Review Article
Treating Depression during Pregnancy: Are We
Asking the Right Questions?
Cara Angelotta * and Katherine L. Wisner
Background: Major depressive disorder (MDD) is a common complication of
pregnancy. Once the diagnosis of MDD is made, the physician must assist
the pregnant woman in developing a treatment plan. Methods: In considering
antidepressants, the benefit of medication treatment for maternal disease
control must be balanced against the risk of the drug to the developing
embryo-fetus. This is an individualized decision depending on the disease
characteristics, likelihood of maternal depression response, probability of
adverse fetal effects, and patient characteristics and values. Results: There is
no “zero risk” solution in caring for the pregnant woman with MDD; both the
disorder and the medication present risks to the mother and the embryo-
fetus. If the decision to use antidepressant medication during pregnancy is
made, the justification is that the disease is associated with greater risk than
the treatment. The goal should be remission of symptoms to maximally
reduce disease risk to the mother and developing fetus. Conclusion:
Optimization of selective serotonin reuptake inhibitor dosing during pregnancy
Introduction
Depression is the leading contributor to disease burden for
women worldwide (World Health Organization, 2008). Major
depressive disorder (MDD) is characterized by at least one of
two symptoms, depressed mood or anhedonia (diminished
interest or pleasure), accompanied by the symptoms dis-
played in Table 1. Five symptoms must persist most of the
day nearly every day for at least 2 weeks and cause impair-
ment in function. Co-existing anxiety is common in pregnant
women with MDD (Abramowitz et al., 2010). Anxious rumi-
nations about pregnancy complications and the baby’s health
are frequent symptoms.
While there is growing recognition that postpartum
depression is a serious and common condition, a frequent
misconception that pregnancy protects against depression.
The prevalence of depression during pregnancy is a striking
12.7% (Gaynes et al., 2005). Unfortunately, mental health
service use (including psychotherapy) among women with
psychiatric disorders in general is low and, among pregnant
women, even lower. Only 25.5% of nonpregnant women
Northwestern University, Feinberg School of Medicine, Department of
Psychiatry
*Correspondence to: Cara Angelotta, Northwestern University, 676 North Saint Clair
Street, Suite 1000, Chicago, IL 60611. E-mail: cara.angelotta@northwestern.edu
Published online in Wiley Online Library (wileyonlinelibrary.com). Doi: 10.
1002/bdr2.1074
C 2017 Wiley Periodicals, Inc.
V
dictates several treatment goals: (1) the drug must be at the optimal dose for
the woman; that is, the dose that produces the best response with tolerable
side effects; (2) a continuous measure of symptoms must be repeated and
adjustments to maintain optimal antidepressant efficacy may be required, due
to pharmacokinetic changes during pregnancy; and (3) the resolution of
pregnancy at birth also requires dose adjustment in accord with the woman’s
transition to the nonpregnant, breastfeeding state.
Birth Defects Research 109:879–887, 2017.
C 2017 Wiley Periodicals, Inc.
V
Key words: depression; pregnancy; postpartum; SSRI; antidepressant; preg-
nancy outcome
with a mood disorder received mental services in the prior
year, whereas only 14.3% of pregnant women did (Vesga-
Lopez et al., 2008). Most pregnant women with depression
are neither identified nor treated.
A number of complex factors likely contribute to low
rates of treatment of depression during pregnancy. The
majority of depression care occurs in primary care settings
and nondrug treatments may not be available. Other bar-
riers to care include stigma, cost, and lack of resources, such
as transportation and childcare. Another contributor to low
treatment rates during pregnancy is clinician reticence to
treat depression with medication, because of a lack of exper-
tise and concerns about medicolegal risks. Research ques-
tions in perinatal psychiatry have been largely focused on
risks of medication exposure instead of risks of disease
exposure for the mother and fetus. As a result, many clini-
cians are more concerned about errors of commission
(using an agent that may cause fetal harm) than errors of
omission (having a depressive episode go untreated or
undertreated). Stigma about taking psychotropic medication
during pregnancy may prevent some women from seeking
medical care. Antidepressants during pregnancy have been
scrutinized more closely than other classes of medications.
The media covers research that shows negative outcomes
associated with medication treatment frequently, but rarely
covers the negative effects of depression on maternal–fetal
health. Pregnant women are under tremendous social and
personal pressure to experience pregnancy as a joyous time
(Solomon, 2015), which may also contribute to shame and
reluctance to seek treatment for depression.
880
TABLE 1. DSM-5 Criteria for Major Depressive Episode
1) Depressed mood most of the day, nearly every day, as indicated by
either subjective report (e.g., feels sad, empty, hopeless) or observation
made by others (e.g., appears tearful)
2) Markedly diminished interest or pleasure in all, or almost all, activities
most of the day, nearly every day (as indicated by either subjective
account or observation)
3) Significant weight loss when not dieting or weight gain (e.g., a change
of more than 5% of body weight in a month), or decrease or increase
in appetite nearly every day
4) Insomnia or hypersomnia nearly every day
5) Psychomotor agitation or retardation nearly every day (observable by
others, not merely subjective feelings of restlessness or being slowed
down)
6) Fatigue or loss of energy nearly every day
7) Feelings of worthlessness or excessive or inappropriate guilt (which may
be delusional) nearly every day (not merely self-reproach or guilt about
being sick)
8) Diminished ability to think or concentrate, or indecisiveness, nearly
every day (either by subjective account or as observed by others)
9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal
ideation without a specific plan, or a suicide attempt or a specific plan
for committing suicide
Five or more of the following symptoms (at least one of the symp-
toms is either [1] depressed mood or [2] loss of interest or pleasure)
have been present and documented during the same 2-week period
and represent a change from previous functioning (American_
Psychiatric_Association, 2013).
IMPACT OF DEPRESSION DURING PREGNANCY
Depression during pregnancy has a negative impact on the
maternal–fetal pair. It is associated with obesity; poor nutri-
tion; smoking, alcohol, and other substance use; poverty;
and intimate partner violence, all factors associated with
worse pregnancy outcomes (Leight et al., 2010; Dunkel
Schetter & Tanner, 2012). Suicide is a tragic outcome of
depression. Women are more likely to attempt suicide than
men but less likely to complete (Hirschfeld and Russell,
1997). The incidence of suicide during the perinatal period
(including pregnancy and the first postpartum year) is
between 3 and 3.7 per 100,000 (Gressier et al., 2017).
Among individuals with at least one lifetime hospitalization
for unipolar major depression, the lifetime risk of dying by
suicide is approximately 15% (Keller and Boland, 1998).
While depression in some cases is self-limited, the risk for
chronic depression increases with longer duration of un-
treated symptoms and the number of episodes (Keller and
Boland, 1998). Functional impairment from severe
TREATING DEPRESSION DURING PREGNANCY
depression can lead to unemployment, with loss of both
income and access to health care.
The prevalence of MDD in the first 3 months postpartum
is 7.1% (Gaynes et al., 2005). Approximately half of women
who present with MDD after birth had depression during
pregnancy or a chronic course of depression that preceded
pregnancy (Dietz et al., 2007). Suicide leads to 20% of
deaths in postpartum women and is the second leading
cause of death in the first postpartum year (Lindahl et al.,
2005). Postpartum depression also interferes with mother–
infant attachment (Paris et al., 2009) (Moses-Kolko et al.,
2010) and is associated with reduced maternal functioning
(Barkin et al., 2016). Maternal depression is associated with
childhood behavioral problems (Korhonen et al., 2014;
Gjerde et al., 2017).
In addition to maternal harms, MDD exposure in utero is
associated with poor outcomes for infants. Severe maternal
antenatal stress increases the risk for diseases across multi-
ple organ systems, including eye, ear, respiratory, digestive,
skin, musculoskeletal, and genitourinary diseases (Tegethoff
et al., 2011). High maternal stress, after adjustment for many
potential confounders, is also associated with increased risk
for orofacial defects (cleft palate and lip) and cardiac defects
(transposition of the great arteries and tetralogy of Fallot)
(Carmichael et al, 2007), although the effect may be more
modest than initially reported (Carmichael et al., 2014). The
presence of MDD increases the risk for preterm birth and
small for gestational age infants (Grote et al., 2010). Depres-
sion and anxiety are associated with a threefold risk for pree-
clampsia, which may be related to the increased sympathetic
activity characteristic of these psychiatric states (Kurki et al.,
2000).
Infants exposed to maternal MDD in utero have higher
cortisol concentrations than infants of mothers who are not
depressed (Ashman et al., 2002; Essex et al., 2002). This is a
biochemical change that continues through adolescence
(Halligan et al., 2004) and places the offspring at higher risk
for developing mental illness. Exposure to depression in
pregnancy may induce epigenetic changes in exposed off-
spring that are detectable at birth (as DNA methylation
changes, particularly in the immune system) and that per-
sist in the adult brain (Nemoda et al., 2015). High levels of
perceived maternal stress during pregnancy are associated
with shorter telomere length in exposed offspring (Send
et al., 2017), which may predispose to an increased risk of
disease later in life, because telomeres are essential to chro-
mosomal integrity.
Antenatal depression and anxiety may, in a subset of
pregnant women, activate glucocorticoids and an inflam-
matory response that affects fetal growth and neural sys-
tem development. For example, there are variations in
brain structures that are important in emotional regulation
and mood disorders (such as the amygdala) in offspring
exposed to depression and anxiety in utero. Offspring
genotype and the postnatal environment likely moderate
BIRTH DEFECTS RESEARCH 109:879–887 (2017)
the effect of antenatal depression and anxiety on repro-
ductive outcomes (O’Donnell and Meaney, 2017).
MEDICATION TREATMENT OF DEPRESSION DURING PREGNANCY:
DISENTANGLING RISKS OF MEDICATION FROM RISKS OF ILLNESS
With increased recognition of the untoward effects of MDD
during pregnancy, selective serotonin reuptake inhibitor
(SSRI) antidepressants have become one of the most
common classes of drugs prescribed to pregnant women
(Mitchell et al., 2011). Between 1998 and 2005, a threefold
increase in the rate of antidepressant use among pregnant
women was observed, with 8.1% of pregnant women taking
antidepressants at some point during pregnancy in 2005
(Alwan et al., 2011). Nearly half of the women stopped the
drug by the third month after conception when pregnancy
was recognized (Alwan et al., 2011). Pregnant women who
discontinue antidepressant medication are at risk for recur-
rent depression. The rate of recurrence was 68% in women
who stopped their medication proximal to conception, com-
pared with 26% among those who continued antidepressant
treatment (Cohen et al., 2006). Almost half of the pregnant
women who discontinued medication required reintroduc-
tion of antidepressants, the majority in the first trimester
(Cohen et al., 2004).
Studies that adjust for factors inherent in maternal
depression and are also associated with antidepressant expo-
sure (such as disease severity) demonstrated that adverse
outcomes were strongly affected by confounding variables,
rather than medication exposure (Huybrechts et al., 2014).
Meta-analytic studies suggested that cardiac defects were
associated with SSRI exposure, particularly in infants ex-
posed to paroxetine (Grigoriadis et al., 2013). However, a
large American population-based cohort study (n 5
949,504) used propensity score stratification to compare
women with depression with similar risk factors (such as
obesity, other drug use, and smoking), but who varied on
SSRI exposure. This strategy addresses the differences in
women with depression who take SSRIs, compared with
those who do not on a broad range of potential confounders.
The association between antidepressant use and cardiac
defects was attenuated with increasing levels of adjustment.
The relative risk of any cardiac defect with the use of SSRIs
was 1.25 (95% confidence interval [CI], 1.13 to 1.38) in
unadjusted analysis compared with 1.12 (95% CI, 1.00 to
1.26) in the analysis restricted to women with MDD (no
other psychiatric disorders). This restriction increased the
diagnostic similarity of the samples that were compared.
The relative risk interval of cardiac defects was further
reduced to 1.06 (95% CI, 0.93 to 1.22) in adjusted (with
propensity score stratification) analysis. The association
between SSRI use and cardiac defects was largely due to
confounding factors associated with MDD rather than SSRI
exposure (Huybrechts et al., 2014). Similar findings were
reported for prenatal SSRI exposure and autism (Sorensen
et al., 2013); that is, after adjusting for confounding factors,
881
the association was not significant (Hviid et al., 2013).
Although the risk of any exposure for birth defects can never
be proven to be zero, the reduction of risk by defining the
proportion due to confounding is an important advance in
this body of research.
Like exposure to MDD in utero, exposure to antidepres-
sants is associated with risks to the fetus, which are briefly
reviewed here and discussed extensively elsewhere in this
issue. The potential risks of drug exposure are to fetal devel-
opment and growth, obstetrical outcomes, infant adaptation,
and long-term development. The literature on SSRI expo-
sure has evolved across more than 2 decades with substan-
tial variability in the methodology and results across
studies. Antenatal SSRI exposure has been associated with a
two to threefold increase in risk for preterm birth (Kallen,
2004; Lattimore et al., 2005). However, a large prospective
cohort study found that offspring exposed to SSRI in utero
were at lower risk of preterm birth, compared with off-
spring exposed to untreated maternal psychiatric disorder
(Malm et al., 2015). Late pregnancy exposure to SSRIs has
been associated with a small increase in the absolute risk
for persistent pulmonary hypertension of the newborn in a
subset of cases, directly due to vascular remodeling though
the increase in risk is marginal (adjusted odds ratio 1.28
(95% CI, 1.01–1.64) for SSRI-exposed infants versus 1.14
(95% CI, 0.74–1.74 for non–SSRI-exposed infants) (Occhiog-
rosso et al., 2012; Huybrechts et al., 2015). Poor neonatal
adaptation has been reported in up to 30% of infants
exposed to SSRIs (particularly paroxetine and fluoxetine)
during the third trimester.
While there is no consensus definition, neonatal adapta-
tion syndrome is characterized by a constellation of signs,
including restlessness, rigidity, tremor, tachypnea, hypogly-
cemia, temperature instability, irritability, weak cry, and,
rarely, seizures (Moses-Kolko et al., 2005; Sanz, De-las-
Cuevas et al., 2005). Most cases are mild (Moses-Kolko et al.,
2005), although signs may persist in at least some SSRI-
exposed infants (Salisbury et al., 2016). Tapering of SSRI
during the third trimester has not been demonstrated to
reduce the risk of neonatal adaptation syndrome (Salisbury
et al., 2016). Malm et al. (2016) found an increased risk of
depression in adolescence in children who were exposed to
SSRI in utero (8.2%) compared with children exposed to
psychiatric disorder but not SSRI (1.9%). However, although
severity of maternal psychiatric disorder was similar
between treated and untreated groups on some indicators,
it was not directly assessed and residual confounding is
likely. While cognitive development in children exposed to
SSRI in utero is similar to cognitive development in children
exposed to prenatal depression in utero and to children
unexposed to SSRI or prenatal depression (Suri et al., 2011;
Nulman et al., 2012; Santucci et al., 2014; El Marroun et al.,
2017), infants exposed in utero to SSRIs may have less
favorable motor development, although within normal limits
of development (Casper et al., 2003, 2011; Hanley et al.,
882
2013; Santucci et al., 2014). It is not yet known how fetal
genotype and the postnatal environment may moderate the
effect of medication exposure on (finish sentence).
Reproductive risk information is uncovered through the
long-term evolution of case reports, case series, small obser-
vational studies, case–control studies, and prospective non-
randomized studies, because of ethical restrictions on
randomized study designs in pregnant women. MDD and
associated conditions, coupled with the observational meth-
ods used to evaluate the impact of medications used in
pregnancy, have challenged the field to use sophisticated
statistical techniques that address confounding. The conclu-
sion from two large-scale case control studies of antenatal
SSRI use in 2007: “specific defects (if any) are rare and
absolute risks are small” has been supported across time
(Greene, 2007). Following a risk–benefit decision-making
process (Piontek et al., 2000), SSRIs are a reasonable treat-
ment option for pregnant women with a history of
depression.
Optimize Pharmacotherapy During Pregnancy
To date, the majority of research on drug treatment of
depression during pregnancy has focused on clarifying the
risks to the fetus, and to a lesser extent, the risks of
untreated or undertreated depression to the maternal-fetal
pair. Much less attention has been paid to determine the
benefits of treatment to the pregnant women and her devel-
oping infant. Optimal treatment of depression during preg-
nancy reduces the symptom burden for the mother, with
improved quality of life and functioning. The maternal–fetal
pair benefits from improved nutrition and adherence to pre-
natal care, reduced risk of postpartum depression and sui-
cide, and facilitation of attachment. Maternal treatment of
MDD during pregnancy normalizes infant cortisol concen-
trations (Brennan et al., 2008), which may decrease the risk
of later offspring mental illness, compared with infants with
high cortisol levels.
Infants whose mothers were treated with antidepres-
sants during pregnancy had improved P50 auditory sensory
gating responses, a marker of attention, compared with
infants who were exposed to maternal anxiety in utero. Pre-
natal antidepressant exposure mitigated the deleterious
effect of prenatal maternal anxiety on infant attention func-
tioning (Hunter et al., 2012). Given that approximately 50%
of cases of postpartum depression began during or before
pregnancy (Dietz et al., 2007), effective treatment of depres-
sion during pregnancy reduces the maternal–child harms
associated with postpartum depression. Treating postpar-
tum depression improves maternal functioning (Barkin
et al., 2016).
Many pregnant women with MDD receive inadequate
treatment. The benefits of SSRI treatment for MDD during
pregnancy cannot be determined without first optimizing
treatment. Population-based epidemiologic studies have
TREATING DEPRESSION DURING PREGNANCY
shown that treatment rates are low for women with MDD in
general (26%), and lower for pregnant women with MDD
(14%) and postpartum women (14%) (Vesga-Lopez et al.,
2008). Even among pregnant women who do receive treat-
ment for MDD, symptoms are often not significantly
reduced, due to inadequate dosing. Among women who con-
tinue antidepressants during pregnancy, one out of four do
not sustain benefit from the medication (Cohen et al., 2006).
An explanation for high rates of relapse in pregnant
women maintained on antidepressants is inadequate dosing,
due to dramatic changes in pharmacokinetics (PK) in gravid
women. In pregnancy, the activities of the cytochrome P
(CYP) 450 isoenzymes that metabolize SSRIs are altered
(Tanaka, 1999). The activity of CYP3A4, CYP2D6, CYP2C9,
and CYP2A6 is increased, which leads to more rapid drug
metabolism and reduced serum plasma concentrations.
Drugs predominantly metabolized by these enzymes may
need to be increased to maintain efficacy. Conversely,
CYP1A2 and CYP2C19 activity is decreased during pregnancy,
which leads to reduced drug metabolism and increased
serum drug plasma levels. Thus, drugs predominantly metab-
olized by these enzymes may need be decreased to avoid
drug toxicity (Stika and Frederiksen, 2001; Freeman et al.,
2008; Sit et al., 2008, 2011; Avram et al., 2016).
In a community sample of obstetrical patients, the rate
of MDD recurrence was the same in women who continued
antidepressants as those who stopped antidepressants
(Yonkers et al., 2011). However, the average doses of pre-
scribed SSRI were only marginally higher than the usual
starting doses for these medications. For example, the aver-
age dose of sertraline prescribed for the pregnant women in
the study was 68 mg/day. In a double-blind dose escalation
study of postpartum women, 96% of women who achieved
remission required a dose of at least 100 mg per day (Wis-
ner et al., 2006). Furthermore, it is likely that pregnant
women require higher doses than postpartum women, due
to the reduction in sertraline plasma concentrations from
enhanced CYP450 activity (Sit et al., 2009). Thus, the preg-
nant women in the community obstetrical sample who took
antidepressants received doses of medication that were
likely inadequate. This illustrates that treatment of MDD in
pregnancy may not be delivered optimally due to PK
changes, or may be less effective due to pharmacodynamic
changes or both.
TREATMENT RECOMMENDATIONS
Once a strategy for optimal pharmacologic treatment for
pregnant women is developed, studies exploring potential
benefits alongside risks can be undertaken to balance the
extensive literature on risks. Taken together, these data
suggest that a strategy for optimal pharmacologic treat-
ment for pregnant women with MDD is a pressing clinical
need. Current best practices (Yonkers et al., 2009) include
a collaborative decision-making process with the patient,
with careful review of risks and benefits of treatment
BIRTH DEFECTS RESEARCH 109:879–887 (2017)
TABLE 2. DSM-5 Criteria for Manic Episode
1) Inflated self-esteem or grandiosity
2) Decreased need for sleep
3) More talkative or pressured speech
4) Flight of ideas or racing thoughts
5) Distractibility
6) Increased goal-directed activity or psychomotor agitation
7) Excessive involvement in activities with high potential of negative
consequences
Elevated or irritable mood and persistently increased energy or
activity accompanied by three or more (four if mood is only irritable)
of the following symptoms have been present and documented dur-
ing the same 1-week period and represent a change from usual
behavior (American_Psychiatric_Association, 2013). The criteria for
a hypomanic episode are the same as a manic episode except for
the symptoms last 4 days (and not 1 week) and are not severe
enough to cause marked impairment in functioning.
compared with the risks of untreated disease (Piontek
et al., 2000).
The treatment of a pregnant woman with a major
depressive episode begins with a careful diagnostic assess-
ment. The major differential diagnosis for a major depres-
sive episode in pregnancy is bipolar depression. The
lifetime prevalence of bipolar spectrum illness is approxi-
mately 2.4% (Merikangas et al., 2011). Unipolar depres-
sion must be distinguished from bipolar depression
because the treatment is different. Monotherapy with an
antidepressant in bipolar I disorder may precipitate hypo-
manic or manic episodes (Table 2) and rapid cycling
(Practice Guidelines for the Treatment of Patients with
Major Depressive Disorder, 3rd edition, 2010). To differen-
tiate bipolar depression from unipolar depression, a care-
ful history for prior hypomanic or manic episodes should
be collected. Validated instruments, such as the Mood Dis-
order Questionnaire (MDQ) (Hirschfeld et al., 2000), are a
useful tool to screen for bipolar disorder in pregnant and
postpartum women (Clark et al., 2015).
A family history of bipolar disorder or psychotic ill-
nesses signals an increased risk for bipolar disorder. A
history of feeling more agitated, wired, or worse from anti-
depressants may also indicate bipolar depression (Pies,
2007). Typical symptoms of bipolar mania or hypomania
may be present during the depressive episode; for exam-
ple, racing thoughts or irritable mood (Pies, 2007). Agita-
tion is more common in bipolar depression than unipolar
depression in the perinatal period (Fisher et al., 2016).
The differential diagnosis for pregnant women who pres-
ent with a history of depression or anxiety symptoms
should also include thyroid disorders. Hypothyroidism
associated with depressive symptoms or hyperthyroidism
883
triggering anxiety can be identified with laboratory assess-
ment of thyroid hormones.
Standardized tools to quantify the severity of symp-
toms are useful adjuncts to the clinical interview, and may
also be used across time to assess treatment response.
The 10-item Edinburgh Postnatal Depression Scale has
been validated as a screen for depression during preg-
nancy, for which the recommended cutoff score for MDD
is 15 or more (Evans et al., 2001). The Edinburgh Post-
natal Depression Scale has also been used effectively as a
symptom monitoring measure in efficacy studies of psy-
chotherapy (Spinelli and Endicott, 2003) and pharmaco-
therapy (Ververs et al., 2009) during pregnancy. The
number of prior depressive episodes is directly related to
the risk of recurrence without medication treatment.
In nonpregnant populations, the risk for recurrence is
50% after one episode of MDD and 80% after two epi-
sodes (Burcusa and Iacono, 2007). The number of prior
episodes is relevant to the decision to continue or discon-
tinue medication during pregnancy (Cohen et al., 2006;
Yonkers et al., 2011). Exploration of the woman’s prior
medication trials, duration, and response is essential to
guide treatment recommendations.
The pregnant woman’s concerns, values, and preferen-
ces, with respect to medication during pregnancy, are
essential to formulating treatment recommendations and
alternatives (Piontek et al., 2000). The patient should be
informed of the risks of medication during pregnancy, the
risks of untreated depression during pregnancy, the poten-
tial benefits of treatment during pregnancy, and the alter-
natives to medication management of depression. Likely
outcomes of treatment (e.g., improved symptom control
and functioning), as well as anticipated outcomes of lack
of treatment (continued or worsening symptoms), should
be discussed with the patient (Wisner et al., 2000). Psy-
chotherapy should be offered to pregnant women with
MDD (Sockol et al., 2011). Unfortunately, psychotherapy is
not available in many practice settings and may not be
feasible for some pregnant women. Light therapy, if avail-
able and desired by the patient, should also be considered
for pregnant women with depression (Wirz-Justice et al.,
2011).
Reproductive data on SSRIs is more robust than data
available for other classes of antidepressants. If the
woman has never been treated with an antidepressant,
SSRI are the first-line drug. Sertraline is the most fre-
quently prescribed drug and is minimally excreted in
breast milk. Other classes of antidepressant medications,
including selective norepinephrine reuptake inhibitors,
tricyclic antidepressants, and atypical antidepressants
(bupropion, mirtazapine, and trazodone), are reasonable
options if the woman has achieved good symptom control
on these medications. Changing antidepressants is not gen-
erally recommended, as this would expose the maternal–
fetal pair to the risk of nonresponse to the new agent and
884
the risks of illness. Lithium, lamotrigine, or atypical anti-
psychotic may be considered as augmentation strategies
for unipolar depression, refractory to monotherapy treat-
ment with an SSRI, SNRI, or atypical antidepressant.
The lowest effective dose of medication should be used
with emphasis on the word effective. There is a dearth of
reproductive data to guide treatment decisions related to
using multiple psychotropic medications during pregnancy.
Minimal data are available on the impact of polypharmacy
on reproductive outcomes and drug-drug interactions dur-
ing pregnancy. Nonetheless, in our clinical experience, this
strategy is often needed for adequate control of severe
depressive episodes.
If a decision to treat with an antidepressant is made,
the goal should be complete remission of symptoms so
that the fetus is not exposed to both undertreated illness
and medication. Increased physician awareness of PK
changes across pregnancy and the possible need for
increased SSRI doses may lead to improved patient out-
comes. An observational study in which patients and their
physicians received information about PK changes during
pregnancy and the subjects’ depressive symptom scores
from the study team led to significantly lower depressive
symptom levels (Wisner et al., 2009). Women with contin-
uous MDD and no SSRI exposure had mean depression
scores on the Hamilton Depression Rating Scale (Hamilton,
1960) that were significantly higher (14.9 6 4.4) than
either SSRI-treated women (8.4 6 5.1) or controls with
neither exposure (4.2 6 3.2; p < 0.01). These data demon-
strate treatment efficacy in the SSRI group, although the
scores reflect suboptimal symptom reduction. For preg-
nant women who have an inadequate response to an
adequate trial of SSRI, cross-titration to a different anti-
depressant should be done. For women with a partial res-
ponse to an adequate trial of SSRI, augmentation should
be pursued with the goal of remission of symptoms.
CONCLUSIONS
Women need effective treatment of depression during
pregnancy to promote maternal–fetal health. Once the
diagnosis of MDD is made, the prescriber must assist the
pregnant woman in deciding whether the benefit of con-
tinuing treatment for disease control outweighs the risk of
the drug to the developing embryo–fetus. This is an indi-
vidualized decision depending on the disease charac-
teristics, likelihood of various fetal toxicity and depression
outcomes, and patient characteristics and values (Wisner
et al., 2000). Treatment planning for the depressed preg-
nant woman requires skilled decision making. There is no
“zero risk” solution in caring for the pregnant woman with
MDD; both the disorder and the medication present risks
to mother and the embryo–fetus. Too often the risks of
medication are emphasized more than the risks of under-
treated or untreated depression.
TREATING DEPRESSION DURING PREGNANCY
If the decision to use SSRI during pregnancy is made,
the goal of treatment should be complete remission of
symptoms, so as not to expose the developing fetus to
both the risk of disease and the risk of medication. SSRI
should be considered the first-line medication option for
pregnant women with depression. Optimization of SSRI
dosing during pregnancy dictates several treatment goals:
(1) the drug must be at the optimal dose for the woman;
that is, the dose that produces the best response with tol-
erable side effects; (2) a continuous measure of symptoms
must be repeated and adjustments to maintain optimal
antidepressant efficacy may be required; (3) and the reso-
lution of pregnancy at birth also requires dose adjustment
in accord with the woman’s transition to the nonpregnant,
breastfeeding state. An investigation is under way to
develop guidelines for dose management of SSRI in preg-
nancy (Avram et al., 2016).
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