Monitoring the health of children born to women who attempted suicide while pregnant can shed light on which medicines and what doses are particularly dangerous to developing fetuses, according to researchers from Hungary who publish their findings in a series of reports in a special issue of Toxicology and Industrial Health, published this week by SAGE.
Information about the harm particular drugs can do to unborn children – a measure known as tetrogenic potential – is generally extrapolated from experimental animal investigations before the drug is approved for sale, because ethical considerations prevent regulated tests of safe doses being conducted in women who are pregnant.
However, because it is difficult to translate the findings from animal models to a real human situation, regulators err on the side of caution, and frequently prohibit the use of potentially beneficial agents in pregnant women.
"Many drugs are subject to contraindications or special warnings because their effects have not been sufficiently studied during pregnancy or non-clinical studies revealed adverse teratogenic or fetotoxic effects," explain the authors. "Data from self-poisoned pregnant women provide an appropriate source of information for use in better estimating the potential human risks of exposure to drugs during pregnancy."
In desiging their study, the Hungarian researchers reasoned that if no congenital abnormalities occur in children born to women who ingest very large doses of a drug during critical developmental periods, then this information supports the notion that the ingested drug is not a human teratogen. What is more, they report, self-poisoned women present the opportunity to gather data on dose-response relationships, which are difficult to ascertain from animal models, because they are hospitalised and undergo extensive pharmacological tests.
To test their hypothesis that self-poisoned pregnant women could give useful drug-safety data, the researchers studied outcomes of all such admissions to the Department of Toxicological Internal Medicine, Korαnyi Hospital, Budapest. During the study period of 1960-1993, 1044 pregnant women were admitted and 1021 of these attempted suicide with drugs (the other 23 pregnant women had accidental intoxication due to poisonous mushroom ingestion or carbon monoxide).
Among them, these women had 411 live-born infants, and 367 exposed children were evaluated with cognitive and behavioural tests as they grew up. The test results were compared with results for siblings whose gestational periods were normal. The researchers recorded occurances of congenital abnormalities, retardation in fetal growth (the most sensitive indicator of a fetotoxic effect of drugs), rates of preterm and low birthweight babies, and the deatials of the particular drug and dose taken by mothers.
Diazepam was one of the most frequently used drugs, with 229 pregnant women using it to attempt suicide. 112 women went on to deliver live babies, 15 of whom had congenital abnormalities. However, according to the researchers, when they further analysed the doses and timing of drug ingestion, they discovered that most of the congenital abnormalities could not be considered a teratogenic effect of diazepam because the time of suicide attempts did not overlap with the critical period for producing the defects.
"Although suicide attempts with large doses of diazepam would be expected to produce an extreme pathological condition in the embryos and fetuses, such was not observed," note the authors. "Thus congenital abnormalities in the offspring of pregnant women with psychiatric disorders are mainly associated with psychiatric disorders and related lifestyle (eg, multiple alcohol and substance abuse) or their interaction, but not by diazepam itself."
Although the authors acknowledge there are limitations to the method – including the fact that pregnant women who attempt suicide are younger and with lower average socioeconomic status than the general population, and they tend to combine excess medications with large amounts of alcohol, tobacco, or other drugs – they conclude that using the self-poisoning model for estimating human teratogenic risks of drugs is feasible and potentially beneficial.
They suggest that an international registry of self-poisoned pregnant women should be set up to enable more in-depth study of the effects of various doses of medication in pregnancy.
Toxicology and Industrial Health, Vol.24, No.1-2, is published this week by SAGE. The journal is available online from http://tih.sagepub.com/current.dtl. The special issue will be free for one month.
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