Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of linked databases in Wales, Norway and Funen, Denmark

Sue Jordan, Joan Morris, Gareth Davies, David Tucker, Daniel Thayer, Johannes Luteijn, Margery Morgan, Ester Garne, Anne Hansen, Kari Klungsoyr, Anders Engeland, Breidge Boyle, Helen Dolk

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background  Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).
Methods and Findings  Three population-based EUROCAT congenital anomaly registries- Norway (2004±2010), Wales (2000±2010) and Funen, Denmark (2000±2010)Ðwere linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06±2.11), and the composite adverse outcome of 'anomalyor stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03±1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99±1.21). Adjusting for socioeconomic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12±1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.

Conclusion  The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.
LanguageEnglish
Pages1-26
JournalPLoS ONE
Volume11
Issue number12
Early online date1 Dec 2016
DOIs
Publication statusE-pub ahead of print - 1 Dec 2016

Fingerprint

antidepressants
Wales
Serotonin Uptake Inhibitors
Denmark
Norway
serotonin
Antidepressive Agents
pregnancy
Databases
Pregnancy
Congenital Heart Defects
Prescriptions
heart
Defects
Preconception Care
Teratogenesis
teratogenicity
Stillbirth
fetal death
Public health

Keywords

  • Congenital Anomalies
  • SSRI
  • Antidepressants
  • EUROmediCAT

Cite this

Jordan, Sue ; Morris, Joan ; Davies, Gareth ; Tucker, David ; Thayer, Daniel ; Luteijn, Johannes ; Morgan, Margery ; Garne, Ester ; Hansen, Anne ; Klungsoyr, Kari ; Engeland, Anders ; Boyle, Breidge ; Dolk, Helen. / Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of linked databases in Wales, Norway and Funen, Denmark. In: PLoS ONE. 2016 ; Vol. 11, No. 12. pp. 1-26.
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abstract = "Background  Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).Methods and Findings  Three population-based EUROCAT congenital anomaly registries- Norway (2004±2010), Wales (2000±2010) and Funen, Denmark (2000±2010){\DH}were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95{\%} confidence intervals (ORs, 95{\%}CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26{\%}] vs. 865/506,155 [0.17{\%}] OR 1.50, 1.06±2.11), and the composite adverse outcome of 'anomalyor stillbirth' (473/12962, 3.65{\%} vs. 15829/506,155, 3.13{\%}, OR 1.13, 1.03±1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09{\%} [400/12,962] vs. 2.67{\%} [13,536/506,155] OR 1.09, 0.99±1.21). Adjusting for socioeconomic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12±1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.Conclusion  The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.",
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Jordan, S, Morris, J, Davies, G, Tucker, D, Thayer, D, Luteijn, J, Morgan, M, Garne, E, Hansen, A, Klungsoyr, K, Engeland, A, Boyle, B & Dolk, H 2016, 'Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of linked databases in Wales, Norway and Funen, Denmark', PLoS ONE, vol. 11, no. 12, pp. 1-26. https://doi.org/10.1371/journal.pone.0165122

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of linked databases in Wales, Norway and Funen, Denmark. / Jordan, Sue; Morris, Joan; Davies, Gareth; Tucker, David; Thayer, Daniel; Luteijn, Johannes; Morgan, Margery; Garne, Ester; Hansen, Anne; Klungsoyr, Kari; Engeland, Anders; Boyle, Breidge; Dolk, Helen.

In: PLoS ONE, Vol. 11, No. 12, 01.12.2016, p. 1-26.

Research output: Contribution to journalArticle

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T1 - Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of linked databases in Wales, Norway and Funen, Denmark

AU - Jordan, Sue

AU - Morris, Joan

AU - Davies, Gareth

AU - Tucker, David

AU - Thayer, Daniel

AU - Luteijn, Johannes

AU - Morgan, Margery

AU - Garne, Ester

AU - Hansen, Anne

AU - Klungsoyr, Kari

AU - Engeland, Anders

AU - Boyle, Breidge

AU - Dolk, Helen

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background  Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).Methods and Findings  Three population-based EUROCAT congenital anomaly registries- Norway (2004±2010), Wales (2000±2010) and Funen, Denmark (2000±2010)Ðwere linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06±2.11), and the composite adverse outcome of 'anomalyor stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03±1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99±1.21). Adjusting for socioeconomic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12±1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.Conclusion  The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

AB - Background  Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP).Methods and Findings  Three population-based EUROCAT congenital anomaly registries- Norway (2004±2010), Wales (2000±2010) and Funen, Denmark (2000±2010)Ðwere linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06±2.11), and the composite adverse outcome of 'anomalyor stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03±1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99±1.21). Adjusting for socioeconomic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12±1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression.Conclusion  The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

KW - Congenital Anomalies

KW - SSRI

KW - Antidepressants

KW - EUROmediCAT

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DO - 10.1371/journal.pone.0165122

M3 - Article

VL - 11

SP - 1

EP - 26

JO - PLoS ONE

T2 - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

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ER -