Discussions
In this study, we observed that approximately 60% of pregnancies in WWE were unplanned, which was more common among WWE with a lower education level. More importantly, we found that planned pregnancy was associated with more optimized AEDs treatment patterns, better seizure control, more appropriate folic acid supplementation and less adverse fetal outcomes with pregnancy planning as independent risk factor. Our results indicate that pregnancy planning may be a critical strategy for WWE to fulfill satisfactory seizure control and improve their chances of having a healthy baby.
Although pregnancy planning is critical for WWE, more than half of the pregnancies in WWE were unplanned. The result from EBCR web-based survey of 1,144 WWE showed that 65.0% of their pregnancies were unintended.18 The data from the Pregnancy Risk Assessment Monitoring System (PRAMS), including 13 states in the United States from 2009 to 2014, demonstrated that 55% of WWE pregnancies were unintended.22 They reported that unintended pregnancies were more common in WWE with younger ages, lower incomes, or who were members of racial minority groups or Hispanic.22 The population in our study was Han Chinese. We found that WWE in the unplanned-pregnancy group had a lower level of education and tended to reside in areas that were more rural compared with the planned-pregnancy group. These patients often have limited access to medical advice.
The greatest concern for WWE is the teratogenicity of AEDs. Accumulating evidence suggests that different AEDs and dosages have different teratogenic risks,23-25 and that the newer generation AEDs, such as LTG, LEV, and OXC, are not associated with significantly increased risks of congenital malformations compared with no AED exposure control.15, 16 In this study, we found that more than 50% of pregnancies in the unplanned-pregnancy group were not prescribed AEDs during pregnancy, which may be because those patients feared drug teratogenicity and had rarely consulted epileptologist before and during pregnancy for relevant knowledge of epilepsy and AED compliance. This absence AED use may also explain the greater number of GTCS attacks in the unplanned-pregnancy group.
The most commonly used AEDs as monotherapy in first trimester were LTG, LEV, and OXC in the planned group, which is in accordance with current guidelines and opinions.14, 26, 27 However, in the unplanned group, LTG and VPA were among the medications most commonly prescribed. In Shaanxi Province, in the last decade, we have been implementing a program on rational drug selection for WWE. This program could make many WWE in this study be prescribed with LTG at the onset of illness. VPA is a broad-spectrum AED with potent antiepileptic effects in WWE.23, 24 Additionally, it is the most teratogenic AED, with a several-fold increase in MCMs risk.15, 16, 25 In the planned-pregnancy group, no WWE took VPA as monotherapy. This finding could also be attributed to the promotion of our program.
Compared with planned-pregnancy group, the unplanned group had a relatively high rate of induced abortions. This choice was likely made because of the following reasons: 1) fear of the effect of frequent seizures on the fetus; 2) fear of AEDs teratogenicity, or 3) abnormal prenatal examination. In addition, the unplanned group tended to have a greater rate of SFL, which could be also attributed to more GTCS attacks in the unplanned-pregnancy group.
Adverse fetal outcomes of WWE mainly include MCMs, cognitive outcomes such as impaired intellectual and verbal performance, autism spectrum disorder, and growth restriction (i.e., being small for gestational age or smaller than normal head circumference).23, 28-30Our study focused on MCMs. MCMs are defined as structural abnormalities with significant interference with function and/or require surgery for correction.31, 32 Results from Swedish registries demonstrated that among the 1,429,652 included births, MCM prevalence among AED-exposed offspring was 6.7% and was 4.7% in offspring of WWE without AED treatment.4 Recent data from the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) showed that prevalence of MCMs in offspring exposed prenatally to AED monotherapy ranged from 2.8% to 10.3%, depending on the type of AEDs.15 In the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study, adverse fetal outcomes including fetal loss and MCMs were significantly more common in WWE than in healthy pregnant women.33
In our study, the MCM rate was significantly lower in the planned-pregnancy group (1.6%) than in the unplanned-pregnancy group (7.5%). This decrease in MCMs rate could be partly because of the relatively less use of VPA, PB, phenytoin (PHT), CBZ, and topiramate (TPM) in the planned-pregnancy group than in the unplanned group. The five aforementioned AEDs were reported in the EURAP registry to be related to a high prevalence of MCMs.15 For types of MCM, cardiac defect was most common in both the planned and unplanned group, which was consistent with the finding of the EURAP registry.15 However, in the unplanned-pregnancy group, except for cardiac defect, there were cases of bifid spine, cleft lip/palate, hypospadias, conjoined twins, and anotia. Encouragingly, the planned-pregnancy group only had an MCM prevalence of 1.6%, which indicates that optimized pregnancy management can significantly decrease the risk of offspring adverse outcomes.
This study has several limitations. First, our study assessed a relatively small sample and was conducted at a single site in a university hospital setting. Thus, validation of our findings in different areas and with a large sample would be necessary to better define the importance of pregnancy planning. Second, instead of all types of seizures, we recorded only the number of GTCS during pregnancy, which has been reported to have significant negative effects on the offspring of WWE. Notably, because of the nature of this retrospective study, recording an accurate number of seizures other than GTCS was difficult. Third, detailed information on neonates such as birth weight and Apgar score was not available at the time of our study, which prevented comprehensive analysis of the effect of pregnancy planning on neonatal outcomes. Our study also did not record minor congenital malformations such as ocular hypertelorism, lop ear, hypoplastic fingernails, and ankyloglossia, etc. In addition, tobacco smoking and alcohol consumption during pregnancy were not recorded. These factors have also been reported to affect fetal outcomes.34, 35