Pregnancy outcomes following first-trimester exposure to topical retinoids: a systematic review and meta-analysis.

Evaluation of human data regarding the outcomes of topical-retinoid-exposed pregnancies is important in terms of counselling pregnant women with inadvertent exposure. The objective of this study was thus to determine whether exposure to topical retinoids leads to an increase in the risk of adverse pregnancy outcomes. We carried out a search using the Medline, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases from inception to 4 December 2014. The selection, review and quality assessment of the studies were carried out by two independent reviewers according to predetermined inclusion criteria. Odds ratios (ORs) were calculated by the random effects method. This meta-analysis, including a total of 654 pregnant women who were exposed to topical retinoids, and 1375 unexposed control pregnant women, did not detect significant increases in rates of major congenital malformations [OR 1·22, 95% confidence interval (CI) 0·65-2·29], spontaneous abortions (OR 1·02, 95% CI 0·64-1·63), stillbirth (OR 2·06, 95% CI 0·43-9·86), elective termination of pregnancy (OR 1·89, 95% CI 0·52-6·80), low birthweight (OR 1·01, 95% CI, 0·31-3·27) or prematurity (OR 0·69, 95% CI 0·39-1·23). No significant heterogeneity was detected among the studies for the evaluated outcomes. The present meta-analysis ruled out a major increase in the rates of major congenital malformations, spontaneous abortions, low birthweight and prematurity. This result may be used primarily in reassuring women who were inadvertently exposed to topical retinoids during their pregnancy. However, the statistical power is not adequate to justify the use of topical retinoids during pregnancy.

Variation in the CYP2D6 genotype is not associated with carvedilol dose changes in patients with heart failure.

WHAT IS KNOWN AND OBJECTIVE: Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. METHODS: Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. RESULTS AND DISCUSSION: The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. WHAT IS NEW AND CONCLUSION: Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.

Identifying the behavioural phenotype in Fetal Alcohol Spectrum Disorder: sensitivity, specificity and screening potential.

BACKGROUND: In most cases of Fetal Alcohol Spectrum Disorder (FASD), the pathognomonic facial features are absent making diagnosis challenging, if not impossible, particularly when no history of maternal drinking is available. Also because FASD is often comorbid with Attention Deficit Hyperactivity Disorder (ADHD), children with FASD are frequently improperly diagnosed and receive the wrong treatment. Since access to psychological testing is typically limited or non-existent in remote areas, other diagnostic methods are needed to provide necessary interventions. OBJECTIVES: To determine if a characteristic behavioural phenotype distinguishes children with FASD from typically developing children and children with ADHD and use this information to create a screening tool for FASD diagnosis. METHODS: Parents and caregivers completed the Child Behavior Checklist (CBCL), a well-established standardized tool for evaluating children's behavioural problems. Results from 30 children with Fetal Alcohol Syndrome or Alcohol-Related Neurodevelopmental Disability, 30 children with ADHD, and 30 typically developing healthy children matched for age and socioeconomic status with FASD were analyzed. Based on our previous work, 12 CBCL items that significantly differentiated FASD and control groups were selected for further analyses. Stepwise discriminant function analysis identified behavioural characteristics most strongly differentiating groups and Receiver Operating Characteristics (ROC) curve analyses determined sensitivity and specificity of different item combinations. RESULTS: Seven items reflecting hyperactivity, inattention, lying and cheating, lack of guilt, and disobedience significantly differentiated children with FASD from controls. ROC analyses showed scores of 6 or higher on these items differentiated groups with a sensitivity of 86%, specificity of 82%. For FASD and ADHD, two combinations of items significantly differentiated groups with high sensitivity and specificity (i) no guilt, cruelty, and acts young (sensitivity = 70%; specificity = 80% (ii) acts young, cruelty, no guilt, lying or cheating, steals from home, and steals outside (sensitivity = 81%; specificity = 72%). These items were used to construct a potential FASD screening tool. CONCLUSIONS: Our findings identifying the behavioural characteristics differentiating children with FASD from typically developing children or children with ADHD have the potential for development of an empirically derived tool for FASD tool to be used in remote areas where psychological services are not readily available. This technique may speed up diagnosis and intervention for children without ready access to formal assessments.

Using corticosteroids during pregnancy. Are topical, inhaled, or systemic agents associated with risk?

QUESTION: I am concerned about use of corticosteroids during pregnancy. Some of my women patients of reproductive age are using topical, inhaled, or oral preparations, and I am not sure what to advise. ANSWER: Both topical and systemic corticosteroids are used for a variety of autoimmune and inflammatory conditions. Results of first-trimester studies were inconclusive and underpowered. Recent meta-analyses suggest a small but significant association between use of systemic corticosteroids during the first trimester and oral clefts. This is consistent with results of animal studies. No similar evidence exists for topical or inhaled corticosteroids, probably because of much lower systemic exposure.

Binge alcohol consumption by non-alcohol-dependent women during pregnancy affects child behaviour, but not general intellectual functioning; a prospective controlled study.

Effects of binge ethanol consumption during early gestation on child neurodevelopment have not been elucidated. To study whether binge drinking affects cognitive abilities and behavior of exposed children, a prospective observational study comparing 51 children exposed to binge drinking during the first trimester of pregnancy to 51 children not exposed to any teratogens was conducted. The children's physical development, intelligence, language abilities and behavior were assessed. Temperament test results showed that children exposed in utero to maternal binge drinking displayed a greater degree of disinhibited behavior and that this behavior was associated with early drinking variables. Although binge alcohol drinking by non-alcohol-dependent women during the first trimester of pregnancy does not appear to affect intelligence or cognitive and language development of young children, binge drinking in pregnancy does increase the likelihood of certain behavioral characteristics that might predispose these children to later behavioral dysfunction.

The Toronto experience in diagnosing alcohol-related neurodevelopmental disorder: a unique profile of deficits and assets.

BACKGROUND: Fetal alcohol syndrome (FAS), which involves the triad of features reflecting facial dysmorphology, growth retardation and intellectual impairments, encompasses a relatively small proportion of the children affected prenatally by alcohol. Unfortunately, in the absence of facial dysmorphology, the diagnosis is difficult in the majority of children, who are considered to have alcohol-related neurodevelopmental disorder (ARND). Because accepted clinical methods are not pathognomonic, a novel profile approach was used to examine neuropsychological abilities and disabilities to identify children with ARND who do not meet the diagnostic criteria of FAS. OBJECTIVE: To establish a set of criteria, to be validated in future studies, for characterizing the neuropsychological profile of children with ARND. By describing the procedures at this preliminary stage of our work, the goal is to draw attention to this neglected topic and to suggest a model that can be replicated and validated by others, and to provide the first systematic clinical report on diagnosing ARND in Canada. PROCEDURES: On the basis of the literature, parents' descriptions and the authors' own experience with ARND, a profile of neuropsychological characteristics, including both deficits and assets, that are associated with prenatal alcohol exposure was hypothesized. A group of children was then evaluated, mostly adoptees or children in foster care, who were referred for learning and behavioural problems potentially associated with gestational exposure. Their results were submitted to a profile analysis by comparing their deficits and assets according to a list describing a hypothetical ARND profile to determine whether each child fit or did not fit the ARND profile. Groups were compared for background characteristics, FAS symptomatology, and results on specific neuropsychological and behavioural tests. Finally, the characteristics most strongly differentiating the two groups were identified. SETTING: Hospital-based outpatient program. PARTICIPANTS: Fifty-two children aged four to 18 years who were referred for a diagnostic assessment related to suspected or known prenatal alcohol exposure. OUTCOME MEASURES: Each child's assessment results were compared against a list of 21 deficits and six assets by two independent raters. Children with an average of more than 60% deficits and 50% assets were considered to have ARND, while the remainder were not. RESULTS: Twenty-eight children (54%) were assigned to the ARND group and 24 to the non-ARND group. The groups did not differ in physical features or home background characteristics, with the exception of higher parental intelligence quotient in the non-ARND group. The ARND group was more likely to have repeated a grade or received special education and scored lower on standardized measures of intelligence, language and memory abilities. Frequency of behaviour or social problems were equivalent in both groups. CONCLUSIONS: A profile approach used to identify children with ARND discriminates problems in neuropsychological but not behavioural domains. Because elevated scores on behavioural tasks in both ARND and non-ARND groups were clinically significant, more research is needed to identify what behavioural problems are unique to children with ARND compared with other clinic-referred children.

Neurodevelopment of children exposed in utero to treatment of maternal malignancy.

Cancer is the second most common cause of death during the reproductive years, complicating approximately 1/1000 pregnancies. The occurrence of cancer during gestation is likely to increase as a result of a woman's tendency to delay childbearing. Improved diagnostic techniques for malignancies increases detection of cancer during pregnancy. Malignant conditions during gestation are believed to be associated with an increase in poor perinatal and fetal outcomes that are often due to maternal treatment. Physicians should weigh the benefits of treatment against the risks of fetal exposure. To date, most reports have focused on morphologic observations made very close to the time of delivery with little data collected on children's long-term neurodevelopment following in utero exposure to malignancy and treatment. Because the brain differentiates throughout pregnancy and in early postnatal life, damage may occur even after first trimester exposure. The possible delayed effects of treatment on a child's neurological, intellectual and behavioural functioning have never been systematically evaluated. The goal of this report was to summarize all related issues into one review to facilitate both practitioners' and patients' access to known data on fetal risks and safety.

Neurodevelopment of adopted children exposed in utero to cocaine: the Toronto Adoption Study.

BACKGROUND: Published studies of children's neurodevelopment after in utero exposure to cocaine have not separated intrauterine from postnatal environmental effects as cocaine-using mothers cluster in low socioeconomic classes and have other risk factors. METHODS: To overcome this limitation, a study was done to assess physical and neurodevelopmental characteristics of 52 children: 26 were adopted by parents who sought counselling in the Motherisk Program at the University of Toronto for prenatal cocaine exposure, and 26 were controls matched for maternal intelligence quotient (IQ), socioeconomic status and gestational age. MAIN OUTCOME MEASURES: Head circumference, McCarthy General Cognitive Index (GCI) score, language performance and temperament tests. RESULTS: The children in the study group had smaller head circumferences (34th versus 54th percentiles p = 0.009), lower McCarthy GCI scores (102.8 versus 114.2, p = 0.02), poorer receptive and expressive language performance on the Reynell test, and higher activity levels, less persistence and increased distractibility on temperament tests. On multivariate analysis, cocaine exposure was significantly (p = 0.001) associated with lower IQ and poorer language development independent of intrauterine growth retardation and other potential confounders. INTERPRETATION: By controlling for postnatal environmental factors, this adoption study documents intrauterine developmental risks associated with cocaine exposure. Follow-up into school years is warranted to evaluate the extent of these effects.

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.

BACKGROUND: Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited. METHODS: We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies. RESULTS: In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]). CONCLUSIONS: Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.

Anticonvulsants and breast feeding: a critical review.

Progress in the diagnosis and management of seizure disorders and the availability of effective anticonvulsive medications has enabled increasing numbers of epileptic women of child-bearing age to raise families. Breast feeding, which these women may wish to choose, provides health, nutritional, immunological, developmental, social, economic and environmental benefits. The traditional anticonvulsants, such as phenytoin, carbamazepine and valproic acid (valproate sodium), are generally considered safe for use during breast feeding; however, observation for adverse effects is recommended. The use of phenobarbital while breast feeding is controversial because of its slow elimination by the nursing infant. The newer anticonvulsants, such as clobazam, felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin, are used mainly as adjunctive therapy. Data on the use of these drugs in pregnancy and lactation, and regarding long term effects on cognition and behaviour, are sparse. Weighing the benefits of breast feeding against the potential risk to the nursing infant, breast feeding is considered to be safe when the mother is taking carbamazepine, valproic acid or phenytoin. Infant monitoring for potential adverse effects is advisable when the mother is taking phenobarbital, clobazam, gabapentin, lamotrigine, oxcarbazepine or vigabatrin. Monitoring of infant serum drug concentrations is advisable but not compulsory. The use of felbamate, tiagabine and topiramate during breast feeding should await further study.

Neurodevelopment after in utero amiodarone exposure.

It is not known whether amiodarone is neurotoxic to the fetus, as it is to adults. We evaluated neurodevelopment of a historical cohort (N = 10) of children exposed transplacentally to amiodarone. Scores on standardized tests of cognitive and language skills were compared (by Wilcoxon signed rank test) between eight toddlers and matched controls. It was not possible to obtain controls for older amiodarone-exposed children (aged 9.7 and 12.0 years), whose test results were compared descriptively with normative data. There was no difference in IQ scores between amiodarone-exposed toddlers and controls. All had favorable temperaments. However, amiodarone-exposed toddlers showed expressive language skills that were relatively poorer than verbal skills, when compared with controls (p = 0.046). One amiodarone-exposed toddler exhibited global developmental delay. The older amiodarone-exposed children had well-developed social competence, favorable global IQ scores, but problems with reading comprehension, written language, and arithmetic. This picture is reminiscent of the Nonverbal Learning Disability Syndrome. There may be neurotoxicity associated with transplacental exposure to amiodarone. Follow-up is warranted, although most mothers were happy with the development of their children.

Treatment of epilepsy in pregnancy.

Pregnant women with epilepsy constitute 0.5% of all pregnancies. Proper seizure control is the primary goal in treating women with epilepsy. The commonly used anticonvulsants are established human teratogens. Factors such as epilepsy, anticonvulsant-induced teratogenicity, patient's genetic predisposition and the severity of convulsive disorder may attribute to adverse pregnancy outcome for the children of women with epilepsy. Anticonvulsant interaction with folic acid and phytomenadione (vitamin K) metabolism may lead to an increased risk for neural tube defect and early neonatal bleeding. Psychological, hormonal and pharmacokinetic changes in pregnancy may escalate seizure activity. Preconceptional counselling should include patient education to ensure a clear understanding of risks of uncontrolled seizures and possible teratogenicity of anticonvulsants. Genetic counselling should be performed if both parents have epilepsy or the disease is inherited. Seizure control should be achieved at least 6 months prior to conception and, if clinically possible, by the lowest effective dose of a single anticonvulsant according to the type of epilepsy. The new anticonvulsants are not recommended in pregnancy and require further research to prove their safety in humans. Folic acid 5 mg/day should be administered 3 months before conception and during the first trimester to prevent folic acid deficiency-induced malformations. Antenatal management should include assessment of patients for anticonvulsant-associated birth defects through detailed ultrasound examination and levels of maternal serum alpha-fetoproteins. Therapeutic drug monitoring should be performed monthly, or as clinically indicated. If phenobarbital, carbamazepine or phenytoin is administered, maternal phytomenadione supplementation should begin 4 weeks before the expected date of delivery. In order to prevent convulsions during labour, proper seizure control should be achieved during the third trimester. Benzodiazepines or phenytoin are found to be effective for seizure cessation during labour and delivery. Phytomenadione should be administered immediately after birth to the newborn. The neonate should be assessed carefully for epilepsy and anticonvulsant-associated dysmorphology. Advising the patient on postpartum management regarding contraception and breast-feeding will help maximise the best possible outcome for the newborn and mother. With proper preconceptional, antenatal and postpartum management up to 95% of these pregnancies have been reported to have favourable outcomes.

Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety.

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.

Long-term neurodevelopmental risks in children exposed in utero to cocaine. The Toronto Adoption Study.

Children exposed in utero to cocaine are at risk for long-term neurobehavioral damage not just because of the drug itself; but also because of clustering of other health determinants, including low socioeconomic status, low maternal education, and maternal addiction, to mention a few. One methodologic approach to separate the direct neurotoxic effects of cocaine from these synergistic insults is to follow up a cohort of children exposed in utero to cocaine and given up for adoption to middle-upper class families. The Toronto Adoption Study, supported by Health Canada, has proven the direct neurotoxic effects of cocaine on IQ and language. These effects are mild to moderate as compared to those measured in children exposed in utero to cocaine and reared by their natural mothers.

Fetal alcohol syndrome. Role of the family physician.

QuestionOne of my female patients drinks heavily. Although she is not planning to conceive, I worry that her lifestyle might lead to pregnancy and danger for her fetus. What do you recommend?AnswerYou should counsel your patient on effective contraception and advise her about the advantages of the various methods available.

Characteristics of pregnant women who engage in binge alcohol consumption.

OBJECTIVE: To characterize pregnant women who engage in binge drinking and to identify other risk behaviour that these women engage in. DESIGN: Observational study based on retrospective review of records. SETTING: A telephone and outpatient counselling service in Toronto that advises pregnant women about exposure to drugs, chemicals, radiation and infections during pregnancy and lactation. PARTICIPANTS: All pregnant women who sought counselling concerning fetal risk of exposure to binge drinking from 1985 to 1994 as well as those counselled by telephone from 1993 to 1994, and an equal number of control women who sought counselling. OUTCOME MEASURES: Information about binges, demographic factors, history of elective and spontaneous abortion, and use of psychotropic drugs and cigarettes as well as marijuana, cocaine and other illicit drugs. RESULTS: Of the 3800 women seen in the clinic, 119 (3.1%) reported binge drinking during pregnancy; of the 19,991 women counselled by telephone, 153 (0.8%) reported binge drinking during pregnancy. The mean number of drinks per binge was 7.2 (standard deviation 2.5). None of the women was an alcoholic; 83.1% had binged fewer than 10 times during their pregnancy. A large majority (84.0%) of the women had a binge early in the first trimester (before 6 weeks' gestation). In comparison with control women, the women who had engaged in binge drinking were significantly younger (mean 30.0 v. 27.9 years, p < 0.0001) and more likely to be single (12.2% v. 54.6%, p < 0.0001), to be white (69.2% v. 92.9%, p < 0.004), to smoke (19.3% v. 57.1%, p < 0.0001) and to use cocaine (1.1% v. 11.0%, p < 0.0001), marijuana (3.0% v. 19.3%, p < 0.0001) and other illicit drugs (0.7% v. 9.2%, p < 0.0001). CONCLUSIONS: Pregnant women who report binge alcohol consumption often report use of cigarettes, cocaine, marijuana and other illicit drugs as well, all of which represent a significant risk to the fetus. Rigorous efforts should be made to prevent the socially accepted binge consumption of alcohol among young, sexually active women.

Neurodevelopment of children exposed in utero to antidepressant drugs.

BACKGROUND: Many women of reproductive age have depression, necessitating therapy with either a tricyclic antidepressant drug or a drug, such as fluoxetine, that inhibits the reuptake of serotonin. Whether these drugs affect fetal neurodevelopment is not known. METHODS: We studied the children of 80 mothers who had received a tricyclic antidepressant drug during pregnancy, 55 children whose mothers had received fluoxetine during pregnancy, and 84 children whose mothers had not been exposed during pregnancy to any agent known to affect the fetus adversely. The children's global IQ and language development were assessed between 16 and 86 months of postnatal age by age-appropriate Bayley Scales of Infant Development or the McCarthy Scales of Children's Abilities (for IQ) and the Reynell Developmental Language Scales. RESULTS: The mean (+/-SD) global IQ scores were 118+/-17 in the children of mothers who received a tricyclic antidepressant drug, 117+/-17 in those whose mothers received fluoxetine, and 115+/-14 in those in the control group. The language scores were similar in all three groups. The results were similar in children exposed to a tricyclic antidepressant drug or fluoxetine during the first trimester and those exposed throughout pregnancy. There were also no significant differences in temperament, mood, arousability, activity level, distractibility, or behavior problems in the three groups of children. CONCLUSIONS: In utero exposure to either tricyclic antidepressant drugs or fluoxetine does not affect global IQ, language development, or behavioral development in preschool children.

Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: independent effects of epilepsy and medications.

Our objective was to evaluate the patterns of malformations in children exposed in utero to phenytoin (DPH) and carbamazepine (CBZ) monotherapy, and to compare them prospectively with matched mother-child pairs exposed to nonteratogens, and to separate the effects of antiepileptic drugs (AEDs) from those of epilepsy by collecting groups of untreated epileptics and those treated with DPH and CBZ for conditions other than epilepsy. This was a prospective, controlled, and blinded observational study. Thirty-six mother-child pairs exposed to CBZ monotherapy, 34 pairs exposed to DPH monotherapy, and 9 nonmedicated epileptic women and their children were compared with matched mother-child pairs exposed to nonteratogens. The control mothers were matched for maternal age, time of consultation, obstetric history, and socioeconomic status (SES). One main outcome measures a "blinded" morphological assessment of the offspring. We found that minor anomalies were significantly more common among children of epileptics on either drug (P = 0.01) and among DPH-treated nonepileptic offspring (P = 0.03). Among epileptics, the relative risk for minor anomalies following DPH (2.1) was similar to that after exposure to either DPH (P = 0.006) or CBZ (P = 0.01). Increased rates of hypertelorism were detected among DPH-exposed offspring. High forehead, frontal bossing, malar hypoplasia, epicanthus and micrognathia were associated with untreated epilepsy, as well as with DPH and CBZ treatment.