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Fetal Effects of Selective Serotonin Reuptake Inhibitor Treatment During Pregnancy: Immediate and Longer Term Child Outcomes
Bromley R.L1*., Wieck, A2., Makarova D3., Tower C4., Wood, A3. & Clayton-Smith J5,6.
1 Division of Clinical Psychology, School of Psychological Science, University of Manchester
2 Department of Psychiatry, Manchester Mental Health and Social Care Trust
3 School of Psychology, University of Birmingham
4 Maternal and Fetal Health Research Centre, Manchester Academic Health Sciences Centre
5 Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre
6 Department of Biomedical Science, University of Manchester
* Correspondence to Dr Rebecca Bromley, Division of Clinical Psychology, School of Psychological Science, University of Manchester, Oxford Road, M13 9PL. .+44 161 306 0400. [email protected] .
Introduction
It is estimated that 20% of women experience symptoms of depression during pregnancy (1)
and antidepressant medication is prescribed for between 2% and 8% of pregnant women
depending on the country of report(2-4). In the UK antidepressant prescribing during
pregnancy increased fourfold from 1992 to 2006, with Selective Serotonin Reuptake
Inhibitors (SSRIs) most often chosen (5). SSRIs cross the human placenta, with fetal levels
varying according to treatment type (6, 7) and are found in amniotic fluid (8). The
significance of prenatal exposure to SSRIs and outcomes in terms of the physical health and
the neurodevelopment of the infant and child remain unclear.
Several prescribed medications are known to be human teratogens, causing increased
prevalence of a range of physical and neurodevelopmental deficits in exposed infants (9).
Research into infant outcomes following prenatal exposure is challenging. Ethical constraints
do not permit the most rigorous design for investigation, i.e. randomized double-blind
controlled studies. In addition, variations in drug type, timing of exposure, dose, duration of
exposure, placental passage and genetic factors all require consideration alongside maternal
and infant demographic influences (e.g. maternal illness, socioeconomic status).
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Furthermore, a specific outcome type may be associated with specific risk variables and
require targeted investigation.
Maternal depression itself, either directly or indirectly, has been reported to influence
obstetric and neonatal outcomes (10-12). Although beyond the scope of this review,
research often fails to consider infant exposure in the womb to antidepressants (11, 12) .
Maternal antenatal depression is an important predictor of postnatal depression which may
also impact on infant neurodevelopment (13). Understanding the risks of maternal
depression and its treatment with regard to the development of the child is of paramount
importance for clinical decision making.
Serotonin is known to play a role in the development and physiology of the central nervous
system, the gastrointestinal and the cardiovascular systems (14). In the fetal brain serotonin
modulates different developmental processes including neurogenesis, apoptosis and axon
branching and therefore alterations in the serotonin system may directly impact on later
neuronal development (15). The role of serotonin in fetal development raises the possibility
that SSRI exposure in utero predisposes to structural birth defects and poorer longer term
outcomes, however, to date such a relationship is unclear.
This review aims to bring together clinical research that examines the immediate and longer
term physical and developmental risks to the child that may be associated with prenatal
exposure to SSRIs. The article also examines the methodological issues that may contribute
to conflicting findings.
Method
Inclusion criteria
Types of participants
Studies were included if they reported on the physical or neurodevelopmental outcome of
children exposed prenatally to an SSRI. Inclusion was not dependent on maternal illness
type. Exposure to the following SSRIs were considered: citalopram, sertraline, paroxetine,
escitalopram, fluoxetine and fluvoxamine.
Types of studies
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Studies were eligible for inclusion, if they had any of the following designs:
- case-control
- randomised controlled trials
- prospective observational
- retrospective observational
- record linkage
Included studies were limited to full peer reviewed articles, and to the English language.
Conference abstracts were excluded due to the limited amount of information on the
methodology utilised.
Types of outcome selected for review
Outcomes considered included aspects of neonatal health, childhood health, presence of
congenital malformations and neurodevelopmental outcome. Neonatal health outcomes
included growth parameters, withdrawal/adaptation and illness. Finally,
neurodevelopmental outcomes included IQ, language, motor, attention and other forms of
cognitive functioning as well as the presence of neurodevelopmental diagnoses such as
autistic spectrum disorder, attention deficit hyperactivity disorder and pervasive
developmental disorder.
Outcomes are reviewed by SSRI exposure type where possible. Studies that investigated
child outcomes following exposure to any one of the SSRIs, but reported them as a single
group are reported separately, due to the bias this later group may convey.
Searches
Literature searches were conducted using MEDLINE (OVID 1946-week 2 2012), EMBASE
(OVID 1980-week 15 2012) and PsycINFO (OVID 1946- June 2012). The following search
strategy was initiated: Pregnancy OR prenatal OR fetus OR fetal OR foetal OR uterine OR
utero OR gestation OR Exposure OR teratogenicity OR teratogen NOT animal AND
depression OR antidepressive OR antidepressant OR serotonin uptake inhibitors OR SSRI OR
citalopram OR fluoxetine OR paroxetine OR sertraline OR escitalopram OR Fluvoxamine AND
birth OR obstetric OR newborn OR weight OR neonatal, gestation OR illness OR
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abnormalities OR malformation OR defect OR dysmorphology OR growth OR development
OR discontinuation OR withdrawal OR adaptation OR child development OR
neurodevelopment OR neuropsychology OR cognitive OR neurobehavioural OR
neurobehavioral OR intellectual disability OR mental retardation OR IQ OR autistic disorder
OR autism OR attention deficit OR language. The final search update was conducted on 30
March 2012.
The search outcomes were cross-checked against drug summaries in the Reprotox Database
and against other review articles to ensure search reliability.
Data extraction
The search results were downloaded into reference manager software. Abstracts were
scrutinized for eligibility by a single author (R.B). Where eligibility was not clear from the
abstract the full text article was reviewed. The full text of all articles was reviewed to
confirm eligibility.
Studies where groups of children were exposed to a wide range of antidepressant types and
where there was no specific investigation into an SSRI group were excluded.
There is no recommended technique for the considering the quality of studies investigating
prenatal exposure to medications. A modified version of the Newcastle Ottawa Scale (16)
has been utilised to demonstrate strengths of study methodology in a previous review of a
related area(17). Based on this assessment, data was extracted from the methods sections
of the included studies, consistent with the areas outlined by the Newcastle-Ottawa Scale:
ascertainment, comparability and outcomes. Important considerations regarding dose of
exposure were also record, due to its significance within teratology (18).
Results
The search results generated 4840 abstracts and citations of which 904 were duplicates.
Hand checking of the abstracts removed 3,810 results. The full text of 126 articles were
reviewed to ensure eligibility. Seventy one studies met the inclusion criteria. Included
studies varied by their employed methodology and included: cohort studies; record linkage
and case-control. Investigations into neonatal health and/or major malformation prevalence
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represented the largest group of reported outcomes across studies, with few studies
investigating neurodevelopmental outcome.
Neonatal outcomes
Gestational age at birth
SSRIs
An increased prevalence of reduced gestational age at birth following SSRI exposure was
reported in seven studies investigating SSRI exposed cohorts (19-24). SSRI exposure was also
associated with a higher prevalence of preterm birth in five identified studies (20, 24-27).
Not all, however, confirmed such an association, with seven studies failing to replicate an
association (28-34). The study by Oberlander et al(22) employed a large record linkage
design (n=1575 early exposed and 1925 later exposed), with prospective ascertainment of
information through medical records and found an association between length of SSRI
exposure and gestational age at birth.
Several studies report that continuous or later gestational exposure is associated with
reduced gestational age (20, 22) and leads to higher rates of preterm birth(24). One study
that investigated the effect of dose of SSRI concluded that only higher than average doses
were associated with premature delivery and reduced gestational age (24), however the
slightly larger study by Hendrick et al(29) failed to find an association. Few studies
considered the impact of important maternal and child variables associated with the risk of
preterm birth, and when adjustment for confounding variables did occur it differed between
studies (Table 1).
Outcomes by SSRI type
Few studies have investigated preterm birth prevalence for specific SSRI exposures, but
there are single studies demonstrating that paroxetine(35) and fluoxetine(36) are associated
with preterm birth. Longer duration of fluoxetine exposure (n= 254) was positively
associated with preterm birth(36). Cohen et al(37), Pastuszak et al(38) and Suri and
colleagues(39) however did not demonstrate an association with preterm birth for
fluoxetine, although they failed to consider timing of exposure. Only one identified study
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investigated citalopram exposure (n=132) and failed to demonstrate an association
between exposure and preterm birth, however 50% of this cohort altered their dose or
discontinued citalopram prior to the end of the pregnancy(40).
Birth weight
SSRI
Six independent studies (seven publications) found an association between prenatal
exposure to SSRIs and reduced birth weight (often defined by authors as <2500g) or an
increase in the number of infants classified as small for gestational age (19, 22, 25, 28, 30,
34, 41, 42). The report by Kallen (25) extended the earlier report by Ericsson et al(43) from
the Swedish Birth Register and highlighted that the larger sample size altered the
conclusion. Seven studies failed to demonstrate an association (21, 24, 29, 31-33), however
these tended to include smaller sample sizes (Table 1).
The large record linkage study by Oberlander et al(22, 41) demonstrated that greater
duration of SSRI exposure was associated with lower birth weight. Although this was not
replicated in the study by Casper et al(20), a smaller cohort with reduced power to an detect
effect (n=55).
Outcomes by SSRI type
Fluoxetine
A possible association between fluoxetine exposure and lower birth weight has been
addressed in four identified studies (36, 37, 39, 44). Diav-Citrin et al(44) reported
significantly lower birth weight in infants exposed to fluoxetine (n=346), however no
adjustment for confounding variables was made. In another study, late exposure to
fluoxetine was reportedly associated with lower birth weight in an adjusted model, however
its relationship with low birth weight was confounded with maternal weight gain making the
association unclear(36). Finally, Cohen et al(37) found no association between early (n=11)
or late (n= 74) fluoxetine exposure and reduced birth weight, however the group of early
exposures was small.
Paroxetine
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No association between paroxetine and low birth weight was found in 55 paroxetine treated
infants (35), which differs from a larger study (n=410), which reported an association(44).
Neither study reported the influence of confounders on birth weight in their cohorts, which
may account at least in part for the contrasting findings.
Kallen(25) compared rates of small for gestational age infants following prenatal exposure
to paroxetine against an ‘other SSRI’ group and did not find significant differences in the
prevalence of infants being born 2 standard deviations below the mean. No comparison was
made been paroxetine exposure infants and infants not exposed to an SSRI in this study.
Citalopram
In 125 infants exposed for at least the first trimester to citalopram there was no difference
in birth weight in comparison to controls matched for maternal age and gestational age at
enrolment(40). No information on the number of women continuing citalopram to the end
of gestation is provided.
Neonatal adaptation
SSRIs
The prevalence of neonatal adaptation syndrome in exposed neonates was found to be
significantly higher in ten studies (11 publications) with estimates ranging from 4-28% (20,
22, 25, 27, 41, 42, 45-49). Across studies the estimated level of neonatal adaptation
symptoms ranged from 5%-30% of SSRI exposed neonates. The large range in prevalence
estimates may be accounted for by infant differences are likely accounted for by SSRI type
and possibly dose(7). Exposure later in pregnancy may be a significant factor in infants
within mixed type SSRI groups (22, 27). Neonate respiratory distress is frequently reported
(22, 25, 27), but is not noted in all cohorts (45).
Three studies failed to demonstrate an association between SSRI exposure and neonatal
adaptation (33, 50, 51). Warburton et al(51) reported late gestational exposure to SSRI to
be associated with respiratory difficulties but that the effect disappeared after controlling
for maternal illness, when comparing neonates exposed later in pregnancy versus those
exposed earlier on in gestation. Maternal illness in this study was not measured directly but
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by a number of proxy variables such as frequency of depression diagnosis and visits to a
psychiatrist. It remains to be seen whether there was a relationship between visits to
psychiatrist and dose of SSRI. No association was demonstrated between umbilical cord
concentration of drug and metabolites with neonatal adaptation symptoms in one study,
but participants were limited to 21(33).
Outcomes by SSRI type
A further consideration when analysing outcomes in SSRI treated infants as a single group is
that of the varied half lives of the individual SSRIs. Increased neonatal adaptation symptoms
have been reported in cohorts exposed to monotherapy fluoxetine, citalopram or
paroxetine(35, 36, 40). Fluoxetine exposure in the second and third trimester is reportedly
associated with increased neonatal adaptation problems(36), with a similar pattern
reported for paroxetine and respiratory distress(35). The study by Levinson-Castiel et al
(47)reported a significant correlation between dose of paroxetine and severity of neonatal
symptoms.
Persistent Pulmonary Hypertension
SSRIs
Six studies investigated the prevalence of persistent pulmonary hypertension following
prenatal exposure to SSRIs (52-57) and four demonstrate an association (53-56) (Table 1).
Chambers and colleagues (53) and Kallen and Olausson(54) utilised a case-control designs
and demonstrated an association between exposure to SSRIs and persistent pulmonary
hypertension following later SSRI exposure. Analysis of data from the Swedish Medical Birth
Register reported an increased odds ratios (OR) of 2.56 (95% CI 1.17–4.85) following
exposure later in gestation(56) which was consistent with Kieler et al(55). Two identified
studies whose sample sizes were considerably smaller (52, 57) did not find an association.
Outcomes by SSRI type
The case-control study by Kieler et al(55) demonstrates that the risk for persistent
pulmonary hypertension was similar across all SSRIs studied (sertraline, citalopram,
paroxetine, and fluoxetine) and concluded that this indicated a treatment class effect. No
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other identified studies investigated the prevalence of persistent pulmonary hypertension
following exposure to specific SSRI treatment types.
(Insert table 1 here)
Congenital malformations
SSRIs
Fifteen studies (nineteen publications) failed to demonstrate a significant relationship
between SSRI exposure as a class and an overall increased prevalence of major congenital
malformations (any type) (19, 20, 27-31, 43, 56, 58-66). Only two independent studies
(three publications) indentified a significant association (57, 67, 68) (Table 2).
Significant associations were reported between SSRI exposure and specific malformation
types in seven cohorts (58, 60, 62, 64, 65, 67, 69). A significant association with cardiac
defects was reported in six studies (62, 64, 65, 67, 69) in comparison to four others who
investigated but failed to find an association with cardiac defects (31, 58, 59, 63). Dubnov-
Raz and colleagues (70) reported an association between longer QTc intervals across SSRI
types (n=52). An increase in non-cardiac malformations was reported in two studies (58, 60).
However, the numbers of effected cases were small and different organ systems were
involved in these two studies.
Outcomes by SSRI type
Fluoxetine
Two studies reported a significant association between fluoxetine exposure and major
congenital malformations, regardless of type (56, 63). These two studies represent the
largest record linkage studies to date including over 1,500 pregnancies each and made
adjustment for confounding variables including maternal demographic, mental health and
child variables. Both of these studies represent updates on previous publications with
smaller cohorts, that failed to demonstrate an association previously (30, 60). In contrast,
and once the earlier publications from the Swedish and Finnish Birth Registries are removed
from consideration, five cohort studies failed to report an association (36, 38, 44, 67, 71)
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which was consistent with the negative findings from the case control studies by Pedersen
et al and Alwan et al (58, 65).
A significant relationship between fluoxetine exposure and specific malformations has been
reported in four studies (58, 63, 69, 72), three of which reported a significant association
with cardiac defects (63, 69, 72), with the fourth, a case control study, reporting an
increased risk of craniosynostosis (58). These results are in conflict with the results of four
other studies who examined specific malformation types following prenatal exposure to
fluoxetine but failed to find a significant effect (56, 62, 65, 67).
None of the studies reported above considered the dose or timing of fluoxetine exposure
and their effect on the prevalence and type of congenital malformation.
Paroxetine
Only two identified studies found an association between paroxetine exposure and an
increased prevalence of major congenital malformations in general (44, 73, 74), whilst
seven studies (nine publications) failed to demonstrate such an association (30, 56, 60, 63,
65-67). Interestingly, Berard and colleagues(74) failed to find an association between
paroxetine exposure and birth defects when a single paroxetine group was used. However,
stratification by dose revealed that higher than average daily doses (=/>25mg) were
associated with increased risk of defects, highlighting the methodological importance of
such considerations.
Seven cohorts demonstrated a significant association between paroxetine exposure and
cardiac defects (56, 62, 63, 69, 74, 75) including the Berard et al(74) study that
demonstrated an effect of dose. Six studies investigated but did not find a significant
association between paroxetine exposure and cardiac defects (44, 58, 59, 65, 67, 73, 76).
With the exception of the study by Berard and colleagues(74), no identified study
considered the implications of paroxetine dose on outcome as regards malformations.
Citalopram
No increased prevalence in terms of general major congenital malformation was
demonstrated by any of the identified studies. Three studies reported an association with
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specific malformations varying by type, including neural tube defects (63), cardiac defects
(65), anencephaly, craniosynostosis and omphalocele (58).
Five studies (eight publications) investigated but failed to replicate an association between
citalopram exposure and specific birth defects (40, 56, 59, 60, 62, 67, 69).
No identified studies considered the issues of dose, timing and duration of exposure.
Escitalopram
There were few studies investigating escitalopram, due to the latency between licence and
widespread use, thus limited comment can be made (60, 63, 67, 69). The recent study by
Malm et al(63) failed to find an association between overall or specific malformations in 441
escitalopram exposed infants, which is in contrast to a previous smaller (n=88) study(67). To
date there are no studies where dose, timing or duration of escitalopram has been
investigated.
Sertraline
No identified studies demonstrated a relationship between sertraline exposure and an
increased prevalence in major congenital malformations. Six studies (eight publications)
found no association between sertraline exposure and an increased prevalence of major
congenital malformations, regardless of type (30, 31, 56, 59, 60, 63, 65, 67). For example,
Reis and Kallen(56) found no association between sertraline exposure and a higher
prevalence of major congenital malformations in 3,297 exposed infants.
Three identified cohorts documented an increased risk of cardiac malformations, specifically
septal defects (62, 65, 67). The case control studies of Alwan et al(58) and Louik et al(62)
found an increased risk of omphalocele. Alwan et al did not, however, demonstrate an
increased rate of cardiac malformations, although they did not look at septal defects
specifically by individual SSRI type. An increase in specific malformations was not replicated
in three studies (five publications) (30, 31, 56, 60, 63).
No study addressed the relationship between dose of sertraline and major congenital
malformations and this may contribute to the differences between cohorts.
Fluvoxamine
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Similar to escitalopram, the majority of studies indentified included under 100 fluvoxamine
exposed births(30, 56, 59, 61, 67) and therefore do not undertake analysis specifically on
this SSRI.
(Insert table 2 here)
Neurodevelopment and behaviour
SSRIs
Fifteen studies were identified that reported neurodevelopmental or behavioural outcomes
following exposure to SSRIs as a class (Table 3). A significant difference was reported for
SSRI exposed infants or children in eight studies across one or more area of
neurodevelopment or behaviour (20, 49, 50, 77-81).
The neurodevelopmental outcomes measured differed across developmental domain (Table
3). Delayed motor development or impaired motor skills were the most commonly reported
developmental difficulty reported from six studies (20, 49, 50, 78, 80, 81). Reports included
altered motor activity in the fetal and neonatal period (49, 78, 81) and reduction in motor
performance on formal assessments in the infant years (20, 50). Further, a record linkage
study demonstrated an increased prevalence of motor delay (80) for children prenatally
exposed to SSRIs. In contrast, Simon et al (19) failed to find an increased rate of motor delay
in 185 SSRI exposed infants utilising a record linkage methodology.
Child IQ or global cognitive ability was assessed in three studies (20, 50, 82), but the
potential overlap in cases across two of the studies is not clear (20, 50). Only one of these
three studies employed a control group. Casper et al(50) compared child neurodevelopment
following exposure to SSRIs (n=31) to 13 children born to women with depressive
symptomatology who were not medicated. Klinger et al (82) compared the IQs of 30 infants
with neonatal adaptation with 52 infants without and failed to find that neonatal adaptation
was a significant predictor of later child IQ. Casper and colleagues (20) failed to find an
association between the timing and duration of SSRI exposure (n=55) and infant
neurodevelopmental outcome. The small numbers included in these studies are likely to
have implication for their findings.
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Croen et al(77) investigated whether prenatal exposure to SSRI increased the prevalence of
autistic spectrum disorder in the offspring. Using a case control methodology, Croen
demonstrated that there was an adjusted two-fold increase in diagnosis of autistic spectrum
disorder following prenatal exposure to SSRIs. Possibly consistent with this, Klinger et al (82)
found that children who exhibited withdrawal symptoms following exposure to SSRIs were
at an increased risk of poorer social functioning.
Research into infant and child behaviour following prenatal exposure to SSRIs in the main
has been produced by the research team at the Early Human Experience Unit in British
Columbia, Canada. Oberlander and colleagues report that externalising behaviours
(attention, aggression, attention-deficit/hyperactivity and oppositional or defiant
behaviours) measured by parental and teacher report (n=22) were not significantly
increased in comparison to control children (n=14)(83). A structured observation and rating
of infant behaviour and maternal-child interactions also failed to find significant differences
between the groups. In an additional study (potential overlap with the 2007 study is not
clear) externalising behaviour at 3 years of age was noted to be independent of SSRI
exposure (n=33) but internalising behaviours (withdrawal, anxiety, depression) in 4 year olds
were associated with maternal SSRI use (n=22) (79, 84).
The studies which failed to demonstrate an association between SSRI exposure and
neurodevelopmental or behavioural outcomes varied by outcome type. Figuero et al(85) for
example investigated the association between ADHD diagnosis and prenatal exposure to
SSRIs, Klinger et al(82) investigated IQ and its association to adaptation syndrome, whilst
Heikkinen et al(86) reported that infant neurodevelopment at 1 year of age was normal but
the method taken to investigate this was unclear. The study by Simon et al(19) failed to
demonstrate any association with infant motor or speech delay by utilising record linkage
from a health care database including 185 SSRI exposed infants.
Outcomes by SSRI type
Fluoxetine is the only SSRI to have been investigated as a single SSRI exposure in the
identified studies. Nulman and colleagues(87) prospectively recruited and assessed 55
children exposed prenatally to fluoxetine. Outcomes were assessed using the Bayley Scale of
Infant Development or the McCarthy Scale and the Reynell Scales when the children were
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between 16 and 86 months. The fluoxetine exposed group (n=55) were compared to 84
unexposed children. No significant differences were found between the groups in their
global cognitive ability or language skills when adjusted for maternal and child confounders.
This research group also published data on 40 children exposed to fluoxetine in pregnancy
in 2002 (included 18 fluoxetine exposed infants reported in Nulman et al 1997)(88). In this
later study the 40 children exposed to fluoxetine were compared to 46 children exposed to
tricyclic antidepressants and 36 control children. No significant group differences were
found across the three groups in terms of global cognitive ability measured by either the
Bayley Scales of Infant development or the McCarthy Scales, however it is unclear whether
this statistical comparison controlled for the use of two measures to collect outcome.
Adjustments for confounding variables was undertaken only considering an antidepressant
exposed group and not specifically fluoxetine(88), making conclusion difficult.
(Insert table 3 here)
Discussion
Infant and child outcomes following maternal uses of SSRIs in pregnancy have been
assessed by a variety of study types across a wide range of outcomes. This systematic
review aimed to review the results of studies addressing outcomes from the neonatal
period to childhood considering the reliability of the methodology used.
Neonatal adaptation syndrome and major congenital malformation prevalence had received
the largest amount of research attention, with long term neurodevelopmental outcomes the
lowest. Results obtained from the large record linkage studies into malformation risk
highlighted that outcomes likely differed by SSRI type and therefore studies considering the
single groups of multiple SSRI types may lead to unreliable results. Furthermore,
consideration of the type of malformation also led to the demonstration of differential
outcomes, highlighting that research focusing on overall single/global outcome prevalence
may be unreliable. Therefore an approach to research is needed that considers specific SSRI
treatment types and the potential association with specific outcome types.
Summary of findings
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Prenatal exposure to SSRIs either throughout or from later in gestation appears to be
associated with reduced gestational age and increase rates of preterm birth. At present
there is not enough research evidence to delineate the specific level of risk by individual
SSRI exposure type. The majority of studies investigating birth weight following SSRI
exposure find an association, although the outcomes for specific SSRIs are less clearly
represented. Neonatal adaptation syndrome appears to be relatively common following
SSRI use and likely leads to an increase in admissions to neonatal intensive care facilities
when exposure occurs in the final trimester. Respiratory difficulties in neonates are one of
the more consistently reported symptoms. Dose of SSRI and its correlation with neonatal
adaptation is infrequently considered. There is evidence of a dose effect for paroxetine (47),
although replication is required. Rates of neonatal adaptation syndrome are reported to
differ by type of SSRI due to differences in drug half life(7). Infants exposed to SSRIs in the
final trimester should be considered at risk of adaptation symptoms and should be
monitored accordingly. The critical condition of persistent pulmonary hypertension is
reported across a number of large cohorts to be increased across SSRIs, with Kieler et al(55)
suggesting that there is a class effect. Later exposure is reported to carry the increased risk.
Clinicians should be vigilant when a neonate has a history of prenatal exposure to an SSRI.
There is no clear evidence regarding specific SSRI types or dose effects pertaining to
persistent pulmonary hypertension and further research addressing this is needed.
In terms of congenital malformations, conclusions regarding individual SSRIs are difficult due
to conflicting results, which are hypothesised to be due to methodological differences and
particularly to a lack of consideration of dose and cohort size. Despite confliction it appears
that, on the balance of probability, paroxetine conveys a two fold increase in the risk of
cardiac defects in exposed infants. The publication of two updates of record linkage studies
including 968 and 1208 paroxetine exposed pregnancies respectively and where
adjustments from key confounding variables were made adds weight to this conclusion (56,
63). Dose of paroxetine was not considered and although the reported risk was less than
two fold, this may be larger at higher doses. Three meta-analyses have been published in an
attempt to further define increased risk for paroxetine. Both Bar-OZ et al (89) (OR 1.72; 95%
CI, 1.22-2.42) and Wurst et al(90) (OR 1.46; 95% CI 1.17–1.82) found a significant association
between paroxetine exposure and cardiac malformation, supporting this conclusion. It is of
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note however, that a meta-analysis of case control studies failed to find a significant
association (91). Further research considering dose of paroxetine is urgently required to
inform evidenced based decision making.
Conclusions over the association between exposure to the other SSRIs and heart defects are
less easily drawn. The discrepant findings pertaining to malformations are likely
multifactorial in their cause but group size, consideration of exposure variables and the
control group selected are likely to contribute. For example, the size of a cohort determines
the level of risk that study can reliably detect (92).
No reliable conclusion can be drawn regarding whether prenatal exposure to SSRIs increases
the risk of neurodevelopmental deficits later in the child’s life. This is due to the
multifaceted nature of neurodevelopment, sample size limitations and the use of mixed SSRI
groups. The most commonly investigated aspect of child neurodevelopment is motor
development/functioning which the majority of studies report to be altered following SSRI
exposure. However, control for pre and post natal confounding variables is critically
important and further research is required to understand the risks to neurodevelopment.
At present, as this review demonstrates, the evidence base is conflicting and leaves women
and their doctors with difficult decisions. A number of studies have demonstrated that
discontinuation of treatment in this group is high following confirmation of pregnancy(5),
which is hypothesized to be due in part to concerns over risk to the fetus (93).
Discontinuation of SSRI treatment may place the mother and her unborn child at increased
risk of maternal depression and it comorbidities. There is a need, therefore, for reliable
evidence to be collected and provided to women and their treating physicians to ensure the
best possible outcome for both mother and child.
Methodological considerations
As noted above there is considerable variation within the results across the full range of
infant and child outcomes. This may be due to methodological limitations of the studies and
in particular limitations relating to the SSRI variables of dose, timing and duration of
exposure, the adjustment for confounding variables and cohort size limitations.
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The majority of the studies identified failed to investigate the relationship between dose of
SSRI and outcome, despite it being a key principle of teratology(18). Such a principle has
been highlighted within the literature on antiepileptic drugs where the malformation rate is
dependent on the dose (94). In the context of prenatal SSRI exposure, the study by Berard
et al(74) highlights the critical importance of accounting for dose effects; the association
between paroxetine and cardiac defects was not significant until outcomes were stratified
by daily dose of paroxetine. A dose effect has also been reportedly demonstrated for birth
outcomes (24,47) although not all studies have replicated such an effect (20,29,64).
However, investigations of a dose effect have often been conducted utilising groups of
infants with different SSRI exposure types. Therefore, investigations of a single cohort that
includes a range of doses may cloud the true picture of the drugs risk profile, which in turn
may account, for the conflicting results seen across studies including the large record
linkage studies. In practical terms, where studies show an association this may lead to the
conclusion that the drug is an unfavourable treatment option, when at lower doses the risk
profile may be similar to other medications or no medication. In contrast, studies in which a
greater proportion of lower dose exposures occur may erroneously conclude that the risk
profile is no different to base rates, even in large samples. Without confirming these details,
however, the evidence base upon which treatment decisions must be made remains poor.
The issues of timing and duration of exposure are also key variables to which future studies
need to pay more attention. Women frequently halt antidepressant treatment following
confirmation of pregnancy(5), yet the majority of studies assumed that exposure occurred
throughout the first trimester and therefore the entire period of organogenesis. This is a
particular challenge for the record linkage studies where pharmacy records were utilised as
proxy measures of SSRI taking behaviour. Timing and duration of SSRI exposure is also likely
to be important for neurodevelopmental outcome. The brain continues to develop
throughout all three trimesters, with a peak of activity in the late second and third
trimesters (95). Serotonin has been implicated in the development of neuronal networks
(15) and preclinical studies have demonstrated disruption of normal neuronal development
with the administration of SSRIs (96). Study of this area requires consideration of the timing,
duration and dose of exposure in relation to the key stages of fetal development.
17
Cohort size is critically important and will vary by the size of difference under detection(97).
Large numbers of specific SSRI exposures are required to reliably detect small increases in
risk, when the background incidence of the outcome in question is small (e.g. for congenital
malformations) (92). Smaller samples sizes are adequate for outcomes which more
commonly occur within the general background population (e.g. below average IQ).
Adequately powered cohorts are needed to investigate the full range of infant and child
outcomes following prenatal exposure to SSRIs to ensure reliable information can be
provided to women who are required to make treatment choices.
The failure to adjust for confounding variables is likely to convey further bias within studies
and make comparisons across cohorts difficult. As tables 1-3 highlight, the majority of
studies identified adjust for some demographic factors. However, there is a large amount of
heterogeneity amongst the confounders adjusted for. Some studies undertake no
adjustment at all for confounding variables, whilst others only adjust for a small number.
Infants and children do not develop in a tightly controlled research environment and from
the prenatal months throughout life there is a wealth of known influences on development
including maternal illnesses, medication use, folic acid and other vitamins, diet, maternal
age, maternal weight, socioeconomic status, nicotine, alcohol and illicit drug use amongst
many others. All of these require consideration in research investigating associations
between neonatal outcomes and the medication exposure in question. There are also likely
to be maternal lifestyle factors influencing these studies. For example, Nordeng et al
(31)and Nulman et al(88) document an increased frequency of women who smoked during
their pregnancy in the group who had depression. Folate has been demonstrated to offer a
degree of protection from certain major congenital malformations (98), yet few of the
identified studies investigating malformation prevalence adjust for its use. The importance
of adjustment was highlighted in a number of the identified studies where the significance
level of associations altered following the adjustment for confounding variables (30, 31, 34).
When assessing outcomes in the postnatal period a further set of confounders to those
reported above should be considered. Important variables include gestational age at birth,
growth parameters, childhood illness and medication use, age of the child at point of
assessment and number of siblings. Levels of parental education and IQ/cognitive abilities
are also of critical importance when considering child neurodevelopment. Specific to this
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area of research the impact of maternal mental health must be also considered. There is
evidence that maternal depression in childhood impacts adversely on childhood
development (11). Often studies have attempted to adjust for maternal depression using
proxy measures of visits to doctors or number of prior prescriptions, although the
usefulness of such information is questionable as a treated mother may not be displaying
depressive symptomatology and therefore the influence of mood on child development is
not present. The confounders adjusted for in studies addressing the neurodevelopment of
children exposed to SSRIs in pregnancy vary by study (Table 3), and may in part at least
explain some of the variance in study outcome.
To ensure reliable investigation into the longer term consequences of prenatal exposure to
SSRIs prospective observational studies are required. Recruitment should be during early
gestation with longitudinal follow ups throughout childhood. Neurodevelopment is a
dynamic process throughout the childhood and adolescent years with assessments at
younger ages unlikely to provide reliable and stable estimates of outcome.
This review has a number of strengths including: an a priori inclusion criteria; the systematic
searches; cross validation of the search strategy and systematic extraction of findings. The
adaption of the domains of the Newcastle Ottawa Scale to highlight pertinent
methodological issues enhanced the reporting of indentified studies and sought to highlight
the reliable sources of evidence. Limitations of this review include the exclusion of studies
which report outcomes pertaining to other antidepressants. The assessment for eligibility
for this review would have been enhanced if verified by a second independent reviewer,
although cross referencing findings against the Reprotox database and recent review
articles, sought to validate the search strategy and the eligibility decisions.
Conclusion
Considering the methodological limitations of studies conducted to date it is difficult to
draw firm conclusions around the risk or safety of SSRIs in pregnancy. There is fairly
substantial evidence for an increased risk in neonatal adaptation symptoms, when exposure
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occurs in the third trimester. The longer term consequences of such adaptation symptoms
remain unknown and further investigation is required. Despite differences in methodologies
and frequent failure to investigate dose of SSRI there appears to be evidence that
paroxetine is associated with a small but significant (twofold) increased risk of cardiac
malformations. There is no reliable evidence regarding the longer term neurodevelopmental
outcome of exposed infants and more research utilising adequately powered cohorts, with
standardised assessment and controlling for confounding influences is urgently required.
Across all infant and child outcomes further research is needed addressing the issues of
dose, timing and duration of exposure and undertaking adjustment for important pre and
postnatal confounding variables. Such research is required to ensure that women with a
mood disorder can make informed decisions about their treatment.
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