Prenatal exposure to antidepressants and language competence at age three. Results from a large population based pregnancy cohort in Norway Svetlana Skurtveit, Randi Selmer, Christine Roth, Sonia Hernandez-Diaz and Marte Handal

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Scenario A 35-year-old nulliparous woman with depression consulted you for pre-conception advice. Her depression has been well-controlled by fluoxetine (Prozac), a SSRI, for over 5 years. She has no other medical conditions. She asked, “Is Prozac going to affect my baby’s development?”

Clinical Question Does prenatal SSRI exposure increase the risk of lower language competence in children at age three years?

Background Selective Serotonin Reuptake Inhibitors (SSRIs) are the most frequently used drugs to treat depression Serotonin is important for neurogenesis, migration and differentiation in the developing brain Limited information is available on the effects of prenatal exposure to SSRIs on long term neurocognitive function in children

Background Are you aware of other recently published studies related to the above clinical question? Suggested reading: Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med Dec 19;369(25):

Description of Research ParticipantsNorwegian women who were pregnant between 1999 to 2008 ExposureSelf-reported use of selective serotonin reuptake inhibitors (SSRI) during pregnancy ComparisonThose who did not use SSRI during pregnancy OutcomesLanguage competence of their children at age 3 by maternal evaluation on a language grammar rating scale Study DesignPopulation based prospective cohort study

MoBa participants N= Returned age three-year questionnaire N=58410 MoBa participants N=56662 MoBa participants N=55107 MoBa participants N=52038 Study analysis N= ( 0.7%) SSRI users Plural birth N=1748 Malformation and/or chromosomal abnormalities N=1555 Did not answer all the three questionnaires during pregnancy N=3069 Missing language measure N=290

Data Source: The Norwegian Mother and Child Cohort Study(MoBa) Prospective population-based pregnancy cohort Pregnant women recruited at routine ultrasound examination in week from 1999 – % participation rate (response rate 64 % at three years) Self-administered questionnaires during pregnancy and after birth MoBa cohortNumber of individuals Women Men Children

Establishing SSRI exposure during pregnancy Self-reported use of any SSRI in at least one of the three questionnaires Duration of use: – no use before, during and after pregnancy – use during one period only – use during at least two periods Test of validity – Self-reported SSRI use was validated against data from the Norwegian Prescription Database and showed good agreement

Measurements of symptoms of anxiety and depression Before pregnancy – Having three or more of depressive symptoms simultaneously for a continuous period of two week or more without any particular reason During and after pregnancy – Short version of Hopkins Symptoms Checklist (SCL-5) Twice during pregnancy Twice after birth At maternal evaluation of the child's language competence

A validated language grammar rating scale by maternal evaluation was used Mothers were asked of the category that best described the way her child talked at age three years: –Talking in long and complicated sentences –Talking in fairly complete sentences –Talking in 2-3 –word phrases –Talking in one-word utterances –Talking but unintelligible/Not yet talking Measurement of language competence

Statistical analyses and analyses strategy Multinomial logistic regression Adjusting for symptoms of anxiety and depression before and during pregnancy and other confounders Stratifying on symptoms of anxiety and depression after pregnancy and at the time of evaluation of language competence

Talking in long and complicated sentences Talking in fairly complete sentences Talking in 2-3 –word phrases Talking in one-word utterances Talking but unintelligible/Not yet talking Outcome categories Multinomial logistic regression analysis Long complicated sentences Fairly complete sentences Language delay Outcome categories

Methods Critically appraise and comment on this paper using the Critical Appraisal Skills Programme (CASP) checklist for cohort studies ( How was the use of SSRI ascertained in this study? How to resolve any potential bias from using this method? How does language competence at 3 years correlate with long-term linguistic performance?

Language competence by exposure to SSRIs Language competence SSRI expousure long complicated sentences n (%) fairly complete sentences n (%) two-three word phrases n (%) one word utterances n (%) unintelligible utterances + not yet talking n (%) no (77.1)9736 (19.0)1707 (3.3)190 (0.4)139 (0.3) yes 251 (65.0)111 (28.8)20 (5.2)2 (0.5) one period only 159 (70.7)56 (24.9)8 (3.6)1 (0.4) at least two periods 92 (57.1)55 (34.2)12 (7.5)1 (0.6)

Language competence by symptoms of anxiety and depression Language competence Depression long complicated sentences n (%) fairly complete sentences n (%) two-three word phrases n (%) one word utterances n (%) unintelligible utterances + not yet talking n (%) no (77.6)8646 (18.7)1452 (3.1)152 (0.3)109 (0.2) yes 3152 (72.9)909 (21.0)210 (4.9)27 (0.6)24(0.6) short term 2336 (74.2)651 (20.7)132 (4.2)16 (0.5)15 (0.5) long term 816 (69.6)258 (22.0)78 (6.7)11 (0.9)9 (0.8)

Relative risk ratios of language competence according to SSRI exposure during pregnancy Fairly complete sentences versus long complicated sentences Language delay versus long complicated sentences Unadjusted RRR (95% CI) Adjusted* RRR (95% CI) Unadjusted RRR (95% CI) Adjusted* RRR (95% CI) SSRI exposure No1 (ref) Yes, one time period1.29 ( )1.21( )1.36 ( )0.86 ( ) Yes, at least two time periods2.41 ( )2.28 ( ) 3.44 ( )2.30 ( ) * Independent variables: SSRI use in pregnancy, depression before pregnancy, symptoms of anxiety/depression in pregnancy, maternal work situation, parity, marital status, smoking, BMI and maternal and paternal education

Relative risk ratios of language competence according to symptoms of anxiety and depression Fairly complete sentences versus long complicated sentences Language delay versus long complicated sentences Unadjusted RRR (95% CI) Adjusted* RRR (95% CI) Unadjusted RRR (95% CI) Adjusted* RRR (95% CI) Anxiety/Depression in pregnancy No1 (ref) Yes, short term1.12 ( )1.06 ( )1.45 ( )1.25 ( ) Yes, long term1.24 ( )1.10 ( ) 2.45 ( )1.83 ( ) * Independent variables: SSRI use in pregnancy, depression before pregnancy, symptoms of anxiety/depression in pregnancy, maternal work situation, parity, marital status, smoking, BMI and maternal and paternal education

Outcomes What are the benefits and disadvantages of using language competence at 3 years by maternal evaluation as the primary outcome measure? Were the Patient Reported Outcome Measures (PROMs) used in this study chosen appropriately? (See PROM group, Oxford University:

Take home message Can you briefly summarise the results of this study? How would the results of this study influence your practice?

Authors’ conclusions Extended maternal use of SSRIs in pregnancy and maternal depression symptoms were both independently associated with the risk of a child achieving lower language competence at three years old. None of these findings reliably predict long-term language competence and therefore should not be used as arguments to withhold or stop SSRI in pregnant women with depression.

Authors’ Affiliations Svetlana Skurtveit 1,2, Randi Selmer 1, Christine Roth 1, Sonia Hernandez- Diaz 3 and Marte Handal 1 – 1 Norwegian Institute of Public Health, Div. of Epidemiology, Oslo, Norway – 2 University of Oslo, Norwegian Centre for Addiction Research, Oslo, Norway – 3 Department of Epidemiology, Harvard School of Public Health, Boston, United States Declaration of interest and Funding – All authors declare that they have no conflicts of interest. – This study was funded by the Norwegian Institute of Public Health. The funding source had no role in the study design, statistical analysis and interpretation of data or in the decision to submit the paper for publication. Correspondence to: – Svetlana Skurtveit, professor – Marte Handal, MD, PhD,