Our brain is the most intricated organ of our body. It is, therefore, unsurprising that external factors to which the fetus is exposed to during its development, such as drugs, alcohol, environmental toxicants, and medicines may have lasting effects that extend into adulthood [1,2]. It is proven that the brain undergoes sequential development, starting with the early formation of the brainstem, followed by the later development of the cerebral hemispheres, and concluding with the formation of the cerebellum. Consequently, the timing and severity of gestational insults and toxicants exposure are crucial factors that influence the type of brain injury, the extent of its impact on an individual's function after birth, and the manifestation of specific neurological disorders [3].

In recent months, a case involving two important medicines, with decades of widespread and consolidated use throughout the population, has come to light. We are talking about valproate and topiramate, which are usually prescribed for bipolar disorders, epilepsy management, and migraine prevention [4,5].

Valproate is a simple branched-chain fatty acid and, despite its 40 years of clinical use, its mechanisms of action in epilepsy, bipolar disorders and migranes are still not fully elucidated. Valproate has been shown to increase brain levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) probably by inhibiting succinic semialdehyde dehydrogenase. Evidence also suggests a direct inhibitory effect of valproate on voltage-gated Na⁺ channels, suppressing high-frequency firing of neurons, and possibly indirect effects on non-GABAergic neurotransmission [6].

Topiramate, a second-generation antiepileptic drug (AED), exhibits a multifaceted mechanism of action. It has been demonstrated to block Na⁺ channels, enhance GABA-mediated inhibition of GABA_A receptors, reduce excitatory actions of glutamate via the AMPA receptor, inhibit high-voltage calcium channels, and inhibit carbonic anhydrase [7].

Consequently, of recent findings, restrictions have been implemented in Europe for both medicines, as real-world evidence demonstrated a link between their administration and possible neurodevelopmental disorders in children born from parents taking the drugs [8,9]. Namely, neurodevelopmental disorders encompass developmental challenges that emerge in early childhood, such as autism spectrum disorders, intellectual disabilities, communication disorders, attention deficit/hyperactivity disorders, and movement disorders.

Specifically, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has review data on the potential risk of neurodevelopmental disorders (NDDs) in children exposed in the womb to topiramate-containing medicines and a few months afterwards in children conceived by fathers taking valproate during the 3 months before conception. Subsequently, in September 2023 and January 2024, respectively, PRAC recommended some precautionary measures for both scenarios. Such precautions were endorsed shortly after by EMA’s Coordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh), as recommended. In particular, topiramate must not be used to prevent migraine or manage body weight during pregnancy and patients who can become pregnant must use effective birth control measures. Moreover, the medicine must be avoided during pregnancy even for epilepsy patients, unless there is no other suitable treatment available. As for valproate, male patients should begin treatment while being supervised by a specialist, and doctors must inform patients of potential risks, discuss contraception, and regularly review treatment when planning to conceive [3,4].

As for valproate, this conclusion was reached taking into account results obtained in a retrospective observational study [10] which collected data from national registers of Norway, Denmark, and Sweden. According to preliminary results, 5 out of 100 children born from men taking valproate in the 3 months before conception had a neurodevelopmental disorder, compared to 3 out of 100 children when born to fathers treated with lamotrigine or levetiracetam, which represent alternatives to valproate. Unfortunately, the study did not examine the risk in offspring when fathers ceased valproate use more than 3 months before conception: this could be an interesting gap to fill for future research! Nevertheless, the risk of neurodevelopmental disorders in children due to men taking valproate resulted in being lower than the previously confirmed risk observed in children born to women taking the same drug (5/100 vs 30/100, respectively). Moreover, it is reported that this study on male patients presented some limitations, including the definition of NDDs used in the study and the type of epilepsy patients had. Following the submission of study results, companies reported errors in the Norwegian database to the PRAC, the extent of which remains unclear. Consequently, the PRAC has urged companies to promptly provide analyses of corrected data and additional information to address the identified limitations. Additionally, the study was not large enough to determine for which neurodevelopmental disorders children might face an elevated risk for. Nonetheless, precautionary measures were implemented [3]. It is worth noting that behavioral and neurological alterations were seen in mice exposed in utero to valproate [11]. Valproate is also not recommended for use during pregnancy, due to the potential risk of congenital malformations (birth defects) [12].

For topiramate, two recent observational studies suggested that children born to mothers with epilepsy, exposed to topiramate in utero, face a two- to three-fold increased risk of neurodevelopmental disorders. It must be noted, however, that a third study did not identify such a connection, and that the first two studies used largely the same datasets. It was further noted that birth defects are more likely to occur (4 to 9 out of every 100 children) in pregnancies where topiramate is used, compared to those where the medication is not taken (1 to 3 out of every 100 children), as well as reduced growth of the fetus [9]. Nevertheless, another cross-sectional study from the UK Epilepsy and Pregnancy Register showed that children exposed to topiramate in utero had poorer levels of adaptive behavior with a dose response effect. In particular, significant dose-response associations were observed, with lower adaptive behavior scores in cases of high-dose (>200 mg/d) topiramate exposure [13]. Another recent cohort study revealed higher adjusted hazard ratios for autism spectrum disorder (2.8, 95% CI: 1.4–5.7) and intellectual disability (3.5, 95% CI: 1.4–8.6) following topiramate exposure, surpassing those associated with valproate exposure [14]. Manufacturers marketing topiramate are required to conduct a drug utilization study along with surveys involving healthcare professionals and patients. These efforts aim to evaluate the effectiveness of the previously mentioned implemented measures.

The mechanisms of action underlying the development of NDDs caused by both valproate and topiramate in the brain are not yet fully understood. Various contributing factors, including the drug's pharmacological properties and specific characteristics of the central nervous system disorder, may come into play, as cognitive problems usually have a multifactorial origin [15].

From a clinical perspective, it is crucial for both male and female patients to consult their doctor before discontinuing their medication. Abrupt cessation of epilepsy treatment could potentially trigger seizures. Other options to valproate and topiramate exist, such as metoprolol, propranolol, and timolol for migraine therapy [16], while for epilepsy lamotrigine and levetiracetam are considered safer medication options for use during pregnancy [17]. It's crucial to consult with your healthcare provider to determine the most suitable treatment option for your specific case.

Research on the impact of xenobiotic exposure at various stages of pregnancy on the brain is crucial. This is particularly true as these substances often have specific sensitive time-windows during prenatal development, where exposure may disrupt critical developmental events, thereby increasing the risk of neurodevelopmental disorders. Notably, the majority of these critical periods occur prenatally rather than postnatally [18]. Moreover, if the valproate case is confirmed, it will bring attention to another issue, as it is commonly believed that a father's exposure to xenobiotics will not have any direct effect on the fetus.

It is therefore crucial to conduct ad-hoc well-designed preclinical studies that include comprehensive behavioral analyses of offspring born from parents’ prenatal exposure to drugs directly affecting the brain, especially considering that such chemicals are generally small and highly lipophilic and can thus easily cross the barrier constituted by the placenta. The cases of valproate and topiramate demonstrated that classic reproductive toxicity studies may be lacking in adequately capturing the full spectrum of potential risks and outcomes associated with these medications during pregnancy.