Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child
Background Prenatal exposure to certain anti‐seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM t...
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| Veröffentlicht in: | Cochrane database of systematic reviews 2023-08, Vol.2023 (8), p.CD010224 |
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| creator | Bromley, Rebecca Bromley, Rebecca Adab, Naghme Bluett-Duncan, Matt Clayton-Smith, Jill Christensen, Jakob Edwards, Katherine Greenhalgh, Janette Hill, Ruaraidh A Jackson, Cerian F Khanom, Sonia McGinty, Ronan N Tudur Smith, Catrin Pulman, Jennifer Marson, Anthony G |
| description | Background
Prenatal exposure to certain anti‐seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required.
Objectives
To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child.
Search methods
For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed.
Selection criteria
We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy.
Data collection and analysis
Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta‐analysis was not possible, we reviewed included studies narratively.
Main results
From 12,296 s, we reviewed 283 full‐text publications which identified 49 studies with 128 publications between them. Data from ASM‐exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies.
The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose‐dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 t |
| doi_str_mv | 10.1002/14651858.CD010224.pub3 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10463554</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2858989068</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4263-f969ef6b8880450a56488122f33a476562de5aac7a795e613480470da74d3c593</originalsourceid><addsrcrecordid>eNqFkUtP3DAUhS1EVR7tX0BedjNTv-N0U8G0pZVAbGBZWRfHmTFK7GBnWuXf42gYRNl0ZUv3u-fY5yB0RsmSEsI-U6Ek1VIvV98IJYyJ5bC95wfoeB4s5snhq_sROsn5gRCuala9R0e8UqIiWh2j39cxxHHjEgwTHpODsXdhxLHFbvCdG_KEfcBDcusAwU5fsI1h7YIfocM9dG1MPYw-Bhy3o429yzNe9LDd-K75gN610GX38fk8RXc_vt-ufi6ubi5_rc6vFlYwxRdtrWrXqnutNRGSgFRCa8pYyzmISknFGicBbAVVLZ2iXBSuIg1UouFW1vwUfd3plhB619jyhQSdGZLvIU0mgjf_ToLfmHX8YygRikspisKnZ4UUH7cuj6b32bqug-DiNhtWUqx1TZQuqNqhNsWck2tffCgxczlmX47ZlzO787J49vqVL2v7NgpwsQP-lugnY6PdpOL_H903Lk8LjaDh</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2858989068</pqid></control><display><type>article</type><title>Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child</title><source>MEDLINE</source><source>Cochrane Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Bromley, Rebecca ; Bromley, Rebecca ; Adab, Naghme ; Bluett-Duncan, Matt ; Clayton-Smith, Jill ; Christensen, Jakob ; Edwards, Katherine ; Greenhalgh, Janette ; Hill, Ruaraidh A ; Jackson, Cerian F ; Khanom, Sonia ; McGinty, Ronan N ; Tudur Smith, Catrin ; Pulman, Jennifer ; Marson, Anthony G</creator><creatorcontrib>Bromley, Rebecca ; Bromley, Rebecca ; Adab, Naghme ; Bluett-Duncan, Matt ; Clayton-Smith, Jill ; Christensen, Jakob ; Edwards, Katherine ; Greenhalgh, Janette ; Hill, Ruaraidh A ; Jackson, Cerian F ; Khanom, Sonia ; McGinty, Ronan N ; Tudur Smith, Catrin ; Pulman, Jennifer ; Marson, Anthony G</creatorcontrib><description>Background
Prenatal exposure to certain anti‐seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required.
Objectives
To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child.
Search methods
For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed.
Selection criteria
We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy.
Data collection and analysis
Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta‐analysis was not possible, we reviewed included studies narratively.
Main results
From 12,296 s, we reviewed 283 full‐text publications which identified 49 studies with 128 publications between them. Data from ASM‐exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies.
The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose‐dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83).
For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin‐exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies.
Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine‐exposed children (> 2700). Further, a non‐significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro‐facial clefts. Data for all other ASMs were extremely limited.
Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases.
Authors' conclusions
Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose‐dependent.</description><identifier>ISSN: 1465-1858</identifier><identifier>ISSN: 1469-493X</identifier><identifier>EISSN: 1465-1858</identifier><identifier>EISSN: 1469-493X</identifier><identifier>DOI: 10.1002/14651858.CD010224.pub3</identifier><identifier>PMID: 37647086</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Antiepileptic drugs ; Antiepileptic drugs in broad populations with epilepsy ; Antiepileptic drugs in pregnancy ; Child ; Child health ; Cohort Studies ; Drugs for broad populations ; Epilepsy ; Epilepsy - drug therapy ; Epilepsy - epidemiology ; Epilepsy: drugs for broad populations ; Female ; Humans ; Lamotrigine ; Male ; Medical problems during pregnancy ; Medicine General & Introductory Medical Sciences ; Neurology ; Other ; Phenytoin ; Pregnancy ; Pregnancy & childbirth ; Prenatal Exposure Delayed Effects ; Prospective Studies ; Topiramate</subject><ispartof>Cochrane database of systematic reviews, 2023-08, Vol.2023 (8), p.CD010224</ispartof><rights>Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4263-f969ef6b8880450a56488122f33a476562de5aac7a795e613480470da74d3c593</citedby><cites>FETCH-LOGICAL-c4263-f969ef6b8880450a56488122f33a476562de5aac7a795e613480470da74d3c593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37647086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bromley, Rebecca</creatorcontrib><creatorcontrib>Bromley, Rebecca</creatorcontrib><creatorcontrib>Adab, Naghme</creatorcontrib><creatorcontrib>Bluett-Duncan, Matt</creatorcontrib><creatorcontrib>Clayton-Smith, Jill</creatorcontrib><creatorcontrib>Christensen, Jakob</creatorcontrib><creatorcontrib>Edwards, Katherine</creatorcontrib><creatorcontrib>Greenhalgh, Janette</creatorcontrib><creatorcontrib>Hill, Ruaraidh A</creatorcontrib><creatorcontrib>Jackson, Cerian F</creatorcontrib><creatorcontrib>Khanom, Sonia</creatorcontrib><creatorcontrib>McGinty, Ronan N</creatorcontrib><creatorcontrib>Tudur Smith, Catrin</creatorcontrib><creatorcontrib>Pulman, Jennifer</creatorcontrib><creatorcontrib>Marson, Anthony G</creatorcontrib><title>Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child</title><title>Cochrane database of systematic reviews</title><addtitle>Cochrane Database Syst Rev</addtitle><description>Background
Prenatal exposure to certain anti‐seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required.
Objectives
To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child.
Search methods
For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed.
Selection criteria
We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy.
Data collection and analysis
Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta‐analysis was not possible, we reviewed included studies narratively.
Main results
From 12,296 s, we reviewed 283 full‐text publications which identified 49 studies with 128 publications between them. Data from ASM‐exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies.
The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose‐dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83).
For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin‐exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies.
Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine‐exposed children (> 2700). Further, a non‐significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro‐facial clefts. Data for all other ASMs were extremely limited.
Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases.
Authors' conclusions
Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose‐dependent.</description><subject>Antiepileptic drugs</subject><subject>Antiepileptic drugs in broad populations with epilepsy</subject><subject>Antiepileptic drugs in pregnancy</subject><subject>Child</subject><subject>Child health</subject><subject>Cohort Studies</subject><subject>Drugs for broad populations</subject><subject>Epilepsy</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - epidemiology</subject><subject>Epilepsy: drugs for broad populations</subject><subject>Female</subject><subject>Humans</subject><subject>Lamotrigine</subject><subject>Male</subject><subject>Medical problems during pregnancy</subject><subject>Medicine General & Introductory Medical Sciences</subject><subject>Neurology</subject><subject>Other</subject><subject>Phenytoin</subject><subject>Pregnancy</subject><subject>Pregnancy & childbirth</subject><subject>Prenatal Exposure Delayed Effects</subject><subject>Prospective Studies</subject><subject>Topiramate</subject><issn>1465-1858</issn><issn>1469-493X</issn><issn>1465-1858</issn><issn>1469-493X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>RWY</sourceid><sourceid>EIF</sourceid><recordid>eNqFkUtP3DAUhS1EVR7tX0BedjNTv-N0U8G0pZVAbGBZWRfHmTFK7GBnWuXf42gYRNl0ZUv3u-fY5yB0RsmSEsI-U6Ek1VIvV98IJYyJ5bC95wfoeB4s5snhq_sROsn5gRCuala9R0e8UqIiWh2j39cxxHHjEgwTHpODsXdhxLHFbvCdG_KEfcBDcusAwU5fsI1h7YIfocM9dG1MPYw-Bhy3o429yzNe9LDd-K75gN610GX38fk8RXc_vt-ufi6ubi5_rc6vFlYwxRdtrWrXqnutNRGSgFRCa8pYyzmISknFGicBbAVVLZ2iXBSuIg1UouFW1vwUfd3plhB619jyhQSdGZLvIU0mgjf_ToLfmHX8YygRikspisKnZ4UUH7cuj6b32bqug-DiNhtWUqx1TZQuqNqhNsWck2tffCgxczlmX47ZlzO787J49vqVL2v7NgpwsQP-lugnY6PdpOL_H903Lk8LjaDh</recordid><startdate>20230829</startdate><enddate>20230829</enddate><creator>Bromley, Rebecca</creator><creator>Bromley, Rebecca</creator><creator>Adab, Naghme</creator><creator>Bluett-Duncan, Matt</creator><creator>Clayton-Smith, Jill</creator><creator>Christensen, Jakob</creator><creator>Edwards, Katherine</creator><creator>Greenhalgh, Janette</creator><creator>Hill, Ruaraidh A</creator><creator>Jackson, Cerian F</creator><creator>Khanom, Sonia</creator><creator>McGinty, Ronan N</creator><creator>Tudur Smith, Catrin</creator><creator>Pulman, Jennifer</creator><creator>Marson, Anthony G</creator><general>John Wiley & Sons, Ltd</general><scope>7PX</scope><scope>RWY</scope><scope>ZYTZH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20230829</creationdate><title>Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child</title><author>Bromley, Rebecca ; Bromley, Rebecca ; Adab, Naghme ; Bluett-Duncan, Matt ; Clayton-Smith, Jill ; Christensen, Jakob ; Edwards, Katherine ; Greenhalgh, Janette ; Hill, Ruaraidh A ; Jackson, Cerian F ; Khanom, Sonia ; McGinty, Ronan N ; Tudur Smith, Catrin ; Pulman, Jennifer ; Marson, Anthony G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4263-f969ef6b8880450a56488122f33a476562de5aac7a795e613480470da74d3c593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antiepileptic drugs</topic><topic>Antiepileptic drugs in broad populations with epilepsy</topic><topic>Antiepileptic drugs in pregnancy</topic><topic>Child</topic><topic>Child health</topic><topic>Cohort Studies</topic><topic>Drugs for broad populations</topic><topic>Epilepsy</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy - epidemiology</topic><topic>Epilepsy: drugs for broad populations</topic><topic>Female</topic><topic>Humans</topic><topic>Lamotrigine</topic><topic>Male</topic><topic>Medical problems during pregnancy</topic><topic>Medicine General & Introductory Medical Sciences</topic><topic>Neurology</topic><topic>Other</topic><topic>Phenytoin</topic><topic>Pregnancy</topic><topic>Pregnancy & childbirth</topic><topic>Prenatal Exposure Delayed Effects</topic><topic>Prospective Studies</topic><topic>Topiramate</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bromley, Rebecca</creatorcontrib><creatorcontrib>Bromley, Rebecca</creatorcontrib><creatorcontrib>Adab, Naghme</creatorcontrib><creatorcontrib>Bluett-Duncan, Matt</creatorcontrib><creatorcontrib>Clayton-Smith, Jill</creatorcontrib><creatorcontrib>Christensen, Jakob</creatorcontrib><creatorcontrib>Edwards, Katherine</creatorcontrib><creatorcontrib>Greenhalgh, Janette</creatorcontrib><creatorcontrib>Hill, Ruaraidh A</creatorcontrib><creatorcontrib>Jackson, Cerian F</creatorcontrib><creatorcontrib>Khanom, Sonia</creatorcontrib><creatorcontrib>McGinty, Ronan N</creatorcontrib><creatorcontrib>Tudur Smith, Catrin</creatorcontrib><creatorcontrib>Pulman, Jennifer</creatorcontrib><creatorcontrib>Marson, Anthony G</creatorcontrib><collection>Wiley-Blackwell Cochrane Library</collection><collection>Cochrane Library</collection><collection>Cochrane Library (Open Aceess)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cochrane database of systematic reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bromley, Rebecca</au><au>Bromley, Rebecca</au><au>Adab, Naghme</au><au>Bluett-Duncan, Matt</au><au>Clayton-Smith, Jill</au><au>Christensen, Jakob</au><au>Edwards, Katherine</au><au>Greenhalgh, Janette</au><au>Hill, Ruaraidh A</au><au>Jackson, Cerian F</au><au>Khanom, Sonia</au><au>McGinty, Ronan N</au><au>Tudur Smith, Catrin</au><au>Pulman, Jennifer</au><au>Marson, Anthony G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child</atitle><jtitle>Cochrane database of systematic reviews</jtitle><addtitle>Cochrane Database Syst Rev</addtitle><date>2023-08-29</date><risdate>2023</risdate><volume>2023</volume><issue>8</issue><spage>CD010224</spage><pages>CD010224-</pages><issn>1465-1858</issn><issn>1469-493X</issn><eissn>1465-1858</eissn><eissn>1469-493X</eissn><abstract>Background
Prenatal exposure to certain anti‐seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required.
Objectives
To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child.
Search methods
For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed.
Selection criteria
We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy.
Data collection and analysis
Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta‐analysis was not possible, we reviewed included studies narratively.
Main results
From 12,296 s, we reviewed 283 full‐text publications which identified 49 studies with 128 publications between them. Data from ASM‐exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies.
The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose‐dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83).
For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin‐exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies.
Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine‐exposed children (> 2700). Further, a non‐significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro‐facial clefts. Data for all other ASMs were extremely limited.
Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases.
Authors' conclusions
Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose‐dependent.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>37647086</pmid><doi>10.1002/14651858.CD010224.pub3</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-1858 |
| ispartof | Cochrane database of systematic reviews, 2023-08, Vol.2023 (8), p.CD010224 |
| issn | 1465-1858 1469-493X 1465-1858 1469-493X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10463554 |
| source | MEDLINE; Cochrane Library; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Antiepileptic drugs Antiepileptic drugs in broad populations with epilepsy Antiepileptic drugs in pregnancy Child Child health Cohort Studies Drugs for broad populations Epilepsy Epilepsy - drug therapy Epilepsy - epidemiology Epilepsy: drugs for broad populations Female Humans Lamotrigine Male Medical problems during pregnancy Medicine General & Introductory Medical Sciences Neurology Other Phenytoin Pregnancy Pregnancy & childbirth Prenatal Exposure Delayed Effects Prospective Studies Topiramate |
| title | Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T03%3A33%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Monotherapy%20treatment%20of%20epilepsy%20in%20pregnancy:%20congenital%20malformation%20outcomes%20in%20the%20child&rft.jtitle=Cochrane%20database%20of%20systematic%20reviews&rft.au=Bromley,%20Rebecca&rft.date=2023-08-29&rft.volume=2023&rft.issue=8&rft.spage=CD010224&rft.pages=CD010224-&rft.issn=1465-1858&rft.eissn=1465-1858&rft_id=info:doi/10.1002/14651858.CD010224.pub3&rft_dat=%3Cproquest_pubme%3E2858989068%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2858989068&rft_id=info:pmid/37647086&rfr_iscdi=true |