Risk of Birth Defects Being Induced
4 Teratogens act in specifi c ways (mecha- (mecha-nisms) on developing cells and tissues to
initi-ate abnormal embryogenesis (pathogenesis).
Mechanisms may involve inhibition of a specifi c biochemical or molecular process; pathogenesis may involve cell death, decreased cell prolifera-tion, or other cellular phenomena.
5 Manifestations of abnormal development are death, malformation, growth retardation, and functional disorders.
Principles of Teratology
Factors determining the capacity of an agent to produce birth defects have been defi ned and set forth as the principles of teratology. They include the following:
1 Susceptibility to teratogenesis depends on the genotype of the conceptus and the man-ner in which this genetic composition inter-acts with the environment. The maternal genome is also important with respect to drug Figure 9.3 Abnormal positioning of the lower limbs and clubfeet as examples of deformations. These defects are prob-ably caused by oligohydramnios (too little amniotic fl uid).
A B
Figure 9.4 A,B. Examples of phocomelia. Limb defects characterized by loss of the long bones of the limb. These defects were commonly produced by the drug thalidomide.
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use of a vaccine have nearly eliminated congenital malformations from this cause.
Cytomegalovirus is a serious threat. Often, the mother has no symptoms, but the effects on the fetus can be devastating. The infection can cause serious illness at birth and is sometimes Infectious Agents
Infectious agents that cause birth defects (Table 9.1) include a number of viruses. Birth defects due to rubella (German measles) during preg-nancy (congenital rubella syndrome) used to be a major problem, but development and widespread
TABLE 9.1 Teratogens Associated With Human Malformations
Teratogen Congenital Malformations Infectious agents
Rubella virus Cataracts, glaucoma, heart defects, hearing loss, tooth abnormalities Cytomegalovirus Microcephaly, visual impairment, intellectual disability, fetal death Herpes simplex virus Microphthalmia, microcephaly, retinal dysplasia
Varicella virus Skin scarring, limb hypoplasia, intellectual disability, muscle atrophy Toxoplasmosis Hydrocephalus, cerebral calcifi cations, microphthalmia
Syphilis Intellectual disability, hearing loss
Physical agents
X-rays Microcephaly, spina bifi da, cleft palate, limb defects Hyperthermia Anencephaly, spina bifi da, intellectual disability Chemical agents
Thalidomide Limb defects, heart malformations
Aminopterin Anencephaly, hydrocephaly, cleft lip and palate
Diphenylhydantoin (phenytoin) Fetal hydantoin syndrome: facial defects, intellectual disability Valproic acid Neural tube defects; heart, craniofacial, and limb anomalies Trimethadione Cleft palate, heart defects, urogenital and skeletal abnormalities
Lithium Heart malformations
SSRIs Heart malformations
Amphetamines Cleft lip and palate, heart defects
Warfarin Skeletal abnormalities (nasal hypoplasia, stippled epiphyses) ACE inhibitors Growth retardation, fetal death
Mycophenylate mofetil Cleft lip and palate, heart defects, microtia, microcephaly
Alcohol Fetal alcohol syndrome (FAS), short palpebral fi ssures, maxillary hypoplasia, heart defects, intellectual disability
Isotretinoin (vitamin A) Isotretinoin embryopathy: small, abnormally shaped ears, mandibular hypoplasia, cleft palate, heart defects
Industrial solvents Low birth weight, craniofacial and neural tube defects Organic mercury Neurological symptoms similar to those of cerebral palsy
Lead Growth retardation, neurological disorders
Hormones
Androgenic agents Masculinization of female genitalia: fused labia, clitoral hypertrophy (ethisterone, norethisterone)
DES Malformation of the uterus, uterine tubes, and upper vagina; vaginal cancer;
malformed testes
Maternal diabetes Various malformations; heart and neural tube defects most common Maternal obesity Neural tube defects, heart defects, omphalocele
SSRIs, Selective serotonin reuptake inhibitors; ACE, angiotensin-converting enzyme; DES, diethylstilbestrol.
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Chapter 9 Birth Defects and Prenatal Diagnosis 121
visual impairment, hearing loss, seizures, and intellectual disability.
Radiation
Ionizing radiation kills rapidly proliferating cells, so it is a potent teratogen, producing virtu-ally 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% spontaneously aborted, 25% gave birth to children who died in their fi rst year of life, and 25% gave birth to children who had severe birth defects involving the central nervous system.
Similarly, the explosion of the nuclear reactor at Chernobyl, which released up to 400 times the amount of radiation as the nuclear bombs, has also resulted in an increase in birth defects throughout the region. Radiation is also a muta-genic agent and can lead to genetic alterations of germ cells and subsequent malformations.
Pharmaceutical Drugs and Chemical Agents The role of chemical agents and pharmaceutical drugs (medications) in the production of abnor-malities in humans is diffi cult to assess for two reasons: (1) most studies are retrospective, rely-ing on the mother’s memory for a history of exposure, and (2) pregnant women take a large number of medications. A National Institutes of Health study discovered that pregnant women, on average, took four medications during preg-nancy. Only 20% of pregnant women used no drugs during their pregnancy. Even with this widespread use of medications during pregnancy, insuffi cient information is available to judge the safety of approximately 90% of these drugs if taken during pregnancy.
On the other hand, relatively few of the many drugs used during pregnancy have been posi-tively identifi ed as being teratogenic. One exam-ple 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 abnormality that was usually inherited, had sud-denly increased (Fig. 9.2). This observation led to examination of the prenatal histories of affected children and to the discovery that many moth-ers had taken thalidomide early in pregnancy. The causal relation between thalidomide and mero-melia was discovered only because the drug pro-duced 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.
fatal. On the other hand, some infants are asymp-tomatic at birth, but develop abnormalities later, including hearing loss, visual impairment, and intellectual disability.
Herpes simplex virus and varicella virus can cause birth defects. Herpes-induced abnor-malities are rare and usually infection is trans-mitted to the child during delivery, causing severe illness and sometimes death. Intrauterine infection with varicella causes scarring of the skin, limb hypoplasia, and defects of the eyes and central nervous system. The occurrence of birth defects after prenatal infection with vari-cella is infrequent and depends on the timing of the infection. Among infants born to women infected before 13 weeks’ gestation, 0.4% are mal-formed; whereas the risk increases to 2% among infants whose mothers are infected during 13 to 20 weeks of gestation.
Other Viral Infections and Hyperthermia
Malformations apparently do not occur following maternal infection with measles, mumps, hepati-tis, poliomyelihepati-tis, echovirus, coxsackie virus, and infl uenza, but some of these infections may cause spontaneous abortion or fetal death or may be transmitted to the fetus. For example, coxsackie B virus may cause an increase in spontaneous abortion, while measles and mumps may cause an increase in early and late fetal death and neonatal measles and mumps. Hepatitis B has a high rate of transmission to the fetus, causing fetal and neo-natal hepatitis; whereas hepatitis A, C, and E are rarely transmitted transplacentally. Echoviruses seem to have no adverse effects on the fetus. Also, there is no evidence that immunizations against any of these diseases harm the fetus.
A complicating factor introduced by these and other infectious agents is that most are pyrogenic (cause fevers), and elevated body temperature (hyperthermia) caused by fevers or possibly by external sources, such as hot tubs and saunas, is ter-atogenic. Characteristically, neurulation is affected by elevated temperatures and neural tube defects, such as anencephaly and spina bifi da, are produced.
Toxoplasmosis can cause birth defects.
Poorly cooked meat; feces of domestic ani-mals, especially cats; and soil contaminated with feces can carry the protozoan parasite Toxoplasmosis gondii. A characteristic feature of fetal toxoplasmosis infection is cerebral calcifi -cations. Other features that may be present at birth include microcephaly (small head), mac-rocephaly (large head), or hydrocephalus (an increase in cerebrospinal fl uid in the brain). In a manner similar to cytomegalovirus, infants who appear normal at birth may later develop
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The anticoagulant warfarin is teratogenic.
Infants born to mothers with fi rst trimester exposures typically have skeletal abnormalities, including nasal hypoplasia, abnormal epiphyses in their long bones, and limb hypoplasia. In contrast, the anticoagulant heparin does not appear to be teratogenic.
Antihypertensive agents that inhibit angiotensin-converting enzyme (ACE inhibitors) produce growth retardation, renal dysfunction, fetal death, and oligohydramnios if exposures occur during the second or third tri-mester. Effects of exposure to these compounds in the fi rst trimester are less clear.
Caution has also been expressed regarding a number of other compounds that may dam-age the embryo or fetus. The most prominent among these are propylthiouracil and potassium iodide (goiter and intellectual disability), strepto-mycin (hearing loss), sulfonamides (kernicterus), the antidepressant imipramine (limb deformi-ties), tetracyclines (bone and tooth anomalies), amphetamines (oral clefts and cardiovascular abnormalities), and quinine (hearing loss).
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 mal-formations of the central nervous system have been reported. A comprehensive review of more than 100 publications, however, led to the con-clusion 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, PCP, and cocaine. There is a well- documented association between maternal alcohol ingestion and congenital abnormalities. Because alcohol may induce a broad spectrum of defects, ranging from intellectual disability to structural abnor-malities of the brain (microcephaly, holoprosen-cephaly), face, and heart, the term fetal alcohol spectrum disorder (FASD) is used to refer to any alcohol-related defects. Fetal alcohol syn-drome (FAS) represents the severe end of the spectrum and includes structural defects, growth defi ciency, and intellectual disability (Fig. 9.5).
Alcohol-related neurodevelopmental disor-der (ARND) refers to cases with evidence of involvement of the central nervous system that do not meet the diagnostic criteria for FAS. The incidence of FAS and ARND together has been estimated to be 1 in 100 live births. Furthermore, alcohol is the leading cause of intellectual disability. It is not clear how much alcohol is necessary to cause a developmental problem. The The discovery that a drug like thalidomide
could cross the placenta and cause birth defects was revolutionary and led directly to the science of teratology and founding of the Teratology Society.
Today, thalidomide is still in use as an immuno-modulatory agent in the treatment of people with AIDS and other immunopathological diseases such as leprosy, lupus erythematosis, and graft ver-sus host disease. Limb defects still occur in babies exposed to the drug, but it is now clear that other malformations are produced as well. These abnor-malities include heart malformations, orofacial clefts, intellectual disability, autism, and defects of the urogenital and gastrointestinal systems.
Other drugs with teratogenic potential include the anticonvulsants diphenylhydantoin (phenytoin), valproic acid, and trimethadi-one, which are used by women who have sei-zure disorders. Specifi cally, 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 in these syndromes. The anticonvulsant valproic acid increases the risk for several defects, including atrial septal defects, cleft palate, hypospadius, polydactyly, and cra-niosynostosis, but the highest risk is for the neu-ral tube defect, spina bifi da. The anticonvulsant Carbamazepine also has been associated with an increased risk for neural tube defects and possibly other types of malformations.
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 evi-dence for the teratogenicity of phenothiazines is confl icting, an association between lithium and congenital heart defects, especially Ebstein anom-aly, is better documented, although the risk is small.
Antidepressant drugs that work as selec-tive serotonin reuptake inhibitors (SSRIs) appear to cause birth defects, especially of the heart, and also may produce an increase in spon-taneous abortions. These compounds, which include fl uoxetine (Prozac), paroxetine (Paxil), and others, may act by inhibiting serotonin (5HT) signaling important for establishing later-ality (left–right sidedness) and for heart develop-ment (see Chapter 13).
Mycophenolate mofetil (MMF) is an immu-nosuppressant drug used to prevent rejection in organ transplant patients. Use of the drug in preg-nancy has resulted in spontaneous abortions and birth defects, including cleft lip and palate, microtia (small ears), microcephaly, and heart defects.
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Chapter 9 Birth Defects and Prenatal Diagnosis 123
and norethisterone have considerable androgenic activity, and many cases of masculinization 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 are exogenous agents that interfere with the normal regulatory actions of hormones controlling developmen-tal processes. Most commonly, these agents interfere with the action of estrogen through its receptor to cause developmental abnormali-ties of the central nervous system and repro-ductive tract. For some time, it has been known that the synthetic estrogen diethylstilbestrol (DES), 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 caused in part by 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 mal-formations of the testes and abnormal sperm analysis among these individuals. In contrast to women, however, men do not demonstrate an increased risk of developing carcinomas of the genital system.
Today, environmental estrogens are a con-cern, and numerous studies to determine their effects on the unborn are under way. Decreasing sperm counts and increasing incidences of tes-ticular cancer, hypospadias, and other abnor-malities of the reproductive tract in humans, together with documented central nervous sys-tem abnormalities (masculinization of female brains and feminization 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 progestogens, appear to have a low teratogenic potential. Because other hormones such as DES 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 rab-bits at certain stages of pregnancy causes a high percentage of cleft palates in the offspring. Some recent epidemiologic studies also suggest that dose and timing during gestation are both
criti-cal, but there is probably no “safe” level. Even binge drinking (>5 drinks per sitting) at a critical stage of development appears to increase the risk for birth defects, including orofacial clefts.
Cigarette smoking has been linked to an increased risk for orofacial clefts (cleft lip and cleft palate). It also contributes to intrauterine growth retardation and premature delivery.
Isotretinoin (Accutane), an analogue of vitamin A, has been shown to cause a charac-teristic pattern of malformations known as the isotretinoin embryopathy. The drug is pre-scribed for the treatment of cystic acne and other chronic dermatoses, but it is highly teratogenic and can produce virtually any type of malforma-tion. Even topical retinoids, such as etretinate, may have the potential to cause abnormalities. Vitamin A itself may be teratogenic at high doses, based on animal studies and the fact that isotretinoin is a closely related compound. Precisely how much is potentially harmful (>10,000 or >25,000 IU) is controversial, but the amount of vitamin A typ-ically contained in multivitamins (2,000 to 8,000 IU) is below these doses, unless an individual takes more than one multivitamin a day.
Hormones
Androgenic Agents In the past, synthetic pro-gestins were frequently used during pregnancy to prevent abortion. The progestins ethisterone Figure 9.5 Characteristic features of a child with Fetal alcohol syndrome (FAS), including an indistinct philtrum, thin upper lip, depressed nasal bridge, short nose, and fl at midface.
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Nutritional Deficiencies
Although many nutritional defi ciencies, particu-larly vitamin defi ciencies, have been proven to be teratogenic in laboratory animals, the evi-dence for specifi c cause and effects in humans is more diffi cult to document. One example is endemic cretinism, caused by iodine defi -ciency and characterized by stunted mental and physical growth. Recent evidence also indicates that methyl-defi cient diets alter expression of imprinted genes and may result in birth defects and diseases, such as cancer postnatally. Finally, recent studies show that poor maternal nutri-tion prior to and during pregnancy contributes to low birth weight and birth defects and that severe starvation during pregnancy is associated with a two to threefold increase in schizophrenia in the offspring.
Obesity
Obesity has reached epidemic proportions in the United States and has nearly doubled in the past 15 years. In 2007 to 2008, over one-third of women of reproductive age were obese (body mass index >30).
Prepregnancy obesity, is associated with a twofold increased risk for having a child with a neural tube defect. Causation has not been determined but may relate to maternal meta-bolic disturbances affecting glucose, insulin, or other factors. Prepregnancy obesity also increases the risk for having a baby with a heart defect, omphalocele, and multiple congenital anomalies.
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 alti-tudes 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 cya-notic 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 fi sh had given birth to children with multiple neurological symptoms resembling cerebral palsy. Further examination revealed that the fi sh 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 women who take corticosteroids during
preg-nancy are at a modestly increased risk for having a child with an orofacial cleft.
Maternal Disease
Diabetes Disturbances in carbohydrate metab-olism during pregnancy in diabetic mothers cause a high incidence of stillbirths, neonatal deaths, abnormally large infants, and congenital malformations. The risk of congenital anoma-lies in children born to mothers with preges-tational diabetes (diabetes diagnosed before pregnancy; both type 1 [insulin dependent] and type 2 [non–insulin dependent]) is three to four times that for offspring of nondiabetic moth-ers and has been reported to be as high as 80%
in the offspring of diabetics with long-standing disease. The increased risk is for a wide variety of malformations, including neural tube defects and congenital heart defects. There is also a higher risk for caudal dysgenesis (sirenomelia:
see Figure 5.8, p. 58).
Factors responsible for these abnormalities have not been delineated, although evidence sug-gests that altered glucose levels play a role and that insulin is not teratogenic. In this respect, a signifi cant correlation exists between the sever-ity and duration of the mother’s disease and the incidence of malformations. Also, strict con-trol of maternal glucose levels beginning before conception and continuing throughout gesta-tion reduces the occurrence of malformagesta-tions to incidences approaching those in the general population.
The risk for birth defects associated with ges-tational diabetes (diabetes that is fi rst diagnosed during pregnancy) is less clear, with some, but not all studies showing a slightly increased risk.
Given that the onset of gestational diabetes is believed to be after the critical period for induc-ing structural birth defects (3 to 8 weeks gesta-tion), some investigators have suggested that any observed increased risk may be due to the fact that some women diagnosed with gestational diabetes probably had diabetes before pregnancy, but it was not diagnosed.
Phenylketonuria Mothers with phenylketon-uria (PKU), in which the enzyme phenylalanine hydroxylase is defi cient or reduced, resulting in increased serum concentrations of phenylalanine, are at risk for having infants with intellectual dis-ability, microcephaly, and cardiac defects. Women with PKU who maintain their low-phenylal-anine diet prior to conception and throughout pregnancy reduce the risk to their infants to that observed in the general population.
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abnormalities through a test called nuchal trans-lucency. This test involves measurement of the translucent space at the posterior of the baby’s neck, where fl uid accumulates when Down syn-drome and some other abnormalities are pres-ent. The test is performed at 11 to 14 weeks of pregnancy. Information from this test, combined with maternal serum screening test results and the mother’s age, can be combined to provide a risk estimate. Then, based on this risk assessment, a woman can decide whether she wants invasive testing, such as amniocentesis, which would pro-vide a defi nitive diagnosis.
length, and abdominal circumference—are used (Fig. 9.8). Multiple measurements of these parameters over time improve the ability to deter-mine the extent of fetal growth.
Congenital malformations that can be deter-mined by ultrasound include the neural tube defects anencephaly and spina bifi da (see Chapter 18);
abdominal wall defects, such as omphalocele and gastroschisis (see Chapter 15); and heart (see Chapter 13) and facial defects, including cleft lip and palate (see Chapter 17).
Ultrasound can also be used to screen for Down syndrome and some other chromosome-related
A B
C D
Figure 9.6 Examples of the effectiveness of ultrasound in imaging the embryo and fetus. A. A 6-week embryo.
B. Lateral view of the fetal face. C. Hand. D. Feet.
A B
S
S
Figure 9.7 A. Ultrasound image showing position of the fetal skull and placement of the needle into the amniotic cavity (arrow) during amniocentesis. B. Twins. Ultrasound showing the presence of two gestational sacs (S).
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