The prevalence of anti-thyroid peroxidase antibodies and autoimmune thyroiditis in children and adolescents in an iodine replete area.

BACKGROUND: The iodine supply of the population in Berlin has normalized during the last 5 Years. Therefore autoimmune thyroiditis has become the most important differential diagnosis in children and adolescents with goiter. OBJECTIVE: The aim of the present study was to define the prevalence of anti-thyroid peroxidase (TPO) antibodies and autoimmune thyroiditis in children and adolescents with a normalized iodine intake. DESIGN: To enable the measurement of antibodies to thyroid peroxidase (anti-TPO-Ab) in a large cohort, a method to determine anti-TPO-Ab in dried filter paper blood spots was established. In co-operation with pediatricians the antibody prevalence was assessed and data regarding thyroid size, echostructure and the medical history concerning iodine intake and familial thyroid diseases were collected. METHODS: 660 children and adolescents participated in the study; urinary iodine, TSH and TPO-Ab were measured and an ultrasound of the thyroid gland was performed. RESULTS: The sensitivity of the newly established filter paper assay was 91.8% and specificity was 100%. The results confirmed the improved iodine supply, with a median urinary iodine concentration of 139 microg iodine/g creatinine. The prevalence of anti-TPO-Ab was 3.4% with a female to male ratio of 2.7:1. CONCLUSION: The prevalence of anti-TPO-Ab is lower or equal to data reported from other iodine sufficient areas. Data from a moderate iodine deficiency in schoolchildren range from 0.0 to 7.3%. Using the new filter paper method field studies can be implemented to monitor the effect of changes in iodine nutrition on thyroid autoimmunity. Furthermore, this study on the prevalence of anti-TPO-Ab in a cohort of healthy children and adolescents in an iodine replete area can serve as reference data for future investigations and for the comparison with other groups of patients with increased risks for thyroid autoimmunity.

Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome.

Antiepileptic drugs taken by pregnant epileptic women are known human teratogens. They may also cause pharmacological side effects in the newborn, i.e. sedation and or withdrawal symptoms. We examined the relationship between the maternal antiepileptic therapy, neonatal behaviour and later neurological functions in infancy. The study comprised 40 children exposed in utero to a single antiepileptic drug (phenobarbitone, phenytoin, valproic acid). Valproic-acid-exposed children were the highest compromised, except for apathy, which was most profound in phenobarbitone-exposed neonates. Valproic acid serum concentrations at birth correlated with the degree of neonatal hyper-excitability and neurological dysfunction when children were re-examined 6 years later. We suggest that valproic acid may not only cause malformations but also cerebral dysfunction immediate and long term.

Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome.

We report on 8 patients from two families with Alpers syndrome. The onset in one family was prenatal and in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity were found. The second family presented with an early infantile form. All the affected offspring had micrognathia and one had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all the patients died before age 20 months. Results of comprehensive biochemical and metabolic studies in both families were normal and the diagnosis was supported by demonstration of extensive progressive brain atrophy on CT and typical histological findings. Patients without a detectable defect in energy metabolism and normal liver histology comprise a distinct subset of Alpers syndrome. Until the metabolic defect(s) is defined, we suggest naming the acute neonatal form of this subset of Alpers syndrome "type 1."

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.

Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid.

The association of fetal and neonatal distress, birth measurements, major malformations, and minor anomalies was studied prospectively in 14 infants of women with epilepsy who were receiving valproic acid (VPA) monotherapy and in 12 infants of women with epilepsy who were receiving VPA in combination with other anticonvulsant drugs. Comparison was made with 26 matched-pair controls and 116 controls from a larger study of antiepileptic drugs. During the first trimester, total VPA serum concentrations were well above therapeutic levels (100 to 184 micrograms/ml) in two women receiving high VPA doses (2000 and 1500 mg daily). Although dosage remained the same, serum concentrations decreased during pregnancy to therapeutic levels (33.9 to 57.0 micrograms/ml). The VPA percent free fraction increased in the third trimester and was threefold higher at birth. Almost half of the infants exposed to VPA monotherapy were distressed during labor, and 28% had low Apgar scores. Fetal and neonatal distress may be caused by the high VPA percent free fraction during labor and at birth. Mean body measurements at birth after VPA monotherapy were comparable to those in the matched control group, but were reduced in the group of infants receiving VPA combination therapy. Four infants exposed to VPA monotherapy were born with major malformations. The median number of minor anomalies was four times higher in infants whose mothers received VPA alone or VPA combination therapy than in controls. Seven infants had a pattern of craniofacial and digital anomalies that was distinctly different from that observed after in utero exposure to other anticonvulsant medications. The occurrence of major malformations and the number of minor anomalies may be dose related.

Neonatal behaviour disturbances in infants of epileptic women treated during pregnancy.

Infants exposed in utero to antiepileptic drugs showed significantly more behaviour disturbances such as sedation (p less than 0.05) and hyperexcitability (p less than 0.01) than infants of a control group. The presence of these clinical symptoms and the time of their appearance did not seem to be dependent on the type of maternal medication, nor on the drug serum concentration in cord blood nor on the rate of drug disappearance from the infant's plasma.

Theophylline metabolism in preterm neonates during the first weeks of life.

The effects of prenatal steroids on theophylline metabolism in infants of 27-32 weeks gestation was studied. Although in utero exposure to betamethasone was associated with a more mature theophylline metabolite pattern in the first days of life, initial elimination half-life (t1/2 beta) did not differ significantly between groups. By the second or third week of life the metabolite pattern was similar in all infants. The decline in t1/2 beta seen during theophylline treatment was not directly related to increased metabolite formation. These data suggest that other factors, such as renal clearance, are more important in determining the pharmacokinetics of theophylline in neonates than is hepatic metabolism.

[Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development]. / Antiepileptika während der Schwangerschaft. Eine prospektive Studie über Schwangerschaftsverlauf, Fehlbildungen und kindliche Entwicklung.

In a prospective controlled study 70 children of females with epilepsy and on anticonvulsant medication during pregnancy were investigated. It was shown that epileptic females had stillbirths more frequently than expected. After delivery particularly children on phenobarbitone are sedated. Due to weak suckling this may lead to inadequate food intake. Withdrawal symptoms manifest in affected children as hyperexcitability lasting for weeks. Children of epileptic women on medication are generally smaller, of lower weight and have smaller heads than children from all control groups. Ingestion of more than one anticonvulsant leads to an even more pronounced reduction of infantile body measurements below the expected mean value. Small malformations are observed more frequently after intrauterine exposition to anticonvulsants than in the control groups. Ingestion of more than one anticonvulsant leads to an increase of the number of small malformations in the child than after single drug therapy. Children of epileptic parents are affected more frequently by large malformations than children of nonepileptic parents.

Enzyme induction in neonates after fetal exposure to antiepileptic drugs.

The 13C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to 13C-AP breath tests, neonates have a very low capacity to eliminate 13CO2, which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs 13C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerably stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, 13C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by 13C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between 13C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the 13C breath test data will transport very different informations about enzyme induction in these neonates.

Carbamazepine and carbamazepine-10,11- epoxide during pregnancy and postnatal period in epileptic mother and their nursed infants: pharmacokinetics and clinical effects.

A total of 11 epileptic mothers treated with carbamazepine (CBZ) as well as their 12 newborns were included in this study. Maternal CBZ concentrations remained rather constant during pregnancy and slightly increased after parturition. Carbamazepine-10, 11-epoxide ( CBZE ) levels were less predictable and either increased or decreased during pregnancy. Fetal/maternal serum concentration ratios at birth were 0.78 +/- 0.14 (n = 5) for CBZ and 0.75 +/- 0.09 (n = 5) for CBZE . Neonatal half-lives were 28 +/- 11 hours (n = 4) for CBZ and 20 and 24 hours (n = 2) for CBZE . maternal milk/serum concentration ratios of CBZ and CBZE were 0.39 +/- 0.22 (N = 11) and 0.49 +/- 0.28 (n = 6), respectively. The steady-state CBZ serum levels of nursed infants were about 1.0 micrograms/ml in all cases but one, where a maximum concentration of 4.7 micrograms/ml was reached. One of the infants had major malformations. Minor anomalies were less frequent in the CBZ group, compared to the whole group of infants exposed to anticonvulsive drugs other than CBZ and as frequent as in a matched pair control group of unexposed neonates. Neonatal somatic data were found to be below the corresponding values of neonates exposed to antiepileptic drugs other than CBZ.

Development of N-demethylase activity measured with the 13C-aminopyrine breath test.

The 13C-aminopyrine (AP) breath test was used to measure the normal development of N-demethylase activity in 25 children, aged 2 days to 14 years, with normal liver function. Five mg of 13C-AP per kg body weight were administered orally. After AP-demethylation by the hepatic mixed function oxidase system 13CO2 excess was analysed in expired breath by mass spectrometry. In the first days of life no 13C excretion could be detected in unstimulated newborns. N-demethylase activity then slowly increased and reached adult levels by two years of life. Though the range of normal values showed considerable scattering, patients with liver disease or with enzyme induction following anticonvulsant therapy could be well discriminated. This study of the 13C-aminopyrine breath test in children provides evidence for the assumption that hepatocellular function and development of specific enzymatic activities can be measured by such non-invasive methods. It may be expected that breath tests making use of a broader spectrum of 13C-labeled substrates will prove applicable to study prenatal inducibility and other aspects of developing hepatocellular and intestinal function of children in health and disease.

Phenytoin elimination after intoxication during long-term treatment.

Because of the saturable nature of phenytoin metabolism, intoxication due to overdosage with this drug occurs relatively frequently. The present paper reports on a systematic study of phenytoin elimination in six patients with clinical signs of overdosage and with initial serum phenytoin levels well above the normal therapeutic range (40 mumol/L to 80 mumol/L). On the basis of data obtained, it is recommended that, when a patient presents with symptoms of phenytoin intoxiation, an initial serum phenytoin level should be determined. If this exceeds 130 mumol/L, the drug should be withdrawn for a period of 72 to 84 hours, then the administration should be recommenced at a lower dose.

Pharmacokinetics and tissue distribution of metronidazole in the new born infant.

Metronidazole pharmacokinetics and tissue distribution were studied in 11 infants varying in gestational age from 28 to 40 weeks. Elimination half-life was inversely related to gestational age, and ranged from 22.5 to 109 hours. Hepatic hydroxylation of metronidazole was not evident in infants less than 35 weeks' gestation, unless they had been exposed prenatally to betamethasone. A dosage schedule of 15 mg/kg intravenously as an initial single dose is proposed, and will provide adequate therapeutic levels for 48 hours in the preterm infant and for 24 hours in the term infant. Subsequently a dose of 7.5 mg/kg/12 hours is suggested for the first week of life.

Teratogenic and pharmacokinetic studies of primidone during pregnancy and in the offspring of epileptic women.

Fourteen epileptic women treated with primidone, either alone or in combination with other antiepileptic drugs, were studied prospectively during their pregnancy. Plasma levels of primidone and its metabolites were monitored and correlated to findings in the offspring. Maternal serum concentrations of primidone and metabolites were generally low during pregnancy. The levels of its main metabolites--phenobarbital and PEMA--were found to drop within the first month of pregnancy in two cases. The plasma concentrations remained low until birth and rose sharply thereafter. The phenobarbital/primidone ratio (mean 0.84) and PEMA/primidone ratio (mean 0.56) in pregnant patients were found to be lower than in non-pregnant patients, except when primidone was given in combination with phenytoin in which case the expected phenobarbital/primidone (mean 2.5) and PEMA/primidone (mean 1.5) ratios were found. A ventricular septal defect was found in one of the offspring of the fourteen mothers and five children had microcephaly. There was a high incidence of poor somatic development with dystrophy (n=3) and short stature (n=2). Head circumferences (n=8), lengths (n=4) and/or weights (n=8) were below the 10th percentile in a number of children. Four children showed marked facial dysmorphy. Our preliminary data suggest that primidone intake during pregnancy may be important in the pathogenesis of minor anomalies and in the induction of poor somatic development.

Increased theophylline metabolism in premature infants after prenatal betamethasone administration.

The pattern of theophylline metabolites in plasma was studied in 9 preterm neonates of 28-35 weeks gestation. In infants not exposed to corticosteroids prenatally, metabolite formation was dependent on gestational age, postnatal age and/or duration of theophylline therapy. Infants prenatally exposed to betamethasone clearly showed evidence of demethylation and oxidation of theophylline during the first week of life, indicating prenatal activation of the hepatic monooxygenase enzyme system. Preliminary half-life data suggests that activation of hepatic metabolism may not affect initial elimination of theophylline.