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ev Bras Anestesiol. 2019;69(2):184---196

REVISTABRASILEIRA DEANESTESIOLOGIA Publicação Oficial da Sociedade Brasileira de Anestesiologia

www.sba.com.br

EVIEW ARTICLE

hould maternal anesthesia delay breastfeeding? systematic review of the literature

orenna Ramos e Oliveiraa, Murillo Goncalves Santos a,∗, Débora Alves Audea,odrigo Moreira e Limaa, Norma Sueli Pinheiro Módolob, Lais Helena Navarrob

Universidade Estadual Paulista (UNESP), Faculdade de Medicina de Botucatu, Botucatu, SP, BrazilUniversidade Estadual Paulista (UNESP), Faculdade de Medicina de Botucatu, Departamento de Anestesiologia,otucatu, SP, Brazil

eceived 4 July 2018; accepted 6 November 2018vailable online 26 December 2018

KEYWORDSAnesthetic drugs;Anesthetic effect;Exclusive breastfeeding

AbstractIntroduction: The importance and benefits of breastfeeding for the babies and mothers are wellestablished and documented in the literature. However, it is frequent that lactating mothersneed to undergo general or spinal anesthesia and, due to the lack of information, many of theminterrupt breastfeeding after anesthesia. There are limited data available regarding anestheticstransfer to breast milk. This review aims to develop some considerations and recommendationsbased on available literature.Methods: A systematic search of the literature was conducted by using the following healthscience databases: Embase, Lilacs, Pubmed, Scopus, and Web of Science. The latest litera-ture search was performed on April 6th, 2018. Additional literature search was made via theWorld Health Organization’s website. We used the following terms for the search strategy:‘‘Anesthesia’’ and ‘‘Breastfeeding’’, and their derivatives.Results: In this research, 599 registers were found, and 549 had been excluded by differentreasons. Fifty manuscripts have been included, with different designs of studies: prospectivetrials, retrospective observational studies, reviews, case reports, randomized clinical trials,case---control, and website access. Small concentrations of the most anesthetic agents, aretransferred to the breast milk; however, their administration seem to be safe for lactatingmothers when administered as a single dose during anesthesia and this should not contraindicatethe breastfeeding. On the other hand, high-doses, continuous or repeated administration of

dverse effects on neonates, and should be avoided. Few drugs, suche, produce adverse effects on breastfed babies even in single doses.o be safe if breastfeeding starts 24 h after discontinuation of the

drugs increase the risk of aas diazepam and meperidinDexmedetomidine seems tdrug.

∗ Corresponding author.E-mail: murillogsantos@gmail.com (M.G. Santos).

ttps://doi.org/10.1016/j.bjane.2018.12.006104-0014/© 2018 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Anestesiologia. This is an open access articlender the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Should maternal anesthesia delay breastfeeding? 185

Conclusions: Most of the anesthetic drugs are safe for nursing mothers and offer low risk tothe breastfed neonates when administered in single-dose. However, high-dose and repeatedadministration of drugs significantly increase the risk of adverse effects on neonates. More-over, diazepam and meperidine should be avoided in nursing women. Finally, anesthesiologistsand pediatricians should consider individual risk/benefit, with special attention to prematureneonates or babies with concurrent diseases since they are more susceptible to adverse effects.© 2018 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Anestesiologia.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVEAnestésicos;Efeito anestésico;Aleitamento maternoexclusivo

A anestesia materna deve atrasar a amamentacão? Revisão sistemática da literatura

ResumoIntroducão: A importância e os benefícios do aleitamento materno para os bebês e para asmães estão bem estabelecidos e documentados na literatura. No entanto, é frequente quemães lactantes precisem se submeter à anestesia geral ou raquianestesia e, devido à falta deinformacões, muitas delas interrompem a amamentacão após a anestesia. Existem poucos dadosdisponíveis sobre a transferência de anestésicos para o leite materno. O objetivo desta revisãofoi desenvolver algumas consideracões e recomendacões com base na literatura disponível.Métodos: Uma busca sistemática da literatura foi realizada usando os seguintes bancos de dadosem ciências da saúde: Embase, Lilacs, Pubmed, Scopus e Web of Science. A pesquisa bibliográficamais recente foi realizada em 6 de abril de 2018. Uma pesquisa bibliográfica adicional foirealizada através do site da Organizacão Mundial da Saúde. Usamos os seguintes termos para aestratégia de busca: ‘‘Anestesia’’ e ‘‘Aleitamento materno’’, e seus derivados.Resultados: Nesta pesquisa, 599 registros foram encontrados e 549 foram excluídos pordiferentes razões. Foram incluídos 50 manuscritos, com diferentes modelos de estudos:estudos prospectivos, estudos observacionais retrospectivos, revisões, relatos de casos,ensaios clínicos randômicos, caso-controle e acesso a sites. Pequenas concentracões da maioriados agentes anestésicos são transferidas para o leite materno; entretanto, sua administracãoparece ser segura para mães lactantes quando administrados em dose única durante a anestesiae isso não deve contraindicar o aleitamento materno. Por outro lado, altas doses, administracãocontínua ou repetida dos fármacos aumentam o risco de efeitos adversos em neonatos e devemser evitados. Poucas drogas, como diazepam e meperidina, produzem efeitos adversos embebês amamentados, mesmo quando administradas em doses únicas. Dexmedetomidina pareceser segura se a amamentacão comecar 24 horas após a interrupcão do medicamento.Conclusões: A maioria dos anestésicos é segura para mães que amamentam e oferecem baixorisco para os recém-nascidos amamentados quando a administracão é em dose única. Noentanto, altas doses e repetidas administracões de drogas aumentam significativamente o riscode efeitos adversos em recém-nascidos. Além disso, diazepam e meperidina devem ser evitadosem mulheres que amamentam. Finalmente, anestesiologistas e pediatras devem considerar orisco-benefício individual, com atencão especial para os recém-nascidos prematuros ou bebêscom doencas concomitantes, pois são mais suscetíveis a efeitos adversos.© 2018 Publicado por Elsevier Editora Ltda. em nome de Sociedade Brasileira de Anestesiologia.Este e um artigo Open Access sob uma licenca CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Background

The importance and benefits of breastfeeding are wellestablished and documented in the literature. Human milkprotects the infant against a variety of illnesses andinfectious complications, reduces children mortality, and

1

improves neurological development. It also benefits themother, by reducing risks of breast and ovarian cancer,Type II diabetes, and postpartum depression.1 That is whythe World Health Organization (WHO) and the American

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cademy of Pediatrics (AAP) so strongly support breastfeed-ng, especially in the first six months of life.1,2

It is frequent that lactating mothers need to undergo gen-ral or spinal anesthesia and, due to the lack of information,any of them interrupt breastfeeding because of the theo-

etical exposition of the breastfed baby to the administerednesthetic drugs.3 Most of the times, drug transfer to milk is

egligible and the risks to the newborn are minimal. Hence,he interruption of breastfeeding can be more harmful tohe child than the ingestion of small amounts of anesthetics.

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oreover, the use of labor pain relief medications is a con-roversial issue that has been raising concerns about safety,nterference with labor, and birthing.4 As an example, manyuthors believe that use of labor analgesia causes neonateso exhibit disorganized, ineffective suckling at the breast,nd mothers to proceed to early unintended weaning due toreastfeeding difficulties.5

There are limited data available; accordingly, researchegarding anesthetics transfer to breast milk in humans isare because of ethical implications of studies with mothersnd babies. This review aims to develop some considerationsased on available literature. Also, we aim to encourageurther research to expand current knowledge (Table 1).

ethods

systematic search of the available literature was con-ucted by using the following health science databases:mbase, Lilacs, Pubmed, Scopus, and Web of Science. Theearch terms used were (Anesthesia or Anesthetics or Anes-hetic Drugs or Drugs, Anesthetic or Anesthetic Agents orgents, Anesthetic or Anesthetic Effect or Effect, Anestheticr Anesthetic Effects or Effects, Anesthetic) and (Breasteeding or Feeding, Breast or Breastfeeding or Breast Feed-ng, Exclusive or Exclusive Breast Feeding or Breastfeeding,xclusive or Exclusive Breastfeeding). There was no restric-ion regarding language or date of the article publication.he latest literature search was performed on April 6th,018. Moreover, an additional literature search was madeia the WHO website: http://www.who.int on April 15th,018.

Two authors (MRO and MGS) independently screened therials identified by the literature search. The authors exam-ned each title and abstract to exclude clearly irrelevanttudies and duplicates, and identified potentially relevantrticles to be retrieved as a full-text article. The disagree-ents were resolved by consulting with another author

LHNL), who was also responsible for the quality assurancef the processes. The remaining authors (RML, NSPM, andAA) independently determined the eligibility of full-textrticles retrieved. The names of the author, institution,ournal of publication, and results were unknown to thehree investigators at this time. For the data extraction andanagement, two authors (MRO and MGS) independently

valuated the full-text articles. Any discrepancies wereesolved by discussion with a third author (LHNL) (Table 2).

esults

rom the search of the referred health science databases,99 registers were found. After the analysis of manuscripts’itles, 549 registers were excluded because of the duplic-ty of titles (46 registers) and offtopic manuscripts (503egisters). Fifty articles were eligible. Fig. 1 depicted theummary of the literature search, based on PRISMA 2009 flowiagram.6

The 50 studies included in this systematic review

onsisted of 16 reviews, 13 prospective trials, 4 retrospec-ive observational studies, 6 case reports, 9 randomizedlinical trials, 1 case---control study, and 1 website accessTable 3).

MfTs

M.R. Oliveira et al.

The magnitude of the risk of neonatal exposure torugs in maternal plasma can be expressed by variousndices, such as the milk-to-maternal plasma ratio (M/Patio) and the infant-exposure index.7 The M/P ratio isbtained by dividing the drug concentration in breast milko its concentration in maternal plasma. This ratio mayary according to the time after drug administration inhich milk sample is collected.3,8 If the M/P ratio is <1

less drug in milk than in plasma), it is considered usuallyafe to proceed with breastfeeding.9 The infant-exposurendex is the ratio of the weight-adjusted dose of the infanto the weight-adjusted dose of the mother, and indicateshe cumulative drug exposure.3 This index is calculated byhe assumption of infants’ milk ingestion of approximately50 mL.kg−1.day−1.3,8 It has been suggested that indices10% are unlikely to be of pharmacologic significance.3,9

ffect of the individual class of drugs

enzodiazepinesiazepam should be avoided even in single doses in breast-eeding mothers due to its adverse effects in the neonate.idazolam, on the other hand, seems to be safe when admin-

stered as a single dose.

ypnoticshe main induction agents (propofol, thiopental, and eto-idate) seem to be safe for lactating mothers when

dministered as a single dose at the induction of anesthesia.

nhalational anestheticse have found little or no data regarding the exposure ofursing mothers to inhalation anesthetics. Halothane andenon gas seem to be safe because their concentration inilk were considered negligible. As for isoflurane, enflu-

ane, sevoflurane, and desflurane, the theoretical risk forhe suckling infant is considered low because of their phar-acokinetic profile. Also, regarding nitrous oxide, we have

ot found clinical trials of its intrapartum use with breast-eeding as the primary outcome. But there is some evidencehat it has the potential to cause positive effects on bothomen’s psychoemotional experience of labor and breast-

eeding success.10

lfa2-agonistsexmedetomidine seems to be safe if the breastfeedingtarts 24 h after the discontinuation of the drug (Table 4).

eversing agentseostigmine is safe for lactating mothers when used in highoses for myasthenia gravis treatment. Hence, we can inferhat the small doses of this drug used in anesthesia offer noisk for the breastfed infants.

pioids

eperidine should be avoided even in single doses in breast-

eeding mothers due to its adverse effects in the neonate.he other opioids seem to be safe when administered as aingle dose.

Should m

aternal anesthesia

delay breastfeeding?

187

Table 1 Summary of results from studies regarding Benzodiazepines.

Identification of the study Type of study n Inclusion criteria Anesthetics drugevaluated

Dose of drug Evaluated outcomes Recommendation ofthe study

Patrick MJ et al., 1972 Case report 1 1 week-old baby whosemother was takingDiazepam.

Diazepam 30 mg.day−1 per3 days

Neonate withlethargy, weight lossand EEG consistentwith sedativemedication.

Best to avoid.

Cole et al., 1975 Retrospectiveobservationalstudy

9 Breastfeeding mothersreceiving Diazepam forpost-partumtranquilization due topersistenthypertension.

Diazepam Not mentioned High amounts of theactive substance inone infant 10 daysafter a single dose.

Best to avoid.

Wesson et al., 1985 Retrospectiveobservationalstudy

1 Lactating woman withanxiety andtachycardia.

Diazepam 6---10 mg.day−1 Infant sedation(especially if within8 h after dose).

Best to avoid.

Borgatta et al., 1997 Prospective trial 9 Lactating womanundergoing tubesterilization.

Diazepam 2.5---10 mg Infant-exposureindex = 3%.

Safe as a single dose.

Nitsun et al., 2006. Prospective trial 5 Lactating womenundergoing operativeprocedures withgeneral anesthesia.

Midazolam 2 mg Infant-exposureindex <1.25%.

Safe as a single dose.

Matheson et al., 1990 Randomized study 2 Lactating women whoneeded sleeping pillsafter giving birth (5day-period).

Midazolam 15 mg VO M/P ratio = 0.15. Safe as a single dose.

188

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Oliveira

et al.

Table 2 Summary of results from studies regarding hypnotic drugs.

Identification of the study Type of study n Inclusion criteria Anesthetics drugevaluated

Dose of drug Evaluated outcomes Recommendationof the study

Esener et al., 1992 Randomizedclinical trial

40 Women undergoingelective cesareansection undergeneral anesthesia.

Thiopental andetomidate

20 women received5 mg.kg−1

thiopental at theinduction.20 women received0.3 mg.kg−1

etomidate at theinduction.

Thiopental---colostrum:plasmaratios = 0.67---0.68.Etomidate---colostrum:plasma ratio = 1.2 at30 min. No etomidatedetected in the 2 hplasma samples.

Both drugs aresafe as a singledose.

Andersen et al., 1987 Prospective trial 16 8 lactating womenundergoing minorelective surgery and8 womenundergoing electivecesarean section.

Thiopental Patients received5 mg.kg−1 mean atinduction time.

M/P ratio < 1 in bothgroups.

Safe as a singledose.

Nitsun et al., 2006. Prospective trial 5 Lactating womenundergoingoperativeprocedures withgeneral anesthesia.

Propofol Patients received2.5 mg.kg−1 atinduction ofanesthesia.

Infant-exposureindex < 1.25%.

Safe as a singledose.

Dailland et al., 1989 Randomizedclinical trial

21 Women undergoingelective cesareansection undergeneral anesthesia.

Propofol Group 1:2.5 mg.kg−1 atinduction.Group 2: induction(same dose ofGroup1) + maintenance(5 mg.kg−1.h−1 ofpropofol).

Insignificant exposureof the baby throughbreast milk comparedto the placentaltransfer of the drug.

Propofol wasconsidered safe asa single dose andafter continuousinfusion.

Should maternal anesthesia delay breastfeeding?

Registers found in healthscience databases

(n = 599)

Selec ted registers(n = 599)

Excluded registers (n = 549)Duplicity = 46

Offtopic titles = 503

Eligible titles(n = 50)

Registers included in thisqualitative analysis

(n = 50)

Figure 1 Flowchart regarding the literature search.

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Dhhwdmain metabolite, desmethyl-diazepam, are metabolized bythe enzyme group cytochrome P450 II C8---10, which is genet-ically determined.8,15 Therefore, the amount of diazepam,

Local anestheticsThe main local anesthetics (lidocaine, bupivacaine, and lev-obupivacaine) seem to be safe for lactating mothers whenadministered as a single dose. As for ropivacaine, we havefound limited data regarding its transfer to breast milk. Butwe found no reports of adverse effects on breastfed infantsfollowing maternal analgesia with epidural ropivacaine.

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Table 3 Summary of results from studies regarding inhalational a

Identification ofthe study

Type of study n Inclusion criteria Anedrueva

Coté et al., 1976 Case report 1 Lactatingpracticinganesthetistexposed tohalothane in theoperating room.

Hal

Stuttmann et al.,2010

Case reports 4 Mothersundergoing urgentsurgeries withgeneralanesthesia.

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Table 4 Summary of results from one study regarding dexmedeto

Identificationof the study

Type ofstudy

n Inclusioncriteria

Anesthetics drevaluated

Nakanishiet al., 2017

Prospectivetrial

4 Patientsundergoingcesareansection withsedation.

Dexmedetomi

189

iscussion

ost of the anesthetic drugs are safe for nursing mothersnd offer low risk to the breastfed neonates (Table 5).

The drugs administered to the mother usually pass fromaternal plasma to the breast milk by passive diffusion.7

everal factors affect the excretion of medications intoilk: maternal plasma concentration, protein binding, drug

onization, lipid and water solubility, drug molecular weight,nd presence of active metabolites.7---9,11---34 The susceptibil-ty of the neonate to the drug depends on the maternal dosend duration of therapy, frequency of feeding, volume ofilk consumed, bioavailability, the half-life of the drug in

he infant, and maturity of the baby. Accordingly, prematureabies are more susceptible to the adverse effects causedy medications.7,9,14

enzodiazepines

iazepam is a lipid-soluble drug, unionized in plasma, thusas the potential to easily cross biological barriers, andas long half-life elimination, such as 20---50 h in adults,hich can be even longer in neonates.8,9,15 The M/P ratio ofiazepam ranges from 0.1 to 0.58.8 Both diazepam and its

nd its active metabolite, in serum and in breast milk will be

nesthetics.

stheticsgluated

Dose of drug Evaluatedoutcomes

Recommendationof the study

othane --- Halothaneconcentra-tion in milkafter 5 h ofexpo-sure = 2 ppm.

Theoreticallysafe.

on gas Concentration65%---69%

No traces ofgas werefound inmilk at anytime.

Safe after oneexposition.

midine.

ug Dose of drug Evaluatedoutcomes

Recommendationof the study

dine Notmentioned.

M/P ratio:0.76---0.88.Undetectablein all breastmilk samples at24 h after dis-continuation.

Safe ifreinitiated 24 hafter exposure.

190 M.R. Oliveira et al.

Table 5 Summary of results from one study regarding neostigmine.

Identificationof the study

Type ofstudy

n Inclusioncriteria

Anestheticsdrug evaluated

Dose of drug Evaluatedoutcomes

Recommendationof the study

Fraser et al.,1963

Retrospectiveobserva-tionalstudy

6 Nursingmotherswithmyastheniagravis.

Neostigmine Notmentioned.

No side-effectson theneonates,exceptabdominalcramps in one

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igher if the mother and/or the baby are poor metabolizers.lthough there is some evidence of the safety when a singleose of diazepam is administered in breastfeeding women,3

number of case reports and studies have shown significantdverse effects on breastfed infants whose mothers wereeceiving diazepam.16---18

On the other hand, midazolam has a short half-life (2---5 hn adults) and a low passage rate to breast milk.14,19 As theieces of evidence suggest, it is unlikely that breastfeed-ng after a single dose of midazolam would cause harm tohe neonate, especially if the baby is breastfed more than

h after administration. However, the effects of long-termntravenous or oral midazolam administration were not doc-mented by the studies and may be of concern (Table 6).

ypnotics

lthough the half-life of thiopental is long (8---11 h in adults),he transfer of the drug to milk was considered negligible.20

oreover, thiopental plasma concentration decreases morelowly than etomidate concentration; however, its M/Patio is <1.21 Thus, the use of typical doses of thiopen-al for anesthesia induction should not delay breastfeedingTable 7).

Different from thiopental, propofol has a short half-life4---7 h in adults), but it can circulate for a much longer timemaximum half-life 63 h), probably due to the redistribu-ion from deep compartments.8 However, as it is rapidlyleared from maternal and neonatal circulation, it seemsot to have adverse effects on infants.9,15 All the studiesnd reports analyzed agreed that propofol given as singleose is innocuous for the suckling newborn.22,23 More stud-es are needed, however, to evaluate the safety of propofolhen it is used as a continuous infusion to maintain total

ntravenous anesthesia in lactating mothers.As for etomidate, limited data are available. One

tudy used either thiopental (5 mg.kg−1) or etomidate0.3 mg.kg−1) for induction of general anesthesia duringlective cesarean section.21 The analysis of colostrum sam-les showed a mean concentration of 16.2 ng.mL−1 oftomidate 2 h after its use. The authors concluded that eto-idate is rapidly cleared from colostrum and, therefore,

ay be used in lactating mothers.21

We have not found any published human studies regardinghe breast milk transfer of ketamine. More studies areeeded to guarantee the safety of its use.

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of them.

lfa2-agonists

he use of dexmedetomidine for cesarean section isn analgesic alternative to opioids or benzodiazepines.owever, the dexmedetomidine label states that cautionhould be exercised when the drug is administered to

breastfeeding mother. Recently, a new method (liquidhromatography---tandem mass spectrometry) for determi-ation of dexmedetomidine concentration in human breastilk was developed and tested in four patients that

nderwent sedation with dexmedetomidine for cesareanection.24 The study suggests that breastfeeding can betarted safely at 24 h after discontinuation of the drug.24

nhalational agents

races of halothane have been found in breast milk of lactating practicing anesthetist in a 1976 study.25 Theoncentration of gas in milk was approximately 2 ppm after

h of working exposure, which was consistent with theoncentration within the operating room. The authors con-luded that the amount of drug transferred to the sucklingeonate was too low to cause harm. However, we have notound any published data about the transfer of halothane toreast milk in women exposed to it during general anesthe-ia.

Regarding the use of isoflurane, enflurane, sevoflurane,nd desflurane, we have not found any published studiesegarding their transfer to human breast milk. But, givenheir pharmacokinetics characteristics (low solubility, rapidxcretion, and poor oral bioavailability) and the brief mater-al exposure period, the theoretical risk for the sucklingnfant is considered low according to authors.7,8,12---15

As for nitrous oxide, there is a scarcity of clinicalrials of its intrapartum use with breastfeeding as the pri-ary outcome. Even if the effects vary from woman tooman, nitrous oxide affects hormones that are impor-

ant during labor and birth, including endorphins andpinephrine/norepinephrine, while it does not reduce theelease or effectiveness of endogenous oxytocin.26 Theseata imply that nitrous oxide has the potential to causeositive effects on both women’s psychoemotional expe-ience of labor and breastfeeding success.10 Significant

dverse effects on the neonate have not been reported.27---29

lthough there is no evidence of adverse effects of theaternal use of nitrous oxide or the fetus, the strength of

hat evidence is far from conclusive.

Should m

aternal anesthesia

delay breastfeeding?

191

Table 6 Summary of results from the studies regarding opioids.

Identification of the study Type of study n Inclusion criteria Anesthetics drugevaluated

Dose of drug Evaluated outcomes Recommendation ofthe study

Feilberg et al., 1989 Randomizedclinical trial

5 Lactating womenwho underwentsurgery.

Morphine Epidural: 4 mg ofmorphine in theepidural catheter.General anesthesia:5 mg IV and 5---10 mgof morphine IM.

M/P ratio: 1.1---3.6.Infant exposureindex < 6%

Safe as a singledose.

Robieux et al., 1990 Case report 1 Nursing womenwith severearthritic back painfrom Lupus. Sheused high doses(200 mg.day−1) ofmorphine duringpregnancy andafter giving birth,tapered down thedose to10---20 mg.day−1.

Morphine The morphinedosage was tapereddown from 50 mgevery 6 h to 5 mgevery 6 h. The daybefore the study, themother received10 mg morphineorally every 6 h.During the day of thestudy, she received10 mg.day−1.

The concentrationof the drug inneonate serum was4 ng.mL−1

(potentiallyharmful),compatible withanalgesic effects.However, no adversesymptoms wereobserved in theinfant (probably dueto tolerance toopioids after achronic exposureintra-uterus andthroughbreastfeeding).

Caution withchronic exposure.

Wittels et al., 1990 Randomizedclinical trial

10 5 nursing womenreceiving epiduralanalgesia (PCA)with morphineafter undergoingelective cesareansection.

Morphine Not mentioned The nursingneonates achievedneurobehavioralscores similar tothose of normalneonates afterspontaneous vaginaldelivery.

Safe.

Wittels et al., 1990 Randomizedclinical trial

10 5 Nursing womenreceiving epiduralanalgesia (PCA)with meperidineafter undergoingelective cesareansection.

Meperidine Not mentioned Normeperidineaccumulates inbreast milk and isassociated withneonatalneurobehavioraldepression on the3rd day of life.

Best to avoid.

192

M.R.

Oliveira

et al.

Table 6 (Continued)

Identification of the study Type of study n Inclusion criteria Anesthetics drugevaluated

Dose of drug Evaluated outcomes Recommendation ofthe study

Peiker et al., 1980 Prospective trial 9 Lactating motherswith pain.

Meperidine 50 mg IM M/P ratio: 1.07---1.2.Normeperidine wasnot analyzed.

Safe as a single dose(the activemetabolite was notanalyzed).

Borgatta et al., 1997 Prospective trial 8 Lactating womanundergoing tubesterilization.

Meperidine 35 mg M/P ratio = 2.3.Infantexposure-index:1.2%---3.5%

Safe as a singledose.

Nitsun et al., 2006 Prospective trial 5 Lactating womenundergoingoperativeprocedures withgeneralanesthesia.

Fentanyl 100 mcg Infant-exposureindex < 1.25%.

Safe as a singledose.

Leuschen et al., 1990 Prospective trial 10 Womenundergoing laboranalgesia.

Fentanyl 50---400 mcg IV Infant-exposureindex = 3%.

Safe as a singledose.

Madej et al., 1987 Randomizedclinical trial

50 Womenundergoingelective cesareansection.

Fentanyl Single epidural dosefor analgesia.

No detectable levelsof fentanyl werefound in breast milk.

Safe as a singledose.

Madej et al., 1987 Randomizedclinical trial

50 Womenundergoingelective cesareansection.

Sufentanil Single epidural dosefor analgesia.

No detectable levelsof sufentanil werefound in breast milk.

Safe as a singledose.

Should m

aternal anesthesia

delay breastfeeding?

193

Table 7 Summary of results from the studies regarding local anesthetics.

Identification ofthe study

Type of study n Inclusion criteria Anesthetics drugevaluated

Dose of drug Evaluatedoutcomes

Recommendationof the study

Zeisler et al., 1986 Case report 1 Lactating womanreceiving IVlidocaine forventriculardysrhythmia.

Lidocaine Antiarrhythmicdoses (muchhigher doses thanthe ones withanestheticeffects.)

M/P ratio = 0.4. Safe even in highantiarrhythmicdoses

Ortega et al., 1999 Prospective trial 27 Womenundergoingcesarean section.

Lidocaine andBupivacaine

Lidocaine183 ± 104 mg ANDBupivacaine82 ± 29.4 mg(epiduralanesthesia)

Lowconcentrations oflidocaine andbupivacaine inbreast milk. Mostof the newbornshad a maximalAPGAR score andno adversereactions werereported.

Both are safe.

Giuliani et al.,2001

Prospective trial. 7 Nursing womenundergoing dentaltreatment with alocal anesthetic.

Lidocaine withoutadrenaline

72---144 mg The amount oflidocaine and itsmain metabolitein breast milk wasconsidered verysmall.

Safe.

Naulty et al., 1983 Prospective trial n? Womenundergoing vaginaldelivery withepiduralanesthesia.

Bupivacaine Not mentioned No concentrationof the drug wasdetectable in allmilk samples atthe sensitivitylimit of0.02 mcg.ml−1.

Safe.

Bolat et al., 2014 Randomizedclinical trial.

20 Womenundergoingelective cesareansection.

Bupivacaine/levobupivacaine

Bupi:82.5 ± 12.1 mg.Levobupi:80.0 ± 10.5 mg

M/P ratioBupi = 0.37 ± 0.14.M/P ratio lev-obupi = 0.34 ± 0.13.

Both are safe.

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A recent report described the use of general anesthesian four lactating women using propofol for induction andemifentanil associated with xenon gas for maintenance.mmediately after extubation, there was no trace of xenonas in maternal milk.30 These results seem promising foractating women in the future.

uscle relaxants

ven though we have not found any published studies aboutilk transfer of muscle relaxants, some conclusions cane achieved based on the pharmacokinetic profile of theserugs.

Succinylcholine is rapidly metabolized in mater-al plasma and has a very short elimination half-life3---5 min).7,8,12---15 Hence, its excretion in breast milk cane considered negligible. Similarly, the nondepolarizinggents, including rocuronium, pancuronium, vecuronium,tracurium, and cisatracurium, have poor lipid solubility,o not cross biological membranes easily, and are fullyonized in normal pH. Even if small amounts of the drugs arexcreted into breast milk, they have very poor absorptionrom the neonatal gastrointestinal tract.7,8,12---15 Therefore,hese drugs are theoretically safe for breastfed babies. Annteresting historical fact that confirms the safety of muscleelaxants is that the South American Indians, without anyarm to their babies, ate the meat from animals killed withurare-poisoned arrows.8,12---15

eversing agents

eostigmine has a half-life of 15---30 min and is quicklyleared from plasma after being administered.14 In a studyublished in 1963, neostigmine could not be detected inreast milk of a women treated for myasthenia gravis.31

As for Sugammadex, we have not found any publishedtudies regarding its transfer to human breast milk, prob-bly because it is a new drug. Further research is neededegarding its safety.

pioids

here are contradictory reports regarding the impact ofhe use of opioids on breastfeeding.32 Highly lipophilicrugs, such as fentanyl, can easily cross the placenta,eading to neonatal depression and negatively affectreastfeeding.33,34 The risk of nursing problems seems to beose- and type of opioid-dependent.35,36 On the other hand,here are a series of published reports about the safety ofpidural, intrathecal, or single dose systemic opioids.37---39

Morphine’s half-life is 2---3 h in adults and 12---16 h inewborns.15 It is transferred to breast milk in small amountsnd has an oral bioavailability of only 30%.7 Its main metabo-ite, morphine-6-glucuronide, is more potent than morphinend has a oral bioavailability of 4%.7 Most authors agreedhat the use of a single dose of morphine is considered

afe for breastfeeding,40 while multiple doses41 and PCAorphine35 should be avoided.As for fentanyl, breastfeeding can be considered safe fol-

owing the administration of a single-dose to the mother.22,42

tmct

M.R. Oliveira et al.

owever, we have not found information regarding multiplentravenous doses or continuous infusion. No adverse effectsere observed on newborns after epidural administration of

entanyl.43

Alfentanil and sufentanil have rapid clearance from thelasma, which makes it unlikely that low maternal dosesould cause significant harm to the suckling infant.8,14,15,19

n one study with 50 patients, no detectable levels of fen-anyl or sufentanil were found in breast milk after epiduralnesthesia for cesarean section.43

Regarding remifentanil, we have found no published databout its maternal administration and its influence on thereastfed newborn. However, considering its short context-ensitive half-life (less than 10 min), it may be consideredafe for lactating mothers.7

On the other hand, meperidine, and its main activeetabolite, normeperidine, have long half-lives in adults

nd in neonates (13 h and 63 h, respectively), different fromhe other opioids.7,9 Although no side effects in neonates areemonstrated after maternal treatment with single dosesf meperidine,3,44 there are reports of neonatal respiratoryepression and neurobehavioral depression with multipleoses.35 Hence, most authors agreed that this drug shoulde avoided in long-term treatment.

ocal anesthetics

idocaine has short half-life both in adults (1---2.2 h) and ineonates (2.9---3.3 h).8 It also has poor oral bioavailabilityless than 30%).12---14 Most authors demonstrate that lidocaines excreted into breast milk in low concentrations,45---47 evenhen administered with maximal antiarrhythmic maternaloses.45 Thus, it seems to be safe in nursing women.

Bupivacaine was also considered safe in parturientsndergoing epidural analgesia. No concentration of the drugas detectable in all milk samples at the sensitivity limitf 0.02 mcg.mL−1.48 The safety was also demonstrated forevobupivacaine,11 which has similar M/P ratio profile as theacemic bupivacaine.

Regarding ropivacaine, limited data are available. Buthere are no reports of adverse effects on breastfed infantsollowing maternal analgesia with epidural ropivacaine.13,49

Regarding epidural analgesia for labor, the main concerns that epidural drugs, especially opioids, cross the placentand decrease neonatal neurobehavioral scores, which mayegatively affect breastfeeding. However, it is important toear in mind that the exposure of the baby to the anestheticrugs through breast milk is insignificant compared to thelacental transfer of the drug. Several studies have beenublished regarding this matter, with conflicting results. Aystematic review, regarding the outcomes in breastfeedingollowing labor epidural analgesia, showed 12 studiesemonstrating negative associations between epidurals andreastfeeding success, 10 studies demonstrating no effects,nd 1 study with a positive association.49 The authorsgreed with the publications’ deficiencies mentioned byrevious authors, as following50: inadequate randomiza-

ion, variation of type and dosage of analgesia, differentethods to evaluate breastfeeding success, and failure to

ontrol confounding variables. All these limitations makehe current literature insufficient to make evidence-based

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Should maternal anesthesia delay breastfeeding?

recommendations based on the neonatal neurobehavioralscores. Therefore, further studies are needed.

Conclusion

Breastfeeding is extremely important for the child’s devel-opment and, hence, must be encouraged. Its successdepends on several factors. One of the most important fac-tors is the support from the family and the institution wherethe birth occurs. Epidural analgesia may possibly have a neg-ative influence on breastfeeding’s quality, but the studieshave failed to demonstrate causation, and, for the moment,this form of analgesia is the one with the least side-effectsfor the neonate.

According to current literature, the transfer of the mostcommon anesthetic agents to breast milk is very small whenthey are used on a single-dose treatment. Therefore, therisks for the healthy suckling infant are almost negligi-ble and breastfeeding should not be interrupted. However,high-dose and repeated administration of drugs significantlyincrease the risk of adverse effects on neonates. In thesesituations, the anesthetist, together with the pediatrician,should perform an individual risk/benefit analysis. Anotherimportant consideration is that premature neonates, orbabies with a concurrent disease, are more susceptible todevelop side-effects. In all these situations, mothers mustbe well informed about the risks and benefits of the chosentherapy, as well as its impact on breastfeeding.

Different from the other anesthetic drugs, diazepam andmeperidine should be avoided in nursing women. Althoughsome studies suggest that they are safe in single doses, theadverse effects in neonates reported by other authors arevery important not to be taken into account.

Conflicts of interest

The authors declare no conflicts of interest.

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