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5 The Role of Paternal Mental Health During the Perinatal Period…
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Part II
Safety of Psychotropic Drugs During
Pregnancy and Lactation
Antidepressants inPregnancy
EsraYazıcı andÖzlemAkçayCiner
6.1 Introduction
Pregnancy can be a time of joy and anticipation, but it also brings signicant emotional and physical changes that may increase the risk of developing depression and
anxiety disorders. Women’s depression is prevalent, especially around childbearing
years, affecting 10–23% of women aged 18 or older. Symptoms often include sleeplessness, hopelessness, and low energy (Jahan etal. 2021).
The prevalence of prenatal anxiety disorders exhibits variability across different
studies and evaluations. Anxiety associated with pregnancy is prevalent; 54% of
women indicate experiencing anxiety during at least one trimester. As per recent
investigations, anxiety levels are projected to be 6.6–15% lower during the second
trimester when juxtaposed with the initial and third trimesters, which appear to
present heightened anxiety levels. Indeed, it has been observed that women encounter anxiety in a non-linear trajectory, with the rst and third trimesters of pregnancy
identied as particularly high-risk periods (Karnwal and Sharmila 2024).
An exhaustive analysis of the 26 scholarly articles indicated that a total of 4303
individuals tested positive for depressive disorders within a cohort of 28,248 expectant mothers, resulting in a prevalence rate of 15%. After the elimination of confounding variables, the sample size was recalibrated to 25,771, with 4223 individuals
identied as exhibiting depressive symptoms, thus yielding a revised prevalence
rate of 16.4%. Furthermore, the investigation disclosed that antepartum depression
(AD) is most frequently encountered during the nal trimester of gestation and least
prevalent during the second trimester (Okagbue etal. 2019).
6
E. Yazıcı (*)
Faculty of Medicine, Department of Psychiatry, Sakarya University, Sakarya, Türkiye
Ö. A. Ciner
Düzce State Hospital, Düzce, Türkiye
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
F. Uguz, L. Orsolini (eds.), Perinatal Psychopharmacology,
https://doi.org/10.1007/978-3-031-99720-4_6
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102
E. Yaz ıcı and Ö. A. Ciner
Socioeconomic factors, such as low income and lack of family support, along
with obstetric factors like unplanned pregnancies, are signicant risk factors for
these mental health issues (Nagandla etal. 2017; Adina etal. 2022). The literature
highlights the importance of early screening and intervention to manage these conditions effectively, as they can have adverse effects on both maternal and fetal health
(Karnwal and Sharmila 2024; Okagbue etal. 2019). Overall, while depression is
most pronounced in the rst trimester, anxiety and stress tend to escalate as pregnancy advances, highlighting the need for continuous mental health support
throughout the pregnancy (Karnwal and Sharmila 2024).
Mental disorders during pregnancy challenges can affect not only the well-being
of the mother but also the developing fetus, potentially leading to complications in
both pregnancy and postpartum recovery. Addressing these mental health issues is
crucial, as early intervention and support can help mitigate risks and promote a
healthier environment for both the mother and child. Women may need to use antidepressants during pregnancy due to the signicant risks associated with untreated
depression, which can adversely affect both maternal and fetal health (Desaunay
etal. 2023; Yazici etal. 2015).
Antidepressant prescriptions decrease from 70% before pregnancy to 27% during pregnancy, partly due to concerns over drug effects on the fetus and inadequate
post-diagnosis prescription rells (Jahan etal. 2021). On the other hand, rates of
antidepressant use during pregnancy vary signicantly across different regions,
with estimates indicating that approximately 2–3% of pregnant women in Nordic
countries and up to 10% in the United States utilize these medications (Olivier etal.
2013). A comprehensive study in Denmark revealed that 2.4% of pregnancies
involved at least one antidepressant prescription, with a notable increase from 0.4%
in 1997 to 4.6% in 2011, followed by a decline to 3.1% in 2016 (Sun etal. 2019). In
a cohort analysis across the UK, Norway, and Sweden, including 2,528,916 singleton births, 120,209 (4.8%) of deliveries were exposed to maternal antidepressant
use (Martin et al. 2024). The rising trend in antidepressant prescriptions during
pregnancy highlights the complex interplay between managing maternal mental
health and potential risks to fetal outcomes, necessitating further research to understand the implications of these medications (Urato 2015) (Fabiano etal. 2025).
The use of antidepressants during pregnancy presents a complex balance of risks
and benets that must be carefully considered. On the one hand, untreated maternal
depression is associated with signicant adverse outcomes, including increased
risks of suicidal ideation, miscarriage, neonatal growth problems, and postpartum
depression, which can affect both maternal and fetal health (Gallitelli etal. 2024;
Lam 2023). On the other hand, the use of antidepressants, particularly selective
serotonin reuptake inhibitors (SSRIs) and other classes like duloxetine, mirtazapine,
and atomoxetine, has been linked to risks such as preterm birth, low birth weight,
congenital malformations, and low Apgar scores (Desaunay et al. 2023; Martin
etal. 2024). However, the absolute risks of these outcomes remain relatively low,
and the severity of maternal depression may confound these associations.
Some studies suggest that antidepressant use does not signicantly increase the
risk of preterm birth, one of the complications generally linked to antidepressant use
6 Antidepressants inPregnancy
103
during pregnancy, when accounting for the severity of depression (Amit etal. 2024).
Moreover, the continuation of antidepressants during pregnancy may prevent
relapse of depression, which is crucial for maternal mental health (Knopf 2023).
There existed a robust body of evidence suggesting that the continuation of antidepressant medication throughout the course of pregnancy was not linked to an elevated risk of autism, attention-decit/hyperactivity disorder (ADHD), or intellectual
disability when compared to the cessation of such medications prior to conception
in both our primary and ancillary analyses. Conversely, the evidence was notably
less robust concerning the comparative analyses of the initiation versus noninitiation of antidepressant treatment during pregnancy, with the inherent lack of
precision due to a reduced sample size and broader condence intervals constituting
a signicant limitation (Heuvelman etal. 2023). Importantly, the decision to use
antidepressants during pregnancy should be individualized, involving a multidisciplinary team to weigh the potential risks against the benets of treating maternal
depression (Gallitelli etal. 2024; Yazici etal. 2015). Personalized treatment plans
and careful monitoring can help mitigate risks while addressing the mental health
needs of pregnant women (Dama and Van Lieshout 2023).
In this chapter, we will concentrate on the pharmacology of antidepressants during pregnancy, examining the nuances of medications and their probable
consequences.
6.2 Risks ofMaternal Stress, Anxiety, andDepression
Maternal mortality review committees ascertain that over 80% of all pregnancyassociated fatalities in the United States are avertable. Within the spectrum of avertable fatalities, mental health disorders necessitate specic scrutiny as they have
been identied as the predominant underlying factor (Combellick et al. 2024).
Untreated depression is shown to be a strong predictor of postpartum depression
(Yazici etal. 2015). A study by Nesrin Jahan reviewed 20 cohort studies of antenatally depressed women are more likely to experience severe peripartum complications such as heavy bleeding, vaginal tears, placental abnormalities, and convulsions.
Additionally postpartum problems like fever, urinary/fecal incontinence, and failure
to use a bed net during pregnancy are more prevalent among women with prenatal
depression. Furthermore, there was a strong association between antenatal depression and an increased likelihood of cesarean section (CS) delivery, driven by higher
anxiety levels and fear of labor among depressed women. The study concluded that
psychological distress from depression can hinder uterine contractions, leading to
prolonged labor, stalled progress, and fetal distress, raising the chances of undergoing a cesarean section. Additionally, it’s reported that mothers with severe depression are at a signicantly higher risk of complications like preeclampsia, preterm
birth, fetal demise, and intrauterine growth restriction compared to non-depressed
mothers (Jahan etal. 2021). In a study by Ogunyemi etal., anxiety/depression cases
(6.3%) were analyzed against unaffected pregnancies (93.7%) using logistic regression. A higher likelihood of being Non-Hispanic White, using substances, being
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E. Yaz ıcı and Ö. A. Ciner
unmarried, relying on public insurance, and experiencing medical complications
was observed. Untreated anxiety/depression correlated with adverse maternal outcomes including labor induction (aOR = 2.02) and postpartum hemorrhage
(aOR=2.57), while treated cases saw increased blood transfusions (aOR=4.81)
but decreased cesarean deliveries (aOR= 0.59). Neonatal outcomes for treated
cases included risks for small for gestational age (aOR=3.04) and neonatal seizures
(aOR=12.3), while untreated cases faced hypoxia (aOR=2.83) and encephalopathy (aOR=18.3). The use of multiple psychotropic medications elevated risks for
neonatal adaptation syndrome and hypoglycemia. In conclusion, untreated cases led
to more maternal adverse outcomes, whereas treated cases presented with greater
neonatal complications compared to unaffected pregnancies (Ogunyemi et al.
2018). Maternal depression has long-term outcomes, increased susceptibility to
mental health issues in the child, difculties in social relationships, and a higher
likelihood of behavioral problems as they grow older, as well as fetal and delivery
effects (Nagandla etal. 2017).
Maternal depression during pregnancy has signicant negative effects on both
mothers and their infants. A prospective investigation conducted by Haq et al.
assessed women exhibiting antenatal depression in accordance with Edinburgh
Postnatal Depression Scale (EPDS) scores in a longitudinal manner. The incidence
of preterm delivery was markedly elevated in the study cohort, with 40% of births
categorized as preterm and 23.4% classied as early preterm, in contrast to the gures of 19.1% and 12.4% observed in the control group, respectively. In a similar
vein, the depression group demonstrated lower birth weights alongside diminished
1-minute (20%) and 5-minute Apgar scores. The multivariate regression analysis
indicated a statistically signicant and independent association between maternal
depression and the occurrence of preterm delivery (aOR: 3.27, 95% CI: 1.23–9.47)
(Haq etal. 2024). Another cohort study evaluated 68 mother-baby dyads and found
that maternal depressive symptoms can adversely affect child neurodevelopment,
particularly in emotional processing, as evidenced by altered brain connectivity
(Vartiainen etal. 2024). Furthermore, antenatal depression has been linked to lower
cognitive and motor development in infants at 12months, highlighting the importance of mental health screening during pregnancy (Roy etal. 2022).
The prevalence of depressive symptoms can also lead to long-term maternal
health issues, including postpartum depression, emphasizing the need for integrated
mental health care in maternal health services (Di Vincenzo etal. 2023). Effective
interventions that address maternal mental health during pregnancy can signicantly improve outcomes for both mothers and their infants, fostering healthier family dynamics and promoting overall well-being (Rohanachandra 2021) by providing
essential support systems that not only alleviate maternal stress but also enhance the
emotional and cognitive development of children, ultimately contributing to a more
resilient future generation (Roy etal. 2022).
These empirical ndings highlight the paramount importance of maternal mental
health not solely in relation to pregnancy outcomes but also concerning the enduring development and overall well-being of offspring, thereby necessitating the
establishment of comprehensive support frameworks for expectant mothers.
6 Antidepressants inPregnancy
Furthermore, the effective management of depressive and anxiety disorders, along
with the prevention of relapses of such conditions during gestation, emerges as a
pivotal concern for both maternal and child mental health, as well as for public
health at large.
105
6.3 Impact ofPregnancy onthePharmacokinetics
andPharmacodynamics ofAntidepressants
Understanding how pregnancy alters the pharmacokinetics and pharmacodynamics
of antidepressants is essential for optimizing treatment strategies, as these changes
can affect drug absorption, distribution, metabolism, and excretion in expectant
mothers. This knowledge is vital for clinicians to tailor antidepressant therapies
effectively, ensuring both maternal mental health and fetal safety throughout the
course of pregnancy. Research has shown that certain antidepressants may behave
differently during pregnancy, necessitating careful monitoring and potential dosage
adjustments to maintain therapeutic efcacy while minimizing risks.
Pregnancy leads physiological changes, such as increased blood volume, altered
hormone levels, and enhanced renal and hepatic function and these changes can
modify drug absorption, distribution, metabolism, and excretion, impacting the efcacy and safety of antidepressants, leading to individualized management of treatments (Dodeja etal. 2025; Eke 2022). Specically, the activity of cytochrome P450
enzymes, crucial for drug metabolism, is altered; for instance, CYP2D6 activity
increases, leading to decreased serum concentrations of drugs like paroxetine and
uoxetine, while CYP2C19 activity decreases, affecting drugs like sertraline
(Svensson etal. 2020; Poweleit etal. 2022). These changes can result in subtherapeutic drug levels or an increased risk of adverse effects if not properly managed
(Yue etal. 2023; Schoretsanitis etal. 2020). The variability in pharmacokinetics is
further complicated by genetic polymorphisms in CYP enzymes, which can inuence individual responses to antidepressants during the pregnancy period (Cafaro
etal. 2022). Despite the widespread use of SSRIs as rst-line treatments for depression and anxiety disorders in pregnant women, there is still a lack of comprehensive
pharmacokinetic data, leading to challenges in establishing evidence-based dosing
guidelines (Avram etal. 2016). Studies have shown that dose-adjusted plasma concentrations of certain antidepressants, such as trimipramine and nortriptyline,
decrease signicantly in the third trimester, while others like escitalopram and venlafaxine show negligible changes (Schoretsanitis etal. 2020). The presence of the
feto-placental unit adds another layer of complexity as well as gestational age, fetal
growth, and positions, as drugs can cross the placental barrier, potentially affecting
fetal development (Velasquez etal. 2016). Therefore, therapeutic drug monitoring
and individualized treatment plans are crucial to optimize antidepressant therapy
during pregnancy, ensuring maternal mental health while minimizing risks to the
fetus (Campbell etal. 2016). Further research is needed to better understand these
pharmacokinetic changes and to develop guidelines for safe and effective antidepressant use in pregnant populations (Schoretsanitis etal. 2020; Svensson et al.
106
2020). Understanding the implications of these ndings is essential for healthcare
providers, as it highlights the need for ongoing assessment and adjustment of medication regimens throughout pregnancy to maintain both maternal well-being and
fetal safety.
E. Yaz ıcı and Ö. A. Ciner
6.4 Conception andAntidepressants
Fertility constitutes a signicant topic of contemporary discourse and has been
demonstrated to be inuenced by depressive disorders as well as pharmacological
interventions for depression. Antidepressants, particularly SSRIs, have been shown
to affect conception and fertility in both men and women, though the effects vary. In
men, SSRIs can decrease sperm count and viability, and disrupt sperm morphology,
which can impair fertility (Milosavljević etal. 2022; Santos etal. 2025). For women,
certain SSRIs like paroxetine and escitalopram may negatively impact fertility by
affecting fallopian tube motility, although their use in women undergoing invitro
fertilization (IVF) does not seem to adversely affect outcomes (Milosavljević etal.
2022). Depression itself, independent of antidepressant use, is associated with
reduced fertility and increased time to pregnancy, as well as a higher risk of infertility in both men and women (Liao etal. 2024). The decision to use antidepressants
during conception is complex due to fertility; additionally, the medication during
conception means medication during the rst trimester of pregnancy generally. So
the decision needs weighing its potential risks to fetal development, such as congenital malformations and developmental issues, although these risks are not conclusively proven and may be confounded by the severity of maternal depression
(Cristina 2023; Rotem-Kohavi etal. 2021; Yang etal. 2024; Sujan 2022). Despite
these concerns, untreated depression poses signicant risks to both maternal and
fetal health, including preterm labor and low birth weight, which highlights the
importance of managing depression effectively during the reproductive period
(Zeszutek 2021). Therefore, while antidepressants can affect conception, the decision to use them should carefully weigh the benets of treating depression against
potential risks to fertility and pregnancy outcomes.
6.5 Risk Associated withAntidepressant Use
During Pregnancy
Antidepressant use during pregnancy is not only related to the type of antidepressant. Also age of mother, socioeconomic status, and pre-existing health conditions
can play crucial roles in determining the overall impact on both maternal and fetal
well-being (Desaunay etal. 2023). Comorbid clinical conditions as gestational diabetes, hypertension, and obesity may further complicate the management of depression during pregnancy, necessitating a tailored approach to treatment that considers
both mental health and physical health outcomes for the mother and child.
6 Antidepressants inPregnancy
107
6.5.1 Fetal andNeonatal Outcomes
6.5.1.1 Congenital Malformations
The relationship between antidepressant use during pregnancy and the risk of congenital malformations is complex and varies depending on the type of antidepressant and the specic malformation considered. Studies indicate that SSRIs, such as
sertraline, are associated with an increased risk of congenital heart defects (CHDs),
including only septal heart malformations, not other major malformations and
although the severity of these malformations is generally not extreme (Kolding etal.
2023; Shen etal. 2017). Several studies have explored this association with mixed
results. A study conducted with Mendelian randomization found no signicant
overall association between antidepressant use and congenital malformations,
although specic associations were suggested, such as between uoxetine and nervous system malformations, and SSRIs with respiratory system malformations
(Yang et al. 2024). A population-based cohort study in Hong Kong reported no
robust association between rst-trimester antidepressant exposure and major congenital malformations, but noted increased risks for cardiac and respiratory anomalies, particularly with SSRIs and multiple antidepressant classes (Chan etal. 2024).
In a population-based study, Chan etal. analyzed data from 465,069 women in
Hong Kong who delivered their rst singleton child between 2003 and 2018, focusing on the effects of rst-trimester antidepressant use on the risk of congenital malformations. The study found no overall association between major malformations
and antidepressant use, with a weighted odds ratio of 0.88, but identied increased
risks for specic anomalies, such as cardiac (wOR, 1.82) and respiratory anomalies
(wOR, 4.11). The research highlighted that while exposure to SSRIs and multiple
antidepressant classes was linked to respiratory and cardiac anomalies, respectively,
these associations were not consistently conrmed across sensitivity analyses, indicating a need for further research to clarify the safety of individual antidepressants
regarding specic malformations (Chan etal. 2024).
Similarly, a meta-analysis of cohort studies by Lou etal. (2022), which included
data from eight different studies that examined the outcomes of infants born to
mothers who were exposed to serotonin-norepinephrine reuptake inhibitors (SNRIs)
during early pregnancy, found that SNRIs are not signicantly associated with an
increased risk of overall congenital malformations, but there is a noted increase in
cardiac malformations, although this risk is not statistically signicant when compared to SSRIs or no exposure with clinical indication (Lou etal. 2022).
Another meta-analysis found that SSRIs and SNRIs were associated with
increased odds of congenital heart defects, with specic SSRIs like paroxetine and
uoxetine showing signicant associations. In the aforementioned study, a total of
20 distinct investigations were recognized, which collectively encompassed
5,337,223 instances of pregnancies. The odds ratio associated with maternal administration of any antidepressant during the initial trimester of gestation, in relation to
the occurrence of congenital heart defects, as determined by random effects metaanalysis, was calculated to be 1.28 (95% condence interval [CI] 1.17–1.41).
Reported signicant odds ratios included 1.69 (95% CI 1.37–2.10) for
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E. Yaz ıcı and Ö. A. Ciner
serotonin-norepinephrine reuptake inhibitors (SNRIs) and 1.25 (95% CI 1.15–1.37)
for SSRIs, respectively. Conversely, a non-statistically signicant odds ratio of 1.02
(95% CI 0.82–1.25) was observed for tricyclic antidepressants. Examination of
individual SSRIs yielded signicant odds ratios of 1.57 (95% CI 1.25–1.97), 1.36
(95% CI 1.08–1.72), and 1.29 (95% CI 1.14–1.45) for paroxetine, uoxetine, and
sertraline, respectively. Furthermore, the norepinephrine-dopamine reuptake inhibitor bupropion also demonstrated a signicant odds ratio of 1.23 (95% CI 1.01–1.49)
(Courtney De Vries etal. 2021b). A European register-based study supported the
teratogenic effect of SSRIs for certain anomalies, including specic congenital
heart defects but cannot exclude confounding by indication or associated factors
(Wemakor etal. 2015). However, a systematic review and meta-analysis concluded
that while antidepressants were not associated with an increased risk of overall congenital malformations, there was a statistically signicant, albeit marginal, increased
risk for cardiovascular malformations, particularly with paroxetine (Grigoriadis
etal. 2013). These ndings suggest that while there is no consensus on a broad teratogenic effect of antidepressants, certain drugs, particularly SSRIs, may pose specic risks, warranting careful consideration of the benets and risks of antidepressant
use during pregnancy. Further research is needed to clarify these associations and
the underlying mechanisms (Chan etal. 2024; De Vries etal. 2021b; Grigoriadis
etal. 2013; Lou etal. 2022; Wemakor etal. 2015; Yang etal. 2024).
Furthermore, a prospective cohort study in Central China encompassing
5,337,223 pregnancies reported that maternal antidepressant use before and during
early pregnancy is associated with a higher risk of CHDs. The odds ratio for maternal use of any antidepressant during the rst trimester of pregnancy and the presence of congenital heart defects from the random effects meta-analysis was 1.28
(95% condence interval [CI] 1.17–1.41), with specic phenotypes such as transposition of the great arteries and ventricular septal defects being more prevalent (Sun
etal. 2022). Several studies have shown that sertraline is associated with septal heart
malformations, although the risk of more severe heart malformations is not signicantly increased. This association may be inuenced by confounding factors, such
as the underlying depression itself, and should not deter necessary treatment for
maternal depression (Kolding etal. 2023). Additionally, research using animal models, such as zebrash, suggests that serotonin signaling disruption, particularly
involving the 5-HT2B receptor, may play a role in cardiac development, further
implicating SSRIs in potential cardiac malformations (Kent etal. 2022).
Despite these ndings, the overall risk of congenital malformations with SSRIs,
including sertraline, remains relatively low, and the benets of treating maternal
depression often outweigh the risks (Desaunay et al. 2023; Nunes etal. 2021).
While some studies suggest an increased risk of CHD with antidepressant use
before and during early pregnancy, the evidence is not conclusive, and the risk varies depending on the specic antidepressant and timing of exposure (Sun etal.
2022). Therefore, a careful risk-benet analysis is crucial when considering antide-
pressant therapy during pregnancy, and ongoing research is needed to better understand the mechanisms and mitigate potential risks associated with these medications
(Desaunay etal. 2023; Lou etal. 2022).