VALPROIC ACID | TERIS agent - 1008

TERIS Summary
TERIS Agent Number: 1008 Bibliographic Search Date: 08/2020
Agent Name: VALPROIC ACID    

 

Valproic acid is a commonly used anticonvulsant that is usually taken orally but may be used parenterally. Valproic acid is also used to treat bipolar disorder and neuropathic pain and to prevent migraine headaches.



Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
 
MODERATE TO HIGH

Quality and Quantity of Data on Which Risk Estimate is Based:
 


GOOD TO EXCELLENT

 


Comments:   

1) MAJOR MALFORMATIONS OCCUR IN ABOUT 10% OF INFANTS WHOSE MOTHERS ARE TREATED WITH VALPROIC ACID FOR EPILEPSY DURING THE FIRST TRIMESTER OF PREGNANCY, A RATE THAT IS HIGHER THAN THAT ASSOCIATED WITH MOST OTHER ANTICONVULSANTS (SEE BELOW).

 

2) THE RISK IS GREATER IN WOMEN WHO TAKE VALPROIC ACID IN COMBINATION WITH OTHER ANTICONVULSANTS DURING PREGNANCY THAN IN WOMEN WHO TAKE VALPROIC ACID ALONE (SEE BELOW).

 

3) THE RISK IS GREATER IN WOMEN WHO TAKE VALPROIC ACID IN HIGH DOSES THAN IN WOMEN WHO TAKE VALPROIC ACID IN LOWER DOSES (SEE BELOW).

 

4) DIETARY SUPPLEMENTATION WITH AT LEAST 5 MG/DAY OF FOLIC ACID IS RECOMMENDED TO REDUCE THE RISK OF NEURAL TUBE DEFECTS AMONG THE CHILDREN OF WOMEN WITH EPILEPSY WHO ARE TAKING VALPROIC ACID AND WHO ARE, OR MAY BECOME, PREGNANT (REYNOLDS & GREEN, 2020).

 

5) PRENATAL DIAGNOSIS BY HIGH-RESOLUTION ULTRASOUND EXAMINATION CAN DETECT MOST FETAL NEURAL TUBE DEFECTS AND SHOULD BE OFFERED TO EPILEPTIC WOMEN TREATED WITH VALPROIC ACID DURING PREGNANCY.

 

6) INCREASED RISKS OF COGNITIVE AND BEHAVIOURAL DEFICITS, INCLUDING ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) AND AUTISM SPECTRUM DISORDERS (ASDs) HAVE BEEN ASSOCIATED WITH MATERNAL TREATMENT OF VALPROIC ACID IN PREGNANCY (SEE BELOW).


Summary of Teratology Studies:

MAJOR CONGENITAL ANOMALIES OVERALL

 

Epidemiological studies of malformations in infants born to women who took valproic acid during pregnancy are difficult to interpret because assessment of the effects of anticonvulsant treatment is confounded by many other factors, such as being treated with more than one anticonvulsant at a time and by severity of the underlying condition (Battino & Tomson, 2007; Eadie, 2008; Tomson & Battino, 2009, 2011).

 

The prevalence of major congenital anomalies at one year at birth was 10.3% (95% confidence interval 8.8-12.0) among 1381 infants of mothers treated with valproic acid monotherapy in pregnancy in a longitudinal prospective cohort study from EUROAP, the largest international registry collecting data on antiepileptic medications in pregnancy (Tomson et al., 2018). Similarly, the frequency of major congenital anomalies observed among infants born to 323 women who took valproic acid monotherapy early in pregnancy in the North American AED Registry was 9.3% (95% confidence interval 6.4-13.0) (Hernandez-Diaz et al., 2012).

 

In a comprehensive meta-analysis of 31 studies published between 1974-2015, the pooled estimate of the risk of major congenital anomalies observed among the infants of 2565 women treated during pregnancy with valproic acid monotherapy for seizure disorders was 10.93% (95% confidence interval 8.91-13.13) (Weston et al., 2016; Bromley et al., 2017). In comparison, the rate of congenital anomalies among infants of 2154 mothers without epilepsy was 2.51%.

 

The risk of major malformations among the children of women treated with valproic acid monotherapy early in pregnancy is greater than that seen in the children of women treated with carbamazepine, phenytoin, lamotrigine, or phenobarbital monotherapy during pregnancy (Weston et al., 2016). The risk is even higher among the infants of women who take valproic acid in combination with other anticonvulsant medications during pregnancy (Meador et al., 2008; Harden et al., 2009; Ornoy, 2009; Holmes et al., 2011; Tomson et al., 2011). It appears to be that the risk of major congenital anomalies associated with maternal valproic acid treatment is dose dependent, with higher risks in the children of women who are treated with higher doses or who have higher valproic acid serum concentrations early in pregnancy (Hernandez-Diaz et al., 2012; Weston et al., 2016; Tomson et al., 2018; Blotiere et al., 2019). Genetic factors appear to influence susceptibility to the occurrence of congenital anomalies among women who take valproic acid during pregnancy (Duncan et al., 2001; Kozma, 2001; Malm et al., 2002; Schorry et al., 2005; Duncan, 2007; Kini et al., 2007; Vajda et al., 2013).

 

SPINA BIFIDA

 

An association between the occurrence of spina bifida in infants and maternal use of valproic acid in the first trimester of pregnancy has been demonstrated in many epidemiological studies and clinical series (Moore et al., 2000; Rodriguez-Pinilla et al., 2000; Medveczky et al., 2004; Wide et al., 2004; Duncan, 2007; Werler et al., 2011; Blotiere et al., 2019). The defect observed is usually lumbar or sacral spina bifida; it is often associated with hydrocephalus (Lindhout et al., 1992; Canger et al., 1999). Anencephaly is rarely seen. The best available estimate of the risk of spina bifida among the children of women treated with valproic acid during the first trimester of pregnancy is about 2% in populations in which the background rate of spina bifida is about 1/1000. The risk may be greater in populations with a higher background rate.

 

OTHER CONGENITAL ANOMALIES

 

In a French record-linkage study, 913 mothers were prescribed valproic acid in the first two months of pregnancy had increased risks for the occurrence of specific malformations in their infants, such as spina bifida (n=6; odds ratio=19.4, 95% confidence interval 8.6-43.5), ventricular (n=9; odds ratio=4.0, 95% confidence interval 2.1-7.8) and atrial (n=15; odds ratio=9.0, 95% confidence interval 5.4-15.0) septal defects, and hypospadias (n=8; odds ratio=4.8, 95% confidence interval 2.4-9.8) (Blotiere et al., 2019). In a literature review, the prevalence of orofacial clefts in a total of 4459 infants of mothers treated during pregnancy with valproic acid, either as monotherapy or with other anticonvulsant drugs, was reported to be significantly increased (11.3-fold increased risk for isolated cleft palate and 3.5-fold increased risk for cleft lip and palate) (Jackson et al., 2016).

 

Pooled results of six studies in a meta-analysis, including 465 infants of women treated with valproic acid in pregnancy compared to 303 infants of untreated women with epilepsy, showed significant associations with specific malformations, such as neural tube defects (relative risk=5.30, 95% confidence interval 1.05-26.70), cardiac defects (relative risk=4.85, 95% confidence interval 1.28-18.47), and orofacial clefts/craniofacial defects (relative risk=5.16, 95% confidence interval 1.13-23.69) (Weston et al., 2016).

 

FETAL VALPROATE SYNDROME

 

A distinctive pattern of craniofacial and other anomalies, i.e., a "fetal valproate syndrome," has been described in about half the infants born to women treated with valproic acid during pregnancy (Thisted & Ebbesen, 1993; Moore et al., 2000; Kozma, 2001; Kini et al., 2006; Ornoy, 2009). Features of this syndrome include postnatal growth retardation, microcephaly, trigonocephaly, developmental delay, midface hypoplasia, epicanthal folds, short nose, broad nasal bridge, thin upper lip, thick lower lip, and micrognathia. Orthopedic abnormalities, cardiovascular malformations, genital anomalies, and pulmonary defects may also occur.

 

ADVERSE PREGNANCY AND NEONATAL OUTCOMES

 

In a prospective cohort study in South India, 23 (7.1%) of 322 pregnancies treated with valproic acid monotherapy in the first trimester of pregnancy resulted in spontaneous fetal loss (including spontaneous abortions and stillbirths), compared to five (2.8%) out of 178 unexposed pregnancies (adjusted odds ratio=6.92, 95% confidence interval 1.70-28.18) (Trivedi et al., 2018). Under ascertainment of spontaneous abortions in this study is likely because of the low rates in both exposed and exposed groups.

 

Perinatal distress, transient neonatal hypoglycemia, and unusual neonatal behavior have been noted in infants born to women treated with valproic acid during pregnancy (Ebbesen et al., 2000).

 

A population-based cohort study showed a small (0.1 standard deviation) but statistically significant reduction in mean head circumference among infants whose mothers had been treated with valproic acid monotherapy during pregnancy (Almgren et al., 2009). In a recent record-linkage study from Sweden that included more than 900 exposed women, the average head circumference of infants born to mothers treated with valproic acid during pregnancy was 0.2 standard deviations (95% confidence interval -0.2 to -0.1) smaller than the head circumference of infants born to mothers treated with lamotrigine, another anticonvulsant (Margulis et al., 2019). An increased prevalence of small for gestational age at birth was reported in the North American AED Registry among the infants of 288 mothers treated with valproic acid during pregnancy (odds ratio=1.5, 95% confidence interval 1.0-2.2) (Hernandez-Diaz et al., 2017). This effect on early growth was not seen in the comparator group of infants prenatally exposed to lamotrigine.

 

There are anecdotal reports of afibrinogenemia and hepatic failure in infants born to women who were treated with valproic acid during pregnancy (Legius et al., 1987; Majer & Green, 1987). Similar complications have been reported in children and adults receiving valproic acid therapy.

 

NEURODEVELOPMENTAL OUTCOMES

 

The frequencies of neurodevelopmental disorders (adjusted hazard ratio=2.7, 95% confidence interval 1.8-4.0), pervasive developmental disorders (adjusted hazard ratio=4.4, 95% confidence interval 2.1-9.3) and intellectual disability (adjusted hazard ratio=3.1, 95% confidence interval 1.5-6.3) were significantly increased among 911 children whose mothers were prescribed valproic acid monotherapy during pregnancy compared to the rates of these disorders among children whose mothers were prescribed lamotrigine monotherapy during pregnancy (Blotiere et al., 2020).

 

A reduction in IQ of 8-10 points and specific deficits in verbal skills have been reported among children of mothers treated with valproic acid in pregnancy compared to children of untreated mothers in a cohort study and review of the literature (Bromley et al., 2014; Baker et al., 2015). Fifty-one children prenatally exposed to valproic acid had a significantly higher rate of language impairment, poorer adaptive functioning skills, poorer socialization, communication, and motor function compared to 201 children prenatally exposed to other anticonvulsants as reported in the North American AED Registry (Deshmukh et al., 2016). IQ scores were 7-10 points lower in six-year-old children with prenatal valproic acid exposure (n=49) compared to children prenatally exposed to other antiepileptic drugs in a longitudinal prospective cohort study (Meador et al., 2013).

 

The adverse effect of maternal valproic acid treatment on cognitive development seems to be greatest in children whose mothers took the largest doses of valproic acid dose during pregnancy (Meador et al., 2009, 2013; Nadebaum et al., 2011a, b; Roullet et al., 2013; Deshmukh et al., 2016).

 

In a Danish population-based cohort study, maternal treatment with valproic acid during pregnancy (n=580) was significantly associated with a 48% increased risk of attention-deficit hyperactivity disorder (ADHD) in comparison with children whose mothers were not treated (adjusted hazard ratio=1.48, 95% confidence interval 1.09-2.00) (Christensen et al., 2019). Restricting the analysis to only include women with epilepsy resulted in a similar elevation of risk for childhood ADHD (39%) with prenatal valproic acid exposure (adjusted hazard ratio=1.39, 95% confidence interval 1.00-1.93). Autism spectrum disorders were also more frequently reported than expected among children whose mothers took valproic acid during pregnancy in several cohort studies (Bromley et al., 2013; Christensen et al., 2013; Meador & Loring, 2013).

 

In a systematic review and meta-analysis of 29 cohort studies, including 5100 infants and children of women who took an antiepileptic drug, maternal treatment with valproic acid in pregnancy was significantly associated with cognitive delay (odds ratio=7.40, 95% confidence interval 3.00-18.46), language delay (odds ratio=7.95, 95% confidence interval 1.5-49.13), and psychomotor delay (odds ratio=4.16, 95% confidence interval 2.04-8.75) in the children (Veroniki et al., 2017). An increased risk of autism in children whose mothers took valproic acid during pregnancy was also detected in this meta-analysis (odds ratio=17.3, 95% confidence interval 2.4-217.6).

 

ANIMAL TERATOLOGY STUDIES

 

Increased frequencies of craniofacial and skeletal anomalies as well as of fetal death have been observed among the offspring of rhesus monkeys treated during pregnancy with <1-10 times the maximum human therapeutic dose of valproic acid (Mast et al., 1986; Michejda & McCollough, 1987; Hendrickx et al., 1988). The effect exhibited typical dose-dependence. Exposure of pregnant mice or rats to valproic acid in doses that are associated with blood levels above the human therapeutic range causes embryonic death and malformations in the offspring (Ornoy, 2009; Wlodarczyk et al., 2012). Exencephaly and skeletal anomalies are among the most common malformations observed in mice; cardiac, skeletal, and urinary tract anomalies are seen most often in rats. The teratogenic effect exhibits a typical dose-response relationship in both species.

 

Spina bifida can be produced among the offspring of pregnant mice by treatment with valproic acid in doses 10-25 times those used in humans (Ornoy, 2009; Wlodarczyk et al., 2012). Increased frequencies of neural tube defects have also been observed among the offspring of pregnant hamsters or rats treated, respectively, with 5 or 10-20 times the maximum human dose of valproic acid (Moffa et al., 1984; Briner & Lieske, 1995). The rate of valproic acid-induced exencephaly in rodents can sometimes be reduced by concurrent treatment of the mother with folic acid analogues (Greene & Copp, 2005; Dawson et al., 2006). Genetic susceptibility appears to be important in predisposing some mouse strains to the effects of valproic acid teratogenesis (Bennett et al., 2000; Faiella et al., 2000; Finnell et al., 2000; Lundberg et al., 2004; Downing et al., 2010).

 

Behavioral alterations have been reported among the offspring of rats, mice, or ferrets treated with valproic acid during pregnancy in doses equivalent to or greater than those used in humans (Roullet et al., 2013; Kinjo et al., 2019; Gassowska-Dobrowolska et al., 2020). Treatment of pregnant rats or mice with 5-10 times the maximum human dose of valproic acid produces histopathological changes in the brains of the offspring similar to those seen in children with autism (Roullet et al., 2013; Gassowska-Dobrowolska et al., 2020). Variable presentations of autistic-like features, such as impaired social interaction, pronounced stereotypies, and abnormal visual attention, have been reported among the offspring of monkeys injected with valproic acid twice during gestation, around the time of neural tube closure, in doses up to 5 times those used in humans (Zhao et al., 2019).

Selected References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)

Almgren M, Kallen B, Lavebratt C: Population-based study of antiepileptic drug exposure in utero--influence on head circumference in newborns. Seizure 18(10):672-675, 2009. [E]

 

Baker GA, Bromley RL, Briggs M, Cheyne CP, Cohen MJ, Garcia-Finana M, Gummery A, Kneen R, Loring DW, Mawer G, Meador KJ, Shallcross R, Clayton-Smith J: IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology 84(4):382-390, 2015. [E]

 

Battino D, Tomson T: Management of epilepsy during pregnancy. Drugs 67(18):2727-2746, 2007. [R]

 

Bennett GD, Wlodarczyk B, Calvin JA, Craig JC, Finnell RH: Valproic acid-induced alterations in growth and neurotrophic factor gene expression in murine embryos [published erratum for title appears in Reprod Toxicol 14(2):181, 2000]. Reprod Toxicol 14(1):1-11, 2000. [A]

 

Blotiere P-O, Miranda S, Weill A, Mikaeloff Y, Peyre H, Ramus F, Mahmoud Z, Coste J, Dray-Spira R: Risk of early neurodevelopmental outcomes associated with prenatal exposure to the antiepileptic drugs most commonly used during pregnancy: a French nationwide population-based cohort study. BMJ Open 10(6):e034829, 2020. [E]

 

Blotiere P-O, Raguideau F, Weill A, Elefant E, Perthus I, Goulet V, Rouget F, Zureik M, Coste J, Dray-Spira R: Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs. Neurology 93(2):e167-e180, 2019. [E]

 

Briner W, Lieske R: Arnold-Chiari-like malformation associated with a valproate model of spina bifida in the rat. Teratology 52(5):306-311, 1995. [A]

 

Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, Tudur Smith C, Marson AG: Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 10:CD010236, 2014. [R]

 

Bromley RL, Mawer GE, Briggs M, Cheyne C, Clayton-Smith J, Garcia-Finana M, Kneen R, Lucas SB, Shallcross R, Baker GA: The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry 84(6):637-643, 2013. [E]

 

Bromley RL, Weston J, Marson AG: Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children. JAMA 318(17):1700-1701, 2017. [E]

 

Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, Mamoli D, Palmieri C, Molteni F, Granata T, Hassibi P, Zamperini P, Pardi G, Avanzini G: Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 40(9):1231-1236, 1999. [E]

 

Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M: Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309(16):1696-1703, 2013. [E]

 

Christensen J, Pedersen L, Sun Y, Dreier JW, Brikell I, Dalsgaard S: Association of prenatal exposure to valproate and other antiepileptic drugs with risk for attention-deficit/hyperactivity disorder in offspring. JAMA Netw Open 2(1):e186606, 2019. [E]

 

Dawson JE, Raymond AM, Winn LM: Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice. Toxicol Appl Pharmacol 211(2):124-132, 2006. [A]

 

Deshmukh U, Adams J, Macklin EA, Dhillon R, McCarthy KD, Dworetzky B, Klein A, Holmes LB: Behavioral outcomes in children exposed prenatally to lamotrigine, valproate or carbamazepine. Neurotoxicol Teratol 54:5-14, 2016. [E]

 

Downing C, Biers J, Larson C, Kimball A, Wright H, Ishii T, Gilliam D, Johnson T: Genetic and maternal effects on valproic acid teratogenesis in C57BL/6J and DBA/2J mice. Toxicol Sci 116(2):632-639, 2010. [A]

 

Duncan S: Teratogenesis of sodium valproate. Curr Opin Neurol 20(2):175-180, 2007. [R]

 

Duncan S, Mercho S, Lopes-Cendes I, Seni M-H, Benjamin A, Dubeau F, Andermann F, Andermann E: Repeated neural tube defects and valproate monotherapy suggest a pharmacogenetic abnormality. Epilepsia 42(6):750-753, 2001. [C]

 

Eadie MJ: Antiepileptic drugs as human teratogen. Expert Opin Drug Saf 7(2):195-209, 2008. [R]

 

Ebbesen F, Joergensen A, Hoseth E, Kaad P-H, Moeller M, Holsteen V, Rix M: Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate. Arch Dis Child Fetal Neonatal Ed 83(2):F124-F129, 2000. [E]

 

Faiella A, Wernig M, Consalez GG, Hostick U, Hofmann C, Hustert E, Boncinelli E, Balling R, Nadeau JH: A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression. Hum Mol Genet 9(2):227-236, 2000. [A]

 

Finnell RH, Gelineau-van Waes J, Bennett GD, Barber RC, Wlodarczyk B, Shaw GM, Lammer EJ, Piedrahita JA, Eberwine JH: Genetic basis of susceptibility to environmentally induced neural tube defects. Ann N Y Acad Sci 919:261-277, 2000. [R] & [A]

 

Gassowska-Dobrowolska M, Cieslik M, Czapski GA, Jesko H, Frontczak-Baniewicz M, Gewartowska M, Dominiak A, Polowy R, Filipkowski RK, Babiec L, Adamczyk A: Prenatal exposure to valproic acid affects microglia and synaptic ultrastructure in a brain-region-specific manner in young-adult male rats: relevance to autism spectrum disorders. Int J Mol Sci 21(10):3576, 2020. [A]

 

Greene NDE, Copp AJ: Mouse models of neural tube defects: investigating preventive mechanisms. Am J Med Genet C Semin Med Genet 135C(1):31-41, 2005. [R]

 

Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, Wiebe S, Thurman D, Koppel BS, Kaplan PW, Robinson JN, Hopp J, Ting TY, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Hirtz D, Le Guen C: Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Neurology 73(2):133-141, 2009. [R]

 

Hendrickx AG, Nau H, Binkerd P, Rowland JM, Rowland JR, Cukierski MJ, Cukierski MA: Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: an interspecies comparison. Teratology 38(4):329-345, 1988. [A]

 

Hernandez-Diaz S, McElrath TF, Pennell PB, Hauser WA, Yerby M, Holmes LB: Fetal growth and premature delivery in pregnant women on antiepileptic drugs [published erratum appears in Ann Neurol 83(4):872, 2018]. Ann Neurol 82(3):457-465, 2017. [E]

 

Hernandez-Diaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, Holmes LB: Comparative safety of antiepileptic drugs during pregnancy. Neurology 78(21):1692-1699, 2012. [E]

 

Holmes LB, Mittendorf R, Shen A, Smith CR, Hernandez-Diaz S: Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations. Arch Neurol 68(10):1275-1281, 2011. [E]

 

Jackson A, Bromley R, Morrow J, Irwin B, Clayton-Smith J: In utero exposure to valproate increases the risk of isolated cleft palate. Arch Dis Child Fetal Neonatal Ed 101(3):F207-F211, 2016. [R]

 

Kini U, Adab N, Vinten J, Fryer A, Clayton-Smith J; Liverpool and Manchester Neurodevelopmental Study Group: Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed 91(2):F90-F95, 2006. [E]

 

Kini U, Lee R, Jones A, Smith S, Ramsden S, Fryer A, Clayton-Smith J; Liverpool Manchester Neurodevelopmental Study Group: Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero. Eur J Med Genet 50(6):411-420, 2007. [E]

 

Kinjo T, Ito M, Seki T, Fukuhara T, Bolati K, Arai H, Suzuki T: Prenatal exposure to valproic acid is associated with altered neurocognitive function and neurogenesis in the dentate gyrus of male offspring rats. Brain Res 1723:146403, 2019. [A]

 

Kozma C: Valproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 98(2):168-175, 2001. [R] & [C]

 

Legius E, Jaeken J, Eggermont E: Sodium valproate, pregnancy, and infantile fatal liver failure. Lancet 2(8574):1518-1519, 1987. [C]

 

Lindhout D, Omtzigt JGC, Cornel MC: Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 42(4 Suppl 5):111-118, 1992. [E]

 

Lundberg YW, Cabrera RM, Greer KA, Zhao J, Garg R, Finnell RH: Mapping a chromosomal locus for valproic acid-induced exencephaly in mice. Mamm Genome 15(5):361-369, 2004. [A]

 

Majer RV, Green PJ: Neonatal afibrinogenaemia due to sodium valproate. Lancet 2(8561):740-741, 1987. [C]

 

Malm H, Kajantie E, Kivirikko S, Kaariainen H, Peippo M, Somer M: Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology 59(4):630-633, 2002. [C]

 

Margulis AV, Hernandez-Diaz S, McElrath T, Rothman KJ, Plana E, Almqvist C, D'Onofrio BM, Oberg AS: Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth. PLoS One 14(8):e0214180, 2019. [E]

 

Mast TJ, Cukierski MA, Nau H, Hendrickx AG: Predicting the human teratogenic potential of the anticonvulsant, valproic acid, from a non-human primate model. Toxicology 39(2):111-119, 1986. [A]

 

Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C: Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 81(1):1-13, 2008. [R]

 

Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD Study Group: Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 360(16):1597-1605, 2009. [E]

 

Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW: Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 12(3):244-252, 2013. [E]

 

Meador KJ, Loring DW: Prenatal valproate exposure is associated with autism spectrum disorder and childhood autism. J Pediatr 163(3):924, 2013. [E]

 

Medveczky E, Puho E, Czeizel EA: The use of drugs in mothers of offspring with neural-tube defects. Pharmacoepidemiol Drug Saf 13(7):443-455, 2004. [E]

 

Michejda M, McCollough D: New animal model for the study of neural tube defects. Z Kinderchir 42(Suppl I):32-35, 1987. [A]

 

Moffa AM, White JA, MacKay EG, Frias JL: Valproic acid, zinc and open neural tubes in 9 day-old hamster embryos. Teratology 29:47A, 1984. [A]

 

Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, Dean JCS: A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 37(7):489-497, 2000. [S]

 

Nadebaum C, Anderson V, Vajda F, Reutens D, Barton S, Wood A: The Australian brain and cognition and antiepileptic drugs study: IQ in school-aged children exposed to sodium valproate and polytherapy. J Int Neuropsychol Soc 17(1):133-142, 2011a. [E]

 

Nadebaum C, Anderson VA, Vajda F, Reutens DC, Barton S, Wood AG: Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology 76(8):719-726, 2011b. [E]

 

Ornoy A: Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol 28(1):1-10, 2009. [R]

 

Reynolds EH, Green R: Valproate and folate: congenital and developmental risks. Epilepsy Behav 108:107068, 2020. [R]

 

Rodriguez-Pinilla E, Arroyo I, Fondevilla J, Garcia MJ, Martinez-Frias ML: Prenatal exposure to valproic acid during pregnancy and limb deficiencies: a case-control study. Am J Med Genet 90(5):376-381, 2000. [E]

 

Roullet FI, Lai JKY, Foster JA: In utero exposure to valproic acid and autism--a current review of clinical and animal studies. Neurotoxicol Teratol 36:47-56, 2013. [R]

 

Schorry EK, Oppenheimer SG, Saal HM: Valproate embryopathy: clinical and cognitive profile in 5 siblings. Am J Med Genet A 133(2):202-206, 2005. [C]

 

Thisted E, Ebbesen F: Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero. Arch Dis Child 69(3 Spec No):288-291, 1993. [S]

 

Tomson T, Battino D: Antiepileptic treatment in pregnant women: morphological and behavioural effects. Handb Exp Pharmacol 205:295-315, 2011. [R]

 

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THE NORTH AMERICAN ANTIEPILEPTIC DRUG PREGNANCY REGISTRY

 

A registry on the outcome of pregnancies in women taking any antiepileptic medication for the treatment of seizure or other medical disorder is maintained at the Massachusetts General Hospital, Harvard Medical School in Boston. The Registry is sponsored by AbbVie, AdVnz, Janssen, Greenwich Biosciences, Pfizer, Sunovion, UCB, and Zogenix with Lewis B. Holmes, M.D., as the principal investigator.

Pregnant women who enroll in the Registry will be asked to provide information regarding the health status of their infants. All information is confidential and all findings are analyzed to assess the fetal risk associated with the use of antiepileptic medications during pregnancy.

Health professionals who wish to enroll their patients in the Registry may contact the AED Pregnancy Registry below:

The North American AED Pregnancy Registry
Massachusetts General Hospital
125 Nashua St, Suite 8438
Boston, MA 02114
Telephone: 1-888-233-2334
Fax: 617-643-0071
Website: www.aedpregnancyregistry.org