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Sodium Valproate and the Fetus: A Case Study and Review of the Literature

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Sodium valproate is a teratogen responsible for a wide range of abnormalities, including neural tube defects. It has traditionally been prescribed for epilepsy, but is increasingly used for such psychiatric conditions as bipolar disease. Women of childbearing age taking valproate should be warned of its teratogenicity and advised to plan pregnancies, take a higher dose of folate, discuss reducing the dose of valproate or changing the medication with their physician, and have antenatal screening. After birth, the infant should be examined for a wide range of reported abnormalities. Neurodevelopmental assessment should continue throughout childhood. We present a case that illustrates the need for better education of mothers taking valproate and the medical staff prescribing it.
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VOL. 28, NO. 6, NOVEMBER/DECEMBER 2009 363
NEONATAL N ETWORK
SODIUM VALPROATE (VALPROATE) IS WIDELY USED FOR
epilepsy, but is increasingly prescribed for such non-
epileptic conditions as bipolar disease, migraine, pain relief,
and sleep disorders.1–3 Valproate,
however, is teratogenic, causing
a w ide ra nge of abnormalities
in offspring of many treated
mothers.4–6 A par ticular facial
dysmorphism and spina bifida
in combination with other mus-
culoskeletal disorders have been
described as “feta l valproate
syndrome.” Major abnormali-
ties have been reported in 11
percent of exposed pregnancies
in the U.S.,7 6.2–14.4 percent
in the U.K.,8 and 17.1 percent
in Australia by the Australian
Pregnancy Register for Women
on Anti-Epileptic Medication.9
Women of childbearing age
taking valproate should be counseled regarding its terato-
genic effects, and modification of therapy should be consid-
ered. Folic acid supplementation has been shown to reduce
the recurrence of myelomeningocele in mothers who have
given birth to a previously affected child.10 Although this
effect has not been demonstrated in mothers taking val-
proate, supplementation in a dose of 4–5 mg/day of folic acid
is recommended.11
We present a case of a mother prescribed valproate for
bipolar disease in which neither warning of teratogenicity
nor advice on the need for folic acid supplementation was
recorded. She produced a child with myelomeningocele.
CASE REPORT
A fema le in fant weighing
2,870 g was born at term to a
25-year-old, gravida 1, para 0,
mother. Diagnosed with bipolar
disorder and from a remote
town in Queensland, Australia,
the mother had been taking val-
proate 1,500 mg/day. Her care
had been shared by a general
practitioner and a psychiatrist,
who had prescribed the val-
proate. She had been taking
valproate for about four years;
it was discontinued because of
an improvement in the mother’s
psychological condition with the
fetus at 11 weeks gestation. The
obstetrician had not advised the mother regarding the use of
valproate because the pregnancy was unexpected.
An ultrasound examination at 20 weeks gestation revealed
a myelomeningocele. Termination of pregnancy was offered
but refused. There was no record of discussion about the
teratogenic effects of valproate, and the mother could recall
no such discussions. There was no record of advice on the
value of folate supplementation to reduce the risk of neural
tube defects in general or with special relevance to valproate
therapy. The mother took no folate or vitamin supplementation
Accepted for publication September 2008. Revised November 2008.
Sodium Valproate and the Fetus:
A Case Study and Review
of the Literature
Jacqueline Smith, RSCN, MSc, NNP
Dr. John Whitehall
ABSTRACT
Sodium valproate is a teratogen responsible for a wide
range of abnormalities, including neural tube defects.
It has traditionally been prescribed for epilepsy, but is
increasingly used for such psychiatric conditions as bipolar
disease. Women of childbearing age taking valproate
should be warned of its teratogenicity and advised to plan
pregnancies, take a higher dose of folate, discuss reducing
the dose of valproate or changing the medication with
their physician, and have antenatal screening. After birth,
the infant should be examined for a wide range of reported
abnormalities. Neurodevelopmental assessment should
continue throughout childhood. We present a case that
illustrates the need for better education of mothers taking
valproate and the medical staff prescribing it.
364 NOVEMBER/DECEMBER 2009, VOL. 28, NO. 6
NEONATAL N ETWORK
until she realized she was pregnant. She then began the usual
pregnancy folate supplementation dose of 0.5 mg/day, not
the higher dose of 4–5 mg/day recommended for women at
high risk for neural tube defects.12
The female infant was delivered by cesarean section because
of failure to progress, with a brow presentation. She required
no resuscitation and was admitted to the neonatal unit for
surgical closure of the myelomeningocele (Figure 1).
There were no signs of infant withdrawal from the val-
proate because it had been discontinued at 11 weeks of ges-
tation, nor were there disturbances in hepatic or glucose
homeostasis, which have been reported in infants of mothers
taking valproate throughout pregnancy.13,14 The half-life of
valproate depends on whether the drug is used on its own
or in conjunction with another anti-epileptic drug (AED).
When used in monotherapy, valporates half-life is approxi-
mately 10–12 hours. When used with other agents, its half-
life may be as short as 5–6 hours.15 The myelomeningocele
extended from the second to the fifth lumbar vertebrae and
was associated with mild hydrocephalus and prominent
Arnold-Chiari (Arnold Type II) malformation. Although
the lesion was severe, there was surprising preservation of
movement in the legs; the anus, however, was patulous. The
kidneys and heart were normal on ultrasound examination,
and no other abnormalities were noted. The infant tolerated
surgery and recovered well. She was discharged on day of life
(DOL) 11, but was readmitted on DOL 42 because of rapidly
progressing hydrocephalus that required a ventriculoperito-
neal shunt.
At three months of age, this infant had reached her appro-
priate milestones, though movement of the legs was impaired
in accordance with a myelomeningocele at S1–S4. She was
smiling, following with her eyes, showing interest in people
and her surroundings, and reaching appropriately. Further
follow-up for assessment of growth, intellectual and behav-
ioral development, eyesight, and hearing will be done.
DISCUSSION
The teratogenicity of valproate was reported soon after
this drug became available for treatment of epilepsy in the
late 1970s.16 In 1982, a significant association with spina
bifida was noted.17 In 1984, fetal valproate syndrome was
described.18 Our case emphasizes the teratogenic effect of
certain drugs that may not be well appreciated by physicians
working in subspecialties that are distant from the intricacies
of fetal development.
STATISTICS
In major studies in various countries, maternal treat-
ment with valproate has been associated with a collection
of major and minor anomalies in the neonate. In the U.S.,
two studies reported major congenital anomalies in 10.7 and
20.3 percent of exposed pregnancies.19,20 In Australia, major
and minor anomalies have been described in 17.1 percent, in
England, 14 percent, in Finland, 10.7 percent, in Sweden, 9.7
percent, and in the Netherlands, 6 percent.9,21–24 The rate of
major anomalies in the general population is 1–3 percent.25
There is a slightly higher rate of anomalies in offspring of
mothers with epilepsy because of genetic influences.26 Thus,
the overall relative risk for major anomalies in offspring of
mothers treated with valproate is considered to be 3.77 times
higher than the risk in the general population. When com-
pared with offspring of mothers treated with other AEDs,
the relative risk is considered to be a factor of 2.59.11 By way
of comparison, thalidomide is believed to have been associ-
ated with a 20–30 percent rate of anomalies in offspring of
treated mothers.27
ANOMALIES
Antenatal screening should be performed for major anom-
alies. Short-term effects of maternal valproate use that would
be of particular concern to neonatal nurses include not only
congenital anomalies, but signs of withdrawal, which occur
soon after birth. These signs and symptoms include hypo-
glycemia, irritability, jitteriness, hypotonia or hypertonia,
feeding problems, and seizures.14 One study reported with-
drawal symptoms in 20 percent of exposed neonates. These
infants require follow-up developmental studies that should
continue beyond infancy through childhood to identify late-
presenting problems such as joint laxity, connective tissue
weakness, otitis media with effusion, and minor malforma-
tions of the digits.4
A particular facial dysmorphism of thin arched eyebrows
with medial deficiency, broad nasal bridge, short anteverted
nose, and smooth, long philtrum with thin upper lip has been
described.21 A wide range of anomalies, including neural tube
defects, has also been described (Table 1). A review of 69
cases in the literature from 1978 to 2000 reported consistent
facial phenotype and abnormalities in the musculoskeletal
system (43 cases), the cardiovascular system (18 cases), the
genitourinary tract (15 cases), the skin (21 cases), the respira-
tory tract (11 cases), and the eyes and ears. Abnormalities in
FIGURE 1 Myomeningocele
VOL. 28, NO. 6, NOVEMBER/DECEMBER 2009 365
NEONATAL N ETWORK
the neurologic system included neural tube defects (2 cases)
and problems in neuronal migration and organization that
resulted in intellectual and behavioral difficulties, including
autism spectrum disorder, in as many as 20 of the infants.28
Verbal intelligence quotients, in particular, have been reported
to be reduced.29,30
Comparison between studies is difficult because of varying
methods of reporting, inexact amount of drug exposure, age
of the child at examination, mode of evaluation of develop-
ment, and such confounding influences as cultural differ-
ences and social status.31 Data from a 20-year study period
in India revealed that 8.9 percent of those exposed to val-
proate in utero became autistic.32 In Canada and the U.K.,
a lengthy review revealed that 28 percent of exposed infants
suffered developmental delay, and another 10.9 percent expe-
rienced behavioral disorders with normal development.4 (See:
Pharmacokinetics—Anticonvulsant, Antipsychotic.)
TERATOGENIC EFFECTS
The teratogenic effects of valproate are not well under-
stood and appear to be multifactorial. These include an
effect on genes that control the early patterning of the fetus,
a direct disruption of cell differentiation and proliferation
that could interfere with the development of the neural tube
and neuronal development, and an interference with folate
metabolism, which is necessary for cell division. Widespread,
dose-dependent, neuronal apoptosis has been observed in the
rat model exposed to valproate.33 The therapeutic effect of
valproate appears to involve an increase in inhibitory neuro-
transmitters and alteration in ion channels that may indi-
rectly interfere with neuronal migration and organization
in the developing brain.34–39 The development of the brain
may thus be interrupted by exposure in all trimesters of preg-
nancy.40 The embryopathy has been seen to be repeated in
siblings, so there may be a congenital susceptibility in some
families.41
Folic acid is known to reduce the incidence of neural
tube defects in the offspring of women not receiving anti-
epileptic drugs.25 A dose of 0.5 mg/day is recommended for
all women likely to become pregnant. A dose of 5 mg/day is
recommended for those at high risk as suggested by a family
history of neural tube defect.11 It is recommended that 5 mg
be ta ken daily by women who are receiving valproate for
whatever reason and who intend to become pregnant, but
there is more hope than evidence for effect.2,9,19
COMMUNICATION
Fai lure to inform t he mother fully about t he risks of
valproate therapy is not unusual. According to a review of
records of women attending a mental health institution in
England, 138 women of childbearing age were prescribed
mood-stabilizing drugs including valproate, but documented
warning of teratogenicity was found in only 29 cases (21
percent). Thirty-three women (24 percent) had been advised
about contraception, and 14 (10 percent) conceived while on
TABL E 1 Major and Minor Malformations Seen with Maternal
Valproate Use
Epicanthal folds
Upturned nose/flat nasal bridge
Shallow philtrum
Thin upper vermillion border
Low-set ears
Hypospadias
Neural tube defects
Congenital heart disease
Genitourinary abnormalities
Laxity in joints
Glue ear
Valproate Pharmacok i netics
Anticonvulsant, Antipsychotic
Site and mode
of action
Not yet fully established. Valproate’s
anticonvulsant effect is attributed to the
blockage of voltage-dependent sodium
channels. However, there are some
inconsistencies in the data. A combination
of mechanisms that involves the excitatory
amino acids, sodium flux, and potassium-
mediated inhibition may be operative.
Absorption Rapidly, almost completely absorbed in
fasting patients following oral dosing with
Epilim plain tablets, syrup, and sugar-free
liquid. Absorption is delayed, however, if the
medicine is taken with food. Peak blood levels
occur within 1–4 hours.
Distribution Rapidly distributed and most likely restricted
to the circulation and rapidly exchangeable
extracellular water. Cerebrospinal fluid and
breast milk levels were found to be 5–15%
and 1–10%, respectively, with 90% bound
to plasma proteins, but only 60% bound to
albumin.
Excretion Valproate almost completely metabolized
prior to excretion
Use in lactation Only about 5% of valproate passes through
to the breast milk, and even less enters
through the baby’s bloodstream. How
valproate affects the infant is unknown, and
most breastfed infants whose mothers are
on valproate experience no side effects. The
American Academy of Neurology and the
American Epilepsy Society both recommend
breastfeeding in women with epilepsy, and
neurologists have the veiw that the benefits
far outweigh the risk.
Adapted from: www.sanofi-aventis.com.au/products/aus_pi_epilim.pdf
366 NOVEMBER/DECEMBER 2009, VOL. 28, NO. 6
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the mood-stabilizing drugs. Extrapolating to the whole of
the U.K., it was predicted that between 7,000 and 11,000
women of childbearing age would have been prescribed such
drugs without documented discussion of risks.1
In Australia, prescriptions for valproate (presumably for
psychiatric reasons) increased by 10 percent in 2004, reach-
ing an approximate total of 660,000 in 2006. If each patient
had four prescrptions each over a year, a quarter of women of
childbearing age may be using this drug in 2008.42
War nings of the d rug’s teratogenic ef fects should be pro-
vided and recorded in the patient’s medical record. Ideally,
pregnancy should be planned and folate supplementation
taken. The health care provider should work with the patient
to find an alternate neuropsychiatric medication if possible.
Alternative medications for maternal epilepsy include lamo-
trogine and carbamazepine, and alternative medication for
psychological disorders, such as bipolar disorder, include
lithium. Adverse effects have been described with these med-
ications also, but at a rate lower than with valproate.43 If an
alternative medication cannot be used, the minimum dose of
valproate for effect should be given, divided into several daily
doses to minimize peak levels. Embryopathy is reported to
be unlikely if the mother is receiving less than 1,000 mg/day,
but the rate increases with dose, especially beyond 1,400 mg/
day, when normal metabolism of the drug might be saturated
and breakdown products accumulate.44 Risks and benefits,
therefore, need careful assessment, and full understanding by
the mother and by the whole team of providers is essential.
(R. Schwarz, perinatal psychiatrist, personal communication,
2008).
Contrary to other reviews,24,30,45,46 Vajda reports that
monotherapy is associated with a higher rate of abnormali-
ties in Australia than polytherapy, but considers the higher
rate due to higher doses of valproate (Personal communica-
tion, 2008). Rat models, however, suggest greater apoptosis
with polytherapy because of damaging synergism between
various anti-epileptic drugs.33 Some studies have reported
lower developmental quotients in infants of mothers on
polytherapy.46
CONCLUSION
A major adverse effect in any change of established therapy
is destabilization of the mother, and the underlying principle
should not be forgotten: The infant needs a healthy mother.
It is important to remember that withdrawal of anti-epileptic
drugs for the mother may precipitate a catastrophic recur-
rence of seizures in which the fetus may be damaged from
hypoxia. Indeed the overall death rate is higher in epileptic
mothers, and uncontrolled seizures are considered a cause.26
There is a need for more study of the effects of anti-epilep-
tic drugs in pregnancy. Health care providers should consider
encouraging affected mot hers to join national registries.
Valproate has been prescribed for epilepsy for almost 30 years,
during which time its teratogenic effects have been recog-
nized. Those effects, however, may not be well known by
those who prescribe valproate for psychological conditions.
The effects of congenital abnormalities and withdrawal are of
immediate concern to neonatal nurses, who are also in the
position to advocate for long-term developmental assessment.
Awareness of these effects should encourage consideration of
alternative or reduced therapy.
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About the Authors
Jacqueline Smith is an NNP at a Level III tertiary neonatal unit
in Queensland, Australia. She has worked in the neonatal specialty for
many years and still has the enthusiasm and dedication she had on her
first day. She is currently working toward a doctorate in nursing science
at James Cook University; her main work is thermoregulation and tem-
perature taking in the preterm and term neonate.
Dr. John Whitehall is the director of neonatology at The Townsville
Hospital, North Queensland, and a professor in the School of Public
Health and Tropical Medicine at James Cook University, Queensland.
He is a graduate of Sydney University, trained and worked as a general
pediatrician in Africa and Australia, and then subspecialized in
neonatology.
For further information, please contact:
Jacqueline Smith RSCN, MSc, NNP
E-mail: jacquelinej_smith@health.qld.gov.au
... Adverse pregnancy outcomes are unlikely to occur in women receiving less than 1,000 mg a day (J. Smith & Whitehall, 2009). The incidence of birth defects, including NTDs, is considered increased above the background when daily doses reach 1,400 mg or higher (Ornoy, 2009;J. ...
... ependent relationship between VPA and an increased incidence of birth defects. Adverse pregnancy outcomes are unlikely to occur in women receiving less than 1,000 mg a day (J. Smith & Whitehall, 2009). The incidence of birth defects, including NTDs, is considered increased above the background when daily doses reach 1,400 mg or higher (Ornoy, 2009;J. Smith & Whitehall, 2009). While VPA is a known folic acid antagonist, no studies of VPA have demonstrated a decrease in the rate of neural tube defects after supplementing with 4-5 mg/day of folic acid (Ornoy, 2009). ...
... tal anticonvulsant syndrome" or "anti-epileptic drug (AED) syndrome" are often seen in children exposed to AEDs in utero (Ornoy, 2009). Facial findings include a smooth, long philtrum with thin upper lip, midface hypoplasia, flat nasal bridge, small anteverted nose, down-turned angles of the mouth, and thin arched eyebrows (DiLiberti, et al., 1984;J. Smith & Whitehall, 2009). Children with features of AED syndrome often have other congenital anomalies and cognitive delays. It is unknown the exact percentage of children exposed to VPA in utero that develop AED syndrome. A study by Kini and colleagues found that of 274 children exposed to AEDs, 47% were correctly identified by dysmorphologists as being expose ...
Article
Mood disorders are the most common form of mental illness and one of the leading causes of morbidity worldwide. Major depressive disorder and bipolar disorder have a lifetime prevalence of 16.2% and 4.4%, respectively. Women comprise a substantial proportion of this population, and an estimated 500,000 pregnancies each year involve women with a psychiatric condition. Management with psychotropic medications is considered standard of care for most patients with mood disorders. However, many of these medications are known human teratogens. Because pregnant women with mood disorders face a high risk of relapse if unmanaged, the obstetrician faces a unique challenge in providing the best care to both mother and baby. It has been suggested that many obstetricians overestimate the teratogenic risks associated with psychotropic medications, while concurrently underestimating the risks associated with unmanaged mood disorders. This may be due a knowledge gap regarding the most current teratogen information, and lack of official management guidelines. Therefore, the purpose of this study is to determine the current knowledge base of obstetricians regarding the teratogenic effects of common psychotropic medications, as wells as to capture current management practices for pregnant women with mood disorders. A total of 117 Texas obstetricians responded to a survey regarding teratogen knowledge and management practice. It was common for respondents to encounter women who disclose both having a mood disorder and taking a psychotropic medication during pregnancy. Many respondents did not utilize up-to-date drug counseling resources, and were unaware of or over-estimated the teratogenic risks of common medications used to treat mood disorders. Finally, many respondents reported wanting to refer pregnant patients with mood disorders to psychiatrists for co-management, but are reportedly restricted in doing so due to accessibility or insurance issues. This study demonstrates that there is a knowledge gap among obstetricians regarding the teratogenicity of common psychotropic medications utilized to manage a patient population they frequently encounter. Further, obstetricians have vastly different risk perceptions of these medications, resulting in various management approaches and recommendations. Future research should focus on establishing standard practice guidelines, as well as better accessibility to psychiatric services for pregnant women.
... Дефицит фолиевой кислоты у беременных женщин может влиять на риск самопроизвольного прерывания беременности и возникновения дефектов нервной трубки у плода. В многочисленных исследованиях было показано, что употребление поливитаминов с высоким содержанием фолиевой кислоты или богатой фолатом пищи до зачатия и в ранние сроки беременности снижает частоту дефектов нервной трубки -как у матерей, уже имеющих ребенка с такой патологией, так и у женщин без этого ВПР у плода в анамнезе [34]. В ранее проведенных многочисленных исследова-ниях была показана исключительная роль фолиевой кислоты в предотвращении дефектов нервной трубки [35]. ...
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The risks associated with in utero antiepileptic drug (AED) exposure are of great importance for both epileptic women and their offspring. This review considers the basic mechanisms of valproate-induced teratogenesis. It discusses the mechanisms of fetal valproic acid accumulation, oxidative stress, folate antagonism, and histone deacetylase inhibition. Analysis of the literature has shown a large number of studies that prove and disprove different mechanisms of valproate-induced teratogenesis. Histone deacetylase inhibition and oxidative stress have the most pronounced teratogenic effect; moreover, both mechanisms are particularly important in the first trimester of pregnancy when DNA dysregulation has the greatest impact on organogenesis. All the described mechanisms (and possibly many others) along with individual genetic characteristics, environmental factors, and lifestyle, each of which has not been defined, may lead to an increased risk for the teratogenic effects of valproic acid.
... These unfortunate individuals presented with limb abnormalities and neural tube closure defects [7]. Sodium valproate is a widely prescribed anti-epileptic and mood stabilizing agent which is also a histone deacetylase inhibitor and known teratogen [9][10][11][12][13]. Though women who may potentially become pregnant are advised to avoid valproate, unintentional exposure may occur during the first days of pregnancy at the zygote, morula, blastocyst, and gastrulation stages prior to detection of pregnancy. ...
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Teratogens are compounds that can induce birth defects upon exposure of the developing fetus. To date, most teratogen studies utilize pregnant rodents to determine compound teratogenicity in vivo. However, this is a low throughput approach that cannot easily meet the need for comprehensive high-volume teratogen assessment, a goal of the US Environmental Protection Agency. In addition, rodent and human development differ substantially, and therefore the use of assays using relevant human cells has utility. For these reasons, interest has recently focused on the use of human embryonic stem cells for teratogen assessment. Here we present a highly standardized and quantitative system for the detection and analysis of teratogens that utilizes well-characterized and purified highly pluripotent stem cells. We have devised strategies to mass-produce thousands of uniformly sized spheroids of human ESCs (hESCs) that can be caused to undergo synchronous differentiation to yield embryoid bodies (EBs) in the presence and absence of suspected teratogens. The system uses all human cells and rigorously controlled and standardized EB culture conditions. Furthermore, the approach has been made quantitative by using high-content imaging approaches. Our system offers distinct advantages over earlier EB systems that rely heavily on the use on mouse ESCs and EB aggregates of stochastic sizes. Together, our results show that thousands of suspected teratogens could be assessed using human EB-based approaches.
... Epilepsy, which affects one in every 300 women of childbearing age, is also considered a maternal disease that can interfere with originally normal child development. This is because anticonvulsants have proven teratogenic effect and represent an additional risk factor in these cases causing predisposition of orofacial clefts, distal phalanx hypoplasia and neural tube defects [45]. ...
Article
Birth defects (BDs) or congenital anomalies include all structural and functional alterations in embryonic or fetal development resulting from genetic, environmental or unknown causes, which result in physical and/or mental impairment. BDs occur in about 3% of newborn babies and in most cases of pregnancy loss. BDs are a very complex and heterogeneous group of single or multiple changes that, in most cases, are of unknown etiology. Among the risk factors are advanced maternal and paternal ages, parental consanguinity, teratogenic agents such as infectious agents and drugs, and poor nutrition, in particular folic acid deficiency. One of the consequences of these defects is the high death rate within the first year of life. Information on BDs is becoming increasingly more important throughout the world so that preventive measures can be taken. Knowledge of BDs enables the development of therapeutic and preventive strategies besides adequate genetic counseling.
... • Relatively few clinical and epidemiological data are available (Smirnova et al. 2014). Well-accepted exceptions are tragic events such as the large-scale methylmercury poisoning in Minamata (Ekino et al. 2007) or the identification of the fetal valproate syndrome because of the widespread treatment of pregnant epileptic patients with valproic acid (Ozkan et al. 2011;Smith and Whitehall 2009); • Neurotoxicity is typically not characterized by cytotoxicity (i.e., neuronal cell death), but rather by impact of toxicants on connectivity, structure, and function of the nervous system during development or at maturity (Giordano and Costa 2012); • Extrapolation of data from animal experiments to the human situation may be challenging due to interspecies differences ("humans are no 70 kg mice" (Leist and Hartung 2013); • In vitro studies on neurotoxicity usually use transformed or cancer cell lines, which have a response pattern significantly different from normal cells (Kadereit et al. 2012;Stiegler et al. 2011). ...
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Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration–response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration–response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds.
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Congenital anomalies present with significant financial, social, and moral issues and questions to the family and society and are difficult to rehabilitate. In utero exposure to teratogenic agents and infection are the two most important causes of nongenetic acquired anomalies presenting at birth. Teratogens such as drugs, adverse maternal conditions, and toxins are environmental factors that cause permanent structural or functional malformations or death of the embryo or fetus. Teratogens may cause significant congenital anomalies if encountered during the organogenesis period of 3–8 weeks of fetal life, which is the stage of tissues and organs formation, whereas minor morphological and functional disorders may occur with exposure during the fetal period of first 2 weeks. TORCH group infections (toxoplasmosis, others, rubella, cytomegalovirus, and herpes) are the most serious infectious diseases during pregnancy due to the severity of possible embryo-fetal lesions. With expanding scientific knowledge and clinical experience about the association of these toxins and infections with significant, at times crippling congenital anomalies, the avoidance of exposure to pregnant mothers has become the most important part of their prevention and management.
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N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (∼60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.
Chapter
Stem cells have the capacity to undergo self‐renewal and also to give rise to differentiated cells upon receiving appropriate developmental cues. The action of stem cells is crucial for proper embryonic development in vivo, and even in adult life, endogenous adult stem cells are central players in tissue homeostasis and organ renewal. Not surprisingly, insults to pluripotent and multipotent stem cells of the embryo and fetus can result in birth defects. More subtle impacts upon resident adult stem and progenitor cells can cause degenerative disorders of many organs, to include neurological deficits. Embryonic stem cells (ESCs) are derived from the inner cell mass of blastocyst‐stage embryos, and induced pluripotent stem cells (iPSCs) can be produced by the artificial reprogramming of terminally differentiated cells. ESCs and iPSCs have been used to develop in vitro platforms to investigate teratogen action and also serve as models for human developmental and degenerative disorders. This chapter provides an overview of basic features of pluripotent and adult stem cells and their use for human teratological studies and disease modeling and finally, discusses emerging trends in pluripotent stem cell research for teratology and disease modeling.
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Introduction: Diabetic sensorimotor polyneuropathy (DSP) affects 50% of diabetes patients and is painful in about 26%. Although disease-modifying therapies are not available for DSP, symptomatic treatments for painful diabetic neuropathy (PDN) are effective. Areas covered: We performed a MEDLINE search on PubMed using the search terms: treatment diabetic neuropathy and treatment PDN. This review outlines the problem posed by DSP, the clinical presentation and the characterization of PDN. A discussion of disease-modifying interventions, including the benefits of strict glycemic control, is followed by a focus on interventions for PDN including antidepressants, anticonvulsants and other treatments. Expert opinion: Disease modification in DSP remains an unmet need in clinical medicine affecting a large percentage of the population with concomitant healthcare costs. Strict glycemic control and attention to potential risk factors such as hypertension, hyperlipidemia and obesity may minimize DSP. Many patients benefit from treatment of their painful symptoms with anticonvulsants or antidepressants, but all are associated with significant side effects that limit their usefulness. There is a need for treatments of PDN with fewer side effects and more effective pain relief.
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ABSTRACTQUESTION The new Motherisk Guidelines suggest 5 mg/d of folic acid. Why was the dose increased? What is the time frame for taking such a dose?ANSWER Recent data from Ontario reveal that 40% of women of reproductive age still do not achieve therapeutic systemic levels of folate needed to prevent neural tube defects. Compliance is less than optimal among women using prenatal vitamins, rendering many women unprotected against neural tube defects. Taking a higher dose of folate will allow achievement of protective folate levels, even with partial compliance. Five mg of folate should be used daily several months before conception until the end of the first trimester.
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The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing such during the periconceptional period. The extent to which folic acid supplementation can reduce the first occurrence of defects is not known. We conducted a randomized, controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects. Women planning a pregnancy (in most cases their first) were randomly assigned to receive a single tablet of a vitamin supplement (containing 12 vitamins, including 0.8 mg of folic acid; 4 minerals; and 3 trace elements) or a trace-element supplement (containing copper, manganese, zinc, and a very low dose of vitamin C) daily for at least one month before conception and until the date of the second missed menstrual period or later. Pregnancy was confirmed in 4753 women. The outcome of the pregnancy (whether the fetus or infant had a neural-tube defect or congenital malformation) was known in 2104 women who received the vitamin supplement and in 2052 who received the trace-element supplement. Congenital malformations were significantly more prevalent in the group receiving the trace-element supplement than in the vitamin-supplement group (22.9 per 1000 vs. 13.3 per 1000, P = 0.02). There were six cases of neural-tube defects in the group receiving the trace-element supplement, as compared with none in the vitamin-supplement group (P = 0.029). The prevalence of cleft lip with or without cleft palate was not reduced by periconceptional vitamin supplementation. Periconceptional vitamin use decreases the incidence of a first occurrence of neural-tube defects.
Adverse effects of antiepileptic drugs (AEDs) are common, can have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients. The adverse effect profiles of AEDs differ greatly and are often a determining factor in drug selection because of the similar efficacy rates shown by most AEDs. The most common adverse effects are dose dependent and reversible. Cognitive impairment is of particular concern, especially for patients who work or study. Idiosyncratic effects, such as skin rashes, and chronic effects, such as weight gain, can lead to high rates of treatment discontinuation and complicate clinical management. Nearly all conventional AEDs increase the risk of congenital malformations when taken during pregnancy, with valproate posing a potentially greater risk, whereas the potential teratogenicity of new generation AEDs is largely unknown. Most conventional AEDs have a poor record when it comes to drug interactions, largely because of their tendency to interfere with hepatic drug metabolism. Some newer AEDs have no effect on hepatic drug metabolizing enzymes and are renally excreted, resulting in a lower potential for drug interactions. However, further research is needed to confirm the apparent improvement in tolerability offered by some of the newer AEDs.
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To assess the risk of major congenital abnormalities associated with specific antiepileptic drug regimens, a large retrospective cohort study was performed. The study comprised 1,411 children born between 1972 and 1992 in four provinces in the Netherlands who were born to mothers with epilepsy and using antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of major congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose–response relationship for valproate. The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoin monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk. Furthermore, there were significantly increased relative risks for the combination of carbamazepine and valproate and the combination of phenobarbital and caffeine with other antiepileptic drugs. This study shows that most antiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose–response relationship) and carbamazepine monotherapy, benzodiazepines in polytherapy, and caffeine comedication in combinations with phenobarbital.
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The risk of having a child with congenital abnormalities is 2 to 3 times higher for a mother who took antiepileptic drugs during pregnancy compared with a nonepileptic mother. The increased risk seems to be related in part to the epilepsy itself. Among the malformations cleft lesions and congenital heart lesions seem to be predomenant. If there is a causal relationship between antiepileptic drugs and congenital abnormalities, it is still an open issue. If antiepileptic drugs do act in a teratogenic way, the effect is weak. The frequency and the type of risk do not justfy discouraging a woman who needs antiepileptic medication from having a child. It is reason enough, however, for extensive counseling with the aim of reducing all possible risk factors for malformations. What steps can be taken before pregnancy begins? A family history of malformations should be regarded as a contraindication. A pregnancy should not be encouraged if one or more of the following factors do exist: age over 25 years, diabetes mellitus of the mother, former miscarriage, or stillborn children. To keep the risk at the lowest, all combinations of antiepileptic drugs should be avoided insofar as possible, trying to limit therapy to as few substances as possible. Even the frequently prescribed combination of hydantoins and barbiturates, instead of just one of these drugs, could mean an addition or even multiplication of teratogenic influences. What can be done if a woman has become pregnant? Regular serum concentration controls with adjustment of dosage downward are recommended. In the critical twentieth to fortieth days of pregnancy, a reduction of any teratogenic factors is valuable. An additional prescription of vitamin B12 or folic acid has not been justified up to now, neither by clinical experience nor by experiments. Just the chance that folic acid could increase the frequency of seizures, or has been given while the woman is not yet pregnant and could increase fertility does not sound very attractive.
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The antiepileptic drug valproic acid (2-propylpentanoic acid; [VPA]) is teratogenic in humans and a number of animal species. Using a murine model, we studied the mechanism of VPA-induced teratogenesis during a period of organogenesis sensitive to interference with closure of the neural tube (days 8 to 9). Teratogenic doses of valproic acid altered the pattern of folate metabolites in the embryo: Levels of 5-formyl- and 10-formyl-tetrahydrofolates decreased, and the level of tetrahydrofolate increased. These changes could be explained by VPA-mediated inhibition of transfer of the formyl group via glutamate formyltransferase. Neural-tube defects, alteration of embryonic folate metabolism, and inhibition of the specific enzyme are all produced by comparable doses and levels of the drug. A closely related structural analog of VPA (2-en-VPA, 2-propyl-2-pentenoic acid), which exhibits antiepileptic activity but not teratogenicity, did not influence the embryonic folate metabolism. Our results suggest that interference with embryonic folate metabolism might be an important aspect of the induction of neural-tube defects by VPA. The novel techniques described also should prove useful in studying the teratogenic mechanisms of other drugs.
Article
We evaluated seven children who had been exposed to sodium valproate (or valproic acid) in utero. A consistent facial phenotype was observed in all seven in addition to other birth defects in four. The facial changes consisted of epicanthal folds which continued inferiorly and laterally to form a crease or groove just under the orbit, flat nasal bridge, small upturned nose, long upper lip with a relatively shallow philtrum, a thin upper vermillion border, and downturned angles of the mouth. Hypospadias, strabismus, and psychomotor delay were found in two males; two children had nystagmus and two had low birth weight.