What are the risks of untreated depression and anxiety during pregnancy?

Untreated depression/anxiety during pregnancy has been associated with

  • Self-neglect
  • Poor maternal eating habits
  • Disrupted sleep-wake cycles
  • Suicidal thinking
  • Substance/Drug abuse
  • Inadequate weight gain
  • Hypertension
  • Pre-eclampsia
  • Preterm birth
  • Spontaneous abortion
  • Intrauterine growth retardation (IUGR)
  • Low birth weight
  • Depressive-like behavior in the infant
  • Neurobehavioral changes in the infant

In addition, untreated depression during pregnancy and the postpartum period has been associated with an increased risk for mood and anxiety disorders in their children later in life.  It isn’t surprising that evidence suggests infants born to mothers with anxiety disorders have impaired auditory gating–a marker of an infant’s ability to focus. However, maternal use of antidepressants in pregnancy improves this ability in prenatally exposed infants.  When considering the use of medications during pregnancy, careful risk-benefit decisions are best made on a case-by-case basis by an informed patient in combination with her doctor. 

A study of 201 pregnant women with a history of depression found that 43% relapsed during pregnancy.  Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared with women who maintained their medication.  Thus, among the women who maintained their antidepressant medication throughout pregnancy, 26% relapsed, compared with 68% of those who discontinued their medication.

Sources: Koren et al Canadian Medical Association Journal 2005;172:1437-9; Byatt et al Acta Psychiatrica Scandivica 2013;127:9-114; Markus and Miller J Clin Psychiatry 2009; Hunter et al Am J psychiatry 2012;169:616-24; Cohen et al JAMA 2006;295:499-507

Are antidepressants safe during pregnancy?

When it comes to risk, it seems everyone has an opinion about antidepressants in pregnancy. And the lay press does not provide any clarity. As physicians, we aren’t interested in unsubstantiated opinions formulated from under-powered, biased, and poorly designed studies. But because pregnant women are typically excluded from clinical trials it is very difficult to find well designed, adequately powered, randomized double-blind placebo controlled trials–the gold standard of evidence-based medicine. That being said, the selective serotonin reuptake inhibitors (SSRIs) as a class have been studied the most and are generally the safest (although many other antidepressants have been used safely for years). Below is a summary of the current data on SSRIs. The short answer is this…SSRIs are not major teratogens.

…A special thanks to Dr. Burt and colleagues for the information provided below…

Risk of Malformations

“Current data on SSRI exposure shows no consistent information to support specific morphological congenital defects.  Data from a large, prospective cohort study found that exposure to SSRIs during the first trimester was not associated with an increased risk of congenital anomalies, including cardiovascular malformations (Nordeng et al:  J Clin Psychopharm. 2012;32:186-194). A more recent large study in the New England Journal of Medicine funded by the Agency for Healthcare Research and Quality and the National Institutes of Health (Huybrechts et al 2014:370:2397-407) found no statistically significant risk of any cardiac malformation with first trimester exposure to any antidepressants (SSRIs, SNRIs, Bupropion).”

“While some studies have suggested that there may be an increased risk for cardiac defects (1/100 versus the background risk of 0.7/100) or other defects, these studies did not appropriately control for depression or anxiety and therefore no conclusions can be made about cause/effect.  In particular, a recent publication suggesting a possible neurostructural increased risk with prenatal SSRIs was limited by small sample sizes, a lack of controlling for maternal depression in pregnancy, no adjustment for confounds like smoking, alcohol, substance abuse, nutritional and other factors that increase risks for birth defects (Knickmeyer et al Neuropsychopharmacology 2014;May 19. Doi: 10.1038/npp.2014.114). The  authors of this study stated that replication of this data is required before any definitive conclusions could be made.  Such studies should be done with larger samples, and with better control over potentially confounding variables.  The authors correctly concluded that their findings should not inform prescription practices in pregnancy.”

Risk of Miscarriage

“Some early data suggested an increased risk for miscarriage with antidepressant use, but the data was confounded by psychiatric illness, drug use, maternal age, and smoking.  As noted by a recently published consensus report by representatives from the American College of Obstetricians and Gynecologists (ACOG) and the American Psychiatric Association (APA), “Studies with adequate control for potential confounding variables, especially age, which is a strong  predictor of spontaneous abortion, are needed before an association can be established” (Yonkers et al Gen Hosp Psychiatry 2009;31:403-13/ OB-Gyn 2009;114:702-13). A recent large meta-analysis found no significant association between antidepressant exposure and spontaneous abortion (Ross LE et al JAMA Psychiatry 70:436-443, 2013).”

Effects on Birth Weight

While reduced birth weight has been associated with SSRI use in pregnancy, not all studies show this association. It has been suggested that the reduction in birth weight could be attributed to the slightly shorter duration of pregnancy associated with SSRIs (about 2-3 days shorter which is clinically insignificant). Nevertheless, if this is true, then the absolute difference in birth weight independent of gestational age-adjustments is very small–75 grams [2.6 ounces] or lower (Ross LE et al JAMA Psychiatry 70:436-443, 2013).

Risk of Preterm Delivery/Preterm Birth

“Some studies suggest SSRI use is associated with an increased incidence of preterm delivery, defined as <37 weeks of pregnancy (Huybrechts KF et al PLoS One 2014;9:e92778).  Generally the effect is modest, on the order of one week or less for exposed babies  (Ross LE et al JAMA Psychiatry 70:436-443, 2013). Other studies, such as the large prospective cohort study by Nordeng et al (J Clin Psychopharmacol 2012;32:186-194) found no increased risk for preterm birth with SSRI exposure in pregnancy.”

Neonatal Adaptation Syndrome

“Neonatal irritability and respiratory difficulties that are mild and self limiting have been linked to late trimester antidepressant exposure. If symptoms occur they are typically temporary and resolve by 2 weeks or sooner after delivery.  The risk for these neonatal adaptive difficulties is probably on the order of 15-30%.  The risk of persistent pulmonary hypertension of the newborn (PPHN), a more concerning condition, is much lower. The base rate for PPHN is 0.5 to 2 per thousand, and may be elevated to 3-6 per 1000 among infants with late term SSRI exposure.  Notably, in December 2011, the FDA published an update, which stated that after a review of different studies regarding the issue of possible increased risk of PPHN with prenatal SSRI use, ‘it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.’  The FDA now recommends that health care professionals not alter their current clinical practice of treating depression during pregnancy on the basis of a perceived risk for PPHN with in utero SSRI exposure.  Nevertheless, because of the increased risk for neonatal adaptive difficulties, it is generally recommended that infants exposed to SSRIs (or the dual acting antidepressants, SNRIs) remain in hospital for 48 hours following delivery for observation.”

Risk of Autism Spectrum Disorder

“Three articles (Croen et al. 2011; Harrington et al 2014; Rai et al 2013) have reported an association between autism and maternal use of antidepressants in pregnancy.  Although these studies attempted to control for possible relevant variables, they had multiple limitations, and did not adequately control for severity of maternal mental illness during pregnancy. Since then, two large Danish studies have been published. The first study found that if data was restricted to children of mothers with prenatal mood disorders, there was no statistically significant increased risk in autistic spectrum disorders in offspring prenatally exposed to SSRI antidepressants (Sorensen et al.  Clinical Epidemiology.  5:449-459, 2013).  The second study supported the conclusions of the first Danish publication.  These authors found that treatment with SSRIs prior to pregnancy, but not during pregnancy, were associated with a significant association between maternal use of SSRI antidepressants during pregnancy and autistic spectrum disorder in exposed offspring (Hviid et al.  NEJM.  369:2406-15, 2013).  As noted in the 2014 article by Harrington et al, the great increase in autism diagnoses over the past decades is unlikely to be explained by the gestational use of antidepressants such as SSRIs.  Furthermore, the authors note that gestational maternal depression increases the risk for adverse developmental effects in infants and children.  For these reasons, the benefits of treating depression in pregnancy must be weighed carefully against any potential risk of harm. Maternal mental illness, often occurring in the context of treatment with antidepressants, may well be more likely to explain any apparent increase in autism in offspring of women on antidepressants during pregnancy.”

“In August 2009, the American College of Obstetricians and Gynecologists (ACOG) and the American Psychiatric Association (APA) released a joint statement on treatment recommendations for depression during pregnancy. The recommendations state that women with major depressive disorder who are contemplating pregnancy or who are currently pregnant can safely start and/or continue taking antidepressants. Women who prefer to avoid or discontinue medications should be monitored closely and may benefit from psychotherapy. Clinicians and patients need to balance the small risks associated with antidepressants such as SSRIs (and presumably SNRIs) against those associated with partial or no treatment.”

Are SSRIs Safe in Breast Feeding?

“SSRIs are not contraindicated in breast-feeding mothers. However, it is important to remember that breast-feeding is often accompanied by even greater sleep deprivation than occurs in non-nursing postpartum mothers.  The postpartum is a time of especially high risk for psychiatric illness, especially in women with past histories of psychiatric disorders.  Sleep is most important to ensure emotional stability and this is especially true when new mothers are caring for other children at home. Sleep deprivation significantly increases the risk of mood destabilization in individuals with significant histories of psychiatric disorders. Therefore, formula feeding is highly recommended in women with histories of psychiatric disorders who are taking antidepressants. This will minimize the likelihood of sleep-deprivation and allow aggressive pharmacological treatment of depression or anxiety in the mother to prevent a relapse or worsening of symptoms which could put the infant and mother at increased risk.”

**A special thanks to Vivien Burt, PhD, MD and colleagues for their expertise!**

 

Summary

(1) Selective Serotonin Reuptake Inhibitors with most data on safety (and generally thought of as the safest):

  • Sertraline (Zoloft)
  • Fluoxetine (Prozac)
  • Citalopram/Escitalopram (Celexa/Lexapro)

(2) Selective Serotonin Reuptake Inhibitors to avoid, if possible, due to elevated (albeit small) risk of adverse outcomes:

  • Paroxetine (Paxil)

(3) Selective Serotonin Reuptake Inhibitors secreted the least in breast milk:

  • Sertraline (Zoloft)
  • Paroxetine (Paxil)

 

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