Prenatal exposure to valproic acid during pregnancy and limb deficiencies: a case-control study

We conducted a case-control study using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) on the relationship between prenatal exposure to valproic acid (VPA) and the presence of limb deficiencies in newborn infants. Among a total of 22,294 consecutive malformed infants (once we excluded genetic syndromes) and 21,937 control infants with specified data on antiepileptic drugs during gestation, 57 malformed infants and 10 control infants were exposed to VPA during the first trimester of pregnancy. Of the total of malformed infants exposed to VPA, 36.8% (21/57) presented with congenital limb defects of different types (including overlapping digits, talipes, clubfoot, clinodactyly, arachnodactyly, hip dislocation, pre- and postaxial polydactyly, etc.), three of them having limb deficiencies. The result of the case-control analysis shows a risk for limb deficiencies of odds ratio = 6.17 [confidence interval (CI) 1.28-29.66, P = 0.023], after controlling for potential confounder factors. If we consider that in our population the prevalence at birth of this type of defect is 6.88 per 10,000 livebirths (95% CI 6.43-7.36) we can estimate that the risk for women treated with VPA of having a baby with limb deficiencies would be around 0.42%. The limb deficiencies in the three patients exposed to VPA were the following: the first case was a newborn infant with hypoplasia of the left hand, the second patient was a newborn infant with unilateral forearm defect and hypoplastic first metacarpal bone in the left hand, and the third patient presented with short hands with hypoplastic first metacarpal bone, absent and hypoplastic phalanges, retrognathia, facial asymmetry, hypospadias, teleangiectatic angioma in skull, and hypotonia.     

Prenatal exposure to misoprostol and vascular disruption defects: A case‐control study

Prenatal exposure to misoprostol has been associated with Moebius and limb defects. Vascular disruption has been proposed as the mechanism for these teratogenic effects. The present study is a multicenter, case‐control study that was designed to compare the frequency of prenatal misoprostol use between mothers of Brazilian children diagnosed with vascular disruption defects and matched control mothers of children diagnosed with other types of defects. A total of 93 cases and 279 controls were recruited in eight participating centers. Prenatal exposure was identified in 32 infants diagnosed with vascular disruption defects (34.4%) compared with only 12 (4.3%) in the control group (P < 0.0000001). Our data suggest that prenatal exposure to misoprostol is associated to the occurrence of vascular disruption defects in the newborns. Am. J. Med. Genet. 95:302–306, 2000. 2000 Wiley‐Liss, Inc.     

Diaphragmatic defects,limb deficiencies,and ossification defects of the skull: A distinctive malformation syndrome

We report on prenatal and postnatal findings in 4 consecutive fetuses with a pattern of severe congenital anomalies who were born to a healthy nonconsanguineous couple. The spectrum of malformations includes diaphragmatic defects, hypoplastic lungs, omphalocele, limb deficiencies, syndactyly of toes, and ossification defects of the skull. This specific spectrum of anomalies is not fully compatible with that of any established syndrome. No prenatal exposure to any possible teratogen was found. Family history is suggestive for autosomal recessive inheritance, even though germ-line mosaicism in one of the parents cannot completely be excluded. © 1996 Wiley-Liss, Inc.     

Parahydrogen‐induced polarization of carboxylic acids: a pilot study of valproic acid and related structures

Parahydrogen‐induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non‐Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. ¹³C), thus improving the signal‐to‐noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the ¹H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized ¹³C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP‐based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. Copyright © 2014 John Wiley & Sons, Ltd.     

Congenital limb deficiencies and major associated anomalies in Alberta for the years 1980–2012

There is a wide range of the proportion of congenital anomalies associated with limb deficiencies reported in the literature. This variation is primarily attributed to methodology and classification differences. The distribution of associated anomalies among cases with congenital limb deficiencies in Alberta born between January 1, 1980 and December 31, 2012 is described. Of the 170 cases identified, most were live born (75.3%), male (61.8%), had longitudinal limb deficiencies (78.8%), and had associated anomalies outside the musculoskeletal system (77.6%). Significant associations between the preaxial longitudinal group and the central nervous, gastrointestinal, and cardiovascular systems are reported as well as between the postaxial longitudinal group and congenital hip and foot anomalies. Probable and possible syndrome diagnoses are described for cases with recognized malformation patterns.     

“ADAM complex” (amniotic deformity,adhesions, mutilations)—A pattern of craniofacial and limb defects

We report eight patients with the craniofacial defects and limb anomalies of the (amniotic deformity, adhesions, mutilations) ADAM complex. Facial abnormalities comprise clefts and distortion and dislocation of craniofacial structures; limbs show various combinations of amputation, secondary syndactyly, and constriction. From previous reports and our cases it is obvious that the clinical picture of the ADAM complex varies enormously; a less severe type combines cleft lip and palate with amputations or amniotic bands. Clinical and experimental data suggest that these malformations are of symptomatic (exogenous) origin. Nosologic differentation from other conditions phenotypically similar but of genetic etiology is important for genetic counseling. Observation of the ADAM complex in two members of a family suggests that genetic factors might operate in some cases.     

Upper limb deficiencies and associated malformations: A population-based study

As part of an ongoing analysis of limb deficiencies occurring among 1,213,913 consecutive livebirths in British Columbia during the years 1952–1984, all cases with deficiencies of the upper limbs were analysed with a view to identifying associated patterns of anomalies. This analysis resulted in seven subgroups. For each subgroup, incidence figures for cases with and without additional anomalies were calculated separately. The proportion of cases with additional anomalies varied markedly by subgroup. For example, 89% of cases with longitudinal defects of the radius had additional malformations, while only 28% of cases with transverse defects of the radius had other organ anomalies (χ² = 40.55; P < 0.001, one degree of freedom). A preponderance of males was found among the cases with associated defects, particularly in the group with longitudinal defects of the radius (28 males, 14 females; χ² = 14.10; P < 0.001). Clustering of specific patterns of associated malformations is described within subgroups. © 1992 Wiley-Liss, Inc.     

A family study on isolated congenital radial and tibial deficiencies in Hungary, 1975–1984

Czeizel AE, Vitéz M, Kodaj I, Lenz W. A family study on isolated congenital radial and tibial deficiencies in Hungary, 1975–1984. Clin Genet 1993: 44: 32–36. © Munksgaard, 1993
Radial and tibial deficiencies are frequently (70%) associated with non-limb abnormalities. Isolated radial and tibial deficiencies may have a different etiology: in this study radial deficiencies were more frequent, there were milder subtypes and one-limb involvement was found in 70% of cases, tibial deficiencies were rare, mild subtypes did not occur and in general more limbs were involved. Among multimelic cases, one case had hypoplasia of the tibia with polydactyly and two cases had tibial aplasia with split hand \pm foot of autosomal dominant inheritance. Of 40 cases, four were familial. Findings of a case-control study on this population-based and validated 10-year cohort showed a lower mean birth weight and a higher rate of low birth weight in cases with isolated radial and tibial deficiency.     

Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid

Experiments in rodents have indicated that maternal valproic acid (VPA) exposure has permanent adverse effects upon neurological and behavioral development. In humans, prenatal exposure to VPA can induce fetal valproate syndrome, which has been associated with autism. The present study examined mouse pups exposed in utero to VPA, measuring physical development, olfactory discrimination, and social behavior as well as expression of plasticity-related genes, brain derived neurotrophic factor (BDNF) and NMDA receptor subunits NR2A and NR2B. VPA-exposed mice showed delayed physical development, impaired olfactory discrimination, and dysfunctional pre-weaning social behavior. In situ hybridization experiments revealed lower cortical expression of BDNF mRNA in VPA animals. These results support the validity of the VPA mouse model for human autism and suggest that alterations in plasticity-related genes may contribute to the behavioral phenotype.     

Narcolepsy with cataplexy and pregnancy: a case–control study

This was a retrospective case–control study in 25 patients with narcolepsy with cataplexy and 75 women in the control group. Patients completed the questionnaire by Maurovich‐Horvat et al. (J. Sleep Res., 2013, 22: 496–512). We personally interviewed 25 patients with narcolepsy with cataplexy using the administered questionnaire regarding conception, pregnancy, delivery, perinatal and breastfeeding periods. Patients with narcolepsy with cataplexy reported 59 pregnancies versus 164 in the control group. In 16 cases (27.1%), a disease before pregnancy was present compared with eight cases (4.9%) in the control group (P < 0.001); among them, extrinsic asthma was reported 11 times in the narcolepsy with cataplexy group (P < 0.005). Patients with narcolepsy with cataplexy more often had a single pregnancy compared with controls (P < 0.05). Gestational diabetes was more frequent in patients with narcolepsy with cataplexy (P < 0.05). Induced deliveries were higher in controls (P < 0.009). No differences were found between the groups in terms of duration of pregnancies and complications during and after delivery, as during the puerperium. Neonates from patients had heavier birth weight (P < 0.015). The breastfeeding period was longer in patients (P < 0.01). Modafinil and methylphenidate were the drugs administered in six pregnancies. No significant differences in depression during pregnancy and during puerperium were found between patients and controls. This is the first case–control study in women with narcolepsy with cataplexy related to pregnancy, delivery, childbirth and puerperium. Data suggest that patients have pregnancy outcomes similar to controls. The prevalence of gestational diabetes was higher in women with narcolepsy with cataplexy. Caesarean sections, complications during delivery and normal perinatal period for infants were similar in both groups. Breastfeeding was longer in patients.     

Maternal nutrient intake and fetal gastroschisis: A case‐control study

Fetal gastroschisis is a paraumbilical abdominal wall defect with herniation of the abdominal organs. This multifactorial malformation occurs in young pregnant women, and the underlying cause of the disease remains unknown; however, nutritional factors may play a role in its development. This case‐control study explored the association of maternal nutrient intake with the occurrence of gastroschisis. The gastroschisis group (GG) comprised 57 pregnant women with fetuses with gastroschisis, and the control group (CG) comprised 114 pregnant women with normal fetuses matched for maternal age, gestational age, and preconception body mass index classification. Nutritional assessments related to the preconception period were obtained using the food consumption frequency questionnaire, and nutrient intakes were calculated using nutrition programs. The median daily calorie intake was higher (2,382.43 vs. 2,198.81; p = .041) in the GG than in the CG. The median intake of methionine (763.89 vs. 906.34; p = .036) and threonine (1,248.34 vs. 1,437.01; p = .018) was lower in the GG than in the CG. Pregnant women with fetuses with gastroschisis have a diet characterized by higher calorie intake and lower levels of essential amino acids (methionine and threonine) during the preconception period than pregnant women with normal fetuses.     

Patterns of prenatal alcohol exposure and associated non-characteristic minor structural malformations: a prospective study

The characteristic facial features of the more severe end of Fetal Alcohol Spectrum Disorders (FASD) include smooth philtrum, thin vermillion of the upper lip, and short palpebral fissures. A systematic evaluation of a comprehensive list of minor structural defects in association with varying patterns of prenatal exposure to alcohol has not been performed. We examined the patterns and timing of prenatal alcohol exposure to minor structural malformations occurring in at least 5% of the sample. Patterns of drinking were evaluated by drinks per day, number of binge episodes, and maximum number of drinks. Timing of exposure was evaluated 0-6 weeks post-conception, 6-12 weeks post-conception, first trimester, second trimester, and third trimester. Naevus flammeus neonatorum is significantly associated with various patterns of drinking during the second half of the first trimester (RR 1.14, 95% CI 1.04, 1.24 for average number of drinks per day; RR 1.04, 95% CI 1.02, 1.07 for number of binge episodes; RR 1.08, 95% CI 1.01, 1.15 for maximum number of drinks in one episode) and similar for number of binge episodes in all categories of timing of exposure and in the second trimester for average number of drinks per day. Other minor malformations occurring in at least 5% of the sample were not found to be significantly associated with prenatal alcohol exposure. Expected minor malformations were not found to be significantly associated with prenatal alcohol exposure. Naevus flammeus neonatorum appears to be part of the spectrum of features associated with prenatal alcohol exposure.