Version May 2024
INTRODUCTION — A congenital anomaly refers to an anatomic structural anomaly present at birth. These defects can be caused by genetic abnormalities and/or environmental exposures, although the underlying etiology is often unknown [1]. Congenital anomalies can be isolated or present in a characteristic combination or pattern that may affect one or more organ systems. What is, then, a genetic disorder? It is an abnormality caused by a change or pathogenic variant in the genome that often leads to medical consequences. Even though most genetic disorders are congenital, they may have a delayed clinical presentation or adult onset. These disorders can be inherited or the result of a new pathogenic variant.
This topic discusses the causes of congenital anomalies. The epidemiology, types, patterns, and evaluation of congenital anomalies are discussed in detail separately, as well as the specific congenital anomalies. (See "Congenital anomalies: Epidemiology, types, and patterns" and "Congenital anomalies: Approach to evaluation".)
OVERVIEW — The causes of congenital anomalies are genetic and nongenetic [2].
Genetic abnormalities include:
●Chromosomal disorders (eg, Down syndrome). (See "Down syndrome: Overview of prenatal screening" and "Down syndrome: Clinical features and diagnosis".)
●Single-gene (monogenic) disorders are disorders that present with different modes of inheritance including autosomal recessive, autosomal dominant, or X-linked disorders. The following are examples of single-gene disorders causing limb malformations:
•Autosomal dominant (eg, ectrodactyly, ectodermal dysplasia, cleft lip, and cleft palate [EEC]). Dominant pathogenic variants in the p63 gene are associated with EEC and other related syndromes [3,4]. Ectrodactyly is a major limb malformation characterized by absence or underdevelopment of central metacarpals and/or metatarsals leading to a so-called split hand/foot deformity.
•Autosomal recessive (eg, some forms of Adams-Oliver syndrome). This rare disorder is characterized by limb reduction defects (limb hypoplasia, absent digits, absent feet, syndactyly) often seen in association with cutis aplasia of the scalp. Although autosomal dominant forms are more common, this syndrome may be caused by pathogenic variants in recessive genes such as the dedicator of cytokinesis 6 (DOCK6) gene [5].
•X linked (eg, focal dermal hypoplasia or Goltz syndrome). This syndrome is caused by pathogenic variants in the protein-serine O-palmitoleoyltransferase porcupine homolog (PORCN) gene at Xp11.23, which lead to severe limb malformations (absent digits, polydactyly, syndactyly) as well as cutaneous-dermal defects with fat herniation [6,7].
Nongenetic teratogenic etiologies include:
●Maternal phenylketonuria (PKU) or diabetes (see 'Maternal illnesses' below and "Overview of phenylketonuria", section on 'Phenylalanine embryopathy (maternal PKU)' and "Infants of mothers with diabetes (IMD)")
●Drugs and chemical agents (eg, alcohol, oral isotretinoin) (see 'Drug exposure' below and 'Chemical agents' below)
●Infections during the prenatal period (cytomegalovirus [CMV], rubella, Zika virus) (see 'Infectious agents' below and "Overview of TORCH infections" and "Zika virus infection: Evaluation and management of pregnant patients")
●Fetal crowding due to multiple gestations (see "Neonatal complications of multiple births", section on 'Congenital anomalies')
Multifactorial disorders are conditions that result from the interaction of multiple genes and environmental factors. They include:
●Nonsyndromic cleft lip/palate (see "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate" and "Overview of craniofacial clefts and holoprosencephaly")
●Nonsyndromic congenital heart disease (see "Congenital heart disease: Prenatal screening, diagnosis, and management" and "Cardiac causes of cyanosis in the newborn")
●Neural tube defects (see "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management")
GENETIC ABNORMALITIES — Genetic abnormalities can range from a point mutation in a single gene disrupting developmental pathways or proteins, to the presence of additional or missing chromosomal material (copy number variation) that can affect from a small segment to an entire chromosome. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Genetic variation'.)
Chromosomal disorders — Chromosomal aberrations are due to a change in the normal chromosome number (aneuploidies) or a change in the structure of a chromosome (sizable deletions, microdeletions, duplications, translocations, and inversions).
The syndromes caused by congenital aneuploidies have several common characteristics:
●More than 90 percent of embryos/fetuses with congenital chromosomal abnormalities do not survive to term. In trisomy 21, for example, 40 percent of fetuses are lost after 12 weeks of gestation. Even higher embryonic and fetal loss rates are found with monosomy X (45,X or Turner syndrome) [8].
●Multiple organ systems tend to be involved, especially the central nervous system (CNS). Intellectual disability, in particular, is a common abnormality in viable infants with chromosome disorders.
●The longevity and fertility of persons with these aneuploidies and other chromosomal disorders tend to be reduced. That also includes carriers of balanced chromosome translocations.
Congenital chromosomal disorders are reviewed in greater detail separately. (See "Congenital cytogenetic abnormalities" and "Sex chromosome abnormalities" and "Chromosomal translocations, deletions, and inversions" and "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)" and "Microduplication syndromes".)
Disorders due to single-gene defects — There is a wide range of congenital anomalies caused by single-gene defects. These defects encompass point mutations (pathogenic variants) and intragenic changes causing small insertions or deletions (indels), leading to disruption of gene transcription and protein synthesis. Current nomenclature changes have replaced the use of the term "mutations" with "pathogenic variants." The pattern of inheritance may be autosomal dominant, autosomal recessive, or sex linked. A single defect in a gene on an autosome (not a sex X or Y chromosome) may cause a disorder with autosomal dominant inheritance. In this case, the patient is heterozygous for the genetic defect, and one single change is sufficient to cause disease, hence the name "dominant." In disorders with autosomal recessive inheritance, both alleles (copies) of a defective gene on an autosomal chromosome pair are mutated (paternal and maternal copies). The pathogenic variants can be either the same (homozygous pathogenic variants) or two distinct pathogenic variants (compound heterozygous). Autosomal recessive conditions are more common when there is parental consanguinity (ie, related as second cousins or closer). The last form of inheritance is sex linked or linked to the sex chromosomes. X-linked recessive inheritance is the most common example. (See 'Overview' above and "Genetic counseling: Family history interpretation and risk assessment" and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)".)
Single-gene disorders and the environment — Genetic changes can be directly connected to alterations in environmental exposures such as the diet. A series of patients with multiple congenital malformations (cardiac and vertebral defects) underwent whole exome or whole genome sequencing to identify a possible genetic defect [9]. The affected individuals were found to have pathogenic loss-of-function variants in two genes (HAAO, encoding 3-hydroxyanthranilic acid 3,4-dioxygenase, and KYNU, encoding kynureninase) that are involved in the kynurenine pathway. This pathway results in the de novo synthesis of nicotinamide adenine dinucleotide (NAD) through catabolism of dietary tryptophan. In vitro activity of the truncated enzymes was low to absent, upstream metabolites were elevated, and downstream metabolites were reduced. In Haao-null or Kynu-null mice, supplementation of dietary niacin during gestation corrected the NAD deficiency, preventing intrauterine death and abnormal embryogenesis. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Diagnosis of complex diseases'.)
Genetic disorders with non-Mendelian patterns of inheritance — Other genetic variations that can cause disorders include imprinting (gamete-specific gene silencing) disorders leading to differential expression of genetic material depending upon whether the gene or gene region is imprinted (eg, Beckwith-Wiedemann syndrome). (See "Beckwith-Wiedemann syndrome".)
TERATOGENS — A teratogen is an agent that can cause abnormalities in the form or function of a developing fetus (table 1). It acts by producing cell death, altering normal growth of tissues, or interfering with normal cellular differentiation or other morphologic processes. The consequences of these actions can be fetal loss, fetal growth restriction, congenital anomaly (eg, a limb reduction), or impaired neurologic performance (eg, altered neural connections in the central nervous system [CNS] in fetal alcohol syndrome).
Approximately 4 to 6 percent of congenital anomalies are caused by exposure to teratogens in the environment [10]. These include maternal illnesses (eg, diabetes mellitus or phenylketonuria [PKU]), infectious agents (eg, TORCH [Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus, and Herpes] infections), physical agents (eg, radiation or heat exposure), and drugs (eg, thalidomide, antiseizure medications) and chemical agents (eg, mercury).
Response to the teratogenic agent is highly individualized and is influenced by multiple factors. These include maternal and fetal genotypes (genetic susceptibility), the dose of the agent, route of exposure, timing of exposure, and concurrent exposures or illnesses during gestation.
Genetic susceptibility — The genetic makeup of both the fetus and the mother determines the relative resistance or susceptibility to teratogenic agents. The degree of genetic susceptibility is separate from any specific genetic conditions that are known direct causes of congenital anomalies.
As an example, albeit an oversimplified one, fetuses with defects in folate metabolism (eg, methylenetetrahydrofolate reductase [MTHFR] gene pathogenic variants) appear to be at increased risk for structural malformations such as neural tube defects [11], cleft lip and palate, and cardiac malformations [12]. The risk of these malformations may be decreased by maternal supplementation with folic acid in the preconceptional period and in early pregnancy [13,14]. Thus, a malformation such as an open neural tube defect may result from genetic susceptibility related to a combination of factors consisting of the presence of a fetal MTHFR gene defect and a state of inadequate maternal folate intake.
Another example is that some fetuses have low or deficient epoxide hydrolase activity that results in increased levels of teratogenic oxidative metabolites when they are exposed to antiseizure medications [15].
Finally, certain congenital anomalies may be seen with different frequencies across races or sexes. For example, postaxial polydactyly is more common among Black Americans (approximately 1 percent) than White Americans (approximately 0.1 percent) [16]. Neural tube defects are more common in White Americans than Black Americans. Pyloric stenosis and cleft lip are more common in males than females.
The genetic makeup of the mother and her state of health also play a role in teratogenesis. The production of a malformation is dependent upon the ability of a female to absorb and metabolize a teratogen. In addition, maternal medical disease states can act as teratogens. (See 'Maternal illnesses' below.)
Route of exposure — The route of exposure can also impact teratogenic effects. For example, the absorption and action of a drug is usually different if exposure occurs through the dermis versus systemic delivery. The systemic route may cause abnormalities, while the dermal delivery may not. As an example, topical fluconazole applied to the skin is considered safe, but systemic fluconazole is potentially teratogenic [17]. Another example is topical use of retinoic acid versus oral/systemic use.
Dose and duration of exposure — The dose and duration of the embryo's exposure to a teratogen are also important. Most drugs exhibit threshold effects (ie, there is a dose below which the incidence of embryonic death, malformation, growth restriction, or functional impairment is not greater than for unexposed controls). Such thresholds are usually one to three orders of magnitude below the teratogenic dose of the drug [18].
When no human data are available, a dose teratogenic in animals that is less than 10-fold higher than the maximum human therapeutic dose suggests a high risk that the drug may be teratogenic in humans. A 100-fold difference between the animal teratogenic dose and the maximal human dose indicates a low risk of potential human teratogenicity. However, teratogenic agents may have different effects in different species. As an example, lenalidomide, a thalidomide analog, is not teratogenic in rabbits but is in humans [19]. By contrast, thalidomide is strongly teratogenic in both rabbits and humans but is not teratogenic in rats or mice [20,21]. Aspirin is not teratogenic in humans but is strongly teratogenic in other animals [22]. In addition, many drugs produce malformations in animals when given at 10 to 1000 times the normal dose administered to humans. Extrapolating teratogenic risk using these data is potentially problematic. As an example, high doses of meclizine given to mice cause cleft palate due to appetite suppression, but force feeding the mice prevents the defect [23].
One teratogen may be more harmful in a single, large dose than in the same dose spread over several days, while another teratogen may be more harmful when an exposure is prolonged at a lower dose than if the same dose were given all at once. As an example, binge drinking of seven alcoholic beverages may be more harmful to the fetus than daily intake of only one drink for a week. Conversely, an occasional very high maternal blood glucose in an otherwise well-controlled diabetic mother is probably less harmful than a persistently moderately elevated blood glucose. (See "Alcohol intake and pregnancy" and "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management".)
Drug-drug interactions can also be important. Two drugs administered together may have synergistic effects, the drugs may act completely independently, or one drug may protect against the teratogenic effects of the other. As an example, the vitamin folic acid may protect against the increased risk of open neural tube defects when taken by females who are taking antiseizure medications, such as valproic acid and carbamazepine [24]. However, valproic acid should not be used in pregnancy, if possible [25]. For specific interactions, use the drug interactions program included within UpToDate. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)
Timing — The pattern and type of malformation depend in part upon the time of exposure and/or the site of gene action. A brief review of human embryonic development indicates the system likely to be affected by a problem occurring at that time.
Fertilization is the first step and occurs within 24 hours of ovulation. Of note, embryonic age is counted from fertilization (conception) and starts two weeks after gestational age, which is counted from the first day of the last menstrual period. The following are other important milestones in development (figure 1):
●Preimplantation and implantation on days 5 to 11
●Differentiation into three germ layers (ectoderm, mesoderm, and endoderm) by day 16
●Formation of the neural plate by day 19
●Closure of the neural tube by day 27
●Appearance of limb buds by day 30
●Formation of the branchial arches, clefts, pouches, and optic vesicle between weeks 4 and 5
●Formation of the mature heart and kidneys by weeks 5 to 7
●Achievement of mature limb architecture by week 8
●Sexual differentiation of the internal and external genitalia between weeks 7 to 10
●Rotation of the intestines and return into the abdominal cavity in week 10
A significant exposure that occurs during the first 10 to 14 days after fertilization may result in cell death. If enough cells die, spontaneous abortion may occur (see "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology"). If only a few cells are damaged, then their roles may be compensated by other cells. This is known as the all-or-none theory. An example is an early and significant exposure to radiation, which usually results in either pregnancy loss or no abnormalities.
The embryo is most vulnerable to teratogenic insults since organogenesis is occurring during the embryonic period of development. The embryonic period in humans can be defined as from fertilization until the end of the 10th week of gestation (8th week postconception) [26].
During the fetal period, teratogens can cause cell death, retardation of cell growth, or inhibition of normal differentiation. This may result in fetal growth restriction or disorders of the CNS that may not be apparent at birth. The eyes, genitalia, CNS, and hematopoietic systems continue to develop during the fetal period and remain susceptible to teratogenic insults.
As an example, the risks associated with angiotensin-converting enzyme (ACE) inhibitor exposure, a widely used medicine to treat hypertension, are significant during the second and third trimesters due to blockade of conversion of angiotensinogen I to angiotensin II in the developing fetal kidney. This exposure results in hypotension, renal tubular dysplasia, anuria/oligohydramnios, growth restriction, and calvaria defects. However, these drugs can cause other defects, such congenital heart defects, during the first trimester [27].
Misoprostol, a prostaglandin E1 analog, can cause severe vascular disruptions in the first trimester (ie, terminal limb defects, Moebius syndrome). It has also been widely used to induce abortions in the first and second trimesters. However, this drug is safe to use during delivery for uterine cervix ripening and to induce labor [28].
Some teratogens act within a narrow window. As an example, the teratogenic effect of thalidomide for limb defects is limited to 21 to 36 days postconception, when limb bud development begins.
Mechanisms of teratogenesis — Teratogenesis is thought to occur after fertilization and results from many diverse mechanisms. These include cell death (eg, radiation); blocking of metabolic processes (eg, thioureas, iodides); alterations in cellular growth and proliferation, migration, and apoptosis (eg, alcohol exposure, fetal alcohol spectrum disorder); and interactions between cells or between cells and tissues.
Exposure prior to conception may theoretically cause genetic pathogenic variants, a process known as toxic mutagenesis, although this is a controversial topic. The timing of this process differs in males and females. In females, deoxyribonucleic acid (DNA) replication occurs during oogenesis in the fetus, many years before ovulation. In contrast, continuing spermatogenesis makes males susceptible to pathogenic variants throughout their reproductive life. Examples include the potential effects of ionizing radiation on spermatogenesis [29] and potential effects of chemotherapy drugs in the reproductive system [30].
Specific teratogens — Numerous teratogens in the environment can lead to congenital anomalies. Common agents are listed below and in the table (table 1).
Infectious agents — Exposure to infectious agents can result in a variety of problems in the fetus and neonate, including malformations, congenital infection, short- and long-term disability, and death. The pathogenesis of the fetal defects is usually direct invasion of fetal tissues leading to damage from inflammation and cell death. Agents known to be toxic to the fetus or embryo are toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis (the so-called TORCH infections), as well as varicella, parvovirus B19, Zika virus, and lymphocytic choriomeningitis virus (LCMV). (See "Overview of TORCH infections" and "Syphilis in pregnancy" and "Varicella-zoster virus infection in pregnancy" and "Parvovirus B19 infection during pregnancy" and "Rubella in pregnancy" and "Prenatal evaluation of women with HIV in resource-rich settings" and "Viral meningitis in children: Clinical features and diagnosis", section on 'Other viruses' and "Seasonal influenza and pregnancy" and "Zika virus infection: Evaluation and management of pregnant patients".)
Nonspecific sonographic signs suggestive of fetal infection include:
●Microcephaly
●Cerebral or hepatic calcifications
●Intrauterine growth restriction
●Hepatosplenomegaly
●Cardiac malformations, limb hypoplasia, hydrocephalus
●Hydrops
Congenital anomalies associated with disorders of movement and muscle tone, chorioretinitis or cataracts, hearing impairment, hepatosplenomegaly, skin rash, thrombocytopenia, jaundice, or low birth weight are suggestive of congenital infection.
Fever associated with infection also can be teratogenic. (See 'Physical agents' below.)
Maternal illnesses — Several maternal illnesses are associated with birth defects. The mechanism is diffusion of a metabolite or antibody across the placenta that is toxic to the fetus.
●Insulin-dependent diabetes mellitus is associated with a two- to threefold increase in risk of congenital anomalies, including congenital heart disease, cleft palate, colobomas, and spina bifida, and, less commonly, caudal regression and focal femoral hypoplasia. (See "Infants of mothers with diabetes (IMD)".)
●Maternal phenylketonuria (PKU) if not diet controlled is associated with microcephaly, intellectual disability, and congenital heart disease. (See "Overview of phenylketonuria".)
●Androgen-producing tumors of the adrenal glands or ovaries can produce virilization of female fetuses.
●Maternal antibodies present in autoimmune disorders can cross the placenta and cause toxicity in the fetus. Examples include myasthenia gravis leading to transient neonatal myasthenia, maternal Grave disease causing fetal and neonatal thyrotoxicosis, immune thrombocytopenia (ITP) resulting in fetal and neonatal thrombocytopenia, and systemic lupus erythematosus causing fetal heart block. (See "Overview of the treatment of myasthenia gravis" and "Hyperthyroidism during pregnancy: Treatment" and "Thrombocytopenia in pregnancy" and "Pregnancy in women with systemic lupus erythematosus".)
Maternal obesity and hypertensive disorders (including preeclampsia and preexisting hypertension) [31] are also associated with an increased risk of certain types of congenital anomalies. The mechanism is unknown, but one hypothesis is that these disorders lead to aberrant early implantation or impair early blood supply to the fetus. (See "Obesity in pregnancy: Complications and maternal management", section on 'Congenital anomalies'.)
Physical agents — Physical agents, such as heat and radiation, have been implicated in the pathogenesis of congenital anomalies. Heat exposure may be due to the use of a hot tub or sauna or even maternal fever. Elevation of maternal core temperature more than 1.5°C in the first trimester of pregnancy for at least 24 hours may be associated with an increased risk of neural tube defects [32-34]. Other clinical findings associated with high maternal temperature include microcephaly, intellectual disability, hypertonia, hypotonia, and seizures. (See "Intrapartum fever", section on 'Consequences'.)
Excessive exposure to ionizing radiation has the potential to produce fetal death, growth disturbances, somatic abnormalities, mutations, chromosome fragmentation, and malignancies. In general, toxic levels are not achieved with diagnostic imaging. However, knowledge of a pregnancy should, in most circumstances, result in a reappraisal of the necessity for and mode of imaging. (See "Diagnostic imaging in pregnant and lactating patients" and "Radiation-related risks of imaging".)
Drug exposure — Maternal drug ingestion, including prescription and over-the-counter medications as well as recreational drugs, can also cause adverse fetal and neonatal outcomes. However, it can be extremely difficult to determine whether a particular substance is teratogenic. In addition, the timing of exposure during pregnancy can affect the teratogenicity of a drug. A partial list of additional known teratogens is provided in the table (table 1).
The US Food and Drug Administration (FDA) requires that all prescription drugs be tested in animal models, usually one rodent and one nonrodent model. Testing establishes both the lowest observed adverse effect level (LOAEL) and the no observed adverse effect level (NOAEL). If the human exposure level is 100 times lower than the NOAEL, adverse effects in humans are considered unlikely. However, results from animal models may not always apply to humans (see 'Dose and duration of exposure' above). A study of drugs approved by the US FDA from 2000 to 2010 found that the teratogenic risk in human pregnancy was "undetermined" for 98 percent of the drugs approved for human use [35].
Due to the limitations of drug testing, data regarding the association of drugs or chemicals and congenital anomalies occurring at the time of birth come primarily from case reports of exposed patients. However, these also do not always establish teratogenicity and often need validation by epidemiologic studies. Two promising approaches to providing somewhat better information are prospectively collected exposure data from teratogen information agencies and large-scale birth defects registries [36]. Postmarketing drug registries are also used to monitor for teratogenicity, but they rely on active participation of clinicians and pregnant patients and as such are not comprehensive in their surveillance. As previously discussed, some of the drugs can be potentially teratogenic during specific times of fetal development but be innocuous otherwise. (See 'Timing' above.)
In 2015, the US FDA switched from labeling prescription drugs for use during pregnancy with one of five categories (A, B, C, D, or X), ranging from drugs posing no risk to the fetus to those known to be teratogenic, to the Pregnancy and Lactation Labeling Rule (PLLR or final rule) [37]. The PLLR "requires that the labeling include a summary of the risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation."
Some common teratogenic medications include:
●Angiotensin-converting enzyme (ACE) inhibitors (see "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and 'Timing' above)
●Antiseizure medications [38] (see "Risks associated with epilepsy during pregnancy and the postpartum period")
●Antineoplastic agents (see "Gestational breast cancer: Epidemiology and diagnosis" and "Management of classic Hodgkin lymphoma during pregnancy")
●Thalidomide, methylene blue, misoprostol, penicillamine, fluconazole, and lithium
Additional known teratogens include the following:
●Folic acid antagonists (eg, trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, primidone, methotrexate) increase the risk of neural tube defects and possibly cardiovascular defects, oral clefts, and urinary tract defects [24,39].
●Oral isotretinoin, used to treat severe acne, is associated with ear anomalies (microtia with or without atresia of the ear canal), CNS malformations, hydrocephalus, neuronal brain migration defects, cerebellum abnormalities, severe intellectual disability, seizures, optic nerve/retinal abnormalities, conotruncal heart defects, thymic defects, and dysmorphic features [40,41]. (See "Acne vulgaris: Overview of management", section on 'Pregnant individuals'.)
●The widely used cholesterol-lowering agents, such as statins (HMG-CoA reductase inhibitors) are completely contraindicated during pregnancy because they may cause severe congenital anomalies due to disruption of cholesterol biosynthesis, which is important in cell membrane morphogenesis. Reported congenital anomalies include limb malformations, congenital heart disease, and CNS abnormalities [42,43].
●Infants of mothers who consumed substantial quantities of alcohol during pregnancy [44] can have a neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE), alcohol-related birth defects (ARBD), fetal alcohol syndrome, or they may be normal (table 2). (See "Alcohol intake and pregnancy" and "Substance use during pregnancy: Screening and prenatal care" and "Fetal alcohol spectrum disorder: Clinical features and diagnosis".)
●Cigarette smoking is associated with poor fetal growth mostly due to effects on the placenta [45,46]. Smoking is also linked to increased limb deficiencies in epidemiologic studies [47]. The failure or disruption in formation of limbs or digits may result from vasoactive effects of cigarette compounds on blood vessels. Prenatal exposure can also lead to impaired function of the endocrine, reproductive, respiratory, cardiovascular, and neurologic systems [48]. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate".)
Chemical agents — Chemical agents that can act as teratogens include lead and mercury.
High plasma lead levels are associated with adverse neurobehavioral effects in infants and children. Intrauterine exposure may have similar consequences [49]. Studies of potential associations between parental lead exposure and congenital malformations in offspring have not demonstrated a consistent increase in risk or pattern of defects, but often lack biologic indices of exposure at developmentally significant times [50]. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Lead'.)
Methylmercury exposure, primarily through ingestion of contaminated fish, can cause severe CNS damage [51], as well as milder intellectual, motor, and psychosocial impairment [52-54]. Some limitations on fish intake during pregnancy are recommended. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy" and "Nutrition in pregnancy: Assessment and counseling", section on 'Counseling'.)
Resources — Several resources are available for information on possible teratogenic exposure. These include:
●Reproductive Toxicology Center
REPROTOX
Columbia Hospital for Women Medical Center
Washington, DC
703-203-6040
TERIS and Shepard's Catalog of Teratogenic Agents
Seattle, WA
206-543-2465
●Pregnancy Exposure Registries
●Organization of Teratology Information Specialists (OTIS)
877-311-8972
The Teratology Society publishes a free teratology primer
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Newborn appearance (The Basics)")
SUMMARY
●Definition and etiology – A congenital anomaly refers to an anatomic structural anomaly present at birth. These defects can be caused by genetic abnormalities and/or environmental exposures (teratogens), although the underlying etiology is often unknown. (See 'Introduction' above and 'Overview' above.)
●Types of congenital anomalies and patterns of malformations – Specific terms are used to describe congenital anomalies (table 3). In addition, multiple malformations are often grouped in a recognizable pattern (table 4). (See "Congenital anomalies: Epidemiology, types, and patterns", section on 'Types and patterns of defects'.)
●Genetic causes – Genetic causes of congenital anomalies include chromosomal disorders, single-gene disorders, somatic mutation/mosaicism, and disorders that result from the interaction of multiple genes and environmental factors (multifactorial disorders). (See 'Genetic abnormalities' above.)
●Environmental causes – Environmental causes of congenital anomalies include multiple gestation pregnancy and teratogens. A teratogen is an agent that can cause abnormalities in the form or function of a developing fetus (table 1). The pattern and type of malformation depend in part upon the time of exposure and/or the site of gene action. (See 'Teratogens' above.)
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