Chapter 9: Birth Defects and Prenatal Diagnosis


Birth Defects

Birth defect, congenital malformation, and congenital anomaly are synonymous terms used to describe structural, behavioral, functional, and metabolic disorders present at birth. Terms used to describe the study of these disorders are teratology (Gr. teratos; monster) and dysmorphology. Dysmorphologists are usually within a department of clinical genetics. Major structural anomalies occur in approximately 3% of liveborn infants and birth defects are a leading cause of infant mortality, accounting for approximately 25% of infant deaths. They are the fifth leading cause of years of potential life lost prior to age 65 and a major contributor to disabilities. They are also nondiscriminatory; the frequencies of birth defects are the same for Asians, African Americans, Latin Americans, Whites, and Native Americans.

In 40% to 45% of persons with birth defects, the cause is unknown. Genetic factors, such as chromosome abnormalities and mutant genes, account for approximately 28%; environmental factors produce approximately 3% to 4%; a combination of genetic and environmental influences (multifactorial inheritance) produces 20% to 25%; and twinning causes 0.5% to 1%.

Minor anomalies occur in approximately 15% of newborns. These structural abnormalities, such as microtia (small ears), pigmented spots, and short palpebral fissures, are not themselves detrimental to health but, in some cases, are associated with major defects. For example, infants with one minor anomaly have a 3% chance of having a major malformation; those with two minor anomalies have a 10% chance; and those with three or more minor anomalies have a 20% chance. Therefore, minor anomalies serve as clues for diagnosing more serious underlying defects. In particular, ear anomalies are easily recognizable indicators of other defects and are observed in virtually all children with syndromic malformations.

Types of Abnormalities

Malformations occur during formation of structures, for example, during organogenesis. They may result in complete or partial absence of a structure or in alterations of its normal configuration. Malformations are caused by environmental and/or genetic factors acting independently or in concert. Most malformations have their origin during the third to eighth weeks of gestation (Fig. 9.1).

Figure 9.1. Graph showing the times in gestation versus the risks of birth defects being induced.

Graph showing the times in gestation versus the risks of birth defects being induced

The most sensitive time is the embryonic period during the third to eighth weeks. The fetal period begins at the end of the eighth week and extends to term. During this time, the risk for gross structural defects being induced decreases, but organ systems may still be affected. For example, the brain continues to differentiate during the fetal period, such that toxic exposures may cause learning disabilities or intellectual disability. The fact that most birth defects occur prior to the eighth week makes it imperative to initiate birth defects prevention strategies prior to conception. Unfortunately, most women do not appear for their first prenatal visit until the eighth week, which is after the critical time for prevention of most birth defects.

Disruptions result in morphological alterations of already formed structures and are caused by destructive processes. Vascular accidents leading to transverse limb defects and defects produced by amniotic bands are examples of destructive factors that produce disruptions (Fig. 9.2).

Figure 9.2. Defects produced by amniotic bands as examples of disruptions.

Defects produced by amniotic bands as examples of disruptions

A. Cleft lip. B. Toe amputations. C. Finger amputations. Strands of ammion may be swallowed or become wrapped around structures causing various disruption-type defects. The origin of the bands of amniotic tissue is unknown.

Deformations result from mechanical forces that mold a part of the fetus over a prolonged period. Clubfeet, for example, are caused by compression in the amniotic cavity (Fig. 9.3). Deformations often involve the musculoskeletal system and may be reversible postnatally.

Figure 9.3. Abnormal positioning of the lower limbs and clubfeet as examples of deformations.

Abnormal positioning of the lower limbs and clubfeet as examples of deformations

These defects are probably caused by oligohydramnios (too little amniotic fluid).

A syndrome is a group of anomalies occurring together that have a specific common cause. This term indicates that a diagnosis has been made and that the risk of recurrence is known. In contrast, association is the nonrandom appearance of two or more anomalies that occur together more frequently than by chance alone, but the cause has not been determined. An example is the VACTERL association (vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies). Although they do not constitute a diagnosis, associations are important because recognition of one or more of the components promotes the search for others in the group.

Environmental Factors

Until the early 1940s, it was assumed that congenital defects were caused primarily by hereditary factors. With the discovery by N. Gregg that rubella (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 W. Lenz linked limb defects to the sedative thalidomide and made it clear that drugs could also cross the placenta and produce birth defects (Fig. 9.4). Since that time, many agents have been identified as teratogens (factors that cause birth defects) (Table 9.1).

Figure 9.4. A,B. Examples of phocomelia. Limb defects characterized by loss of the long bones of the limb.

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.

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 calcifications, microphthalmia
Syphilis Intellectual disability, hearing loss
Physical agents
X-rays Microcephaly, spina bifida, cleft palate, limb defects
Hyperthermia Anencephaly, spina bifida, 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 fissures, 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
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.

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 conceptus 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), during gastrulation (day 14), at the early limb bud stage (fifth week), or when the palatal shelves are forming (seventh week). Furthermore, whereas most abnormalities are produced during embryogenesis, defects may also be induced before or after this period; no stage of development is completely safe (Fig. 9.1).
  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 9.1) include a number of viruses. Birth defects due to rubella (German measles) during pregnancy (congenital rubella syndrome) used to be a major problem, but development and widespread 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 fatal. On the other hand, some infants are asymptomatic 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 abnormalities are rare and usually infection is transmitted 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 varicella is infrequent and depends on the timing of the infection. Among infants born to women infected before 13 weeks’ gestation, 0.4% are malformed; 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, hepatitis, poliomyelitis, echovirus, coxsackie virus, and influenza, 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 neonatal 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 teratogenic. Characteristically, neurulation is affected by elevated temperatures and neural tube defects, such as anencephaly and spina bifida, are produced.

Toxoplasmosis can cause birth defects. Poorly cooked meat; feces of domestic animals, especially cats; and soil contaminated with feces can carry the protozoan parasite Toxoplasmosis gondii. A characteristic feature of fetal toxoplasmosis infection is cerebral calcifications. Other features that may be present at birth include microcephaly (small head), macrocephaly (large head), or hydrocephalus (an increase in cerebrospinal fluid in the brain). In a manner similar to cytomegalovirus, infants who appear normal at birth may later develop visual impairment, hearing loss, seizures, and intellectual disability.


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% spontaneously aborted, 25% gave birth to children who died in their first 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 mutagenic agent and can lead to genetic alterations of germ cells and subsequent malformations.