今日の臨床サポート

授乳婦への薬物投与

著者: 西村あや子1) 北海道大学病院 薬剤部

著者: 鈴木小夜2) 慶應義塾大学 薬学部

監修: 石川洋一 明治薬科大学 小児医薬品評価学 

著者校正/監修レビュー済:2021/02/17
参考ガイドライン:
  1. 日本産科婦人科学会日本産婦人科医会:産婦人科診療ガイドライン産科編2020

概要・推奨   

  1. 授乳婦が薬剤使用を必要とする場合、安易に母乳育児を禁止せず、個々の薬剤の母乳移行、児への影響を評価することが推奨される(推奨度1)。
  1. 児への影響とともに、医薬品の有益性・必要性および母乳栄養の有益性を説明したうえで、母乳育児を行うか否かの授乳婦自身の決定を尊重し、支援することが推奨される(推奨度2)。
  1. 情報が不十分な場合には、授乳婦に対する相談機関を利用することが推奨される(推奨度2)。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
西村あや子 : 未申告[2021年]
鈴木小夜 : 特に申告事項無し[2021年]
監修:石川洋一 : 未申告[2021年]

改訂のポイント:
  1. 定期レビューを行い、母乳のメリット、近年使用の多い薬剤について加筆修正を行った。

まとめ

まとめ  
  1. 母乳育児が望ましいとされ多くの母親もそれを望んでいるが、添付文書の「妊婦、産婦、授乳婦等への投与」の記載の多くは授乳回避/中止となっており、添付文書に従えば授乳しながら薬物治療を行うことは多くの場合において難しい。
  1. 母乳への薬剤移行性は薬剤により異なり、授乳されている児に対する影響は移行性以外の多くの因子も関わっているため、それらを統合的に考慮すると実際には授乳中に服薬しても臨床上問題のない薬剤も多い。
  1. 医療従事者がきちんとしたデータに基づいた薬剤選択と投与、情報提供を行うことは、授乳中の母親の治療効果を上げ、児への影響を回避するうえで非常に重要である。

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文献 

著者: Ruud H J Verstegen, Shinya Ito
雑誌名: 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.
PMID 30663176  J Obstet Gynaecol Res. 2019 Mar;45(3):522-531. doi: 10.・・・
著者: Section on Breastfeeding
雑誌名: 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.

PMID 22371471  Pediatrics. 2012 Mar;129(3):e827-41. doi: 10.1542/peds.・・・
著者: Shinya Ito, Jane Alcorn
雑誌名: 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.

PMID 12706548  Adv Drug Deliv Rev. 2003 Apr 29;55(5):653-65.
著者: Johan W Jonker, Gracia Merino, Sandra Musters, Antonius E van Herwaarden, Ellen Bolscher, Els Wagenaar, Elly Mesman, Trevor C Dale, Alfred H Schinkel
雑誌名: 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.

PMID 15685169  Nat Med. 2005 Feb;11(2):127-9. doi: 10.1038/nm1186. Epu・・・
著者: J Alcorn, X Lu, J A Moscow, P J McNamara
雑誌名: 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.

PMID 12388627  J Pharmacol Exp Ther. 2002 Nov;303(2):487-96. doi: 10.1・・・
著者: S Ito
雑誌名: N Engl J Med. 2000 Jul 13;343(2):118-26. doi: 10.1056/NEJM200007133430208.
Abstract/Text
PMID 10891521  N Engl J Med. 2000 Jul 13;343(2):118-26. doi: 10.1056/N・・・
著者: American Academy of Pediatrics Committee on Drugs
雑誌名: 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.

PMID 11533352  Pediatrics. 2001 Sep;108(3):776-89.
著者: Line Alleslev Larsen, Shinya Ito, Gideon Koren
雑誌名: 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.

PMID 12921514  Ann Pharmacother. 2003 Sep;37(9):1299-306. doi: 10.1345・・・
著者: Hari Cheryl Sachs, Committee On Drugs
雑誌名: 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/).

PMID 23979084  Pediatrics. 2013 Sep;132(3):e796-809. doi: 10.1542/peds・・・

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