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Maternal use of SSRIs, SNRIs and NaSSAs: practical
recommendations during pregnancy and lactation
S D Sie,1 J M B Wennink,2 J J van Driel,2,3 A G W te Winkel,4 K Boer,5 G Casteelen,6
M M van Weissenbruch1
▶ Appendix A is published
online only. To view this file
please visit the journal online
(http://adc.bmjgroup.com)
1Department
of Neonatology,
VU University Medical Center,
Amsterdam, The Netherlands
2St. Lucas Andreas Hospital,
Amsterdam, The Netherlands
3Department of Pediatrics,
VU University Medical Center,
Amsterdam, The Netherlands
4Teratology Information
Service, Netherlands
Pharmacovigilance Centre,
‘s-Hertogenbosch,
The Netherlands
5Department of Obstetrics
& Gynaecology, Academic
Medical Center, Amsterdam,
The Netherlands
6Department of Psychiatry,
Academic Medical Center,
Amsterdam, The Netherlands
Correspondence to
S D Sie, Department of
Neonatology, VU University
Medical Center, PO Box 7057,
1007 MB Amsterdam,
The Netherlands;
[email protected]
Accepted 15 June 2011
Published Online First
28 July 2011
ABSTRACT
Selective serotonin reuptake inhibitors (SSRIs) are
increasingly used during pregnancy and lactation,
with 1.8–2.8% exposed pregnancies. Given the
risks of untreated maternal depression for both
mother and child, adequate treatment is essential. If
pharmacological treatment with SSRIs is indicated,
the fetal and neonatal effects of SSRIs have to be
considered, as SSRIs cross the placenta and are
excreted into breast milk. The overall risk of major
congenital malformations during SSRI exposure in the
first trimester does not appear to be greatly increased.
Depending on the variability in pharmacokinetic
properties between the different SSRIs and the
individual drug metabolism of mother and child, SSRI
exposure during late pregnancy can lead to serotonin
reuptake inhibitor-related symptoms in up to 30% of
exposed infants postnatally. Symptoms are generally
mild and self-limited, but need observation during at
least 48 h as some infants develop severe symptoms
needing intervention. Limited data are available about
the long-term neurodevelopmental outcomes after SSRI
exposure during pregnancy and lactation, but currently,
cognitive development seems normal, while behavioural
abnormalities may be increased.
In this article, the available clinical data are reviewed.
Additionally, the authors provide a multidisciplinary
guideline for the monitoring and management of
neonates exposed to SSRIs during pregnancy and
lactation.
INTRODUCTION
Depression is a common mental disorder with
a lifetime prevalence rate of 16.2%.1 Women,
especially during their childbearing age, are at
increased risk for fi rst onset of major depression
and have a lifetime rate of major depression 1.7–
2.7 times greater than men. 2 During pregnancy,
prevalence rates vary widely from 1% to 20%,
depending on the classification used. 3–7
Besides maternal morbidity and mortality,
untreated or undertreated depression is associated with perinatal complications like caesarean delivery, prematurity and low birth weight,
lower-quality interactions between mother and
child and higher levels of psychiatric disturbances
among children.4 5 8 Cohen et al9 described that
68% of women who discontinued antidepressant
medication experienced a relapse of major depression during pregnancy, compared with 26% who
maintained their medication. Given the potential
serious consequences of perinatal depression for
both mother and child, adequate treatment is
essential. However, only few pregnant women
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seek treatment and only very few, small studies
compare obstetric and neonatal outcomes after
treated and untreated depression.6 10–12
Treatment of depression consists of non-pharmacological strategies, like psychotherapy, and
pharmacological treatment with antidepressants.
Although non-pharmacological interventions can
be effective, most studies focus on pharmacological treatment.13 Nowadays, selective serotonin
reuptake inhibitors (SSRIs) are widely prescribed
for the treatment of both depression and anxiety
disorders. They are the most commonly used
antidepressant medication in general and during
pregnancy,8 with 1.8–2.8% pregnancies exposed
to SSRIs.12 14–16 It is also used in anxiety disorders.
Recently, Yonkers et al17 developed algorithms
for periconceptional and antenatal management
of depression. As SSRIs are frequently used during pregnancy, practical recommendations for the
management of neonates exposed to SSRIs during
the third trimester of pregnancy and during lactation are given.
SSRIS
Serotonin is a neurotransmitter released from
serotonergic neurons and dysregulation of serotonergic activity may lead to mood and behaviour
problems. SSRIs selectively inhibit the reuptake
of serotonin into the presynaptic cell, leading to
increased levels of serotonin in the synaptic cleft.
Other, increasingly used, antidepressants are
venlafaxine, a serotonin-noradrenalin reuptake
inhibitor (SNRI) or mirtazapine, a noradrenergic
and specific serotonergic antidepressant (NaSSA).
Differences are observed with respect to
the pharmacokinetic properties among SSRIs
(table 1).18 Furthermore, pharmacodynamics are
affected by enzyme polymorphism and individual drug metabolism.
Side effects of SSRIs and SNRIs tend to be similar and include gastrointestinal symptoms, headache, insomnia and agitation. Tremors, excessive
sweating and weight changes are also reported.
Somnolence is seen in patients using mirtazapine,
due to its antihistaminergic effect.
FETAL EFFECTS
Initially, small studies on humans observed no
increased risk of major congenital malformations
after in utero exposure to SSRIs or SNRIs, nor
as a class, nor individually.19–23 However, more
recent data with larger cohorts suggested an association with congenital heart defects, especially
septal defects and, in particular, after exposure to
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Table 1
Pharmacokinetic properties of SSRIs, SNRIs ands NaSSAs
SSRI
Paroxetine
Fluoxetine
Sertraline
Citalopram
Escitalopram
Fluvoxamine
SNRI
Venlafaxine
NaSSA
Mirtazapine
Time to peak
(hours)
Elimination
half-life (hours)
Daily dose
(mg)
6–10
6–8
4–8
3–4
5
3–8
15–20
96–144
26
36
27–32
15–26
20–50
20–60
50–200
20–60
10–20
50–100
6–9
5–11
75–375
1–2
37 (Female), 26 (Male)
30–45
NaSSA, noradrenergic and specific serotonergic antidepressant; SNRIs,
serotonin-noradrenalin reuptake inhibitors; SSRIs, selective serotonin
reuptake inhibitors.
paroxetine.24 25 However, after adjustment for potential confounders, there was no significant association with cardiac
malformations for paroxetine in the fi rst study. 26 Källén et al
extended their data with more patients resulting in a lower
OR (1.66, 95% CI 1.09 to 2.53) for paroxetine and risk of any
cardiovascular defect. 27 28 Several small studies thereafter gave
inconclusive results.14 29–38 Methodological differences make
comparison between the studies difficult. Considering the
known incidence of congenital heart defects in the general
population and the possible small increased risk associated
with SSRIs, the overall risk of congenital heart defects is still
relatively low. Nevertheless, it seems prudent to perform fetal
echocardiograpy to women taking paroxetine during pregnancy and possibly to those taking other SSRIs. Regarding
the overall risk for other malformations, until now the prevalence of major birth defects does not appear to be greatly
increased.8
The available clinical data for specific antidepressants
vary widely. Fluoxetine, paroxetine, citalopram and citalopram are the most studied SSRIs (more than 5000 subjects),
compared with fluvoxamine, escitalopram and mirtazapine
(around 300 subjects) and venlafaxine (around 1300 subjects).
Currently, there is no association with major congenital malformations and use of venlafaxine or mirtazapine during
pregnancy. 28 33 39–42
EFFECTS ON THE NEWBORN
A variety of symptoms have been reported after prenatal exposure to SSRIs and to a lesser extent to SNRIs and NaSSAs. These
symptoms include tremors, jitteriness, irritability, muscle tone
regulation disorders, excessive crying, sleep disturbances, tachypnoea and feeding problems.43–45 Less frequently, lethargy,
weak cry and convulsions have been reported.46 47 Symptoms
generally occur within 2 days after birth and are usually selflimiting.44 45 48 Some retrospective cohort studies report an
increased OR for hypoglycaemia after in utero SSRI exposure.
However, indications (like jitteriness or feeding problems) for
glucose measurements are not reported. Therefore, no recommendations can be given on whether routine glucose measurements are indicated. 28 49–51
Although non-specific, these clinical features are similar to the signs seen in adult SSRI discontinuation syndrome
and resemble the neonatal withdrawal syndrome. However,
the clinical picture is indistinguishable from direct toxicity
of SSRIs/SNRIs, leading to overstimulation of the serotonergic system.44 Large pharmacological studies to distinguish
withdrawal from toxicity are lacking. It is conceivable that the
underlying mechanism might be different between patients
and specific SSRIs/SNRIs, reflecting withdrawal in one and
toxicity in another individual patient. Therefore, the term
serotonin reuptake inhibitor (SRI)-related symptoms is used.
The SRI-related symptoms occur in approximately 30% of
in utero exposed infants.45 48 Several additional factors, like
maternal dose and metabolism, the specific SSRI used, the
individual drug clearance and possibly genetic predisposition,
may be needed for symptoms to develop. 52 Levinson-Castiel
et al48 used the Finnegan score to identify and classify SRIrelated symptoms in 60 prenatally exposed neonates. In the
symptomatic group, 10 showed mild and 8 showed severe SRIrelated symptoms. No infant required any specific treatment.
The Finnegan score is an objective method used in the observation of neonatal withdrawal symptoms in neonates exposed
to hard drugs to identify the patients needing intervention.48 53
A Finnegan score ≥8 indicates severe symptoms with the need
of intensification of the observation and measurements. If
Finnegan scores remain high, pharmacological intervention
should be considered. Although the Finnegan score is a nonvalidated tool in antidepressant-exposed infants, until now
other objective tools are not available. 53 One should take into
account that most studies focus on SSRIs and that less data
about SNRIs and NaSSAs are available.
Persistent pulmonary hypertension of the neonate (PPHN)
is a serious and sometimes fatal condition occurring in one or
two infants per 1000 live births. A case-control study of risk
factors for PPHN, found an association between late prenatal
exposure to SSRIs and the occurrence of PPHN. In the PPHN
group, 3.7% was exposed to SSRIs after 20 weeks of gestation, adjusted OR 6.1 (95% CI 2.2 to 16.8). 54 Reis et al found
an increased risk of PPHN after 15 cases of SSRI exposure
in early pregnancy, RR 2.30 (95% CI 1.29 to 3.80). 28 54 Drug
use late in pregnancy was not documented unless it was prescribed by the antenatal clinic. Two small retrospective cohort
studies found no increased risk. Andrade et al 55 compared 1104
infants exposed to antidepressants in the third trimester (85%
SSRIs) and 1104 controls, no difference in prevalence of PPHN
between the two groups were found. In Rochester, 16 cases
of PPHN among 25.214 deliveries were observed, not between
the 808 SSRI users.42 In another case-control study, 377 cases
of PPHN were reviewed for possible risk factors. SSRI use was
not a risk factor. Wilson et al also did not observe SSRI use as a
risk factor for PPHN. 56 57
Based on the available literature to date, no reliable conclusions about associations between PPHN and SSRI exposure can
be made. However, it appears that the absolute risk of PPHN
after SSRI exposure is not greatly increased. 58
NEUROBEHAVIOURAL DEVELOPMENT
Only few studies examined the effect of exposure to antidepressants on neurobehaviour and cognitive functioning. In
a review about long-term effects after prenatal and postnatal exposure to SSRIs, 13 studies with 387 children in total
were reviewed. In 11 studies (paroxetine=69, fluoxetine=216,
fluvoxamine=1, sertraline=8, citalopram=11), no impairment
in neurodevelopment after prenatal or postnatal SSRI exposure is demonstrated. Two studies suggested possible subtle
effects on motor development (fluoxetine=7, paroxetine=8,
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fluvoxamine=1, sertraline=15, not specified=50). 59 A prospective study conducted by Oberlander et al60 did not observe a
relationship with externalising behaviour of 4-year-old children after prenatal SSRI exposure. Klinger et al assessed the
long-term neurodevelopment of children who developed SRIrelated symptoms. Infants with SRI-related symptoms had
normal cognitive ability, but were at increased risk for socialbehavioural abnormalities.61
Most studies evaluated neurodevelopmental outcome in the
fi rst years, which is a poor predictor for neurodevelopmental
and cognitive functioning later in life. Also, the majority of
these studies concerned fluoxetine and to a lesser extent paroxetine exposure, so the effects of other SSRIs, SNRIs and
NaSSAs are even less established. Due to methodological limitations and the lack of large population-based studies with
extended follow-up, so far the long-term neurodevelopmental
outcome remains unclear.
EFFECTS DURING LACTATION
SSRIs and SNRIs are excreted into breast milk in greater or
lesser extent. In general, drug excretion depends on several
factors like lipid solubility, maternal dose and metabolism,
composition of fore and hind milk and time to milk peak concentration.62 Also, bioavailability of the drug in newborns and
the infant’s individual metabolism play a role in the infant’s
exposure to the drug during breastfeeding.63 Thus, there is
a great variability in milk concentrations between breastfed
infants as well as between the individual drugs.
Several methods, like the theoretic infant dose (ID) and
the milk-to-plasma ratio (M/P ratio) are used to establish the
amount of drugs excreted into breast milk and the risks during breastfeeding. The M/P ratio represents the ratio of drug
concentration in breast milk to drug concentrations in maternal plasma.63 The theoretical ID is the multiplication of the
drug concentration in milk and the amount of milk taken. The
relative ID is the percentage of the theoretic ID/kg/day and
the maternal dose/kg/day. A relative ID above 10% is considered to be of potential clinical significance.64 Table 2 gives the
relative ID for and the experience with the specific antidepressants. Note that some SSRIs, venlafaxine and mirtazapine are
less well studied during lactation.
Both fluoxetine and its effective metabolite norfluoxetine
have a long elimination half-life (4–6 days and 4–16 days,
respectively) and a relative ID of 6.5–11%.62 Due to its
long elimination half-life, fluoxetine can accumulate in the
newborn, subsequently resulting in an increased relative
ID. Several case reports describe short-term complications
Table 2
Management of maternal depression or anxiety disorder
is best evaluated and adjusted before conception to ensure
proper treatment during pregnancy. Regarding the adverse
outcomes of maternal depression, recognising the symptoms
and adequate treatment are essential. The different treatment
options should be carefully evaluated and if possible, nonpharmacological treatment is preferred. If pharmacological
treatment is indicated, several factors are of influence in the
choice of antidepressants: prior response to pharmacological
treatment, gestation, intention to breast feed and the safety
profi le based on the available experience.
In patients already receiving SSRIs, clinicians, for example,
psychiatrists, should evaluate if pharmacological treatment has
to be continued. In general, treatment should be unchanged in
patients whose symptoms are well controlled. Some patients
may be candidates for medication taper and discontinuation or
switching to a more ‘safe’ antidepressant may be considered.
Meanwhile, their clinicians should be alert to the relapse of
depressive symptoms.12 17
Postnatal management
After prenatal SSRI/SNRI exposure during the third trimester,
infants should be closely observed for SRI-related symptoms,
preferably close to their mothers on the maternity ward.
An observation period of at least 48 h should be sufficient to
identify infants with SRI-related symptoms needing intervention. Finnegan scores every 8 h are a useful instrument for an
objective observation (Appendix A).
Available data (n)64 66
Selective serotonin reuptake inhibitor
Fluoxetine
6.5–11
116
Paroxetine
1.13–1.25
123
Sertraline
0.2
146
Fluvoxamine
1.34–1.38
13
Citalopram
4.4–5.1
72
Escitalopram
12
Serotonin-noradrenalin reuptake inhibitor
Venlafaxine
6.5
10
Noradrenergic and specific serotonergic antidepressants
Mirtazapine
±2
10
fetalneonatal214239.indd Sec1:3
PRACTICAL RECOMMENDATIONS
Preconception and pregnancy
Relative infant dose and available clinical data during lactation
Relative infant dose (%)
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during exposure to fluoxetine in lactation.62 To minimise
infant exposure, milk peak concentrations can be avoided by
‘pump-and-dump’ breast milk during the time interval when
peak concentrations in milk is established, however, the time
to peak concentration in milk is individually determined.65
There is a debate whether breast feeding can ameliorate SRIrelated symptoms, which would be conceivable in the case of
a withdrawal mechanism. Until now, no comparative studies
are available. Whether chronic exposure during lactation to
SSRIs, SNRIs or NaSSA affects the developing human brain
remains unanswered.
The benefits of breast feeding are well established. When
decisions have to be made concerning lactation during maternal use of antidepressants, these benefits should be taken into
consideration, especially in this particular group of patients.
Available data (n)67
Lactation
200
131
143
14
76
9
Discourage
Preference
Preference
Consider
Consider
Consider
15
Consider
9
Consider
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untreated depression and/or the benefits of breast feeding.
Moreover, both clinicians and parents should be aware of the
limited available data about long-term neurodevelopmental
outcome after SSRI exposure during pregnancy and lactation.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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Figure 1 Practical recommendations for maternal use of SSRIs,
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13.
14.
Finnegan score <4: no SRI-related symptoms.
Finnegan score 4–7: mild SRI-related symptoms; symptoms are usually self-limiting and supportive care is usually sufficient.
▶ Finnegan score ≥8: serious SRI-related symptoms; intensification of Finnegan scores every 2 h. If Finnegan scores
remain ≥8 in three subsequent measurements, treatment is indicated, for example, with phenobarbitone and
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Neurodevelopmental follow-up focusing on behaviour
should be considered in infants with significant SRI-related
symptoms.
▶
▶
Lactation
Currently, there is no evidence that breast feeding should be
actively discouraged in maternal use of sertraline or paroxetine; less is known about other antidepressants. There is one
exception: due to the long elimination half-life of fluoxetine
and the risk of accumulation, we discourage breast feeding in
the case of maternal use of fluoxetine.
A summary of the practical recommendations is provided
in figure 1.
Overall, when making a decision on the continuation of
SSRIs during pregnancy and lactation, the fetal and neonatal effects of SSRIs have to be balanced out to the risks of
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Arch Dis Child Fetal Neonatal Ed 2012;97:F472–F476. doi:10.1136/archdischild-2011-214239
9/29/2012 4:38:58 PM
Downloaded from fn.bmj.com on November 7, 2012 - Published by group.bmj.com
Maternal use of SSRIs, SNRIs and NaSSAs:
practical recommendations during
pregnancy and lactation
S D Sie, J M B Wennink, J J van Driel, et al.
Arch Dis Child Fetal Neonatal Ed 2012 97: F472-F476
doi: 10.1136/archdischild-2011-214239
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