ABSTRACT
Until recently epidemiological evidence was not regarded as helpful in determining cause and effect. It generated associations that then had to be explained in terms of bio-mechanisms and applied to individual patients. A series of legal cases surrounding possible birth defects triggered by doxylamine (Bendectin) and connective tissue disorders linked to breast implants made it clear that in some instances epidemiological evidence might have a more important role, but the pendulum swung too far so that epidemiological evidence has in recent decades been given an unwarranted primacy, partly perhaps because it suits the interests of certain stakeholders. Older and more recent epidemiological studies on doxylamine and other antihistamines are reviewed to bring out the ambiguities and pitfalls of an undue reliance on epidemiological studies.
Subject(s)
Causality , Forensic Sciences/legislation & jurisprudence , Pharmacoepidemiology/legislation & jurisprudence , Pharmacovigilance , Abnormalities, Drug-Induced/epidemiology , Antiemetics/adverse effects , Antiemetics/toxicity , Breast Implantation/adverse effects , Breast Implantation/statistics & numerical data , Connective Tissue Diseases/epidemiology , Dicyclomine/adverse effects , Dicyclomine/toxicity , Doxylamine/adverse effects , Doxylamine/toxicity , Drug Combinations , Female , Forensic Sciences/organization & administration , Humans , Pharmacoepidemiology/organization & administration , Pharmacology/legislation & jurisprudence , Pharmacology/methods , Pregnancy , Pyridoxine/adverse effects , Pyridoxine/toxicityABSTRACT
Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).
Subject(s)
Antiemetics/toxicity , Cyclohexanecarboxylic Acids/toxicity , Dicyclomine/toxicity , Doxylamine/toxicity , Pregnancy, Animal/drug effects , Pyridines/toxicity , Pyridoxine/toxicity , Teratogens , Abnormalities, Drug-Induced , Animals , Drinking Behavior/drug effects , Drug Combinations/toxicity , Feeding Behavior/drug effects , Female , Litter Size , Male , Pregnancy , Rats , Rats, Inbred Strains , Reference ValuesSubject(s)
Abnormalities, Drug-Induced/prevention & control , Pregnancy , Benzodiazepines/toxicity , Caffeine/toxicity , Dicyclomine/toxicity , Doxylamine/toxicity , Drug Combinations/toxicity , Epidemiologic Methods , Female , Humans , Hydantoins/toxicity , Immunosuppressive Agents/toxicity , Lithium/toxicity , Lithium Carbonate , Phenothiazines/toxicity , Pyridoxine/toxicity , Registries , Risk , Rubella Vaccine/toxicity , Solvents/adverse effects , Spermatocidal Agents/toxicity , Trimethadione/toxicity , Valproic Acid/toxicityABSTRACT
We investigated the incidence of birth defects in the offspring of women who took Bendectin during pregnancy. Copies of all prescriptions issued for Bendectin in two Cities, Leeds and Liverpool, over periods of 12 and 14 months, respectively, were scanned and a record initiated for each patient. Birth notifications were later searched for matching with indexed patients. Births were traced for 2,298 patients and the incidence of major defects compared with those in the relevant populations. We found no evidence to suggest that Bendectin is teratogenic in humans.
