The studies contain limited numbers of exposed pregnancies and for the studies that suggest an increased risk it is considered that the results may be affected by confounding. Clinical studies examining the effect of polytherapy are more limited and are restricted to data from the UK Epilepsy and Pregnancy Registry and the Australian Pregnancy Registry, involving more than 300 exposed pregnancies. Non-clinical studies in the published scientific literature in rodents showed neurodegenerative changes in the cerebral cortex and hippocampus of fetuses exposed to gabapentin during early and mid-pregnancy (Prakash et al 2008 and Badawy et al 2019). However, limitations in the design of these studies make them insufficient to determine the effects of gabapentin on the developing nervous system. An unpublished Good Laboratory Practice compliant study in pregnant rats showed non-dose-related behavioural changes in the performance of the offspring during tests of activity and emotionality but the changes were not statistically significantly different from those of the control animals. Overall, the non-clinical data does not provide clear evidence that exposure to gabapentin during pregnancy adversely affects the development of the central nervous system.
Systematic review
- A group of disorders in which the development of the central nervous system is disturbed.
- A statistical range of numbers with a specific probability that a particular value lies within this range.
- The incidence of disease in the exposed group is compared with the incidence of disease in the unexposed group.
- The brain can be divided into specific regions which have specific functions.
- When habituation occurs, the action potentials that result from the stimulus dampen down over time.
The available clinical data on the risk of neurodevelopmental disorders with levetiracetam is extremely limited and involves data on around 100 children (Shallcross et al 2011, Bech et al 2018, Huber-Mollema et al 2019 and 2020). Levetiracetam was also included in the meta-analysis by Veroniki et al (2017b). The available data do not suggest an increased risk of cognitive developmental delay, psychomotor developmental delay and autism/dyspraxia. However, as the cerebrumiq numbers of exposures remains limited this cannot be concluded definitively and so it is important that any emerging data is kept under close review.
It has been known for many years that valproate can cause physical birth abnormalities in the child. More recent studies have also shown that it can seriously affect the child’s brain development which may become more apparent as they grow up, particularly in relation to learning and thinking abilities. Before planning a pregnancy women are encouraged to have pre-conception counselling. Pre-conception counselling is an appointment, or series of appointments, with a doctor or nurse who knows about pregnancy and epilepsy. This discussion will take into account each woman’s circumstances and help them decide which dose of which epilepsy medicine or combination of medicines is best for them and their baby during pregnancy. Non-clinical data report reduced fetal weights in offspring exposed to topiramate during pregnancy.
Given the limited data, no firm conclusions can be drawn with regards to the safety of use of these antiepileptic drugs during pregnancy and the risks remain unclear. Non-clinical studies report reduced fetal body weights in rats and rabbits following exposure to pregabalin during pregnancy but this occurred at plasma concentrations sufficiently higher than human therapeutic concentrations. Dosing of pregabalin during gestation and lactation induced offspring developmental toxicity in rats at exposures 5 times or greater than the maximum recommended human exposure. A further study by Trivedi et al 2018 in the Kerala Pregnancy Registry investigated spontaneous fetal loss in pregnancies exposed to phenytoin compared with pregnancies in non-exposed women with epilepsy.
Confidence intervals (CI) are used to assess the true difference in risk between two groups, and usually accompany ratio values such as odds ratios, hazard ratios and ‘observed versus expected’ ratios. A 95% CI suggests that there is a 95% chance that the real difference between two groups is within this interval. If a 95% CI does not cross 1, the ratio is regarded as statistically significant.
Mental development index
- To help people with CVI find things, they need them to stay where they are, so they can remember where to find them (because looking is difficult).
- The Good Laboratory Practice studies are well designed for the purposes of detecting teratogenic effects of substances.
- One of the three 3-month periods that a human 9-month pregnancy can be divided into.
- Overall, the data are supportive of a median prevalence of congenital malformations with topiramate of 4–5% and an increased risk compared with unexposed women with or without epilepsy.
- When we have this congruence in our society then we will find it also in our children.
Limited published non-clinical studies report of teratogenicity in rodents however, in company sponsored studies no teratogenicity was reported in rodents and rabbits at plasma concentrations far exceeding human therapeutic doses. In considering the conflicting data regarding the teratogenic potential of pregabalin, no firm conclusions can be drawn of its potential teratogenic effect. Prescribing trend data show that prescribing prevalence rates for pregabalin are high and have been increasing over time but this is reflective of the increasing use in the pain and anxiety indications. In June 2019, the rate was 75.94 prescriptions per 10,000 eligible women of childbearing age women (CPRD GOLD), making pregabalin the second most frequently prescribed antiepileptic drug in women of childbearing age among the drugs which have been prioritised for review.
During the critical period, synapses that receive visual stimulation and pass on action potentials into the visual cortex are retained and strengthened. Synapses that do not receive visual stimulation, so the neurones between them are not firing, are removed. This means that if visual stimulation does not occur during the critical period (i.e. if a baby is born with cataracts which obscure vision or if they are born in a cave) then their visual cortex will not develop properly because many of the synapses will have been destroyed. Evidence for a ‘critical period’ comes from some ethically-dubious experiments on kittens (see below). The visual cortex is a region at the back of our brains and forms part of the cerebral cortex. Neurones in the visual cortex receive information from either our right or left eye and are clustered together in structures called ocular dominance columns.
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A group of disorders in which the development of the central nervous system is disturbed. The disorders can affect emotion, learning ability, self-control and memory. They can also manifest as conditions such as attention deficit hyperactivity disorder or autism spectrum disorder. NICE guidance recommends that pregabalin may be considered by the tertiary epilepsy specialist in the treatment of focal seizures if adjunctive treatment is not effective or not tolerated. Therefore, its use in epilepsy is likely limited and the product information reflects that the available data on pregnancy outcomes is also limited. A regulatory-compliant company-sponsored study in pregnant rats reported an increased incidence of fetal malformations at human therapeutic doses (approximately 1.2 to 4 times the maximum human recommended dose).