|TERIS Agent Number:||1008||Bibliographic Search Date:||08/2020|
|Agent Name:||VALPROIC ACID|
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:
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).
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.
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).
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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