ABSTRACT:

Objective:

To classify the drugs used during childbirth in relation to risks in breastfeeding, by using different sources of information and determining their disagreements.

Methods:

Cross-sectional study, within the 2015 Pelotas Birth Cohort. Information about the use of drugs was collected, classified and compared regarding risk according to: 1) Brazil Ministry of Health Manual (MS), 2) World Organization (WHO), 3) Newton and Hale’s classification and 4) American Academy of Pediatrics (AAP).

Results:

A total of 1,409 mothers participated, and they had used 14,673 medicines, with 143 different drugs, of which 28 showed discordant classification with regard to breastfeeding risk. These 28 drugs included the following: morphine (64%), classified by AAP and WHO as compatible and as judicious use use by MS and Newton and Hale; hyoscine (23%), classified as judicious use by MS and compatible (A) by AAP; and metoclopramide (18%), classified as compatible by MS, of effects unknown (D) by AAP, and should be avoided according to WHO. Of the total drugs, 49.7% were classified as compatible during breastfeeding. Almost all women used oxytocin (97.4%), followed by lidocaine (75%), ketoprofen (69%), cephalothin (66%) and diclofenac (65%), which were classified as compatible.

Conclusion:

There was extensive use of drugs by mothers in labor during admission, most of the drugs being classified at the same risk and almost half classified as compatible with breastfeeding. However, there was disagreement between the sources for 19.6% of the drugs analyzed, which could endanger the infant’s health or leave doubts about the use of the drug or breastfeeding.

Keywords:
Breastfeeding; Pharmaceutical preparations; Adverse drug reactions; Lactation; Drug utilization

INTRODUCTION

The use of medications in the immediate postpartum period is very common, occurring in almost all postpartum women¹1. Lamounier JA, Cabral CM, Oliveira BC, Oliveira AB, Oliveira Jr. AM, Silva APA. O uso de medicamentos em puérpuras interfere nas recomendações quanto ao aleitamento materno? J Pediatria 2002; 77(1): 57-61., which may be a reason for not breastfeeding. The World Health Organization (WHO) recommends breastfeeding for at least 2 years of age and exclusively until the sixth month²2. World Health Organization. Report of the expert consultation on the optimal duration of exclusive breastfeeding [Internet]. Genebra: World Health Organization; 2001 [acessado em 6 mar. 2019]. Disponível em: Disponível em: https://www.who.int/nutrition/publications/infantfeeding/WHO_NHD_01.09/en/
https://www.who.int/nutrition/publicatio... , as breastfeeding is related to several nutritional, immunological, cognitive, psycho-affective, economic and social advantages³3. Chaves RG, Lamounier JA, César CC. Medicamentos e amamentação: atualização e revisão aplicadas à clínica materno-infantil. Rev Paul Pediatr 2007; 25(3): 276-88. http://dx.doi.org/10.1590/S0103-05822007000300014
https://doi.org/http://dx.doi.org/10.159... , but breastfeeding time in Brazil and in several other countries does not meet this recommendation⁴4. Passanha A, Benício MHDA, Venâncio SI, Reis MCG. Influence of the support offered to breastfeeding by maternity hospitals. Rev Saúde Pública 2015; 49: 85.. According to Victora et al.⁵5. Victora CG, Bahl R, Barros AJ, França GV, Horton S, Krasevec J, et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 2016; 387(10017): 475-90. https://doi.org/10.1016/S0140-6736(15)01024-7
https://doi.org/https://doi.org/10.1016/... , if breastfeeding was extended to an almost universal level, it could prevent 823,000 deaths of children under 5 years each year and 20,000 deaths from breast cancer, with the additional benefit of saving 300 billion dollars.

Care should be taken when making a decision about whether a medication taken during breastfeeding is safe, where the risk to the baby and the benefit to the mother need to be assessed⁵5. Victora CG, Bahl R, Barros AJ, França GV, Horton S, Krasevec J, et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet 2016; 387(10017): 475-90. https://doi.org/10.1016/S0140-6736(15)01024-7
https://doi.org/https://doi.org/10.1016/... . The oral bioavailability of drugs in the gastrointestinal tract of infants also needs to be considered, since many drugs are not absorbed by their gastrointestinal system. Greater amounts of medications can be transferred to mother’s milk in the colostral phase, but only minimal quantities are transferred to the infant, due to the limited volume of colostrum. On the other hand, with mature milk, there is a larger volume, but less drugs are transferred to breast milk because of the tight junctions between cells⁷7. Rowe H, Baker T, Hale TW. Maternal medication, drug use, and breastfeeding. Pediatr Clin North Am 2013; 60(1): 275-94. https://doi.org/10.1016/j.pcl.2012.10.009
https://doi.org/https://doi.org/10.1016/... . Characteristics related to the drug, such as molecular weight, liposolubility, binding to plasma proteins and half-life, are also very important to determine the amount that reaches maternal milk³3. Chaves RG, Lamounier JA, César CC. Medicamentos e amamentação: atualização e revisão aplicadas à clínica materno-infantil. Rev Paul Pediatr 2007; 25(3): 276-88. http://dx.doi.org/10.1590/S0103-05822007000300014
https://doi.org/http://dx.doi.org/10.159... .

It is known that the use of medications by mothers can influence the success of breastfeeding. Studies suggest that more than 50% of women in the postpartum period need to use at least one medication ⁸8. Saha MR, Ryan K, Amir LH. Postpartum women’s use of medicines and breastfeeding practices: a systematic review. Int Breastfeed J 2015; 10: 28. https://doi.org/10.1186/s13006-015-0053-6
https://doi.org/https://doi.org/10.1186/... . Taking into account the fact that these women may interrupt breastfeeding or not adhere to treatment for fear of exposing the baby to the drug through breast milk⁹9. Ito S, Lee A. Drug excretion into breast milk - overview. Adv Drug Deliv Rev 2003; 55(5): 617-27. https://doi.org/10.1016/s0169-409x(03)00034-6
https://doi.org/https://doi.org/10.1016/... , it is believed very important to understand the risks of medications for the mother and the baby, and knowing the existing risk classifications as well.

The main risk classifications of drugs in breastfeeding, and also the most cited, are those established by the Ministry of Health of Brazil (MS)¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010., American Academy of Pediatrics (AAP)¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... , WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. and Newton and Hale¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... . They include information on drugs and breastfeeding, guiding health professionals on the use of medicines in this phase of a woman’s life¹⁴14. Costa JM RL, Rocha LM, Santos CM, Abelha LL, Almeida KCA. Análise das prescrições medicamentosas em uma maternidade de Belo Horizonte e classificação de riscos na gestação e amamentação. Rev Bras Farm Hosp Serv Saúde 2012; 3(1): 32-6.; however, these publications must be constantly updated to afford health care professionals with greater assurance in providing care for breastfeeding mothers, as new medications appear every day on the market and since information is controversial in some situations.

The objective of the present study was to classify the risks of medications used during hospitalization for delivery by breastfeeding women participating in the 2015 Pelotas Birth Cohort. Different sources of information were used, and disagreements between the sources were determined; the possible interferences with breastfeeding or baby health were described.

METHODS

We conducted a cross-sectional study from June to October 2015, which was included in the perinatal follow-up of the 2015 Pelotas Birth Cohort. More details on the 2015 cohort can be found in the methodological article¹⁵15. Hallal PC, Bertoldi AD, Domingues MR, Silveira MFD, Demarco FF, da Silva ICM, et al. Cohort Profile: The 2015 Pelotas (Brazil) Birth Cohort Study. Int J Epidemiol 2018; 47(4): 1048-1048h. https://doi.org/10.1093/ije/dyx219
https://doi.org/https://doi.org/10.1093/... .

Daily, trained interviewers collected data through the mothers’ medical records, after hospital discharge, regarding prescription and use of medications during the entire hospitalization period for delivery. The following information was also collected: hospitalization; type of anesthesia (spinal anesthesia; epidural; topical; general; none); and type of delivery (vaginal or cesarean).

The mothers’ sociodemographic data were obtained in an interview shortly after delivery, still in the hospital, by trained interviewers. The variables analyzed were: age (categorized as: 13-19, 20-30 and 31-45 years old), economic classification, according to the Brazilian Market Research Association of Research¹⁶16. Associação Brasileira de Empresas de Pesquisas. Critério 2015 [Internet]. Brasil: Associação Brasileira de Empresas de Pesquisas; [acessado 6 mar. 2019]. Disponível em: Disponível em: http://www.abep.org/
http://www.abep.org/... (A, B, C and D/E), self-reported skin color (white, black and brown) and education (categorized as: 0-4, 5-8, 9-11 and 12 or more years of study).

Medications used by mothers were classified according to the risk in breastfeeding by the MS manual¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010., WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p., Newton and Hale’s classification¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... and AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... . These classifications place drugs in risk categories for use while breastfeeding, due to unwanted effects on the infant or milk production.

Newton and Hale’s classification has the following categories:

The MS manual uses the colors green, red and yellow for the classification of drugs, which indicate, respectively, compatible use with breastfeeding, contraindicated use and do not have reliable information about its use during breastfeeding (judicious use)¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. The AAP classifies medicines into the following groups:

WHO classifies drugs as compatible use, judicious use and to be avoided during breastfeeding ¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002..

Taking into account that each source uses different criteria to classify drugs, we considered them to be concordant so that the classifications could be compared:

The information was entered into a tablet and transferred to the computer, and the data were analyzed in the Stata statistical package version 12.0 (StataCorp., College Station, TX, USA). Descriptive analysis was performed. First, the prevalence of drugs in each risk class (compatible, judicious use, contraindicated) was detailed, and the absolute and relative frequencies of each medication used were then calculated. For continuous variables, we used the mean and standard deviation (SD) or median and interquartile range (IQR) when the distribution was not normal. For categorical variables, we determined the proportion of each category of the variable. The proportion of drugs with concordant classification in each risk category and the total proportion with their 95% confidence intervals were also calculated for the concordant and discordant medications.

The study was approved by the Research Ethics Committee of the School of Medicine, Federal University of Pelotas, under Certificate of Presentation for CAAE the No. 26746414.5.0000.5313.

RESULTS

The study included 1,409 women, with an average age of 27 ± 7 (13 to 45) years. Of these, 70.3% were white, 15.4% black and 14.3% brown. The majority (48.7%) belonged to economic class C, and 33.9% had 9 to 11 years of schooling.

Cesarean was the most frequent delivery form, as was spinal anesthesia, both at a rate of 67%. A detailed description of the sociodemographic and hospitalization characteristics of the sub-sample studied can be found in a previous study¹⁸18. Silveira MPT, Miranda VIA, Silveira MF, Pizzol TSD, Mengue SS, Bertoldi AD. Drug use in delivery hospitalization: Pelotas births cohort, 2015. Rev Saúde Pública 2019; 53. http://dx.doi.org/10.11606/s1518-8787.2019053000913
https://doi.org/http://dx.doi.org/10.116... . After analysis (not shown in the results, since it was only done for comparative purposes), it was shown that the mothers participating in this sub-study were similar to the others in the cohort with regard to sociodemographic characteristics.

The median number of medications used by mothers was 6 (IQR_25-75 3 - 9), with 14,673 being the total number of drugs. The number of different drugs used was 143. Table 1 shows the percentages of drugs used there were considered compatible, judicious use or contraindicated in each of the classifications used. The number of possible medications to be classified was different between the sources, since the sources did not contain all the drugs used. Through the MS manual it was possible to classify 112 (78.3%) medications, while 38 (26.6%) according to the Newton and Hale classification, 49 (34.3%) by AAP, and 65 (45.5%) by WHO. Among the drugs used, 71 (49.7%; 95%CI 41.2 - 58.1) were considered compatible regardless of the classification source. Only two (1.4%) were seen as contraindicated according to MS and Newton and Hale. The WHO classification included the most studied drugs in the category to be avoided during breastfeeding, which we identified as contraindicated (n = 9, 6.3%).

As seen by the agreement between at least two classifications, of the total number of drugs used (n = 143), 49.7% (71; 95%CI 41.2 - 58.1), were classified as compatible and could be taken during breastfeeding. On the other hand, 11.9% (17; 95%CI 7.1 - 18.4) were classified as judicious use, and 1.4% (2; 95%CI 0.7 - 5.0) contraindicated. Disagreements were found for 28 (19.6%; 95%CI 13.4 - 27.0) medications, and for 25 (17.5%; 95%CI 11.6 - 24.7), there was no information.

Chart 1 lists the medications most used during hospitalization for delivery (at a rate more than 10%) that did not show disagreements between the study classifications. Included are oxytocin (n = 1,372, 97.4%), which is compatible with breastfeeding when used for a short time. Its prolonged use should be avoided, as it can cause maternal dependence¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.. Next in order are lidocaine (n = 1,058; 75%), paracetamol (n = 767; 54.4%), dipyrone (n = 730; 51.8%), ondansetron (n = 512; 36.3%), bupivacaine (n = 374; 26.5%) and fentanyl (n = 156; 11.1%).

On the other hand, the most widely used drugs that showed disagreements between the classifications were: morphine (n = 905), which was classified by MS as for judicious use, by Newton and Hale as possibly compatible (L3) and by AAP and WHO as compatible; hyoscine (n = 324), classified by MS as judicious use and by AAP as compatible; and metoclopramide (n = 256), considered by MS as compatible and AAP as of unknown effects and which the WHO recommends being avoided during breastfeeding. Metronidazole and haloperidol are considered compatible with breastfeeding according to MS, and WHO recommends avoiding them, but they were respectively used by 1.6 and 0.1% of the mothers in this study. Ciprofloxacin was classified as compatible by AAP, as possibly compatible by Newton and Hale, as for judicious use by MS and as should be avoided by WHO with regard to breastfeeding (Chart 2).

DISCUSSION

The aim of this study was to classify the medications used during hospitalization for delivery regarding the risks of breastfeeding, by using four sources and determining the agreement between them. Of the total number of medications used, almost half were considered compatible with breastfeeding, while 6% were contraindicated. For one-fifth of the drugs, we found disagreements between the classifications.

One limitation of this study we can point out is the difficulty of reconciling, in the same risk category, drugs classified by different sources, as they resort to different nomenclatures to establish the risks, which led us to carry out a reclassification, to try to find concordances and divergences referring to the risk of the medication during breastfeeding. This lack of standardization and the disagreement between the classifications can result in uncertainty among health care professionals, often causing doubt about whether a medication is compatible or not with breastfeeding, which can lead to the discontinuation of breastfeeding or the medication that could be necessary.

The main factors that can explain these disagreements are:

In a study by Long and Montouris¹⁹19. Long L, Montouris G. Knowledge of women’s issues and epilepsy (KOWIE-II): a survey of health care professionals. Epilepsy Behav 2005; 6(1): 90-3. https://doi.org/10.1016/j.yebeh.2004.11.006
https://doi.org/https://doi.org/10.1016/... based on the responses to questionnaires given to 202 professionals who participated in the annual meeting of the American College of Physicians in 2003, of which 92% were physicians, it was reported that more than 50% did not know that most anticonvulsants are safe when taken during breastfeeding. Therefore, constant update on medication safety is essential to avoid interruption of breastfeeding. Doctors should choose to prescribe medications already studied for their safety in breastfeeding¹1. Lamounier JA, Cabral CM, Oliveira BC, Oliveira AB, Oliveira Jr. AM, Silva APA. O uso de medicamentos em puérpuras interfere nas recomendações quanto ao aleitamento materno? J Pediatria 2002; 77(1): 57-61..

With regard to the choice of sources used, the use of the WHO classification was due to the fact that it is known worldwide and that of the Ministry of Health because the study was carried out in this country. The other two were the most cited in scientific articles; we found AAP to be the most cited. The Food and Drug Administration (FDA) classification was not mentioned here, since a new FDA classification came into effect in June 2015, Pregnancy and Lactation Labeling Rule, for use of drugs during pregnancy and lactation. Therefore, considering that it was being incorporated recently and that it did not allow us to compare it with the other classifications that were already being analyzed in the study, we chose not to use it, since it does not place drugs in risk categories, but rather exposes the risks to the infant or to milk production.

Of the four classifications studied, the one with the highest number of medications was that of MS (n = 112), followed by the WHO classification (n = 65). The Newton and Hale and AAP classifications showed fewer drugs (38 and 49, respectively). Looking at the recommendation for use during breastfeeding, the WHO classification had the highest number of contraindicated drugs, appearing to be the most rigorous classification.

Regarding the nomenclature used by the classifications mentioned, all with the exception of Newton and Hale, are very clear and objective. In the case of Newton and Hale, it was difficult to see the difference between L2 (probably compatible) and L3 (possibly compatible). Therefore, to be able to compare the classifications and considering greater safety for the infant, we chose to group L2 and L1 (compatible). L3 was considered as judicious use like in the other classifications, and L4 (possibly dangerous), grouped with L5 (contraindicated).

In the discussion of the results, emphasis was placed on medications that showed disagreements in the study classifications and/or whose effects were considered important. The drugs whose disagreements were greater and that had a higher prevalence of use were morphine, hyoscine, metoclopramide, promethazine, povidone-iodine, atropine and ephedrine.

The narcotic pain reliever morphine (n = 905) is excreted in low concentrations in breast milk²⁰20. Bar-Oz B, Bulkowstein M, Benyamini L, Greenberg R, Soriano I, Zimmerman D, et al. Use of antibiotic and analgesic drugs during lactation. Drug Saf 2003; 26(13): 925-35. https://doi.org/10.2165/00002018-200326130-00002
https://doi.org/https://doi.org/10.2165/... ^,2121. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001.. WHO and AAP consider its use compatible with breastfeeding ¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... ^,1212. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p.^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.. MS⁸8. Saha MR, Ryan K, Amir LH. Postpartum women’s use of medicines and breastfeeding practices: a systematic review. Int Breastfeed J 2015; 10: 28. https://doi.org/10.1186/s13006-015-0053-6
https://doi.org/https://doi.org/10.1186/... and Newton and Hale¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... consider it to be for judicious use. Although AAP classifies this drug as safe, it recommends that its serum level be measured in babies ¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... , a procedure that is difficult in clinical practice²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001.. Morphine can cause significant effects on suckling, apnea, bradycardia and cyanosis¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... ^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002. and sedation in infants¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. Prolonged treatment, at high doses, can increase its plasma concentration, leading to greater levels in breast milk, so the risk-benefit of breastfeeding should be evaluated¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... ^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.^,2222. Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994; 38(2): 94-103. https://doi.org/10.1111/j.1399-6576.1994.tb03848.x
https://doi.org/https://doi.org/10.1111/... . MS recommends that breastfeeding should be stopped when there is maternal dependence on opioids¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010..

Hyoscine (n = 324) is classified as judicious use by MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. and compatible with breastfeeding by AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... . Although babies are sensitive to anticholinergic effects²²22. Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994; 38(2): 94-103. https://doi.org/10.1111/j.1399-6576.1994.tb03848.x
https://doi.org/https://doi.org/10.1111/... , AAP considers hyoscine safe, perhaps due to the fact that it is excreted in breast milk in insignificant amounts, with no side effects reported in infants¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.^,2121. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001..

Metoclopramide (n = 256) is classified as compatible with breastfeeding according to MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. and contraindicated by WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p., while AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... classifies it as judicious use. It is excreted in breast milk, accumulating after repeated doses. This drug stimulates the release of prolactin in women with reduced or inadequate milk production¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.^,2323. Hagemann TM. Gastrointestinal medications and breastfeeding. J Hum Lact 1998; 14(3): 259-62. https://doi.org/10.1177/089033449801400321
https://doi.org/https://doi.org/10.1177/... . MS considers the drug compatible when used for a short period. When used for more than four weeks, agitation, sedation and extrapyramidal manifestations have been described in the nursing mother¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010., and infants may experience problems in neural development¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002. and symptoms of gastrointestinal discomfort²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001.. Metoclopramide apparently does not pose a risk for the infant with the use of maternal doses of up to 45 mg per day²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001..

Promethazine (n = 189) is considered by WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. and MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. to be compatible with breastfeeding when taken in a single dose, but Newton and Hale¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... consider it as judicious use. When repetitive doses are used, some adverse effects should be monitored, such as drowsiness¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002., dry mouth, extrapyramidal symptoms and risk of apnea¹³13. Newton ER, Hale TW. Drugs in Breast Milk. Clinical Obstetrics and Gynecology 2015; 58(4): 868-84. https://doi.org/10.1097/GRF.0000000000000142
https://doi.org/https://doi.org/10.1097/... in infants. In lactating women, milk flow may be reduced¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010..

As for povidone-iodine (n = 153), repetitive topical applications of the solution should be avoided, as it can be absorbed and concentrate in breast milk, reaching a toxic level in the infant. Therefore, its chronic use is not recommended and it is recommended to monitor the baby’s thyroid function¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... considers the substance to be compatible with breastfeeding and MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. for judicious use, while WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. contraindicates its use. It is advisable to monitor infants for hypothyroidism¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002., as it was observed that breastfed newborns of mothers who used this medication had a 25 to 30-fold increase in the rate of congenital hypothyroidism compared to bottle-fed babies²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001.. MS reports that there may be an increase in iodine level in breast milk and, consequently, changes in the neonatal concentration of thyroid stimulating hormone¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.^,2121. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001.. This increase in iodine in breast milk causes a strong odor from the baby’s skin¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... ^,2121. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001..

Atropine (n = 129) is classified as compatible by WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. and AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... and as judicious use by MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. It is excreted in breast milk in small amounts, with peak plasma concentration occurring at one hour¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. When used at high doses, it can cause decreased lactation. Although neonates are susceptible to anticholinergic effects, AAP and WHO consider this drug to be safe²²22. Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994; 38(2): 94-103. https://doi.org/10.1111/j.1399-6576.1994.tb03848.x
https://doi.org/https://doi.org/10.1111/... .

Ephedrine (n = 103) is classified as compatible during lactation by WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. and AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... and as judicious use according to MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. It is recommended that irritability and disturbed sleep in infants be monitored¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.; these effects resolve spontaneously 12 hours after discontinuation of breastfeeding²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001.. In mothers, the decrease in milk production must be monitored¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010..

Methylergometrine (n = 89) is classified as compatible with breastfeeding according to WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. and as judicious use by MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. It is excreted in breast milk, which can cause ergotism²⁴24. Wells RE, Turner DP, Lee M, Bishop L, Strauss L. Managing Migraine During Pregnancy and Lactation. Curr Neurol Neurosci Rep 2016; 16(4): 40. https://doi.org/10.1007/s11910-016-0634-9
https://doi.org/https://doi.org/10.1007/... , vomiting, diarrhea and seizures in the baby²⁵25. Rozas A. Medicamentos na gravidez e lactação. Rev Fac Ciênc Méd Sorocaba 2004; 6(1): 38-43., and lactation and prolactin inhibition in the mother¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.^,2424. Wells RE, Turner DP, Lee M, Bishop L, Strauss L. Managing Migraine During Pregnancy and Lactation. Curr Neurol Neurosci Rep 2016; 16(4): 40. https://doi.org/10.1007/s11910-016-0634-9
https://doi.org/https://doi.org/10.1007/... . During the use of this drug, the infant’s growth must be closely monitored³3. Chaves RG, Lamounier JA, César CC. Medicamentos e amamentação: atualização e revisão aplicadas à clínica materno-infantil. Rev Paul Pediatr 2007; 25(3): 276-88. http://dx.doi.org/10.1590/S0103-05822007000300014
https://doi.org/http://dx.doi.org/10.159... .

Benzodiazepine such as diazepam (n = 35) and their metabolites are excreted in breast milk²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001., but WHO classifies them as compatible with breastfeeding if taken in a single dose. In repeated doses, however, they should be avoided when possible¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p.. MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. and AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... consider the drug as judicious use. If a benzodiazepine is necessary, short-term ones should be preferred¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.^,1717. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.. This medication, when used by lactating women, has adverse effects on babies, such as slowness, sedation¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002., low suction¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010., weight loss, apnea, irritability, minimal risk of central nervous system depression²⁶26. Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr 2012; 161(3): 448-51. https://doi.org/10.1016/j.jpeds.2012.03.003
https://doi.org/https://doi.org/10.1016/... and electrocardiogram consistent with the use of sedative drug¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010.. These effects may be present if breastfeeding occurs less than eight hours after the use of the drug, as the peak concentration in maternal plasma occurs between one and two hours after administration¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. and when the infant is premature or is underweight¹⁷17. World Health Organization. Breastfeeding counselling. A training courses. Participants’ manual. Genebra: World Health Organization ; 2002.^,2121. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001..

The active metabolite (oxazepam) has been found in the newborn’s urine, but not in the mother’s plasma or milk, even though showing a long half-life ub the baby. It is known that doses greater than 30 mg per day of diazepam should be avoided during lactation, while doses of 10 mg or less do not produce significant adverse effects in infants. However, more recently, significant effects have been noted with doses between 6 and 10 mg²²22. Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994; 38(2): 94-103. https://doi.org/10.1111/j.1399-6576.1994.tb03848.x
https://doi.org/https://doi.org/10.1111/... .

In regard to metronidazole (n = 23), WHO¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p. contraindicates its use, and AAP¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... considers it as judicious use, while MS¹⁰10. Brasil. Ministério da Saúde. Amamentação e uso de medicamentos e outras substâncias. Brasília: Secretaria de Atenção à Saúde / Departamento de Ações Programáticas e Estratégicas; 2010. views it compatible with breastfeeding. There is little systemic absorption with topical use, when used in low doses, and in short-term therapy it does not interfere with breastfeeding²⁰20. Bar-Oz B, Bulkowstein M, Benyamini L, Greenberg R, Soriano I, Zimmerman D, et al. Use of antibiotic and analgesic drugs during lactation. Drug Saf 2003; 26(13): 925-35. https://doi.org/10.2165/00002018-200326130-00002
https://doi.org/https://doi.org/10.2165/... . However, if the exposure is prolonged, it presents a potential risk of toxicity²⁷27. Huang V, Leung Y, Nguyen GC, Seow CH. Management of Inflammatory Bowel Disease in Pregnancy: A Practical Approach to New Guidelines. Can J Gastroenterol Hepatol 2016; 2016: 9513742. https://dx.doi.org/10.1155%2F2016%2F9513742
https://doi.org/https://dx.doi.org/10.11... . This drug is excreted in breast milk and can cause some adverse effects in infants, such as diarrhea, lactose intolerance²¹21. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: a reference guide to fetal and neonatal risk. 9ª ed. Filadélfia: Wolters Kluwer; 2001. and changes in the baby’s intestinal flora⁶6. Ponti M, Stewart K, Amir LH, Hussainy SY. Medicine use and safety while breastfeeding: investigating the perspectives of community pharmacists in Australia. Aust J Prim Health 2015; 21(1): 46-57. https://doi.org/10.1071/PY13012
https://doi.org/https://doi.org/10.1071/... , in addition to the fact that it imparts an unpleasant taste in the milk. Therefore, it is recommended to discontinue breastfeeding for 12-24 hours after use by the mother¹¹11. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108(3): 776-89. https://doi.org/10.1542/peds.108.3.776
https://doi.org/https://doi.org/10.1542/... ^,2020. Bar-Oz B, Bulkowstein M, Benyamini L, Greenberg R, Soriano I, Zimmerman D, et al. Use of antibiotic and analgesic drugs during lactation. Drug Saf 2003; 26(13): 925-35. https://doi.org/10.2165/00002018-200326130-00002
https://doi.org/https://doi.org/10.2165/... ^,2727. Huang V, Leung Y, Nguyen GC, Seow CH. Management of Inflammatory Bowel Disease in Pregnancy: A Practical Approach to New Guidelines. Can J Gastroenterol Hepatol 2016; 2016: 9513742. https://dx.doi.org/10.1155%2F2016%2F9513742
https://doi.org/https://dx.doi.org/10.11... . An alternative to not discontinuing breastfeeding in this case is to collect the breast milk and store it in the refrigerator, in order to breastfeed the baby during this period¹²12. World Health Organization; UNICEF. Breastfeeding and maternal medication. Recommendations for drugs in the eleventh WHO model list of essential drugs. Genebra: WHO; 2002. 35 p.. Australian studies show that a third of doctors and pharmacists are unaware that metronidazole is compatible with breastfeeding when used as recommended⁶6. Ponti M, Stewart K, Amir LH, Hussainy SY. Medicine use and safety while breastfeeding: investigating the perspectives of community pharmacists in Australia. Aust J Prim Health 2015; 21(1): 46-57. https://doi.org/10.1071/PY13012
https://doi.org/https://doi.org/10.1071/... .

As future perspectives, it is important to carry out studies with the drugs used by puerperal women, analyzing their effects on milk production and on important outcomes in the baby in the short and long term, to confirm the compatibility of these substances with this period in a woman’s life.

FINAL CONSIDERATIONS

It is important that the mother and health care providers know the risks of the medications taken during breastfeeding, so that it is not interrupted if the use of medications is truly necessary, or that the patient does not stop using any needed medication because of concern that it may cause some risk to the child, or that if the medication is not safe, breastfeeding must be halted or another safer therapeutic option must be sought.

References

Publication Dates

History