Safety of the selective serotonin reuptake inhibitors (SSRIs) during pregnancy is a question of major clinical importance as up to 6% of pregnant women are reported to use SSRIs [1
]. Every sixth pregnant woman suffers from major depressive disorder, and while untreated prenatal depression can have devastating consequences for the mother and her family, it has also been linked to poor perinatal outcome [2
]. SSRIs are not major teratogens but neonatal adaptation problems are common after prenatal exposure [4
] and an increased risk has been observed for other perinatal complications including persistent pulmonary hypertension [8
]. Consequently, both patients and clinicians frequently need to balance between the risks of untreated depression and the potential risks associated with continuing antidepressant treatment during pregnancy.
Serotonin has a crucial role in neural development and maturation [11
] and studies in rodents have demonstrated that manipulation of serotonin (5-HT) levels by exposing the animals to SSRIs at a vulnerable stage of central nervous system development can lead to permanent behavioral changes, paradoxically presented as increased depression and anxiety-related behavioral phenotypes [12
In humans, long-term effects of prenatal SSRI exposure on childhood neurodevelopment have not been extensively studied. While small, non-population based cohort studies observed no excess risk by age four or seven [16
], one population-based study suggested an increased risk of autism spectrum disorders in prenatally exposed offspring [19
]. A major challenge remains to disentangle the effects of maternal depression and maternal use of SSRIs on later neurodevelopment in offspring. This study represents the epidemiological part of an international, collaborative research project which is part of a Conte Center project for the Neuroscience of Mental Disorders at Columbia University (http://columbiapsychiatry.org
). This innovative collaboration consists of several linked research projects addressing the fundamental questions of altered serotonin signalling and prenatal SSRI exposure on brain structure, function, and long-term behavioural outcomes. Other projects in this collaboration include basic and experimental research with animal models, and clinical neurobiological studies on infant/childhood outcomes following prenatal SSRI exposure.
These studies will help to interpret and validate our findings derived from epidemiologic research, while our findings may help generate novel hypotheses to be tested in animal models. This concept of translating basic research findings to epidemiology and vice versa
constitutes a model of bidirectional translational epidemiology [20
]. Because of the steadily increasing use of SSRIs during pregnancy, this is one of the most challenging questions in prenatal psychiatric epidemiology at present and carries significant public health importance.
The objective of the nationwide Finnish Register-Based Study on Infant and Childhood Neurodevelopmental Outcomes Following Prenatal Exposure to Selective Serotonin Reuptake Inhibitors (FinESSI) is to investigate if prenatal SSRI exposure increases the risk of adverse psychiatric or neurodevelopmental outcome until age 14, controlling for maternal depression. The aim of this methods paper is to describe the study design, the national registers included in the study, and linkage of the registers. We also report the trends in SSRI use during pregnancy during the study period, the prevalence of diagnosed depression and depression-related psychiatric disorders in the pregnant population, and the cumulative incidence of psychiatric and neurodevelopmental disorders in the whole offspring population.