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Animal studies further suggest that sertraline can be teratogenic, causing skeletal
abnormalities and cleft palate in mice, although these ndings are not directly translatable to humans (Cabrera etal. 2020). Moreover, sertraline use during the peripartum period has been associated with increased pup mortality and altered calcium
metabolism in animal models, indicating potential risks to both the mother and offspring (Sheftel etal. 2020). Despite these risks, sertraline is often preferred over
other SSRIs like paroxetine, which has a stronger association with fetal cardiovascular defects (Desaunay etal. 2023). Overall, while sertraline is a viable option for
managing depression during pregnancy, its use requires careful consideration of
potential fetal risks, particularly concerning cardiac and developmental outcomes.
6.6.1.2 Paroxetine
Paroxetine, an SSRI, exhibits unique side effects compared to other SSRIs, particularly when used during pregnancy. One of the most signicant concerns associated
with paroxetine is its potential to increase the risk of cardiac malformations in
infants when used during the rst trimester. Studies have shown that paroxetine
exposure is linked to a higher incidence of major congenital malformations, including cardiac defects such as bulbus cordis anomalies, anomalies of cardiac septal
closure, atrial septal defects, and right ventricular outow tract defects (Bérard
etal. 2016).
Paroxetine exposure during pregnancy has been associated with an increased risk
of birth defects, particularly cardiac malformations. Several studies and metaanalyses have consistently reported this association. For instance, a systematic
review and meta-analysis found that rst-trimester exposure to paroxetine was
linked to an increased risk of major congenital malformations, including cardiac
defects, with a pooled odds ratio (OR) of 1.23 for any major malformations and 1.28
for major cardiac malformations. In a study by Yan Gao etal., 29 cohort studies
involving over 9 million births were analyzed. SSRIs were linked to a heightened
risk of major congenital anomalies (MCAs, RR 1.11, 95% CI 1.03 to 1.19) and
congenital heart defects (CHD, RR 1.24, 95% CI 1.11 to 1.37). No signicant risk
increase was found in women with psychiatric diagnoses (MCAs, RR 1.04, 95% CI
0.95 to 1.13; CHD, RR 1.06, 95% CI 0.90 to 1.26). Signicant associations were
noted with maternal citalopram (MCAs, RR 1.20, 95% CI 1.09 to 1.31; CHD, RR
1.24, 95% CI 1.02 to 1.51), uoxetine (MCAs, RR 1.17, 95% CI 1.07 to 1.28; CHD,
RR 1.30, 95% CI 1.12 to 1.53), and paroxetine (MCAs, RR 1.18, 95% CI 1.05 to
1.32; CHD, RR 1.17, 95% CI 0.97 to 1.41), with analyses in psychiatric populations
yielding no statistically signicant results (Gao etal. 2018).
In addition to congenital malformations, research ndings have indicated that
exposure to paroxetine is correlated with particular cardiac anomalies, including
bulbus cordis anomalies and defects in cardiac septal closure, with an odds ratio
(OR) of 1.42, as well as atrial septal defects, which exhibit an OR of 2.38 (Bérard
etal. 2016). Similarly, a meta-analysis reported signicant odds ratios for paroxetine, indicating an increased risk of congenital heart defects, with an OR of 1.57
(Courtney De Vries etal. 2021a). The FDA issued a warning in 2005 about the
increased risk of cardiac malformations with paroxetine. According to subsequent
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meta-analyses and systematic reviews; compared to other SSRIs, paroxetine has
been consistently associated with a higher risk of these specic cardiac anomalies,
although the absolute risk remains relatively small (Alwan etal. 2016; Gao etal.
2018; Wemakor etal. 2015). Additionally, paroxetine, like other SSRIs, is associ-
ated with other adverse pregnancy outcomes such as preterm birth, low birth weight,
and potential neurodevelopmental disorders in children (Domingues etal. 2023).
However, the risk of cardiac malformations appears to be more pronounced with
paroxetine than with other SSRIs, such as uoxetine or sertraline, which have been
linked to different types of congenital anomalies (Gao etal. 2018; Wemakor etal.
2015). The decision to use paroxetine during pregnancy should involve a careful
consideration of the risks and benets, taking into account the potential for untreated
maternal depression to also adversely affect pregnancy outcomes. Therefore, healthcare providers often recommend alternative treatments or additional prenatal monitoring for women who require antidepressant therapy during pregnancy.
6.6.1.3 Fluoxetine
Fluoxetine, a widely prescribed SSRI, exhibits unique side effects compared to
other SSRIs, particularly when used during pregnancy. One notable concern is its
impact on fetal development. Thus, in a population-based case-malformed control
study conducted in 12 EUROCAT CA registries covering 2.1 million births, uoxetine exposure has been associated with congenital anomalies, including cardiac
defects such as Tetralogy of Fallot and Ebstein’s anomaly, as well as non-cardiac
anomalies like ano-rectal atresia and renal dysplasia (Wemakor etal. 2015). Such
risks haven’t been replicated in new studies and confounding factors are limiting the
study’s results but additionally, uoxetine has been linked to neurodevelopmental
disorders, including an increased risk of autism spectrum disorders in offspring,
potentially due to serotonergic dysregulation during critical periods of brain development (Maloney etal. 2017). Furthermore, uoxetine exposure during pregnancy
can impair synaptic transmission and plasticity in the offspring’s medial prefrontal
cortex, leading to cognitive and affective disorders, with a distinct sex-dependent
sensitivity observed in female offspring (Bobula etal. 2024). In terms of physical
development, uoxetine has been shown to compromise bone health in neonates,
resulting in reduced bone mineral density and shorter femurs (Weaver etal. 2019).
Research indicates that SSRIs, including uoxetine, are associated with delayed
neonatal adaptation, which manifests as low Apgar scores, the need for resuscitation
at birth, or admission to neonatal intensive care units for respiratory support. This
risk is dose-dependent and particularly pronounced with uoxetine and escitalopram, suggesting a causal relationship between SSRI exposure and neonatal adaptation issues (Cornet et al. 2024). Additionally, prenatal SSRI exposure has been
linked to changes in brain morphology, such as reduced cerebral gray matter and
altered amygdala volume, although some of these changes may not persist into adolescence (Koc etal. 2023). The increase in maternal and fetal serotonin levels due to
SSRI use can lead to vasoconstriction in the uterine and placental vascular beds,
potentially reducing blood perfusion and impacting fetal development, resulting in
outcomes like low birthweight and preterm birth (Domingues et al. 2023).
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121
Specically, uoxetine has been shown to reduce placentome growth and gestation
length, leading to decreased birthweight and neonatal acidemia in animal models,
which suggests intrauterine growth restriction (Domingues etal. 2022). Furthermore,
SSRI exposure is associated with increased risks of preterm birth and neonatal
respiratory distress, with these risks escalating with higher doses (Bandoli etal.
2020). Placental histopathology studies have also found that SSRI use correlates
with fetal vascular malperfusion lesions, which are linked to adverse neonatal outcomes (Levy etal. 2020). Despite these risks, the teratogenic potential of SSRIs is
considered low, and the decision to use these medications during pregnancy should
be individualized, balancing the benets of treating maternal depression against
potential neonatal risks. Overall, while SSRIs, including uoxetine, are commonly
prescribed during pregnancy, their use requires careful consideration of the potential impacts on fetal and neonatal health.
6.6.1.4 Escitalopram andCitalopram
Escitalopram, an SSRI, presents specic risks during pregnancy that may differ
from other SSRIs in terms of fetal exposure and neonatal outcomes. Studies have
shown that SSRI use, including escitalopram, is associated with delayed neonatal
adaptation, which encompasses symptoms such as low Apgar scores, respiratory
distress, and the need for neonatal intensive care unit (NICU) admission.
Escitalopram, along with uoxetine, has been identied as having a higher risk for
these outcomes compared to other SSRIs, suggesting a type and dose-dependent
relationship with delayed neonatal adaptation (Cornet etal. 2024). Additionally,
escitalopram exposure during pregnancy has been linked to increased rates of neonatal adaptation syndrome and NICU admissions, with these risks being particularly pronounced when exposure occurs in the third trimester (Marks etal. 2020).
While SSRIs in general are associated with adverse neonatal outcomes such as preterm birth and low birth weight, the specic risks associated with escitalopram may
be more pronounced due to its pharmacokinetic properties and placental transfer
rates (Febrianti 2024; Hwang etal. 2023). Furthermore, the potential for fetal death,
including stillbirth, has been associated with SSRI exposure, although escitalopram
is not specically highlighted in this context, indicating a need for further research
to delineate its unique risks (Desaunay etal. 2024). Despite these concerns, it is
crucial to balance the risks of escitalopram use against the potential consequences
of untreated maternal depression, which can also lead to adverse outcomes such as
preterm birth and low birth weight (Zeszutek 2021). Overall, while escitalopram
shares some common risks with other SSRIs, its association with delayed neonatal
adaptation and NICU admissions suggests it may pose distinct challenges in managing depression during pregnancy.
6.6.1.5 Fluvoxamine
Fetal exposure to uvoxamine, an SSRI, has been studied to assess its impact on
neonatal outcomes. Research indicates that uvoxamine, like other SSRIs, can cross
the placental barrier, potentially affecting fetal development. In animal studies, neonatal administration of uvoxamine in rats led to increased lethality, reduced body
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weight, and delayed motor reex maturation, suggesting that early exposure can
alter the serotoninergic system and delay physical and motor development (Glazova
etal. 2014). In human studies, uvoxamine exposure during pregnancy has been
associated with poor neonatal adaptation (PNA), a condition characterized by
symptoms such as respiratory distress, jitteriness, and feeding difculties, which
occur in approximately 20–30% of infants exposed to SSRIs in utero (Kieviet etal.
2015). However, a prospective study comparing uvoxamine-exposed pregnancies
to those exposed to other SSRIs and non-teratogenic agents found no signicant
increase in major congenital malformations or adverse neonatal outcomes, such as
miscarriage or prematurity, suggesting that uvoxamine does not pose a higher teratogenic risk than other SSRIs (Einarson etal. 2009; Sivojelezova 2004). Additionally,
while some studies have reported increased risks of delayed neonatal adaptation
with SSRI exposure, these ndings are often dose-dependent and vary with the type
of SSRI used, with uvoxamine not being specically highlighted as having a
higher risk compared to others like escitalopram and uoxetine (Cornet etal. 2024).
Overall, while uvoxamine exposure during pregnancy is associated with certain
risks, these are generally consistent with those observed for other SSRIs, and careful consideration of the benets and risks is essential when prescribing uvoxamine
to pregnant women.
6.6.2 SNRIs
The comparative efcacy of SNRIs during pregnancy, particularly concerning fetal,
neonatal, and maternal outcomes, reveals a complex risk-benet prole when compared to other antidepressant classes such SSRIs. SNRIs have been associated with
an increased risk of hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia, with studies indicating a signicantly higher
risk compared to SSRIs and unexposed groups. In recent research conducted by
Benevent etal., out of a total of 156,133 pregnancies, a cohort of 143,391 was incorporated into the study population, which comprised 210 (0.1%) individuals in the
SNRI category, 1316 (0.9%) individuals in the SSRI category, and 141,865 (98.9%)
individuals in the unexposed category. Following the adjustment for the severity of
depression and additional mental health conditions, the incidence of hypertensive
disorders of pregnancy (HDP) was markedly elevated among women who were
exposed to SNRIs (n= 20; 9.5%) in comparison to those who were exposed to
SSRIs (n=72; 5.5%; adjusted odds ratio [aOR] [95% CI]=2.32 [1.28–4.20]) and
to women who were not exposed (n=6224; 4.4%; aOR [95% CI]=1.89 [1.13–3.18])
(Benevent etal. 2023). In terms of fetal and neonatal outcomes, both SNRIs and
SSRIs have been linked to transient neonatal behavioral changes, such as poor neonatal adaptation and an increased rate of persistent pulmonary hypertension of the
newborn (PPHN), although the absolute risk remains low (Nörby etal. 2016; Ornoy
and Koren 2019). The potential for congenital malformations, particularly cardiac
anomalies, has been noted, albeit with a small increased risk, and these risks are
similar across different antidepressant classes (Goracci et al. 2015; Ornoy and
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Koren 2017). Furthermore, untreated maternal depression itself poses signicant
risks, including adverse effects on child development and increased maternal morbidity, which necessitates a careful evaluation of the risks associated with discontinuing antidepressant treatment during pregnancy (Desaunay et al. 2023). The
decision to use SNRIs or other antidepressants during pregnancy should therefore
be guided by a thorough assessment of the maternal benets against the potential
fetal and neonatal risks, with a focus on maintaining the minimal effective dose to
mitigate adverse outcomes. Overall, while SNRIs present certain risks, particularly
concerning maternal hypertension, the broader context of maternal mental health
and the potential consequences of untreated depression must be considered in clinical decision-making.
6.6.2.1 Duloxetine
Duloxetine, an SNRI, is one of the antidepressants used during pregnancy. Studies
have shown that duloxetine exposure is associated with an increased risk of preterm
birth, although the risk of being born small for gestational age is not signicantly
elevated compared to other antidepressants like SSRIs and venlafaxine (Ankarfeldt
etal. 2023; Huybrechts etal. 2020). Additionally, duloxetine has been linked to
congenital malformations, although the evidence is not consistent across all studies,
and the risk is not signicantly higher than that associated with other antidepressants (Febrianti 2024). A cohort study utilizing data from Sweden and Denmark
encompassed over 2 million births, with 1512 instances of duloxetine exposure and
compared with duloxetine-nonexposed groups, which yielded an odds ratio (OR) of
0.98 (95% condence interval [CI] 0.74 to 1.30, p=0.909) concerning major malformations, an OR of 1.09 (95% CI 0.82 to 1.45, p=0.570) for minor malformations, and an OR of 1.18 (95% CI 0.43 to 3.19, p=0.749) relating to stillbirths. In
terms of the individual subtypes of malformations, certain ndings reached statistical signicance; however, these were accompanied by considerable statistical
uncertainty attributable to the exceedingly limited number of occurrences. The principal limitations of a study stemmed from the unavailability of data regarding the
indication for duloxetine, as well as the lack of a direct assessment of depression
severity, which could not be incorporated as covariates (Ankarfeldt etal. 2021a, b).
Notably, duloxetine-exposed infants have higher rates of neonatal intensive care
unit (NICU) admissions and adaptation syndromes compared to those exposed to
other antidepressants, such as escitalopram (Marks etal. 2020). Furthermore, duloxetine exposure during pregnancy has been associated with an increased risk of postpartum hemorrhage and a potential, albeit small, increased risk of cardiac
malformations (Huybrechts etal. 2020). While duloxetine does not appear to signicantly increase the risk of spontaneous or elective abortions compared to SSRIs,
it does show a higher risk of elective abortions when compared to non-exposed
groups but confounders still need to be claried (Ankarfeldt etal. 2021a, b). These
ndings highlight the importance of carefully weighing the benets of treating
maternal depression with duloxetine against the potential risks to the fetus and neonate, considering the specic adverse outcomes associated with this medication
compared to other antidepressants.
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6.6.2.2 Venlafaxine
Comparative studies investigating fetal exposure risks of venlafaxine versus other
antidepressants have yielded varied results, highlighting both potential risks and the
need for further research. Venlafaxine, an SNRI, has been associated with increased
risks of fetal cardiac anomalies in animal studies, suggesting alterations in serotonin
signaling as a potential mechanism (Laurent etal. 2016). However, human studies
present a more nuanced picture. Venlafaxine has been associated with a higher incidence of specic birth defects, such as anencephaly and craniorachischisis, with
adjusted odds ratios indicating signicant risk even after accounting for underlying
maternal conditions (Anderson etal. 2020). Furthermore, venlafaxine exposure has
been associated with respiratory defects in human studies, highlighting its potential
impact on fetal development (Bérard etal. 2017, 2019).
Lassen etal. conducted a systematic analysis encompassing eight cohort studies
that elucidate the outcomes associated with in utero exposure to venlafaxine or
duloxetine during the rst trimester. The aggregated data pertaining to venlafaxine
included 3186 exposed infants and 107 instances of major malformations, culminating in a relative risk estimate and a 95% condence interval of 1.12 (0.92–1.35). In
contrast, the relevant data for duloxetine comprised 668 infants and 16 major malformations, yielding a relative risk estimate and a 95% condence interval of 0.80
(0.46–1.29). The ndings indicate that rst-trimester in utero exposure to venlafaxine is not correlated with an elevated risk of major congenital malformations.
Although the volume of data concerning duloxetine is considerably smaller, it does
not imply a clinically signicant increase in risk (Lassen etal. 2016). Similarly, a
large Nordic cohort study found no substantial increase in overall cardiac birth
defects among infants exposed to venlafaxine or SSRIs, although there was a noted
increase in specic defects like septal and right ventricular outow tract defects,
which were not supported by sibling-controlled analyses, suggesting potential confounding factors rather than a direct teratogenic effect (Furu etal. 2015) Compared
to other antidepressants, venlafaxine-exposed infants also showed higher rates of
transient tachypnea of the newborn (TTN) (Marks etal. 2020). The WHO Safety
Database analysis also identied venlafaxine among antidepressants associated
with fetal death, particularly when exposure occurs during the rst trimester, indicating a need for cautious use during early pregnancy (Desaunay et al. 2024).
Despite these ndings, the literature suggests that the benets of treating maternal
depression with antidepressants, including venlafaxine, may outweigh potential
risks, especially considering the adverse effects of untreated maternal depression on
fetal development.
Maternal hypertensive disorders during pregnancy, such as gestational hypertension and pre-eclampsia, have been associated with adverse fetal outcomes, and the
use of antidepressants, including venlafaxine, may further complicate these risks.
Venlafaxine, an SNRI, has been linked to an increased risk of hypertensive disorders
of pregnancy (HDP) compared to SSRIs and non-exposure to antidepressants, with
adjusted odds ratios indicating a signicantly higher risk of HDP in women treated
with SNRIs (Benevent etal. 2023). This increased risk of HDP is concerning given
6 Antidepressants inPregnancy
125
that hypertensive disorders are associated with adverse neonatal outcomes such as
preterm birth and small-for-gestational-age infants (Gallitelli etal. 2024).
Overall, while venlafaxine does not appear to signicantly increase the risk of
major congenital malformations compared to other antidepressants, the evidence
suggests that venlafaxine may pose specic risks during pregnancy, particularly
concerning cardiac and respiratory outcomes, the potential for specic cardiac
defects and the impact of confounding factors necessitate careful consideration and
further research to clarify these associations (Furu etal. 2015; Lassen etal. 2016).
6.6.3 TCAs
The comparative analysis of tricyclic antidepressants (TCAs) versus other antidepressants during pregnancy reveals nuanced outcomes for fetal, neonatal, maternal,
and long-term effects. A systematic review analyzed a total of 16 studies encompassing 4,564,798 pregnancy outcomes. The mixed-methods meta-analysis revealed
an odds ratio of 1.22 (95% CI: 1.11 to 1.33) for maternal antidepressant use and
congenital heart defects. Class-specic analyses indicated an odds ratio of 1.50
(95% CI: 1.19 to 1.89) for rst-trimester SNRI use and congenital heart defects,
while SSRIs showed a signicant odds ratio of 1.22 (95% CI: 1.12 to 1.33); no
increased odds ratio was observed for TCAs. Individual antidepressants demonstrated signicant odds ratios of 1.53 (95% CI: 1.25 to 1.88) for paroxetine, 1.28
(95% CI: 1.01 to 1.62) for uoxetine, 1.28 (95% CI: 1.14 to 1.45) for sertraline, and
1.23 (95% CI: 1.01 to 1.50) for bupropion (De Vries etal. 2020). However, the use
of antidepressants, including TCAs, during pregnancy is associated with increased
risks of preterm birth, low birth weight, and neonatal adaptation syndromes,
although these risks are often confounded by the underlying maternal psychiatric
conditions (Marks etal. 2020; Martin etal. 2024; Uguz 2021). Specically, maternal antidepressant use is linked to adverse neonatal outcomes such as preterm delivery and low Apgar scores, with TCAs like amitriptyline showing fewer associations
with these outcomes compared to other antidepressants (Martin etal. 2024).
Long-term outcomes for children exposed to antidepressants in utero, including
TCAs, suggest associations with affective disorders but not consistently with neurodevelopmental or other psychiatric disorders, indicating that many observed effects
may be attributed to the underlying maternal condition rather than the medication
itself (Rommel etal. 2020). Furthermore, while antidepressant use is associated
with increased risks of adverse outcomes, these risks are often comparable to those
in untreated depression, suggesting that the decision to continue medication should
be individualized (Mitchell and Goodman 2018). Overall, while TCAs may present
a lower risk for certain congenital anomalies compared to SSRIs and SNRIs, the
broader implications of antidepressant use during pregnancy necessitate careful
consideration of both maternal and fetal health outcomes.
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6.6.4 Atypical/Other Antidepressants
6.6.4.1 Vortioxetine
The available literature does not provide evidence of a cohort study specically
focused on vortioxetine use during pregnancy. However, there are case studies and
series that offer some insights into the effects of vortioxetine during pregnancy. A
case study from Japan highlighted that vortioxetine exposure during pregnancy
could lead to severe neonatal asphyxia, although the drug’s transfer into breast milk
was minimal, suggesting limited neonatal exposure and no adverse developmental
effects in the infant (Kiribayashi etal. 2024). In animal studies, prenatal and lactational exposure to vortioxetine resulted in increased motor activity and anxiety in
offspring, indicating potential neurodevelopmental risks, although emotional learning and memory were unaffected (Ergun etal. 2024). Another study from the Israeli
Teratology Information Service documented outcomes of 19 pregnancies with rsttrimester exposure to vortioxetine, resulting in 12 live births without malformations,
alongside some adverse outcomes like miscarriages and stillbirths, though these
were not conclusively linked to vortioxetine alone. However, the limited data on
vortioxetine, especially from small sample sizes, necessitates further research to
fully understand its safety prole during pregnancy (Shweiki and Diav-Citrin 2021).
Vortioxetine’s adverse effects, such as gastrointestinal issues and mood-related
symptoms, are similar to those of SSRIs, but it also has unique unlisted adverse
reactions like hyperprolactinemia and edema (Ekhart etal. 2022; Verma and Kumar
2021). Overall, while vortioxetine shares some risks with SSRIs, its unique pharma-
cological prole and adverse effects warrant careful consideration and further investigation to ensure maternal and neonatal safety (Gastaldon etal. 2023a, b).
6.6.4.2 Bupropion
Bupropion, a norepinephrine-dopamine reuptake inhibitor, presents distinct risks
during pregnancy compared to other antidepressants, particularly concerning fetal
exposure and neonatal outcomes. Unlike SSRIs and SNRIs, which are commonly
associated with PNAS and withdrawal symptoms, bupropion does not show a signicant association with neonatal withdrawal syndrome, as evidenced by a pharmacovigilance study that found no disproportionate reporting for bupropion compared
to other antidepressants (Gastaldon etal. 2023a, b). However, there are concerns
regarding bupropion’s potential to increase the risk of cardiac malformations, as
suggested by data from a bupropion pregnancy registry (The Medical Letter 2024).
A retrospective cohort study which assessed 2741 pregnant women and focused
on ve specic antidepressants (bupropion, citalopram, escitalopram, uoxetine,
sertraline) reported that women continuously prescribed antidepressants throughout
pregnancy had lower NICU admissions if they lacked third trimester exposure to
bupropion (aOR 0.43, 95% CI 0.21–0.90) or escitalopram (aOR 0.49, 95% CI
0.28–0.85). Those previously on escitalopram without third-trimester exposure
exhibited decreased odds of adaptation syndrome (aOR 0.19, 95% CI 0.07–0.48).
No signicant differences were observed in other outcomes for women on different
antidepressants or for those with no early pregnancy drug exposure versus
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127
continuous exposure (Tharp etal. 2022). Furthermore, when bupropion is used in
combination with serotonergic drugs, there is a potential risk of serotonin syndrome,
which can lead to severe neonatal outcomes such as encephalopathy and abnormal
movements, highlighting the importance of monitoring maternal medication lists
during pregnancy (Brajcich etal. 2021). Overall, while bupropion may have a lower
risk of certain neonatal adaptation issues compared to SSRIs and SNRIs, its potential association with cardiac malformations and the risks associated with polypharmacy necessitate careful consideration and monitoring during pregnancy.
6.6.4.3 Mirtazapine
The use of mirtazapine during pregnancy presents several considerations regarding
fetal safety and pregnancy outcomes. A nationwide cohort study in Denmark found
no signicant association between mirtazapine exposure and major congenital malformations, spontaneous abortion, stillbirth, or neonatal death, suggesting that mirtazapine may not increase these risks compared to unexposed pregnancies (Ostenfeld
etal. 2022). A study reviewed 41 observational studies over the data of 2343 mirtazapine exposed pregnancies and concluded that mirtazapine may share some risks
common to antidepressants, such as congenital malformations; the evidence is not
consistent across all studies (Ostenfeld et al. 2025). Additionally, mirtazapine’s
impact on the offspring’s brain function and behavior has been studied in animal
models, where it was found to have anxiolytic effects and inuence neuroplasticity,
potentially mitigating some negative effects of maternal stress and depression
(Dubiel-Hoppanova etal. 2025). Unlike SSRIs, which have been associated with
increased risks of neonatal seizures and other adaptation syndromes, mirtazapine
does not appear to signicantly increase the risk of neonatal seizures or adaptation
syndromes, as indicated by studies comparing various antidepressants (Martin etal.
2024; Uguz 2019). Furthermore, mirtazapine was not associated with increased
risks of preterm delivery or low Apgar scores, which are concerns with other antidepressants (Martin etal. 2024).
Overall, Mirtazapine has emerged as a promising treatment for hyperemesis
gravidarum (HG), particularly in cases resistant to conventional therapies. Studies
and case reports indicate that mirtazapine can signicantly reduce symptoms of HG
scores and improve overall maternal health outcomes (Galletta etal. 2022).
6.7 Statistical Significance Versus Clinical Significance
The distinction between clinical signicance and statistical signicance in the context of antidepressant use during pregnancy is crucial for understanding the implications of research ndings. Statistical signicance refers to the likelihood that a
result is not due to chance, often determined by p-values or condence intervals. For
instance, studies have shown that antidepressant use during pregnancy is statistically associated with increased risks of preterm birth and congenital malformations,
with specic hazard ratios and condence intervals indicating these associations are
unlikely to be due to random variation (Martin et al. 2024). However, clinical
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signicance considers whether these statistically signicant ndings have meaningful implications for patient care. As another example in a study, from the Danish
national registers involving 21,785 children born to 13,941 mothers by Rommel
et al., the impact of intrauterine exposure to antidepressants on birth outcomes,
specically gestational age and birthweight, while considering genetic liability to
maternal major depression was investigated. The antidepressant continuation group
had signicantly reduced mean gestational ages (adjusted β ranges: 1.7–4.5 days,
p<0.001–0.008) and lower mean birthweights (adjusted β ranges: 58.6–165.4 g,
p=0.001–0.008) than the discontinuation and unexposed groups. The difference
between groups was 1.7–4.5 days as gestational age and 58.6–165.4 grams as
weight (Rommel etal. 2024).
Thus, while statistical signicance provides a foundation for understanding
potential risks, clinical signicance guides practical decision-making in managing
depression during pregnancy.
6.8 Conclusion
Table 6.1 shows expert recommendations based on scientic evidence and clinical
experience). This chapter can be summarized as follows:
Importance of Mental Health Maternal mental health during pregnancy is a critical factor for both maternal and fetal well-being, and managing depression and
anxiety should be prioritized to prevent long-term complications.
Table 6.1 Expert recommendations based on scientic evidence and clinical experience
Prioritize managing maternal depression and anxiety during pregnancy to enhance both
maternal and fetal well-being
Stay updated with clinical guidelines and research to ascertain the safest use of SSRIs and
other antidepressants during pregnancy, especially concerning congenital malformations.
Tailor antidepressant treatment plans to the specic trimester of pregnancy to mitigate
associated risks
Adjust antidepressant dosages carefully during pregnancy to account for physiological
changes that affect drug metabolism
Emphasize the benets of treating maternal depression, such as preventing relapse and
promoting better overall maternal health
Assess both statistical and clinical signicance when considering the use of antidepressants to
ensure the benets outweigh potential risks
Develop individualized treatment plans that consider the severity of the mother’s depression
and the safety of the fetus
Involve a multidisciplinary team, including obstetricians, psychiatrists, and pediatricians, in
the management of pregnancies exposed to antidepressants
Remain vigilant about potential neonatal risks from antidepressant use, such as adaptation
issues and long-term developmental challenges
Emphasize shared decision-making between the patient and healthcare providers to ensure that
treatment decisions align with the patient’s values and preferences