Comparative safety of antiepileptic drugs during pregnancy.

OBJECTIVE: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy. METHODS: The study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months' gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression. RESULTS: The risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0-8.5) for valproate, 2.9 (1.4-5.8) for phenobarbital, and 2.2 (1.2-4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip. CONCLUSIONS: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy.

BACKGROUND: Pregnancy registries for women taking anticonvulsant drugs have been developed to determine more efficiently the fetal risks of each drug. A total of 722 drug-exposed pregnancies are needed to identify a sevenfold increase in the rate of occurrence of a specific abnormality, such as spina bifida, with a frequency of 1 in 1,000. METHODS: The infants with major malformations born to the 791 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry were identified. Medical records were obtained from the affected infants' doctors. A total of 107 of the 791 infants or pregnancies were excluded. RESULTS: A total of 16 (2.3%) of 684 infants exposed to lamotrigine had major malformations that were identified at birth. Five infants (7.3/1,000) had oral clefts: isolated cleft palate (3), isolated cleft lip (1), and cleft lip and palate (1). The rate among the lamotrigine-exposed infants showed a 10.4-fold increase (95% CI: 4.3-24.9) in comparison to 206,224 unexposed infants surveyed at birth at Brigham and Women's Hospital in Boston, where the prevalence of isolated oral clefts was 0.7/1,000. A comparison was made also to 1,623 infants exposed to lamotrigine, as monotherapy, who had enrolled in five other registries. There were four infants with oral clefts: prevalence 2.5/1,000 (RR: 3.8, 95% CI: 1.4-10.0). CONCLUSIONS: The infant exposed in the first trimester of pregnancy to the anticonvulsant drug lamotrigine has an increased risk to have an isolated cleft palate or cleft lip deformity.

Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): a possible locus for Fryns syndrome.

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect that can occur in isolation or as part of a malformation complex. Considerable progress is being made in the identification of genetic causes of CDH. We applied array-based comparative genomic hybridization (aCGH) of approximately 1Mb resolution to 29 CDH patients with prior normal karyotypes who had been recruited into our multi-site study. One patient, clinically diagnosed with Fryns syndrome, demonstrated a de novo 5Mb deletion at chromosome region 1q41-q42.12 that was confirmed by FISH. Given prior reports of CDH in association with cytogenetic abnormalities in this region, we propose that this represents a locus for Fryns syndrome, a Fryns syndrome phenocopy, or CDH.

Increased rate of major malformations in offspring exposed to valproate during pregnancy.

OBJECTIVE: To determine the rate of occurrence of major malformations in infants whose mothers had taken the drug valproic acid (VPA) as monotherapy during the first trimester of pregnancy and had enrolled in the North American Antiepileptic Drug Pregnancy Registry. METHODS: Data were collected from pregnant women throughout the United States and Canada through telephone-based interviews. Each woman was interviewed at enrollment, at 7 months' gestation, and postpartum. With her written permission, the medical records of each mother and her infant were obtained. The major malformations tabulated were those identified at or before 5 days of age. The prevalence of congenital malformations among offspring of monotherapy VPA-exposed women was compared with that among infants of women exposed to all other antiepileptic drugs (internal comparison group) and with that among newborns in the Active Malformations Surveillance Program at Brigham and Women's Hospital (external comparison group). RESULTS: Sixteen affected cases were identified among 149 VPA-exposed women (proportion: 10.7%; 95% CI: 6.3 to 16.9%). The prevalence in the internal comparison group was 2.9% (95% CI: 2.0 to 4.1%; odds ratio: 4.0, 95% CI: 2.1 to 7.4; p < 0.001). Assuming a 1.62% prevalence in the external comparison group, the relative risk of having an affected offspring for VPA-exposed women was 7.3 (95% CI: 4.4 to 12.2; p < 0.001). CONCLUSION: Maternal exposure to valproic acid during the first trimester of pregnancy significantly increased the risk of major malformations.

Craniofacial skeletal deviations following in utero exposure to the anticonvulsant phenytoin: monotherapy and polytherapy.

OBJECTIVE: To identify and quantify the craniofacial effects from prenatal exposure to phenytoin monotherapy and polytherapy using cephalometric, hand-wrist, and panoramic radiographs and to determine if such deviations persist with age. DESIGN: Craniofacial structures of 28 anticonvulsant-exposed individuals were evaluated using 20 landmarks in lateral cephalometric radiographs and 19 landmarks in frontal cephalometric radiographs. Skeletal maturity was assessed using hand-wrist radiographs. Dental maturity and the presence of dental anomalies were evaluated using panoramic radiographs. Eleven individuals were re-evaluated 7 years later, on average, to determine the persistence of any measured deviations. SETTING AND SAMPLE POPULATION: Department of Growth and Development, Harvard School of Dental Medicine and Massachusetts General Hospital. Patients were recruited from several sources. OUTCOME MEASURE: The evaluated dimensions included linear, angular, and proportional measures. RESULTS: The most common deviations were decreased height and length of the maxilla, decreased length of the posterior cranial base, length of the mandible, cranial width and level of the cribriform plate, and a decrease in the Wits Appraisal assessment. The deviations were more significant in the polytherapy-exposed individuals than in the monotherapyexposed individuals. These deviations, especially in the maxilla, persisted with age as revealed in a re-evaluation of 11 individuals. CONCLUSION: The craniofacial skeletal findings among individuals exposed in utero to phenytoin monotherapy or phenytoin polytherapy, when considered in aggregate, suggest a mild pattern of maxillary hypoplasia that becomes more pronounced with age.

Limb deficiencies in newborn infants.

OBJECTIVE: The prevalence rate of all types of limb reduction defects in general and those that potentially are caused by vascular disruption in particular is needed to provide a baseline for the evaluation of infants who are exposed in utero to teratogens that cause vascular disruption. The objective of this study was to determine this prevalence rate. METHODS: All infants with any limb deficiency among 161 252 liveborn and stillborn infants and elective terminations were identified in a hospital-based Active Malformations Surveillance Program in Boston in the years 1972 to 1974 and 1979 to 1994. An extensive search was made to identify infants who were missed by the Surveillance Program; an additional 8 infants (7.3% of total) were identified. The limb reduction defects were classified in 3 ways: 1) by the anatomic location of the defect, that is longitudinal, terminal, intercalary, etc; 2) for infants with absence/hypoplasia of fingers or toes, a tabulation of which digit or digits were affected; and 3) by apparent cause. RESULTS: The prevalence rate for all types of limb deficiency was 0.69/1000. The apparent causes included single mutant genes, familial occurrence, and known syndromes (24%); chromosome abnormalities (6%); teratogens (4%); vascular disruption (35%); and unknown cause (32%). CONCLUSIONS: A hospital-based surveillance program can be used to establish the prevalence of limb reduction defects, if ascertainment is extended to include elective terminations for fetal abnormalities. An apparent cause can be established for most limb defects when the clinical findings are used rather than reliance only on the International Classification of Diseases, Ninth Revision, codes of the discharge diagnoses. The prevalence rate of limb reduction defects as a result of presumed vascular disruption was 0.22/1000.

Congenital microcephaly: phenotypic features in a consecutive sample of newborn infants.

OBJECTIVE: We compared the prevalence of major and minor anomalies in a consecutive sample of newborn infants with congenital microcephaly with that among normocephalic infants. STUDY DESIGN: Head measurements from >19,000 liveborn infants at 1 hospital during the years 1991 and 1992 were reviewed. Infants whose head circumference was in the lowest quartile (n = 850) were remeasured by research assistants to identify all whose head circumference was 2 SD below the mean for gestational age; 106 infants with congenital microcephaly were identified. Infants with microcephaly (n = 65) and 294 infants in a control group were examined systematically for major malformations and minor physical features. RESULTS: Four (6.2%) of the 65 infants examined either had a major malformation or were considered dysmorphic. One of the 4 had a specific multiple malformation syndrome, and 1 dysmorphic infant had a rare metabolic defect. Overall, the infants with microcephaly did not have a higher frequency of minor anomalies. However, there was a higher frequency of frontal bossing, small chin, and short nose with anteverted nares, which was associated with small body size rather than microcephaly. CONCLUSIONS: Congenital microcephaly is infrequently accompanied by major malformations and occurs rarely as part of a recognizable syndrome.

Declining insulin requirement in the late first trimester of diabetic pregnancy.

OBJECTIVE: To investigate whether pregnancies complicated by type 1 diabetes are associated with a decrease in first-trimester insulin requirement. RESEARCH DESIGN AND METHODS: We examined the weekly insulin requirement (as units per kilogram per day) during the first trimester of pregnancy in diabetic women in the Diabetes in Early Pregnancy Study (DIEP) with accurate gestational dating, regular glucose monitoring, daily insulin-dose recording, and monthly glycohemoglobin measurements. RESULTS: In pregnancies that resulted in live-born full-term singleton infants, a significant 18% increase in mean weekly dosage was observed between weeks 3 and 7 (P = 0.000), followed by a significant 9% decline from week 7 through week 15 (P = 0.000). Further testing localized a significant change in insulin dose in the interval beginning weeks 7-8 and ending weeks 11-12 (P = 0.014). Within this interval, the maximum decrease was between weeks 9 and 10 (mean), 10 and 11 (median), and 8 and 9 (most frequent maximal decrease). To determine whether prior poor glucose control exaggerated these trends, we categorized the women based on their glycohemoglobin values: <2 SDs above the mean of a normal population (subgroup 1), 2-4 SDs (subgroup 2), and >4 SDs (subgroup 3) at baseline. Late first-trimester declines in dosage were statistically significant in subgroup 2 (P = 0.002) and subgroups 2 and 3 together (P = 0.003). Similarly, women with BMI >27.0 had a greater initial insulin rise and then fall compared with leaner women. CONCLUSIONS: Observations in the DIEP cohort disclose a mid-first-trimester decline in insulin requirement in type 1 diabetic pregnant women. Possible explanations include overinsulinization of previously poorly controlled diabetes, a transient decline in progesterone secretion during the late first-trimester luteo-placental shift in progesterone secretion, or other hormonal shifts. Clinicians should anticipate a clinically meaningful reduction in insulin requirement in the 5-week interval between weeks 7 and 12 of gestation.

Prenatal diagnosis and molecular cytogenetics in a case of partial trisomy 14 and monosomy 21.

We report an unbalanced translocation involving chromosomes 14 and 21 which presented as fetal ventriculomegaly at 33 weeks gestation. Second trimester ultrasound had indicated normal fetal anatomy, including normal intracranial structures. Parental karyotypes showed a paternal balanced translocation: 46,XY,t(14;21)(q12;q21). The unbalanced translocation in the fetus resulted in trisomy for 14pter-->q12 and monosomy for 21pter-->q21. Postnatal examination showed that the male infant had a cleft palate, but no cleft lip, and mild dysmorphic features. Postnatal MRI revealed bilateral and symmetric dilatation of the occipital horns, atria, and temporal horns of the lateral ventricles. Molecular cytogenetic techniques were used to delineate further the breakpoint on chromosome 14 to a site distal of the D14S1071 locus and the breakpoint on chromosome 21 to a region between D21S1918 and D21S1902. More precise definitions of chromosomal breakpoints in such clinical cases should provide more accurate prognosis for individuals with unbalanced karyotypes and assist in the identification of putative developmentally important genes.

The teratogenicity of anticonvulsant drugs.

BACKGROUND: The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as the anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant drugs in utero. However, whether the abnormalities are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known. METHODS: We screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. RESULTS: The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants. CONCLUSIONS: A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

Anticonvulsant teratogenesis 4: inter-rater agreement in assessing minor physical features related to anticonvulsant therapy.

BACKGROUND: We report on inter-rater agreement in the assessment of newborn infants with respect to a range of minor physical features in a cohort study of the fetal effects of maternal anticonvulsant use during pregnancy. METHODS: Infants from three groups (exposed to anticonvulsants, seizure history but no medication exposure, and unexposed controls) were examined by both a pediatrician/teratologist, who was blinded with respect to the mother's exposure status, and an unblinded research assistant. Agreement on assessments for selected anomalies associated with anticonvulsant therapy was measured by kappa-statistics, as well as by more sensitive log-linear modeling techniques, which allow examination of possible covariate effects on the strength of agreement. Although the physician and research assistant agreed on a high proportion of cases (80-90%), kappa values were modest (0.2-0. 5), partly because of the low prevalence of the anomalies considered. To explore how agreement varies within subgroups, we used recently developed methods for studying agreement based on log-linear models. RESULTS: Log-linear modeling indicated that there was substantial variation in pattern of agreement between different individual research assistants but that other factors (e.g., exposure category, sex, and birthweight) did not appear to be related to agreement. Our results suggest that research assistants with more experience showed the highest degree of agreement with the physicians. CONCLUSIONS: Our results have implications for both clinical practice and epidemiologic research and underline the importance of thorough training of staff in the definitions to be used and also the need for multiple independent assessments of these subtle anomalies.

Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome.

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism.

Digit effects produced by prenatal exposure to antiepileptic drugs.

The hypothesis tested was that digit anomalies among individuals exposed in utero to antiepileptic drugs (AED) are best identified by a systematic search, including radiographs and dermatoglyphics, rather than relying only on visual inspection. A systematic search was made for five types of digit abnormalities in 46 AED-exposed individuals ages 5-29 years in comparison with controls: visible anomalies, size of fingernails, dermal ridge patterns, length of metacarpals and phalanges, and qualitative changes in the distal phalanges. Among the AED-exposed, nail size was not decreased. However, there was a 10.8% frequency of digit anomalies, a 12% frequency of three or more arch patterns, and significant shortening and qualitative changes in the distal phalanges, all of which are consistent with the fetal effects of AED. Among the 42 individuals who underwent all evaluations, 14.3% had two or more of these abnormalities, most of which would not be identified by clinical inspection. This frequency is much higher in these AED-exposed individuals than in the general population. Radiographs in 13 individuals over a period of several years showed that the changes in the phalanges and metacarpals persisted.

Intelligence and physical features of children of women with epilepsy.

The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6-l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the "anticonvulsant face" or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy.

Heterotaxy: associated conditions and hospital-based prevalence in newborns.

PURPOSE: To provide insight into the possible etiology and prevalence of heterotaxy, we studied conditions associated with heterotaxy in a consecutive hospital population of newborns. METHODS: From 1972 to March, 1999 (except February 16, 1972 to December 31, 1978), 58 cases of heterotaxy were ascertained from a cohort of 201,084 births in the ongoing Active Malformation Surveillance Program at the Brigham and Women's Hospital. This registry includes livebirths, stillbirths, and elective abortions. Prevalence among nontransfers (i.e., patients whose mothers had planned delivery at this hospital) was calculated as approximately 1 per 10,000 total births (20 of 201,084). RESULTS: We analyzed a total of 58 patients consisting of 20 (34%) nontransfers and 38 (66%) transfers. Patients were categorized by spleen status as having asplenia (7 nontransfers, 25 total), polysplenia (8, 20), right spleen (4, 11), normal left (0, 1), and unknown (1, 0). Among the 20 nontransfer and 59 total heterotaxy patients, the following associated medical conditions were present: chromosome abnormality (1 nontransfer, 2 total), suspected Mendelian or chromosome microdeletion disorder (1 nontransfer, 6 total), and maternal insulin-dependent diabetes mellitus (1 nontransfer, 2 total). There were 6 twins (1 member each from 6 twin pairs including 1 dizygous, 4 monozygous, 1 conjoined; 2 were nontransfers). An associated condition occurred in 5 (25%) nontransfer and 16 (28%) total patients, or among 10 of 53 singleton births (19%). CONCLUSIONS: Although most cases of heterotaxy in this series were sporadic events, an associated condition was present in about one-fourth of the cases. Not all of these conditions would be considered causative etiologies. Based on this small series alone, maternal insulin-dependent diabetes cannot be viewed as a risk factor for heterotaxy. However, the specific association of diabetes with polysplenia with/without left atrial isomerism is noteworthy, and adds weight to animal and epidemiologic case-control data.

Pattern of skeletal malformations produced by Dominant hemimelia (Dh).

The hindlimb malformations in adult mice heterozygous for the dominant gene Dominant hemimelia (Dh) and +/+ littermates were characterized in skeletons that had been fixed, stained, and cleared. When the tibia was shortened, the deficiency was always an absence of the distal portion, and never the proximal portion. Although tibial hemimelia has been well documented in Dh mice, this study demonstrated a distinctive pattern of shortening of the tibia. Measurements of the length of the tibia (relative to the length of the humerus) showed only three patterns of shortening of the tibia (i.e., mild, moderate, and severe), rather than a continuous spectrum of shortening from mild to complete absence. The hindlimb malformation of Dh/+ mice occurred in association with a reduced number (five) of lumbar vertebrae. The interrelationship of the hindlimb malformations and the reduction in the vertebral number suggests a relationship between the development of the axial skeleton and the abnormal limb.

Under-recognition of prenatal alcohol effects in infants of known alcohol abusing women.

Medical records of 124 women and their infants were analyzed for: (1) documentation of maternal alcohol and other substance abuse and (2) evaluation of exposed infants. These results were compared with the study interview and infant examination. More obstetric nurses documented the presence or absence of alcohol and substance abuse than did pediatricians. More women reported using alcohol in the study interview than documented in the medical records. There was slightly better documentation for cocaine use than for alcohol use in the medical records. One of the 19 infants with documentation of maternal alcohol use was noted to have possible alcohol-related features by the pediatrician, in contrast to 7 infants identified by the study examiner. In addition, 2 of these 19 infants were determined by the study examiner to have fetal alcohol syndrome; neither case was diagnosed by the pediatricians. Continued efforts at education regarding the importance of asking about prenatal alcohol exposure and the spectrum of fetal alcohol effects are needed for early diagnosis.