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WP4 - Antiepileptic Drugs and Insulin Analogues



Work Undertaken (Deliverables)

  • Creation of diabetic cohorts and linkage to CA registers (Dataset C, see Table 4.1 (Deliverable 14)
  • Literature review and case malformed control study on the risk of specific CA in relation to new AEDs (Deliverable 15)
    • Study of risk of congenital anomaly in relation to exposure to the econd generation AED topiramate
  • Literature review on the risk of specific CA in relation to insulin analogues (Deliverable 16)
  • Diabetic cohort study investigating the relationship between specific CA and insulin analogues (Deliverable 17)


Table 4.1 Overview of datasets generated by EURomediCAT

Final report Table 4.1

WP4 Results and Foreground


The main objective of WP4 was to assess the relationship between AEDs and insulin analogues and congenital anomalies. This process was initiated by extensive literature reviews to search for signals of specific congenital anomalies in relation new AEDs (vigabatrin, oxcarbamazepine, felbamate, lamotrigine, topiramate, gabapentine, levetiracetam, pregabalin and zonisamide) and insulin analogues (lispro, aspart, glulisine, glargine, degludec and determir). The signals of specific congenital anomalies associated with AED use found in these literature searches, were further evaluated in the EUROCAT database using a case-malformed control study (signal evaluation). No signals were detected for insulin analogues compared to human insulin use and therefore no signal evaluation was involved in the diabetic cohort study.



Literature review of new antiepileptic drugs


This literature review aimed to collect signals indicating an association between a new AEDs and specific congenital anomalies. Any strong signal will be investigated further in a case-malformed control study using the EUROCAT AED database as part of a signal evaluation process. 

Pubmed and Embase were systematically searched for studies with pregnancies exposed to new AEDs in relation to specific congenital anomalies. The anomalies found were classified according to the EUROCAT classification. The prevalence of specific congenital anomalies of fetuses exposed to individual AEDs of the combined studies were calculated and compared to the prevalence of the general population. A significant higher prevalence based on two or more cases among the exposed fetuses was considered a signal. Eight signals related to either lamotrigine or topiramate monotherapy were found of whom only the signal of topiramate and cleft lip with or without cleft palate could be evaluated as strong evidence. For levetiracetam, gabapentin and oxcarbazepine no signals were found. The other 11 new AEDs had few or no exposed pregnancies in this literature review.

Conclusions from the study: We concluded that the signal of topiramate and cleft lip with or without cleft palate should be further evaluated (Deliverable 15, Part A).



Evaluation of the signal Topiramate and orofacial clefts


We evaluated the signal for Topiramate and risk of orofacial clefts found in the literature review as part of signal evaluation. Topiramate is licensed for use both in treatment for epilepsy and migraine and the use has increased among pregnant women. 

To assess the risk of orofacial clefts (OCs) in infants whose mothers had taken Topiramate during the first trimester of pregnancy we performed a population-based case-control study with malformed controls using the EUROCAT AED Database. This database including data from 19 population-based registries of congenital anomaly in Europe with a total coverage of 8.0 million births from 1995 to 2011. Cases were 10,802 nonsyndromic OC registrations, of whom 8,919 were isolated; and 6,827 were cleft lip with or without cleft palate (CL/P). Controls were 136,838 nonchromosomal, non-OC registrations. We compared first trimester Topiramate use vs no-AED use, for mono and polytherapy. Exposure to Topiramate monotherapy was recorded for a total of 12 registrations, with 1 registration in the case group (isolated cleft palate) and 11 in the control group (OR 1.15, 95% CI: 0.03-7.93 for OC relative to other malformations and OR 4.02, 95% CI: 0.09-27.7 for isolated cleft palate). There was no registration of CL/P in Topiramate monotherapy exposure. There were 36 registrations with Topiramate polytherapy exposure, of whom 6 with isolated CL/P, 3 with cleft palate and 27 in the control group. Out of 36 of Topiramate polytherapy, 19 included valproic acid, 8 included carbamazepine and 4 included lamotrigine. The unadjusted ORs for TPM polytherapy vs no AED use was 4.23 (95% CI 1.75- 9.26) for OC, 4.36 (95% CI 1.31- 11.5) for isolated CL/P and 3.27 (95%CI 0.38-13.0) for isolated cleft palate. The risk estimation of OCs, CL/P or cleft palate in relation to Topiramate monotherapy/polytherapy did not change when adjusted for maternal age or region.

Conclusions from the study: Our study did not show a specific increased risk of OCs relative to other malformations due to first trimester Topiramate monotherapy exposure. The prevalence of Topiramate monotherapy exposure was five times lower in our data than reported in the United States which limited our ability to confirm or refute previous findings. First trimester use of Topiramate polytherapy was associated with CL/P. The present data should be interpreted with caution due to the small sample size and wide confidence interval. The observed association of Topiramate polytherapy exposure with increased risk of CL/P needs to be confirmed by others. However, we should keep the absolute risk in perspective. Approximately 1 in 1000 infants is born CL/P; assume our results are valid, our observed OR of approximately 4 would lie to translate into a risk in the order of 4 per 1000 Topiramate -exposed pregnancies. The teratogenic risk should be balanced against the risk of alternative therapeutic choices (others AEDs among others valproic acid and carbamazepine) as well as the comparative effectiveness of Topiramate treatment (Deliverable 15, Part B).

Literature review insulin analogues


Insulin analogues are now commonly used in diabetic pregnant women. Diabetic pregnancies, especially in case of pre-gestational diabetes, have higher risks of congenital anomalies. To avoid additional risks in diabetic pregnancies, it is important to know whether the exposure to insulin analogues in pregnancy has any higher risk of specific congenital anomalies in the offspring than exposure to human insulin. Therefore we performed a literature review to investigate the risk of specific congenital anomalies among diabetic pregnancies, exposed in the first trimester to insulin analogues, compared to human insulin.

We searched Pubmed and Embase for articles meeting the following inclusion criteria:

  • original, non-overlapping studies including pregnancies of women with pregestational diabetes
  • exposure to insulin lispro, aspart, glulisine, glargine, detemir or degludec in the first trimester (<12 weeks of gestation)
  • detailed information on congenital anomalies
  • randomized controlled trials, cohort studies or observational studies with ≥ 5 exposed pregnancies

The studies were analysed to compare the rate of infants with congenital anomalies among insulin analogues exposed pregnancies with human insulin exposed pregnancies. We compared the prevalence of specific major malformations, by reclassification according to the congenital anomaly subgroups of EUROCAT. A significant higher risk of a specific congenital anomaly among fetuses exposed to insulin analogues compared to human insulin was considered as a signal. We found 32 studies: 2 randomized controlled trials, 16 cohort studies and 14 observational studies of pregnancies exposed to insulin lispro, aspart, glargine or detemir. No studies were found on insulin glulisine or degludec. 

No significant difference was found in the anomaly rate among fetuses exposed to lispro, aspart, glargine and detemir compared to human insulin (respectively Relative Risk= 0.88 (95% CI 0.60-1.28), 0.92 (0.37-2.29), 0.73 (0.38-1.40), and 0.91(0.35-2.39)). The prevalence of specific congenital anomaly subgroups was not significantly higher in insulin analogues exposed fetuses compared to human insulin exposed fetuses. The congenital anomalies found were known as associated with diabetes in pregnancy and the prevalences were comparable to those found in the general diabetic pregnant population. 


Conclusions from the study: In this literature review no increased risk of specific congenital anomalies was found among the offspring of women with pre-gestational diabetes exposed to insulin analogues in the first trimester of pregnancy compared to human insulin exposure.

Diabetic cohort study 

Insulin analogues have been available on the market since the mid- 1990s and it is known from clinical and experimental data that insulin analogues result in improved glycemic control, fewer hypoglycemic episodes and improved patients satisfaction. In this context, insulin analogues may be particularly useful in pregnancy. The use of insulin analogues in pregnancy is increasing in Europe (see WP6), but information on teratogenic risks is lacking. It is not clear whether insulin analogues use in pregnancy is related to any risk of congenital anomaly (CA). Insulin analogues may decrease the risk of diabetes-associated malformations by promoting better glycemic control (HbA1C-value), or increase the risk of these or other CA through specific effects relating to the pharmacological properties of analogues. Available studies on insulin analogues during pregnancy are not sufficiently powered to evaluate the risk of specific major CA. We evaluated the risk of major congenital anomalies associated with insulin analogues use in women with pre-gestational diabetes.


A population-based cohort of pre-gestational diabetic pregnancies (dataset C) was established retrospectively using medical records from 7 European regions (Denmark, Germany, Malta, Antwerp, Northern Netherlands, Wales) covered by EUROCAT congenital anomaly registries and linked to the malformation register. A total of 1,877 births to women with pre-gestational diabetes were enrolled in the study during 1996-2012. During the first trimester, 870 births (46.3%) were exposed to only human insulin, 397 births (21.2%) to only insulin analogues, 394 births (20.1%) to both human insulin and insulin analogues. The proportion of still birth and spontaneous abortion (4.0%) are higher among only insulin analogue group compared to only human insulin group (1.4%). Overall, 132 births (7.0%) with major congenital malformation were detected, of which 7 were chromosomal. The prevalence of major congenital anomalies in births exposed to only insulin analogues (3.8%) during the first trimester was significantly lower than those exposed to only human insulin (8.6%); relative risk = 0.42 (95% CI: 0.24-0.73). This is largely due to the decreased prevalence of non-chromosomal congenital heart defects (CHD): relative risk = 0.18 (95% CI: 0.05-0.58). This decreased prevalence remained after adjusting for glycaemic control and region. The prevalence of non-CHD congenital anomalies among births exposed to only insulin analogues in the first trimester (3.0%) was also lower than those exposed to only human insulin (4.0%), but not statistically significant.


Conclusions from the study: This study shows that first trimester exposure to insulin analogues did not increase the risk of congenital anomalies compared to exposure to human insulin. The decrease risk of CHDs among the insulin analogues exposed provides a further piece of evidence of the safety of insulin analogues with regards to CA. The higher risk of fetal death in relation to insulin analogues warrants further investigation.