Common Antidepressants Carry Very Small Risk of Birth Defects

Most selective serotonin reuptake inhibitors (SSRIs) and the newer selective norepinephrine reuptake inhibitors (SNRIs) are approved by the Food and Drug Administration (FDA) to treat major depression and, for many of these drugs, certain anxiety disorders such as obsessive-compulsive and panic disorders. These illnesses often afflict women of childbearing age.[1] Accordingly, women on such drugs may wonder whether they should use these drugs during pregnancy or discontinue them due to the possible risk of birth defects.

SSRIs include citalopram (CELEXA), escitalopram (LEXAPRO), fluoxetine (PROZAC, SARAFEM), fluvoxamine (LUVOX; FDA-approved only for obsessive-compulsive disorder), paroxetine (PAXIL, PEXEVA) and sertraline (ZOLOFT). SNRIs include desvenlafaxine (PRISTIQ), duloxetine (CYMBALTA, DRIZALMA) and venlafaxine (EFFEXOR XR).

Animal studies have found that use of SSRIs and SNRIs at dosages higher than the maximum recommended human dosages cause decreased fetal growth and survival, as well as fetal malformations.[2],[3] The FDA-approved product labeling for some of these drugs notes that some studies have linked SSRI use by women during pregnancy to an increased risk of fetal heart malformations, but a causal link has not been established.[4]

A new study recently published in the Journal of the American Medical Association (JAMA) Psychiatry shed new light on the association between the use of specific antidepressants during early pregnancy and the risk of birth defects.

The new study

The JAMA Psychiatry study, which was published online on Aug. 5, 2020, examined a very large national database of births to evaluate the risk of birth defects associated with use of individual SSRIs, SNRIs and other antidepressants during early pregnancy, which was defined as the first month before conception through the third month of pregnancy.[5]

The study researchers used the National Birth Defects Prevention Study database to compile data on birth-defect cases and controls from 1997 to 2011 and across 10 states. Cases were just over 30,600 live, stillborn or terminated births, all with at least one of 33 specific birth defects, including abnormalities of the heart, oral cleft, brain, spinal cord, skull, eyes, gastrointestinal tract and limbs. Controls were approximately 11,500 randomly selected live birth infants without any birth defects.

Six weeks to 24 months after delivery, the researchers asked the mothers of both the case and control infants about medication use — including specifically about use of the antidepressants citalopram, fluoxetine, paroxetine, sertraline, venlafaxine and bupropion (APLENZIN, WELLBUTRIN) — during the three months before conception or during pregnancy.

The mothers of infants with birth defects overall had a slightly higher rate of antidepressant use early in pregnancy — when the developing baby is most susceptible to damage from drug exposure — than mothers of control infants, 5.1% versus 4.1%, respectively (an absolute difference of only 1%).

Analyses that involved comparisons of birth defects in infants of women who used antidepressants during early pregnancy with women who did not use antidepressants before or during pregnancy found several statistically significant associations between use of specific antidepressants during early pregnancy and certain specific birth defects. For example, compared with no exposure to any antidepressant before or at any time during pregnancy, maternal use of fluoxetine during early pregnancy was 2.6 times more likely to be associated with giving birth to an infant with major defects in the veins connecting the lungs to the heart. Also, maternal use of citalopram was approximately five times more likely to be associated with giving birth to an infant with a diaphragmatic hernia (a defect in the muscle separating the chest from the abdomen that allows gastrointestinal organs to move into the chest cavity).

Compared with no exposure to any antidepressant before or during pregnancy, maternal use of venlafaxine during early pregnancy was associated with especially high odds of certain birth defects. For example, maternal use of this antidepressant was over nine times more likely to be associated with giving birth to an infant with anencephaly (absence of a major portion of the brain and skull) and craniorachischisis (the entire spinal cord and brain are exposed). Note that the Centers for Disease Control and Prevention cites that one in 4,600 babies in the U.S. is born with anencephaly and almost all of those infants die shortly after birth.[6]

To account for the possibility that depression or anxiety disorders themselves (or other factors associated with these disorders besides antidepressant use during early pregnancy) increase the risk of birth defects, the researchers conducted additional analyses comparing women who used antidepressants during early pregnancy with women who used these drugs before pregnancy or later in pregnancy.

These additional analyses found that the associations between specific SSRI use early in pregnancy and certain specific birth defects were reduced, especially with respect to heart birth defects. For example, compared with exposure to an antidepressant before or later during pregnancy, maternal use of fluoxetine during early pregnancy was only 1.9 times more likely to be associated with giving birth to an infant with major defects in the veins connecting the lungs to the heart, an association that was no longer statistically significant. By notable comparison, these analyses accounting for underlying conditions did not markedly change the observed associations between use of venlafaxine early in pregnancy and many birth defects, including the association with anencephaly and craniorachischisis.

The JAMA Psychiatry study results reinforce the concern that use of common antidepressants during early pregnancy may be associated with a small increased risk of birth defects. However, like many prior observational studies, it has limitations that preclude making definitive conclusions about whether these drugs do cause birth defects.

What You Can Do

If you are pregnant or attempting to conceive and you need treatment for depression or anxiety, consult with your doctors about your options to cope with your emotional challenges throughout your pregnancy. Note that the diagnosis and treatment of depression is often complex, so consultation with mental health professionals is essential. If you and your doctor determine that antidepressant medication is the best approach, work closely with you doctor to identify the lowest dose possible, and keep in mind that studies such as the one described above indicate that
 

References

[1] Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020 Aug 5:e202453. doi: 10.1001/jamapsychiatry.2020.2453.

[2] Drug profile: Selective serotonin reuptake inhibitors (SSRIs). WorstPills.org. July 30, 2020. /monographs/view/53. Accessed October 26, 2020.

[3] Lilly. Label: duloxetine (CYMBALTA). May 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021427s053lbl.pdf. Accessed October 26, 2020.

[4] Lilly. Label: fluoxetine (PROZAC). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/018936s109lbl.pdf. Accessed October 26, 2020.

[5] Anderson KN, Lind JN, Simeone RM, et al. Maternal use of specific antidepressant medications during early pregnancy and the risk of selected birth defects. JAMA Psychiatry. 2020 Aug 5:e202453. doi: 10.1001/jamapsychiatry.2020.2453.

[6] Centers for Disease Control and Prevention. Facts about anenchaphaly. December 5, 2019. https://www.cdc.gov/ncbddd/birthdefects/anencephaly.html. Accessed October 26, 2020.