Antidepressant use during pregnancy is associated with modest increases in the risk for various psychiatric disorders in offspring, including autism spectrum disorder, mood disorders, somatoform disorders, and behavioral and emotional disorders, according to a large observational study from Denmark.
However, the investigators urge caution in interpreting the findings.
“These results were present when we compared children born to mothers who continued to take selective serotonin reuptake inhibitor (SSRIs) during pregnancy to children born to mothers who discontinued the treatment. The observed associations may be attributable to the severity of underlying maternal psychiatric disorders in combination with in utero antidepressant exposure,” Xiaoqin Liu, MD, and Trine Munk-Olsen, PhD, of Aarhus University, told Medscape Medical News.
The study was published online September 6 in the BMJ.
Personalized Decision Making
The researchers analyzed data from 905,383 children born from 1998 to 2012 in Denmark. Participants were followed for up to 16.5 years. The children were categorized into four groups according to mothers’ antidepressant use within 2 years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).
Overall, psychiatric disorders were diagnosed in 32,400 children. The average age at first psychiatric diagnosis was 8.5 years.
The adjusted 15-year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval [CI], 7.9% – 8.1%) in the unexposed group, 11.5% (95% CI, 10.3% – 12.9%) in the antidepressant discontinuation group, 13.6% (95% CI, 11.3% – 16.3%) in the continuation group, and 14.5% (95% CI, 10.5% – 19.8%) in the new user group.
“We observed increased risks of psychiatric disorders in all three groups of antidepressant users (discontinuation, continuation and new user groups), compared with the unexposed group,” the authors report.
Overall, the risk for psychiatric disorders among offspring was higher in the continuation group than the discontinuation group (hazard ratio [HR], 1.27; 95% CI, 1.17 – 1.38). This was evident after adjustment for demographic and psychiatric characteristics of the mothers, including inpatient and outpatient psychiatric treatment and comorbid psychotropic drug use.
“The population attributable fraction was 0.5%, indicating that continuous antidepressant use during pregnancy explained 0.5% of psychiatric cases in the study population, assuming an unconfounded causal association,” the investigators note.
The highest risk was among children whose mothers used both SSRI and non-SSRI antidepressants (HR, 1.72; 95% CI, 1.40 – 2.11). A higher risk was seen in children whose mothers took antidepressants for more than 180 days (HR, 1.40; 95% CI, 1.26 – 1.56).
In comparision with the discontinuation group, the continuation group was at increased risk for autism spectrum disorder (HR, 1.23; 95% CI, 1.01 – 1.51), mood disorders (HR, 2.76; 95% CI, 1.59 – 4.78), somatoform disorders (HR, 1.62; 95% CI, 1.36 – 1.94), and behavioral disorders (HR, 1.13; 95% CI, 1.01 – 1.27), but not mental retardation (HR, 1.21; 95% CI, 0.78 – 1.90).
Weigh Risks and Benefits
“To date, population-based studies of long-term neurodevelopmental outcomes have focused primarily on autism spectrum disorder in children exposed to SSRIs in utero. Our findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive,” Dr Liu and Dr Munk-Olsen told Medscape Medical News.
They note that when providing clinical guidance, it is important to consider “both the presented risks of the present study, but also acknowledge that discontinuation of antidepressant treatment can lead to worsening of depressive symptoms with subsequent negative short- and long-lasting adverse effects on both the mother and child.”
According to current clinical guidelines, patients with no or mild depressive symptoms during a 6-month period may be candidates for discontinuation before conception, whereas patients with a history of severe, recurrent depression may not be suitable candidates for drug discontinuation before or during pregnancy.
“Personalized decision-making tools and treatment algorithms to identify subgroups of women who can be tapered off antidepressants safely are urgently needed,” Dr Liu and Dr Munk-Olsen note. “Importantly, any final decision on antidepressant continuation should be individualized and weighed against a nuanced presentation of current knowledge both about possible effects of SSRI use in pregnancy and consequences of untreated depression. Notably, such decisions should be made jointly by health professionals and patients.”
In an accompanying editorial, Hedvig Nordeng, PharmD, and two colleagues from the PharmacoEpidemiology and Drug Safety Research Group at the University of Oslo in Norway, say that reporting absolute risks, as the researchers do in this study, is important to facilitate communication between clinicians and pregnant women.
“For example, if prenatal exposure to antidepressants is associated with a 23% increased risk of autism in children, and assuming a baseline prevalence of autism of 1%, then for every 10,000 women who continue treatment during pregnancy 23 additional cases of autism would occur. This number may be alarming to some patients and reassuring to others,” the editorialists write.
They add that it is equally important to note that pregnant women are not prescribed antidepressants at random. In this study, among the the patients who continued to receive antidepressants, 7.7% underwent inpatient psychiatric treatment up to 2 years before becoming pregnant, and 28.5% received outpatient psychiatric treatment, compared with 4.3% and 2.5% among the women who discontinued antidepressant use during pregnancy.
“Only the most severely sick women have drugs prescribed in pregnancy. Consequently, confounding by indication is a major challenge in pharmacoepidemiological studies,” Dr Nordeng and colleagues write.
“Including a disease comparison group with women discontinuing antidepressants before pregnancy, as in Liu and colleagues’ study, offers an important advantage over studies using only healthy comparison groups, as it allows researchers to disentangle the effect of antidepressants from the underlying maternal psychiatric disease,” they add.
“Observational studies, for all their flaws, are a necessary piece of the puzzle, and healthcare databases such as the one used for this study provide a rich resource, particularly if they are augmented by additional data sources to reduce confounding,” Dr Nordeng and colleagues write.
However, these studies still need to be supplemented with data from a range of other types of research, including laboratory, animal, and genetic studies, to obtain a more complete picture of the mechanisms by which drugs may act on the developing fetus, they conclude.
The study was supported by iPSYCH, the Lundbeck Foundation Initiative for Integrative Psychiatric Research. The authors have disclosed no relevant financial relationships.
BMJ. Published online September 6, 2017. Full text, Editorial
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