Among the 61 WWE included in this study, 57.4% were seizure-free during pregnancy. Thomas SV  reported a proportion of 47.8%, while Battino D and Galappatthy P  reported 66.6% and 64%, respectively, so our finding was within the above range, with no significant difference. In addition, 73.8% of WWE had no significant changes in epileptic frequency. Therefore, even if WWE have special physiological changes during pregnancy, epileptic frequency during pregnancy is not affected in most patients. Although 15 WWE had an increased frequency of seizures during pregnancy in this study, there is currently insufficient evidence that pregnancy can induce seizures or affect epileptic frequency.
Most WWE could take AED regularly during pregnancy. Only a small number of WWE adjusted AED dose or type when they were pregnant, and during follow-up, it was found that these WWE generally considered that AED may have side effects on the fetus. However, they ignored the greater risk that epileptic seizures may bring to the fetus. There is insufficient awareness of the risk of adverse pregnancy outcomes, and the initiative of treatment is not high. Therefore, clinicians need to educate the WWE to make them realize the importance of seizure control for themselves and their fetuses.
This study found that new AEDs such as levetiracetam and lamotrigine are increasingly used, while sodium valproate has gradually been reduced during pregnancy. As levetiracetam and lamotrigine are currently recognized to have the least impact on fetal teratogenicity, they have become the most commonly used AEDs for women of childbearing age. Sodium valproate has significant teratogenicity to the fetus, and an obvious impact on the cognitive function of newborns[7, 8]. Although sodium valproate is effective in treatment of epilepsy, clinicians do not consider it as the first choice in treatment of WWE of childbearing age. Especially for WWE during pregnancy, given the relatively high teratogenicity risk of traditional AEDs to the fetus, the new AEDs have been used as the main drugs in WWE of childbearing age. As a traditional AED, carbamazepine has higher teratogenicity than new AEDs. However, in this study, carbamazepine was the most commonly used AED during pregnancy, and similar results were observed in previous studies[5, 9], which may be due to different types of epileptic seizures, and the rate of use in this study was based on monotherapy. Patients who did not take AED or were treated with polytherapy were excluded, resulting in a smaller sample size and higher utilization of carbamazepine.
The cesarean section rate of WWE is higher than the general population[10–12]. In 2014, China’s Maternal and Child Health Annual Report mentioned that the cesarean section rate in China was 35%. In this study, the cesarean section rate of WWE was 73.8%, which was significantly higher. Such a high cesarean section rate may be related to the following factors: due to social trends, increasing number of pregnant women choose cesarean section to reduce the pain during childbirth, and this trend is particularly obvious among urban women. Patients in this study were all from developed coastal areas such as Shanghai, Jiangsu and Zhejiang provinces, so the difference may be even greater. Moreover, obstetricians may worry about sudden seizures during natural childbirth, leading to adverse pregnancy outcomes for the mother and baby, and therefore recommend patients to have a cesarean section, which may have led to an obvious difference in this study given the small sample size.
Although most WWE can give birth smoothly and most of their babies are healthy, the risk of adverse pregnancy outcomes in these patients is higher than the general population[14, 15]. The main adverse pregnancy outcomes include spontaneous abortion, infants below gestational age, premature infants, low birth weight infants, and pre-eclampsia. Other adverse pregnancy outcomes include induction of labor, prenatal hemorrhage, postpartum hemorrhage, low Apgar score (< 7 points) and fetal loss (fetal death after 20 weeks of pregnancy). In this study, the probability of adverse pregnancy outcomes was 14.8%, which was lower than previously reported. Seizures and medication may have caused this difference.
We compared seizures before pregnancy, seizures during pregnancy, as well as medications between WWE with adverse pregnancy outcomes and WWE with normal pregnancy outcomes. It was found that whether AED was taken during pregnancy had no effects on pregnancy outcomes of WWE, which is consistent with a previous study. It is currently believed that polytherapy and traditional AEDs are teratogenic to fetuses of WWE. The malformation of fetuses is closely related to adverse pregnancy outcomes. Therefore, polytherapy and traditional AEDs have an impact on adverse pregnancy outcomes. However, this study did not show similar findings, which may be because the majority of WWE took monotherapy and new AEDs. Monotherapy and new AEDs are widely used for WWE of childbearing age, and well recognized by clinicians.
However, this study also found that WWE have a significantly higher probability of adverse pregnancy outcomes. A previous study showed that epileptic seizures during pregnancy can lead to increased mortality in patients, and the risk of adverse pregnancy outcomes was also higher than the general population. Therefore, the control of seizures during pregnancy is directly related to the health of mothers and babies.
In addition, this study found that epilepsy within one year before pregnancy had a statistically significant effect on pregnancy outcomes. This may be because seizures within one year before pregnancy can predict epileptic recurrence during pregnancy. Hence, we analyzed the factors that may predict seizures during pregnancy, and found that taking AEDs during pregnancy and the number of AEDs had no predictive effects on seizures during pregnancy. A previous study found that WWE who were not treated with AED during pregnancy and those who were treated with polytherapy were more likely to have seizures during pregnancy. There were fewer patients who did not receive AED and polytherapy in this study, which is inconsistent with the previous study result.
Meanwhile, changes in pharmacokinetics of AEDs during pregnancy may lead to lower drug concentrations in the blood, and increase the risk of seizures during pregnancy, especially for new AEDs such as lamotrigine and levetiracetam. Blood concentration of lamotrigine was found to be decreased most significantly during pregnancy, and WWE taking lamotrigine were more likely to have seizures during pregnancy. Therefore, we compared and analyzed WWE taking traditional AEDs and new AEDs, and found that although WWE taking new AEDs were more likely to have seizures during pregnancy than those taking traditional AEDs, there was no statistical significance. Therefore, AED type cannot be used as a predictor of seizures during pregnancy. Additionally, WWE who took new AEDs did not monitor blood drug concentration, so it was not considered that seizures of these patients during pregnancy were caused by decrease of AED concentration. Consequently, we recommend that WWE taking lamotrigine, levetiracetam and other new AEDs should undergo regular blood drug concentration monitoring if they have frequent seizures during pregnancy.
It was also found that WWE who reduced medication by themselves during pregnancy had a higher probability of seizures than those taking AED regularly, but it was not statistically significant after analysis, although patients’ compliance in this study did not predict seizures during pregnancy. We do not recommend that patients reduce AED dose or switch AED type after confirming their pregnancy. They should consult a clinician and obtain a reasonable treatment plan after comprehensive evaluation.
Seizures within one year before pregnancy is called active epilepsy, and seizure-free for more than one year is called inactive epilepsy, and active epilepsy is considered to be an important predictor of seizures during pregnancy, which is consistent with the result of our study. Therefore, if WWE plan to get pregnant, they must inform the clinician and adhere to outpatient follow-up, so as to develop a perfect treatment plan for epilepsy during pregnancy, and achieve safe and smooth delivery, ensuring the health of mothers and babies.
Even though fetuses exposed to AED have a higher rate of teratogenicity than normal fetuses, no fetal or neonatal abnormalities were found in this study. This could be due to the following reasons: the risk of teratogenicity in fetuses exposed to AED in utero is higher than normal fetuses, but the overall incidence is small, and such statistics require multi-center and large samples. Studies have shown that WWE taking traditional AEDs during pregnancy, especially sodium valproate, may have cognitive impairment, developmental delay, and mental retardation in their offspring[18, 19], so WWE chose to take lamotrigine, levetiracetam or other low-teratogenic new AEDs during pregnancy in this study, which further decreased the teratogenic rate of fetuses exposed to AEDs.