From: Exposure to Psychotropic Medications and Other Substances during Pregnancy and Lactation: A Handbook for Health Care Providers
Selective serotonin reuptake inhibitors or SSRIs: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa)
Serotonin/norepinephrine reuptake inhibitors or SNRIs: venlafaxine (Effexor)
Tricyclic antidepressants or TCAs: amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Tofranil)
Others: bupropion (Wellbutrin/Zyban), trazodone (Desyrel), mirtazapine (Remeron)
Twice as many women as men experience depression and up to 20 per cent of women of childbearing age (i.e., ages 14 to 46) are diagnosed with the condition.1 Depression is most prevalent between ages 25 and 44 for both women and men: approximately 10 to 15 per cent of these women experience depression during pregnancy and postpartum. Antidepressants are used to treat several anxiety disorders and are prescribed for these disorders in rates similar to those for depression. A substantial proportion of women are therefore likely to be taking antidepressants when they become pregnant.
Summary and Recommendations
- Current evidence suggests that, as a group, antidepressants are relatively safe to take during pregnancy and breastfeeding and that women should not abruptly discontinue their use.
- In cases where women are taking antidepressants during late pregnancy, babies should be observed for longer than one to two days postpartum to detect possible neonatal symptomatology (e.g., respiratory distress, constant crying, convulsions).
- Since babies may react differently to even very small amounts of a drug, if a mother is taking antidepressants while breastfeeding, her baby should be observed for any changes (e.g., drowsiness, difficulty feeding).
- Women should be reassured about the safety of antidepressant use. Emerging evidence strongly suggests that untreated depression poses its own risk, not only to maternal health but also to the infant’s health.2 A woman who is in optimal mental health is equipped to give the best possible care to her baby.
Tricyclic antidepressants have been on the market since 1958 and, as a group, they are not associated with an increased risk for major malformations.3 The newer antidepressants have also not been found to increase this risk.4,5
In fall 2005, GlaxoSmithKline published on its website the results of a claims database study, which found that infants exposed to paroxetine may be at higher risk of congenital malformations, in particular cardiovascular defects. The study was based on outcomes of 815 infants; the reported incidence of cardiovascular malformations, unspecified in terms of severity, was two per cent.6 An update was presented at a meeting in 2006, in which the data had been re-analyzed and the incidence was adjusted to 1.5 per cent.7
A recent study8 reported the outcomes of 1,170 cases, collected prospectively from teratogen information services throughout the world, of infants who were exposed to paroxetine in the first trimester of pregnancy. These infants were compared to a non-exposed cohort to determine the rates of cardiovascular defects. The rate of heart defects in the paroxetine group was 0.8 per cent versus 0.7 per cent in the non-exposed group, both of which are within the range of expected cardiovascular malformations in the general population.
In 2006, a study documented a one per cent increased risk for persistent pulmonary hypertension in the newborns of mothers who took SSRIs during pregnancy.9
Several studies that examined antidepressant use during pregnancy have suggested an increased rate of spontaneous abortions in women exposed to antidepressants compared to non-exposed women; however, the results were not statistically significant due to the small sample sizes. A meta-analysis of these studies, conducted to determine baseline rates for spontaneous abortions and antidepressant effects, found that the rate of spontaneous abortions was significantly higher (i.e., by 3.9 per cent) in women taking antidepressants. The class of antidepressants taken did not affect the rate.10 (This increase may be related to depression itself, rather than to the effects of antidepressants.)
Poor neonatal adaptation has been reported in some babies following in utero exposure to antidepressants, with increased admissions to neonatal intensive care units.11 Clinical manifestation of poor neonatal adaptation includes such usually transient and self-limiting symptoms as jitteriness, tachycardia, hypothermia, vomiting, hypoglycemia, irritability, constant crying, increased tonus, eating and sleeping difficulties, convulsions and respiratory distress. This pattern of symptoms may occur in up to 30 per cent of all babies exposed to SSRIs during late pregnancy. However, in studies with comparative groups, this same pattern of symptoms occurred in six to nine per cent of babies who were not exposed to antidepressants in late pregnancy.11
Long-term effects on the child
To determine whether fluoxetine and TCAs cause adverse neurodevelopmental sequelae, researchers conducted a long-term assessment of children’s temperament, mood, arousability, activity level, distractibility and, most importantly, global IQ and language development.12 The assessment found no association between gestational use of TCAs or fluoxetine and any of the outcomes that were examined.
By contrast, for women with untreated depression, the child’s global IQ and language development showed negative effects in relation to the duration of the depression and the number of postnatal depressive episodes. These results suggest that children of mothers with depression have decreased global IQ and language development as compared to children of non-depressed women.12 Another study found similar results: in a case where internalizing behaviours (e.g., depression, anxiety and withdrawal) were examined in four-year-old children of mothers who had taken SSRIs while pregnant, the mother’s impaired mood had an identified impact on her child.13
Most antidepressants are excreted into breast milk in small amounts and, as a group, are considered compatible with breastfeeding.14 Of the SSRIs, fluoxetine is excreted in the highest amount (i.e., five to nine per cent of the maternal dose enters the breast milk.)
Despite the relative safety of using antidepressants while breastfeeding, providers should be aware that babies may react differently even to very small amounts of the drug. It is important to observe babies for changes such as drowsiness and difficulty feeding.
Withdrawal effects on the mother
Many women who are pregnant or breastfeeding abruptly discontinue taking their antidepressant medication,15 but such sudden cessation may cause the mother to experience discontinuation symptoms or re-emergence of the depression. The discontinuation symptoms, which tend to occur within days of stopping treatment, may include general somatic, gastrointestinal, and affective and sleep disturbances. Recurrence of the depression occurs gradually, and usually within weeks. While reinstituting the antidepressant medication mitigates the discontinuation symptoms (within 24 hours), the depression may take several weeks to respond to treatment.
One study reported that 11 out of 36 women who abruptly discontinued their antidepressant reported suicidal ideation; four were admitted to hospital.15
Effects of untreated illness
Untreated depression during pregnancy appears to carry substantial risks to the mother, fetus and infant, including risks due to unhealthy maternal behaviours arising from the depression (e.g., suicidal ideation) and an increased risk for spontaneous abortion, hypertension, pre-eclampsia, lower birth weight and postpartum depression.
A 2006 study of pregnant women diagnosed with depression who were followed longitudinally throughout their pregnancies found that pregnancy does not have a protective effect against depression and concluded that women should be treated with antidepressants if necessary.16 Depression in the mother can impact a child’s emotional and cognitive development;2 a depressed or withdrawn mother may fail to bond with her baby or respond to her infant’s cues (e.g., cooing in response to her baby, making eye contact).
Taken as a whole, the evidence suggests that untreated depression, rather than treatment with antidepressants during pregnancy, results in adverse outcomes.2
- Bhatia, S.C. & Bhatia, S.K. (1999). Depression in women: Diagnostic and treatment considerations. American Family Physician, 60 (1), 225–234, 239–240.
- Bonari, L., Pinto, N., Ahn, E., Einarson, A., Steiner, M. & Koren, G. (2004). Perinatal risks of untreated depression during pregnancy. Canadian Journal of Psychiatry, 49 (11), 726–735.
- Altshuler, L.L., Cohen, L., Szuba, M.P., Burt, V.K., Gitlin, M. & Mintz, J. (1996). Pharmacologic management of psychiatric illness during pregnancy: Dilemmas and guidelines. American Journal of Psychiatry, 153 (5), 592–606.
- Einarson, T.R. & Einarson, A. (2005). Newer antidepressants in pregnancy and rates of major malformations: A meta-analysis of prospective comparative studies. Pharmacoepidemiology and Drug Safety, 14 (12), 823–827.
- Djulus, J., Koren, G., Einarson, T.R., Wilton, L., Shakir, S., Diav-Citrin, O. et al. (2006). Exposure to mirtazapine during pregnancy: A prospective, comparative study of birth outcomes. Journal of Clinical Psychiatry, 67 (8), 1280–1284.
- GlaxoSmithKline Advisory. October 2005. Available: http://ctr.gsk.co.uk/welcome.asp. Accessed October 27, 2006.
- Cole, A., Ng, E., Ephross, S., Cosmatos, I. & Walker, A. (2006, August). Paroxetine in the First Trimester and Prevalence of Congenital Malformations. Abstract presented at the 22nd International Conference on Pharmacoepidemiology and Therapeutic Risk Management.
- Einarson, A., Pistelli, A., DeSantis, M., Chambers, C.D., Malm, H., Paulus, W.E. et al. (2007, June). Paroxetine Use in Pregnancy: Is There an Association with Congenital Cardiovascular Defects? Abstract presented at the meeting of the Teratology Society, Pittsburgh, PA.
- Chambers, C.D., Hernandez-Diaz, S., Van Marter, L.J., Werler, M.M., Louik, C., Jones, K.L. et al. (2006). Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New England Journal of Medicine, 354 (6), 579–587.
- Hemels, M.E., Einarson, A., Koren, G., Lanctôt, K.L. & Einarson, T.R. (2005). Antidepressant use during pregnancy and the rates of spontaneous abortions: A meta-analysis. Annals of Pharmacotherapy, 39 (5), 803–809.
- Koren, G., Matsui, D., Einarson, A., Knoppert, D. & Steiner, M. (2005). Is maternal use of selective serotonin reuptake inhibitors in the third trimester of pregnancy harmful to neonates? Canadian Medical Association Journal, 172 (11), 1457–1459.
- Nulman, I., Rovet, J., Stewart, D.E., Wolpin, J., Gardner, H.A., Theis, J.G. et al. (1997). Neurodevelopment of children exposed in utero to antidepressant drugs. New England Journal of Medicine, 336 (4), 258–262.
- Misri, S., Reebye, P., Kendrick, K., Carter, D., Ryan, D., Grunau, R.E. et al. (2006). Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. American Journal of Psychiatry, 163 (6), 1026–1032.
- Hale, T.W. (2006). Medications and Mothers’ Milk: A Manual of Lactational Pharmacology (12th ed.) (pp. 113, 365, 613, 814–815, 871, 895). Amarillo, TX: Hale Publishing.
- Einarson, A., Selby, P. & Koren, G. (2001). Abrupt discontinuation of psychotropic drugs during pregnancy: Fear of teratogenic risk and impact of counselling. Journal of Psychiatry and Neuroscience, 26 (1), 44–48.
- Cohen, L.S., Altshuler, L.L., Harlow, B.L., Nonacs, R., Newport, D.J., Viguera, A.C. et al. (2006). Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Journal of the American Medical Association, 295 (5), 499–507.
Exposure to Psychotropic Medications and Other Substances during Pregnancy and Lactation: A Handbook for Health Care Providers
General issues and background
Psychotropic medications and other substances: Properties, effects and recommendations
Index of drugs