This week’s ‘Got Questions?’ answer comes from Rob Ring, PhD, Autism Speaks vice president of Translational Research, and Joe Horrigan, MD, Autism Speaks assistant vice president, head of medical research.
To bring readers up to speed, the above question stems from two reports: In July, a group of California researchers reported a modest increase in the risk that a child would develop autism if his or her mother took selective serotonin uptake inhibitors (SSRIs) during pregnancy. The results were based on a very small sample of children exposed to antidepressants during the time their mothers were pregnant—just 20 children with autism compared to 50 without autism. This past month, another team of scientists reported that rats fed SSRIs as newborn pups exhibited abnormalities in brain development.
Given the great hunger for information about what causes autism, both studies made headlines. Unfortunately, the media stories may have served to alarm without putting these early and inconclusive scientific findings into perspective.
First and foremost, research with animals and investigations looking at a small number of cases are both important for guiding larger, more informative studies. But in and of themselves, these two particular studies don’t come close to reaching the bar at which scientific evidence is reliable enough to warrant a change in behavior. We feel this is particularly true of important medical decisions such as the need to treat depression, which can be a serious and life-threatening illness.
Take, for instance, the small number of children in the California study. This small “sample size” increases the likelihood that the results were due to chance or other unrelated factors. In other words, they may not represent real differences in risk. It is very common in science for such preliminary findings to vanish when researchers repeat the analysis with a larger, more “statistically significant” number of cases.
In addition, among women taking SSRIs, there may be other, hidden factors responsible for raising autism risk among their future children. For example, we know that anxiety is common among persons with an autism spectrum disorder (ASD). In fact, many of those who learn, as adults, that they have an ASD do so when they seek treatment for anxiety and/or related depression. A common type of medicine prescribed in these instances is SSRIs. We also know that ASDs tend to run in families. So it may be that family genetics—not SSRIs—produced the above-mentioned finding of a modest increase in the prevalence of autism among children whose mothers took these antidepressants during pregnancy.
And the rat study? While it’s useful for guiding the focus of further research, we simply can’t extrapolate results from rats to humans.
Finally, we worry about the consequences of women going off antidepressants when they truly need these medications. Certainly if a woman is pregnant or trying to become pregnant, she should discuss all her medicines with her physician—so that with guidance she can weigh the risks and benefits of continuing or discontinuing one or more of them. Certainly, a woman’s untreated depression can itself pose a danger to her pregnancy or newborn child. The bottom line: If you have concerns regarding your medications during pregnancy, discuss them with your physician, who can help you make the best decision for you and your family.
We hope that we’ve lent some helpful perspective to this issue. Please keep your questions coming (GotQuestions@autismspeaks.org).
Last month, a group of California researchers reported an increased risk of autism among babies whose mothers took a certain catergory of antidepressant medications–selective serotonin reuptake inhibitors (SSRIs)—during the first trimester of pregnancy. You may know these drugs by such brand names as Prozac, Effexor, Paxil, and Celexa.
So what do these results mean for pregnant women? First, caution is needed before rushing to judgment. The study was relatively small, and the increase in the risk of autism was modest. So more study is clearly needed to confirm the link and clarify how great a risk, if any, is associated with a mother using this type of antidepressant during pregnancy.
Further caution is needed because the effects of a mother’s anxiety and depression during pregnancy and early infancy are well known. In fact, it’s not clear whether the autism risk associated with taking antidepressants during pregnancy is, in fact, related to the women’s depression rather than the drugs themselves.
For these reason, many doctors have argued that the benefits of SSRIs outweigh concerns about risks that SSRI exposure may pose to a fetus or infant during pregnancy and nursing. Clearly, more research is needed.
Beyond SSRIs, researchers have looked at several other medications to see if their use during pregnancy increases the risk that a baby will go on to develop autism. Among the most thoroughly researched is the anti-seizure medication valproic acid (U.S. brand name Depakote). Studies show that, as a group, children whose mothers take valproic acid during their first trimester of pregnancy are more likely to develop an autism spectrum disorder (ASD) than are children who are not exposed.
Autism Speaks has supported research into how valproic acid might contribute to the development of ASDs. Through the study of donated brain tissue, for example, we have learned that individuals with autism share some “neuropathologies,” or altered brain features, with those who were exposed to valproic acid before birth. In addition, several studies show that exposure to valproic acid during critical periods of brain development can produce autism-like behaviors in animal models.
So the good news is that our research has deepened understanding about how valproic acid during pregnancy can contribute to the development of ASDs. The bad news is that it can be quite dangerous for women with epilepsy to stop taking this medication during pregnancy—owing to their increased risk of seizures. As a result, such decisions should be made carefully with a physician can discuss alternative drugs.
Findings are still emerging with other medications given during pregnancy. For instance, relatively small studies (such as this one) suggest an increased risk for ASD in babies whose mothers were given the medication terbutaline to stop premature labor. Another small study suggested increased risk of autism related to women taking high doses of the anti-ulcer drug misoprostol early in pregnancy. (This drug is also used to induce labor later in pregnancy.) But in many cases, such preliminary research has yet to move past the “interesting” stage to reach enough certainty to change medical practices.
Other, larger studies hint at an increased risk of autism in the babies of women who take certain broad classes of medications such as antipsychotics or mood stabilizers during pregnancy. Still the question remains: Is the autism risk due to the medications or to the underlying medical conditions that the drugs are being used to treat?
Beyond medications, studies have revealed a number of other pregnancy complications and events that appear to contribute to the risk that a baby will go on to develop autism. These include the pregnant mother’s exposure to toxic chemicals, infections such as flu, and her diet and nutrition at the time of conception as well as during pregnancy.
Autism Speaks continues to fund a number of important studies looking at autism risk factors during pregnancy. If you have at least one child already diagnosed with an ASD, find out more about participating in the EARLI study (link at left) before or at the start of your next pregnancy. Or consider enrolling your child and family in the CHARGE study, which looks at risk factors before, during, and after your child’s birth.
We will be continuing to update you on the science as it emerges. If you have any concerns about the medications you are taking during pregnancy, please discuss them with your doctor. For more resources, we also recommend the Organization of Teratology Information Specialists.
by Alycia Halladay, Ph.D, Director of Environmental Science
Research using identical and fraternal twins is typically used to identify genetic influences on the development of ASD. This year, researchers studied a large group of twins and examined the concordance of different types of symptoms (1). Using this approach, the researchers found that the concordance of severe autism between identical twins and fraternal twins was about the same, indicating a strong environmental component to ASD severity. But what are those environmental factors? Epidemiological studies are providing clues.
At this year’s IMFAR, new data was presented that focused on studying groups of people and their exposures to a number of environmental factors. Each used different designs with their own unique advantages. For example, at UC Davis, the CHARGE study (www.beincharge.ucdavis.edu) examined the risk of developing autism following exposure to a number of factors that were identified through self report or medical records. Those that showed an association were antidepressant SSRI use (2) and metabolic disorders including hypertension and diabetes (3). On the other hand, a previously identified factor, maternal infection, was not associated (4). Why not? The researchers suggested that fever, not infection per se, may be a factor. Using self-report and medical records obtained prior to study entry may not accurately capture all relevant information, and an infection or fever may be missed in some reports. However, other types of information, such as method of birth, is easier to gather accurately. An analysis revealed that non-emergency or elective c-section deliveries did not show a significant association with autism, addressing a concern that many public and community stakeholders have expressed (5).
As an alternative to retrospective reports, the Early Markers of Autism Study in California is obtaining samples of blood from pregnant women by obtaining extra blood taken during the alpha-fetal protein screen that is banked. Not all states bank these samples for research, so this is a unique resource. By examining the levels of mercury in blood taken during pregnancy together with newborn blood spots, the researchers can get a more comprehensive picture of the prenatal environment. They reported no difference in mercury levels compared to those of non-affected children during gestation, and also reported no difference in thyroid hormone levels (6,7). Examination of subgroups of autism with regression did not change the results. While these data are incredibly novel and valuable, these studies were not designed to capture information throughout the entire pregnancy nor capture factors after birth
Another way to study exposures during pregnancy is through birth certificate data. In some states, the birth certificate contains information such as the place of birth and the occupation of the mother and the father. Using this information, scientists found that occupational exposures in mothers to certain chemicals resulted in an increased risk of ASD in offspring (8).
While each approach brings unique strengths, all researchers agree that the most comprehensive way to capture all information accurately, is a prospective design. This means identifying children as soon as possible and following them from that point on to gather every piece of relevant information from medical reports to blood samples. Autism Speaks is proud to co-sponsor such a study: the Early Autism Risk Longitudinal Investigation (EARLI). This groundbreaking project will provide even more answers to what causes autism, and needs the help of the community to do so.
So how can researchers blend or expand their research if they are using only one type of design? Autism Speaks and the National Institutes for Environmental Health Sciences are sponsoring a network of projects called the Environmental Epidemiology of Autism Research Network (EEARN). The goal of this network is to improve communication among researchers in this field, identify opportunities for collaborative projects and improve research tools for both existing, and new projects. Over 20 studies from 8 countries are represented in the network. We will keep you updated on the activity of the network, and we hope you will keep checking in for updates.
1. Understanding Clinical Variability In Autism: Results From a California Twin Study. W. Froehlich*1, S.
Cleveland1, A. Torres1, J. M. Phillips1, B. Cohen2, A. Fedele3, T. Torigoe2, J. Collins4, K. S. Smith5, L. Lotspeich1, L. A. Croen4, S. Ozonoff6, C. Lajonchere7, J. K. Grether5, N. Risch8 and J. Hallmayer1, (1)Stanford University, Stanford, CA, (2)Autism Genetic ResourceExchange, Los Angeles, CA, (3)Autism Speaks, Westmont, NJ,
United States, (4)Kaiser Permanente, Division of Research, Oakland, CA, (5)California Department of Public Health, Richmond , CA, (6)UC Davis MIND Institute, Sacramento, CA, (7)Autism Speaks, Los Angeles, CA, United States, (8)University of California San Francisco, San Francisco, CA
2. SSRI Use During Pregnancy and Risk of ASD or Developmental Delay In Children. R. A. Harrington*1,L. C. Lee1, C. K. Walker2, R. L. Hansen3, S. Ozonoff3 and I. Hertz-Picciotto4, (1)Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, (2)Department of Public Health Sciences, University of California at Davis, Davis, CA, (3)MIND Institute, University of California at Davis, Sacramento, CA, (4)Department of Public Health Sciences, University of California Davis, Davis, CA
3. The Role of Maternal Diabetes and Related Conditions In Autism and Other Developmental Delays. P. Krakowiak*1,2, A. A. Bremer3, A. S. Baker1, C. K. Walker1,4, R. L. Hansen2,3 and I. Hertz-Picciotto1,2, (1)Public Health Sciences, University of California, Davis, Davis, CA, (2)M.I.N.D. Institute, Sacramento, CA, (3)Pediatrics, University of California, Davis, Sacramento, CA, (4)Obstetrics & Gynecology, University of California, Davis, Sacramento, CA
4. Prenatal Influenza or Fever and Risk of Autism/Autism Spectrum Disorders. O. Zerbo*1, I. Hertz- Picciotto2,3, A. M. Iosif4, R. L. Hansen5,6,7 and C. K. Walker8, (1)Sacramento, CA, (2)University of California, Davis, Davis, CA, (3)Department of Public Health Sciences, University of California Davis, Davis, CA, (4)UC Davis, Davis, CA, (5)University of California, Davis, MIND Institute, Sacramento, CA, (6)MIND Institute, University of California at Davis, Sacramento, CA, (7)MIND Institute and Dept. of Pediatrics, University of California Davis, Davis, CA, (8)Department of Public Health Sciences, University of California at Davis, Davis, CA
5. Cesarean Birth and Autism Spectrum Disorder. C. K. Walker*1, P. Krakiowiak2, A. S. Baker3, R. L. Hansen4, S. Ozonoff5 and I. Hertz-Picciotto6, (1)Obstetrics & Gynecology, UC Davis, Sacramento, CA, (2)Public Health Sciences, UC Davis, Sacramento, CA, (3)Public Health Sciences, UC Davis, Davis, CA, (4)Pediatrics, M.I.N.D. Institute, UC Davis, Sacramento, CA, (5)Psychiatry and Behavioral Sciences, M.I.N.D. Institute, UC Davis, Sacramento, CA, (6)Public Health Sciences, M.I.N.D. Institute, UC Davis, Davis, CA
6. Prenatal and Neonatal Peripheral Blood Mercury Levels and Autism Spectrum Disorders. L. A. Croen*1, M. A. Lutsky1, C. Yoshida1, C. P. Alaimo2, M. Kharrazi3, J. K. Grether4 and P. Green2, (1)Kaiser Permanente Division of Research, Oakland, CA, (2)Civil and Environmental Engineering, Univ. of California Davis, Davis, CA, (3)Genetic Disease Screening Program, California Department of Public Health, Richmond, CA, (4)California Department of Public Health, Richmond, CA
7. Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorder. M. A. Lutsky*1, C. Yoshida1, B. Lasley2, M. Kharrazi3, J. K. Grether4, G. Windham4 and L. A. Croen1, (1)Kaiser Permanente Division of Research, Oakland, CA, (2)Department of Population Health and Reproduction, UC Davis, Davis, CA, (3)Genetic Disease Screening Program, California Department of Public Health, Richmond, CA, (4)California Department of Public Health, Richmond, CA
8. Autism Spectrum Disorders In Relation to Parental Occupational Exposures During Pregnancy. G. Windham*1, J. K. Grether2, A. Sumner3, S. Li4, E. Katz5 and L. A. Croen6, (1)California Department of Public Health, Richmond, CA, (2)California Department of Public Health, Richmond, CA, (3)Vermont Department of Health, Burlington, VT, (4)Kaiser Permanente Divison of Research, Oakland, CA, (5)Occupational Health Branch, CA Department of Public Health, Richmond, CA, (6)Kaiser Permanente Division of Research, Oakland, CA
“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community. We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.
Many families have emailed us and asked what exposures in pregnancy result in an increased risk for an Autism Spectrum Disorder diagnosis. The answer is not simple. No single environmental factor or single gene is responsible for causing ASD. Instead research suggests that a combination of multiple genetic and environmental factors lead to the multiple symptoms of autism.
By studying large populations, research on environmental exposures in autism has identified some exposures that increase the risk of autism in specific populations. Interestingly, these exposures have been linked to poor neurological outcome in general, and may lead to a wider range of neurodevelopmental conditions that includes autism. Three exposures have been shown to increase the risk for ASD in at least two published studies:
Pesticides: Two separate studies examining families living in California reported an increased risk of autism spectrum disorders following prenatal pesticide exposure. In the first study, Dr. Brenda Eskinazi at the University of California Berkley studied a group of Mexican-American children with known organophosphate exposures. She found that children who had increased levels of the break-down products of these pesticides were more likely to have impaired cognitive development at young ages as well an increased risk for pervasive developmental disorder (as reported by parents). In another study, Dr. Eric Roberts and his colleagues at the California Department of Public Health used informational databases to study possible connections between an ASD diagnosis and organochlorine pesticide exposure during different points of gestation. They found that those living closest to the area of pesticide application early in the 2nd trimester of pregnancy were at the highest risk for developing ASD.
Following up on these epidemiological studies, Autism Speaks is funding researchers who are utilizing animal models to determine possible genetic susceptibilities and neurobiological mechanisms. For example, animals that have been bred to display an altered expression of the REELIN protein show particular sensitivity to organophosphate pesticides. Prenatal exposure to organophosphates disturbs the migration of developing neurons especially in animals that have lower levels of REELIN. Altered effects on the developing neurons can lead to atypically-connected adult brain circuits—a finding commonly observed in ASD.
Valproic Acid: Valproic Acid, or Valproate, is an anti-epileptic drug which targets the GABA receptor in the brain and has been effectively used to treat seizures. When taken by the mother during the first few weeks of pregnancy, it can cause limb malformations, developmental delays, and musculoskeletal abnormalities, called “fetal valproate syndrome”. The first report of autism in an individual with fetal valproate syndrome was published in 1994, with follow up in an animal model soon after. Since then, four epidemiological studies have been published which show an increased rate of autism compared to the general population in individuals exposed prenatally with valproic acid. In an animal model, valproic acid results in some of the same neuropathological and behavioral abnormalities seen in autism: reduction in cerebellar Purkinje cells and an increase in social impairment.
Because this is a drug used to treat a life-threatening illness, women with epilepsy should consult their obstetrician before stopping this or any prescribed medication. Interestingly, the use of other anti-epileptic drugs during pregnancy has not revealed any elevated risk for ASD. The differences in the detailed mechanism of action between valproate and other anti-epileptic drugs may inform our understanding of the causes of autism. Autism Speaks is supporting two investigations into the biological mechanisms that lead to brain and behavioral changes after prenatal exposure to valproate
Challenges to the immune system: Multiple lines of converging evidence suggest that the immune system plays a significant role in ASD. This evidence includes studies that analyze the immune system profiles of mothers of children with autism, as well as the immune system of individuals with autism themselves. Family history of autoimmunity or immune dysfunction and a history of bacterial infection in mothers have been associated with an increased risk of ASD. More targeted studies on how immune system activation during pregnancy affects outcome in animal models are being funded by Autism Speaks to determine how the nature, origin, and timing of immune system activation can influence the developing brain.
Numerous other exposures have been studied and have shown an elevated risk but are still in the early stages of analysis. These include, but are not limited to: phthalates (substances added to plastics), in-vitro fertilization technologies, terbutaline (a treatment used to delay premature labor), and extreme maternal stress.
In addition to environmental exposures, factors such as parental age and season of birth are likely to play a role in how the body handles exposure during the reproductive years. For more information on what studies Autism Speaks is funding on environmental risk factors for autism, please click here.
While individual studies are needed to identify potential exposures of interest, participation and support in these studies is essential to allow researchers to study these questions. Three major Autism Speaks-supported studies currently addressing these questions are the CHARGE study, the EARLI study, and the Infant Brain Imaging Study. Another important study examining environmental risk factors related to health, including autism is the National Children’s Study. Each study employs a unique design to recruit families and identify individuals with ASD for better identification and evaluation of exposures of interest, and all of them have great potential to shed light on prenatal risk factors for ASD.