The clinical dilemma--prescribing in pregnancy.

Antipsychotic prescription in pregnancy is a complex topic and raises a great deal of anxiety in professionals. There is limited data about atypical antipsychotic prescription in pregnancy and its possible teratogenicity. There are no randomised controlled studies of atypical antipsychotic use in pregnancy due to obvious reasons of ethical issues. We present two cases where a choice had to be made as to whether to prescribe Olanzapine during pregnancy, with different results.

Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.

Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6-19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.

Carpal tunnel syndrome accompanying radial dysplasia due to thalidomide embryopathy.

We performed endoscopic carpal tunnel release in four hands in three patients suffering from radial dysplasia due to thalidomide embryopathy. Carpal canal pressure measurements results confirmed the diagnoses. All operations were successfully performed and resulted in no complications. Tingling sensation and sensory disturbances of the hands subsided.

Teratogenic mechanisms of longitudinal deficiency and cleft hand.

In order to better understand the teratogenic mechanisms of congenital defects of the digits, we analyzed clinical cases and induced similar types of congenital hand anomalies in rat fetuses by oral administration of busulfan. In clinical cases, radial and ulnar deficiencies had common characteristic features. We induced radial and ulnar deficiencies in rat fetuses with the same drug. Radial and ulnar deficiencies induced in rats have similar clinical manifestations and these anomalies might be caused by the same teratogenic mechanism. Then, the formation of the digital rays was examined histologically. The results of histological examination suggested that these deficiencies were not caused by localized damage of the limb bud. They also suggested that the cause of missing digits in longitudinal deficiency is closely related to a deficit of mesenchymal cells in the limb bud. Cleft hand is considered to be one of the types of longitudinal deficiency. However, several investigators have suggested that the abnormal induction of finger rays in the process of formation of fingers induced central polydactyly, osseous syndactyly and also cleft hand. X-rays of the clinical cases and skeletal changes of the anomalies induced in rats appear to demonstrate that cleft hand formation proceeds from osseous syndactyly and central polydactyly. The results of our experimental study show that the critical periods of central polydactyly, osseous syndactyly and cleft hand are the same. They also suggest that central polydactyly, syndactyly and cleft hand might be induced when the same teratogenic factor acts on embryos at the same developmental stage in the human being. Because they have a similar causation, cleft hand, syndactyly and central polydactyly should be classified into the same entity, that is, abnormal induction of digital rays. Based on these clinical and experimental studies, we modified the Swanson classification. In our modified classification, typical cleft hand, syndactyly and polydactyly are included in the same category of abnormal induction of digital rays as the fourth new category.

Fetal hydantoin syndrome with rheumatic valvular heart disease.

Research has shown that anticonvulsants are teratogens and pose a risk for fetal malformations. Though Fetal Hydantoin Syndrome (FHS) was first reported by Langhman and others, wide phenotypic variability of this syndrome has lead many clinicians to question its very existence. We report a twelve year old girl with FHS with rheumatic valvular heart disease.

Biochemical and molecular teratology of fetal hydantoin syndrome.

Animal and human research has clearly shown that anticonvulsants are teratogens and pose a risk for fetal malformations. In the case of dilantin it appears that fetal susceptibility correlates with the fetal level of the microsomal detoxifying enzyme epoxide hydrolase. The genetics of seizures in the parents does not predict the risk for fetal teratogenesis. The clinician must work with a mother who has seizures prior to conception to achieve the best control of seizures with a single anticonvulsant at the lowest effective dose to minimize the teratogenic potential, but even if this is done there is still a risk of fetal malformations and developmental delays. Each pregnancy in a woman on anticonvulsants is at risk, and appropriate counseling should be accomplished before conception so the family can make an informed decision. The exact risk of teratogenesis is lower than previously recorded. Dilantin poses approximately a 10% risk, tegretol less than 10%, and valproic acid causes a threefold increase in the risk of neural tube defects as well as an increased risk of other malformations. The positive aspect is that with good medical management and good prenatal care approximately 90% of infants exposed to anticonvulsants in utero will not show evidence of teratogenesis. Finally, it is important to stress that all pregnancies carry a 3% risk for a major birth defect independent of any exposures or genetic history.

Limb deficiency with or without Möbius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy.

Misoprostol, a synthetic analog of prostaglandin, has been widely used in Brazil as an abortifacient. Abortion is illegal in Brazil. An uncertain number of these abortion attempts are unsuccessful and the pregnancy continues. We report on 7 patients whose mothers attempted to abort using this drug in the first trimester of gestation without success. The 7 patients presented with limb defects and in 4 of them a diagnosis of Möbius sequence was made.

[An unusual case of intercalary type of limb abnormalities]. / A végtaghiányos rendellenesség-csoporton belüli intercalaris típus szokatlan esete.

Authors report about a case of total lack of middle phalanxes on the 3d and 4th fingers and a hypoplasia of the surrounding phalanges on the left hand. This is the first report on this type of intercalary type in congenital limb deficiency group. They call attention to one of the so far not sufficiently emphasized hazard of previous periconceptional oral contraceptive use. If there is not enough time left for the total regeneration after the discontinuation of contraceptives, such kind of malformation may develop in the fetus due to the insufficiency of fetal-placental circulation.

[Hydantoin fetal syndrome]. / Syndrome foetal à l'hydantoïne.

We report a case of distal finger hypoplasia associated with foetal hydantoin syndrome (FHS). The occurrence of this syndrome is thought to be due to abnormalities of collagen, cytochrome P 450 and arachidonic acid metabolism. The risk of developing FHS could be evaluated by counting the glucocorticoid receptors of lymphocytes or by measuring epoxide hydrolase activity through amniocentesis. FHS can be prevented by taking folates during pregnancy.

Major and minor birth malformations and antiepileptic drugs.

In a study of infants of parents with epilepsy, malformations were twice as prevalent in these children as in controls. Children of mothers with epilepsy had more minor anomalies than those of fathers with epilepsy or controls. At 1 year of age, a greater number of minor anomalies was seen in children of mothers with epilepsy who had received treatment with antiepileptic drugs (AEDs) during pregnancy, whereas at 4 years, no difference was observed. Type of epilepsy, seizures during pregnancy, plasma levels of phenytoin or phenobarbital in the medium range, and fetal intrauterine growth did not correlate with the number of minor anomalies. We suggest that the special genetic background that predisposes to epilepsy also renders the fetus more vulnerable to major and minor anomalies. Although linkage between epilepsy and malformation is stronger than between AEDs and malformations, valproate, phenytoin, and phenobarbital show specific teratogenic effects. In addition, all AEDs unspecifically increase the number of minor anomalies. Under therapeutic conditions, valproate may be regarded as considerably teratogenic and all other observed AEDs as weakly teratogenic.