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MAGDALENA: study protocol of a randomised, placebo-controlled trial on cognitive development at 2 years of age in children exposed to SSRI in utero
  1. Essi Heinonen1,2,
  2. Barbara Szymanska-von Schultz3,4,
  3. Viktor Kaldo5,6,7,
  4. Josefine Nasiell3,4,
  5. Ewa Andersson8,
  6. Mikaela Bergmark6,
  7. Margareta Blomdahl-Wetterholm6,
  8. Lisa Forsberg1,2,
  9. Erik Forsell5,6,
  10. Anna Forsgren1,
  11. Sandra Frööjd6,
  12. Amy Goldman6,
  13. Eva-Mari Nordenadler6,
  14. Myrto Sklivanioti6,
  15. Mats Blennow1,2,
  16. Katarina Wide1,2,
  17. Lars L Gustafsson9,10
  1. 1 Division of Paediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Huddinge, Stockholm
  2. 2 Department of Paediatrics, Karolinska University Hospital, Stockholm, Sweden
  3. 3 Division of Obstetrics and Gynaecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
  4. 4 Department of Obstetrics and Gynaecology, Karolinska University Hospital, Stockholm, Sweden
  5. 5 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  6. 6 Psychiatry South West, Stockholm Health Care Region, Stockholm, Sweden
  7. 7 Department of Psychology, Faculty of Health and Life Sciences, Linnaeus University, Stockholm, Växjö, Sweden
  8. 8 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
  9. 9 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
  10. 10 Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden
  1. Correspondence to Mrs. Essi Heinonen; essi.heinonen{at}ki.se

Abstract

Introduction Ten per cent of all pregnant women are depressed. Standard therapy of pregnant women with moderate depression is selective serotonin reuptakeinhibitors (SSRI). Observational studies on neurodevelopment after fetal SSRI exposure show conflicting results. Our primary objective is to compare the cognitive development in children exposed to sertraline and maternal depression with those exposed to maternal depression and placebo in utero. We hypothesise that there is a significant neurodevelopmental difference between the groups. As a secondary objective, we study the add-on effect of sertraline to internet-based cognitive behavioural therapy (ICBT) to treat moderate depression during pregnancy.

Methods and analysis MAGDALENA is a randomised, placebo-controlled, double-blinded trial in Stockholm Healthcare Region with 2.3 million inhabitants. The women are recruited in weeks 9–21 of pregnancy either through Antenatal Health Clinics or through social media. They are to be diagnosed with moderate depression without ongoing antidepressive therapy or any serious comorbidity. The women in the intervention arm receive sertraline combined with a 12-week period of ICBT; the control arm is treated with placebo and ICBT. We assess the cognitive development in the offspring at the age of 2 years using Bayley Scales of Infant and Toddler Development, third edition (BSID-III). We aim at recruiting 200 women, 100 women in each treatment arm, to ensure statistical power to detect a clinically relevant difference between the groups.

Ethics and dissemination This randomised trial will provide long-sought evidence about the effects of SSRI and maternal depression during pregnancy on the neurodevelopment in the offspring. The study is approved by the Regional Ethical Review Board at Karolinska Institutet in Stockholm and the Swedish Medical Products Agency. It is registered with the European Clinical Trials Database (EudraCT), Number: 2013-004444-31. Results will be disseminated at scientific conferences, published in peer-reviewed journals and made available to the public.

Trial registration number EudraCT2013-004444-31; Pre-results.

  • antenatal depression
  • internet-based cognitive behaviour therapy
  • serotonin reuptake inhibitors
  • neurodevelopment
  • pregnancy
  • drug metabolism

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Contributors EH and LLG wrote the initial study protocol article with the help of BS-vS, LF and AF. KW is the principal investigator and JN, LLG, MB and VK are members of the governing study board. MB is the sponsor and the main applicant and receiver of our initial groundbreaking funding decision from the Swedish Research Council. MB is also a senior researcher with full responsibility of the study design and participation in completion of the manuscript. JN, KW and MB conceived the study protocol, and KW wrote the initial draft of the study protocol. EA is developing an exploratory study protocol studying attachment in a subgroup of the pregnant women. MB, SF and EH launched the open recruitment through different social media platforms. VK and EF adapted the ICBT procedure for use in our pregnant women and are responsible for the ICBT treatment. They also directed the pilot study. AF is the study midwife coordinating the visits and the day-to-day management of the study. MB-W, MS and AG are the study psychiatrists responsible for the initial assessment and inclusion in the study as well as for the clinical decisions about pharmacotherapy. EMN is the psychiatry nurse responsible for the treatment evaluations. All authors have in different ways been involved in different degrees in the development of study design and take responsibility for the final study design. All authors have contributed to the protocol development and have read and approved the final protocol that we now use after revisions as well as this manuscript. EH and LLG coordinated the completion of the study protocol article.

  • Funding The study was funded by Vetenskapsrådet (521-2012-3466), Stockholms Läns Landsting (533069, 571301), Lilla Barnets Fond.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval The Regional Ethical Review Board at Karolinska Institutet in Stockholm approved this study with the approval number 2014/952–31 with the last amendment approved 20180507.

  • Provenance and peer review Not commissioned; externally peer reviewed.