Antidepressants in Pregnancy: No Impact on Kids' IQ

Batya Swift Yasgur, MA, LSW

July 17, 2017

There is no significant association between intellectual disability in children and maternal use of antidepressants during pregnancy, new research shows.

A team of researchers from the Icahn School of Medicine at Mount Sinai, in New York City, found that intellectual disability (ID) was diagnosed in 37 children (0.9%) who had been exposed to antidepressants vs 819 (0.5%) who had not been exposed.

Although there was a higher estimate of relative risk (RR) for intellectual disability, once confounding factors such as parental age and psychiatric history were accounted for, the risk was no longer deemed statistically significant.

"The take-home message to clinicians from our study is that although there is an association between antidepressant use in pregnancy — especially SSRIs [selective serotonin reuptake inhibitors] —and intellectual disability in offspring, it is probably not due to the medication," study author Abraham Reichenberg, PhD, professor of psychiatry, Icahn School of Medicine, told Medscape Medical News

"Based on results of this study, the association is due to other characteristics in parents that we know are related to intellectual disability, including history of psychiatric disorders, older age of mothers or fathers, and psychiatric disorders in the mother before pregnancy," he said.

The study was published online July 12 in JAMA Psychiatry.

Increasing Use in Pregnant Women

Intellectual disability, defined as IQ <70 along with adaptive deficits that impair everyday functioning, is frequently attributable to genetic and environmental factors, including chromosomal and heredity factors, factors that affect fetal development, or toxic agents, the authors note.

Conventional medications used in pregnancy, including certain antiepileptic and mood stabilizing medications, "have been associated with poor cognitive development and lower IQ in exposed offspring," the authors write.

Antidepressants in general and SSRIs in particular are increasingly being used by pregnant women. These agents, which pass the placenta, have been implicated in abnormalities of offspring in animal models and in some human observational studies.

Moreover, "ID commonly co-occurs with autism spectrum disorder, which has been associated with maternal antidepressant medication during pregnancy in many but not all studies," the authors write.

To further investigate the impact of antidepressant use during pregnancy with diagnosed ID in the offspring, the researchers conducted a population-based cohort study of 179,007 children conceived from July 1, 2005, and born between January 1, 2006, and December 31, 2007. Data were drawn from Swedish national registries.

Medication periods were calculated from at the dispensation date through the last dispensed dose, with the assumption that one pill was consumed per day.

The offspring were classified as being unexposed to antidepressants if they had been born to mothers for whom there was no antidepressant medication periods that overlapped the pregnancy. Antidepressant medication period was defined as the period from estimate conception date until the birth date. Offspring were considered to have been exposed if the mother had had at least two dispensations of antidepressants with medication periods that overlapped the pregnancy.

Because a previous study had shown an increase in prevalence of childhood psychiatric disorders over time by year of birth, and increase over time was also observed in the current cohort, the researchers adjusted for potential temporal trends by including the birth date of the offspring as the number of days from January 1, 2005, to the birth date.

Maternal and paternal ages at childbirth were categorized as follows: >20 years; 20 through 29 years; 30 through 39 years; and 40 years or older. The age range 20 through 29 years was used as the reference.

Maternal and paternal educational levels were included in the analysis as a measure of socioeconomic status. To adjust for potential confounding by indication, the researchers included maternal and paternal psychiatric disorders diagnosed in the Swedish National Patient Register before childbirth within several psychiatric disorder subgroups.

They also included paternal psychotropic medication use that overlapped the pregnancy and maternal medication use with psychotropic drugs other than antidepressants that overlapped the pregnancy.

Role of Confounding Factors

The researchers performed separate analyses for offspring born to mothers with only a single antidepressant dispensation and any number of antidepressant dispensations with medication period that overlapped pregnancy, compared with offspring who had not been exposed during pregnancy.

Of the 179,007 children included in the study (mean age at end of follow-up, 7.9 years [SD 0.6]; 92,133 [51.5%] male, 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) who had been exposed to antidepressants and in 819 children (0.5%) children who had not been exposed.

Of the cohort, 3982 children (2.2%) were born to mothers with two or more dispensations of antidepressant medication that overlapped the pregnancy; 172,646 children (96.4%) were born to mothers who had no antidepressant medication dispensations that overlapped the pregnancy. The unadjusted RR of ID in exposed children was estimated at 1.97 (95% confidence interval [CI], 1.42 - 2.74).

After the researchers adjusted for potential confounders, the RR was estimated at 1.33 (95% CI, 0.90 - 1.98). Analyses restricted to clinically relevant subsample (n = 8021) were comparable.

SSRIs were the most commonly used antidepressants (3178 women [79.8%] used SSRIs; 804 women [20.2%] used non-SSRI antidepressants). Other psychotropic medications were dispensed during pregnancy to an additional 1626 (0.9%) women who were not treated with antidepressants.

The researchers conducted analyses adjusted for all included confounders and found an estimated RR of ID in the offspring of 1.48 (95% CI, 0.98 - 2.23) for SSRI antidepressants, 0.81 (95% CI, 0.33 - 2.00) for non-SSRI antidepressants, and 1.31 (95% CI, 0.75 - 2.27) for nonantidepressant psychotropic medications.

Analyses of children of mothers who used a single antidepressant medication or any number of antidepressant medications during pregnancy revealed lower RRs than the main analysis but "similar patterns of gradual attenuation," the researchers report.

"We observed a higher RR of ID among offspring born to mothers treated with antidepressants during pregnancy (0.9% of children affected), compared with offspring of mothers not treated with antidepressants during pregnancy (0.5% of children affected) before adjustment for confounding factors.

"However, with incremental adjustment for maternal and paternal confounding factors, this association was gradually attenuated to a statistically nonsignificant RR estimated at 1.33 (95% CI, 0.90 - 1.98)," the researchers write.

They note several study limitations. The use of registry data captured only the number of medications prescribed and collected; it did not capture adherence to these medications.

Additionally, the Swedish National Patient Register does not provide information from primary care, so diagnoses of ID obtained in that context were not included. The study also could not adjust for other confounding factors, such as uncontrolled diabetes and infectious or toxic agents.

"The evidence we have so far regarding autism and intellectual disability in mothers who used antidepressants during pregnancy is that the medications per se are not what increase the risk but rather it is what the mother may carry genetically or other confounding factors that may increase the risk. And even the increased risk is very small," said Dr Reichenberg.

Proxy Risk Factor

Commenting on the study for Medscape Medical News, Tim F. Oberlander, MD, investigator, BC Children's Hospital, Vancouver, Canada, called the study "a methodologically appropriate approach to distinguishing mood from antidepressant effects."

"This study attempted to control for maternal mental health related risk," because "in this setting, we can't study drug effects with randomized controlled trials. Instead, we turn to comparing outcomes between children of mothers who used antidepressants during pregnancy with children where mothers who had a diagnosis of a mood disorder before childbirth and did not use antidepressants during pregnancy," he said.

He noted, "Ultimately, it may be that for some children, developmental risk is conferred through shared environmental or genetic pathways that led to prenatal antidepressant exposure."

This perspective suggests that " SSRI exposure may be a 'hitchhiker' on top maternal genetic and/or environmental risk factors – a sort of proxy risk factor, not the main contributor to the developmental outcome, which is reflected in the findings in this paper," said Dr Oberlander, who is also of the Department of Pediatrics, University of British Columbia.

"It is important not to assume causality from this or the previous studies examining the prenatal SSRI exposure and developmental risk," he cautioned.

"At its core, prenatal SSRI exposure is an issue of mothers' mental health during pregnancy, and in this sense, poor maternal mental health during pregnancy should be seen as a major public health issue," he said.

"Untreated depression during pregnancy carries its own risks, such as preterm birth and neurobehavioral problems during infancy and childhood. The potential risks to the child have to be balanced with the risks associated with poorly or untreated depression. Nontreatment is never an option," he emphasized.

He added, "Disentangling the effects of maternal mood disorders on the shared genetic risk for intellectual and developmental disorders is ultimately our critical next step."

Dr Reichenberg agreed. "Women should not automatically get off medications, and physicians should not use results from one study, as big as it may be, to change how they practice or the guidelines that we use."

However, "The increase in risk is very small, so it should be very carefully thought about and discussed with physicians."

Additionally, "Physicians should follow up on new literature and larger studies that are coming that will make the results more convincing."

The study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the Beatrice and Samuel A. Seaver Foundation. The Canada Research Chairs Program, the Canadian Institutes of Health Research Foundation program, the Fredrik and Ingrid Thuring Foundation, and the Swedish Society of Medicine supported individual investigators. Dr Reichenberg and Dr Oberlander have disclosed no relevant financial relationships. Other authors' disclosures are listed in the published article.

JAMA Psychiatry. Published online July 12, 2017. Full text

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