Use of selective serotonin reuptake inhibitors during pregnancy

Obstetricians often see pregnant patients with psychiatric disorders, the most common being depression. Treatment includes both nonpharmacologic and pharmacologic options. This article focuses on use of selective serotonin reputake inhibitors (SSRIs), the drugs most often used to treat depression in pregnancy.¹

Scope of the issue

A woman has a 10% to 25% risk of being diagnosed with major depressive disorder at some point in her life, with the greatest risk occurring during the childbearing years.² It is estimated that 14% to 23% of pregnant women will experience a depressive episode while pregnant.³

The number of pregnant women in the United States using antidepressants during pregnancy ranges from 7% to 13%.⁴ As the number of pregnant women taking antidepressants has increased over the past 10 to 15 years, so has the body of literature investigating the safety and effects of these medications during pregnancy. Most of the studies are nonrandomized, increasing the risk of confounding and ascertainment bias. Results from many studies are conflicting, in part because past studies did not take into account the effect of depression or its severity.⁵ More recent studies, however, have incorporated propensity score matching, which attempts to equalize the variables among treated and untreated depressed women.³

The potential effects of SSRI exposure on the newborn are discussed here.

Poor neonatal adaptation

If SSRIs are abruptly stopped, neonates may demonstrate a constellation of symptoms similar to the withdrawal-type phenomenon seen in adults. Exposure in late pregnancy to SSRIs confers a 10% to 30% risk of poor neonatal adaptation (PNA) syndrome, although the true risk is not known.⁶ In most cases symptoms are mild and self-limiting. Some infants will require observation for a few days postnatally. It should also be noted that PNA may not be related to medication withdrawal at all. It could also reflect medication side effects (toxicity), nicotine withdrawal, or other factors common to women who take antidepressants.

To reduce the risk of PNA, or to possibly ameliorate neonatal symptoms, some researchers have suggested stopping SSRIs near term. This can have deleterious consequences for the mother and neonate, particularly in the vulnerable postpartum period. One recent study looked at the neonatal effects of continuing SSRIs until delivery compared to stopping them 14 days prior to delivery.⁷ Stopping SSRIs prior to term did not appear to improve neonatal outcomes. Importantly, these researchers used propensity score matching in an attempt to control for disease severity, although they did acknowledge limitations such as not controlling for maternal race and alcohol or tobacco use. Most studies in the past did not take into account the possible effects of depression or control for the severity of it. Thus establishing causal relationships between medication use and adverse outcomes proved difficult. Only recently has the focus shifted to also taking into account the effects of the disease itself.

Table 1 lists some of the features suggestive of PNA. This cluster of findings has also been called neonatal withdrawal or neonatal abstinence syndrome. It is unclear whether PNA is a withdrawal phenomenon or possibly reflects serotonin toxicity. It is important to alert a patient's pediatrician about maternal SSRI use and to counsel the patient about the possibility of PNA. As noted in a recent review examining risks versus benefits, if pharmacotherapy is indicated the potential benefits outweigh the possible risks of PNA.⁸

Persistent pulmonary hypertension of the newborn

Also known as persistent fetal circulation, persistent pulmonary hypertension of the newborn (PPHN) is a serious condition in which the pulmonary vascular resistance does not decrease after birth. As a result, pulmonary blood flow is decreased and right-to-left shunting of deoxygenated blood occurs across the foramen ovale and ductus arteriosus to the systemic circulation. PPHN occurs primarily in term or post-term infants, with a reported incidence of 2 per 1000 live births. Mortality ranges from 5% to 10% and is often associated with the presence of congenital anomalies such as heart disease and congenital diaphragmatic hernia.

            A possible link between late SSRI exposure (> 20 weeks’ gestation) and PPHN was suggested in a case-controlled study and another study using data from the Swedish Medical Birth Register.^9,10 Neither study controlled for mode of delivery. In one of these studies, there were only 14 SSRI exposures and a 6-fold risk of PPHN with SSRI exposure was demonstrated.⁹ The absolute risk of PPHN, however, remained extremely small (3–12/1000 live births). Since these studies, several others have failed to demonstrate an association between SSRI exposure and PPHN. Two studies-a multicenter retrospective cohort of 1104 exposures and a case-controlled study looking at all births over a 6-year period-did not observe an association.^11,12 A strength of these 2 studies was the elimination of any recall bias because data ascertainment was based on a prospectively collected database.

            Most recently a large multinational cohort that looked at 1.6 million births over an 11-year period in 5 countries suggested an association between SSRI exposure after 20 weeks’ gestation and PPHN.¹³ The absolute risk, however, remained very small (3/1000). In a review of this study certain weaknesses were noted.¹⁴ In particular are the inherent confounders when analyzing data from a registry and the failure to control for untreated depression, the latter a concern in many studies attempting to link SSRIs with adverse perinatal outcomes. The reviewer goes on to state that clinicians should not change their practice of prescribing SSRIs if indicated based on the findings of this study.

            The biologic mechanisms by which SSRI exposure might cause PPHN are unknown. Serotonin’s vasoconstrictive properties and mitogenic effects on pulmonary smooth muscle have been postulated. Still, if there is a risk of PPHN with SSRI use, in my opinion, the absolute risk is very small and the benefits likely outweigh this marginal risk.⁸

Congenital anomalies

Despite the limitations of a small sample size, most studies have failed to demonstrate a link between SSRI exposure and fetal malformations. In 2005, a report by the drug manufacturer of paroxetine noted a 1.5-fold risk of cardiac defects (primarily atrial and ventricular septal defects) in children exposed in utero to paroxetine. This prompted the FDA to change the pregnancy category of paroxetine from C to D and issue an advisory for clinicians to consider discontinuation of this medication, or to reduce the dose to decrease the risk of PNA and PPHN.¹⁵ The data in this report were not published in a peer-reviewed journal and were derived from a Swedish registry and a US insurance-claims database, sources with inherent bias and methodologic limitations.

A December 2006 Committee Opinion from the American College of Obstetricians and Gynecologists does not specifically state that paroxetine is absolutely contraindicated during pregnancy but advises that its use preconceptionally or during gestation should be avoided if possible.¹⁶ The opinion added that “the benefits of paroxetine therapy in a given pregnant patient may outweigh the potential risks” and “fetal echocardiography should be considered for women who were exposed to paroxetine in early pregnancy.”¹⁶ Subsequently, prospectively ascertained data from teratology information services worldwide with the largest number of paroxetine exposures (1174) to date did not show an association between paroxetine exposure in early pregnancy and cardiac malformations.¹⁷

Two large case-controlled studies examining the relationship between first-trimester SSRI exposure and congenital anomalies were published in the same issue of The New England Journal of Medicine.^18,19 The results were conflicting. In the National Birth Defects Prevention (NBDP) Study, data from 9622 infants with congenital anomalies over a 6-year period were compared with over 4000 controls.¹⁸ No significant association was found between maternal use of SSRIs overall and congenital heart defects or most other birth defects. There was an increased odds ratio with maternal SSRI use, however, for anencephaly, craniosynostosis, and omphalocele. The use of paroxetine significantly increased the risk of this latter pooled group. Prior to this study, paroxetine was not linked to any of these anomalies. Importantly, the numbers were extremely small to paroxeting. From a total of 214 infants with anencephaly, only 9 were exposed to SSRI’. Data from the Slone Epidemiology Center Birth Defects Study investigating exposures in 9849 infants compared to 5860 controls over a 12-year period did not demonstrate the association noted in the NBDP study.¹⁹ An editorial in the same issue addressing these conflicting results concluded that specific defects (if any) are rare and absolute risks are small.²⁰

A recent retrospective cohort study was published analyzing data over a 10-year period obtained from national population-based registers in Finland.²¹ An association between fluoxetine and paroxetine with isolated ventricular septal defects and right ventricular outflow tract defects, respectively, was noted. In addition, citalopram use was found to be associated with neural tube defects. Again the absolute risks were small. Importantly, despite the high prevalence of fetal alcohol spectrum disorders this study has been criticized for not controlling for alcohol use and other confounders.²²

Data from the first prospective study to examine the effects of escitalopram, a relatively new SSRI, were recently analyzed and no association with major congenital anomalies was found.²³ Further, a large retrospective cohort study used birth data obtained from the Danish Medical Birth Register to analyze more than 4000 first-trimester SSRI exposures. Only a small 2-fold increase in the risk of cardiac septal defects was noted.²⁴ Once more, the absolute risks remained small.

In summary, evidence that SSRI exposure increases the risk of congenital anomalies is conflicting, but reassuring overall. If there is indeed an increased risk, the question of biologic plausibility remains. All SSRIs are rated pregnancy category C, with the exception of paroxetine, which is a category D as previously discussed (Table 2).

Adverse perinatal outcomes

Many studies have looked at the association between SSRI use and preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA). Results are conflicting, and many studies were underpowered to detect a difference.³ When propensity score matching is used to control for maternal disease, there appears to be a statistically significant association between these adverse perinatal outcomes and SSRI use during pregnancy. Still, whether these are clinically significant associations that would warrant a change in practice is a key question.

A meta-analysis of 23 studies published earlier this year looked at exposure to various antidepressants and the relationship with adverse perinatal outcomes.²⁵ Most of the antidepressants were SSRIs. No association was noted between exposure and spontaneous abortions. A significant association was noted between antidepressant exposure and preterm birth, SGA, lower birth weight, and lower Apgar scores. For preterm birth and length of gestation, the statistically significant association remained when compared only to untreated depressed mothers. For birth weight, when compared to the infants of untreated depressed mothers, the association with antidepressant exposure was no longer significant. The take-home message from this important study is that even if certain associations persist after considering the effect of depression itself, the differences are small and unlikely to be clinically significant.

In a recent prospective, population-based study performed in the Netherlands, birth outcomes included preterm birth, LBW, and SGA.²⁶ Among the 7696 patients included in this study, 99 were exposed to SSRIs and 570 had untreated depression. The SSRI-exposed group showed a reduced fetal head circumference but not reduced body growth. In addition, SSRI exposure was associated with preterm birth, even when compared to untreated depressed mothers. However, the untreated depressed group showed reduced fetal head and body growth. The researchers acknowledge that more data are needed to assess medication effect versus the effect of untreated depression.

Developmental effects

Few studies have examined the long-term developmental effects of SSRI exposure in utero. Earlier studies did not reveal any differences in IQ, language, behavior, or temperament when a fluoxetine-exposed group was compared to an unexposed, nondepressed group.²⁷ This study was one of the first to assess the effect of depression itself on outcomes. Despite the lack of an unexposed group with depression, with the use of multiple regression analysis, the authors were able to demonstrate an adverse effect on child development as it relates to the duration of depression and the number of depressive episodes. This adverse effect was not associated with fluoxetine exposure.  A recent prospective cohort did include a group of untreated depressed women.²⁸ Children’s intelligence and behavior outcomes were evaluated once between ages 3 years and 7 years. Both groups with depression showed a higher but nonsignificant rate of behavioral issues. The investigators concluded that factors other than antidepressant exposure predicted children’s intellect and behavior.

A possible association between autism spectrum disorder (ASD) and SSRI exposure during pregnancy was suggested in a recent study that received considerable media attention.²⁹ The sample in this population-based, case-controlled study was drawn from the Childhood Autism Perinatal Study, and it included 298 children with ASD and 1507 unaffected controls matched for age, sex, and area of residence within Northern California. The study found a correlation between a prescription filled for an SSRI and a diagnostic code for ASD. Maternal use of an SSRI during the year before delivery was associated with a 2-fold increased risk of ASD, although this finding was not statistically significant. The strongest effect was associated with treatment during the first trimester (adjusted OR, 3.8 [95% CI, 1.8-7.8]). Among the children whose mothers had a history of mental health treatment but did not take SSRIs, the risk of ASD was not increased.

This study was limited by a small number of SSRI exposures in both the ASD and control groups. In addition, ASD as a variable was not taken into account.

It would be prudent for clinicians to await prospectively ascertained data before more firm conclusions can be drawn regarding the link between SSRI exposure and ASD.

Breastfeeding

The American Academy of Pediatrics considers all SSRIs compatible with lactation.³⁰ SSRI molecules do pass into the mother’s milk due to their low molecular weight, but the infant dose remains minimal. In a review of antidepressant use during lactation, the researchers prefer sertraline and paroxetine due to their low infant dose as compared with other SSRIs.³¹ Some have suggested that continuing SSRIs in the postpartum period may reduce the risk of PNA if it is a withdrawal phenomenon. There are no adequate studies looking at this. Women with depression are particularly at risk of postpartum depression, which can have grave consequences if untreated. At this time, irrespective of the specific SSRI, it is reasonable for women to continue their SSRI in the vulnerable postpartum period and to be encouraged to breastfeed.

Summary

A history of depression is a strong risk factor for developing postpartum depression, and depression late in pregnancy is the strongest predictor.⁸ Other concerns associated with maternal depression during pregnancy include increased use of other pharmacologic agents such as hypnotics, opiates, and tobacco, and poorer compliance with prenatal care. When discontinuing medication during pregnancy, the relapse rate can be significant, with an increased risk of suicidal ideations.³² As noted previously, the risk of adverse outcomes may also be increased in untreated depressed mothers. The clinician must individualize treatment, informing patients of both the possible risks and benefits of continuing (or in some cases, initiating) medication. It is also important to document these discussions. Table 3 provides a guide to aid in this discussion.

Patients should know that their SSRI doses may have to be increased during pregnancy, although symptoms are often controlled with the same dose that was used prior to pregnancy. There are no recommendations regarding dose adjustments once a patient becomes pregnant. Table 4 lists some commonly used SSRIs and their suggested doses.

References

1. Bennett HA, Einarson A, Taddio A, et al. Prevalence of depression during pregnancy: systematic review. Obstet Gynecol. 2004;103:698–709.

2. Marcus SM, Flynn HA, Blow FC, Barry KL. Depressive symptoms among pregnant women screened in obstetrics settings. J Womens Health (Larchmt). 2003;12:373–380.

3. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol. 2009;114:703–713.

4. Andrade SE, Raebel MA, Brown J, et al. Use of antidepressant medications during pregnancy: a multisite study. Am J Obstet Gynecol. 2008;198:194.e1–194.e5.

5. Palmsten K, Hernández-Díaz S. Can nonrandomized studies on the safety of antidepressants during pregnancy convincingly beat confounding, chance, and prior beliefs? Epidemiology. 2012;23:686–688.

6. Koren G, Finkelstein Y, Matsui D, Berkovich M. Diagnosis and management of poor neonatal adaptation syndrome in newborns exposed in utero to selective serotonin/norepinephrine reuptake inhibitors. J Obstet Gynaecol Can. 2009;31:348–350.

7. Warburton W, Hertzman C, Oberlander TF. A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health. Acta Psychiatr Scand. 2010;121:471–479.

8. Koren G, Nordeng H. Antidepressant use during pregnancy: the benefit–risk ratio. Am JObstet Gynecol. 2012;207:157–163.

9. 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.

10. Källén B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2008;17:801–806.

11. Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18(3):246–252.

12. Wilson KL, Zelig CM, Harvey JP, et al. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors.Am J Perinatol. 2011;28:19–24.

13. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries.BMJ. 2012;344:d8012.

14. Saade G. ACP Journal Club. SSRI use in late pregnancy was associated with increased persistent pulmonary hypertension in newborns. Ann Intern Med. 2012;156:JC511.

15. Food and Drug Administration. Public health advisory: Paxil; 2005. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm051731.htm. Accessed July 5, 2013.

16. American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 354: Treatment with selective serotonin reuptake inhibitors during pregnancy. Obstet Gynecol. 2006;108:1601–1603.

17. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am JPsychiatry. 2008;165:749–752.

18. Alwan S, Reefhuis J, Rasmussen SA, et al; National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356:2684–2692.

19. Louik C, Lin AE, Werler MM, et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356:2675–2683.

20. Greene MF. Teratogenicity of SSRIs-serious concern or much ado about little? N Engl J Med. 2007;356:2732–2733.

21. Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol. 2011;118:111–120.

22. Pupco A, Bozzo P, Koren G. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol. 2011;118:959–960.

23. Klieger-Grossmann C, Weitzner B, Panchaud A, et al. Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study. J Clin Pharmacol. 2012;52:766–770.

24. Jimenez-Solem E, Andersen JT, Petersen M, et al. Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study. BMJ Open. 2012;2(3).

25. Ross LE, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry. 2013;70:436–443.

26. EI Marroun H, Jaddoe VW, Hudziak JJ, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry. 2012;69:706–714.

27. Nulman I, Rovet J, Stewart DE, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002;159:1889–1895.

28. Nulman I, Koren G, Rovet J, et al. Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression. Am J Psychiatry. 2012;169:1165–1174.

29. Croen LA, Grether JK, Yoshida CK, et al. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. 2011;68:1104–1112.

30. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108:776–789.

31. Sie SD, Wennink JM, van Driel JJ, et al. Maternal use of SSRIs, SNRIs and NaSSAs: practical recommendations during pregnancy and lactation. Arch Dis Child Fetal Neonatal Ed. 2012;97:F472–F476.

32. 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.