Malformed pregnancy rates
Fetal malformations occurred in 109 of the 1733 pregnancy offspring (6.3%). Malformations were present in five of the 147 offspring not exposed to AEDs in at least the first trimester of pregnancy (3.4%), with malformations in 104 of the remaining 1586 (6.6%) first-trimester AED-exposed pregnancies: odds ratio (OR) = 0.50 (0.2, 1.25). Further details of the malformation rates related to intrauterine exposure to the more commonly used AEDs employed in monotherapy are shown in Table 1, together with total exposures to each AED, alone or in combination with others.
Table 1. Exposure to individual AEDs, occurring in >10 pregnancies, and associated malformation rates for the drugs used in monotherapy
|AED||AED total exposures||AED in monotherapy||Malformations||% Malformed|
The malformation rates for all the drugs collectively, used in monotherapy (72.3% of all AED exposures) and in AED combinations (27.7% of all AED exposures), were relatively similar, being for monotherapy 72 of 1147 = 6.28% and for polytherapy 32 of 439 = 7.29%; OR = 0.85 (0.56, 1.31). The malformation rate associated with VPA exposure in monotherapy was statistically significantly higher that associated with all the other AEDs in monotherapy, 37 of 271 = 13.65% vs 35 of 876 = 4.00%; OR = 3.80 (2.34, 6.17). In contrast, the malformation rate associated with exposure to all non-VPA AEDs in monotherapy (4.00%) was not statistically significantly greater than the rate in pregnancies unexposed to AEDs in at least the first trimester, viz. 5 of 147 = 3.40%; OR = 0.85 (0.33, 2.20).
Relationship between various parameters and malformed fetus rates
Because restricting analysis to pregnancy offspring exposed to only a single AED appreciably reduced the amount of information available, multivariate logistic regression was applied to the combination of AED monotherapy and polytherapy data in subsequent analyses in this article.
The contributions of various recorded data items to the risk of a malformed fetus occurring were assessed, Table 2 showing the various regression partial coefficients and their P values. The only statistically significant regression coefficients (P < 0.05) were those for having (i) siblings with malformations and (ii) exposure during pregnancy to (a) VPA and (b) topiramate (TPM). The association with the presence of malformations in siblings, but not with malformations in other family members, is probably related to maternal AED exposure in earlier pregnancies in the same woman and not necessarily to genetic factors.
Table 2. Coefficients of a multiple variable logistic regression for risk of a malformed fetus on various data items and the corresponding P values. Statistically significant P values are shown in bold type
| ||Value|| P |
|Family history of malformations, excluding siblings||−0.666971||0.5048|
|Siblings with malformations||+1.006052|| 0.0144 |
|Exposure to CBZ||+0.217983||0.4275|
|Exposure to LTG||−0.148383||0.5622|
|Exposure to VPA||+1.173438|| <0.0001 |
|Exposure to LEV||−0.395008||0.4105|
|Exposure to TPM||+0.746239|| 0.0341 |
|Exposure to PHT||+0.308261||0.5338|
|Exposure to CZP||−0.545252||0.3021|
|Exposure to GPT||−15.284823||0.9918|
|Exposure to OxCBZ||−14.757867||0.9931|
|Exposure to PB or PMD||+0.245157||0.8153|
|Exposure to ETHO||−14.961495||0.9933|
|Exposure to VGT||−14.747880||0.9942|
|Folate intake before conception||−0.132718||0.5573|
In view of the relative paucity of data and high P values, exposure to the less frequently used AEDs was not pursued further.
Malformations associated with particular AEDs
The recorded malformations in the 104 malformed fetuses among the 1586 exposed to AEDs during pregnancy, and in the 147 not so exposed, are set down in Table 3. Because multiple malformations were often present in the same fetus, the total of individual malformations exceeds the total number of fetuses. In the Table, the malformations are often classified in terms of the affected regions of the body—dealing with the matter at the level of the numerous individual malformations within regions would have often resulted in numbers too small to be useful. Drugs not associated with malformations are not included in the Table.
Table 3. Fetal malformations and the associated AEDs. Numbers of AEDs associated with individual malformations may exceed the numbers of the malformation because a malformation may occur in a fetus exposed to more than one AED
|Malformation||All AEDS||CBZ||LTG||VPA||LEV||TPM||PHT||No AED|
|Total with malformations||104||28||27||54||5||11||5||5|
Logistic regression was used to explore relationships between exposure to individual drugs and the more frequently encountered individual malformations (Table 4). There appeared to be statistically significant associations between (i) VPA and spina bifida, malformations of the heart and great vessels, digits, skull bones, and brain; (ii) CBZ and a number of different urinary tract abnormalities; and (iii) TPM and hypospadias and various abnormalities of the brain. While spina bifida and hypospadias are discrete abnormalities, the other categories of abnormality that appeared associated with particular AEDs involved a mix of individual types of malformation, none occurring in any great number. Among the 15 fetuses with malformations of the heart or great vessels associated with VPA exposure, there were 12 instances of defects in the interatrial or interventricular septa, but logistic regression (details not shown) found the association with the drug was significant only at a P = 0.0693 level.
Table 4. Logistic regressions for individual malformations of the form: logit risk = a + b1 + ….. bn, where b values represent exposures to particular AEDs. Statistically significant P values are shown in bold type
| || a ||CBZ||LTG||VPA||LEV||TPM||PHT||CZP|
|P value||<0.0001||0.6219||0.3013|| 0.0075 ||0.9988||0.3498||0.9990||0.9986|
|P value||<0.0001||0.2288||0.8615|| 0.0142 ||0.4789||0.6848||0.9102||0.7386|
|P value||<0.0001||0.2925||0.1929||0.6398||0.5264|| 0.0186 ||0.9230||0.9291|
|P value||<0.0001|| 0.0045 ||0.5896||0.1212||0.1926||0.0706||0.9984||0.9980|
|P value||<0.0001||0.2917||0.1806|| 0.0079 ||0.8706||0.7716||0.3718||0.9303|
|P value||<0.0001||0.6419||0.7949|| 0.0060 ||0.9034|| 0.0297 ||0.9964||0.998|
For the VPA-associated abnormalities of digits (N = 12), skull bones (N = 8), brain (N = 10), and face (N = 5), the most common ones were, respectively, extra digits (N = 7), plagiocephaly (N = 4), and hydrocephalus and Arnold-Chiari malformations (N = 5).
No single renal tract abnormality (N = 8) was associated with CBZ more than twice, and the three brain abnormalities associated with TPM exposure were all different. One may suspect that, with more data, statistically significant evidence of an association between VPA and defects in the cardiac septa might emerge, but with the arguable exception of hypospadias, there are too few data to warrant undue confidence in accepting associations between CBZ and individual renal tract malformations and between TPM and the various brain malformations found.
The statistically significant association between TPM exposure and hypospadias in the full population studied may partly explain why there were 54 male offspring, but only 41 female offspring with malformations (the sexes of some aborted fetuses were not recorded, although the natures of their malformations were). Logistic regression analysis was applied only to male offspring of pregnancy (i.e. a baby boy), relating the presence of hypospadias to (i) exposure to the individual commonly used AEDs, and (ii) exposure to the other AEDs but with the actual TPM dosages employed (Table 5; Fig. 1). There were statistically significant relationships between the occurrence of hypospadias and exposure to TPM, and also to TPM dosage (150, 200, 300, and 400 mg per day in the affected pregnancies), the P value being smaller in case of the latter association (0.0192 vs 0.0105).
Table 5. Logistic regressions for presence of hypospadias of the form: logit risk = a + b1 + …..bn, where b values represent exposures to particular AEDs in the upper equation, but TPM dose (mg per day) rather than TPM exposure is shown in the lower equation. Statistically significant P values are shown in bold type
| || a ||CBZ||LTG||VPA||LEV||TPM||TPM Dose||PHT||CZP|
|P value||<0.0001||0.3224||0.1487||0.5226||0.3938|| 0.0192 || ||0.8874||0.8568|
|P value||<0.0001||0.2373||0.1138||0.5996||0.3161|| || 0.0105 ||0.8185||0.8888|
Figure 1. Calculated regression for risk of hypospadias relative to topiramate dose, with the upper 95% confidence limit of the regression line.
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If the data are approached in another way, there were four instances of hypospadias among the 60 male infants exposed to TPM during pregnancy (6.67%) and 10 in the 681 males exposed to AEDs apart from TPM (1.47%; OR = 4.79; 95% CI = 1.46, 15.77). However, the rates of occurrence of hypospadias in TPM-exposed fetuses (6.67%) were not statistically significantly higher than those in the males not exposed to AEDs (3 of 65, i.e. 4.62%: OR = 1.48, 95% CI = 0.32, 6.89). It has been shown that if a woman taking AEDs gives birth to a malformed fetus, she is at increased risk of having malformed fetuses in subsequent pregnancies [8, 9]. Because of the possibility that this effect could have influenced the hypospadias findings, the comparisons made immediately above were repeated after excluding pregnancies in which there was a history of fetal malformations in siblings or other family members. The hypospadias rates were then three in 39 (7.70%) for the TPM-exposed pregnancies and eight in 503 (1.59%) for pregnancies exposed to other AEDs (OR = 5.16; 95% CI = 1.31, 20.3), and for the pregnancies not exposed to AEDs, three in 65, that is, 4.62% (OR = 1.72; 95% CI = 0.38, 8.99).