Evidence-Based Reviews

Treating anxiety during pregnancy: Just how safe are SSRIs?

Current Psychiatry. 2008 February;7(2):39-52

Staggering SSRI and benzodiazepine use during the first and third trimesters may help reduce potential risks to the fetus.

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References

1. Ross LE, McLean LM. Anxiety disorders during pregnancy and the postpartum period: a systematic review. J Clin Psychiatry 2006;67(8):1285-98.

2. Labad J, Menchon JM, Alonso P, et al. Female reproductive cycle and obsessive-compulsive disorder. J Clin Psychiatry 2005;66(4):428-35.

3. Adewuya AO, Ola BA, Aloba OO, Mapayi BM. Anxiety disorders among Nigerian women in late pregnancy: a controlled study. Arch Womens Ment Health 2006;9(6):325-8.

4. Field T, Hernandez-Reif M, Diego M, et al. Stability of mood states and biochemistry across pregnancy. Infant Behav Dev 2006;29(2):262-7.

5. Teixeira JM, Fisk NM, Glover V. Association between maternal anxiety in pregnancy and increased uterine artery resistance index: cohort based study. BMJ 1999;318(7177):153-7.

6. Monk C, Myers MM, Sloan RP, et al. Effects of women’s stress-elicited physiological activity and chronic anxiety on fetal heart rate. J Dev Behav Pediatr 2003;24(1):32-8.

7. Egliston KA, McMahon C, Austin MP. Stress in pregnancy and infant HPA axis function: conceptual and methodological issues relating to the use of salivary cortisol as an outcome measure. Psychoneuroendocrinology 2007;32(1):1-13.

8. Levey L, Ragan K, Hower-Hartley A, et al. Psychiatric disorders in pregnancy. Neurol Clin 2004;22(4):863-93.

9. Oberlander TF, Reebye P, Misri S, et al. Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch Pediatr Adolesc Med 2007;161(1):22-9.

10. Misri S, Reebye P, Kendrick K, et al. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry 2006;163(6):1026-32.

11. Copper RL, Goldenberg RL, Das A, et al. The Preterm Prediction Study: maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks’ gestation. Am J Obstet Gynecol 1996;175(5):1286-92.

12. Sutter-Dallay AL, Giaconne-Marcesche V, Glatigny-Dallay E, Verdoux H. Women with anxiety disorders during pregnancy are at increased risk of intense postnatal depressive symptoms: a prospective survey of the MATQUID cohort. Eur Psychiatry 2004;19(8):459-63.

13. Nierop A, Bratsikas A, Zimmermann R, Ehlert U. Are stress-induced cortisol changes during pregnancy associated with postpartum depressive symptoms? Psychosom Med 2006;68(6):931-7.

14. Weissman MM. Recent non-medication trials of interpersonal psychotherapy for depression. Int J Neuropsychopharmacology 2007;10(1):117-22.

15. Ward RK, Zamorski MA. Benefits and risks of psychiatric medications during pregnancy. Am Fam Physician 2002;66(4):629-36.

16. Bastani F, Hidarnia A, Montgomery KS, et al. Does relaxation education in anxious primigravid Iranian women influence adverse pregnancy outcomes? A randomized controlled trial. J Perinat Neonatal Nurs 2006;20(2):138-46.

17. Fricchione G. Generalized anxiety disorder. N Engl J Med 2004;351(7):675-82.

18. Källén BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol 2007;79(4):301-8.

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20. Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-analysis and consideration of potential confounding factors. Clin Ther 2005;29(5):918-26.

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Ms. K, age 25, is 6 weeks pregnant and is taking medications for generalized anxiety disorder (GAD). When she was diagnosed with GAD at age 19, her symptoms included 6 months of excessive anxiety—insomnia, fatigue, difficulty with concentration, and psychomotor agitation—without mood symptoms. These symptoms interfered greatly with her schoolwork and other daily activities.

For 6 years Ms. K has been taking the selective serotonin reuptake inhibitor (SSRI) paroxetine, 15 mg/d, and the benzodiazepine clonazepam, 0.5 mg as needed, with good symptom control. Now that she is pregnant and her primary care doctor has refused to continue these medications, she is seeking treatment and advice.

Not enough is known about how to safely treat anxiety disorders during pregnancy, and physicians are not sure what to do with patients such as Ms. K. Without evidence-based guidelines, we feel anxious about potential risks to mother and fetus as we try to provide appropriate drug therapy.

Clinical Point

Offspring of high-anxiety mothers exhibit neurobehavioral differences compared with those of calmer mothers

To help you and your patients weigh the risks and benefits of perinatal treatments for anxiety disorders, this article briefly summarizes the evidence on:

anxiety disorders’ natural history during pregnancy
how untreated maternal anxiety affects the fetus
nonpharmacologic therapies for anxiety disorders
a plan to manage fetal risks by staggering SSRI and benzodiazepine use during the first and third trimesters.

Anxiety during pregnancy

Nearly one-third of women experience an anxiety disorder during their lives, with peak onset during childbearing years.^1,2 Compared with research on perinatal depression, far fewer studies have examined anxiety disorders’ onset, presentation, prevalence, and treatment.¹

The literature includes no studies of the course of preexisting GAD or posttraumatic stress disorder (PTSD) and no evidence that symptoms of preexisting obsessive-compulsive disorder (OCD) change during pregnancy. Some studies of panic disorder show symptoms improving during pregnancy, whereas others do not (Table 1).¹

One small study done in late pregnancy found a significant association between the prevalence of an anxiety disorder, maternal primiparity, and comorbid medical conditions. Thus, a woman in her first pregnancy may be at increased risk to develop an anxiety disorder if she has a comorbid medical condition.³ As in the case of Ms. K, however, continuation of preexisting anxiety appears more likely than onset of a new anxiety disorder during pregnancy.

Table 1

How pregnancy affects the course of 4 anxiety disorders

Disorder	Prevalence	Effect
Generalized anxiety disorder (GAD)	8.5% of women experience GAD during the third trimester, compared with a 5% prevalence in the general population	No studies have reported on the course of GAD in pregnant women with preexisting disorder
Obsessive-compulsive disorder (OCD)	2% to 12% of OCD outpatients of childbearing age report onset during pregnancy	Preexisting OCD usually shows no change during pregnancy but may worsen postpartum
Panic disorder (PD)	1.3% to 2% in pregnant women, compared with 1.5% to 3.5% in the general population	Panic symptoms in women with preexisting PD may improve during pregnancy and worsen postpartum
Posttraumatic stress disorder (PTSD)	2.3% to 7.7% in pregnant women and 0% to 6.9% postpartum, compared with 1% to 14% in the community	No studies have reported on the course of PTSD in pregnant women with preexisting disorder
Source: References 1,2

Fetal risks from maternal anxiety

Fetal risk from severe maternal anxiety is not zero. Offspring born to high-anxiety mothers exhibit neurobehavioral differences compared with offspring of calmer mothers. Changes in high-anxiety mothers’ offspring include:

altered EEG activation and vagal tone
increased time in deep sleep and less time in active alert states
lower performance on the Brazelton Neonatal Behavior Assessment Scale.⁴

A cohort study by Teixeira et al⁵ found an association between maternal anxiety in pregnancy and uterine artery resistance, suggesting a possible mechanism by which a mother’s psychologic state may affect fetal development. High anxiety and self-reported life stress during pregnancy also are associated consistently with abnormal, high-frequency heart rate variability in infants—a finding linked with negative infant behavior and later adult hostility.⁶

Exposure to maternal high anxiety has been associated with mental developmental delays in infants and increased risk for behavioral and emotional problems in young children.^7-10 Anxiety may not directly cause intrauterine growth retardation and preterm delivery, but it is significantly associated with prenatal tobacco, alcohol, and narcotics use—which predicts these and other negative neonatal outcomes.¹¹

Clinical Point

Before pregnancy, explain to the patient the risks of medications if she were to become pregnant and ask about contraception

Anxiety during pregnancy is a risk factor for postnatal depressive symptoms, independent of depressed mood and family or marital stressors during pregnancy.¹² Mothers with postpartum depression appear less able to respond sensitively and competently to their newborns, and these infants may be at increased risk of behavioral, emotional, and cognitive problems.