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Effective communication between healthcare providers and expectant mothers is
essential to ensure that mental health concerns are addressed, allowing for informed
decisions regarding treatment options while prioritizing both maternal well-being
and fetal safety.
6.5.1.2 Preterm Birth
The relationship between antidepressant use during pregnancy and the risk of preterm birth (PTB) is complex and multifaceted, with studies presenting varying
results. Several studies indicate that antidepressant use, particularly SSRIs, is associated with an increased risk of PTB.For instance, a systematic review and metaanalysis found that maternal antidepressant use is linked to a signicantly increased
risk of PTB, especially in women with depression, with SSRIs showing a similar
trend (Chang etal. 2020). Another study highlighted that late SSRI exposure during
pregnancy is associated with a higher risk of PTB and low birth weight, suggesting
that the timing of exposure is crucial and late exposure is more risky (OR=1.5 to
nonexposed group) (Hwang etal. 2023). However, other research suggests that the
risk of PTB is more closely related to maternal depression itself rather than antidepressant use. This cohort study analyzed the effects of antidepressant use and maternal depression on the risk of PTB using data from 216,070 deliveries in the UK
between January 1996 and February 2019. The study found that exposure to antidepressants, specically SSRIs, during the rst 22weeks of gestation did not signicantly increase the risk of preterm birth (PTB) compared to unexposed patients (HR
1.08, CI [0.98,1.18], P=0.11). Additionally, a history of depression was associated
with an increased risk of PTB among untreated patients (HR 1.10, CI [1.04,1.15],
P<0.01). Overall, antidepressant treatment does not increase the risk of PTB in
pregnant women with depression (Amit etal. 2024). Similarly, another study concluded that antidepressant use alone was not associated with increased odds of
spontaneous PTB, although opioid use was (Padilla-Azain etal. 2024). Furthermore,
a large cohort study across multiple countries analyzed electronic health record data
from over 2.5 million singleton births across the UK, Norway, and Sweden to investigate the impact of maternal antidepressant use during pregnancy on various birth
outcomes, including stillbirth, preterm delivery, and low Apgar scores. It was found
that maternal antidepressant use during pregnancy is associated with an increased
risk of preterm delivery, with an adjusted odds ratio (aOR) of 1.26 (95% CI 1.23 to
1.30), but the absolute risks remained low, and confounding factors such as the
severity of depression could not be entirely ruled out (Martin etal. 2023). The decision to use antidepressants during pregnancy should therefore be carefully weighed
against the risks of untreated maternal depression, as untreated depression itself is a
known risk factor for adverse birth outcomes (Chen etal. 2021; Febrianti 2024).
Overall, while there is evidence suggesting an association between antidepressant
use and PTB, the potential confounding effects of underlying maternal depression
and other factors must be considered in clinical decision-making.
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6.5.1.3 Low Birth Weight
Several studies indicate that antidepressant use during pregnancy is associated with
an increased risk of low birth weight (LBW) in infants. For instance, a meta- analysis
found that children whose mothers used antidepressants during pregnancy had a
higher risk of LBW compared to those born to untreated depressed women (Xing
etal. 2020) Similarly, another study reported that antidepressant exposure was asso-
ciated with adverse outcomes at birth, including lower gestational age and preterm
birth, although it did not nd a direct association with LBW when compared to
untreated depression (Fitton etal. 2020). However, the evidence is not entirely consistent. Nevertheless, the data is not completely uniform. Some research indicates
that the detected correlations could be inuenced by the existing maternal depression instead of the use of antidepressants themselves. For instance, a comprehensive
review that evaluated 20 meta-analyses regarding the neonatal outcomes of antidepressants taken during pregnancy pointed out that the likelihood of negative neonatal outcomes, such as low birth weight, may be more linked to maternal depression
than to the exposure to antidepressants (Uguz 2021). Additionally, a study focusing
on SSRIs found no signicant increase in the risk of LBW when comparing exposed
and unexposed groups, suggesting that the medication itself might not be the primary factor (Amit etal. 2024).
At this point, it’s important to understand the difference between clinical signicance and statistical signicance. For instance, in the case of LBW that we are currently examining, it has been found that women who continue to use antidepressants
during pregnancy have a statistically signicantly lower infant birth weight.
According to the data from the study, the difference between the two groups is 71.9
grams (Wartko etal. 2021).
Overall, while there is wide evidence linking antidepressant use during pregnancy to LBW; the role of maternal depression as a confounding factor complicates
the interpretation of these ndings. Further research is needed to disentangle the
effects of antidepressants from those of untreated maternal depression to provide
clearer guidance for clinical decision-making during pregnancy.
6.5.1.4 Stillbirth
The risk of stillbirth associated with antidepressant use during pregnancy has been
a subject of extensive research, with varying conclusions across studies. A systematic review and meta-analysis indicated a small increased risk of stillbirth with antidepressant use during pregnancy, with a summary effect estimate of 1.19, although
this nding was likely inuenced by confounding factors and the low quality of
included studies (Martin etal. 2023). A large cohort study using data from the UK,
Norway, and Sweden found that maternal antidepressant use was associated with
increased odds of stillbirth (adjusted odds ratio [aOR] 1.16), but the absolute risk
remained low, and the association was attenuated when restricted to women with
depression or anxiety (Martin etal. 2024). In contrast, a population-based cohort
study from Nordic countries found no signicant association between SSRI use during pregnancy and stillbirth after adjusting for maternal characteristics and previous
psychiatric hospitalization (Stephansson etal. 2013). Similarly, another study using
6 Antidepressants inPregnancy
111
the Danish Fertility Database reported no association between SSRI use and stillbirth across different trimesters of pregnancy (Jimenez-Solem etal. 2013). A systematic review and disproportionality analysis in the WHO Safety Database
suggested an increased risk of fetal death, including stillbirth, with antidepressant
exposure, particularly SSRIs during the rst trimester, but highlighted the need for
further research to address potential indication bias (Desaunay etal. 2024). Overall,
while some studies suggest a modest association between antidepressant use and
stillbirth, the evidence is inconsistent, and confounding factors such as the severity
of maternal psychiatric conditions and familial environment may play a signicant
role. Therefore, the decision to use antidepressants during pregnancy should be
individualized, weighing the potential risks against the benets of treating maternal
mental health conditions (Desaunay etal. 2023; Yazıcı and Şahin 2023).
6.5.1.5 Low APGAR Scores
The prevalence of low Apgar scores among newborns whose mothers used antidepressants during pregnancy is notably higher compared to those unexposed. A study
analyzing data from the UK, Norway, and Sweden found that maternal antidepressant use was associated with increased odds of a low Apgar score, dened as less
than 7 at 5min post-delivery, with an adjusted odds ratio (aOR) of 1.83 (95% CI
1.75 to 1.91) (Martin et al. 2024). This association was consistent even when
accounting for familial and environmental confounding factors, as indicated by a
modest association with paternal antidepressant use (Martin etal. 2024). Another
study focusing on SSRIs reported that infants exposed to SSRIs in late pregnancy
had a higher incidence of delayed neonatal adaptation, which includes low Apgar
scores, with a relative risk of 2.52 (95% CI 2.36 to 2.70) compared to unexposed
infants (Cornet etal. 2024). Furthermore, a systematic review and meta-analysis
conrmed increased risks for low Apgar scores among infants exposed to serotoninreuptake inhibitors (SRIs) during pregnancy, although the clinical signicance of
these ndings remains debated due to data quality issues (Kautzky etal. 2022).
These ndings collectively suggest that prenatal exposure to antidepressants, particularly SSRIs and SRIs, is associated with an increased risk of low Apgar scores,
although the absolute risk remains relatively low. The studies emphasize the importance of weighing the benets of treating maternal depression against potential neonatal risks, advocating for the lowest effective dose of antidepressants during
pregnancy (Cornet etal. 2024; Kautzky etal. 2022; Martin etal. 2024).
6.5.1.6 Persistent Pulmonary Hypertension oftheNeonate (PPHN)
The prevalence of persistent pulmonary hypertension of the neonate (PPHN) in
infants exposed to maternal antidepressants during pregnancy is a signicant concern, with studies indicating an increased risk associated with SSRIs and other antidepressants. For instance, one study found that 2.7% of infants exposed to SSRIs
experienced delayed neonatal adaptation, which includes PPHN as a severe outcome (Cornet et al. 2024). Additionally, a comprehensive analysis of 2,528,916
births revealed that maternal antidepressant use was linked to adverse outcomes,
including a higher likelihood of low Apgar scores and stillbirths, although the
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absolute risks remained low (Martin etal. 2024). Risk factors for PPHN include the
type and dosage of antidepressants, as well as maternal health conditions such as
pulmonary hypertension, which affects approximately 0.04% of pregnant women
and is associated with signicantly higher rates of adverse cardiovascular events
and maternal mortality (Maligireddy etal. 2024). In research conducted by Garm
etal. (2024), a total of 33,776 newborns were examined. Discontinuation of antidepressants during pregnancy was linked to a signicantly lower risk of hospitalization in comparison to ongoing exposure to Citalopram throughout the pregnancy.
Additionally, halting monotherapy was associated with a signicant reduction in the
risk of PPHN compared to continued exposure to Citalopram (Gram etal. 2024). In
that study, the basis of the decision to continue or discontinue antidepressant medication is not known. Certain female patients might cease pharmacological treatment
upon observing alleviation of symptoms, whereas others may persist in their regimen as a preventive measure against recurrence. The clinical signicance of the
ndings and potential inuences of confounding variables must be assessed during
the decision-making process (Vigod etal. 2024).
6.5.1.7 Neonatal Adaptation Syndrome
Neonatal adaptation syndrome (NAS) is a complex condition that can arise in newborns exposed to certain medications during pregnancy, including antidepressants.
It is often referred to as neonatal abstinence syndrome, a condition observed in
newborns following in utero exposure to antidepressants, particularly SSRIs and
SNRIs. The syndrome is characterized by a range of withdrawal symptoms such as
irritability, jitteriness, lethargy, and feeding difculties, which can vary in severity
from mild to severe. Studies have shown that antidepressants like venlafaxine, a
common SNRI, can lead to NAS symptoms such as hypothermia and lethargy in
neonates, necessitating medical intervention (Oswald etal. 2024). The prevalence
and severity of NAS in infants exposed to SSRIs and SNRIs are not routinely
screened, which can lead to underdiagnosis and lack of treatment (Arulandoo and
Kugathasan 2023). Disproportionality analyses using databases like VigiBase have
identied signicant reporting odds ratios for neonatal withdrawal syndrome associated with various antidepressants, indicating a moderate signal of risk across different classes, including SSRIs and tricyclic antidepressants (TCAs) (Gastaldon
etal. 2023a, b). In a study which compared the Neonatal Abstinence Score (NAS)
in neonates exposed to antidepressants in utero with those who were not exposed, a
total of 221 women were recruited, with 83in the exposed group and 138in the
control group. The results indicated that 3% of infants in the exposed group showed
severe abstinence symptoms, while 28% exhibited mild abstinence symptoms, compared to 7% in the control group. Additionally, the study found that 10% of infants
prenatally exposed to antidepressants experienced neonatal hypoglycemia, in contrast to only 1% in the control group. The ndings highlight the importance of
informing obstetric and neonatal teams about the mother’s medication, as infants
may require a review by neonatology after delivery due to potential withdrawal
symptoms (Murad 2022). Maternal CYP polymorphisms were investigated to
understand variability in NAS symptoms, but no signicant association was found,
6 Antidepressants inPregnancy
113
suggesting other factors may contribute to the syndrome’s manifestation (Shea etal.
2021). Meta-analyses have identied specic withdrawal signs such as hypoglyce-
mia, tremors, and respiratory distress in neonates exposed to SSRIs and venlafaxine, highlighting the need for careful management of antidepressant use during
pregnancy (Wang and Cosci 2021). Comparisons with second-generation antipsychotics (SGAs) show similar rates of poor neonatal adaptation syndrome (PNAS),
suggesting a common underlying mechanism for NAS across different psychotropic
medications (Viguera etal. 2023). Despite the observed risks, the clinical relevance
of these ndings remains debated due to variability in study quality and outcomes,
claiming the need for more systematic research to guide clinical practice. Prospective
cohort studies have conrmed that while severe NAS is relatively rare, mild symptoms are common, and healthcare providers improve multiprofessional counseling
in the many women dealing with MDD, perinatal anxiety and stress during pregnancy and the peripartum, and should be prepared to manage these cases effectively
(Kautzky etal. 2022). Overall, the evidence suggests that while NAS associated
with antidepressant exposure is generally mild and self-limiting, it requires awareness and appropriate management to ensure optimal neonatal outcomes.
6.5.2 Long-Term Outcome ofAntidepressant Use
During Pregnancy
6.5.2.1 Emotional andPsychiatric Disorders
The effects of maternal antidepressant use during pregnancy on emotional and psychiatric disorders in children are complex and multifaceted, as evidenced by the
studies of Bliddal and Koc, among others. Bliddal etal. conducted a comprehensive
Danish register study that followed over a million children and found that those
exposed to SSRIs in utero had a higher incidence of depressive, anxiety, or adjustment disorders, with an earlier onset compared to unexposed children. However, the
study also highlighted that these associations might be inuenced by the severity of
maternal illness and other confounding factors, as similar risks were observed with
paternal SSRI use and maternal use post-pregnancy (Bliddal etal. 2023). Koc etal.’s
study, on the other hand, focused on the brain morphologic trajectory and found that
prenatal SSRI exposure was associated with changes in brain regions involved in
emotional regulation, such as the amygdala and fusiform gyrus, although these
changes did not persist into early adolescence (Koc etal. 2023). Other studies, such
as those by Lee et al. in a cohort of Taiwan National Health Insurance system
between 2004 and 2016 antidepressant-exposed pregnancies and antidepressantunexposed group (n=2,245,689) and Suarez etal. in a cohort of 145,702 antidepressant-exposed and 3,032,745 unexposed pregnancies, suggest that while there is
an association between prenatal antidepressant exposure and neurodevelopmental
disorders like ASD and ADHD, these associations are likely confounded by maternal mental health conditions and genetic factors rather than the medication itself
(Lee etal. 2024; Suarez etal. 2022). Furthermore, a systematic review by Rommel
et al. indicated that while there are associations with affective disorders, many
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observed outcomes are driven by the underlying maternal disorder rather than the
antidepressant exposure per se (Rommel etal. 2020). Overall, while there is evidence of increased risks of emotional and psychiatric disorders in children exposed
to antidepressants in utero, these risks are often intertwined with maternal mental
health and other confounding factors, necessitating careful consideration in clinical
decision-making.
6.5.2.2 Neurodevelopmental Disorders
The impact of antidepressant use during pregnancy on neurodevelopmental outcomes in children has been extensively studied, with a focus on specic antidepressant types and neurodevelopmental disorders such as autism spectrum disorder
(ASD) and attention-decit/hyperactivity disorder (ADHD). Several studies suggest that while there is an observed association between prenatal antidepressant
exposure and increased risks of ASD and ADHD, these associations are often confounded by maternal depression and other genetic and environmental factors rather
than the antidepressant use itself. For instance, a study in Taiwan found increased
risks of ASD and ADHD with prenatal antidepressant exposure, but these risks were
not signicant when comparing exposed children to their unexposed siblings, indicating that the association might be due to maternal depression rather than the medication (Lee etal. 2024). Similarly, research in the UK using various causal inference
methods found little evidence of a substantial association between continued antidepressant use during pregnancy and neurodevelopmental disorders, although there
was some inconsistent evidence regarding the initiation of antidepressants and
autism (Heuvelman etal. 2023). A large cohort study in the United States also found
no signicant association between antidepressant use and neurodevelopmental disorders after adjusting for confounders, suggesting that antidepressant exposure may
be a marker for the need for early screening rather than a direct cause of these disorders (Suarez et al. 2022). Furthermore, studies examining specic antidepressants, such as SSRIs, indicate that while SSRIs like uoxetine and paroxetine may
affect neuronal development invitro, these effects are not necessarily observed
invivo, and the adverse outcomes are more likely linked to maternal depression
(Hosseini etal. 2024). In a study of public-school children in Denmark, children
(age 7–17) whose mothers used antidepressants during pregnancy had a statistically
signicant 2-point lower mathematics test score compared to those whose mothers
did not. The small magnitude of this difference raises questions about its clinical
relevance, necessitating consideration of the benets of treating maternal depression during pregnancy (Christensen etal. 2021). Overall, the literature suggests that
while prenatal antidepressant exposure is associated with some neurodevelopmental
decits, these are largely attenuated or eliminated when accounting for maternal
depression and other confounding factors, indicating that antidepressants may not
be the direct cause of these outcomes (Andrade 2022). Therefore, the decision to
use antidepressants during pregnancy should be carefully considered, weighing the
benets of treating maternal depression against potential risks, with a focus on
shared decision-making between the patient and healthcare provider.
6 Antidepressants inPregnancy
115
6.5.2.3 Cognitive andMotor Development
The impact of maternal antidepressant use during pregnancy on the cognitive and
motor development of children is a complex issue with mixed ndings across various studies. Research indicates that prenatal exposure to SSRIs like uoxetine, citalopram, and paroxetine can affect neurodevelopment, although the exact mechanisms
and outcomes remain debated. For instance, invitro studies have shown that uoxetine and paroxetine can reduce neurite outgrowth and dysregulate genes associated
with neuronal development, suggesting potential adverse effects on neural development independent of serotonin transporter activity (Hosseini etal. 2024). Animal
studies further support these ndings, with maternal uoxetine exposure impairing
synaptic transmission and plasticity in the medial prefrontal cortex of offspring,
particularly affecting female mice, which exhibited deteriorated cognitive performance and altered serotonergic neuron structure (Bobula etal. 2024). However,
human cohort studies present a more nuanced picture. A 3-D study examined 1489
mother-child pairs, with 61 (4.1%) reporting prenatal antidepressant use. Prenatal
exposure correlated negatively with motor development (B=−0.91, 95% CI −1.73,
−0.09 for ne motor; B=−0.89, 95% CI −1.81, 0.02 for gross motor), but not with
cognitive (B=−0.53, 95% CI −1.82, 0.72) or language (B=4.13, 95% CI −3.72,
11.89) development. The ndings indicate a negative correlation between prenatal
antidepressant exposure and motor development at age two, with a minimal effect
size of approximately one Bayley Scales of Infant and Toddler Development (BSIDIII) point lower on average, even after controlling for maternal distress (Tanguay
etal. 2023). Longitudinal studies have also observed changes in brain morphology,
such as reduced gray matter and altered amygdala development, in children exposed
to SSRIs, although these changes may not persist into adolescence (Knopf 2023;
Koc etal. 2023). There is a lack of data about newer antidepressants and their association with neurodevelopment; a study suggests that newer antidepressants like
vortioxetine may have some slight adverse effects on neurodevelopment (Ergun
etal. 2024). Overall, while there is evidence of potential risks associated with prenatal antidepressant exposure, the ndings are inconsistent, and the role of maternal
mental health and genetic factors is signicant, necessitating further research to
clarify these associations.
6.5.3 Maternal Outcomes
The use of antidepressants during pregnancy, delivery, and postpartum can have
several side effects on the mother, although these must be weighed against the risks
of untreated depression. SSRIs are the most commonly prescribed antidepressants
during pregnancy, and their use has been associated with a modestly increased risk
of adverse events such as postpartum hemorrhage, miscarriage, preterm birth, and
cesarean delivery (Ushkalova and Ushkalova 2023; Smithson and Mitchell 2015).
On the other hand, untreated maternal depression poses signicant risks, including
preeclampsia, poor prenatal care, and increased likelihood of postpartum depression, which can adversely affect maternal-infant bonding and child development
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E. Yaz ıcı and Ö. A. Ciner
(Dubovicky etal. 2017; Zeszutek 2021). For example, a study evaluated the maternal and neonatal outcomes of 281 pregnant women with depressive disorders, comparing those treated with pharmacotherapy to those who were untreated, against a
control group of 200 healthy pregnant women. Results indicated that untreated
women experienced higher rates of cesarean sections, preterm deliveries, and lower
neonatal weights and APGAR scores, while treated women had a reduced rate of
cesarean sections but still exhibited lower APGAR scores. The ndings suggest that
pharmacological treatment during pregnancy is associated with better outcomes for
both mothers and newborns, emphasizing the importance of managing depressive
disorders to mitigate complications. The study concludes that untreated depressive
disorders lead to poorer pregnancy outcomes compared to those who receive appropriate psychotropic treatment (Parpinel etal. 2022).
6.5.3.1 Postpartum Hemorrhage
The relationship between postpartum hemorrhage (PPH) and antidepressant use,
particularly SSRIs, has been a subject of investigation due to the potential for
increased bleeding risk associated with these medications. Several studies have
identied a correlation between the use of antidepressants during late pregnancy
and an elevated risk of PPH.For instance, a systematic review highlighted that antidepressant use in late pregnancy especially for exposures occurring within 30days
of delivery, compared with unexposed deliveries. is associated with an increased
risk of PPH, although the causal link remains debated (Bobo etal. 2024). This association is further supported by ndings that SSRIs can impair platelet aggregation,
thereby increasing the risk of hemorrhage (Salkeld etal. 2008). A cohort study utilizing Medicaid data indicated that PPH prevalence was 2.8% among women with
mood/anxiety disorders unexposed to antidepressants, 4.0% among current serotonin reuptake inhibitor users, and 3.8% among current non-serotonin reuptake
inhibitor users, revealing a 1.47-fold increased risk of PPH for those exposed to
SSRIs near delivery compared to non-exposed individuals, with comparable risks
noted for non-serotonin reuptake inhibitors (Palmsten etal. 2013). Such studies
necessitate replication while controlling for confounding variables such as obesity,
age, and comorbidities. The pharmacological mechanism underlying this increased
risk is thought to involve the inhibition of serotonin uptake into platelets, which is
crucial for platelet aggregation and vasoconstriction, thus potentially prolonging
bleeding times (Heerdink 2013).
6.5.3.2 Eclampsia, Hypertension
The prevalence of eclampsia and hypertension among mothers who used antidepressants during pregnancy is a signicant concern, as highlighted by multiple studies. Antidepressant use, particularly SNRIs, has been associated with an increased
risk of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia. For instance, a study using the EFEMERIS database found
that women exposed to SNRIs had a signicantly higher risk of HDP compared to
those exposed to SSRIs and unexposed women, with adjusted odds ratios indicating
a notable increase in risk (Benevent etal. 2023). Similarly, another study reported
6 Antidepressants inPregnancy
117
that SNRI use was independently associated with a higher risk of developing HDP,
use of SNRIs (adjusted risk ratio=9.10, 95% condence interval=[3.82, 21.67])
and unmedicated depression (adjusted risk ratio = 3.11, 95% condence interval= [1.32, 7.35]) suggesting a strong link between SNRI use and hypertensive
complications during pregnancy (Galbally etal. 2023). Furthermore, a systematic
review indicated that antidepressant use during pregnancy, particularly SSRIs and
SNRIs, was associated with a moderately increased risk of gestational hypertension
and preeclampsia, although the data were not conclusive due to methodological
limitations (Uguz 2017). Additionally, a retrospective cohort study found that
women who continued antidepressant use beyond 20weeks of gestation had an
increased risk of gestational hypertension, with signicant associations observed
for SSRIs and prolonged use (Zakiyah etal. 2018). These ndings are corroborated
by another study that highlighted the increased risk of preeclampsia among women
who used antidepressants, especially if the medication was continued after the 16th
week of gestation (Bernard etal. 2019). Overall, while the exact prevalence rates of
eclampsia and hypertension among antidepressant users during pregnancy are not
uniformly reported, the evidence suggests a heightened risk of hypertensive disorders, necessitating careful monitoring and consideration of antidepressant use during pregnancy.
6.6 Review ofRisks ofMedications
6.6.1 SSRIs
SSRIs are the most commonly prescribed antidepressants during pregnancy due to
their extensive study and relatively favorable safety prole, particularly sertraline,
which is noted for its low placental transfer and minimal presence in breast milk,
making it a preferred choice for nursing mothers (Ushkalova and Ushkalova 2023).
However, SSRIs are associated with several adverse outcomes, including preterm
birth, low birth weight, and neonatal adaptation issues, such as low Apgar scores
and increased neonatal intensive care unit admissions (Cornet etal. 2024; Febrianti
2024; Martin etal. 2024). These risks are not unique to SSRIs, as other antidepres-
sants like duloxetine and mirtazapine also show associations with congenital malformations and similar neonatal outcomes (Febrianti 2024). The potential for
delayed neonatal adaptation is particularly noted with SSRIs, with a dose-dependent
relationship observed, especially with escitalopram and uoxetine (Cornet etal.
2024). Long-term outcomes for children exposed to SSRIs in utero include altered
brain development trajectories, particularly in regions associated with emotional
regulation, although some changes, such as those in the amygdala, may not persist
into adolescence (Knopf 2023; Koc etal. 2023). Additionally, prenatal SSRI exposure has been linked to an increased risk of emotional disorders in offspring,
although this may be confounded by the severity of maternal depression (Bliddal
etal. 2023). Confounding factors, such as maternal depression, can signicantly
affect the observed associations between SSRI exposure and birth defects. Maternal
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depression itself is linked to adverse pregnancy outcomes, including preterm birth,
low birth weight, and fetal growth restriction, which complicates the isolation of
effects solely attributable to antidepressant exposure (Febrianti 2024). The severity
of maternal depression, which often necessitates antidepressant use, may independently contribute to these adverse outcomes, suggesting that observed associations
might be confounded by the underlying condition rather than the medication itself
(Bliddal etal. 2023; Martin etal. 2024). For instance, studies have shown that when
restricting analyses to women with depression or anxiety, the association between
antidepressant exposure and adverse outcomes like stillbirth attenuates, indicating
that the severity of the underlying condition could be a confounding factor (Martin
etal. 2024). Additionally, genetic predispositions related to maternal depression, as
explored through polygenic scores, suggest that genetic liability may also play a
role in these associations, although this relationship is not straightforward (Rommel
etal. 2024). Furthermore, the timing of antidepressant exposure during pregnancy,
such as early versus late exposure, can inuence outcomes like preterm birth and
low birth weight, which may reect confounding by the progression and management of maternal depression (Hwang etal. 2023). The potential for confounding by
indication is also highlighted in studies that show associations between paternal
antidepressant use and adverse outcomes, suggesting that familial or environmental
factors could contribute to the observed risks (Martin etal. 2024) (Bliddal etal.
2023). Overall, while sertraline and other SSRIs have been associated with specic
congenital malformations, such as septal heart defects, these associations may be
inuenced by systematic errors and confounding factors, including the severity of
maternal depression and genetic predispositions, necessitating careful consideration
in clinical decision-making (Kolding etal. 2023).
6.6.1.1 Sertraline
Sertraline, a commonly prescribed SSRI during pregnancy, presents unique side
effects compared to other SSRIs, particularly concerning fetal cardiac health.
Studies have shown that sertraline is associated with an increased risk of septal heart
malformations, such as atrial and ventricular septal defects, although it is not linked
to more severe cardiac malformations (Kolding etal. 2023; Shen etal. 2017). This
association may be inuenced by confounding factors, but it remains a consideration for pregnant women undergoing treatment for depression. Additionally, sertraline exposure during pregnancy has been linked to congenital cardiovascular
disorders, with data from the FDA Adverse Event Reporting System highlighting
heart disease congenital and patent ductus arteriosus as common outcomes Beyond
cardiac concerns, sertraline has been implicated in other adverse pregnancy outcomes, such as low birth weight, preterm birth, and intrauterine growth restriction,
likely due to its impact on serotonin homeostasis and placental blood perfusion.
Maternal SSRI usage elevates serotonin levels in both mother and fetus. This elevation may induce vasoconstriction in uterine and placental vessels, thereby diminishing blood ow to the uterus, placenta, and fetus, potentially affecting placental
functionality and fetal growth (Domingues etal. 2023).