Nils Conradi

Teratogenic effects of benzodiazepine use during pregnancy

Eight children exposed in utero to benzodiazepines had characteristic dysmorphic features, growth aberrations, and central nervous system abnormalities from birth. Their dysmorphic characteristics resembled those of the fetal alcohol syndrome, although they had greater focal involvement of cranial nerves, with a sullen and expressionless face, and they more often had impairment of vitality at birth. One infant died and at autopsy had varying degrees of distortion of neuronal migration, with concomitant heterotopias. Five of the eight mothers had regularly consumed benzodiazepines, and the three remaining mothers had blood samples during pregnancy revealing benzodiazepine concentrations indicative of regular use. Our findings indicate that maternal consumption of benzodiazepines may be teratogenic in humans.

Histologic activity of childhood chronic hepatitis B related to viremia levels, genotypes, mutations, and epidemiologic factors.

Background Despite high viral load, children with chronic hepatitis B virus (HBV) infection may lack significant biochemical signs of liver dysfunction. Failure to develop abnormal liver chemistriesis is probably due to immunologic hyporeactivity. Despite the absence of biochemical abnormalities in these patients, there is still a risk for long-term complications. The pathogenic importance of viral load and genetic variability is less well studied in children than in adults. Methods We evaluated viremia levels, genotypes, and mutations related to histologic evidence of liver damage in 71 HBV carriers, aged 2 to 18 years, all of non-Swedish origin. Results None of the of 22 children who were hepatitis B e antigen (HBeAg) negative had severe liver disease or had HBV DNA levels greater than 104.6 copies/mL (mean 103.2); 3 (14%) of them had increased alanine aminotransferase (ALT). The 49 HBeAg-positive children had a mean HBV DNA level of 108.0 copies/mL, and increased ALT was seen in 28 (55%). Core promoter mutations (at nt 1764) or precore mutations (at codon 1, 2, or 28) were rare; they were seen in four and one HBeAg-positive children, and in four and nine HBeAg-negative children, respectively, without association to liver damage. C-1858 was associated with more liver inflammation. Genotype did not significantly influence liver damage. Children with horizontal transmission had a faster rate of seroconversion and more inflammation of the liver. Conclusions Severe HBeAg-negative hepatitis with high HBV DNA levels and mutations in the core promoter or precore regions seems to be less common in children than in adults. C-1858 strains may be more pathogenic, but this requires further study. Epidemiologic factors influence the course of infection.

Predictive factors and virological response to interferon treatment in children with chronic hepatitis B.

Further knowledge about factors predicting response to interferon treatment for chronic hepatitis B in children is required, in particular as the benefits of therapy are uncertain. In the present study, baseline characteristics were related to virological and histological responses in 27 children given interferon-alpha for 24 weeks after steroid priming. HBe seroconversion was seen in 8 of 27 HBeAg positive patients and was accompanied by a sustained virological response (SR), with a median 4.1 log HBV DNA reduction. Pretreatment viraemia level was the only baseline parameter associated with SR. After 12 weeks of IFN (mid-treatment), viraemia was significantly reduced in all patients, with a median of 3.0 (range 0.6–5.2) log decline in SR compared with 0.6 (range −0.5–3.6) log decline in non-sustained responders (NSR). HBV DNA levels below 1 million copies/ml at week 12 predicted sustained response with a positive predictive value of 75% and a negative predictive value of 89%. During the latter half of the IFN treatment HBV DNA tended to increase by a mean of 0.4–0.5 log for all patient groups. Flares during IFN treatment were rare or mild as measured by ALT. Pretreatment anti-HBc IgM was associated with liver damage but not with response. Histological inflammation scores were improved in SR. Thus, pretreatment HBV DNA levels were associated with IFN response, and the virological response at week 12 predicts SR and may be useful in the decision to continue or modify therapy.

BENZODIAZEPINE OVERCONSUMPTION IN PREGNANCY

The extreme variations of oestradiol levels found by Guirgis are difficult to interpret because we are not told whether the patient is having her first implant or her tenth. An oestradiol as low as 37 pmol 16 months after a 100 mg oestradiol implant is hard to believe, and an oestradiol level in excess of 2000 pmol/l after a single implant is outside our experience7.8 although it would be possible with repeated oestrogen overdosage given over several years. Even so, there is no evidence that these most unusual oestradiol values are associated with an increased incidence of deep venous thrombosis or carcinoma of the breast. Even the highest oestradiol levels found are

Psychotropic drug use in pregnancy and perinatal death

The psychotropic drug use in mothers to all 73 perinatally dead infants in the city of Gothenburg, Sweden, in 1985–86, was compared to a control group of mothers to 73 surviving infants. Information regarding medication in pregnancy and pre‐ and perinatal data was collected retrospectively. In addition, serum samples obtained in early pregnancy were screened for benzodiazepines Eighteen case‐mothers used psychotropic drugs during pregnancy compared with 7 control‐mothers. The association between psychotropic drug use and perinatal death was significant (p = 0.01). Psychotropic drug use and maternal disorder were closely correlated, but within the case group there were no significant differences between mothers using or not using psychotropic drugs in terms of age, parity or smoking habits. Although the etiology of death could be discussed in the individual infant, we find it noteworthy that the use of psychotropic drugs was so frequent in the mothers of perinatally dead infants.

Teratogenic Effects of Benzodiazepine Use during Pregnancy

Eight children exposed in utero to benzodiazepines had characteristic dysmorphic features, growth aberrations, and central nervous system abnormalities from birth. Their dysmorphic characteristics resembled those of the fetal alcohol syndrome, although they had greater focal involvement of cranial nerves, with a sullen and expressionless face, and they more often had impairment of vitality at birth. One infant died and at autopsy had varying degrees of distortion of neuronal migration, with concomitant heterotopias. Five of the eight mothers had regularly consumed benzodiazepines, and the three remaining mothers had blood samples during pregnancy revealing benzodiazepine concentrations indicative of regular use. Our findings indicate that maternal consumption of benzodiazepines may be teratogenic in humans.