Medication Safety Review Series: SSRIs

This series will review a medication (commonly used in mental health treatment) weekly to describe its safety profile and answer five important questions.

The Selective Serotonin Reuptake Inhibitors, or SSRIs, include sertraline (brand name: Zoloft), escitalopram (brand name: Lexapro), citalopram (brand name: Celexa), fluoxetine (brand name: Prozac), fluvoxamine (brand name: Luvox) and paroxetine (brand name: Paxil).

What are SSRIs and what are they used for?

SSRIs are the first line medications for treatment mood and anxiety illnesses during pregnancy, postpartum, and outside the reproductive period. These medications act on the serotonin neurochemical in the brain in order to treat conditions such as depression, panic attacks, obsessive thoughts, and generalized anxiety.

How safe are they in early pregnancy?

When we think about medication safety in early pregnancy, we are specifically concerned with exposure in the first trimester, when organs are forming. This is the risky time for the potential formation of a birth defect. It is important to keep in mind the baseline risk for birth defects when making comparisons, which is about 2-4%.

Repeat research has not found an association between exposure to these medications and birth defects. Early data suggested a relationship between paroxetine and cardiac defects, but more recent data has not supported this association. However, because of this early data, a woman on paroxetine may consider switching to a different SSRI medication if it would not be destabilizing to her mental health.

Studies have also looked at the association between exposure to these medications and the incidence of miscarriage. There are many investigations out there with conflicting data, often because they cannot distinguish the risk of the medication compared to the risk of the underlying disease for which the medication is being prescribed. One large study (of over one million women) last year attempted to parse this out by comparing women who were taking SSRI medications in the first trimester and those who had discontinued SSRI medication at least 3-12 months prior to conception. They did not find a statistical difference in the rates of miscarriage. This means that a women should not discontinue her SSRI medication prior to pregnancy if she is concerned about miscarriage.

How safe are they in later pregnancy and delivery?

In thinking about SSRIs in later pregnancy and at delivery, there are two conditions that have been researched.

Neonatal Adaptation
This is a form of a mild withdrawal-like syndrome that infants whose mothers are taking SSRIs towards the end of their pregnancy can experience. The baby might be more irritable, jittery, tremulous, and have some difficulty with feeding. It occurs in less than a third of babies whose mothers take these medications, and when it does occur, it is often mild and resolves within two weeks. Some have said it is hard to tell the difference between this adaptation syndrome and a temperamental infant. Pediatricians are also quite familiar with this and adept at counseling parents.

PPHN – Persistent Pulmonary Hypertension of the Newborn
This is a condition where the vessels in the baby’s circulation develop poorly, leading to decreased blood flow through the lungs and significant hypoxemia, a condition of decreased oxygen in the blood. At baseline, this occurs in 1-2 infants per 1000. In the mid-2000s, a study came out that taking SSRI medications in late pregnancy increased the risk of this condition 6-fold.

However, subsequent half a dozen studies were conflicting, with half confirming an increased risk and half not finding this risk. The most recent and large investigation of this condition noted that there may be an increased risk, but it is much less than previously estimated – the risk of PPHN was increased to 2-3 infants per 1000, and this increased risk was decreased when depression was taken into account.

Are there any long-term consequences of these medications?

A small study came out several years ago that noted an association between SSRI medications and future diagnosis of autism spectrum disorders. Several larger studies since then have not been able to find a causal relationship between SSRI medication exposure in a fetus and subsequent diagnosis of autism. Most recently, a study came out a few weeks suggesting that taking these medications in later pregancny correlated with a future diagnosis of autism in a child. There are five confounding factors associated with these studies.

  1. The first is that the illness of depression itself may be linked with the future development of autism, and hence it is important to control for illness severity, which is quite difficult to do. Even this latest article was unable to do this – it did not take into account that fact that women with more severe depression are the ones taking medication while those with milder illness use non medication forms of treatment
  2. Second, many of these studies use registry pharmacy data, meaning they assume a woman is taking medication based on whether or not she fills a prescription, rather than by directly asking a woman if she is taking the medication. A number of my own patients fill prescriptions but then do not take the prescribed medication.
  3. Additionally, not all studies were able to take lifestyle behaviors into account, such as whether or not a woman smokes, and the influence of these lifestyle choices on their child’s development of autism.
  4. Furthermore, studies did not always take into account parental or sibling autism traits, which is an important limitation because autism spectrum conditions are very heritable (meaning genetically passed down).
  5. Finally, studies did not always account for other confounding factors such as premature birth or low birth weight (both of which, for example, are associated with the illness of depression).

In conclusion, when a woman asks me if an SSRI medication can cause autism in her child, I explain the above and note that while a causal relationship has not yet been established, it is important to carefully weigh the risks and benefits of medication.

Women also often ask about other long-term effects, such as will this change my baby’s motor development or cognitive development? To date, studies have not found any link between prenatal exposure to SSRI medication and cognitive development, as tested up to about age 7. Several studies have noted subtle differences in gross motor and language skills, but many have not, and this remains a topic for further investigation. Unfortunately, there are no studies looking at the functioning of these children beyond 7 years old, and doing so would be a challenge given the importance of the impact of environment and genetics.

Are they safe in breastfeeding?

This is a two-part question. First, does the medication cross into the breast milk? Yes, but in small amounts. Studies have found that less than 1% of sertraline crosses into the breastmilk and levels are generally undetectable in babies. The largest concentrations have been found with the medication citalopram, which is still less than 9%.

Second, does that exposure have any consequences? To date, the data suggests no significant adverse problems with exposure to SSRIs through breast milk.

Want to learn more about SSRIs and related topics?
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Selected References:
Gentile, S. Prenatal antidepressant exposure and the risk of autism spectrum disorders in children. Are we looking at the fall of Gods? Journal of Affective Disorders 182 (2015) 132-137.

Andersen, J.T. et. al. Exposure to selective serotonin reuptake inhibitors in early pregnancy and the risk of miscarriage. Obstetrics and Gynecology 124 (2014) 655-61.
Huybrechts, K.F. et. al. Antidepressant use late in pregnancy and the risk of persistent pulmonary hypertension of the newborn. JAMA 313 (2015) 2142-2151.
Suri, R., Lin, A.S., Cohen, L.S., Altshuler, L.L. Acute and long-term behavioral outcomes of infants and children exposed in utero to either maternal depression or antidepressants: A review of the literature. Journal of Clinical Psychiatry 75 (2014) 1142-52.
Stuebe, Alison. Reports linking SSRIs with autism are greatly exaggerated. December 17, 2015. http://www.huffingtonpost.com/alison-stuebe/reports-linking-ssris-with-autism-are-greatly-exaggerated_b_8824334.html