EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations

Joanne Given, Maria Loane, Johannes M. Luteijn, Joan K. Morris, Lolkje T. W. de Jong van den Berg, Ester Garne, Marie-Claude Addor, Ingeborg Barisic, Hermien de Walle, Miriam Gatt, Kari Klungsoyr, Babak Khoshnood, Anna Latos-Bielenska, Vera Nelen, Amanda J. Neville, Mary O'Mahony, Anna Pierini, David Tucker, Awi Wiesel, Helen Dolk

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aims
To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.

Methods
Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.

Results
13/27 CA-medication exposure signals, based on 3-89 exposed cases, passed data validation. There was some prior evidence in the literature to support 6 signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining 6 signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.

Conclusion
Signals which strengthened prior evidence should be prioritised for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.
LanguageEnglish
Pages1094-1109
Number of pages16
JournalBritish Journal of Clinical Pharmacology
Volume82
Issue number4
Early online date29 Mar 2016
DOIs
Publication statusPublished - Oct 2016

Fingerprint

Hypospadias
Gastroschisis
Anti-Asthmatic Agents
Syndactyly
Hydralazine
Serotonin Receptor Agonists
Levonorgestrel
Laxatives
Ethinyl Estradiol
Pulmonary Valve Stenosis
Reverse Transcriptase Inhibitors
Ovulation
Nucleosides
Hypoglycemic Agents
Gonadotropin-Releasing Hormone
Anticonvulsants
Registries
Heart Diseases
Extremities
Salts

Keywords

  • congenital anomalies
  • drug-induced anomalies
  • pharmacoepidemiology
  • pharmacovigilance
  • pregnancy
  • signal evaluation

Cite this

Given, Joanne ; Loane, Maria ; Luteijn, Johannes M. ; Morris, Joan K. ; de Jong van den Berg, Lolkje T. W. ; Garne, Ester ; Addor, Marie-Claude ; Barisic, Ingeborg ; de Walle, Hermien ; Gatt, Miriam ; Klungsoyr, Kari ; Khoshnood, Babak ; Latos-Bielenska, Anna ; Nelen, Vera ; Neville, Amanda J. ; O'Mahony, Mary ; Pierini, Anna ; Tucker, David ; Wiesel, Awi ; Dolk, Helen. / EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations. In: British Journal of Clinical Pharmacology. 2016 ; Vol. 82, No. 4. pp. 1094-1109.
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title = "EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations",
abstract = "Aims To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.MethodsData from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50{\%} false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.Results13/27 CA-medication exposure signals, based on 3-89 exposed cases, passed data validation. There was some prior evidence in the literature to support 6 signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95{\%} CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95{\%} CI 1.99-14.20/OR 28.20, 95{\%} CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95{\%} CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95{\%} CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95{\%} CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining 6 signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.ConclusionSignals which strengthened prior evidence should be prioritised for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.",
keywords = "congenital anomalies, drug-induced anomalies, pharmacoepidemiology, pharmacovigilance, pregnancy, signal evaluation",
author = "Joanne Given and Maria Loane and Luteijn, {Johannes M.} and Morris, {Joan K.} and {de Jong van den Berg}, {Lolkje T. W.} and Ester Garne and Marie-Claude Addor and Ingeborg Barisic and {de Walle}, Hermien and Miriam Gatt and Kari Klungsoyr and Babak Khoshnood and Anna Latos-Bielenska and Vera Nelen and Neville, {Amanda J.} and Mary O'Mahony and Anna Pierini and David Tucker and Awi Wiesel and Helen Dolk",
year = "2016",
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doi = "10.1111/bcp.12947",
language = "English",
volume = "82",
pages = "1094--1109",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
number = "4",

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Given, J, Loane, M, Luteijn, JM, Morris, JK, de Jong van den Berg, LTW, Garne, E, Addor, M-C, Barisic, I, de Walle, H, Gatt, M, Klungsoyr, K, Khoshnood, B, Latos-Bielenska, A, Nelen, V, Neville, AJ, O'Mahony, M, Pierini, A, Tucker, D, Wiesel, A & Dolk, H 2016, 'EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations', British Journal of Clinical Pharmacology, vol. 82, no. 4, pp. 1094-1109. https://doi.org/10.1111/bcp.12947

EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations. / Given, Joanne; Loane, Maria; Luteijn, Johannes M.; Morris, Joan K.; de Jong van den Berg, Lolkje T. W.; Garne, Ester; Addor, Marie-Claude; Barisic, Ingeborg; de Walle, Hermien; Gatt, Miriam; Klungsoyr, Kari; Khoshnood, Babak; Latos-Bielenska, Anna; Nelen, Vera; Neville, Amanda J.; O'Mahony, Mary; Pierini, Anna; Tucker, David; Wiesel, Awi; Dolk, Helen.

In: British Journal of Clinical Pharmacology, Vol. 82, No. 4, 10.2016, p. 1094-1109.

Research output: Contribution to journalArticle

TY - JOUR

T1 - EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations

AU - Given, Joanne

AU - Loane, Maria

AU - Luteijn, Johannes M.

AU - Morris, Joan K.

AU - de Jong van den Berg, Lolkje T. W.

AU - Garne, Ester

AU - Addor, Marie-Claude

AU - Barisic, Ingeborg

AU - de Walle, Hermien

AU - Gatt, Miriam

AU - Klungsoyr, Kari

AU - Khoshnood, Babak

AU - Latos-Bielenska, Anna

AU - Nelen, Vera

AU - Neville, Amanda J.

AU - O'Mahony, Mary

AU - Pierini, Anna

AU - Tucker, David

AU - Wiesel, Awi

AU - Dolk, Helen

PY - 2016/10

Y1 - 2016/10

N2 - Aims To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.MethodsData from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.Results13/27 CA-medication exposure signals, based on 3-89 exposed cases, passed data validation. There was some prior evidence in the literature to support 6 signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining 6 signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.ConclusionSignals which strengthened prior evidence should be prioritised for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.

AB - Aims To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.MethodsData from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.Results13/27 CA-medication exposure signals, based on 3-89 exposed cases, passed data validation. There was some prior evidence in the literature to support 6 signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining 6 signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.ConclusionSignals which strengthened prior evidence should be prioritised for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.

KW - congenital anomalies

KW - drug-induced anomalies

KW - pharmacoepidemiology

KW - pharmacovigilance

KW - pregnancy

KW - signal evaluation

U2 - 10.1111/bcp.12947

DO - 10.1111/bcp.12947

M3 - Article

VL - 82

SP - 1094

EP - 1109

JO - British Journal of Clinical Pharmacology

T2 - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 4

ER -