Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study

Erika Cifuentes  Castro; Anna-Belle Beau; Anthony  Caillet; Félix  Frémont; AJ Neville; E Ballardini; Helen Dolk; Maria Loane; E Garne; B Khoshnood; N Lelong; A Rissmann; M O’Mahony; A Pierini; M Gatt; JEH Bergman; M.R.  Krawczynski; Anna Latos-Bielenska; L.E. Gonzalez de Gariba; Clara Cavero‑Carbonell; MC Addor; D Tucker; S. Jordan; E Den Hond; V Nelen; I Barisic; Florence Rouget; H Randrianaivo; Jonathan  Hoareau; Monique  Courtade-Saïdi; C Damase-Michel; Charlotte  Dubucs

doi:10.1002/bdr2.2435

Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study

Erika Cifuentes Castro, Anna-Belle Beau, Anthony Caillet, Félix Frémont, AJ Neville, E Ballardini, Helen Dolk, Maria Loane, E Garne, B Khoshnood, N Lelong, A Rissmann, M O’Mahony, A Pierini, M Gatt, JEH Bergman, M.R. Krawczynski, Anna Latos-Bielenska , L.E. Gonzalez de Gariba, Clara Cavero‑CarbonellMC Addor, D Tucker, S. Jordan, E Den Hond, V Nelen, I Barisic, Florence Rouget, H Randrianaivo, Jonathan Hoareau, Monique Courtade-Saïdi, C Damase-Michel, Charlotte Dubucs

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Background
In Europe, the prevalence of congenital ocular anomaly (COA) is estimated at 3.7 per 10,000 births. While certain COAs have a genetic origin, the cause for most patients remains unknown. The role of medications administered during pregnancy in COA genesis in humans is unclear.
Objective
To investigate any association between fetal exposure in the first trimester of pregnancy to medications and the occurrence of COA.
Methods
We conducted a case-malformed-control study using data on 298,351 cases registered as having congenital anomalies (CA) from 19 registries and one healthcare database in 13 European countries. Two analyses were performed: (i) A signal confirmation analysis of signals from the literature, examining associations between COA and specific medications (nitrofurantoin, NSAIDs, opioids, alprazolam, antihypertensives, asthma medications, pyridoxine, and hydroxyethylrutoside). (ii) A signal detection analysis of all medications reported in the database.
Results
We identified 4185 COA cases and 232,718 nongenetic and 38,409 genetic controls. We confirmed the association between prenatal opioid exposure and COA (aROR: 2.66, 95% CI: 1.18, 6.02, and 3.22, 95% CI: 1.35, 7.69, for nongenetic and genetic controls, respectively). Signal detection analysis revealed consistent associations for antiglaucoma preparations and miotics (p < 0.01) related to COA. Other associations included congenital cataracts and lens anomalies with desloratadine, congenital glaucoma with antiepileptics, and eyelid malformations with dermatological hydrocortisone.
Conclusions
This pharmacoepidemiological study in Europe analyzing COA following fetal medication exposure confirmed reported signals regarding opioids and COA and identified new associations. Validation in independent datasets is necessary to consolidate these findings.

Original language	English
Article number	e2435
Pages (from-to)	e2435
Number of pages	17
Journal	Birth Defects Research
Volume	117
Issue number	2
Early online date	31 Jan 2025
DOIs	https://doi.org/10.1002/bdr2.2435
Publication status	Published (in print/issue) - 28 Feb 2025

Bibliographical note

Publisher Copyright:
© 2025 Wiley Periodicals LLC.

Data Access Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Keywords

Abnormalities, Drug-Induced - epidemiology
Adult
Case-Control Studies
Europe
Eye Abnormalities - chemically induced - epidemiology - genetics
Female
Humans
Male
Maternal Exposure - adverse effects
Pregnancy
Pregnancy Trimester, First
Prenatal Exposure Delayed Effects - chemically induced
Registries
Risk Factors
congenital ocular anomaly
in utero exposure
medications
pharmacology
pregnancy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/bdr2.2435

Cite this

Castro, E. C., Beau, A.-B., Caillet, A., Frémont, F., Neville, AJ., Ballardini, E., Dolk, H., Loane, M., Garne, E., Khoshnood, B., Lelong, N., Rissmann, A., O’Mahony, M., Pierini, A., Gatt, M., Bergman, JEH., Krawczynski, M. R., Latos-Bielenska , A., Gonzalez de Gariba, L. E., ... Dubucs, C. (2025). Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study. Birth Defects Research, 117(2), e2435. Article e2435. https://doi.org/10.1002/bdr2.2435

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title = "Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study",

abstract = "BackgroundIn Europe, the prevalence of congenital ocular anomaly (COA) is estimated at 3.7 per 10,000 births. While certain COAs have a genetic origin, the cause for most patients remains unknown. The role of medications administered during pregnancy in COA genesis in humans is unclear.ObjectiveTo investigate any association between fetal exposure in the first trimester of pregnancy to medications and the occurrence of COA.MethodsWe conducted a case-malformed-control study using data on 298,351 cases registered as having congenital anomalies (CA) from 19 registries and one healthcare database in 13 European countries. Two analyses were performed: (i) A signal confirmation analysis of signals from the literature, examining associations between COA and specific medications (nitrofurantoin, NSAIDs, opioids, alprazolam, antihypertensives, asthma medications, pyridoxine, and hydroxyethylrutoside). (ii) A signal detection analysis of all medications reported in the database.ResultsWe identified 4185 COA cases and 232,718 nongenetic and 38,409 genetic controls. We confirmed the association between prenatal opioid exposure and COA (aROR: 2.66, 95% CI: 1.18, 6.02, and 3.22, 95% CI: 1.35, 7.69, for nongenetic and genetic controls, respectively). Signal detection analysis revealed consistent associations for antiglaucoma preparations and miotics (p < 0.01) related to COA. Other associations included congenital cataracts and lens anomalies with desloratadine, congenital glaucoma with antiepileptics, and eyelid malformations with dermatological hydrocortisone.ConclusionsThis pharmacoepidemiological study in Europe analyzing COA following fetal medication exposure confirmed reported signals regarding opioids and COA and identified new associations. Validation in independent datasets is necessary to consolidate these findings.",

keywords = "Abnormalities, Drug-Induced - epidemiology, Adult, Case-Control Studies, Europe, Eye Abnormalities - chemically induced - epidemiology - genetics, Female, Humans, Male, Maternal Exposure - adverse effects, Pregnancy, Pregnancy Trimester, First, Prenatal Exposure Delayed Effects - chemically induced, Registries, Risk Factors, congenital ocular anomaly, in utero exposure, medications, pharmacology, pregnancy",

author = "Castro, {Erika Cifuentes} and Anna-Belle Beau and Anthony Caillet and F{\'e}lix Fr{\'e}mont and AJ Neville and E Ballardini and Helen Dolk and Maria Loane and E Garne and B Khoshnood and N Lelong and A Rissmann and M O{\textquoteright}Mahony and A Pierini and M Gatt and JEH Bergman and M.R. Krawczynski and Anna Latos-Bielenska and {Gonzalez de Gariba}, L.E. and Clara Cavero‑Carbonell and MC Addor and D Tucker and S. Jordan and {Den Hond}, E and V Nelen and I Barisic and Florence Rouget and H Randrianaivo and Jonathan Hoareau and Monique Courtade-Sa{\"i}di and C Damase-Michel and Charlotte Dubucs",

note = "Publisher Copyright: {\textcopyright} 2025 Wiley Periodicals LLC.",

year = "2025",

month = feb,

day = "28",

doi = "10.1002/bdr2.2435",

language = "English",

volume = "117",

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journal = "Birth Defects Research",

issn = "2472-1727",

publisher = "John Wiley & Sons, Inc.",

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Castro, EC, Beau, A-B, Caillet, A, Frémont, F, Neville, AJ, Ballardini, E, Dolk, H , Loane, M, Garne, E, Khoshnood, B, Lelong, N, Rissmann, A, O’Mahony, M, Pierini, A, Gatt, M, Bergman, JEH, Krawczynski, MR, Latos-Bielenska , A, Gonzalez de Gariba, LE, Cavero‑Carbonell, C, Addor, MC, Tucker, D, Jordan, S, Den Hond, E, Nelen, V, Barisic, I, Rouget, F, Randrianaivo, H, Hoareau, J, Courtade-Saïdi, M, Damase-Michel, C & Dubucs, C 2025, 'Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study', Birth Defects Research, vol. 117, no. 2, e2435, pp. e2435. https://doi.org/10.1002/bdr2.2435

TY - JOUR

T1 - Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study

AU - Castro, Erika Cifuentes

AU - Beau, Anna-Belle

AU - Caillet, Anthony

AU - Frémont, Félix

AU - Neville, AJ

AU - Ballardini, E

AU - Dolk, Helen

AU - Loane, Maria

AU - Garne, E

AU - Khoshnood, B

AU - Lelong, N

AU - Rissmann, A

AU - O’Mahony, M

AU - Pierini, A

AU - Gatt, M

AU - Bergman, JEH

AU - Krawczynski, M.R.

AU - Latos-Bielenska , Anna

AU - Gonzalez de Gariba, L.E.

AU - Cavero‑Carbonell, Clara

AU - Addor, MC

AU - Tucker, D

AU - Jordan, S.

AU - Den Hond, E

AU - Nelen, V

AU - Barisic, I

AU - Rouget, Florence

AU - Randrianaivo, H

AU - Hoareau, Jonathan

AU - Courtade-Saïdi, Monique

AU - Damase-Michel, C

AU - Dubucs, Charlotte

PY - 2025/2/28

Y1 - 2025/2/28

N2 - BackgroundIn Europe, the prevalence of congenital ocular anomaly (COA) is estimated at 3.7 per 10,000 births. While certain COAs have a genetic origin, the cause for most patients remains unknown. The role of medications administered during pregnancy in COA genesis in humans is unclear.ObjectiveTo investigate any association between fetal exposure in the first trimester of pregnancy to medications and the occurrence of COA.MethodsWe conducted a case-malformed-control study using data on 298,351 cases registered as having congenital anomalies (CA) from 19 registries and one healthcare database in 13 European countries. Two analyses were performed: (i) A signal confirmation analysis of signals from the literature, examining associations between COA and specific medications (nitrofurantoin, NSAIDs, opioids, alprazolam, antihypertensives, asthma medications, pyridoxine, and hydroxyethylrutoside). (ii) A signal detection analysis of all medications reported in the database.ResultsWe identified 4185 COA cases and 232,718 nongenetic and 38,409 genetic controls. We confirmed the association between prenatal opioid exposure and COA (aROR: 2.66, 95% CI: 1.18, 6.02, and 3.22, 95% CI: 1.35, 7.69, for nongenetic and genetic controls, respectively). Signal detection analysis revealed consistent associations for antiglaucoma preparations and miotics (p < 0.01) related to COA. Other associations included congenital cataracts and lens anomalies with desloratadine, congenital glaucoma with antiepileptics, and eyelid malformations with dermatological hydrocortisone.ConclusionsThis pharmacoepidemiological study in Europe analyzing COA following fetal medication exposure confirmed reported signals regarding opioids and COA and identified new associations. Validation in independent datasets is necessary to consolidate these findings.

AB - BackgroundIn Europe, the prevalence of congenital ocular anomaly (COA) is estimated at 3.7 per 10,000 births. While certain COAs have a genetic origin, the cause for most patients remains unknown. The role of medications administered during pregnancy in COA genesis in humans is unclear.ObjectiveTo investigate any association between fetal exposure in the first trimester of pregnancy to medications and the occurrence of COA.MethodsWe conducted a case-malformed-control study using data on 298,351 cases registered as having congenital anomalies (CA) from 19 registries and one healthcare database in 13 European countries. Two analyses were performed: (i) A signal confirmation analysis of signals from the literature, examining associations between COA and specific medications (nitrofurantoin, NSAIDs, opioids, alprazolam, antihypertensives, asthma medications, pyridoxine, and hydroxyethylrutoside). (ii) A signal detection analysis of all medications reported in the database.ResultsWe identified 4185 COA cases and 232,718 nongenetic and 38,409 genetic controls. We confirmed the association between prenatal opioid exposure and COA (aROR: 2.66, 95% CI: 1.18, 6.02, and 3.22, 95% CI: 1.35, 7.69, for nongenetic and genetic controls, respectively). Signal detection analysis revealed consistent associations for antiglaucoma preparations and miotics (p < 0.01) related to COA. Other associations included congenital cataracts and lens anomalies with desloratadine, congenital glaucoma with antiepileptics, and eyelid malformations with dermatological hydrocortisone.ConclusionsThis pharmacoepidemiological study in Europe analyzing COA following fetal medication exposure confirmed reported signals regarding opioids and COA and identified new associations. Validation in independent datasets is necessary to consolidate these findings.

KW - Abnormalities, Drug-Induced - epidemiology

KW - Adult

KW - Case-Control Studies

KW - Europe

KW - Eye Abnormalities - chemically induced - epidemiology - genetics

KW - Female

KW - Humans

KW - Male

KW - Maternal Exposure - adverse effects

KW - Pregnancy

KW - Pregnancy Trimester, First

KW - Prenatal Exposure Delayed Effects - chemically induced

KW - Registries

KW - Risk Factors

KW - congenital ocular anomaly

KW - in utero exposure

KW - medications

KW - pharmacology

KW - pregnancy

UR - http://www.scopus.com/inward/record.url?scp=85216780462&partnerID=8YFLogxK

U2 - 10.1002/bdr2.2435

DO - 10.1002/bdr2.2435

M3 - Article

SN - 2472-1727

VL - 117

SP - e2435

JO - Birth Defects Research

JF - Birth Defects Research

IS - 2

M1 - e2435

ER -

Risk of congenital ocular anomaly after prenatal exposure to medications; a EUROmediCAT study

Abstract

Bibliographical note

Data Access Statement

Keywords

UN SDGs

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