Background
There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue ...taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available.
Objectives
To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child.
Search methods
We searched the Cochrane Epilepsy Group Specialized Register (September 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 11), MEDLINE (via Ovid) (1946 to September 2015), EMBASE (1974 to September 2015), Pharmline (1978 to September 2015), Reprotox (1983 to September 2015) and conference s (2010‐2015) without language restriction.
Selection criteria
We included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Participants were women with epilepsy taking AEDs; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy.
Data collection and analysis
Three authors independently selected studies for inclusion. Five authors completed data extraction and risk of bias assessments. The primary outcome was the presence of a major congenital malformation. Secondary outcomes included specific types of major congenital malformations. Where meta‐analysis was not possible, we reviewed included studies narratively.
Main results
We included 50 studies, with 31 contributing to meta‐analysis. Study quality varied, and given the observational design, all were at high risk of certain biases. However, biases were balanced across the AEDs investigated and we believe that the results are not explained by these biases.
Children exposed to carbamazepine (CBZ) were at a higher risk of malformation than children born to women without epilepsy (N = 1367 vs 2146, risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36) and women with untreated epilepsy (N = 3058 vs 1287, RR 1.50, 95% CI 1.03 to 2.19). Children exposed to phenobarbital (PB) were at a higher risk of malformation than children born to women without epilepsy (N = 345 vs 1591, RR 2.84, 95% CI 1.57 to 5.13). Children exposed to phenytoin (PHT) were at an increased risk of malformation compared with children born to women without epilepsy (N = 477 vs 987, RR 2.38, 95% CI 1.12 to 5.03) and to women with untreated epilepsy (N = 640 vs 1256, RR 2.40, 95% CI 1.42 to 4.08). Children exposed to topiramate (TPM) were at an increased risk of malformation compared with children born to women without epilepsy (N = 359 vs 442, RR 3.69, 95% CI 1.36 to 10.07). The children exposed to valproate (VPA) were at a higher risk of malformation compared with children born to women without epilepsy (N = 467 vs 1936, RR 5.69, 95% CI 3.33 to 9.73) and to women with untreated epilepsy (N = 1923 vs 1259, RR 3.13, 95% CI 2.16 to 4.54). There was no increased risk for major malformation for lamotrigine (LTG). Gabapentin (GBP), levetiracetam (LEV), oxcarbazepine (OXC), primidone (PRM) or zonisamide (ZNS) were not associated with an increased risk, however, there were substantially fewer data for these medications.
For AED comparisons, children exposed to VPA had the greatest risk of malformation (10.93%, 95% CI 8.91 to 13.13). Children exposed to VPA were at an increased risk of malformation compared with children exposed to CBZ (N = 2529 vs 4549, RR 2.44, 95% CI 2.00 to 2.94), GBP (N = 1814 vs 190, RR 6.21, 95% CI 1.91 to 20.23), LEV (N = 1814 vs 817, RR 5.82, 95% CI 3.13 to 10.81), LTG (N = 2021 vs 4164, RR 3.56, 95% CI 2.77 to 4.58), TPM (N = 1814 vs 473, RR 2.35, 95% CI 1.40 to 3.95), OXC (N = 676 vs 238, RR 3.71, 95% CI 1.65 to 8.33), PB (N = 1137 vs 626, RR 1.59, 95% CI 1.11 to 2.29, PHT (N = 2319 vs 1137, RR 2.00, 95% CI 1.48 to 2.71) or ZNS (N = 323 vs 90, RR 17.13, 95% CI 1.06 to 277.48). Children exposed to CBZ were at a higher risk of malformation than those exposed to LEV (N = 3051 vs 817, RR 1.84, 95% CI 1.03 to 3.29) and children exposed to LTG (N = 3385 vs 4164, RR 1.34, 95% CI 1.01 to 1.76). Children exposed to PB were at a higher risk of malformation compared with children exposed to GBP (N = 204 vs 159, RR 8.33, 95% CI 1.04 to 50.00), LEV (N = 204 vs 513, RR 2.33, 95% CI 1.04 to 5.00) or LTG (N = 282 vs 1959, RR 3.13, 95% CI 1.64 to 5.88). Children exposed to PHT had a higher risk of malformation than children exposed to LTG (N = 624 vs 4082, RR 1.89, 95% CI 1.19 to 2.94) or to LEV (N = 566 vs 817, RR 2.04, 95% CI 1.09 to 3.85); however, the comparison to LEV was not significant in the random‐effects model. Children exposed to TPM were at a higher risk of malformation than children exposed to LEV (N = 473 vs 817, RR 2.00, 95% CI 1.03 to 3.85) or LTG (N = 473 vs 3975, RR 1.79, 95% CI 1.06 to 2.94). There were no other significant differences, or comparisons were limited to a single study.
We found significantly higher rates of specific malformations associating PB exposure with cardiac malformations and VPA exposure with neural tube, cardiac, oro‐facial/craniofacial, and skeletal and limb malformations in comparison to other AEDs. Dose of exposure mediated the risk of malformation following VPA exposure; a potential dose‐response association for the other AEDs remained less clear.
Authors' conclusions
Exposure in the womb to certain AEDs carried an increased risk of malformation in the foetus and may be associated with specific patterns of malformation. Based on current evidence, LEV and LTG exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.
Summary Background Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic ...drugs on cognitive outcomes in children up to 6 years of age. Methods In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov , number NCT00021866. Findings We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94–101) than to carbamazepine (105, 102–108; p=0·0015), lamotrigine (108, 105–110; p=0·0003), or phenytoin (108, 104–112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ ( r =–0·56, p<0·0001), verbal ability ( r =–0·40, p=0·0045), non-verbal ability ( r =–0·42, p=0·0028), memory ( r =–0·30, p=0·0434), and executive function ( r =–0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 93% of 187 children), right-handedness was less frequent in children in our study overall (185 86% of 215; p=0·0404) and in the lamotrigine (59 83% of 71; p=0·0287) and valproate (38 79% of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106–111) than they were in unexposed children (101, 98–104; p=0·0009). Interpretation Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal ( vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies. Funding US National Institutes of Health, UK Epilepsy Research Foundation.
KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with ...intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.
Background
Despite high levels of prenatal alcohol exposure in the UK, evidence on the prevalence of fetal alcohol spectrum disorders (FASD) is lacking. This paper reports on FASD prevalence in a ...small sample of children in primary school.
Methods
A 2‐phase active case ascertainment study was conducted in 3 mainstream primary schools in Greater Manchester, UK. Schools were located in areas that ranged from relatively deprived to relatively affluent. Initial screening of children aged 8–9 years used prespecified criteria for elevated FASD risk (small for age; special educational needs; currently/previously in care; significant social/emotional/mental health symptoms). Screen‐positive children were invited for detailed ascertainment of FASD using gold standard measures that included medical history, facial dysmorphology, neurological impairment, executive function, and behavioral difficulties.
Results
Of 220 eligible children, 50 (23%) screened positive and 12% (26/220) proceeded to Phase 2 assessment. Twenty had a developmental disorder, of whom 4 had FASD and 4 were assessed as possible FASD. The crude prevalence rate of FASD in these schools was 1.8% (95% CI: 1.0%, 3.4%) and when including possible cases was 3.6% (2.1%, 6.3%). None of these children had previously been identified with a developmental diagnosis.
Conclusions
FASD was found to be common in these schools and most of these children's needs had not previously been identified. A larger, more definitive study that uses a random sampling technique stratified by deprivation level to select schools is needed to make inferences regarding the population prevalence of FASD.
A two‐phase active case ascertainment study in mainstream primary schools in the UK where 220 children aged 8‐9 years were screened for elevated FASD risk and screen positive children were invited for detailed ascertainment of FASD using gold standard measures. The crude prevalence rate of FASD was 1.8% (95%CI: 1.0%, 3.4%). The rate was 3.6% (2.1%, 6.3%), if any possible cases were included. FASD was found to be common in these schools, but limitations to the sampling restrict inferences to a population prevalence.
In this cohort study, children exposed in utero to valproate monotherapy had significantly lower IQ scores at 3 years of age than did children exposed in utero to monotherapy with other commonly used ...antiepileptic drugs. These findings support a recommendation that valproate should not be used as a first-choice drug in women of childbearing potential.
Children exposed in utero to valproate monotherapy had significantly lower IQ scores at 3 years of age than did children exposed in utero to monotherapy with other commonly used antiepileptic drugs.
Women with epilepsy are at increased risk for poor pregnancy outcomes, although most of their children are normal.
1
In animals, fetal exposure to antiepileptic drugs at doses lower than those that result in structural malformations can produce behavioral and cognitive deficits, alter neurochemistry, and reduce brain weight.
2
,
3
The effects of in utero exposure to antiepileptic drugs in humans may contribute to poor neurodevelopmental outcomes,
4
but this risk must be balanced against potentially grave risks to both mother and fetus posed by seizures.
5
Antiepileptic drugs may have differential risks in pregnancy, but studies have been lacking to guide the choice . . .
Objective
This study was undertaken to assess the utility of the Ages and Stages Questionnaire–3rd Edition (ASQ‐3) and the Vineland Adaptive Behavior Scales–2nd Edition (VABS‐II) as ...neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large‐population signal generation initiatives.
Methods
Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development–3rd Edition (BSID‐III), the VABS‐II, and the ASQ‐3 (n = 223). The sensitivity and specificity of the ASQ‐3 and VABS‐II to identify developmental delay at 24 months were examined, using the BSID‐III to define cases.
Results
The ASQ‐3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ‐3 and BSID‐III at 24 months, the ASQ‐3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut‐points resulted in improved properties and may be preferred in certain contexts. The VABS‐II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID‐III referral data (sensitivity = 100.0%, specificity = 96.6%).
Significance
Both the ASQ‐3 and VABS‐II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at‐risk groups. These findings identify the ASQ‐3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS‐II has excellent psychometric properties, it is more labor‐intensive for both the research team and participants and is available in fewer languages than the ASQ‐3.
Despite widespread monotherapy use of lamotrigine or levetiracetam during pregnancy, prospectively collected, blinded child development data are still limited. The NaME (Neurodevelopment of Babies ...Born to Mothers With Epilepsy) Study prospectively recruited a new cohort of women with epilepsy and their offspring for longitudinal follow-up.
Pregnant women of <21 weeks gestation (n = 401) were recruited from 21 hospitals in the UK. Data collection occurred during pregnancy (recruitment, trimester 3) and at 12 and 24 months of age. The primary outcome was blinded assessment of infant cognitive, language, and motor development on the Bayley Scales of Infant and Toddler Development (3rd edition) at 24 months of age with supplementary parent reporting on the Vinelands Adaptive Behavior Scales (2nd edition).
There were 394 live births, with 277 children (70%) completing the Bayley assessment at 24 months. There was no evidence of an association of prenatal exposure to monotherapy lamotrigine (-.74, SE = 2.9, 95% confidence interval CI = -6.5 to 5.0, p = .80) or levetiracetam (-1.57, SE = 3.1, 95% CI = -4.6 to 7.7, p = .62) with poorer infant cognition, following adjustment for other maternal and child factors in comparison to nonexposed children. Similar results were observed for language and motor scores. There was no evidence of an association between increasing doses of either lamotrigine or levetiracetam. Nor was there evidence that higher dose folic acid supplementation (≥5 mg/day) or convulsive seizure exposure was associated with child development scores. Continued infant exposure to antiseizure medications through breast milk was not associated with poorer outcomes, but the number of women breastfeeding beyond 3 months was low.
These data are reassuring for infant development following in utero exposure to monotherapy lamotrigine or levetiracetam, but child development is dynamic, and future follow-up is required to rule out later emerging effects.
To assess the utility of integrating genomic data from next-generation sequencing and phenotypic data to enhance the diagnosis of bilateral congenital cataract (CC).
Evaluation of diagnostic ...technology.
Thirty-six individuals diagnosed with nonsyndromic or syndromic bilateral congenital cataract were selected for investigation through a single ophthalmic genetics clinic.
Participants underwent a detailed ophthalmic examination, accompanied by dysmorphology assessment where appropriate. Lenticular, ocular, and systemic phenotypes were recorded. Mutations were detected using a custom-designed target enrichment that permitted parallel analysis of 115 genes associated with CC by high-throughput, next-generation DNA sequencing (NGS). Thirty-six patients and a known positive control were tested. Suspected pathogenic variants were confirmed by bidirectional Sanger sequencing in relevant probands and other affected family members.
Molecular genetic results and details of clinical phenotypes were identified.
Next-generation DNA sequencing technologies are able to determine the precise genetic cause of CC in 75% of individuals, and 85% patients with nonsyndromic CC were found to have likely pathogenic mutations, all of which occurred in highly conserved domains known to be vital for normal protein function. The pick-up rate in patients with syndromic CC also was high, with 63% having potential disease-causing mutations.
This analysis demonstrates the clinical utility of this test, providing examples where it altered clinical management, directed care pathways, and enabled more accurate genetic counseling. This comprehensive screen will extend access to genetic testing and lead to improved diagnostic and management outcomes through a stratified medicine approach. Establishing more robust genotype-phenotype correlations will advance knowledge of cataract-forming mechanisms.
DDX3X (Xp11.4) encodes a DEAD‐box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X‐linked intellectual disability (ID) (MRX102, MIM: ...300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss‐of‐function variants in this gene are suspected to be male lethal. Through whole‐exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.
Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous ...entities have been grouped as PIK3CA‐Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low‐level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient‐specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi‐system and often complex medical issues seen with PROS. In March 2019, macrocephaly‐capillary malformation (M‐CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M‐CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.
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