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Antenatal depression: Guidelines for when to use pharmacotherapy

An in-depth and individualized discussion with the pregnant woman of available treatment options ensures patient adherence and an optimal outcome for the pregnancy.

Sarah T. Bot, PA-C

Sarah Bot practices at the Paul Larson Ob/Gyn Clinic in Edina, Minnesota. She has indicated no relationships to disclose relating to the content of this article.

One in 10 pregnant women suffers from depression;^1-3 this rate increases to 13% in the later stages of pregnancy.⁴ In the past 10 to 15 years, the medical community has paid increasing attention to treatment options for women with depression during pregnancy, or antenatal depression. Historically, uncertainty regarding the safety of antidepressants during pregnancy has precluded their widespread use; and current FDA labeling practices and a relatively small number of prospective studies on antidepressant use during pregnancy have continued to limit the role of antidepressants during pregnancy. However, acceptance of using drugs to treat depression during pregnancy is growing. This article discusses the risk factors and screening tools for depression, explores the recommended clinical approach to antenatal depression, and details the information to provide in a risk-benefit decision-making discussion with a woman who has antenatal depression.³

Women who may need to make a risk-benefit decision regarding treatment options for antenatal depression present in various ways. Some women may have received a diagnosis of major depression and seek preconception counseling; others are already pregnant and have questions regarding the safety of continuing their antidepressant therapy. Alternately, one-third of the women who become depressed during pregnancy are experiencing a first episode.² These women present for prenatal care with occult depressive symptoms that require further investigation. Yet another group of patients is more acutely distressed because they have abruptly discontinued their antidepressant medication, either because they are afraid to continue or because they have been advised to stop.⁵

Risk factors for antenatal depression include a personal history of depression, marital discord, limited psychosocial support, recent stressful life events, low socioeconomic status, and an unwanted pregnancy.² Health care providers should pay special attention to women with a history of major depressive episodes because these women have a greater risk of developing antenatal depression than do women without such a history.^1,2

Two screening tools have been validated for diagnosing antenatal depression: the Beck Depression Inventory (BDI) and the Edinburgh Postnatal Depression Scale (EPDS).⁴ One study that assessed the prevalence of antenatal depression found similar rates of depression with the EPDS compared to using a structured interview conducted by a trained professional, but a higher prevalence of antenatal depression was uncovered by the BDI compared to conducting a structured interview.⁴ A possible explanation is that the EPDS focuses on nonsomatic symptoms of pregnancy.² In pregnant women, sleep and appetite disturbances, diminished libido, and low energy are common findings. Symptoms of anhedonia; feelings of guilt, worthlessness, and hopelessness; and suicidal ideation are the clinical features most clearly indicative of depression in gravid patients.^2,4

When evaluating a patient for antenatal depression, anemia, thyroid dysfunction, and gestational diabetes should be considered as part of the initial differential diagnosis or as complications in a patient with antenatal depression.²

CLINICAL APPROACH

Once a diagnosis of depression has been established in a pregnant woman or in a woman desiring pregnancy, treatment options should be presented via a risk-benefit decision-making discussion. Before presenting treatment options, however, the clinician must obtain a full obstetrical history, including prior as well as current complications, and a complete psychiatric history, including number and severity of prior episodes, medications, and efficacy of treatment. The histories will help the clinician to individualize the risks and benefits of each treatment option for the patient. Table 1 lists the relevant information to obtain during an initial interview.³ Risk-benefit decision-making discussion topics include treatment options (pharmacotherapy, psychotherapy, and electroconvulsive therapy [ECT]) and the risks of each treatment option as well as the risks of not treating the patient’s depression.²

In the model presented by Wisner and colleagues, the clinician and the patient each have a valuable role in making the final decision.³ The clinician presents an individualized assessment of the risks, benefits, and treatment options and carries out the problem-solving tasks. The patient appraises each option presented and quantifies her perception of the associated risks of each option according to her values. Interestingly, Wisner’s team found that some patients perceive voluntarily taking a medication during pregnancy as a greater risk than the consequences of depression.³ Other influential factors include financial stability, social stressors, family responsibility, familiarity with medications, and history of symptom relief from antidepressant use.³

TREATMENT OPTIONS

Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine has the most extensive prospective and retrospective data available, and for that reason, some health care providers have deemed it the SSRI of choice for treating antenatal depression.⁶ The risk of major congenital malformations or intrauterine death was not increased by antenatal fluoxetine exposure.^2,6 Special considerations regarding fluoxetine may be related to the drug’s long half life and the presence of neonatal toxicity in 31% of infants exposed to the drug during the third trimester.^6,7 Fluoxetine use during the third trimester was also associated with premature births. One study reported that 14% of fetuses exposed to fluoxetine during the third trimester were born prematurely, defined as less than 37 weeks’ gestation.⁷ Additionally, poor neonatal adaptation is thought to be a result of SSRI-induced serotonergic overstimulation; SSRI withdrawal following birth did not have this effect, an indication that withdrawing or reducing the maternal dose in the days leading up to delivery may reduce neonatal symptoms.⁸ However, this decision should be made on a case-by-case basis, weighing the benefits of this action against the likelihood of the mother experiencing a depression relapse.⁸

Other SSRIs considered to be acceptable options for pregnant patients include citalopram, paroxetine, fluvoxamine, and sertraline.⁹ A meta-analysis of these newer SSRIs found information on their safety to be limited; however, no evidence was found that major malformations or intrauterine death was associated with exposure to these drugs during pregnancy.² One study found that exposure to paroxetine, fluvoxamine, or sertraline during pregnancy did not increase the risk of major malformations or the rates of spontaneous abortion, stillbirth, or preterm birth; birth weight and gestational age also were not adversely affected.¹⁰ A more recent meta-analysis found first-trimester exposure to paroxetine to be associated with a slightly higher risk for fetal cardiac defects.¹¹ Women taking antidepressants during pregnancy were more likely to utilize ultrasound; likewise, infants born to women who took antidepressants during pregnancy were more likely to undergo echocardiograms during their first year of life.¹¹ Initiating paroxetine therapy in a woman who is pregnant or considering pregnancy is not recommended; however, the decision may be made to continue paroxetine during pregnancy for women whose symptoms are currently well-controlled with this medication.¹²

Another study found no evidence of major fetal malformation or intrauterine death associated with citalopram use.¹³ This study noted that the incidence of prematurity was slightly higher in SSRI-exposed infants but that infant survival was not impacted. After controls for maternal age, parity, body mass index, cigarette smoking, and gestation duration were applied, maternal citalopram use had no effect on fetal birth weight.¹³ The shorter half life of some newer SSRIs may limit the perinatal toxicity associated with their use.^6,10 However, information on sertraline suggests that despite its shorter half life, transient perinatal toxicity is associated with this drug.^6,14

SSRI use after 20 weeks’ gestation was associated with a small but significantly increased risk of persistent pulmonary hypertension of the newborn in one case-control study.¹⁵ Although the findings of the study do not prove causality, they do warrant consideration and further study.¹⁵

Tricyclic antidepressants (TCAs) First-trimester exposure to TCAs is not associated with increased rates of intrauterine death or major congenital malformations;^2,6,16 however, transient neonatal toxicity is reported.² Nortriptyline is the TCA of choice during pregnancy because it produces fewer anticholinergic effects and less orthostatic hypotension.^2,6

Serotonin-norepinephrine reuptake inhibitors In a multicenter, prospective, controlled study of 150 pregnant women, venlafaxine (37.5-300 mg/d) was not associated with increased rates of intrauterine death or major congenital malformations.¹⁷ The pregnancies resulted in 125 live births, 18 spontaneous abortions, and 7 elective abortions, with no cases lost to follow-up. Two infants were born with major malformations (one with hypospadias and one with neural tube defect with club foot), but this does not exceed the baseline rate of major malformations in nonteratogen-exposed pregnancies. This study did not attempt to evaluate the potential for neurobehavioral teratogenicity.¹⁷

Other antidepressants No prospective data is available for mirtazapine, nefazodone, trazodone, or monoamine oxidase inhibitors (MAOIs), and their use is not recommended during pregnancy.² Additionally, MAOIs can precipitate a hypertensive crisis during labor and delivery if a tocolytic such as terbutaline is used.² The manufacturer of bupropion has set up a pregnancy registry and collected reports of 166 first-trimester exposures to the drug. Of the 166 cases, three cases of major malformations have been reported; this level is within the expected baseline risk of major malformations.²

If a patient’s depression is being successfully managed with any of these agents, therapy should continue. When implementing pharmacotherapy in an antidepressant-naïve patient, however, one of the short-acting, newer SSRIs, such as sertraline, may be a reasonable first choice in an effort to limit neonatal toxicity.

Electroconvulsive therapy ECT is indicated for refractory depression and is also safe during pregnancy.^3,9 In the 300 case reports of ECT during pregnancy published over the past 50 years, there have been four reports of premature labor and no reports of premature rupture of membranes.² Side effects of ECT include confusion and memory loss, which is occasionally permanent but most often resolves within days to a couple of weeks.⁹

Interpersonal therapy (IPT) Of the various psychotherapy and cognitive behavior therapy modalities available, IPT is recommended for pregnant women with mild to moderate depression. IPT can be presented as a treatment option for women who do not want pharmacotherapy. This approach focuses on grief, interpersonal disputes, role transitions, and interpersonal deficits. The emphasis on interpersonal functioning and role transition is especially valuable for couples that are facing the adjustment period that follows the arrival of a new child.^2,3

TREATMENT-RELATED RISKS TO THE FETUS

The clinician must delineate the areas of potential risk for both the mother and the developing fetus when discussing the risks and benefits of the various treatment options. Potential risks to the fetus include intrauterine fetal death, low birth weight, neurobehavioral teratogenicity, neonatal toxicity, and major congenital malformations. Health care providers should explain that these risks exist even if the mother does not take antidepressant medications. The rate for major congenital malformations developing in a fetus that is not exposed to teratogens is 1% to 3%.^1-3,5 Neurobehavioral teratogenicity, defined as postbirth effects caused by prenatal exposure to toxic agents, includes learning problems, abnormal activity levels, and impaired problem-solving skills.⁶ Neonatal toxicity, also known as poor neonatal adaptation, includes jitteriness, hypoglycemia, hypothermia, poor muscle tone, respiratory distress, weak/absent crying, and desaturation on feeding.⁶

Patients should be given concrete timelines in regard to organogenesis when the risks of fetal malformations are explained. Patients will have a truer reflection of the actual risks to their fetus if they are educated about fetal embryogenesis. Women who are not educated about fetal development tend to overestimate the risks of therapy. This results in exacerbated fear and anxiety about antidepressant therapy during pregnancy.^3,5

Both the properties of the drug and the amount of time of fetal exposure to the drug play a role in assessing the risk of malformation. The period of greatest risk for CNS structural and neurochemical abnormalities, which is of particular concern for these patients, is thought to be during days 14 through 35. At this time, maternal-placental circulation is established and neural tube closure occurs.⁶ The heart forms from days 21 to 56. Development of the lip and palate occurs from days 42 to 63; however, craniofacial anomalies can also occur after the first trimester.¹⁸

Neurobehavioral teratogenicity from drug exposure becomes a concern after the first trimester.¹⁸ In their landmark study, Nulman and colleagues established the basis of the current guarded clinical belief that prenatal exposure to fluoxetine and TCAs do not lead to neurobehavioral teratogenicity.¹⁹ This prospective, double-blind study followed the children of 80 women treated with TCAs, 55 women treated with fluoxetine, and 84 women with no known exposure to teratogenic agents. The children were tested for cognitive function, temperament, and general behavior at age 16 to 86 months. No differences in temperament, mood, arousability, activity level, distractability, or behavior problems were found between the control and study groups.¹⁹ However, further research using larger groups of study participants is needed to confirm the findings of the Nulman study, as well as the findings of the studies of the other classes of antidepressants.

This is the extent of the information available to help patients assess the potential risks for behavioral teratogenicity following antenatal antidepressant exposure. Therefore, health care providers must explain the rationality of extrapolating the safety of an antidepressant medication from the results of the Nulman study. For example, after weighing the possibility of neurobehavioral teratogenicity against the detrimental effects of maternal depression and anxiety, it may be considered less of a risk to take medication.²⁰

RISKS OF NOT TREATING DEPRESSION

Not treating antenatal depression can also have adverse maternal and fetal outcomes. Risks to the mother include, but are not limited to, suicidality; hospitalization and associated disruption to work and home life; impairment of self care; weight loss; preeclampsia; increased risk for alcohol, cigarette, and illegal drug abuse; and postpartum depression.^1-5,20 Risks to the fetus include, but are not limited to, growth impairment; poor outcomes associated with maternal drug, alcohol, and cigarette abuse; pregnancy termination; preterm birth; dyslexia; autism; attention-deficit/hyperactivity disorder (ADHD); schizophrenia; preeclampsia; and risks associated with small-for-gestational-age infants.^1-5,19,20

Depression relapse For some women, antidepressant discontinuation is carried out after thoughtful consideration and the risks of continuing therapy are believed to outweigh the benefits. However, substantial evidence exists that antidepressant discontinuation is associated with high rates of relapse in nonpregnant patients, and the risk of relapse is even higher in pregnant women. Approximately 75% of women who discontinue antidepressant medication proximate to pregnancy experience a relapse.² The consequences of relapse are suicidal ideation, hospitalization, and termination of a pregnancy that was desired prior to the relapse.⁵

Indirect effects of untreated antenatal depression Pregnant women suffering from depression may have impaired self-care and adhere poorly or not at all to prenatal care plans, which can lead to poor pregnancy outcomes. Similarly, decreased appetite, a symptom of depression, is associated with insufficient maternal weight gain during pregnancy and low birth weight infants. Antenatal depression also increases the likelihood of cigarette, alcohol, or illicit drug abuse, all of which can have devastating effects on the developing fetus.^1-3 In women with bipolar depression, additional risks include resistance to treatment following repeated or prolonged relapses and impulsive behaviors that may result in negative outcomes for both mother and fetus.¹ Furthermore, untreated antenatal depression increases a woman’s risk of developing postpartum depression,^4,21 which is associated with negative outcomes on infant attachment, behavior, and cognitive development.^21,22

Direct effects of untreated antenatal depression A clear link between antenatal depression and poor fetal outcomes has not been solidly established; however, an association between antenatal depression and factors that predict a poor neonatal outcome—preterm birth, low birth weight, small head circumference, and low Apgar scores—has been established.² Maternal anxiety in the third trimester has been linked to impaired fetal neurologic development, which can influence disorders such as dyslexia and autism.²⁰ Glover and O’Connor proposed four possible explanations for this link: (1) poor outcomes are attributed to reduced birth weight as a result of shortened gestation; (2) preterm birth is the single largest perinatal risk factor for later morbidity, including ADHD and schizophrenia; (3) studies suggest that in humans, maternal cortisol crosses the placenta and altered fetal exposure to this hormone is responsible for negative fetal sequelae; and (4) increased maternal anxiety in late pregnancy is associated with impaired blood flow through the uterine arteries, precipitating intrauterine growth restriction, preeclampsia, and small-for-gestational-age infants.²⁰

SAFETY DURING BREASTFEEDING

Women who take antidepressant medication during pregnancy and elect to continue pharmacotherapy during the postpartum period may have questions and concerns regarding the safety of antidepressant use while breastfeeding. The health care provider should also provide safety information regarding antidepressant use when breastfeeding during a prenatal visit.

Maternal use of nortriptyline, paroxetine, and sertraline usually produces undetectable serum levels of the drug in exposed infants. Fluoxetine produces the highest proportion of infants (22%) with serum levels that are more than 10% of maternal levels. Infants with serum levels of antidepressants that are more than 10% of maternal levels usually display symptoms of toxicity such as irritability, poor feeding, and uneasy sleep. Citalopram is also known to produce elevated levels in infants, but not to the same extent as fluoxetine. Antidepressant use during breastfeeding is generally regarded as safe. However, new mothers who are taking antidepressant medication while breastfeeding need to be alert to the signs of infant toxicity and see their health care provider should problems arise.²³

CONCLUSION

The decision to initiate, continue, or discontinue antidepressant medication during pregnancy is not one to be taken lightly, nor is it a decision to be made by the health care provider alone. Every woman considering pharmacologic management of antenatal depression should be engaged in a risk-benefit decision-making discussion tailored to her psychiatric and social situation. When conducting this discussion, the health care provider should include the significant members of the patient’s support system and provide handouts outlining the material discussed.³

Table 2 presents a summary of commonly prescribed antidepressant medications and their effects on the fetus. The table includes the number of cases in the studies of each drug because this number is relevant to the risk-benefit decision-making strategy. Statistically speaking, 800 patients must participate in a study to detect a two-fold risk of relatively common malformations; thousands of patients must participate in a study to detect rare defects.¹³ Therefore, the number of patients studied in each category impacts the relative value of the safety information.

Providing this information in handout form will help a pregnant woman whose depression is clouding her ability to assimilate new information and will also facilitate discussion of her options with the members of her support system who were unable to attend the risk-benefit decision-making dicussion.³ Depression is a real and debilitating illness that affects approximately 10% of all pregnant women. If a woman has accurate and up-to-date information, she will be able to work with her health care provider to formulate a depression management strategy that is best suited to her needs. JAAPA

DRUGS MENTIONED

Bupropion (Wellbutrin)
Citalopram (Celexa)
Fluoxetine (Prozac, Sarafem)
Fluvoxamine
Mirtazapine (Remeron)
Nefazodone
Nortriptyline (Aventyl, Pamelor)
Paroxetine (Paxil, Pexeva)
Sertraline (Zoloft)
Terbutaline (Brethine)
Trazodone
Venlafaxine (Effexor)

REFERENCES

	1.	Gold LH. Psychopharmacologic treatment of depression during pregnancy. Curr Womens Health Rep. 2003;3(3):236-241.
	2.	Nonacs R, Cohen LS. Assessment and treatment of depression during pregnancy: an update. Psychiatr Clin North Am. 2003;26(3):547-562.
	3.	Wisner KL, Zarin DA, Holmboe ES, et al. Risk-benefit decision making for treatment of depression during pregnancy. Am J Psychiatry. 2000;157(12):1933-1940.
	4.	Bennett HA, Einarson A, Taddio A, et al. Prevalence of depression during pregnancy: systematic review. Obstet Gynecol. 2004;103(4):698-709.
	5.	Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risks and impact of counseling. J Psychiatry Neurosci. 2001;26(1): 44-48.
	6.	Wisner KL, Gelenberg AJ, Leonard H, et al. Pharmacologic treatment of depression during pregnancy. JAMA. 1999;282(13):1264-1269.
	7.	Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med. 1996;335(14):1010-1015.
	8.	Laine K, Heikkinen T, Ekblad U, Kero P. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry. 2003;60(7):720-726.
	9.	Eisendrath SJ, Lichtmacher JE. Psychiatric disorders. In: Tierney LM Jr, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment 2004. New York, NY: Lange Medical Books/ McGraw-Hill; 2004:1034-1038.
	10.	Kulin NA, Pastuszak A, Sage SR, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279(9):609-610.
	11.	Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther. 2007:29(5):918-926.
	12.	Misri S, Lusskin SI. Management of depression in pregnant women. UpToDate Web site. www.uptodate.com. Accessed August 5, 2008.
	13.	Ericson A, Källén B, Wilhom B. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol. 1999;55(7):503-508.
	14.	Kent LS, Laidlaw JD. Suspected congenital sertraline dependence. Br J Psychiatry. 1995:167(3): 412-413.
	15.	Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579-587.
	16.	Altshuler LL, Cohen L, Szuba MP, et al. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry. 1996;153(5):592-606.
	17.	Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry. 2001;158(10):1728-1730.
	18.	Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. 2004;161(4):608-620.
	19.	Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997;336(4):258-262.
	20.	Glover V, O’Connor TG. Effects of antenatal stress and anxiety: implications for development and psychiatry. Br J Psychiatry. 2002;180:389-391.
	21.	Suri R, Altshuler L. Postpartum depression: risk factors and treatment options. Psychiatr Times. 2004;21(11). http://www.psychiatrictimes.com/display/article/10168/46991. Published October 1, 2004. Accessed August 5, 2008.
	22.	Weissman MM, Feder A, Pilowsky DJ, et al. Depressed mothers coming to primary care: maternal reports of problems with their children. J Affect Disorders. 2004;78(2):93-100.
	23.	Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):1066-1078.