Environmental Factors

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Until the early 1940s it was assumed that congenital defects were caused primarily by hereditary factors. With the discovery by Gregg that German measles affecting a mother during early pregnancy caused abnormalities in the embryo, it suddenly became evident that congenital malformations in humans could also be caused by environmental factors. In 1961 observations by Lenz linked limb defects to the sedative thalidomide and made it clear that drugs could also cross the placenta and produce birth defects (Fig. 7.1). Since that

Thalidomide Infants
Figure 7.1 A. Child with unilateral amelia. B. Child with meromelia. The hand is attached to the trunk by an irregularly shaped bone. Both infants were born to mothers who took thalidomide.

time many agents have been identified as teratogens (factors that cause birth defects) (Table 7.1).

Principles of Teratology

Factors determining the capacity of an agent to produce birth defects have been defined and set forth as the principles of teratology. They include the following:

1. Susceptibility to teratogenesis depends on the genotype of the concep-tus and the manner in which this genetic composition interacts with the environment. The maternal genome is also important with respect to drug metabolism, resistance to infection, and other biochemical and molecular processes that affect the conceptus.

2. Susceptibility to teratogens varies with the developmental stage at the time of exposure. The most sensitive period for inducing birth defects is the third to eighth weeks of gestation, the period of embryogenesis. Each organ system may have one or more stages of susceptibility. For example, cleft palate can be induced at the blastocyst stage (day 6), table 7.1 Teratogens Associated With Human Malformations

Teratogen

Congenital Malformations

Infectious agents Rubella virus Cytomegalovirus Herpes simplex virus Varicella virus HIV

Toxoplasmosis Syphilis Physical agents X-rays

Hyperthermia

Chemical agents Thalidomide Aminopterin Diphenylhydantoin

(phenytoin) Valproic acid

Trimethadione

Lithium

Amphetamines Warfarin ACE inhibitors Cocaine

Alcohol

Isotretinoin (vitamin A)

Industrial solvents Organic mercury Lead Hormones Androgenic agents (ethisterone, norethisterone) Diethylstilbestrol (DES) Maternal diabetes

Cataracts, glaucoma, heart defects, deafness, teeth Microcephaly, blindness, mental retardation, fetal death Microphthalmia, microcephaly, retinal dysplasia Limb hypoplasia, mental retardation, muscle atrophy Microcephaly, growth retardation Hydrocephalus, cerebral calcifications, microphthalmia Mental retardation, deafness

Microcephaly, spina bifida, cleft palate, limb defects Anencephaly, spina bifida, mental retardation, facial defects

Limb defects, heart malformations Anencephaly, hydrocephaly, cleft lip and palate Fetal hydantoin syndrome: facial defects, mental retardation

Neural tube defects, heart, craniofacial, and limb anomalies

Cleft palate, heart defects, urogenital and skeletal abnormalities Heart malformations Cleft lip and palate, heart defects Chondrodysplasia, microcephaly Growth retardation, fetal death Growth retardation, microcephaly, behavioral abnormalities, gastroschisis Fetal alcohol syndrome, short palpebral fissures, maxillary hypoplasia, heart defects, mental retardation Vitamin A embryopathy: small, abnormally shaped ears, mandibular hypoplasia, cleft palate, heart defects Low birth weight, craniofacial and neural tube defects Neurological symptoms similar to those of cerebral palsy Growth retardation, neurological disorders

Masculinization of female genitalia: fused labia, clitoral hypertrophy

Malformation of the uterus, uterine tubes, and upper vagina; vaginal cancer; malformed testes Variety of malformations; heart and neural tube defects most common during gastrulation (day 14), at the early limb bud stage (fifth week), or when the palatal shelves are forming (seventh week). Furthermore, while most abnormalities are produced during embryogenesis, defects may also be induced before or after this period; no stage of development is completely safe.

3. Manifestations of abnormal development depend on dose and duration of exposure to a teratogen.

4. Teratogens act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis). Mechanisms may involve inhibition of a specific biochemical or molecular process; pathogenesis may involve cell death, decreased cell proliferation, or other cellular phenomena.

5. Manifestations of abnormal development are death, malformation, growth retardation, and functional disorders.

Infectious Agents

Infectious agents that cause birth defects (Table 7.1) include a number of viruses. Rubella used to be a major problem, but the ability to detect serum antibody titers and development of a vaccine have significantly lowered the incidence of birth defects from this cause. Today approximately 85% of women are immune.

Cytomegalovirus is a serious threat. Often, the mother has no symptoms, but the effects on the fetus can be devastating. The infection is often fatal, and if it is not, meningoencephalitis caused by the virus produces mental retardation.

Herpes simplex, varicella, and human immunodeficiency (HIV) viruses can cause birth defects. Herpes-induced abnormalities are rare, and usually infection is transmitted as a venereal disease to the child during delivery. Similarly, HIV (the cause of acquired immunodeficiency syndrome, or AIDS) appears to have a low teratogenic potential. Infection with varicella causes a 20% incidence of birth defects.

Other Viral Infections and Hyperthermia

Malformations following maternal infection with measles, mumps, hepatitis, poliomyelitis, ECHO virus, Coxsackie virus, and influenza virus have been described. Prospective studies indicate that the malformation rate following exposure to these agents is low if not nonexistent.

A complicating factor introduced by these and other infectious agents is that most are pyrogenic, and elevated body temperature (hyperthermia) is teratogenic. Defects produced by exposure to elevated temperatures include anencephaly, spina bifida, mental retardation, micropthalmia, and facial abnormalities. In addition to febrile illnesses, use of hot tubs and saunas can produce sufficient temperature elevations to cause birth defects.

Toxoplasmosis and syphilis cause birth defects. Poorly cooked meat; domestic animals, especially cats; and feces in contaminated soil can carry the protozoan parasite Toxoplasmosis gondii. A characteristic feature of fetal toxoplasmosis infection is cerebral calcifications.

Radiation

Ionizing radiation kills rapidly proliferating cells, so it is a potent teratogen, producing virtually any type of birth defect depending upon the dose and stage of development of the conceptus at the time of exposure. Radiation from nuclear explosions is also teratogenic. Among women survivors pregnant at the time of the atomic bomb explosions over Hiroshima and Nagasaki, 28% aborted, 25% gave birth to children who died in their first year of life, and 25% had severe birth defects involving the central nervous system. Radiation is also a muta-genic agent and can lead to genetic alterations of germ cells and subsequent malformations.

Chemical Agents

The role of chemical agents and pharmaceutical drugs in the production of abnormalities in humans is difficult to assess for two reasons: (a) most studies are retrospective, relying on the mother's memory for a history of exposure; and (b) pregnant women take a large number of pharmaceutical drugs. A National Institutes of Health study discovered that pregnant women took 900 different drugs, for an average of 4 per woman. Only 20% of pregnant women used no drugs during their pregnancy. Even with this widespread use of chemical agents, relatively few of the many drugs used during pregnancy have been positively identified as being teratogenic. One example is thalidomide, an antinauseant and sleeping pill. In 1961 it was noted in West Germany that the frequency of amelia and meromelia (total or partial absence of the extremities), a rare hereditary abnormality, had suddenly increased (Fig. 7.1). This observation led to examination of the prenatal histories of affected children and to the discovery that many mothers had taken thalidomide early in pregnancy. The causal relation between thalidomide and meromelia was discovered only because the drug produced such an unusual abnormality. If the defect had been a more common type, such as cleft lip or heart malformation, the association with the drug might easily have been overlooked.

Other drugs with teratogenic potential include the anticonvulsants diphenylhydantoin (phenytoin), valproic acid, and trimethadione, which are used by epileptic women. Specifically, trimethadione and diphenylhydantoin produce a broad spectrum of abnormalities that constitute distinct patterns of dysmorphogenesis known as the trimethadione and fetal hydantoin syndromes. Facial clefts are particularly common to these syndromes. Valproic acid also causes craniofacial abnormalities but has a particular propensity for producing neural tube defects.

Antipsychotic and antianxiety agents (major and minor tranquilizers, respectively) are suspected producers of congenital malformations. The antipsychotics phenothiazine and lithium have been implicated as teratogens. Although evidence for the teratogenicity of phenothiazines is conflicting, that concerning lithium is better documented. In any case, it has been strongly suggested that use of these agents during pregnancy carries a high risk.

Similar observations have been made for the antianxiety agents meproba-mate, chlordiazepoxide, and diazepam (Valium). A prospective study showed that severe anomalies occurred in 12% of fetuses exposed to meprobamate and 11% in those exposed to chlordiazepoxide, compared with 2.6% of controls. Likewise, retrospective studies demonstrate up to a fourfold increase in cleft lip with or without cleft palate in offspring whose mothers took diazepam during pregnancy.

The anticoagulant warfarin is teratogenic, whereas heparin does not appear to be. Antihypertensive agents that inhibit angiotensin-converting enzyme (ACE) inhibitors produce growth retardation, renal dysfunction, fetal death, and oligohydramnios.

Caution has also been expressed regarding a number of other compounds that may damage the embryo or fetus. The most prominent among these are propylthiouracil and potassium iodide (goiter and mental retardation), streptomycin (deafness), sulfonamides (kernicterus), the antidepressant imipramine (limb deformities), tetracyclines (bone and tooth anomalies), amphetamines (oral clefts and cardiovascular abnormalities), and quinine (deafness). Finally, there is increasing evidence that aspirin (salicylates), the most commonly ingested drug during pregnancy, may harm the developing offspring when used in large doses.

One of the increasing problems in today's society is the effect of social drugs, such as LSD (lysergic acid diethylamide), PCP (phencyclidine, or "angel dust"), marijuana, alcohol, and cocaine. In the case of LSD, limb abnormalities and malformations of the central nervous system have been reported. A comprehensive review of more than 100 publications, however, led to the conclusion that pure LSD used in moderate doses is not teratogenic and does not cause genetic damage. A similar lack of conclusive evidence for teratogenicity has been described for marijuana and PCP Cocaine has been reported to cause a number of birth defects, possibly due to its action as a vasoconstrictor that causes hypoxia.

There is a well-documented association between maternal alcohol ingestion and congenital abnormalities, and these defects, together with mental retardation and growth deficiency, make up the fetal alcohol syndrome (FAS) (Fig. 7.2). Even moderate alcohol consumption during pregnancy may be detrimental to embryonic development. The central nervous system is particularly sensitive to alcohol, and alcohol-related neurodevelopmental disorder (ARND) may result from exposure. The incidence of FAS and ARND together is 1 in 100 live births. Furthermore, alcohol is the leading cause of mental retardation.

Fetal Alcohol Syndrome Vulva

Figure 7.2 A. Characteristic features of a child with fetal alcohol syndrome. B. Child with fetal alcohol syndrome illustrating many of the features in the drawing. These children may also have cardiovascular and limb defects.

Figure 7.2 A. Characteristic features of a child with fetal alcohol syndrome. B. Child with fetal alcohol syndrome illustrating many of the features in the drawing. These children may also have cardiovascular and limb defects.

Cigarette smoking has not been linked to major birth defects, but it does contribute to intrauterine growth retardation and premature delivery. There is also evidence that it causes behavioral disturbances.

Isotretinoin (13-cts-retinoic acid), an analogue of vitamin A, has been shown to cause a characteristic pattern of malformations known as the isotretinoin embryopathy or vitamin A embryopathy. The drug is prescribed for the treatment of cystic acne and other chronic dermatoses, but it is highly teratogenic and can produce virtually any type of malformation. Even topical retinoids, such as etretinate, may have the potential to cause abnormalities. With the recent support for the use of multivitamins containing folic acid, there is concern that overuse of vitamin supplements could be harmful, since most contain approximately 8,000 IU of vitamin A. How much is potentially harmful is controversial, but most scientists agree that 25,000 IU is a threshold level for teratogenicity.

Hormones

Androgenic Agents. In the past synthetic progestins were frequently used during pregnancy to prevent abortion. The progestins ethisterone and norethis-terone have considerable androgenic activity, and many cases of masculiniza-tion of the genitalia in female embryos have been reported. The abnormalities consist of an enlarged clitoris associated with varying degrees of fusion of the labioscrotal folds.

Endocrine Disrupters. Endocrine disrupters are exogenous agents that interfere with the normal regulatory actions of hormones controlling developmental processes. Most commonly these agents interfere with the action of estrogen through its receptor to cause developmental abnormalities of the central nervous system and reproductive tract. For some time it has been known that the synthetic estrogen diethylstilbestrol, which was used to prevent abortion, raised the incidence of carcinomas of the vagina and cervix in women exposed to the drug in utero. Furthermore, a high percentage of these women had reproductive dysfunction due in part to congenital malformations of the uterus, uterine tubes, and upper vagina. Male embryos exposed in utero can also be affected, as evidenced by an increase in malformations of the testes and abnormal sperm analysis among these individuals. In contrast to females, however, males do not demonstrate an increased risk of developing carcinomas of the genital system.

Today environmental estrogens are a concern and numerous studies to determine their effects on the unborn are under way. Decreasing sperm counts and increasing incidences of testicular cancer, hypospadias, and other abnormalities of the reproductive tract in humans, together with documented central nervous system abnormalities (masculinization of female brains and feminiza-tion of male brains) in other species with high environmental exposures, have raised awareness of the possible harmful effects of these agents. Many are formed from chemicals used for industrial purposes and from pesticides.

Oral Contraceptives. Birth control pills, containing estrogens and progesto-gens, appear to have a low teratogenic potential. Since other hormones, such as diethylstilbestrol, produce abnormalities, however, use of oral contraceptives should be discontinued if pregnancy is suspected.

Cortisone. Experimental work has repeatedly shown that cortisone injected into mice and rabbits at certain stages of pregnancy causes a high percentage of cleft palates in the offspring. However, it has been impossible to implicate cortisone as an environmental factor causing cleft palate in humans.

Maternal Disease

Diabetes. Disturbances in carbohydrate metabolism during pregnancy in diabetic mothers cause a high incidence of stillbirths, neonatal deaths, abnormally large infants, and congenital malformations. The risk of congenital anomalies in children of diabetic mothers is 3 to 4 times that for the offspring of nondi-abetic mothers and has been reported to be as high as 80% in the offspring of diabetics with long-standing disease. The variety of observed malformations includes caudal dysgenesis (sirenomelia).

Factors responsible for these abnormalities have not been delineated, although evidence suggests that altered glucose levels play a role and that insulin is not teratogenic. In this respect, a significant correlation exists between the severity and duration of the mother's disease and the incidence of malformations. Also, strict control of maternal metabolism with aggressive insulin therapy prior to conception reduces the occurrence of malformations. Such therapy, however, increases the frequency and severity of hypoglycemic episodes. Numerous animal studies have shown that during gastrulation and neurula-tion, mammalian embryos depend on glucose as an energy source, so that even brief episodes of low blood glucose are teratogenic. Therefore, caution must be exercised in managing the pregnant diabetic woman. In the case of non-insulin-dependent diabetes, oral hypoglycemic agents may be employed. These agents include the sulfonylureas and biguanides. Both classes of agents have been implicated as teratogens.

Phenylketonuria. Mothers with phenylketonuria (PKU), in which the enzyme phenylalanine hydroxylase is deficient, resulting in increased serum concentrations of phenylalanine, are at risk for having infants with mental retardation, microcephaly, and cardiac defects. Women with PKU who maintain their low phenylalanine diet prior to conception reduce the risk to their infants to that observed in the general population.

Nutritional Deficiencies

Although many nutritional deficiencies, particularly vitamin deficiencies, have been proven to be teratogenic in laboratory animals, the evidence in humans is sparse. Thus, with the exception of endemic cretinism, which is related to iodine deficiency, no analogies to animal experiments have been discovered. However, the evidence suggests that poor maternal nutrition prior to and during pregnancy contributes to low birth weight and birth defects.

Obesity

Prepregnancy obesity, defined as having a body mass index (BMI) >29kg/m , is associated with a two- to three-fold increased risk for having a child with a neural tube defect. Causation has not been determind but may relate to maternal metabolic disturbances affecting glucose, insulin, or other factors.

Hypoxia

Hypoxia induces congenital malformations in a great variety of experimental animals. Whether the same is valid for humans remains to be seen. Although children born at relatively high altitudes are usually lighter in weight and smaller than those born near or at sea level, no increase in the incidence of congenital malformations has been noted. In addition, women with cyanotic cardiovascular disease often give birth to small infants, but usually without gross congenital malformations.

Heavy Metals

Several years ago, researchers in Japan noted that a number of mothers with diets consisting mainly of fish had given birth to children with multiple neurological symptoms resembling cerebral palsy. Further examination revealed that the fish contained an abnormally high level of organic mercury, which was spewed into Minamata Bay and other coastal waters of Japan by large industries. Many of the mothers did not show any symptoms themselves, indicating that the fetus was more sensitive to mercury than the mother. In the United States, similar observations were made when seed corn sprayed with a mercury-containing fungicide was fed to hogs and the meat was subsequently eaten by a pregnant woman. Similarly in Iraq, several thousand babies were affected after mothers ate grain treated with mercury-containing fungicides.

Lead has been associated with increased abortions, growth retardation, and neurological disorders.

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Responses

  • jackie
    What are the facial characteristics of fetal hydantoin syndrome?
    8 years ago
  • birikti
    What was thalidomide why was it used and what were the devestating results for thousands babies?
    8 years ago
  • Simon
    How many prenatal deaths and birth defects are caused by drugs?
    8 years ago
  • Cindy
    Do i have a thalidomide baby hand?
    8 years ago
  • holly
    How many children have meromelia?
    8 years ago
  • ralph
    What does thalidomide do to unborn babies?
    8 years ago
  • aamos
    Who discovered thalidomide?
    8 years ago
  • pandora
    Is meromelia heredetary?
    7 years ago

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