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. rebeccalbromley@googlemail.com .

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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