Congenital effects

So, back to the opening question. What is the likelihood of detecting low-incidence, drug-induced congenital effects in a drug development program With our presumed database of 4000 patients, only... 

AVP is mainly used in the replacement therapy in congenital diabetes insipidus (CDI), but has only a short effect of 4-6 h. It is also used in the therapy of gastrointestinal haemorrhage, as a local vasoconstrictor,... 

Concentrations of PCBs in fish from each of the Great Lakes currently exceed the GLWQA objectives for the protection of aquatic life. Similarly, concentrations of some substances (e.g., PCBs, Hg, mirex, toxaphene) in Great Lakes fish continue to exceed acceptable guidelines for human consumption. Documented effects in the Great Lakes include reproductive failure, congenital abnormalities and induction of tumours in various aquatic, terrestrial and avian species (23). 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

Additional studies of the Woburn population have been completed (MDPH 1994). The final report indicated that there was an increased prevalence in choanal atresia, a rare respiratory effect, and hypospadias/congenital chordee. A small increase in eye defects was observed, but there was no association between TCE exposure and heart defects. There was no statistically significant associations between exposure concentrations and birth defects, although analyses was limited by the small number of cases observed. Based on four cases in the Woburn population, a rate of 0.88 was observed in the exposed population, compared to rates of 0.11 and 0.13 in the Atlanta and California comparison populations, respectively. In a prospective study completed after well closure, the rate of choanal atresia was 0.88 (based on 1 case) in Woburn, 0.11 in the surrounding communities, and 0.2 and 0.13 in Atlanta and California, respectively. The study authors cautioned that their study did not rule out moderate increases in rates of the less common adverse reproductive outcomes. For these outcomes only large increases would have been detected. 

Syphilis, caused by the spirochete Treponema pallidum, can have numerous and complex manifestations. Clinician familiarity, stage-specific diagnosis, and effective treatment are vital. Missed or inappropriately treated syphilis may result in cardiovascular complications, neurologic disease, or congenital syphilis. 

Lipo-PGEj was reported to be 10 to 20 times more effective than PGEj in the treatment of ductus dependent congenital heart diseases. It can be used at much lower doses, and accordingly, adverse reactions are reduced (9). The drug is approved for this indication, and has already been used safely in many patients. 

Developmental Effects. Evidence from human studies on congenital anomalies as an end point (Emhart et al. 1985, 1986 McMichael et al. 1986 Needleman et al. 1984) indicate no association between prenatal exposure to low levels of lead and the occurrence of major congenital anomalies. This conclusion is further supported by developmental toxicity studies conducted in rats and mice these studies provide no evidence that lead compounds (acetate or nitrate) are teratogenic when exposure is by natural routes (i.e., inhalation, oral, dermal). Intravenous or intraperitoneal injection of lead compounds (acetate, chloride, or nitrate) into pregnant rats, mice, or hamsters, however, has produced malformations in several studies reviewed by EPA (1986a). 

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