Short summary

The use of serotonin selective reuptake inhibitor (SSRI) antidepressants has been increasing the last decades in the US and worldwide. SSRIs cross the placenta and some studies suggest that the influence of these drugs may affect the development of the fetal brain. Maternal psychiatric well-being also influence the fetus/child. It is thus important to distangle the causality of the adverse associations that exposure to SSRIs in utero may have on long-term offspring health outcomes related to brain development.  

We conduct a cohort study based on the Danish National registers including all women giving birth during 1997-2015. Further we enrich with self-reported baseline characteristics not available (in details) in the registers on a sub-cohort from the Danish National Birth Cohort (n?92,000).

This study assesses the impact of gestational antidepressant exposure on offspring outcomes and disambiguates these effects from familial and environmental contributors. Opposed to previous research, this study extends the window of observation into early adulthood and uses a number of statistical approaches to account for clinical and environmental factors.

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Rationale

The use of serotonin selective reuptake inhibitor (SSRI) antidepressants has been increasing the last decades in the US and worldwide. Current estimates of SSRI use during pregnancy range between 4-8%. All SSRIs cross the placenta, entering fetal circulation at 70-80% of the maternal serum levels, and directly translating maternal use into substantial fetal exposure. Well before it assumes its canonical role as a neurotransmitter in adulthood, serotonin (5-HT) serves as a neural growth factor in gestation, exerting profound effects on developing brain structure and function. Effects of early serotonin fluctuations on brain development are evident in rodent models, but their relevance to higher primates and humans remain unclear. The choices facing physicians and pregnant women are complex, because unlike other exposures such as tobacco or illicit drugs, where the goal is to eliminate use in pregnancy entirely - discontinuing the use of antidepressants and leaving maternal depression untreated itself has deleterious consequences for both mother and child. Thus, we hope that carefully controlled research can help us better understand adverse outcomes of antidepressant exposures and disentangle them from the effects of parental depression per se. Ultimately, we hope that studies such as ours can provide guidance to clinicians and patients that will minimize possible adverse effects on the fetus while allowing appropriate treatment of the affected mother.

Aim:

The goal of the study is to examine adverse offspring health outcomes that may emerge as a result of early gestational (in utero) exposures. We focus mainly on exposures that have the ability to impact fetal brain development, such as use of antidepressants and other medications during the nine months of pregnancy but also on maternal physical and mental illnesses.  

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Description of the cohort

All women giving birth in Denmark during 1997-2015 are included along with their children and the fathers of the children. We define the cohort from the Danish Medical Birth Register.

Data and biological material

• Medical Birth Register will allow us to obtain information on (and linkage across) the mother, father and child, date of birth, sex and gestational age of the offspring, demographic information, qualifiers of tobacco/drug/alcohol use in pregnancy.
• National Patient Register will allow us to obtain information on admission and discharge diagnoses from somatic and psychiatric hospital departments, coded according to International Classification of Diseases (ICD-10)
• National Prescription Register, which includes data (type of drug, strength, quantity, dates of dispensation) on every prescription dispensed from a Danish pharmacy continuously since 1995.
• Cause of Death register, which will allow us to identify deaths through suicides
• Statistic Denmark Registers on Socioeconomic Status will allow us to obtain information on education and income
• The National Insurance Service Health Register informs on services in primary health care (number of visits, cost)
• Civil Person Register will inform on death, in-and emigrations, marital status, place of residence

Furthermore, we enrich a sub-cohort of app. 92.000 women who are represented in the Danish National Birth Cohort (established 1997-2002) with data on baseline characteristics not available in the registers in details (self-reported mental health, BMI, smoking, alcohol intake ect) and self-reported outcome at various time point (5, 7, 11, 18 year postpartum as well from a maternal follow-up 14 years postpartum).

Collaborating researchers and departments

Clinical Pharmacology and Pharmacy, University of Southern Denmark

• Anton Pottegård, PhD

Research Unit Child and Adolescent Mental Health, University of Southern Denmark

• Rikke Thaarup Wesselhöft, M.D. PhD

OPEN Odense Patient data Explorative Network, Odense University Hospital & Department of Clinical Research, University of Southern Denmark

• Mette Bliddal, PhD

Department of Psychiatry, Columbia University, NY, USA

• Jay A. Gingrich, M.D., PhD
• Myrna M. Weissman, PhD
• Ardesheer Talati, PhD

Department of Public Health, University of Copenhagen

• Katrine Strandberg-Larsen