Vol. 12: Fall, 1995
Teratogen Update
Substances of Abuse
It is difficult to obtain an accurate number of women in the US who use substances of abuse during their pregnancy, or the number of infants born who were exposed to illicit drugs and/or excessive ethanol in utero. The effect of such drugs on a developing fetus is determined by the drugs (alone or in combination) that are used, the pattern of use, and maternal/fetal metabolism. These important pieces of information are often missing from studies, and incomplete exposure data complicates the interpretation of study outcomes.
Alcohol
Fetal alcohol syndrome (FAS) results from prenatal exposure to large amounts of alcohol. This syndrome is seen in the offspring of chronically alcoholic mothers, and is not the result of social drinking. The actual incidence of FAS is unknown, although it is probably on the order of 0.33 to 1 per 1000 births.
FAS was first reported in 1969 in the French literature and in 1973 in the English literature. Affected children characteristically demonstrate the following features: prenatal growth deficiency (persisting postnatally), mental retardation/learning disabilities, and a pattern of characteristic minor facial anomalies (short palpebral fissures, maxillary hypoplasia, smooth philtrum, and thin vermillion border of the upper lip).
Over the past 20 years, a wide spectrum of alcohol-related birth defects has been delineated, prompting usage of the term fetal alcohol effects (FAE) to apply to those children with some (but not all) of the features of the fetal alcohol syndrome. However, since the diagnosis of FAE is non-specific, often difficult to substantiate and potentially harmful by causing social/medical discrimination, it has been suggested that the term FAE be abandoned in favor of a more detailed descriptive approach to classification of children with some of the features of FAS.
For example, a child with a history of in utero exposure to alcohol who demonstrates short stature and learning disabilities should be given the following diagnoses: short stature; learning disabilities; in utero exposure to alcohol. We encourage all providers to abandon the diagnosis of FAE in favor of more precise diagnostic descriptions.
The pathogenesis of FAS is far from being understood. Maternal and fetal metabolic characteristics undoubtedly play a role, as suggested by the observations that only 40% of the offspring of chronically alcoholic women have FAS, and that a number of sets of twins discordant for FAS have been reported.
Recent experimental data have suggested mechanisms by which the characteristic facies of FAS arise. Ethanol has been demonstrated to cause migrational abnormalities of developing neurons, neural crest and neuroepithelial cells, and to lead to increased cell death of CNS progenitor cells. Neural crest cells may be particularly susceptible to ethanol damage, since alcohol induces production of free radicals in these cells, which lack the free radical scavenging enzyme superoxide dismutase. These factors lead to deficiencies of the frontonasal prominence in the embryo, ultimately changing the structure of the midface. The face of FAS may not be unique (see toluene), but is predicted to be observed in other disorders associated with hypoplasia of the frontonasal prominence.
See References: Alcohol
Toluene
Solvent abuse (via paint, lacquer, or glue sniffing) is a relatively common form of substance abuse. The active organic solvent is toluene. Toluene abuse is usually performed by the subject saturating a sock or cloth with spray paint, placing it over the nose and mouth, and inhaling. Chronic toluene abuse can lead to muscle weakness, GI disturbances, neuropsychiatric problems, peripheral neuropathy and renal tubular acidosis. It is estimated that 3-4% of teenagers and young adults abuse solvents on a regular basis.
Toluene readily crosses the placenta; however few animal teratology studies are available. The possibility of a human toluene-induced embryopathy was first suggested by Toutant and Lipman in 1979 when they described a boy with phenotypic features suggestive of FAS born to a woman who chronically abused solvents. Also in 1979, Holmberg published a retrospective matched pair case control study of infants with CNS defects, in which significantly more case mothers than control mothers had been exposed to organic solvents during the first trimester of pregnancy.
Subsequently, in two publications Hersh and colleagues described five children born to chronic solvent abusers with a phenotype similar to FAS. This included growth and developmental abnormalities, microcephaly, mild craniofacial and limb anomalies, renal defects, and CNS dysfunction.
Others described 30 pregnancies of 10 solvent abusers, which resulted in 21 newborns. They found an increased incidence of prematurity, perinatal death, and phenotypic features suggestive of FAS in survivors. Finally, Pearson et al examined a cohort of 18 infants with prenatal toluene (and alcohol) exposure, and 83% had craniofacial alterations thought secondary to toluene and alcohol.
Although the available human data suggest teratogenic effects in toluene exposed pregnancies, the magnitude of risk for an individual pregnancy remains unknown. Also unknown are the effects of industrial or workplace exposures, as opposed to the effects of maternal recreational solvent abuse which have been documented.
See References: Toluene
Cocaine
Over the last ten years, the use of cocaine as a recreational drug has increased dramatically, raising the question as to its teratogenic potential.
Animal data regarding cocaine's teratogenicity are inconclusive. Early gestational exposures have not produced a reproducible pattern of malformations in animal models. However, Webster et al have observed structural defects in rat fetuses exposed to cocaine in late gestation, which mimic those observed in humans. These effects were hypothesized to be due to the vasoconstrictive properties of cocaine in late pregnancy, and included hemorrhage and edema of the limbs and tail, leading to necrosis.
Studies of cocaine teratogenicity in humans are significantly limited by lack of precise dosage information, as well as the use of other drugs concomitantly. Bearing in mind such study limitations, there does appear to be an increased incidence of abnormal outcome in exposed pregnancies, when the cocaine use occurred throughout gestation.
Genito-urinary tract anomalies have been observed to be increased in several studies, including a large case control study conducted by the CDC. The risk for urinary tract defects in the offspring of cocaine using women in that study was 4 times that of the controls, while the risk of genital defects was not increased.
Other studies have indicated prenatal onset growth deficiency (including height, weight and head circumference). Placental abruption and uterine rupture have been observed, as have congenital heart defects. A number of structural defects have been suggested to result from decreased placental blood flow and/or fetal hypoperfusion or vascular disruption, including: fetal cerebral infarction, porencephaly, neonatal necrotizing enterocolitis, non-duodenal intestinal infarction or atresia and terminal transverse limb defects.
The exact risk for the individual cocaine exposed pregnancy is unknown. However, the available animal and human data suggest that continuous exposure throughout pregnancy may be more harmful than first trimester exposure alone.
See References: Cocaine
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Teratogen Update Table Of Contents:
Introduction
Medications
Substances of Abuse
Maternal Infections
Maternal Disorders
Mutagens
Etiology of Congenital Malformations in Humans: (Table 1)
Known Human Teratogens: (Table 2)
References
Facts About Neural Tube Defects and Folic Acid
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