Effect of valproic acid on fetal and maternal organs in the mouse: A morphological study

Emmanouil-Nikoloussi, Elpida-Niki; Ng, Foroglou; Kerameos-Foroglou, Ch.; Ja, Thliveris

doi:10.1016/s1286-0115(04)97999-4

Cited by 16 publications

(12 citation statements)

References 26 publications

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“…In the present study with VA, no obvious histopathological differences in the placentae were observed with any of the immune stimulant or VA treatment groups. Although VA is cytotoxic to the placenta in rats (Khera, 1992), our findings concur with those of Emmanouil-Nikoloussi et al (2004), who also found no placental pathology from VA exposure in mice. Detailed morphometric analysis was not conducted that may have identified alterations in specific placental compartments with either VA treatment or maternal immune stimulation; however, if these changes were present, they were slight and not appreciable by diligent visual inspection.…”

Section: Discussionsupporting

confidence: 90%

Valproic acid‐induced fetal malformations are reduced by maternal immune stimulation with granulocyte‐macrophage colony‐stimulating factor or interferon‐γ

Hrubec

Yan

et al. 2006

Anat. Rec.

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Valproic acid, a drug commonly used to treat seizures and other psychiatric disorders, causes neural tube defects (NTDs) in exposed fetuses at a rate 20 times higher than in the general population. Failure of the neural tube to close during development results in exencephaly or anencephaly, as well as spina bifida. In mice, nonspecific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes-induced NTDs. We hypothesized that nonspecific activation of the maternal immune system with interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce valproic acid (VA)-induced defects as well. Female CD-1 mice were given immune stimulant prebreeding: either IFN-g or GM-CSF. Approximately half of the control and immune-stimulated pregnant females were then exposed to 500 mg/kg VA on the morning of gestational day 8. The incidence of developmental defects was determined on gestational day 17 from at least eight litters in each of the following treatment groups: control, VA only, IFN-g only, IFN-g þ VA, GM-CSF only, and GM-CSF þ VA. The incidence of NTDs was 18% in fetuses exposed to VA alone, compared to 3.7% and 2.9% in fetuses exposed to IFN-g þ VA, or GM-CSF þ VA respectively. Ocular defects were also significantly reduced from 28.0% in VA exposed groups to 9.8% in IFN-g þ VA and 12.5% in GM-CSF þ VA groups. The mechanisms by which maternal immune stimulation prevents birth defects remain unclear, but may involve maternal or fetal production of cytokines or growth factors which protect the fetus from the dysregulatory effects of teratogens. Anat

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Section: Discussionsupporting

confidence: 90%

Valproic acid‐induced fetal malformations are reduced by maternal immune stimulation with granulocyte‐macrophage colony‐stimulating factor or interferon‐γ

Hrubec

Yan

et al. 2006

Anat. Rec.

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“…VPA treatment during early neural tube formation (E8 in the mouse) results in exencephaly, which is the rodent equivalent of human anencephaly. Others reported that spina bifida can be induced in some mouse strains when injected three times at 6-h intervals on E9 [Ehlers et al, 1992; Emmanouil-Nikoloussi et al, 2004; Finnell et al, 1988; Menegola et al, 1996]. Pharmacokinetic study showed that VPA can induce neural tube defects in exposed mouse embryos when this drug reaches maternal plasma concentrations of 225 μg/ml, irrespectively of the route of administration [Nau, 1985].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Antiepileptic drugs and pregnancy outcomes

Wlodarczyk

Palacios

George

et al. 2012

American J of Med Genetics Pt A

112

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The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

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“…VPA treatment during early neural tube formation (E8 in the mouse) results in exencephaly, which is the rodent equivalent of human anencephaly. There were also posterior NTDs produced In some mouse strains when injected three times at 6-h intervals on E9 [128–131]. NTDs can be induced by VPA in exposed mouse embryos when the maternal plasma VPA concentration is in excess of 225 μg/ml, irrespective of the route of administration [132].…”

Section: Mechanisms Of Aed Teratogenicitymentioning

confidence: 99%

Teratogenic effects of antiepileptic drugs

Hill

Wlodarczyk

Palacios

et al. 2010

Expert Review of Neurotherapeutics

127

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Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure.

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Effect of valproic acid on fetal and maternal organs in the mouse: A morphological study

Cited by 16 publications

References 26 publications

Valproic acid‐induced fetal malformations are reduced by maternal immune stimulation with granulocyte‐macrophage colony‐stimulating factor or interferon‐γ

Valproic acid‐induced fetal malformations are reduced by maternal immune stimulation with granulocyte‐macrophage colony‐stimulating factor or interferon‐γ

Antiepileptic drugs and pregnancy outcomes

Teratogenic effects of antiepileptic drugs

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