Valproate in the treatment of epilepsy in girls and women of childbearing potential

This document provides guidance on the use of valproate in girls and women of childbearing age from a joint Task Force of the Commission on European Affairs of the International League Against Epilepsy (CEA‐ILAE) and the European Academy of Neurology (EAN), following strengthened warnings from the Coordination Group for Mutual Recognition and Decentralised Procedures‐Human (CMDh) of the European Medicines Agency (EMA), which highlight the risk of malformations and developmental problems in infants who are exposed to valproate in the womb. To produce these recommendations, the Task Force has considered teratogenic risks associated with use of valproate and treatment alternatives, the importance of seizure control and of patient and fetal risks with seizures, and the effectiveness of valproate and treatment alternatives in the treatment of different epilepsies. The Task Force's recommendations include the following: (1) Where possible, valproate should be avoided in women of childbearing potential. (2) The choice of treatment for girls and women of childbearing potential should be based on a shared decision between clinician and patient, and where appropriate, the patient's representatives. Discussions should include a careful risk–benefit assessment of reasonable treatment options for the patient's seizure or epilepsy type. (3) For seizure (or epilepsy) types where valproate is the most effective treatment, the risks and benefits of valproate and other treatment alternatives should be discussed. (4) Valproate should not be prescribed as a first‐line treatment for focal epilepsy. (5) Valproate may be offered as a first‐line treatment for epilepsy syndromes where it is the most effective treatment, including idiopathic (genetic) generalized syndromes associated with tonic–clonic seizures. (6) Valproate may be offered as a first‐line treatment in situations where pregnancy is highly unlikely (e.g., significant intellectual or physical disability). (7) Women and girls taking valproate require regular follow‐up for ongoing consideration of the most appropriate treatment regimen.     

From cutting edge to guideline: A first step in harmonization of the zebrafish embryotoxicity test (ZET) by describing the most optimal test conditions and morphology scoring system

In the last couple of years, the interest in the zebrafish embryotoxicity test (ZET) for use in developmental toxicity assessment has been growing exponentially. This is also evident from the recent proposal for updating the ICHS5 guideline. The methodology of the ZET used by the different groups varies greatly. To further evaluate its successfulness and to take the ZET to the next level, harmonization of procedures is crucial. In the present study, based on literature and empirical data, the most optimal study design regarding temperature, test chamber, exposure period, presence of chorion, solvent use, exposure method, choice of concentrations, and teratogenic classification is proposed. Furthermore, our morphology scoring system is reported in detail as protocol to further enhance study design harmonization.     

Developmental toxic potential of 1,3-dichloro-2-propanol in Sprague–Dawley rats

This study investigated the potential adverse effects of 1,3-dichloro-2-propanol (1,3-DCP) on pregnant dams and the embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague–Dawley rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 10, 30, and 90 mg/kg per day (n = 10 for each group). All dams underwent Caesarean sections on GD 20, and their fetuses were examined for morphological abnormalities. Maternal toxicity was noted at 90 mg/kg/day. Manifestations of toxicity included clinical signs of illness, lower body weight gain, decreased food intake, and increases in the weight of the adrenal glands and the liver. Developmental toxic effects including decreases in fetal body weight and increases in visceral and skeletal variations also occurred at the highest dose. At 30 mg/kg, only a minimal maternal toxicity, including a decrease in maternal food intake and an increase in the liver weight, was observed. No adverse maternal or developmental effects were observed at 10 mg/kg/day. These results revealed that a 14-day repeated oral dose of 1,3-DCP was minimally embryotoxic but not teratogenic at a maternal toxic dose (90 mg/kg/day), and was not embryotoxic at a minimally maternal toxic dose (30 mg/kg/day) in rats. Because the developmental toxicity of 1,3-DCP was observed only in the presence of maternal toxicity, it is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of 1,3-DCP is considered to be 10 mg/kg/day for dams and 30 mg/kg/day for embryo-fetal development.     

Graves’ disease and pregnancy

This section deals with the specificities of managing Graves’ disease during pregnancy. Graves’ disease incurs risks of fetal, neonatal and maternal complications that are rare but may be severe: fetal hyper- or hypothyroidism, usually first showing as fetal goiter, neonatal dysthyroidism, premature birth and pre-eclampsia. Treatment during pregnancy is based on antithyroid drugs alone, without association to levothyroxine. An history of Graves’ disease, whether treated radically or not, with persistent maternal anti-TSH-receptor antibodies must be well identified. Fetal monitoring should be initiated in a multidisciplinary framework that should be continued throughout pregnancy. Neonatal monitoring is also crucial if the mother still shows anti-TSH-receptor antibodies at end of pregnancy or underwent antithyroid treatment. The risk of recurrence of hyperthyroidism in the weeks following delivery requires maternal monitoring. The long-term neuropsychological progression of children of mothers with Graves’ disease is poorly known.     

Review shows that early foetal alcohol exposure may cause adverse effects even when the mother consumes low levels

Aim

Studies are increasingly focusing on the effects of prenatal alcohol exposure (PAE) on child health. The aim of this review was to provide paediatricians with new insights to help them communicate key messages about avoiding alcohol during pregnancy.

Methods

Inspired by the 7th International Conference on Fetal Alcohol Spectrum Disorder, which focused on integrating research, policy and practice, we studied English language papers published since 2010 on how early PAE triggered epigenetic mechanisms that had an impact on the development of some chronic diseases. We also report the findings of a human study using three‐dimensional photography of the face to explore associations between PAE and craniofacial phenotyping.

Results

Animal models with different alcohol exposure patterns show that early PAE may lead to long‐term chronic effects, due to developmental programming for some adult diseases in cardiovascular, metabolic and renal systems. The study with three‐dimensional photographing is very promising in helping paediatricians to understand how even small amounts of PAE can affect craniofacial phenotyping.

Conclusion

Even low levels of PAE can cause adverse foetal effects and not just in the brain. It is not currently possible to determine a safe period and level when alcohol consumption would not affect the foetus.     

Teratologic studies on the Himalayan rabbit: new aspects of thalidomide-induced teratogenesis

The aim of our study was to determine the period of maximum sensitivity for the induction of characteristic malformations with thalidomide (TH) in Himalayan rabbits. TH was administered orally in different doses (50, 100, 150 and 200 mg/kg) four times at 24-h intervals starting at 192 h of gestation. The malformations affected various organs: renal defects (dysplasia) and limb anomalies (dysmelia) — which had never occurred spontaneously in this strain — appeared as dose-dependent effects of the drug. By administering single doses of TH (200 and 300 mg/kg body wt) between hours 192 and 264 of gestation, we discovered the different periods of maximum sensitivity for induction of renal dysplasia (clearly prior to the 220th h of gestation) and dysmelia (between hours 230 and 240 of gestation). The types of limb malformations that we observed in the rabbit were identical to those produced in man following the intake of TH. Three doses of TH (300 mg/kg each) given between hours 222 and 228 of gestation produced characteristic limb malformations in 9 of 11 litters treated. These results make it possible to conduct in vivo experiments on a readily available laboratory animal with minor drug exposure of the gravid dam and under avoidance of toxic side effects.     

Repeated Neural Tube Defects and Valproate Monotherapy Suggest a Pharmacogenetic Abnormality

Valproate (VPA) is an effective, widely used antiepileptic drug. Unfortunately its use in pregnant women is associated with neural tube defects in the offspring. Although the etiology of neural tube defects is multifactorial, there is evidence that underlying genetic susceptibility plays a part. We describe two women taking moderate doses of VPA who repeatedly bore children with neural tube defects, despite folate supplementation. This suggests a pharmacogenetic susceptibility to the teratogenic effects of VPA.