REDUCED HORMONE LEVELS

Menstrual abnormalities, including irregular menstrual cycle, oligo‐, poly‐, or amenorrhea, are more common in women with epilepsy than in the general population.^3,4 Underlying causes are likely multifactorial and include frequent seizures and the use of specific ASM, such as valproate, carbamazepine, or polytherapy. Polycystic ovarian syndrome (PCOS) has been commonly reported in women with epilepsy and was initially attributed to the use of valproate. However, it also affects women taking other ASMs and those who are untreated.⁵

Reduced hormone levels have been reported in men and women with epilepsy. This may be due to ASM, particularly enzyme‐inducers, but a direct effect of epilepsy and seizures, particularly in temporal lobe epilepsy, has also been suggested.⁶

FERTILITY

Birth rates for women with epilepsy are often considerably lower than those in the general population.⁷ This is likely to be multifactorial, including psychosocial factors and biological reasons, such as an increase in anovulatory cycles, frequent occurrence of PCOS, and infertility, which has also been associated with polypharmacy.^8,9

Birth rates in men with epilepsy are also reduced.^10,11 They have been found to have more abnormal sperm motility and morphology compared to controls. This includes men treated with different ASM,¹² but has also been seen in untreated men.¹³ In animal models, valproate has been associated with testicular reversible toxicity,^14,15 but this has not been reported in humans.

Women 

ASM exposure during pregnancy has been associated with teratogenicity and obstetric complications, but the magnitude of the risk varies by ASM. The risk seems greater at higher doses and with polytherapy compared to monotherapy. Issues include foetal loss, intrauterine growth retardation, congenital malformations, impaired neurodevelopmental development, and behavioural problems. Valproate carries the highest risk of currently used ASM, with a risk of congenital malformations of around ten per cent.²¹ There are also cognitive concerns, as almost half of exposed children have extra educational needs,²² and neurodevelopmental disorders such as autism spectrum disorder.²³ This led to measures to reduce valproate use. In many countries, valproate can only be used if other treatment options are ineffective or not tolerated, as judged by experienced specialists. In the United Kingdom, women must also use highly effective contraception and sign an annual Risk Acknowledgement Form.^24,25

A review of the teratogenic effects of ASM used in monotherapy found that lamotrigine and levetiracetam are the safest ASM to use during pregnancy. Overall, data support no increased risk of congenital malformations at the usual maintenance doses for these drugs.²⁶ For lamotrigine, data for an increased risk of malformations at higher doses are contradictory. For other ASM, higher risks have been associated with higher doses.²⁷ The use of carbamazepine, phenobarbital, phenytoin, and topiramate during pregnancy is associated with an increased risk of congenital malformations compared with the general population and unexposed women with epilepsy. Pregabalin may be associated with a slightly increased risk of congenital malformations, but further data are needed. The risks remain uncertain for gabapentin, oxcarbazepine, and zonisamide, and the possibility of increased risk can neither be confirmed nor ruled out. For newer ASM, there is limited data regarding the risks of teratogenicity (Table 16.2).

Concerning the risk of neurodevelopmental disorders, for most ASM, data are limited, so the risks remain uncertain and cannot be ruled out. For phenobarbital and phenytoin, despite some inconsistent findings, evidence supports adverse effects on neurodevelopment. Topiramate is associated with poorer developmental outcomes²⁸ and should not be used during pregnancy. Some countries have introduced rules similar to those for valproate.²⁹ A recent study, including women taking valproate, lamotrigine, topiramate, or untreated, showed an increased risk for autism for children of mothers with epilepsy, even if untreated. The risks were highest with valproate and topiramate, but after adjusting for indication and other confounders, the risk remained only for valproate.³⁰

In most studies, polytherapy has been associated with higher teratogenicity risks; however, the risks of each ASM in the combination may also influence this.³¹

Comprehensive, timely preconception counselling is imperative to ensure women are informed about potential ASM risks. This needs to give sufficient time to instigate changes, if necessary, to reduce potential teratogenicity. Current guidelines recommend that clinicians initiate joint decision‐making with women of childbearing potential to optimise ASM to maximise seizure control and foetal outcomes.³² This should occur at the earliest possible opportunity preconceptionally, and counselling on pregnancy in women with epilepsy should be repeated annually.

Folic Acid

Women with epilepsy are often advised to take folic acid 5 mg daily during pregnancy, rather than the usually recommended 0.4 mg dose. Data supporting the use of folic acid in reducing the risk of major congenital malformations is limited.³³ The optimal folic acid dose and treatment duration to obtain protection remain uncertain. Some recent studies suggested an association between doses >1 mg/day and increased risk of cancer in offspring and mothers, but there were confounders.^34,35 Overall, clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy.³²

Men 

In addition to the potential infertility risks, a recent post‐authorisation safety study evaluated the risk of paternal exposure to valproate.³⁶ This suggested an increase of neurodevelopmental disorders in the children of men taking valproate at the time of conception, compared to fathers taking lamotrigine or levetiracetam. This has led to several countries introducing measures to reduce the use of valproate in men, if considering having children. However, the data and measures have been disputed as other studies have not shown increased risks associated with a man taking valproate or other ASM at the time of conception.^{37, 38} Prospective studies are required to clarify potential risks, enabling men to make informed decisions with accurate information.