
Many mothers are inappropriately advised to discontinue breastfeeding or avoid taking essential medications because of fears of adverse effects on their infants. This cautious approach may be unnecessary in many cases, because only a small proportion of medications are contraindicated in breastfeeding mothers or associated with adverse effects on their infants. Information to inform physicians about the extent of excretion for a particular drug into human milk is needed but may not be available. Previous statements on this topic from the American Academy of Pediatrics provided physicians with data concerning the known excretion of specific medications into breast milk. More current and comprehensive information is now available on the Internet, as well as an application for mobile devices, at LactMed (http://toxnet.nlm.nih.gov). Therefore, with the exception of radioactive compounds requiring temporary cessation of breastfeeding, the reader will be referred to LactMed to obtain the most current data on an individual medication. This report discusses several topics of interest surrounding lactation, such as the use of psychotropic therapies, drugs to treat substance abuse, narcotics, galactagogues, and herbal products, as well as immunization of breastfeeding women. A discussion regarding the global implications of maternal medications and lactation in the developing world is beyond the scope of this report. The World Health Organization offers several programs and resources that address the importance of breastfeeding (see http://www.who.int/topics/breastfeeding/en/).