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Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study.

Ban L, Fleming KM, Doyle P, Smeeth L, Hubbard RB, Fiaschi L, Tata LJ - PLoS ONE (2015)

Bottom Line: CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56.Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks.Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed.

View Article: PubMed Central - PubMed

Affiliation: Division of Epidemiology & Public Health, University of Nottingham, Nottingham, United Kingdom.

ABSTRACT

Background: Antenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear.

Methods: We included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception).

Results: CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy.

Conclusions: Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings.

No MeSH data available.


Related in: MedlinePlus

Percentages of women prescribed folic acid among those with first trimester antiepileptic drug prescriptions (N = 1,259).Monthly prevalence of any folic acid and 5mg folic acid prescribed in the three months before pregnancy and in the first trimester.
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pone.0131130.g001: Percentages of women prescribed folic acid among those with first trimester antiepileptic drug prescriptions (N = 1,259).Monthly prevalence of any folic acid and 5mg folic acid prescribed in the three months before pregnancy and in the first trimester.

Mentions: In mothers prescribed AEDs in the first trimester, 51.9% had high dose folic acid prescribed periconceptionally (Table 1) and the average quantity of each prescription was 30 tablets (interquartile range 28–56). There was a much lower proportion in those of mothers without AEDs (1.6%) or with AEDs only in later pregnancy (13.4%) (Table 1). When examining the monthly prevalence of folic acid prescriptions in those with AEDs in early pregnancy, less than 20% had a prescription for any folic before or in the first month of pregnancy; however, in the second month of pregnancy, the number increased considerably to nearly 50% (Fig 1). A similar pattern was observed for prescriptions of high dose folic acid (Fig 1).


Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study.

Ban L, Fleming KM, Doyle P, Smeeth L, Hubbard RB, Fiaschi L, Tata LJ - PLoS ONE (2015)

Percentages of women prescribed folic acid among those with first trimester antiepileptic drug prescriptions (N = 1,259).Monthly prevalence of any folic acid and 5mg folic acid prescribed in the three months before pregnancy and in the first trimester.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492893&req=5

pone.0131130.g001: Percentages of women prescribed folic acid among those with first trimester antiepileptic drug prescriptions (N = 1,259).Monthly prevalence of any folic acid and 5mg folic acid prescribed in the three months before pregnancy and in the first trimester.
Mentions: In mothers prescribed AEDs in the first trimester, 51.9% had high dose folic acid prescribed periconceptionally (Table 1) and the average quantity of each prescription was 30 tablets (interquartile range 28–56). There was a much lower proportion in those of mothers without AEDs (1.6%) or with AEDs only in later pregnancy (13.4%) (Table 1). When examining the monthly prevalence of folic acid prescriptions in those with AEDs in early pregnancy, less than 20% had a prescription for any folic before or in the first month of pregnancy; however, in the second month of pregnancy, the number increased considerably to nearly 50% (Fig 1). A similar pattern was observed for prescriptions of high dose folic acid (Fig 1).

Bottom Line: CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56.Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks.Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed.

View Article: PubMed Central - PubMed

Affiliation: Division of Epidemiology & Public Health, University of Nottingham, Nottingham, United Kingdom.

ABSTRACT

Background: Antenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear.

Methods: We included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception).

Results: CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy.

Conclusions: Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings.

No MeSH data available.


Related in: MedlinePlus