Fetal effects, direct

Untoward effects of levodopa are dyskinesia and rapid fluctuations related to rigidity, which may suddenly worsen. Psychologic effects such as confusion, disorientation, insomnia, and nightmares are common in 20% of patients. Various transplantation approaches have been tried based on the injection of dissociated fetal cells directly into the substantia nigra. An alternative approach includes the use of genetically modified nonneuronal cells (e.g., fibroblasts), so that they will secrete missing mediators such as dopamine and growth factors.62... 

As mentioned previously, maternal and/or fetal stress associated with sublethal exposures to OP insecticides could lead to an increased incidence of abortions or pre-term births in intoxicated pregnant women and animals. Because of lower levels of detoxifying enzymes (i.e. paraoxonase), the fetus appears to be more susceptible to OP intoxication than adults, and developmental neurotoxicity and growth retardation have been associated with low-level, prenatal exposures of humans to OP insecticides (Desaiah, 1998 Eskanazi et ah, 2008 Peiris-John and Wickremasinghe, 2008). In addition to the maternal and fetal effects, OP insecticides can also have direct toxic effects on the placenta, possibly involving (depending on the species) AChE inhibition within the placental cholinergic system (Pelkonen et ah, 2006). 

The developmental toxicity of a 20% lipid emulsion containing a 3 1 ratio of medium-chain to long-chain triglycerides has been examined in animals. Administration was once-daily intravenously to rats and rabbits during organogenesis. Maternal and embryo/fetal toxicity were also assessed. There were no adverse effects on fetal parameters for rats even in the presence of maternal toxicity. However, embryo and fetal toxicity (resorptions) and skeletal abnormahties were noted in rabbits (135). The adverse fetal effects were probably the result of dietary deprivation, maternal toxicity, or both rather than representing a direct teratogenic effect. 

Stannous chloride, an FDA-approved direct food additive with GRAS status, has also been extensively studied (59—62). In three FDA-sponsored studies, it was determined that stannous chloride is nonmutagenic in rats when administered orally up to 50 mg/kg to pregnant mice for ten consecutive days, stannous chloride has no discernible effect on nidation or on maternal or fetal survival and, when administered orally at 41.5 mg/kg to pregnant rabbits for 13 consecutive days, it produced no discernible effect on nidation or on maternal or fetal survival (63—65). 

Information on the transplacental transfer of americium in humans is not available directly, but the information from experiments with americium and other actinides has been used to derive biokinetic models and perform dosimetric models for the human (NCRP 1998 NRC 1996 Sikov and Kelman 1989). Studies in animals that received parenteral injections of americium have shown that absorbed americium is transferred to the fetus (Hisamatsu and Takizawa 1983 Paquet et al. 1998 Sasser at al. 1986 Schoeters et al. 1990 Weiss et al. 1980) (see Section 3.4.2.1). Limited reports indicate that241 Am may induce fetal death and teratogenic effects in rodents (Moskalev et al. 1969 Rommerein and Sikov 1986). 

Phthalates do not seem to act via direct hormonal mimicking. However, in rodents, some phthalates (BBP, DiBP, DBP, DEP, DEHP, and DiNP) can modulate the endogenous production of fetal testicular testosterone [85-87], resulting in functional and structural impairment of male reproduction and development [85, 88-90], but these effects have not been proved when tested in non-human primates. 

Terbutaline (Brethine, Bricanyl) is a relatively specific P2-adrenoceptor agonist (see Chapters 10 and 39). Terbutaline can prevent premature labor, especially in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate Pj-adrenoceptors. While it appears to be especially selective for P2-receptor activation, terbutaUne does have some Pi activity as well. 

Many drugs and pesticides readily cross the placenta to reach significant concentrations in fetal plasma. However, other chemicals cross the placenta less readily and their concentrations are lower in the fetal plasma than maternal plasma (6). In the case of the latter chemicals, the placenta may be exposed to higher concentrations of the chemical than the embryo. Thus, any adverse effects of the drugs on development may result from direct effects to the embryo and fetus or from indirect effects through altered placental function (7). 

Clark and colleagues (27) found evidence of maternal toxicity influencing fetal findings in studies with diflunisal in rabbits, in which fetal axial skeletal defects were observed. Diflunisal was found to produce severe maternal hemolytic anemia and greatly decreased erythrocyte ATP levels. The authors were able to demonstrate that the skeletal malformations resulted from maternal hypoxia secondary to anemia, rather than from a direct effect of the drug on the embryo or fetus. In addition, it was demonstrated that diflunisal had no effects on rat erythrocyte ATP levels, and the compound was categorized as not teratogenic in rats or mice. 

Examples Where Fetal Adverse Effects Have Been Misinterpreted to Be Caused by Maternal Toxicity Instead of by a Direct Effect on the Embryo... 

If both maternal and embryo-fetal toxicity have ensued, a frequent interpretation is that the maternal toxicity has caused the embryo-fetal toxicity. In the author s view, it is more likely that a dose that is toxic to the adult is going to be toxic to the conceptus, and there is no need to invoke undefined (and probably indefinable) indirect mechanisms. Particularly in the case of small molecules that are lipid-soluble and that can cross the placenta freely, the maternal and fetal systems could be said to constitute a single pharmacokinetic compartment, and the conceptus will be exposed directly to the drug. It would not be surprising if the conceptus manifested effects of toxicity in cases where adult toxicity has been shown. 

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