Prenatal Antidepressant Use: Time for a Pregnant Pause?

This is the nightmare scenario. Your patient is a 32-year-old mother of 4 who has just learned from her gynecologist that she is 2 months pregnant. She has had 7 major depressive episodes over the past 8 years, 3 of which were accompanied by serious suicide attempts. Two episodes occurred postpartum and were accompanied by profound social withdrawal, poor nutritional intake, and thoughts of harming herself or her infant. She is currently taking paroxetine (Paxil), 50 mg/d, with positive results and has been in remission from depression for nearly 2 years. However, the patient has just read a story on the Internet linking maternal antidepressant use during pregnancy with birth defects. She is asking you if she should stop taking the antidepressant at this time. What is your response, and how does it square with the latest research?

The early take on SSRI use during pregnancy

Until quite recently, many psychiatrists were confident that SSRIs were relatively safe during gestation, based on studies done in the 1990s.¹ For example, a study by Pastuszak and coworkers² found no evidence of teratogenicity in 128 women taking fluoxetine (Prozac) during the first trimester, compared with matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. Furthermore, depression itself may also raise the risk of miscarriage.

A study by Chambers and associates³ found no significant differences between fluoxetine treatment in pregnant women and controls in the number of spontaneous pregnancy losses or major structural anomalies; however, the incidence of 3 or more minor anomalies was significantly higher in the fluoxetine cohort, and women who took fluoxetine during the third trimester were at increased risk for perinatal complications. The Chambers study was criticized on a variety of methodologic grounds, including failure to control for coexisting medical illnesses.⁴ Indeed, summarizing the published reports of SSRI use during gestation (N = 2219)--including use of fluoxetine, citalopram (Celexa), paroxetine, sertraline (Zoloft), and fluvoxamine (Luvox)--Newport and colleagues⁵ concluded that, collectively, "these data provide no evidence that prenatal SSRI exposure is associated with an increased incidence of congenital malformation."

The data from the 1990s also suggested little long-term neurobehavioral risk to children exposed to antidepressants in utero. For example, Nulman and associates⁴ found that in utero exposure to either tricyclics or fluoxetine did not affect global IQ, language development, or behavioral development in preschool children. Finally, from 1990 to 2000, reports of neonatal withdrawal syndromes associated with SSRIs were starting to trickle in, and their clinical significance was underplayed.

The picture changes a bit

In most respects, the overall safety of SSRIs and related antidepressants during pregnancy is still supported by studies from the last 5 years--but some yellow lights are now flashing. In December 2005, for example, the FDA issued a public health advisory concerning first-trimester exposure to paroxetine and the risk of congenital malformations.⁶ The FDA had reviewed 2 recent, unpublished epidemiologic studies: 1 using a Swedish national registry database and the other using a US insurance claims database. The net results suggested that the risk of cardiac malformations (eg, atrial or ventricular septal defects) increased 1.5- to 2-fold in infants exposed to paroxetine, compared with unexposed infants or those exposed to other antidepressants. The absolute number of affected infants was small: about 1.5% to 2% in infants exposed to paroxetine versus 1% among controls. The FDA subsequently requested that the manufacturer of paroxetine change its pregnancy category from C to D and add new warnings to its labeling information.

Shortly after this news broke, Chambers and associates⁷ published a study reporting a significant association between the use of SSRIs after the 20th week of pregnancy and the presence of persistent pulmonary hyper-tension of the newborn (PPHN)--a condition associated with significant morbidity and mortality. For example, infants with PPHN may manifest cognitive delay, neurologic abnormalities, and hearing loss.

Finally, to complete the "triple threat," reports of a neonatal abstinence syndrome associated with SSRIs have increased in the past year. One study found that as many as 30% of neonates with third-trimester SSRI exposure showed some type of withdrawal syndrome.⁸ This appeared to peak around 48 hours after birth and was characterized by lack of crying, increased muscle tone, irritability, abnormal breathing, and disrupted sleep.

Putting it all in perspective

If the foregoing was the "bad news," is there any good news regarding these putative risks? Let's start with the data on paroxetine and cardiac risks. Recently, Wulsin and Ignatowski⁹ critically examined the FDA advisory and concluded that it "flunks as evidence-based medicine." These authors reviewed 8 published studies of SSRI use during pregnancy--including 5 involving paroxetine--and concluded that there is no significant increase in birth defects with SSRIs, notwithstanding the data cited by the FDA and unpublished retrospective data from the manufacturer. The conclusion from Wulsin and Ignatowski is in agreement with that of Newport.⁵ In this writer's view, if there is a "signal" of teratogenicity coming from the SSRIs, it is a weak one. But in the absence of randomized, prospective data--sorely lacking in this area of study--we must still be wary.

What about the PPHN risk? Chambers' study⁷ found a 5- to 6-fold increase in risk among SSRI-exposed neonates. However, since PPHN occurs in only about 2 per 1000 live births, the absolute number of PPHN cases should still be quite small among neonates exposed to SSRIs--probably no more than 12 per 1000 births.¹⁰ That may be an acceptable risk level for many mothers facing the rigors of intrapartum or postpartum major depression.

With regard to the neonatal abstinence syndrome associated with SSRIs, this is generally a mild, self-limited condition, lasting just a few days and requiring only supportive care. (There are scattered reports of seizures as part of this syndrome, according to FDA sources,¹¹ but the nature of the FDA's adverse event reporting system makes these claims difficult to evaluate.) It is possible that tapering and discontinuing the antidepressant during the last 7 to 10 days of gestation might be a way of mitigating withdrawal effects, but more research on that issue is needed. By itself, this withdrawal syndrome is surely no reason to withhold antidepressant treatment in mothers at high risk for intrapartum or postpartum major depression.

Back to mom

So what, precisely, do you advise your pregnant, 32-year-old patient with the horrendous history of suicidal depression? First, I would recommend a calm and reassuring "risk-benefit" discussion, ideally involving the patient's gynecologist (Table). This is not the time for knee-jerk reactions, such as the immediate discontinuation of paroxetine (which could precipitate a nasty withdrawal syndrome). Even the FDA advisory noted that "the benefits of continuing paroxetine may out- weigh the potential risk to the fetus" in some cases.⁶ If this patient stays on paroxetine, it is advisable, in my view, to obtain a fetal echocardiogram around week 16 of gestation, similar to guidelines for lithium use in pregnancy.

What about switching to another SSRI, or perhaps, to a nonserotonergic antidepressant, such as bupropion (Wellbutrin, Zyban)? This might be reasonable and is worth discussing with the patient, but there is very little solid evidence demonstrating that such a move would increase the safety or well-being of the average patient in this predicament. The decision might turn, in part, on whether the patient has been successfully treated with other agents (besides paroxetine) in the past--if not, the risks of switching are significant.¹² Indeed, if the patient in our scenario had done poorly with other antidepressants, I would favor keeping her on the same regimen at this point. Of course, electroconvulsive therapy remains a viable option for severely depressed pregnant patients, although it is usually difficult to persuade patients of its benefits.

Whatever the decision, the clinician should always write a detailed chart note indicating that the appropriate options have been discussed with the patient (and her gynecologist); that the patient understands the nature and consequences of these options; and that the risks and benefits of available treatments have been thoroughly explained. Some physicians encourage the patient to sign a statement or chart note to this effect.⁹

Recently, Dr Lee Cohen has presented data showing that relapse rates are very high in euthymic pregnant women with a history of major depression who discontinue antidepressant treatment.¹³ Indeed, the risk of relapse during pregnancy increases about 5-fold with discontinuation--contrary to the old saw that pregnancy is always a time of emotional well-being. Of course, psychosocial support of the depressed pregnant patient is important; indeed, when maternal depression is (or historically has been) relatively mild, psychotherapy alone might be the treatment of choice. But given the risks of resurgent major depression to both mother and infant, the benefits of continuing antidepressant treatment during pregnancy probably outweigh the risks in most cases.

Disclosures:

Dr Pies is clinical professor of psychiatry at Tufts University. His most recent books include Creeping Thyme, a collection of poetry (Brandylane Publishing); Zimmerman's Tefillin, a short story collection (PublishAmerica); and Handbook of Essential Psychopharmacology, 2nd edition, from American Psychiatric Publishing.

References:

1. Pies RW, Rogers DP. Handbook of Essential Psychopharmacology. 2nd ed. Washington, DC: American Psychiatric Publishing; 2005.
2. Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome following first-trimester expo-sure to fluoxetine (Prozac). JAMA. 1993;269:2246-2248.
3. Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med. 1996;335:1010-1015.
4. Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997;336:258-262.
5. Newport DJ, Fisher A, Graybeal S, Stowe ZN. Psychopharmacology during pregnancy and lactation. In: Schatzberg AF, Nemeroff CB, eds. The American Psychiatric Publishing Textbook of Psychopharmacology. 3rd ed. Washington, DC: American Psychiatric Publishing; 2004:1109-1146.
6. US Food and Drug Administration. FDA public health advisory: paroxetine. December 8, 2005. Available at: http://www.fda.gov/cder/drug/advisory/ paroxetine200512.htm. Accessed July 14, 2006.
7. 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;354:579-587.
8. Levinson-Castiel R, Merlob P, Linder N, et al. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med. 2006;160:173-176.
9. Wulsin L, Ignatowski M. Paroxetine in pregnancy? FDA advisory flunks as evidence-based medicine. Curr Psychiatry. 2006;5:45-51.
10. Mills JL. Depressing observations on the use of selective serotonin-reuptake inhibitors during pregnancy. N Engl J Med. 2006;354:636-638.
11. Fisher JE. Reply to letter. Clin Psychiatry News. 2006:34:15.
12. Hasser C, Brizendine L, Spielvogel A. SSRI use during pregnancy. Do antidepressants' benefits outweigh the risks? Curr Psychiatry 2006;5:31-40.
13. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295:499-507.