Maternal Drug Exposure Research Articles

A case-control study on the association between first trimester exposure to lithium and Ebstein's anomaly

Lithium carbonate is considered to be a first-line drug in the management of manic depressive psychosis. According to Food and Drug Administration figures 0.1% of pregnant women are using this medication. 1 During the last 2 decades accumulated data have suggested that lithium carbonate may be teratogenic in humans. 2 The Danish registry has accumulated over 200 cases, among which there was a 10% occurrence rate of cardiac malformations. 3 This rate appears high when compared to the 0.1% risk for such malformations in the general population. 2 In particular, the Danish registry reported 8 cases of the rare Ebstein's anomaly which occurs spontaneously in only 1 of every 20,000 births, suggesting a relative risk of 500-fold above that in the general population. However, the information in this registry has been collected by a voluntary reporting system and does not represent systematically collected data. It has been argued that families and physicians caring for malformed babies are more likely to report adverse fetal outcomes to the registry than normal outcomes, 4 as was the case with retinoic acid. 5 This reporting bias may create a false impression of a teratogen when, in fact, the drug may not be teratogenic. The implication of wrongful incrimination of a drug like lithium may be immense; women may not be optimally treated during conception and pregnancy or, if treated before pregnancy was recognized, they may wish to terminate pregnancy to avoid an increased teratogenic risk. Since our team provides counselling for women in greater Toronto on the safety of drugs and chemicals, we are continuously witnessing both these options being taken by women. To the best of our knowledge no controlled studies have tried to define the teratogenic risk of lithium in humans. In dealing with a rare malformation such as the Ebstein's anomaly, a sample size > 400 women exposed to lithium and a similar group of nonexposed women would have to be collected prospectively in order to detect a 10-fold increased risk with an alpha of 0.05 and power of 0.8. A more realistic approach to try to address this question would therefore be the case-control study where one focuses on the rare event, namely the Ebstein's anomaly, and compares maternal drug exposure in pregnancy of children having this malformation with those of a control group. Because our cardiology division is the tertiary referral center for a population of about 6 million, we have had the rare opportunity to ascertain a large number of cases of Ebstein's anomaly and thus to test the association between first trimester exposure to lithium and this malformation.

Developmental toxicity and pharmacokinetics of oral and intravenous phenytoin in the rat

Correlations between oral and intravenous (i.v.) doses of phenytoin, maternal plasma levels, and subsequent developmental toxicity were examined in the Sprague-Dawley rat. Oral administration of 150 to 1500 mg/kg and i.v. administration of 25 to 100 mg/kg phenytoin from gestational days (GD) 8 to 17 resulted in a dose-dependent increase in maternal death and toxicity [impaired motor function, decreased maternal weight gain (oral dose only)], embryolethality, and intrauterine growth retardation, in addition to significant increases in craniofacial (1125 mg/kg oral; 75 mg/kg i.v.) and urogenital (1125 mg/kg oral) malformations. Pharmacokinetic sampling in oral and i.v. groups on GD 8–9 and 16–17 revealed significant increases in maternal drug exposure over the treatment period, as evidenced by 2- to 3-fold increases in total plasma phenytoin (bound + free) half-life, area under the concentration curve, peak concentration (oral dose only), and decreases in clearance. These findings emphasize the importance of pharmacokinetics in the evaluation of phenytoin-induced developmental toxicity.

Fetal Minoxidil Exposure

To the Editor.— Kaler et al (Pediatrics 1987;79:434-436) provided a case report of hypertrichosis and multiple congenital anomalies with maternal minoxidil use. Reports such as this contribute to alerting national drug safety offices of possible teratologic questions. Maternal drug exposure data, since 1979 when minoxidil was marketed, is available to the Food and Drug Administration (FDA) from 73,000 pregnancies (15,600 birth defects, 4,400 spontaneous abortions, and 53,000 normal outcomes). This yields, in addition to the report by Kaler et al, only two other births with maternal minoxidil exposures:

Strategies for the assessment of the effect of maternal drug exposure on the offspring.

Strategies for the assessment of the effect of maternal drug exposure on the offspring.

Growth, development and activity in rat offspring following maternal drug exposure.

Seventy-nine Sprague-Dawley derived primimparous rats were injected subcutaneously throughout pregnancy and the nursing period with either (1) 30 mg/kg of pure nicotine, (2) 5.0 mg/kg methamphetamine HCL, (3) saline vehicle, or, (4) non-injected. Vital and developmental measures were taken on the offspring throughout the nursing period and for one additional week. Metamphetamine-injected females had a shorter, and nicotine-injected females a longer gestational period, and both gained less weight over the 21-day period than the control groups. The pups of methamphetamine and nicotine dams were significantly underweight at birth and the 28 day postnatal period and exhibited developmental delay. Male offspring were divided into behavioral, aging, and autopsy on Day 28. Male offspring of methamphetamine-injected dams remained significantly lighter in weight for the first 15 months of life (aging groups). Their counterparts in the behavioral groups and the offspring of non-injected dams exhibited significantly greater activity for eight of the first twelve monthly assessments which began at 90 days of age. Additional vital, performance, and sensory measures will continue throughout the lifespan of the animals.

Maternal drug exposure and fetal abnormalities. Material and methods.

Data derived from a cohort of 50,897 pregnancies that occurred between 1959 and 1965 are currently being evaluated to determine whether any associations between maternal drug exposure and abnormalities in the offspring exist. In this report, the cohort being studied is briefly described, and the methods used to identify associations, together with factors that confound them, are outlined. Also presented are the techniques used to control for these factors in evaluating the associations. Issues concerning causal interpretation of associations that remain after confounding factors have been controlled are discussed.

An approach to hypotonia in children.

Hypotonia, a common pediatric symptom, results from either diffuse disease of the central nervous system or involvement of the peripheral nervous system. Central hypotonia should be suspected when there is a history of neonatal trauma, infection, or previous maternal illness or drug exposure. It also is associated with some metabolic and chromosomal abnormalities. In peripheral hypotonia, electromyography will differentiate between myopathic and neurogenic diseases, and muscle biopsy will establish the specific diagnosis.