Fetal Anomalies

OCDD. Signs of maternal toxicity were not observed in rats given 100 or 500 mg/kg/day OCDD. Examination of the fetuses did not reveal changes in fetal body measurements, incidence of fetal resorptions, or incidence of any fetal anomaly among litters or the fetal population. At 500 mg/kg/day, the incidence of subcutaneous edema was significantly increased among the fetal population (23/100 compared with 8/156 in controls) but not among litters (9/18 compared with 6/28 in controls). 

Diuretics Not first-line agents probably safe available data suggest that throughout gestation a diuretic is not associated with an increased risk of major fetal anomalies or adverse fetal-neonatal events. 

One way to circumvent such (unjustified) labeling is to try to prove a causal relationship between the maternal effects and those in offspring, thus trying to show that the latter ones are unspecific secondary consequences of the former ones. So for the sound interpretation of study results it is important to find a good balance between maternal and fetal effects. For example, if a 10% reduction in maternal net weight gain is accompanied by a comparable reduction in fetal weight, then this puts the fetal effects in the correct perspective and would not lead the experimenter to conclude that the compound is a (specific) developmental toxicant. On the other hand if in the same situation the number of fetal anomalies (in particular malformations) is increased, then this could most unlikely be explained as a consequence of maternal toxicity. 

Generoso WM, Rutledge JC, Cain KT, Hughes LA, Downing DJ (1988) Mutagen-induced fetal anomalies and death following treatment of females within hours after mating. Mutat Res, 199 175-181. 

Katoh M, Cacheiro NLA, Cornett CV, Cain KT, Rutledge JC, Generoso WM (1989) Fetal anomalies produced subsequent to treatment of zygotes with ethylene oxide or ethyl methanesulfonate are not likely due to the unusual genetic causes. Mutat Res, 210 337-344. 

Propylthiouracil crosses the placenta as readily as the thioimidazoles, but the rare and probably real association between thioimidazoles and fetal anomalies makes the thioimidazoles less attractive first-line alternatives (103-105). When propylthiouracil is used cautiously in... 

Pregnant mice exposed 12 hours per day to 156.5 or 313 ppm benzene on Gd 6-15 had pups with significant weight retardation and retardation of skeletal development, but no malformations (Ungvary and Tatrai 1985). A parallel study in rabbits showed that inhalation of benzene at 313 ppm caused fetal weight reduction, and an increase in minor fetal anomalies (Ungvary and Tatrai 1985). 

Studies in animals have shown that sulfur mustard may induee developmental and reproductive effects (reviewed in NRC, 1999, 2003). Acute exposures resulting in systemic uptake may have effects on reproductive organs, including inhibition of spermatogenesis. Fetal anomalies were observed in tests with rats given sulfur mustard during gestation but only at maternally toxic doses. 

Hern WM, Zen C, Ferguson KA, Hart V, Haseman MV. Outpatient abortion for fetal anomaly and fetal death from 15-34 menstrual weeks gestation techniques and chnical management. Obstet Gynecol 1993 81(2) 301-6. 

In females, ethylene oxide also induces presumed, dominant, lethal mutations. When females are exposed shortly after mating or during the early pronuclear stage of the zygote, high frequencies of fetal anomalies are induced. 

Open neural tube defects, Down syndrome, and trisomy 18 (discussed separately below) are fetal anomalies that are partially detectable by maternal serum screening. However, because of the large number of pregnancies screened, and the interest in other fetal conditions and their possible association with abnormal maternal serum analyte concentrations, a wealth of associations between rarer conditions and screening results has been pubhshed. These findings are never diagnostic and are reported rarely by the screening laboratory. In certain circumstances, however, the healthcare provider may determine a need for more extensive medical evaluation. 

Measurement of AFP in maternal serum and amniotic fluid is used extensively throughout the United States and the United Kingdom for prenatal detection of some serious fetal anomalies. Use of AFP in nonpregnant patients for monitoring certain cancers is described in Chapter 23,... 

Maternal serum and amniotic fluid AFP are useful tests for detecting some serious fetal anomalies. Maternal serum AFP is elevated in 85% to 95% of cases of fetal open neural tube defect and is low in about 30% of cases of fetal Down syn-drome. Because maternal serum screening for fetal... 

Khera KS. 1991a. Chemically-induced alterations in maternal homeostasis and conceptal histology their etiologic significance in rat fetal anomalies [Abstract]. Teratology 43(5) 414. 

Regarding reproductive toxicity, the teratogenic effects in fetuses were observed in [38] and the study in rats by [29] however, it is reasonable to consider that the observed effects are not the direct effects of test substance but the secondary effects derived from the maternal toxicity. In general, a threshold exists for teratogenicity and when some maternal toxicity occurs, fetal anomaly is observed. Therefore, a dose without any maternal toxicity can be used for risk assessment as the no observed effect level (NOEL) for teratogenicity. Consequently, the NOAEL for developmental effect is established as 500 mg kg per day. 

At the present time, the best we can say is that about half the recognized fetal anomalies are caused either solely or partly by impact on the fetal environment. Here partly means the anomaly evidently involves some combination of genetics and environment. I m not concerned in this book with gross malformations of the fetus—the branch of biomedicine called teratology (dysmorphology)—but with changes in prenatal development due to impact on gene expression that can cause... 

These studies would suggest that the moderately elevated plasma vitamin A levels in the blood of pregnant women who have taken OCA are unlikely to adversely affect a fetus if pregnancy did develop. In fact, the mechanism by which excess of maternal vitamin A in the guinea pig leads to congenital anomalies has not been elucidated. It is well to note that exposure of the maternal rat or mouse to unrelated noxious agents such as radiation, trypan blue, and hypoxia may also lead to similar fetal anomalies (C5). 

An abnormal birth mechanism (abnormal fetal presentation and position) prevents adequate progression of labor just as often as maternal factors. Other fetal causes are macrosomia or fetal anomalies asso-... 

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