Birth Defects Insights: Maternal Depression, Autism and ADHD: Why is it so difficult to determine the causes and the effect of no treatment versus drug therapy during pregnancy?

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It’s a drug group being used more than any other group in pregnancy. They’re drugs often discussed in the popular media, particularly when depression, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are discussed. It’s a group being used by as many as 3-5% of pregnant women and, theoretically, might have various effects, possibly even harmful ones. I’m talking about selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs), relatively large groups of drugs that increase the levels of serotonin (and norepinephrine) in the serotonergic (and noradrenergic) synapses. These drugs are used for the treatment of depression, anxiety and a variety of other mood disorders, but the confusion about their effects on a developing fetus during pregnancy is palpable. Additionally, while there is agreement that SSRIs and SNRIs do not increase the rate of congenital malformations in general, there might be some increase in the rate of certain types of birth defects and various transient negative effects on postnatal adaptation.

The Rise of ASD and ADHD

Due to the alarming increase in the last two decades in rate of ASD as well as other neurodevelopmental problems including ADHD, there is increasing interest in the possible role of prenatal factors in the etiology of these disorders, especially ASD. As a result, many studies evaluating the possible relation between prenatal medications and ASD are being published.

The most solid evidence that an association between prenatal events and ASD may exist is demonstrated with prenatal exposure to the antiepileptic drug valproic acid. Several studies show a 5-10 times increase of ASD among children prenatally exposed to valproic acid. Valproic acid has induced ASD-like symptoms in experimental animal models. In addition, similar associations were reported with several other drugs taken in pregnancy for treatment of depression, including SSRIs. Several case control studies, as well as population registry studies indeed showed about a 50% increase in the rate of ASD following prenatal exposure to SSRIs. Now before you say, “We have an answer!” it’s important to note that several large population-based studies fail to show any association of prenatal SSRI exposure and ASD.

The Confusion Continues

Even meta-analyses and literature reviews show opposing data, and the denial or acceptance of an association depends on the exclusion and inclusion criteria in these meta-analyses. Similarly, some studies reported on a possible association of SSRIs with an increased rate of ADHD. However, other studies showed an association of ASD and ADHD with maternal depression, not related to the SSRIs. In a recent meta-analysis, an association was found between preconception use of SSRIs and ASD but not with its use during pregnancy, clearly demonstrating that the association seems to be between maternal depression and ASD Moreover, depression seems to be a genetic and environmental disorder. ASD similarly has a genetic and environmental origin. Both disorders might share common genes, which could explain the association between depression and ASD.

As far as other possible correlations are concerned, our own cohort studies showed a slightly higher rate of cardiac anomalies in the offspring of women treated with fluoxetine and paroxetine, but no other pregnancy complications, except for difficulties in perinatal adaptation- i.e., adaptation of the newborn infant to extrauterine life.  Moreover, some newborn infants also have withdrawal symptoms that do not seem to have long-term consequences.

Turning Insufficient into Sufficient Once and for All: Where the Science Needs to Improve

In spite of the disagreement in the medical literature, it can be summarized that there is insufficient evidence for a definite association of prenatal SSRIs and ASD or ADHD, as most studies fail to control for maternal disease, for postnatal effects of a non-optimal home environment and especially for genetic factors that might be common to various psychiatric disorders. It seems clear, when reading most robust literature that most of the large population-based studies on the possible effects of SSRIs in pregnancy are based on prescriptions of these drugs during pregnancy, and some studies are based on only one prescription. However, having a prescribed drug does not mean that the drug is taken. Hence, this is a source of potential bias. There are studies showing that many of the women that are prescribed drugs do not take them, especially when they plan pregnancy. Moreover, in many studies there are no appropriate control groups of untreated women with depression.

The literature on neurodevelopmental outcomes generally does not show significant neurodevelopmental damage induced by SSRIs, but the data are mainly on young children, and there seems to be no data on possible effects at adolescence.  This is especially important since it was shown that maternal depression may be associated with behavioral changes at adolescence.

More on the Role of Maternal Depression during Pregnancy

Maternal depression (and anxiety, as they often go together) especially if untreated, may have a profound impact on child development at early life, at school age and at adolescence, thus influencing life-long behavior. In a recent Canadian study, half of a large population of mothers with depression and anxiety disorders were being treated with antidepressants. Their children were examined in kindergarten at the age of 5-6 years. The investigators found an inverse relationship between maternal depression and a child's achievement on an early childhood assessment test. Children born to mothers with depression/anxiety had more problems in communication skills, emotional maturity, language and social competence.

Maternal depression during pregnancy and recurrence of depressive episodes had a higher negative influence on development compared to postnatal (postpartum) depression. These negative influences are more severe in children of parents of lower socio-economic class. These effects were noticed in infants as well as in school aged children.  Adolescents raised during childhood by depressed mothers were more likely to use illicit substances, to engage in risky and/or violent acts and have delinquent behavior also disobeying laws. All these problems were in direct relation with the severity of maternal symptoms.  As a result, it seems that appropriate treatment for depression/anxiety during pregnancy (as well as postpartum) is important, especially if the symptoms are severe. Pharmacological treatment could be offered if the other means of treatment are inadequate. In favor of pharmacological treatment is also the fact that possible negative effects on the fetus of antidepressants in pregnancy are low, if any.

Getting Concrete Answers about Antidepressant Safety in Pregnancy

Often in studies of medications, it is difficult to disentangle the effects of the medication from the effects of the disease that the medication is being used to treat. This challenge is otherwise known as “confounding by indication.” One of the most important issues in epidemiological studies evaluating the safety of antidepressant use during pregnancy is ensuring that confounding factors are controlled for. Moreover, when comparing the outcome of treated and untreated patients with similar psychiatric disorders, one must remember that the women who are treated with SSRIs (or with other antidepressants) generally have a more severe disease compared to those that are not treated. In addition, there are genetic differences in the way people metabolize SSRIs, which should be considered. This is mainly due to differences in the liver cytochrome P 450 enzymes (CYP enzymes) which are the major metabolic pathways for SSRIs and SNRIs. Similarly, there are differences in the metabolism of the various drugs in these groups. Hence, the difficulties in getting precise answers are obvious. It seems that only prospective follow up cohort studies that will accurately assess the severity of maternal depression, long-term children’s neurodevelopmental outcome including their mental status as well as proper genetic studies might give more definitive answers.

Studies have shown that many genes are associated with depression, ASD and ADHD. However, the way they interact with each other and with the environment is still largely speculative. Only after we understand these interactions might we find the way for their prevention.  How far we still have to go is merely speculative.

About the Author

Raised by parents who had survived World War II concentration camps, Asher Ornoy, MD, Professor of Embryology, Teratology and Medical Neurobiology at the Hebrew University Hadassah Medical School, had examples of hard work and perseverance throughout his childhood, inspiring him to work hard at helping others the best way he believed he could – first as a doctor, and in addition as a researcher with a particular interest in prenatal and postnatal development of children. He received his medical degree from Hebrew University Hadassah Medical School in Jerusalem, Israel and Pediatric training at Hadassah University Hospital. He had additional training in clinical teratology and in child development in the Children's hospital, Cincinnati University Medical School, and training in pediatric neurology at the Jefferson Medical College in Philadelphia, PA. He has been a Teratology Society member since 1978. He published about 320 papers in peer reviewed journals in the fields of teratology and child development. Most recently, he was a co-author, along with Kembra Howdeshell, PhD, of a review of the science on the safety of antidepressant use during pregnancy and lactation in the Teratology Society’s Journal, Birth Defects Research: Depression and its Treatments during Pregnancy. It can be read here: http://onlinelibrary.wiley.com/doi/10.1002/bdr2.v109.12/issuetoc

About the Teratology Society

Scientists interested or are already involved in research related to topics mentioned in this blog are encouraged to join the Teratology Society and the 58th Annual Meeting June 23 – 27, 2018, the premier source for cutting-edge research and authoritative information related to birth defects and developmentally-mediated disorders. Teratology Society members include those specializing in cell and molecular biology, developmental biology and toxicology, reproduction and endocrinology, epidemiology, nutritional biochemistry, and genetics, as well as the clinical disciplines of prenatal medicine, pediatrics, obstetrics, neonatology, medical genetics, and teratogen risk counseling. In addition, the Teratology Society publishes the scientific journal, Birth Defects Research.  Learn more at www.Teratology.org. Find the Teratology Society on LinkedIn, Facebook, and Twitter

Suggested Reading:

Ornoy A. Neurobehavioral risks of SSRIs in pregnancy: comparing human and animal data. Reproductive Toxicology 72:191-200, 2017.

Ornoy A, Koren G. Selective Serotonin Reuptake Inhibitors during pregnancy: do we have now more definite answers related to prenatal exposure. Birth Defects Research Part C. 109(12):898-908, 2017.

Comaskey B et al.  Maternal depression and anxiety disorders (MDAD) and child development: a Manitoba population-based study. Plos One 12(5): e0177065, 2017. Available at: https://doi.org/10.1371/journal.pone.0177065

Wickham ME et al. Maternal depressive symptoms during childhood and risky adolescent health behaviors. Pediatrics. 135(1):59-67, 2015.

Howdeshell, K, Ornoy, A. Depression and its treatment during pregnancy: Overview and Highlights" Birth Defects Research Part C. 109(12):877-878, 2017

 

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