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Arch Womens Ment Health (2007) 10: 3951

DOI 10.1007/s00737-007-0173-0

Printed in The Netherlands

Review

SSRIs during breastfeeding: spotlight on milk-to-plasma ratio

S. Gentile1, A. Rossi2, and C. Bellantuono3

1 Department of Mental Health ASL Salerno 1, Mental Health Center n.4, Cava de Tirreni (Salerno), Italy2 Medical Department Eli Lilly Italia, Sesto Fiorentino (FI), Italy3 Section of Psychiatry and Clinical Psychology, Department of Medicine and Public Health, University of Verona, Verona, Italy

Received October 1, 2006; accepted January 13, 2007

Published online February 12, 2007 # Springer-Verlag 2007

Summary

Objective: To investigate the usefulness of the milk-to-plasma (M=P)ratio for assessing the risks for the breastfed infant associated with the

maternal use of SSRIs.

Data sources: Medline, Toxnet, Embase, Current Contents, and

PsycInfo indexed articles from 1980 to September 2006.

Study selection and data extraction:All studies reporting the M=Pratio in mothers taking SSRIs while breastfeeding or studies which such

an information could be calculated from data reported in the article.

Data synthesis: Higher M=P ratios were rarely associated with a

clinically significant impact on the babies during the early phases ofbreastfeeding.

Conclusions: So far no evidence-based information seems to support

the hypothesis that SSRIs characterized by a M=P ratio


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metabolic, and atopic diseases (Allen & Hector, 2005).

Breastfeeding also provides a number of benefits for the

nursing mother, such reduced risks of both ovarian and

breast cancer (Martin et al, 2005; Riman et al, 2004).

Several methods and parameters have been proposed

and utilized to establish the amount of psychoactive

drugs transferred to maternal milk, in order to reduce

the infants exposure as much as possible. Some inves-

tigators actually examined the size, lipid solubility, and

protein binding of the molecule in an attempt to forecast

the extent of passage into maternal milk, also taking into

account the bioavailability of the drug and the infants

competence to excrete the drug and its metabolites (Pons

et al, 1994; Hale, 2002). Another important value is the

theoretic infant dose. It is an estimate of the maximumlikely dose per kilogram per day an infant would get

trough breast milk (Malone et al, 2004). The limitations

of such methods for estimating the infant exposure, how-

ever, are beyond the scope of this article.

One of the parameters most frequently used, however,

is the milk-to-plasma (M=P) ratio, which represents the

ratio of drug concentration in breast milk to drug con-

centrations in maternal plasma. Hence, an M=P ratio less

than 1.0 should indicate that the drug transfer into breast

milk is relatively low, the preferred situation (Malone

et al, 2004). An M=P ratio of 1.0 or more indicates that

the drug may be present in breast milk at higher levels

than in the mothers plasma; such a situation might be

associated with a relatively higher amount of drug trans-

ferred to infants and, consequently, with a theoretical

higher risk of inducing iatrogenic unwanted events.

Indeed, maternal breast milk level seems to be signi-

ficantly correlated with infant plasma level for most

SSRIs, such as citalopram, fluoxetine, and paroxetine

(Weissman et al, 2004). Since milk drug concentrations

depend on several factors (such as time to peak milk

concentration, the dosing schedule, breast modifications

during pregnancy, maternal bodyweight and metabo-

lism) and also fluctuate over the whole duration of lacta-

tion as well as during the course of the day, the best

method for estimating the M=P ratio may be based on

an average of several milk samples.

Moreover, the M=P ratio is also utilized in:

a) calculating the Exposure Index (as percent of weight

adjusted maternal dose), which is directly proportional

to the M=P ratio but inversely proportional to the rate

of clearance of the drug by the infant (Ito, 2000);

b) estimating the infant dose after importing the value

of the M=P ratio in specific equations, such as the

Atkinson formula.

Despite an M=P ratio of>1.0 does not necessarily mean

that the drug is contraindicated during lactation, but

just that is less desirable than a drug characterized by

an M=P ratio


3/14

ratio, SSRIs. A separate search was also run to complete the

electronic search for the six SSRIs: fluoxetine, fluvoxamine,

sertraline, paroxetine, citalopram, and escitalopram. The studies

retrieved were examined for additional references. 135 studies

were recognized.

Inclusion criteria were however represented by the articles

which reported the M=P ratio for this class of antidepressants

or those where the drug concentrations in maternal plasma andmilk were reported, permitting the calculation of this parameter.

Hence, 99 articles were excluded. 34 and 2 studies respectively

meeting the first and the second inclusion criterion were con-

versely reviewed.

Results

Fluoxetine

Preliminary information about the excretion of the med-

ication in human milk and the M=P ratios of both fluox-

etine and its active metabolite became available in 1990:

Isenberg evaluated a woman suffering from dysthymic

disorder often complicated by major depressive episodes

who was treated with fluoxetine while breastfeeding.

The M=P ratios for fluoxetine and norfluoxetine were

both lower than 1.0. The mother and the infants paedia-

trician did not notice any drug-related adverse event.

The infants exposure was not analysed.

A further study by Burch & Wells (1992) conducted

on a woman requiring antidepressant treatment because

of bipolar depression also failed to show adverse behav-

ioral or developmental outcome in the infant. Also in

this study, the M=P ratios for the parent drug and itsmetabolite were lower than 1.0. However, an estimate

of the babys dose, albeit indirect, was possible only by

assuming theoretically that the baby received 0.15 L=kg

of milk per day.

Six year later, four mothers (one affected by obses-

sive-compulsive disorder and three by major depressive

episodes) were studied by Yoshida et al (1998). No ad-

verse events were recorded during the early postpartum

period, despite in some women the M=P ratios for fluox-

etine and its metabolite overcame the notional level of

concern of 1.0. Moreover, the development of the four

infants exposed to fluoxetine until they were 12 months

old and repeatedly assessed by the Bayley Scales of

Infant Development was normal.

A further study was specifically designed to charac-

terize the M=P ratio and the infant dose for fluoxetine

and norfluoxetine in a relatively large number of breast-

feeding women taking the medication for the treatment

of their depression (Kristensen et al, 1999). The absolute

infant dose, calculated as fluoxetine equivalent, was de-

termined by 2 different methodologies (both assuming

an oral availability of 100% and an average milk intake

of 0.15Lkg1 day). Fluoxetine was detected in 5 of

the 9 infants from whom samples were collected, where-

as norfluoxetine was detected in 7. Four infants showed

adverse events. In three of these cases characterized by

the occurrence of unwanted reactions the M=P ratios

was lower than 1.0. Of note, such adverse events wereassessed by interviewing the mother and=or the pae-

diatrician. No specific assessment tools were used.

Moreover, methadone maternal use may have been a

contributing factor in the withdrawal phenomena in

one infant.

Drug-related adverse events requiring hospitalisation

were also described in an infant born to a depressed

mother who took fluoxetine throughout her pregnancy

(Hale et al, 2001). In this study, however, mothers

serum and breast samples were collected at different

days. Hence, no information can be drawn on the true

M=P ratio. In the infants serum, no detectable fluoxetine

levels were recorded; norfluoxetine levels conversely

ranged from 86 to 142 ng=mL.

In the study by Hendrick et al (2001) it was demon-

strated that fluoxetine and norfluoxetine concentrations

in the maternal serum positively correlate with infant

norfluoxetine concentrations in the infants serum. The

authors also demonstrated that peak milk concentrations

occurred approximately 8 h after maternal dosing and

also influenced norfluoxetine levels in the infants se-

rum. Mothers were questioned about potential unwanted

sequelae to their infants and did not report any suchfindings, despite in some of these women the M=P ratio

was broadly higher than 1.0 for both the drugs and its

metabolite.

Such results were confirmed in a further study con-

ducted by the same group of researchers. This study also

matched 3 different methods of estimating the daily dose

to nursing infants (Suri et al, 2002): it was concluded

that the Mathematical Model (consisting of determining

the gradient of excretion of medication into breast milk

at a specified time after the maternal dose, applying such

a gradient to each nursing collection, and finally sum-ming the values for 24 h), rather than the Babys Total

Daily Dose Model or the Atkinson Model, seems to

reflect the infants serum concentration with an higher

degree of accuracy. However, also the Mathematical

Model provides an indirect estimation of the amount

of drug ingested by the infant.

To investigate the pharmacokinetics of fluoxetine and

norfluoxetine during pregnancy, delivery, and lactation, a

number of mothers suffering from depression or panic

SSRIs during breastfeeding 41


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Table2.Fluoxetine(FLX)=norfluoxetine(NFX)

Study=sample

size

Maternalbody

weight(kg)

Maternal

dose(mg)

Postpartum

time

Antidepressant

treatmentduration

Timepost

maternal

dose

M=Pratios

Repercussionson

theclinicaloutcome

Isenberg(1990)

N=A

20

3months

2months

N=A

FLX0.28

irritability

(n

1)

NFX0.21

Burch&Wells(1992)

N=A

20

2months

53days

4h

FLX0.49

no

(n

1)

NFX0.34

Yoshidaetal(1998)

N=A

2040

118days

1252weeks

N=A

FLX:0.521.45

no

(n

4)

NFX0.081.1

Kristensenetal(1999)

mean67.3

2080

N=A

1375days

variable

FLX0.520.84

2casesofcolic

(n

14)

NFX0.350.77

2casesofwithdrawal

syndrome

Haleetal(2001)

(n

1)

N=A

20

day11

themotherstookthe

compoundduringthe

entirepregnancyduration

N=A

mothersserumandmilk

sampleswerecollected

atdifferenttimes

somnolence,lethargy,

fever,unresponsiveness

Surietal(2002)

(n

10)

N=A

2060

5weeks3months

themothersstartedFLX

treatmentduring

breastfeeding(aftera

minimumof6weeks

treatment)

N=A

FLX0.13.92

NFX0.51.4

no

Hendricketal(2001)

(n

19)

N=A

1060

534days

throughoutpregnancy

today4after

parturition

N=A

FLX0.656.09

NFX0.372.08

no

Heikkinenetal(2003)

(n

11)

N=A

2040(mean20)

pregnancy,delivery,

day2,day4,

week2,month2

6womenusedFLX

duringpregnancy;

5startedtakingFLX

laterinpregnancy

(week2235)

N=A

FLX0.32.2

NFX0.11.7

no

Kimetal(2005)

(n

9)

mean74.1

1030

mean3.7months

themotherstookthe

compoundduring

pregnancyfora

minimumof3weeks

priordelivery

variable

R-FLX

mean0.84

S-FLX

mean0.54

R-NFX

mean0.75

S-NFX

no

mean0.55

Berleetal(2004)

(n

1)

N=A

20

N=A

85days

immediatelybefore

administration

ofthe

nextdose

0.31

no

1

Forthesumoffluoxetineandnorfluoxetine.

42 S. Gentile et al


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disorder were recruited in a relatively recent study

(Heikkinen et al, 2003). Common clinical doses of the

medication results in lower trough plasma concentra-

tions of fluoxetine and fluoxetine plus norfluoxetine than

those detected in a clinical setting with similar doses in

the nonpregnant state, because of increased demethyla-

tion of fluoxetine by cytochrome P450 (CYP) 2D6.Indeed, it has been reported that pregnancy specifically

increases CYP2D6 activity (Wadelius et al, 1997).

Nevertheless, also in this study both fluoxetine and its

metabolite were likely to cause M=P ratios higher than

1.0. The infant exposure to fluoxetine through breast

milk was calculated by the Atkinsons model (Atkinson

et al, 1998). The infants evaluated in this study showed

normal growth and development up to 1 year of age:

however, no specific assessment tools were used for the

infants examination.

A recent and well-designed study by Berle et al

(2004) demonstrated that the levels of fluoxetine in a

breastfed infant (as percentage of maternal serum con-

centration) was 6.4, despite a M=P ratio of 0.3. The

baby, however, showed no unwanted reactions.

On the other hand, it was very recently confirmed that

the infant dose is mainly determined by the concentra-

tions of the maternal drug, which in part depend on the

maternal dosage (Kim et al, 2005).

Table 2 shows specific details from the studies on

fluoxetine and norfluoxetine M=P ratios.

Paroxetine

Information about the M=P ratios of paroxetine became

available since 1996. A case report described a woman

who started paroxetine treatment 3 days after delivery

because of exacerbation of her depressive and obsessive

symptoms (Spigset et al, 1996). The M=P ratio was con-

siderably lower than 1.0. The relative infant dose was

calculated indirectly on the basis of information derived

from previously published literature (Isemberg, 1990;

Lester et al, 1993). No adverse events were observed

in the infant during the breastfeeding period.

The amount of paroxetine excreted in breast milk was

also quantified by OOhman et al (1999). The mean par-

oxetine concentrations in hindmilk (the milk secreted at

the end of the feed) were 78% higher than in foremilk

(the milk secreted at the start of the feed), and the in-

crease corresponded to the increase in milk triglyceride

levels. The M=P ratio was close to 1.0. No adverse

events were however recorded in this infant, whose par-

oxetine dose per kg body weight was calculated by a

specific equation.

In the key-study by Begg et al (1999) two different

evaluations were performed. The first involved nursing

mothers who were evaluated over a 24 h dose interval at

steady-state: the total amount of paroxetine in the milk

was calculated which represented the dose to the infant.

The second evaluation involved a different subgroup

of nursing mothers who were studied at steady-state,around a normal feeding time. The relative infant dose

ranged from 0.5 to 1.7 (cumulative excretion in milk,

expressed as percentage of the weight-adjusted maternal

dose) and from 0.38 to 2.24% in the first and second

evaluation, respectively. No adverse events were ob-

served in any infant, despite the paroxetine M=P ratio

widely overcame the notional limit of concern of 1.0.

In a study conducted on a relatively large sample of

women, paroxetine concentrations were present in all

breast milk samples; both paroxetine M=P ratios and its

levels in the infants (quantified by the Mathematical

model) were widely variable: the highest values were 1.3

and 101ng=ml, respectively (Stowe et al, 2000). This

study, however, showed no untoward events in the infants.

Such results were substantially confirmed by Misri

et al (2000). Other relevant findings of the study were

represented by the absence of both detectable paroxetine

levels in all of the infant serum samples and adverse

events in the babies.

No detectable levels of paroxetine were also found

in the breast milk of a woman requiring antidepressant

treatment because affected by panic disorder with agora-

phobia (Hendrick et al, 2000).Berle et al (2004) conversely found that appreciable

paroxetine levels in breast milk (ranging from 18 to

152 nmol=L) are not associated with detectable levels

of the drug in the infants serum.

Further information on the excretion of paroxetine in

breast milk became available in the pooled analysis by

Weissman et al (2004). Table 3 summarizes the most

relevant findings on the M=P ratio for paroxetine.

Sertraline

Altshuler et al (1995) found that sertraline levels in

breast milk varied widely over 24 h, with the peak occur-

ring between hours 1 and 9 after the drug intake. The

M=P ratio was lower than 1.0. Sertraline was also quan-

titated in the infant serum specimens: neither appreci-

able sertraline levels in the infants serum nor adverse

events were demonstrated. However, the desmethyl-

metabolite was not measured.

In the study by Stowe et al (1997) sertraline showed a

gradient from foremilk to hindmilk; the peak in breast-



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Table3.Paroxetine(PAR)

Study=sample

size

Maternalbody

weight(kg)

Maternal

dose(mg)

Postpartumtime

Antidepressant

treatmentduration

Timepost

maternaldose

M=Pratios

Repercussionson

theclinicaloutcome

Spigsetetal(1996)

(n

1)

60

20

milklevelswereobtained

10daysafterparturition,

whereasserumlevels

wereobtainedlater

(afterthematernaldose

hadbeenincreasedto

40mg=day)

milklevelswereobtained

7daysafterparturition,

whereasserumlevels

wereobtainedlater

(aftermaternaldose

hadbeenincreasedto

40mg=day)

milklevelswerecalculated

4hafterdrugintake

0.09

no

OOhmanetal(1999)

(n

6)

5267

2040

N=A

atleast8days

firstevaluation:47h

afterdrugintake

mean

SD

no

lastevalua

tion:24h

afterdrugintake

0.69

0.29

Beggetal(1999)

(n

10)

5386

1030

N=Ainbothevaluations

atleast2weeksatthe

samedosingschedule

(firstevaluation)

firstevaluation:atatime

asclose

aspossibleto

thedrugadministration

0.323.33

no

N=Ainthesecond

evaluation

secondevaluation:Around

anormalinfantfeedingtime

Stoweetal(2000)

N=A

1050

455.2weeks

longerthan10days

15h

0.0561.3

no

(n

16)

Misrietal(2000)

(n

24)

N=A

1040

110.5months

N=A

about6h

0.111.67

no

Hendricketal(2000)

(n

1)

N=A

10

3weeks

3weeks

immediate

lyafter

drugintake

breastmilklevels

werebelowthe

quantificationlimits

no

Berleetal(2004)

(n

6)

N=A

1030

N=A

atleast14days

immediate

lybefore

adminis

trationofthe

nextdose

0.60.9

no

Weissmanetal(2004)

(n

3)

66.9135.8

1030

7.328.1weeks

2156weeks

810h

0.580.79

no

44 S. Gentile et al


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Table4.Sertraline(SER)anditsmetabolites

Study=sample

size

Maternalbody

weight(kg)

Maternal

dose(mg)

Postpartum

time

Antidepressant

treatmentduration

Timep

ost

maternaldose

M=Pratios

Repercussionson

theclinicaloutcome

Altshuleretal(1995)

(n

1)

N=A

100a

3weeks

themotherstarted

antidepressanttreatment

duringpregnancy

12h(m

aternal

serum)

SER0.53

no

Stoweetal(1997)

(n

11)

N=A

25150

4141

3mothersstarted


duringpregnancy,9after

parturition

N=A

SER2.3

1.3

desmethylsertraline1.4

0.8

no no

Stoweetal(2003)

(n

26)

N=A

123.9

62.8

436weeks

12mothersstarted


duringpregnancy,8after

parturition.For1womanthe

informationwasunavailable

N=A

0.484.81(forbothSER

anddesmethylsertraline)

no

Kristensenetal(1998)

(n

8)

mean71.1

50200

1.814.2months

1.184.25months

at0,1,2,3,4,6,

8,12

,and24h

SER1.93

0.16

desmethylsertraline1.640.19

no

Doddetal(2000)

N=A

N=A

N=A

morethan2weekson

426h

SER1.76

1.72

no

(n

10)

fixeddose

Berleetal(2004)

(n

6)

N=A

50100

N=A

atleast14days

immediatelybefore

administration

ofth

enextdose

SER1.23.5

desmethylsertraline0.64.7

no

Weissmanetal(2004)

(n

19)

52.498.0(d

ata

availablefor4=19

women)

50100

4.019.6weeks

N=A

127h

SER0.543.0

norsertraline0.381.66

(dataavailable

for4=19women)

no

a

Themotheralsotooknortriptyline,125mg=day.



8/14

milk occurred however later, between 7 and 10 hours

after dosing; M=P ratios for both the drug and its meta-

bolite were higher than 1.0 without interfering, however,

with the infants well-being. Also in this study, the

Mathematical Model was used for estimating the 24-h

infant medication dose. Such results were substantially

confirmed in a more recent study performed by the sameresearch group (Stowe et al, 2003).

In a further study, neither sertraline nor its metabo-

lite were detected in plasma samples from a few infants

breastfed by mothers who took the compound during the

postpartum period, despite M=P ratios higher than 1.0

for both sertraline and desmethylsertraline. In addition,

these infants showed no acute adverse events and all

achieved normal developmental milestones (Kristensen

et al, 1998). The methodologies used for estimating the

infant dose were analogue to those described in a trial

above reported. (Kristensen et al, 1999).

Reassuring results also emerged from the study by

Dodd et al (2000) conducted on nursing women affected

by major depression. The average dose to the infants

(estimated by the Atkinson model) was less than 2% of

the maternal daily dose, despite the M=P ratio for sertral-

ine was found to be higher than 1.0.

No detectable levels of sertraline were found in 6

infants whose mothers took the compound while breast-

feeding (Berle et al, 2004).

A recent study also provided additional information

on sertraline excretion in breast milk (Weissman et al,

2004). Table 4 highlights the studies documenting theM=P ratios for both sertraline and its metabolite.

Citalopram and escitalopram

Data on the excretion of citalopram into breast milk have

been available since 1997. OOhman et al (1997) found that

the estimated dose to the infant ranged from 5 to 9% of

the weight-adjusted maternal dose for M=P ratios higher

than 1.0 for both citalopram and demethylcitalopram.

In a more detailed study, the average infant dose

was 4.8% of the maternal dose (Jensen et al, 1997).

Citalopram reached a peak concentration in breast milk

6 hours after the drug intake: the resulting M=P ratio was

higher than 1.0 for both the parent drug and its meta-

bolite. However, despite the amount of citalopram trans-

ferred to the baby was determined by theoretically

assuming a milk volume of 0.15 L=kg baby, the volume

of milk produced in 24 h was not determined accurately.

No adverse events occurred in the infants.

Widely ranging values for the relative infant dose

(1.85.9%, calculated by a specific equation) associated

with an M=P ratio higher than 1.0 were also reported by

Spigset et al (1997). No complications were reported in

the infants.

In contrast, a mild adverse event in an infant receiving

5.4% of the maternal dose was reported in a subsequent

study (Schmidt et al, 2000). In this study, the M=P ratio

was found to be more than double the notional limit ofconcern of 1.0.

Rampono et al (2000) demonstrated that peak milk

concentration occurs earlier for citalopram (3.9 h) than

for desmethylcitalopram (5.7 h). The clinical significance

of such a finding, however, remains unknown, as well as

the very high M=P ratios of the drug and its metabolite.

Citalopram was detected in three infants, whereas de-

methylcitalopram in two. Such infants showed normal

development for age as assessed by the Denver develop-

mental screening test.

Relatively low values of relative infant dose (ranging

from 0.2 to 0.3% at the ages of 2 months and 2 weeks,

respectively) was found in a study examining the effi-

cacy and safety of citalopram in relation to concentra-

tions of the drug and its metabolites during pregnancy

and lactation (Heikkinen et al, 2002), despite an M=P

ratio close to 5.0 for didesmethylcitalopram. Citalopram

and desmethylcitalopram also showed high M=P ratios.

The infant exposure to citalopram was quantified by the

Atkinson model. One case of transient neurodevelop-

mental delay (spontaneously resolved without any fur-

ther problem) was reported.

In the study by Berle et al (2004), the ingestion ofcitalopram by the lactating woman was associated with

detectable levels in the infants. However, the clinical

repercussions of such a finding remain unclear.

Other data on the excretion of citalopram into hu-

man milk became available in the pooled analysis by

Weissman et al (2004).

Very recently, Franssen et al (2006) described the case

of an infant who developed irregular breathing, sleep

disorders, and hypotonia evolving into hypertonia after

exposure to citalopram through the placenta and mater-

nal milk. However, all the symptoms disappeared spon-taneously within 3 weeks. The M=P ratio of citalopram

was higher than 1.0 in three consecutive observations,

whereas the levels of the medication in the infants

serum were in the range of 3.77.1 nM.

So far, only one study is available on escitalopram,

the latest SSRI introduced onto the market (Rampono

et al, 2006). No adverse events were observed in 8

infants who showed a relative dose (as a percent of the

maternal weight-adjusted dose) ranging from 4.2 to

46 S. Gentile et al


9/14

Table5.Citalopram(CIT),itsmetabolites,andescitalopram(ESC)

Drug=study=sample

size

Maternal

body

weight(kg)

Maternal

dose(mg)

Postpartum

time

Antidepressant

treatmentduration

Timepost

maternald

ose

M=Pratios

Repercussionson

theclinicaloutcome

OOhmanetal(1997)

N=A

2060

N=A

N=A

3.56.5h

CIT1.812.24

no

CIT(n

2)

demethylcitalopram

2.052.91

Jensenetal(1997)

CIT(n

1)

61

20

N=A

15days

N=A

3forboththedrug

anditsmetabolite

no

Spigsetetal(1997)

CIT(n

3)

6470

2040

210months

N=A

beforethe

daily

doseand4hlater

in2=3ofwomena

CIT1.161.88

no

Schmidtetal(2000)

CIT(n

1)

40

40

N=A

10days

N=A

CIT2.07

uneasysleep,resolved

aftermaternaldose

reduction

Ramponoetal(2000)

CIT(n

7)

mean62.6

mean36

mean4.1months

mean97days

at0,2,4,

6,8,

12,and

24h

CIT1.23.0

demethylcitalopram

1.02.5

no

Heikkinenetal(2002)

CIT(n

11)

N=A

2040

N=A

10womenstarted

CITatthetimeof

conception,1at20

weeksofpregnancy

justbefore

takingthedrug

CIT1.23.3

desmethylcitalopram

1.34.1

didesmethylcitalopram

1.14.6

no

Berleetal(2004)

CIT(n

9)

N=A

2050

N=A

atleast14days

immediate

lybefore

administration

ofthen

extdose

CIT1.14.3

desmethylcitalopram

0.96.3

no

Weissmanetal(2004)

65.373.4

20

1.611.7months

1226weeks

910h

CIT0.931.79

no

CIT(n

2)

desmethylcitalopram

1.361.56

didesmethylcitalopram

1.832.0

Franssenetal(2006)

CIT(n

1)

55

40

at12,25,46,

and53days

afterdelivery

thewomanstarted

takingthedrug

duringpregnancy

N=A

CIT2.02.8

sleepandrespiratory

disturbances,

hypo=hypertonia

Ramponoetal(2006)

ESC(n

8)

5865

1020

N=A

23240days

justbefore

themorning

doseandat2,4,

and6h

afterdose

ESC1.72.7

desmethylescitalopram

1.83.1

no

a

Inthethirdwoman(ahealthyvolunte

er)serumsampleswereobtainedafter1,2,3

,4,5,6,8,10,12,24,48,and72h.Breastm

ilksampleswereobtainedafter2,4,6,8,14,24,48,72h.



10/14

6.4% for escitalopram plus desmethylcitalopram. Both

compounds, however, showed M=P ratios higher than

1.0. Data on the excretion of both compounds are avail-

able in Table 5.

Fluvoxamine

The first study evaluating the excretion of fluvoxamine

in breast milk of a woman affected by post-natal depres-

sion was performed by Wright et al (1991). The M=P

ratio was lower than 1.0. Fluvoxamine concentrations in

the infants serum, however, were quantified indirectly

by the Atkinson model (Atkinson et al, 1998). The

maternal antidepressant intake induced no untoward ef-

fects in this infant.

These results were replicated in a further case report;the infant showed neither acute toxic effects of fluvox-

amine nor neurodevelopmental repercussions at month

21 as assessed by using the Bayley Scales for the Infant

Development, despite the fact that this baby was born by

forceps delivery at week 41 of gestation (Yoshida et al,

1997). The study showed a relatively low M=P ratio.

Fluvoxamine concentrations in the infants serum were

quantified indirectly: indeed, the estimate of the babys

dose was possible only by assuming theoretically that

the baby received 0.15 L=kg1 of milk per day.

In contrast, significantly higher M=P ratios were

reported by Haagg et al (2000), although no unusual reac-

tions were observed in the infant.

An M=P ratio higher than 1.0 (without any complica-

tions in the infants) was also reported in two breastfeed-

ing women (Kristensen et al, 2002). The study did not

include the analysis of serum infant samples.

Further data on the excretion of fluoxetine into hu-

man milk became available in the pooled analysis by

Weissman et al (2004). Table 6 reassumes the available

information on M=P ratio values for fluvoxamine.

Discussion

Human milk is a suspension of protein and fat globules

in a carbohydrate-based suspension (Briggs et al, 1994).

Most drugs are transferred into maternal milk by passive

diffusion, reaching a concentration equilibrium with the

concentration in the blood.

Hence, almost without exception, as the level of the

medication in the mothers plasma begins its rise, the

concentration in milk begins its rise as well. Maternal

blood concentration largely depends on maternal body-

weight and medication dose. (Texas Tech University,

Mechanisms of Drug Entry into Human Milk, Accessed:

July 2, 2006).

However, the antidepressant agents enter milk also

by secretory methods (Hale, 2002). Indeed, medicationsalso may be transferred into breastmilk incorporated

with fat globules or bound to proteins, primarily casein

and lactalbumin (Pediatric Pharmacotherapy, 1996. No

Authors listed).

Morphological changes of the breast occurring during

the first weeks after parturition also influence the amount

of drug excreted in maternal milk. During the first 4 to

10 days of life, large gaps between alveolar cells exist.

These gaps permit an enhanced drug-access to the milk.

Soon after the first week, the alveolar cells swell, sub-

sequently closing the intracellular gaps and limiting

access to the milk (Malone et al, 2004; Whitby & Smith,

2005). Moreover, the composition of breastmilk varies

from the initial colostrum (which shows a relatively

higher protein concentration) to mature milk; thus, drug

concentrations change after the first 3 to 4 days of lacta-

tion (Crisholm and Kuller, 1997).

Furthermore, milk composition varies even during a

single breastfeeding session, with milk expressed to-

wards the end of a feeding having greater fat contents

(Pediatric Pharmacotherapy, 1996. No Authors listed).

Table 6. Fluvoxamine (FVX)

Study=sample size Maternal bodyweight (kg)

Maternal

dose (mg)

Postpartum

time

Antidepressant

treatment duration

Time post

maternal dose

M=Pratios

Repercussions on

the clinical outcome

Wright et al (1991)

(n1)

70 200 14 weeks 2 weeks 4 h and 45 min 0.29 no

Yoshida et al (1997)

(n

1)

N=A 100 17 weeks 2 weeks 3 h 0.29 no

Haagg et al (2000)

(n1)

90 200 3 months 25 weeks every hour during

a 12-h period

1.061.59 no

Kristensen et al

(2002) (n2)

5470 50150 0.7526.5

months

3 6 weeks at 0, 1, 2, 3, 4, 6,

8, 12, and 24 h

mean 1.01 no

Weisman et al

(2004) (n1)

62.4 250 29.1 weeks 94 weeks 9 h 1.02 no

48 S. Gentile et al


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These variations have specific repercussions on the

levels of drugs in maternal milk.

On the part of the infant, sucking patterns, feeding

duration, and volume ingested also determine the amount

of drug ingested. Finally, once a drug has entered the

mothers milk and has been ingested by the infant, it must

traverse through the infants gastrointestinal tract and beabsorbed (Texas Tech University. Mechanisms of Drug

Entry into Human Milk. Accessed: July 2, 2006). Also,

the percentage of babies showing detectable serum drug

levels and, consequently, the magnitude of such levels is

also associated with the individual timing of the infants

hepatic maturation, which usually occurs not before the

third month of life (Warner, 1986).

Hence, a large number of factors regulate the amount

of drug transferred to milk. It should primarily be taken

into consideration, however, that the M=P ratio shows

intrinsic limitations: the primary drawback is that it

relies a one-point determination and does not reflect

the other variables interfering with the drug transfer.

The true M=P ratio also varies significantly during the

same episode of breastfeeding too (Pediatric Pharma-

cotherapy, 1996. No Authors listed).

In addition, most of such factors (and, especially,

maternal bodyweight, maternal dose, specific portion

of breastfeeding, timing of evaluation after parturition,

and timing of antidepressant treatment before evalua-

tion) were widely inhomogeneous in nearly the totality

of the studies focused to estimate the M=P ratio value.

This bias could explain the wide ranges of M=P ratioscalculated in different studies conducted on the same

SSRI.

Thus, it not surprising that the M=P ratio seems to be

associated with no or minimal clinical relevance: indeed,

in several cases appreciable concentrations of antide-

pressant agents in the breast milk were associated with

no detectable levels in infant plasma.

Moreover, because in more than a few studies the

M=P ratio was derived from data obtained at single time

point, its usefulness in attempting to establish the safety

of SSRIs for the breastfed infant was limited and oftenmisleading because it deviated significantly from the

time-averaged value.

Furthermore, all published information was supported

by findings emerging from very small sample sizes: for

this reason, this information is applicable to only a few

women and, hence, is not really generalizable to the

breastfeeding population.

In addition, both studies documenting fluoxetine-

related untoward events in the suckling infants reported

an M=P ratio lower than 1.0, and their results were also

contaminated by two potential confounding factors: ma-

ternal co-medications and=or previous exposure of the

baby through the placenta. A similar number of unsafe

reports were reported for citalopram, whose M=P ratio

ranges from 0.93 to 4.6; however, the baby who suffered

from the most serious adverse event was also exposed tocitalopram during fetal life. Therefore, it is possible that

such events could to be not related to the exposure to the

drug via maternal milk, but to toxic events due to pla-

cental exposure which was prolonged during the first

days after parturition. In addition, in the vast majority

of cases the infant evaluation was based on empirical

observations.

Hence, so far no evidence-based information seems

to support the hypothesis that SSRIs characterized by a

M=P ratio


12/14

quantification of the levels of antidepressant in both

maternal and infant serum.

In any case, if the mother wishes to breastfeed her

infant while taking an SSRI, the baby should be closely

monitored in order to detect any iatrogenic event as soon

as possible.

Acknowledgments

The authors would like to acknowledge Anna Maria Desiati,

Information Specialist, Scientific Information Service, Eli Lilly

Italia SpA, and her colleague Leonardo Pavese. Their support in

the electronic searching and for obtaining full-text articles was

highly valuable and professional. No sources of funding were

used for the preparation of manuscript.

Disclosure of interests

Salvatore Gentile is on the speaker-bureau for Eli Lilly Italia

SpA. In the last 5 years, he also received travel support from

Astra Zeneca, Janssen-Cilag, Lundbeck, GlaxoSmithKline,

Bristol-Meyer Squibb, Pfizer, Novartis, and Recordati.

Andrea Rossi is employed in the Medical Department of Eli

Lilly Italy.

Cesario Bellantuono has received educational grants from Eli

Lilly, Astra Zeneca, Janssen-Cilag, Lundbeck, GlaxoSmithKline,

Bristol-Meyer Squibb.

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Correspondence: Dr. Salvatore Gentile, Department of

Mental Health ASL Salerno 1, Mental Health Center n.4,

Piazza Galdi 84013, Cava de Tirreni (Salerno), Italy; e-mail:

[email protected]



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