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), Italy
Medical Department Eli Lilly Italia, Sesto Fiorentino (FI), Italy
3
Section of Psychiatry and Clinical Psychology, Department of Medicine and Public Health, University of Verona, Verona, Italy
2

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=P
ratio 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 of
breastfeeding.
Conclusions: So far no evidence-based information seems to support
the hypothesis that SSRIs characterized by a M=P ratio <1.0 should be
preferred. Hence, physicians should consider different parameters when
attempting to choose the safest SSRI for the breastfeeding woman. These
parameters might be represented by the number of well-documented
published adverse event reports and the tendency of each SSRI of inducing in the infants serum concentrations that are elevated above 10% of
average maternal serum levels. In any case, if the mother wishes to
breastfeed her infant while taking a SSRI, the baby should be closely
monitored in order to promptly detect any iatrogenic event.
Keywords: Breastfeeding; lactation; milk=plasma ratio; safety;
SSRIs.

Introduction
The postpartum period is associated not only with physiological emotional changes, but also with an increased
vulnerability to mood disorders. Whereas postpartum
blues is generally a common, transient syndrome characterized by irritability, restlessness, hopelessness, and
somatic symptoms (Gale & Harlow, 2003), postpartum
major depression represents a serious mental disorder

(Beck, 2006). It is characterized by low mood, anhedonia,

forgetfulness, and suicidal ideation. Moreover, depressive
episodes at postpartum onset are a specific risk factor for
chronic or recurrent depression (Wolf et al, 2002) and
may severely affect the babys future well-being.
Thus, the need to start antidepressant treatment during
the postpartum period may arise. Treatment with antidepressant drugs of the selective serotonin reuptake inhibitor (SSRI) class has been proposed as a first-line
therapy in postpartum depression; these agents may also
be the treatment of choice for postpartum dysthymia,
panic, and obsessive-compulsive disorders (Boerner &
Moller, 1999; Wisner et al, 2002).
Unfortunately, like all the other antidepressants, SSRIs
cross into breast milk. Short- and long-term effects of the
drug transfer into maternal milk on the suckling infant
remain substantially unknown (Gentile, 2005a), despite a
number of reassuring preliminary reports reviewed elsewhere (Gentile, 2005b).
Moreover, manufacturers information suggests caution when administering such agents in lactating women,
as Table 1 shows (Citalopram, Fluoxetine, Fluvoxamine,
and Sertraline Drug Monographs; Paroxetine US Prescribing Information; Lexapro FAQs).
On the other hand, the benefits of breastfeeding are
well-documented; the American Academy of Pediatrics states that breast milk represents the best and the
only source of nutrition for the infant during the first
6 months of life (American Academy of Pediatrics,
1997). Breastfed infants show lower rates of infectious,

40

S. Gentile et al

Table 1. Manufacturers recommendations for SSRI use in lactating women

Drug

Warning

Fluvoxamine

The safe use of fluvoxamine during lactation has not been established. Therefore, it should not be administered to nursing
mothers, unless in the opinion of the treating physician, the expected benefits to the patient outweigh the possible
hazards to the child

Fluoxetine

The safe use of fluoxetine during lactation has not been established. Therefore, it should not be administered to nursing
mothers, unless in the opinion of the treating physician the expected benefits to the patient markedly outweigh the
possible hazards to the child

Sertraline

The safety of sertraline during lactation has not been established

Paroxetine

Caution should be exercised when paroxetine is administered to a nursing woman

Citalopram

Clinicians should weight expected maternal benefits versus possible hazards for the infant

Escitalopram

Patients should be advised to notify their physician if they are breast feeding an infant. Therefore, the doctor and patient
must decide whether to continue or discontinue either nursing or antidepressant therapy. The decision to continue therapy
should take into account the risks for the infant and the benefits of treatment for the mother

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 investigators 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 maximum
likely 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, however, 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 concentrations 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 transferred to infants and, consequently, with a theoretical
higher risk of inducing iatrogenic unwanted events.
Indeed, maternal breast milk level seems to be significantly 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 metabolism) and also fluctuate over the whole duration of lactation 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 <1.0 (Malone et al, 2004), several professional groups utilize such a parameter to provide clinical
recommendations for the utilization of antidepressant
agents during breastfeeding. However, no studies have
comprehensively examined if a correlation exists between the M=P ratio values and the clinical outcome
of breastfed infants.
Hence, the aim of this paper was to review the studies
evaluating the M=P ratios for SSRIs, in order to investigate the clinical usefulness of such a parameter for
choosing the drug associated with lower risks for the
breastfed infant.
Methods
Electronic searches of Medline=PubMed, TOXNET, EMBASE,
Current Contents, and PsycINFO from 1980 to December 2006
were conducted using the following key words: antidepressants,
breastfeeding, human milk, lactation, mood disorders, M=P

SSRIs during breastfeeding

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 and
milk 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 conversely reviewed.

Results
Fluoxetine
Preliminary information about the excretion of the medication in human milk and the M=P ratios of both fluoxetine 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 paediatrician 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 behavioral or developmental outcome in the infant. Also in
this study, the M=P ratios for the parent drug and its
metabolite 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 obsessive-compulsive disorder and three by major depressive
episodes) were studied by Yoshida et al (1998). No adverse events were recorded during the early postpartum
period, despite in some women the M=P ratios for fluoxetine 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 characterize the M=P ratio and the infant dose for fluoxetine
and norfluoxetine in a relatively large number of breastfeeding women taking the medication for the treatment
of their depression (Kristensen et al, 1999). The absolute
infant dose, calculated as fluoxetine equivalent, was determined by 2 different methodologies (both assuming

41

an oral availability of 100% and an average milk intake

of 0.15 L kg
1 day). Fluoxetine was detected in 5 of
the 9 infants from whom samples were collected, whereas 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 were
assessed by interviewing the mother and=or the paediatrician. 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 demonstrated 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 serum. Mothers were questioned about potential unwanted
sequelae to their infants and did not report any such
findings, 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 conducted 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 summing 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

N=A

N=A

mean 67.3

N=A

N=A

N=A

N=A

mean 74.1

N=A

Burch & Wells (1992)

(n 1)

Yoshida et al (1998)
(n 4)

Kristensen et al (1999)
(n 14)

Hale et al (2001)
(n 1)

Suri et al (2002)
(n 10)

Hendrick et al (2001)
(n 19)

Heikkinen et al (2003)
(n 11)

Kim et al (2005)
(n 9)

Berle et al (2004)
(n 1)

For the sum of fluoxetine and norfluoxetine.

N=A

Isenberg (1990)
(n 1)

Maternal body
weight (kg)

Study=sample
size

20

1030

2040
(mean 20)

1060

2060

20

2080

2040

20

20

Maternal
dose (mg)

Table 2. Fluoxetine (FLX)=norfluoxetine (NFX)

N=A

mean 3.7 months

pregnancy, delivery,
day 2, day 4,
week 2, month 2

534 days

5 weeks3 months

day 11

N=A

118 days

2 months

3 months

Postpartum
time

85 days

the mothers took the

compound during
pregnancy for a
minimum of 3 weeks
prior delivery

6 women used FLX

during pregnancy;
5 started taking FLX
later in pregnancy
(week 2235)

throughout pregnancy
to day 4 after
parturition

the mothers started FLX

treatment during
breastfeeding (after a
minimum of 6 weeks
treatment)

the mothers took the

compound during the
entire pregnancy duration

1375 days

1252 weeks

53 days

2 months

Antidepressant
treatment duration

no

0.31
immediately before
administration
of the next dose

no
R-FLX
mean 0.84
S-FLX
mean 0.54
R-NFX
mean 0.75
S-NFX
mean 0.55

variable

no

FLX 0.32.2
NFX 0.11.7

N=A

no

no

somnolence, lethargy,
fever, unresponsiveness

2 cases of colic
2 cases of withdrawal
syndrome

no

no

irritability

Repercussions on
the clinical outcome

FLX 0.656.09
NFX 0.372.08

NFX 0.51.4

FLX 0.13.92

mothers serum and milk

samples were collected
at different times

FLX 0.520.84
NFX 0.350.77

FLX: 0.521.45
NFX 0.081.1

FLX 0.49
NFX 0.34

FLX 0.28
NFX 0.21

M=P ratios

N=A

N=A

N=A

variable

N=A

4h

N=A

Time post
maternal dose

42
S. Gentile et al

SSRIs during breastfeeding

disorder were recruited in a relatively recent study

(Heikkinen et al, 2003). Common clinical doses of the
medication results in lower trough plasma concentrations of fluoxetine and fluoxetine plus norfluoxetine than
those detected in a clinical setting with similar doses in
the nonpregnant state, because of increased demethylation 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 concentration) 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 concentrations 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 considerably 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
hman et al (1999). The mean paralso quantified by O
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 increase 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 paroxetine dose per kg body weight was calculated by a
specific equation.

43

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 observed 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 101 ng=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 agoraphobia (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 occurring between hours 1 and 9 after the drug intake. The
M=P ratio was lower than 1.0. Sertraline was also quantitated in the infant serum specimens: neither appreciable sertraline levels in the infants serum nor adverse
events were demonstrated. However, the desmethylmetabolite was not measured.
In the study by Stowe et al (1997) sertraline showed a
gradient from foremilk to hindmilk; the peak in breast-

Maternal body
weight (kg)

60

5267

5386

N=A

N=A

N=A

N=A

66.9135.8

Study=sample
size

Spigset et al (1996)
(n 1)

hman et al (1999)
O
(n 6)

Begg et al (1999)
(n 10)

Stowe et al (2000)
(n 16)

Misri et al (2000)
(n 24)

Hendrick et al (2000)
(n 1)

Berle et al (2004)
(n 6)

Weissman et al (2004)
(n 3)

Table 3. Paroxetine (PAR)

1030

1030

10

1040

1050

1030

2040

20

Maternal
dose (mg)

7.328.1 weeks

N=A

3 weeks

110.5 months

455.2 weeks

N=A in both evaluations

N=A

milk levels were obtained

10 days after parturition,
whereas serum levels
were obtained later
(after the maternal dose
had been increased to
40 mg=day)

Postpartum time

2156 weeks

at least 14 days

3 weeks

N=A

longer than 10 days

at least 2 weeks at the

same dosing schedule
(first evaluation)
N=A in the second
evaluation

at least 8 days

milk levels were obtained

7 days after parturition,
whereas serum levels
were obtained later
(after maternal dose
had been increased to
40 mg=day)

Antidepressant
treatment duration

810 h

immediately before
administration of the
next dose

immediately after
drug intake

about 6 h

15 h

first evaluation: at a time

as close as possible to
the drug administration
second evaluation: Around
a normal infant feeding time

0.580.79

0.60.9

breast milk levels

were below the
quantification limits

0.111.67

0.0561.3

0.323.33

0.69  0.29

mean  SD

0.09

milk levels were calculated

4 h after drug intake

first evaluation: 47 h
after drug intake
last evaluation: 24 h
after drug intake

M=P ratios

Time post maternal dose

no

no

no

no

no

no

no

no

Repercussions on
the clinical outcome

44
S. Gentile et al

N=A

N=A

mean 71.1

N=A

N=A

52.498.0 (data
available for 4=19
women)

Stowe et al (1997)
(n 11)

Stowe et al (2003)
(n 26)

Kristensen et al (1998)
(n 8)

Dodd et al (2000)
(n 10)

Berle et al (2004)
(n 6)

Weissman et al (2004)
(n 19)

The mother also took nortriptyline, 125 mg=day.

N=A

Altshuler et al (1995)
(n 1)

Maternal body
weight (kg)

Study=sample
size

Table 4. Sertraline (SER) and its metabolites

50100

50100

N=A

4.019.6 weeks

N=A

N=A

1.814.2 months

436 weeks

123.9  62.8

50200

4141

3 weeks

100a

25150

Postpartum
time

Maternal
dose (mg)

N=A

at least 14 days

more than 2 weeks on

fixed dose

1.184.25 months

12 mothers started
antidepressant treatment
during pregnancy, 8 after
parturition. For 1 woman the
information was unavailable

3 mothers started
antidepressant treatment
during pregnancy, 9 after
parturition

the mother started

antidepressant treatment
during pregnancy

Antidepressant
treatment duration

immediately before
administration
of the next dose
127 h

426 h

at 0, 1, 2, 3, 4, 6,
8, 12, and 24 h

N=A

N=A

12 h (maternal
serum)

Time post
maternal dose

no

SER 1.76  1.72

SER 0.543.0
norsertraline 0.381.66
(data available
for 4=19 women)

no

no

no

SER 1.93  0.16

desmethylsertraline 1.64  0.19

SER 1.23.5
desmethylsertraline 0.64.7

no

no
no

SER 2.3  1.3

desmethylsertraline 1.4  0.8

0.484.81 (for both SER

and desmethylsertraline)

no

Repercussions on
the clinical outcome

SER 0.53

M=P ratios

SSRIs during breastfeeding

45

46

milk occurred however later, between 7 and 10 hours

after dosing; M=P ratios for both the drug and its metabolite 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 same
research group (Stowe et al, 2003).
In a further study, neither sertraline nor its metabolite 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 sertraline was found to be higher than 1.0.
No detectable levels of sertraline were found in 6
infants whose mothers took the compound while breastfeeding (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 the
M=P ratios for both sertraline and its metabolite.
Citalopram and escitalopram
Data on the excretion of citalopram into breast milk have
hman et al (1997) found that
been available since 1997. O
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 metabolite. However, despite the amount of citalopram transferred 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

S. Gentile et al

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 of
concern 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 demethylcitalopram in two. Such infants showed normal
development for age as assessed by the Denver developmental 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 efficacy and safety of citalopram in relation to concentrations 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 neurodevelopmental delay (spontaneously resolved without any further problem) was reported.
In the study by Berle et al (2004), the ingestion of
citalopram 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 human 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 maternal milk. However, all the symptoms disappeared spontaneously 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

61

6470

40

mean
62.6

N=A

N=A

65.373.4

55

5865

Jensen et al (1997)
CIT (n 1)

Spigset et al (1997)
CIT (n 3)

Schmidt et al (2000)
CIT (n 1)

Rampono et al (2000)
CIT (n 7)

Heikkinen et al (2002)
CIT (n 11)

Berle et al (2004)
CIT (n 9)

Weissman et al (2004)
CIT (n 2)

Franssen et al (2006)
CIT (n 1)

Rampono et al (2006)
ESC (n 8)

1020

40

20

2050

2040

mean
36

40

2040

20

2060

Maternal
dose (mg)

N=A

at 12, 25, 46,

and 53 days
after delivery

1.611.7 months

N=A

N=A

mean
4.1 months

N=A

210 months

N=A

N=A

Postpartum
time

23240 days

the woman started

taking the drug
during pregnancy

1226 weeks

at least 14 days

10 women started
CIT at the time of
conception, 1 at 20
weeks of pregnancy

mean
97 days

10 days

N=A

15 days

N=A

Antidepressant
treatment duration

just before the morning

dose and at 2, 4,
and 6 h after dose

N=A

910 h

immediately before
administration
of the next dose

just before
taking the drug

at 0, 2, 4, 6, 8,
12, and 24 h

N=A

before the daily

dose and 4 h later
in 2=3 of womena

N=A

3.56.5 h

Time post
maternal dose

ESC 1.72.7
desmethylescitalopram
1.83.1

CIT 2.02.8

CIT 0.931.79
desmethylcitalopram
1.361.56
didesmethylcitalopram
1.832.0

CIT 1.14.3
desmethylcitalopram
0.96.3

CIT 1.23.3
desmethylcitalopram
1.34.1
didesmethylcitalopram
1.14.6

CIT 1.23.0
demethylcitalopram
1.02.5

CIT 2.07

no

sleep and respiratory

disturbances,
hypo=hypertonia

no

no

no

no

uneasy sleep, resolved

after maternal dose
reduction

no

no

3 for both the drug

and its metabolite
CIT 1.161.88

no

Repercussions on
the clinical outcome

CIT 1.812.24
demethylcitalopram
2.052.91

M=P ratios

In the third woman (a healthy volunteer) serum samples were obtained after 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 h. Breast milk samples were obtained after 2, 4, 6, 8, 14, 24, 48, 72 h.

N=A

hman et al (1997)
O
CIT (n 2)

Maternal body
weight (kg)

Drug=study=sample
size

Table 5. Citalopram (CIT), its metabolites, and escitalopram (ESC)

SSRIs during breastfeeding

47

48

S. Gentile et al

Table 6. Fluvoxamine (FVX)

Study=sample size

Maternal body
weight (kg)

Maternal
dose (mg)

Postpartum
time

Antidepressant
treatment duration

Time post
maternal dose

M=P
ratios

Repercussions on
the clinical outcome

Wright et al (1991)
(n 1)
Yoshida et al (1997)
(n 1)
Hagg et al (2000)
(n 1)
Kristensen et al
(2002) (n 2)
Weisman et al
(2004) (n 1)

70

200

14 weeks

2 weeks

4 h and 45 min

0.29

no

N=A

100

17 weeks

2 weeks

3h

0.29

no

90

200

3 months

25 weeks

1.061.59

no

5470

50150

36 weeks

mean 1.01

no

62.4

250

0.7526.5
months
29.1 weeks

every hour during

a 12-h period
at 0, 1, 2, 3, 4, 6,
8, 12, and 24 h
9h

1.02

no

94 weeks

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 available in Table 5.
Fluvoxamine
The first study evaluating the excretion of fluvoxamine
in breast milk of a woman affected by post-natal depression 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 effects in this infant.
These results were replicated in a further case report;
the infant showed neither acute toxic effects of fluvoxamine 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=kg
1 of milk per day.
In contrast, significantly higher M=P ratios were
reported by Hagg et al (2000), although no unusual reactions were observed in the infant.
An M=P ratio higher than 1.0 (without any complications in the infants) was also reported in two breastfeeding women (Kristensen et al, 2002). The study did not
include the analysis of serum infant samples.
Further data on the excretion of fluoxetine into human 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 bodyweight 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, medications
also 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, subsequently 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 lactation (Crisholm and Kuller, 1997).
Furthermore, milk composition varies even during a
single breastfeeding session, with milk expressed towards the end of a feeding having greater fat contents
(Pediatric Pharmacotherapy, 1996. No Authors listed).

SSRIs during breastfeeding

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 be
absorbed (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 Pharmacotherapy, 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 evaluation) 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 ratios
calculated 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 antidepressant 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 often
misleading 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 fluoxetinerelated untoward events in the suckling infants reported

49

an M=P ratio lower than 1.0, and their results were also
contaminated by two potential confounding factors: maternal 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 to
citalopram 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 placental 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 <1.0 should be preferred.
Conclusions
Studies evaluating this specific safety-facet of SSRIs
for breastfed infants evidence too much limited data in
order to make definitive conclusions. This situation is not
surprising: women and children have been left out of
pharmacological research (Freeman & Anthony, 2004).
As a result, medications that are frequently needed during
puerperium are insufficiently studied in this population.
Hence, physicians should consider different parameters when attempting to choose the safest SSRI for
the breastfeeding woman.
Since there is no appropriate model to predict milk concentrations of drugs in humans (Larsen et al, 2003), these
parameters might be mainly represented by the ratio
between safe and unsafe reports (Breastfed Infants Antidepressant Safety Index BI-ASI Gentile, 2007).
The tendency of each SSRI of inducing in the infants serum concentrations that are elevated above 10%
of average maternal serum levels (Begg et al, 1992;
Weissman et al, 2004; Whitby & Smith, 2005; EberhardGran et al, 2006) may also represent an useful parameter: indeed, the notional safety limit of 10% (also called
relative infant dose, or weight-adjusted maternal
dose sometimes) should not be dismissed. If one considers that most newborns are expected to have 20% or
more of the maternal capacity to clear drug (and this
increases with age to adult levels at about 6 months),
then his 10% of maternal weight-adjusted dose is both
practical and reasonably conservative as a yardstick.
Moreover it is applicable to all drugs with data, even
those for which there is just a single case report. The last
information, however, should be obtained by a direct

50

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:
salvatore_gentile@alice.it