Wednesday, January 6, 2016

Maternal antidepressants and autism

Recently, another study was published showing that SSRI antidepressant use during pregnancy is associated with increased rates of autism in the children. By my count, this is now the tenth study on this topic — all of which found links between SSRI antidepressant use in pregnancy and autism in the offspring. Most of these studies were recently reviewed, and also concluded that SSRI antidepressant use during pregnancy is associated with autism in the children.

So we now have numerous studies in different human populations all showing a link between SSRI use in pregnancy and autism in the children. Yet, much of the news and blogosphere focus on casting doubts about these findings. What is going on here?

Depressed pregnant women should not be ignored

I am deeply concerned about the effects that the SSRI chemicals have on the developing fetal brain. But, let me start by making it perfectly clear that my concerns about the effects that SSRIs have on the developing fetal brain are in no way a call to ignore depression in pregnant women or to tell them what to do. I counsel pregnant women every day in the hospital where I was born and in the community I grew up in. Many of them stay on their antidepressants. Some of them wean off. My experience has taught me a few things.

First off, depressed pregnant women need good treatment and care. This treatment can be with non-drug approaches such as psychotherapy or exercise or with medications. But, whatever treatment approach they choose, depressed pregnant women should not be ignored. Secondly, I don’t think anyone should be telling pregnant women what to do. The key is to provide them with the best available information that the scientific studies are showing and let them decide what is best for themselves. They should then be supported in their decision and continue to be given excellent care. Knowledge is power and we need to empower women in this area...

Currently, pregnant women and the public aren’t getting full information

If serotonin is crucial for the development of the baby’s brain and the SSRIs disrupt that system then it is a recipe for problems. (The only way it wouldn’t be a problem would be if the antidepressant chemicals did not cross the placenta. But we know that they do freely cross over into the baby’s developing brain.)

So if we just think about this issue on a theoretical basis, there is major cause for concern. The basic science is clear that serotonin plays a crucial role in the developing fetal brain and that these manufactured chemical compounds disrupt the serotonin system. But the science goes beyond just theoretical considerations.

Animal studies are showing harm

There have now been numerous animal studies done in this area, and the findings from these studies are very concerning. Again and again, we see that when animals are exposed to SSRI antidepressants during development that they show brain and behavioral problems (or so-called neurobehavioral problems.) There are too many animal studies now that have shown this to review them all in detail, but a few stand out. In 2004, Mark Ansorge and his group published a landmark paper in the journal Science (one of the leading scientific journals in the world). This paper showed that mice that were exposed to Prozac during development had altered emotional behaviors. In the conclusion of that paper (more than ten years ago!) Ansorge warned: “The use of SSRI medications in pregnant mothers and young children may pose unsuspected risks of emotional disorders later in life.” In 2011, Kimberly Simpson and her group studied the effects of Celexa on rats, and they also found concerning changes in the brains and behaviors of the exposed offspring. They warned: “Our findings are consistent with the possibility that dysregulation/dysfunction of the 5-HT [serotonin] system during early brain development may be the critical contributing factor in the etiology of ASD [autism spectrum disorder].”.
Human studies are showing harm

So what the scientific research is showing us makes sense. Serotonin is a molecule that is crucial for a baby’s brain development. The SSRIs disrupt the serotonin system. The animal studies show brain abnormalities and neurobehavioral problems. So when we do human studies in this area we would expect to see brain abnormalities and neurobehavioral problems. And that is, in fact, what we do see. Study after study in humans shows that the exposed babies have brain abnormalities including Chiari I malformations and smaller head size and neurobehavioral problems including autism, ADHD, motor problems, and anxiety.

What the public isn’t getting: human studies always have some flaws

What I find so astounding/frustrating in this area is that when the human studies show effects on the developing baby’s brain — like autism (effects that we would expect from the basic science and animal studies), reporters and editorialists immediately rush to cast doubt on the human studies. They highlight the limitations of doing large epidemiologic studies and how many problems these studies might have.

It is true that studying something like the link between antidepressants and autism in human populations is very challenging. There are lots of confounding factors, caveats, and limitations. There is no “gold standard” randomized controlled trial available because most researchers don’t think it would be ethical. But, at the end of the day, the human studies are confirming what basic science, animal studies, and common sense would tell us: putting brain-altering synthetic chemicals into a developing baby’s brain can alter development. The simple question for those who doubt the basic science, animal data, and human research is: “What do you think happens to the baby’s brain when it’s exposed to these chemicals throughout its development?” Why wouldn’t there be an effect on the baby’s developing brain?


Depressed pregnant women need good treatment and care, and I counsel patients in my community on this issue every day. There is no “one size fits all” or “right” answer for every patient. But what my patients (and the public) need here is the correct information so that they can make informed choices. The best available scientific evidence shows, 1) that serotonin is crucial for a baby’s brain formation; 2) that the SSRI antidepressants disrupt the serotonin system; 3) that the drugs freely cross the placenta; and, 4) that animal studies show brain effects in exposed offspring. When a human study comes out showing brain effects (autism) from exposure to these drugs (point #5 of my argument), then we should use this as an opportunity to inform the public rather than cast doubts on the findings of human studies and further confuse the issue.

There are non-drug approaches to depression that have been shown to work for many women, including psychotherapy and exercise. And, given what we know about the effects of these drugs, it makes sense to prioritize these non-drug approaches in pregnant women and women of childbearing age. However, some women will opt for antidepressants; that’s their choice, and they should be fully supported and given good care. This is not about telling women how to manage their depression. The key here is informing patients and the public so that they can make the best decisions for themselves.
Courtesy of:


  1. Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr. 2015 Dec 14:1-8. doi: 10.1001/jamapediatrics.2015.3356. [Epub ahead of print]



    The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.


    To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression.

    Design, Setting, and Participants:

    We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145 456 singleton full-term infants born alive and whose mothers were covered by the Régie de l'assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015.


    Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes.

    Main Outcomes and Measures:

    Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs.


    During 904 035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97).

    Conclusions and Relevance:

    Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.

  2. Man KK, Tong HH, Wong LY, Chan EW, Simonoff E, Wong IC. Exposure to selective
    serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies. Neurosci Biobehav Rev. 2015 Feb;49:82-9.


    This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case-control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case-control studies were 2.13 (95% CI 1.66-2.73) and 1.81 (95% CI 1.47-2.24) respectively. Low heterogeneity was observed between studies. The two population-based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed.

  3. 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 Oct 29;306(5697):879-81.


    Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

  4. 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 Nov 8;108(45):18465-70.


    Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

  5. Hi, could you please tell me your opinion on SSRI use during breastfeeding? Does it pose any of the same risks to the infant as exposure in utero? Thanks.

  6. Apropos of Holly's comment (I profess no authority on this subject):

    Tran H, Robb AS. SSRI use during pregnancy. Semin Perinatol. 2015

    The Society of Maternal and Fetal Medicine recently had a conference on the use of medications during pregnancy, delivery, and breast-feeding. One of the most important topics covered during that 2-day conference was major depression (MDD) and the use of Serotonin Selective ReuptakeInhibitors (SSRIs). This article will review the current state of knowledge about MDD during and immediately after pregnancy and treatment with SSRIs during pregnancy and breast-feeding.

    From the article:

    Effects on later development
    A review by Gentile examined the long-term neurocognitive development of infants whose mothers took SSRIs during pregnancy or breast-feeding. The studies noted that SSRI levels in breast milk varied depending on the medication the mother was taking, with highest levels for fluoxetine and citalopram > fluvoxamine and paroxetine > sertraline. The only findings of adverse neurodevelopmental outcomes seen with SSRI treatment were in rodent studies and not in any of the human studies reviewed. However, the author noted that fluoxetine and paroxetine were associated with increased fetal plasma cortisol levels and detrimental effects on the organization of thalamocortical somatosensory barrels during development in animals. What these findings translate into during human development remains unknown. We do, however, have an extensive body of literature that shows children of mothers with untreated depression are at higher risk of developing both anxiety and depression…

    Should mothers choose to breast-feed while taking SSRIs, sertraline and fluoxetine may be best choices as a window of highest levels in breast milk occurs 8−9 hours after ingestion and would allow milk with the highest antidepressant concentrations to be discarded rather than fed to the infant. Knowing the risks and benefits of SSRI treatment before and after birth allows the mother, obstetrician, psychiatrist, and pediatrician to have a rational discussion about the treatment of the mother’s depression and ensures an optimal outcome for both her and her newborn. (see also next comment)

  7. Pinheiro E, Bogen DL, Hoxha D, Ciolino JD, Wisner KL. Sertraline and breastfeeding: review and meta-analysis. Arch Womens Ment Health. 2015 Apr;18(2):139-46.

    We examined the risk-benefit profile of sertraline treatment during breastfeeding, summarized the available literature on sertraline use, presented previously unpublished data, and performed a correlation-based meta-analysis of sertraline serum levels in mother-infant pairs. We conducted a search of PubMed and the National Library of Medicine LactMed database. We performed a meta-analysis to examine correlations between maternal and infant serum sertraline levels in the existing literature and in previously unpublished data. Of 167 available infant sertraline levels, 146 (87.4 %) were below the limit of detection, and the meta-analysis found no significant relationship between maternal and infant sertraline concentrations. Of 150 infant desmethylsertraline levels, 105 (70.0 %) were below the limit of detection. The correlation analysis revealed a significant relationship between maternal and infant desmethylsertraline concentrations, but this metabolite has only a fraction of the activity of sertraline. A significant relationship was also found for the sum of sertraline and desmethylsertraline, which stems primarily from the contribution of desmethylsertraline. Sertraline is a first-line drug for breastfeeding women due to documented low levels of exposure in breastfeeding infants and very few adverse events described in case reports. Based on the current literature, neither routine serum sampling nor genotyping is warranted for breastfeeding mothers taking sertraline and/or their infants. Routine pediatric care is appropriate monitoring for breastfed infants of women who take sertraline monotherapy.

  8. Orsolini L, Bellantuono C. Serotonin reuptake inhibitors and breastfeeding: a systematic review. Hum Psychopharmacol. 2015 Jan;30(1):4-20.

    The postnatal period represents a critical phase for mothers because of physiological hormonal changes, the increase of emotional reactions and a greater susceptibility for the onset/recrudescence of psychiatric disorders. Despite the evidence of an increasing utilization of antidepressant drugs during breastfeeding, there is still few reliable information on the neonatal safety of the selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs) [serotonin reuptake inhibitors (SRIs)] in nursing mothers. The aim of this study is to provide a systematic review on the neonatal safety profile of these drugs during breastfeeding, also assessing the limits of available tools.
    MEDLINE and PubMed databases were searched without any language restrictions by using the following set of keywords: ((SSRIs OR selective serotonin inhibitor reuptake OR SNRIs OR selective serotonin noradrenaline inhibitor reuptake) AND (breastfeeding OR lactation OR breast milk)). A separate search was also performed for each SSRIs (paroxetine, fluvoxamine, fluoxetine, sertraline, citalopram and escitalopram) and SNRIs (venlafaxine and duloxetine).
    Sertraline and paroxetine show a better neonatal safety profile during breastfeeding as compared with other SRIs. Less data are available for fluvoxamine, escitalopram and duloxetine. Few studies followed up infants breastfeed for assessing the neurodevelopmental outcomes.
    Literature review clearly indicates paroxetine and sertraline as the drugs that should be preferred as first line choice in nursing women who need an antidepressant treatment.

  9. In a study published in Molecular Psychiatry, Harvard Medical School investigators at Massachusetts General Hospital report that while a diagnosis of autism spectrum disorder was more common in the children of mothers prescribed antidepressants during pregnancy compared with those with no prenatal exposure, when the severity of the mother’s depression was accounted for, that increased risk was no longer statistically significant.

    An increased risk for attention-deficit hyperactivity disorder (ADHD), however, persisted even after controlling for factors related to a mother’s mental health. 

    “We know that untreated depression can pose serious health risks to both mother and child, so it’s important that women being treated with antidepressants who become pregnant, or who are thinking about becoming pregnant, know that these medications will not increase their child’s risk of autism,” said Roy Perlis, HMS associate professor of psychiatry at Mass General and senior author of the report...

    The children’s information was paired with their mothers’, noting any factors related to the diagnosis and treatment of major depression or other mental illness, including prescriptions for antidepressants and other psychotropic drugs. A similar analysis was done for almost 2,250 children with an ADHD diagnosis, compared with more than 5,600 matched controls with no ADHD diagnoses. 

    Prenatal exposure to antidepressants did increase the risk for either condition, but in the autism-focused comparison, adjusting for factors indicating more severe maternal depression reduced the strength of that association to an insignificant level. Taking antidepressants with stronger action in the serotonin pathway, which has been suspected of contributing to a possible autism risk, did not increase the incidence of the disorder. In addition, the children of mothers who took a serotonin-targeting nonantidepressant drug for severe morning sickness had no increased autism incidence.

    Prescriptions for antipsychotic drugs sometimes used to treat severe, treatment-resistant depression, as well as psychotic disorders, did appear to increase the risk for autism. For ADHD, however, the increased risk associated with prenatal antidepressant exposure remained significant, although reduced, even after adjustment for the severity of maternal depression.
    Courtesy of Doximity 

  10. Clements CC, Castro VM, Blumenthal SR, Rosenfield HR, Murphy SN, Fava M, Erb JL, Churchill SE, Kaimal AJ, Doyle AE, Robinson EB, Smoller JW, Kohane IS, Perlis RH. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015 Jun;20(6):727-34.

    Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.