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Clinical Case Conference
Management of Major Depression During Pregnancy
Victoria Hendrick, M.D.
traception. She was a nonsmoker and did not use illicit
drugs. She used alcohol socially.
Lori Altshuler, M.D.
Course of Treatment
The initial consultation included a detailed review of
psychiatric treatment options during pregnancy and a re-
view of the risks and benefits associated with the use of
n this report, we describe the case of a woman with re- antidepressant medications. Approaches to antidepres-
sant medication management during pregnancy were
current major depression who wished to get pregnant.
discussed, including 1) tapering and discontinuing the an-
She was taking a daily antidepressant and sought infor- tidepressant before attempting conception, 2) continuing
mation on the safety of the medication after conception.
to take the antidepressant until she had a positive preg-
This case illustrates 1) the dilemmas that arise in the psy- nancy test, followed by immediate discontinuation, and
chiatric treatment of pregnant and nursing women, 2) the 3) continuing to take the antidepressant throughout
risk-benefit assessments that are involved in the pharma- pregnancy. After listening to her options, Ms. A expressed
cological treatment of depression during pregnancy and interest in discontinuing the antidepressant once she had
lactation, and 3) approaches to minimize the risk of such a positive pregnancy test. She was reluctant to stop tak-
ing the medication before conception out of concern that
premenstrual dysphoric disorder and/or major depres-
sion would recur.
Case Report
Since the fluoxetine metabolite (nor-
fluoxetine) has an extremely long
Ms. A was a 36-year-old married
elimination half-life (7–10 days), the
woman with a history of recurrent
developing fetus would continue to be
major depression who sought consul-
exposed to this drug for several weeks
tation regarding the safety of anti-
after medication discontinuation. The
depressant medications during preg-
plan was therefore made to switch to
nancy. She and her husband hoped to
a shorter-acting medication. Alterna-
conceive in the near future but were
tive medications were discussed, in-
concerned about Ms. A’s use of fluoxe-
cluding side effect profiles and family
tine, 20 mg/day. The husband came to
histories of response. Ms. A mentioned
the appointment with his wife.
that her sister had responded well to
sertraline and that she would like to
History
try this agent. A switch was therefore
studies, as is the case for initiated from fluoxetine, 20 mg/day,
Ms. A had a history of three epi-
to sertraline, 75 mg/day, over the next
sodes of major depression between
ages 24 and 33. She was treated with
Ms. A was encouraged to begin
psychotherapy for her first episode
individual psychotherapy, and she
and found it helpful in relieving her symptoms. She
agreed to this plan. She was given a list of therapists, in-
continued, however, with recurrent premenstrual dys-
cluding several with experience in working with preg-
phoria. After experiencing her second episode of major
nant women and new mothers. She chose a therapist
depression, on the advice of her psychotherapist, she
with an eclectic approach that combined psychody-
sought psychopharmacological consultation for both
namic and supportive modalities.
the depression and the premenstrual mood symptoms.
At a follow-up visit 6 weeks later, Ms. A remained eu-
She started taking fluoxetine, 20 mg/day, which was
thymic and reported no relapse of premenstrual symp-
highly effective in treating both conditions. After a year
toms. She and her husband continued to agree with the
of treatment, she switched to luteal-phase use of flu-
plans that were discussed at the first visit and felt that
oxetine. However, she experienced a relapse of major
they were ready to stop using contraception.
depression within 8 months. Her depression symptoms
After 4 months of attempting to conceive, Ms. A called
included low energy, anhedonia, irritability, poor appe-
to report that a pregnancy test that morning had given
tite, insomnia, and low self-esteem. Prompt resumption
positive results. She discontinued the sertraline as of that
of fluoxetine, 20 mg/day, produced a full and sustained
day. At her visits 2 and 4 weeks later, she remained eu-
remission of symptoms, with no recurrence up to the
thymic. Follow-up visits were then scheduled monthly.
present time. She had no history of suicidality or psychi-
She continued to be well until her sixth month of preg-
atric hospitalizations.
nancy, when she reported that her mood had deterio-
Ms. A’s medical history was unremarkable. She was a
rated. Ms. A increased her individual therapy to twice-
healthy Caucasian woman with regular menstrual cycles
weekly meetings. Two weeks later, she reported that her
and no prior pregnancies. She used a diaphragm for con-
depression and hopelessness hampered her motivation
Am J Psychiatry 159:10, October 2002 CLINICAL CASE CONFERENCE
for therapy. She added that her appetite was poor and
opinions on the optimal treatment of depression in preg- that she had ceased to gain weight. She reported no sui-
nant women (1). The information to date will be reviewed.
cidality but felt apathetic about the pregnancy and had
The largest amount of information on prenatal antide- lost her ability to take pleasure in activities she had pre-
pressant exposures involves fluoxetine. Neither retrospec- viously enjoyed, such as attending the theatre or meet-
ing with friends. The potential risks and benefits associ-
tive nor prospective studies have found a greater risk of ated with the prenatal use of antidepressants in the
miscarriage or major congenital malformations with anti- second and third trimesters were reviewed. After consid-
depressant treatment (2–8). Third-trimester use of fluoxe- ering the information, Ms. A chose to initiate fluoxetine,
tine has been linked with higher rates of perinatal compli- 20 mg/day. Within 2 weeks, Ms. A felt substantially bet-
cations (e.g., tachypnea, jitteriness, premature delivery) in ter, and by 1 month she was euthymic.
some (3, 4), but not all (5–8), studies. A study of 226 prena- At 39½ weeks’ gestation, Ms. A delivered a healthy
tal exposures to sertraline, paroxetine, and fluvoxamine baby girl with 1- and 5-minute APGAR scores of 7 and 9,
(9) found the rates of major malformations and preterm respectively. She took the same dose of fluoxetine after
delivery and, in a phone appointment 2 weeks after the
labor were no higher than those of nonexposed compari- birth, reported feeling tired but generally euthymic.
son subjects. A prospective study that used the Swedish However, at a psychiatric visit 3 weeks after delivery, Ms.
Birth Registry (6) reported 969 cases of prenatal exposure A reported difficulty sleeping even when the infant was
to antidepressants, including citalopram (375 cases), par- asleep. She also described a growing apathy toward her
oxetine (122 cases), sertraline (33 cases), and fluoxetine parenting responsibilities, which produced a great deal
(16 cases) and reported rates of perinatal complications of guilt. Furthermore, she reported a lack of confidence
and congenital malformations comparable to population in herself as a mother and wept as she said this. A deci-
norms. Among 150 women who took venlafaxine during sion was made to add nortriptyline, 50 mg, at bedtime.
pregnancy, the incidence of major malformations was no This medication was chosen not only to augment fluoxe-
tine but also to help with sleep. At a visit the next week,
higher than the expected rate of 1%–3% (10).
Ms. A reported that her sleep had improved. Her serum
Prenatal use of tricyclic antidepressants similarly does concentration of nortriptyline at that time was 70 ng/ml.
not appear to increase the risk of congenital anomalies (5, Ms. A added that the infant was feeding well and ap-
6), although these medications may produce transient peared healthy. At a psychiatric visit 6 weeks after deliv-
neonatal toxicity or withdrawal symptoms when used ery, Ms. A reported feeling much better. She held her
near the time of delivery. These symptoms have included daughter tenderly and spoke about her with pride. Ms. A
continued individual psychotherapy but reduced the fre-
lethargy, hypotonia, and anticholinergic effects, such as quency to weekly visits.
constipation, tachycardia, and urinary retention (5, 11, In visits at 3 and 6 months postpartum, Ms. A remained
12). Nortriptyline and desipramine are preferable to other well. At 6 months postpartum, she weaned her daughter.
tricyclic antidepressants during pregnancy because of She also discontinued the antidepressants since she felt
their lower likelihood of anticholinergic and hypotensive she no longer needed them. Furthermore, she believed
side effects. Their doses may need to be adjusted over the that the nortriptyline had impeded her efforts to lose the
course of pregnancy since serum concentrations may fall weight she had gained during her pregnancy. Ms. A’s
below the therapeutic window (13). A small case series (N= menstrual cycles returned at 8 months postpartum.
7) of mirtazapine use in pregnancy (14) found no perinatal She experienced a recurrence of premenstrual mood
changes, and the decision was made to resume taking
complications or congenital malformations in the infants.
fluoxetine, which had helped her premenstrual symp-
A study of 21 prenatal exposures to monoamine oxidase toms before her pregnancy. She reported no further
inhibitors (MAOIs) (15) found a relative risk for congenital premenstrual mood changes in subsequent months of
malformations of 3.4. In contrast, a more recent case re- follow-up.
port of phenelzine use throughout pregnancy (16) de-scribed a healthy outcome for the patient and her infant.
Discussion
Nevertheless, MAOIs are best avoided in pregnant women This case illustrates the issues that commonly arise in because of the risk of hypertensive crisis. Additionally, the treatment of depression in women who are pregnant MAOIs contraindicate the use of tocolytic agents (e.g., or trying to conceive. The patient wisely sought consulta- terbutaline), which may be necessary to prevent prema- tion before pregnancy, thus allowing time for a preconcep- ture labor. At present, to our knowledge, no published tion treatment plan to be reviewed and implemented. Pre- studies exist on bupropion or nefazodone in pregnancy.
conception evaluations provide an opportunity to discuss When selecting an antidepressant medication for a data on exposures to antidepressant medications during pregnant woman, clinicians should be cautious in their pregnancy and lactation, to review a woman’s likelihood of use of the Food and Drug Administration (FDA) use-in- a depressive relapse during pregnancy and the postpar- pregnancy ratings. These ratings categorize medications tum period, and to institute supportive and prophylactic into one of five groups on the basis of known risk to the fe- interventions that may reduce the risk of relapse. Ideal tus: an “A” rating indicates that controlled studies of the management that minimizes risk to both mother and in- medication show no risk to pregnant women; a “B” rating fant remains uncertain since data on the impact of differ- indicates that no evidence of risk exists to date in humans; ent treatment approaches for pregnant patients are in- a “C” rating is used when risk cannot be ruled out; a “D” complete. Even experts in the field express differing rating indicates positive evidence of risk; and an “X” rating Am J Psychiatry 159:10, October 2002 CLINICAL CASE CONFERENCE
indicates that the medication is contraindicated in preg- drawal symptoms (23) and is associated with a risk of re- nancy. A medication carrying an FDA pregnancy category lapse to depression over the course of the pregnancy of up B rating is not necessarily safer to use in pregnancy than a to 75% (24, 25). For women like our patient who seek medication with a pregnancy category C labeling. Medica- counseling before conception and obtain supportive and tions may receive the category B rating in the absence of prophylactic interventions, it is possible that the relapse human data, provided that animal reproduction studies risk is lower. Each case must be evaluated on an individual have not demonstrated a fetal risk. A category C medica- basis by taking into account the number of previous epi- tion for which there are human data showing low risk may sodes of major depression and the time to relapse after be preferable to a category B medication for which there previous attempts at medication discontinuation.
are no human studies, as is the case for bupropion. An ad- For women with histories of rapid and severe relapse of ditional concern regarding fetal exposure to bupropion major depressive episodes after medication discontinua- arises from the medication’s seizure-inducing potential.
tion, the antidepressant may need to be maintained In contrast to morphological teratogenesis, behavioral throughout the pregnancy. These recommendations are teratogenesis has received minimal attention. Behavioral consistent with the Expert Consensus Guideline Series on teratogenesis refers to the neurological or behavioral im- Treatment of Depression in Women 2001 (1).
pact that may result in children from prenatal exposure to Women who are pregnant or attempting to conceive centrally acting medications. Use of antidepressant med- should be encouraged to initiate psychotherapy if they ications during pregnancy exposes the child’s brain to are not already obtaining it. Interpersonal psychother- psychoactive agents at a time of maximal development of apy—a form of therapy that examines role transitions and the CNS (17, 18). Furthermore, the relatively small pro- disputes and deficits in interpersonal interaction—has portion of myelin in fetal brains allows medications to ac- been evaluated for pregnant women and appears to be cumulate in the CNS (19). Therefore, the safety of antide- pressant use in pregnant women cannot be ensured until The risk-benefit discussion should be recorded in the possible behavioral consequences are studied. Data on patient’s file along with a statement indicating that the pa- the developmental outcomes in children exposed to anti- tient understands the information provided and is in depressants during pregnancy are reassuring but limited.
agreement with the plan. Whenever possible, the partner Two prospective studies (8, 20) and one case series (21) and other health care providers should be included in the have reported developmental outcomes in children pre- natally exposed to antidepressants. The first study evalu-ated 55 children who were prenatally exposed to fluoxe- Impact of Depression on Pregnancy
tine, 80 children who were prenatally exposed to tricyclic A number of studies have reported an association be- antidepressants, and 84 unexposed children (8) and tween maternal anxiety/stress during pregnancy and neg- found no significant differences in global IQ, language ative pregnancy outcomes, such as preterm labor and low- development, temperament, mood, distractibility, or be- birth-weight infants (27–37), even after control for con- havior in children up to the age of 7. The second study founding variables such as socioeconomic status, mater- (20), which included 86 infants prenatally exposed to cit- nal weight gain, and health habits during pregnancy.
alopram, fluoxetine, paroxetine, or sertraline, evaluated Fewer investigations have evaluated the impact of mater- the children at age 18 months with the Bayley Scales of In- nal major depression on pregnancy outcomes. A recent fant Development and found scores in the age-appropri- study of 623 women followed prospectively over preg- ate range. In the case series (21), developmental mile- nancy (38) reported a significant relationship between de- stones among nine children aged 4 months to 3 years pression (as measured with the Beck Depression Inven- were normal for chronological age after prenatal expo- tory) and preeclampsia. In another prospective study of 389 women of low socioeconomic class (39), depression While these data are reassuring, the total number of re- during the first trimester of pregnancy was associated with ported exposures remains small. Therefore, discontinua- a greater risk of low-birth-weight infants and preterm de- tion of an antidepressant before conception is a reason- livery. In contrast, a prospective study that administered able approach for women who are stable and, by history, psychiatric interviews to 94 women across pregnancy (40) appear likely to remain well for at least several months found no relationship between maternal mood during while not taking the medication. Continuation of the anti- pregnancy and infant birth weights or gestational ages.
depressant until conception is another reasonable option.
This study also found no association between maternal If the antidepressant is discontinued at the time of a posi- depression during pregnancy and children’s cognitive tive pregnancy test (i.e., approximately 12–14 days post- scores on the McCarthy Scales at age 4 years.
conception), the developing embryo will receive minimal In summary, maternal anxiety and stress during preg- medication exposure since the uteroplacental circulation nancy appear to predict adverse pregnancy outcomes.
does not form until 10–12 days postconception (22). It is The impact of maternal major depression on pregnancy important to keep in mind, however, that short-term dis- outcomes is less clear at this time and requires further continuation of an antidepressant may produce with- Am J Psychiatry 159:10, October 2002 CLINICAL CASE CONFERENCE
Risk Factors for Postpartum Relapse
represents a substantial risk for poor developmental out-comes. Underscoring the importance of intervention, re- Our patient experienced a recurrence of major depres- search has found that if maternal depression is prevented, sion in the postpartum period, in which she had chosen to infant problems associated with maternal depression, remain medication-free while nursing. A woman with a such as behavioral problems and insecure attachment history of major depression, like Ms. A, is at approximately (57) and decline in IQ (46), can also be prevented.
a 25% risk for relapse of depression after childbirth (post-partum depression). Depressive symptoms during preg- Treatment of Postpartum Depression
nancy raise the risk even higher (41). Other risk factors in- A number of treatment interventions are helpful for clude a conflictual relationship with the baby’s father (42), postpartum depression and include psychotherapy, sup- stressful life events (42), low socioeconomic status (43), port groups, and referrals to self-help and national organi- and frequent health problems in the infant (44).
zations such as Postpartum Support International (805- Postnatal Depression and Children’s Outcomes
967-7636) or Depression After Delivery (800-944-4773). In-terpersonal and cognitive behavior therapy are forms of Ms. A experienced postpartum depression with symp- individual psychotherapy that have been found effective toms including apathy, low energy, guilt, and low self- for treatment of postpartum depression (58, 59).
confidence. Her decision to restart the antidepressant Antidepressants are also helpful in relieving postpartum medication helped her significantly and may also have depression (59–61). The choice of antidepressant should been beneficial for her infant. A substantial literature take into account whether or not the patient is nursing documents the potential negative impact of maternal since antidepressant medications traverse readily into postnatal depression on children. Most studies have in- breast milk. To date, the largest literature on the use of an- cluded women with depression occurring within 3–12 tidepressants by nursing women involves the selective se- months of delivery rather than the shorter time frame of 4 rotonin reuptake inhibitors (SSRIs). A study compared 26 weeks that DSM-IV defines for “postpartum onset.” nursing infants whose mothers took fluoxetine with 28 Therefore, we will use the term “postnatal” rather than nursing infants whose mothers did not take the medica- “postpartum” when referring to depression occurring tion (62) and reported a significantly lower growth rate within the first year after delivery.
(although within the normal range) among the fluoxe- Compared with children of nondepressed mothers, tine-exposed group over the first 6 months of age. The children of mothers who have experienced postnatal de- study was retrospective and did not control for the impact pression perform worse on cognitive and behavioral mea- of maternal depression on breast-feeding behavior. Also, sures (45–51) and exhibit higher rates of insecure attach- two case reports (63, 64) attributed uneasy sleep and colic ment (45, 46, 52). Children of mothers who experienced to breast-feeding infants exposed to citalopram and flu- depression in the child’s first year of life appear to be at oxetine, respectively, through breast milk, with resolution greater risk for adverse cognitive outcomes than children after discontinuation or diminution of breast-feeding.
who were older when their mothers experienced depres- However, several studies totaling more than 210 mother- sion. Children’s exposure to subsequent relapses of mater- infant pairs (12, 21, 65–77) observed no adverse effects of nal depression also appears to increase their risk for poor SSRI exposure in nursing infants. The majority of these studies involved fluoxetine, sertraline, and paroxetine.
Several researchers have evaluated the mechanisms These data show that in many cases women can safely mediating the negative effect of parental depression on continue breast-feeding while taking an antidepressant children’s development and have identified negative parenting behaviors that occur commonly among de- A consideration for new mothers who have recently pressed parents. For example, depressed mothers have weaned their infants is the potential occurrence of pre- been observed to be intrusive or withdrawn and disen- menstrual mood changes once menstrual cycles resume gaged when interacting with their infants (53, 54) and less (78). This is of particular concern for women with histories sensitively attuned to their infants than healthy women of premenstrual dysphoric disorder. As in this case, Ms. A’s (55). The disturbances in mother-infant interactions ob- postpartum major depression returned soon after antide- served among depressed mothers were found to highly pressant discontinuation and remitted with reinstitution predict poor infant cognitive outcomes at 18 months (55).
of treatment. High relapse rates have been reported for A recent study of 2,017 parents of children ages 0–3 years postpartum major depression after treatment discontinu- (56) identified parental depressive symptoms as the most ation (79), supporting the need for ongoing treatment for consistent predictors of negative parenting behaviors (e.g., yelling, hitting, shaking) after controlling for socio-economic status, ethnic group, parental years of educa- Summary
tion, parental age, and parental employment status. For Women with histories of major depression may relapse each depressive symptom, the odds that the parent would during pregnancy or the postpartum period. Depression engage in at least one form of negative interaction rose by during pregnancy can present risks to the mother and fe- 25% for mothers and 43% for fathers (56). These studies tus, such as inadequate maternal weight gain and, in the indicate that children’s exposure to parental depression extreme, suicidality. After childbirth, maternal depression Am J Psychiatry 159:10, October 2002 CLINICAL CASE CONFERENCE
may interfere with mother-child bonding and may be det- 11. Altshuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J: rimental to the infant’s development. Psychotherapeutic Pharmacologic management of psychiatric illness during preg- approaches, including individual psychotherapy, couples nancy: dilemmas and guidelines. Am J Psychiatry 1996; 153:592–606 counseling, and support groups, can help treat major de- 12. Wisner KL, Perel JM, Blumer J: Serum sertraline and N-desme- pression during pregnancy and the postpartum period. If thylsertraline levels in breast-feeding mother-infant pairs. Am J a woman remains depressed despite nonpharmacologic interventions or if her depression is associated with signif- 13. Altshuler LL, Hendrick V: Pregnancy and psychotropic medica- icant morbidity, antidepressant medications should be tion: changes in blood levels. J Clin Psychopharmacol 1996; 16: considered. Given the data on birth outcomes after prena- tal exposure to several antidepressant medications and 14. Saks BR: Mirtazapine: treatment of depression, anxiety, and hyperemesis gravidarum in the pregnant patient: a report of 7 the accumulating data on the use of antidepressant medi- cases. Archives of Women’s Ment Health 2001; 4:165–170 cations by breast-feeding women, the relative benefits of a 15. Heinonen OP, Slone D, Shapiro S: Birth Defects and Drugs in medication to treat depression in pregnant or nursing Pregnancy. Littleton, Mass, Publishing Science Group, 1977 women may outweigh the theoretical risk of its use.
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