Autism Awareness Day: Antidepressants in Pregnancy

Editorial Note: This post is by Adam Urato MD, the Chairman of Obstetrics and Gynecology at MetroWest Medical Center in Framingham, Massachusetts, as well as a Maternal-Fetal Medicine specialist at Tufts Medical Center in Boston, Massachusetts. He cares for pregnant women on a daily basis.

Autism rates are on the rise, with the latest report from the US Centers for Disease Control showing 1 in 50 children to be affected (1). Prozac, the first of the SSRI (selective serotonin reuptake inhibitor) antidepressants, was launched in 1987 and sales have risen since then. Women of childbearing age make up a large percentage of SSRI users so the issue of pregnancy exposure is important. Estimates are that up to 13% of US pregnancies are exposed (2) (or around 500,000 US pregnancies per year).

How the SSRIs affect pregnancy has been an area of increasing concern (3). Current evidence suggests that use of antidepressants during pregnancy is associated with miscarriage (4), birth defects (5), preterm birth (6), and newborn behavioral syndrome (7) along with other pregnancy complications such as preeclampsia (8) and low birth weight (9).

We know the SSRIs are associated with pregnancy complications, but a major area of concern is what the effects are on the developing brain of embryos and fetuses exposed to these drugs. Available scientific data from animal and human studies raise serious concerns that exposure to SSRIs during pregnancy damages the developing brain and may cause neurodevelopmental abnormalities, including autism.

Serotonin: a crucial neurotransmitter

Serotonin is the first neurotransmitter expressed in the developing embryo and it plays a crucial role in human brain formation. Serotonin has been shown to be essential for the growth and development of certain areas of the brain. It is involved in such basic processes as cell division, differentiation, migration, and synaptogenesis (10). In short, proper functioning of the serotonin system is essential for the brain to form and function normally. In the adult brain serotonin plays a key role in cognition, mood, anxiety, sleep, aggression, and sexual function.

But serotonin’s critical role in development doesn’t end with the brain. Among other organ systems, serotonin is also found in the intestinal tract, the bone, the lungs, and in the platelets of the blood. The SSRIs are believed to exert their effects by blocking the reuptake of serotonin into neurons (the nerve cells that are the “basic” cell of the brain). For a developing baby, such blockade is occurring throughout the body (including the brain) and throughout pregnancy development.

It is now well-established scientifically that autism is characterized by changes in the serotonin system. Hyperserotonemia is the most consistent neurochemical change in autism (11).

Animal studies of exposed pregnancies are concerning

Most of the data we have on developmental effects of the SSRIs on the brain comes from animal studies on small mammals (mice and rats). The majority of these studies show significant changes in the brains and behavior of exposed animals and these results are very concerning.

In 2004, in the journal Science (one of the world’s leading scientific publications), Mark Ansorge and his coauthors published their research showing that exposing mice to Prozac (fluoxetine) during development led to abnormal emotional behaviors when those mice were adults (12).

In 2011, Kimberly Simpson and her colleagues at the University of Mississippi showed that rats exposed to Celexa (citalopram) had changes in the structure and function of their brains and showed impaired social behavior. Males were more severely affected than females.This gender difference (with males being affected more than females) is well-established in human studies on autism (13).

These are just two examples of the many, many animal studies that show changes in the brain and behavior that result when the serotonin system is altered during development by the use of the SSRI antidepressants. These animal studies have been published in some of the world’s leading scientific journals like Science and The Proceedings of the National Academy of Sciences. At the end of every scientific paper there is a “Discussion” section. In the Discussion of these animal studies, again and again, the authors warn us that their findings (of harmful effects on offspring from exposure to SSRIs during brain development) should make us concerned with using them in humans.

Human studies are also finding problems

Several human studies looking at the effects of SSRI exposure during pregnancy have shown brain and behavioral changes in exposed children.

In 2003 Regina Casper showed that SSRI exposure during pregnancy had effects on motor development and motor control in young children (14). In 2010 Lars Pedersen demonstrated that SSRI-exposed children sat up and walked later than their unexposed peers and that they had behavioral changes (15). In 2013 Gillian Hanley showed that children prenatally exposed to SSRIs scored lower on gross motor, social-emotional, and adaptive behavior testing (16). And these are just 3 of many studies that show changes in exposed children.

The most important study regarding the SSRI antidepressants, pregnancy and autism came out in 2011. In this study, Lisa Croen and her colleagues showed that SSRI exposure during pregnancy was associated with a doubling of the risk of autism. Even more importantly, for first trimester exposure to the SSRIs, the risk was almost quadrupled. Very importantly, her study looked at depressed women who were not on SSRIs and in this group there was no increased risk of autism. It was the antidepressant use that was linked to the autism and not the depression (17).

Basic science: “Brain damage proteins”

It is not possible to examine the brains of exposed human children in the same way that researchers can study rat and mice brains to look for effects of the SSRI antidepressants. But there is ongoing basic science research in humans looking at evidence of brain injury in exposed babies.

S100B is an important brain protein that has been found to be lowered in babies who were exposed to alcohol and cocaine in utero. In 2009, Jodi Pawluski and her colleagues in Vancouver published a landmark study showing decreased S100B levels in human babies who were exposed to the SSRI antidepressants in utero (18).

Activin A is a brain protein that is increased in cases of brain injury. It is known as a “brain damage marker.” In 2011 Valentina Bellisima and her colleagues in Italy showed that babies who are exposed to SSRI antidepressants in utero have dramatically higher levels of this brain damage marker in their blood and amniotic fluid (19). This study leaves us with the question, why is the brain damage marker protein (Activin A) so elevated in the SSRI-exposed children?

Common sense: Putting it all together

A developing embryo and fetus is loaded with serotonin receptors and serotonin plays an absolutely critical role in development. Why wouldn’t chemically interfering with this system affect human development—particularly in the brain? Why would we expect that the addition of such a chemical to human development would not cause significant and likely harmful effects? The SSRI antidepressants have been shown to be linked to miscarriage, birth defects, preterm birth, preeclampsia, and other pregnancy complications that suggest that the drugs can cause injury to the developing baby/pregnancy. It should come, then, as no surprise that such medications could injure the fetal brain. Animal data shows brain injury from exposure to these drugs during development and human data shows altered brain damage proteins from such exposure. Finally, human studies in child development show that exposed babies have worsened neurobehavioral outcomes and increased rates of autism.

Conclusion: Autism Awareness Day and the importance of public awareness

Today is Autism Awareness Day and we are in the midst of a growing epidemic of autism. While many factors are likely contributing to the epidemic, we can no longer ignore the role of the widespread use of the SSRI antidepressants by pregnant women.

The complications of SSRI use might be considered tolerable if there was solid evidence of benefit with the use of antidepressants by pregnant women. Sadly, in 25 years of study, not a single study has ever shown improvements in pregnancy outcomes in the antidepressant-treated group. And, in studies of nonpregnant populations, there is little evidence of clinically significant benefit with the use of antidepressants (when compared with placebo) by most patients with depression.

Today, on Autism Awareness Day, it is essential that we raise public awareness of the issues surrounding antidepressant exposure during pregnancy and the ever-growing evidence of harm that we see in the scientific studies. At this point, we do not know with 100% certainty that the SSRI antidepressants are causing autism, but several lines of evidence point strongly in that direction, and the evidence that these drugs can injure the developing brain is clear and consistent. Pregnant women suffering from depression need treatment and care. But, with good evidence that non-drug therapies, such as psychotherapy and exercise, provide at least as much benefit in the treatment of depression (if not more), it makes sense to first use these approaches in women of childbearing age—approaches that have not been linked to autism.

References

(1) Blumberg, Stephen J, et al. Changes in Prevalence of Parent-reported Autism Spectrum Disorder in School-aged U.S. Children: 2007 to 2011–2012. CDC National Health Statistics Reports. March 20, 2013.

(2) Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007; 196: 544.e1-5.

(3) Domar AD, Moragianni VA, Ryley DA, Urato AC. The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum Reprod. 2013; 28: 160-71.

(4) Nakhai-Pour HR, Broy P, Bérard A. Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ. 2010; 182: 1031-7.

(5) Pedersen, L. H., Henriksen, T. B., Vestergaard, M., Olsen, J., & Bech, B. H. (2009). Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. British Medical Journal, 339, b3569 .

(6) Roca A, Garcia-Esteve L, Imaz ML, Torres A, Hernández S, Botet F, Gelabert E, Subirà S, Plaza A, Valdés M, Martin-Santos R. Obstetrical and neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitors: the relevance of dose. J Affect Disord. 2011; 135: 208-15.

(7) Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006; 160:173-176.

(8) De Vera MA, Bérard A. Antidepressant use during pregnancy and the risk of pregnancy-induced hypertension. Br J Clin Pharmacol. 2012; 74: 362-9.

(9) Grzeskowiak LE, Gilbert AL, Morrison JL. Neonatal outcomes after late-gestation exposure to selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 2012; 32: 615-21.

(10) Bonnin A, Levitt P. Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience. 2011; 197:1-7.

(11) Hadjikhani N. Serotonin, pregnancy and increased autism prevalence: is there a link? Med Hypotheses. 2010 May;74(5):880-3.

(12) Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science. 2004; 306: 879-81.

(13) Simpson KL, Weaver KJ, de Villers-Sidani E, Lu JY, Cai Z, Pang Y, Rodriguez-Porcel F, Paul IA, Merzenich M, Lin RC. Perinatal antidepressant exposure alters cortical network function in rodents. Proc Natl Acad Sci U S A. 2011; 108: 18465-70.

(14) Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. JPediatr. 2003; 142: 402-8.

(15) Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age. Pediatrics. 2010; 125: e600-8.

(16) Hanley GE, Brain U, Oberlander TF. Infant developmental outcomes following prenatal exposure to antidepressants, and maternal depressed mood and positive affect. Early Hum Dev. 2013 Feb 2. doi:pii: S0378-3782(13)00015-7. 10.1016/j.earlhumdev.2012.12.012.

(17) Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. 2011;68:1104-12.

(18) Pawluski JL, Galea LA, Brain U, Papsdorf M, Oberlander TF. Neonatal S100B protein levels after prenatal exposure to selective serotonin reuptake inhibitors. Pediatrics. 2009;124:e662-70.

(19) Bellissima V, Visser GH, Ververs TF, van Bel F, Termote JU, van der Heide M, Florio P, Li Volti G, Gazzolo D. Antenatal maternal antidepressants drugs affect Activin A concentrations in maternal blood, in amniotic fluid and in fetal cord blood. J Matern Fetal Neonatal Med. 2011;24 Suppl 2:31-4.