Albert Schweitzer once said, "Man can hardly even recognize the devils of his own creation." The most alarming of these creations is man's assault upon his own environment, in the contamination of air, earth, water, and himself.
Fetal effects of maternal bacterial and viral infections (measles, cytomegalic, herpes, etc.) are well documented. However, drug and chemical effects are less recognized and understood, and actually there was very little in the literature about these effects until recently (Table 1).
Since the placenta is known to be an ineffective barrier between the maternal and fetal circulations, actually any drug or chemical dangerous to the infant may be considered potentially dangerous to the fetus when given to the mother. Fortunately, many drugs toxic to infants may not reach dangerous fetal levels when administered to the mother. In general, however, drugs associated with jaundice should be avoided in the pregnant woman at parturition, as well as in the neonatal infant.
Evidence is overwhelming that the nonbarbiturate, sleep-inducing drug thalidomide produced severe malformations of the extremities (phocomelia - "seal extremities") in numerous newborns in Germany and other parts of Western Europe in the early 1960s. Sixteen infants are suspected of having been deformed through its use in the United States, but, fortunately, it was not permitted to be sold in this country by the FDA. However, the only medications known definitely and absolutely to be teratogenic in the human are folic-acid antagonists (primarily aminopterin), thalidomide, and masculinizing steroids. Cortisone and its analogues, suspect in cleft palate, should be avoided if possible, particularly in the first trimester of pregnancy. Oral anticoagulants pass readily through the placental barrier and can have teratogenic effects. Heparin should be used instead, since it cannot cross the placental barrier. Maternal hypervitaminosis A has also been documented as having teratogenic effects on the fetus. Anticonvulsants can be teratogenic, especially diphenylhydantoin (neural crest tumors [neuroblastoma] have also been reported).1 The fetus is particularly vulnerable to x-ray radiation during the first six weeks of pregnancy, a time when pregnancy may not even be suspected.
Drugs suspected or associated with increased risk to the fetus and neonate are listed in Table 2 and include thiouracil, its derivatives, and iodine, which can be thyrotoxic; naphthalene, synthetic vitamin K, and other drugs that may cause hemolysis and associated jaundice and hyperbilirubinemia, hence increased risk of kernicterus; some substances that are metabolized by the liver (chloramphenicol); and drugs associated with hepatic toxicity (Chlortetracycline, phenothiazines, anticonvulsants, and acetaminophen in large doses); sulfonamides and other drugs that cause bilirubin-albumin dissociation; certain antibiotics that may be nephrotoxic or ototoxic; agents that cause neonatal respiratory depression (morphine and derivatives); those that may produce hemorrhagic phenomena (phenothiazine derivatives, tripelennamine, oral anticoagulants (except for heparin), barbiturates, reserpine, and acetylsalicylic acid (aspirin). Aspirin prevents the release of adenosine diphosphate and reduces platelet stickiness, which in turn produces a prolonged bleeding time and bleeding tendencies. Its use during the last trimester of pregnancy is being discouraged.
Although no ill effects in the fetus have been clearly documented from the use of any antibiotics during pregnancy, the newer antibiotics should be used cautiously in the treatment of the pregnant woman at term. Drugs not yet standardized for use in newborns should be avoided.
The most important factor in the production of fetal malformation depends on the vulnerability of the particular structure affected (eye, heart, etc.) and the actual teratogenic agent employed. For example, in the fetus exposed to thalidomide, it was the limb buds that were susceptible, and their period of maximum vulnerability was between the 18th and 28th day of gestation. There is a critical time during gestation for each organ to be affected by teratogenic agents, and this time coincides with greatest mitotic activity in that organ (Table 3).
CATEGORICAL EFFECTS OF MATERNAL AGENTS ON THE FETUS-NEWBORN
The concentration of drug in the fetus is important. A large single dose taken by the mother in the late months of pregnancy may not be so damaging as smaller doses taken before or early in pregnancy. Indeed, the danger may not be so much from teratogenic drugs taken occasionally during pregnancy as from the habitual taking of drugs by women of childbearing age who may subsequently become pregnant. The woman is not sure whether she is pregnant until a month or more after actual conception, and by then the fetus has been exposed.
It is relevant to consider whether assays of teratogenic influences can be made by easy methods. The recent literature is replete with after-the-fact reports of congenital abnormalities in infants whose mothers had taken one or another drug during pregnancy. Such reports supply numerators without denominators in that they do not record the number of cases in which use ofthat particular drug did not produce malformations; neither do they take into account the natural incidence of abnormalities (2 per cent of all births). Nor do animal experiments, as yet, provide an easier approach to the problem. For instance, human beings are exquisitely sensitive to the teratogenic effects of thalidomide, but the common test animals are much less so. People, for example, are 60 times more sensitive to the drug than mice, 100 times more sensitive than rats, 200 times more sensitive than dogs, and 700 times more sensitive than hamsters.
EFFECTS OF MATERNAL DRUG USE NEAR TERM
RELATIVE TIMING OF CERTAIN MALFORMATIONS2
Other primates are the only animals in which these drugs produce effects comparable to those in human beings. As a result, even tests in several species with enormous doses of thalidomide might not have been enough to show its potential danger to a human fetus. If a large-scale, long-range, allout effort by physicians were made to keep total records of medications taken by pregnant women, including drugs sold "over the counter," and these complete tabulations were made retrievable, the desired information on the teratogenic effects of various drugs might soon be acquired with considerable degree of certainty. A recent study has shown that the average gravida in the United States uses six prescribed and four over-thecounter drugs. Genetic factors also are important in that they can modify the effect of exogenous factors so that the teratogenic effect can vary between individuals, strains, and species. For example, only 20 per cent of the women who had taken thalidomide had abnormal children.
FETAL ALCOHOL SYNDROME
Since the reports linking vaginal adenocarcinoma in young girls to diethylstilbestrol therapy in their mothers during pregnancy, the use of this drug as a "morning-after" contraceptive pill has been largely discontinued. At the recent Fifth International Conference on Birth Defects, evidence was presented to show that the women who had malformed children (congenital heart disease and other malformations) were 30 per cent more likely to have used birth control pills immediately before conception or during early pregnancy.3* The latest evidence not only indicates a causal relationship between cigarette smoking during pregnancy and low infant birth weight but also points to a strong probable association between smoking and a higher fetal and infant mortality. In a recent New England Journal of Medicine report on 633 pregnant women,4 17 per cent of the heavy drinkers' children had serious birth defects as against 3 per cent of the babies of nondrinkers. Chronic alcoholism in the mother can produce fetal abnormalities (the "fetal alcohol syndrome") (Table 4). Alcohol readily crosses the placenta and goes directly into the fetus. The ancient rulers of Sparta and Carthage recognized that alcohol may have disastrous effects on the fetus, and they had strict laws prohibiting the use of alcohol by newly married couples.
The vast number of infections (viral and bacterial) as nonchemical contaminants on gestation and infant growth have been documented and are well understood. The serious implications of congenital cytomegalovirus are continually reported. Adults infected with the ubiquitous organism are usually asymptomatic - but infections acquired in utero can cause microcephaly, mental retardation, auditory defects, chorioretinitis, periventricular calcification, and some degree of brain damage in an estimated 5,000 infants per year. Gestational rubella infections and congenital rubella (autism) are well recognized. In addition, herpesvirus hominis, mumps, gestational herpes, Coxsackie virus group B, infectious hepatitis, influenza, echo virus 7, and adenovirus are all suspect of being teratogenic.
Assorted heavy metals are probably the leading and most serious environmental pollutants affecting the fetus. Trace metals may enter and be stored in the human body by several mechanisms. Accumulation may result from inborn metabolic errors of various transport systems. A classic example is Wilson's disease (progressive hepatolenticular degeneration), in which copper accumulates in the liver and brain.
A second route of accumulation may be impaired excretion because of a concomitant disease, such as renal failure, or because of developmental immaturity. This route is important to the fetus because of the varying rates in maturation of detoxifying and excretory systems as well as the extent of environmental exposure.
The third route of accumulation is through ingestion or absorption of large amounts from contaminated food and water.
Known sources of mercury contamination of our environment are discharges from chloralkali plants, mercury catalysts in industry, fungicides used in the pulp and paper industry and in seed treatments, and residues from the burning of fossil fuels. Other, miscellaneous sources include medical and scientific wastes, naturally occurring geologic formations, and the processing of raw materials containing mercury. Marine paint may also add mercury to water. Agreement is general that alkylated mercury compounds are significantly more toxic than nonalkylated mercury compounds. Toxicologically and environmentally, the most important alkylated compound is methyl mercury.
Once inorganic mercury is released into the environment, methylation can occur in the sediment of waterways through bacterial action. Methyl mercury then becomes available to the food chain, reaching humans via edible fish. Wild and domestic animals fed contaminated grains are another source of mercury contamination.
Since methyl mercury has a long retention in the human body, propensity for central nervous system damage, and known toxic effect on developing tissue, mercury poses a particular hazard for the fetus. Methyl mercury crosses the placenta easily and may attain a 30 per cent higher concentration in fetal erythrocytes than in maternal ones.
A relationship between shellfish mercury contamination in Minimata Bay, Japan, and a cerebral-palsy-like illness now seems well established. Six per cent of children born in the villages near Minimata Bay over the five-year period ending in 1959 were afflicted with mild to moderate spasticity, chorea, ataxia, coarse tremors, seizures, and severe intellectual deficiencies in various combinations. Two autopsied patients showed depletion of cerebellar granular cells and damage to the cerebral cortex of a nonspecific nature, similar to the lesions seen in the adult form of fatal Minimata disease. Dying infants had high levels of mercury in their brains, livers, and kidneys, approximating the levels found in adults dying of mercury poisoning. Living children who were studied had an abnormally high content of mercury in their hair (range 15 to 412 /xg/gm.). The dietary shellfish were believed contaminated by the effluent of a plastics plant.
Mercury can be excreted into breast milk, and this can be a source of the metal for the suckling infant, especially when the mother has had long exposure to high environmental levels of mercury. Hence, an acquired as well as a congenital pathogenesis may be invoked for fetal Minimata disease.
Further implication of methyl mercury's role as harmful to the fetal central nervous system comes from the report of an incidence of mercury poisoning during pregnancy in New Mexico. The mother's toxicity occurred from the ingestion of contaminated pork. This meat came from pigs that had been fed seed grain previously treated with methyl mercury fungicide. The resultant full-term boy had severe tremors, which persisted for several days. His urinary mercury level during the first day of life was 2.7 parts per million (ppm). This is 100 times more than the level for normal adult urine. At six weeks of age, the infant was hypertonic and irritable, though mercury could no longer be detected in his urine. At eight months of age, he began to have myoclonic seizures and was now hypotonic, irritable, grossly retarded, and probably cortically blind. This baby had never been breast-fed, providing more support that this case was actually intrauterine mercury poisoning. The mother was asymptomatic despite having elevated mercury levels during the third trimester. Ingestion of the contaminated pork was thought to have occurred between the third and sixth months of gestation.
Lead, while apparently less toxic for the fetus than mercury, may have greater implications for future generations, since lead is more widespread and the effects of environmentally encountered concentrations may be more subtle. For over 100 years it has been known that women employed in occupations that have heavy exposures to lead may give birth to stunted and neurologically abnormal infants. They also have had a higher stillbirth and miscarriage rate.
The normal daily dietary intake of lead is 0.20.4 mg. Water is not significantly contaminated, but lead pollutants in air from the burning of lead alkyl additives (antiknock ingrethents) in automotive fuels are a serious problem. In 1968, more than 500 million pounds of lead were introduced into the atmosphere from this source, and the lead concentration in the atmosphere of some urban areas is rising by 5 per cent per year (inhaled lead has a 10-fold more toxic potential than ingested lead). Infants and growing children living in old, rundown housing, where layer after layer of lead paint has been applied for years, are particularly prone to lead poisoning from pica and from contaminated food and water. An average-sized peeling of old paint may contain 100 mg. or more of lead. In addition, minority children, most likely living in such areas, are often victims (approximately 15 per cent in healthy American black males and only 1 per cent in Caucasians) of glucose-6-phosphate dehydrogenase deficiency (G-6-PD), and, unfortunately, it has been documented that they have an increase of blood lead levels of 12 per cent when intimately exposed.
Our environment is thoroughly contaminated with lead. It may be present in drinking water, milk (breast milk contains little or no detectable lead), canned fruit juice, vegetation growing beside roads, toothpaste, air particulates, dirt, pencils, cigarette ash, newsprint (particularly tinted pages or sections), putty, and numerous other materials in everyday use. The yellow coloring of some newspaper inserts contains as much as 29,000 ppm of lead. The red coloring has 4,100 ppm, while black print has 275 ppm. Legal limit of lead in house paint is 5,000 ppm. The cumulative effect of these lead sources may be biologically significant.
Within the past 25 years the use of cadmium in industry has been increasing. Cadmium is a product of coal combustion, and high contents of it have been reported in shellfish, seafoods, roasted peanuts, and filter cigarette smoke. Of considerable interest is the finding of extremely high percentages of cadmium in some commercial phosphate fertilizers and high levels of cadmium in plants grown after use of these fertilizers (plant concentration of cadmium has doubled over the past 50 years in Sweden). Furthermore, the cadmium content of green plants is inversely related to the distance between plants and heavily traveled highways, implying that automobile traffic may be another source of cadmium pollution. Because it is an element, cadmium will riot just "up and go away." It has a biologic half-life of 20 to 30 years, which means it tends to accumulate in the body over a lifetime and is almost impossible to get rid of. It has been linked tentatively to prostate cancer, hypertension, and teratogenicity.
As recently as 1969, it was believed that cadmium was absent from the full-term human fetus. Current fetal-tissue measurements using more precise techniques prove that cadmium can cross the placenta and is retained in the human fetus, reaching levels of 50 Mg/kg. body weight or more. The concentration is maximal in the liver. Human breast milk also contains cadmium, but to a minimal degree. Animal studies have shown cadmium to be selectively retained within mammary tissues and thus prevented from incorporation in milk; this mechanism may help to protect the suckling newborn.
Animal experimentation suggests that cadmium may compete with zinc in some organs and in some enzyme systems. If this is true for human beings, then a plethora of effects might be expected from cadmium in fetal tissues, since zinc is one of nature's most common cofactors in biologic enzyme systems. Of pertinence in this regard is the report of environmental water pollution with cadmium, lead, and zinc in Japan. The resulting disease itai-itai, or "ouch-ouch," disease) is characterized by severe osteomalacia and renal tubular defects, occurring mostly in postmenopausal women. The staples of the local diet, rice and soybean, were shown to have an average concentration of cadmium, zinc, and lead approximately twice as great as the same foods in areas where this disease is not endemic. It is theoretically possible that a high concentration of zinc could prevent many of cadmium's inhibitory effects on zinc-dependent enzyme systems. The role of the high lead concentrations in this situation is unclear.
Titanium is the third most common element to be found in the earth's crust. Biologically, titanium would be expected to be a strong reducing agent because of its tendency to lose electrons. Some algae are able to concentrate titanium up to 10,000 times, thereby having the potential to introduce large quantities of this metal into the food chain. Although titanium is generally believed nontoxic, all of the acute toxicity studies have dealt only with water-insoluble titanium salts. It has been documented that half of studied fetuses and newborns have some demonstrable titanium in their tissues, confirming transplacental transport of the element.
Nickel, widely used in industry, is found in highest concentrations in wood and steel products. It attains extremely high concentrations in cigarette smoke. In the newborn, nickel is found in highest concentrations in the lung and gastrointestinal tract. Throughout life, lung concentrations increase while gastrointestinal levels remain constant. This suggests that airborne sources of nickel are the main source of human contamination, perhaps due to smoking. Nickel is regarded as having very little toxicity. No fetal effects are known to occur.
Tin, like nickel, is widespread because of its use in industry. There are sizable amounts of tin in the air of many North American cities, less in suburban air. Tin has never been found in the fetus or newborn, raising the question whether tin crosses the human placenta.
Vanadium, another ubiquitous metal, is concentrated in many lipids of plant and animal origin. It has been found in only one infant less than six weeks old and never in any studied fetus. A toxic effect for vanadium on the fetus would not be predicted.
Niobium (formerly columbium), present in soil, seawater, plants, and animals, has no current wide use in industry. It has never been found in the human fetus or newborn. It has, however, been found in rat breast milk and newborn rat tissues after large amounts were fed to the mother, proving experimentally that transplacental transport is possible when maternal exposure is great.
Large amounts of arsenic are measurable in the air or water of many large American cities. Arsenic exists in two valence states. The penta valent form is nontoxic, whereas the trivalent form is extremely dangerous. There is no reliable way currently to determine the valence state in which arsenic is present in a given sample. Since trivalent arsenic is a potent inhibitor of thiol-containing enzymes, such as ketone-oxides and succinic, malic, and lactic dehydrogenases, the expected effects of fetal toxicity from trivalent arsenic would be stillbirth or abortion. Obviously, the pentavalent form must be the one most prevalent in the environment, but the ratio is not known.
Numerous other, but not well-documented, environmental causes of fetal morbidity and birth defects are being discussed by the news media more often than in the medical literature. Some of these are:
1. The well-known herbicide 2, 4, 5-trichlorophenoxyacetic acid (2, 4, S-T) is teratogenic and fetocidal in two strains of mice and one strain of rats.
2. Nitrilotriacetic acid (NTA), as an alternative to phosphate compounds in detergents, increases the toxicity of mercury and cadmium in water, contributing to an increase in fetal abnormalities and death in mice and rats.
3. Food additives of all kinds, including cyclamates, saccharin, nitrites, monosodium glutamate (MSG), and food colorings (coal-tar dyes) have all been implicated in producing toxic effects in fetal animals or being carcinogenic.
4. Intensity of airport noise.
5. Polychlorinated biphenyls (PCB) have wide industrial uses (electric wires, motors, plasticizers, etc.) because of their high dielectric constant and their thermal and chemical stabilities. PCB contamination sites are found to be almost universal, including human milk, human adipose tissue, and brain and liver of small children. Little is known about the toxic effects of PCB in human beings, but an endemic poisoning ("yusho") by rice oil contaminated with PCB has been reported in Japan;
6. The recent discovery of water sources heavily contaminated with asbestos (Lake Superior) is of much public concern. It is a well-known carcinogen, and mesothelioma of the pleura and peritoneum has been linked to asbestos. The drinking of asbestos-contaminated water over many years raises the question of its chronic effect on the gastrointestinal tract. The fact, however, that no dust deposition of coal miners or hard-rock miners has been recorded in the GI tract or mesenteric nodes suggests that in man transmigration of ingested asbestos particles through the intestinal mucosa is not likely.
7. Does eating blighted potatoes by pregnant women (in countries where potatoes are the main food staple) produce neural tube defects, such as anencephaly, spina bifida, meningocele, or meningomyelocele in the fetus? If so, they must be eaten during the first month of pregnancy, because the neural tube closes between the 19th and 28th days of gestation. Although there is no firm basis for the blighted-potato hypothesis, a long-standing recommendation, not only for pregnant women but for the population as a whole, is to avoid food that is moldy or spoiled in any way.
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2. Smith, D. W. Recognizable Patterns of Human Malformation. Philadelphia: W. B. Saunders Company, 1970.
3. Janerich, D. Birth defects from sex hormones avoidable. J.A.M.A. 238 (1977), 1808.
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Boreus, L. O. Fetal Pharmacology. New York: Raven Press, 1973.
Hansson, J. W., et al. Fetal alcohol syndrome, experience with 41 patients. J.A.M.A. 235 (1976), 1458.
Idänpän-Heikkilä, T., et al. Placental transfer of trioated tetrahydrocannabinol. N. Engl. J. Med. 281 (1969), 330.
Miller, R. K. Drugs as teratogens; fetal alcohol syndrome: fetal hydantoin syndrome; fetal warfarin syndrome. Drug Ther. (Hasp. Edit.) (June, 1979), 57-64.
Miller, R. W. Delayed radiation effects in atomic-bomb survivors. Science 166 (1969), 569-574.
Mulville, J. ]., and Yeager, A. M. Fetal alcohol syndrome. Teratology 13 (1973), 345.
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Waddell, W. J. Localization and metabolism of drugs in the fetus. Fed. Proc. 31 (1972), 52-62.
CATEGORICAL EFFECTS OF MATERNAL AGENTS ON THE FETUS-NEWBORN
EFFECTS OF MATERNAL DRUG USE NEAR TERM
RELATIVE TIMING OF CERTAIN MALFORMATIONS2
FETAL ALCOHOL SYNDROME