Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter IV.2. Congenital Anomalies and Teratogenesis
Greigh I. Hirata, MD
August 2002

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Ms. T is a 17 year old G3P0Tab2 who presents in her 18th week of pregnancy seeking prenatal counseling. She states she has been a type II diabetic under poor control for 4 years and does not regularly take her oral hypoglycemic agent. She is also taking lithium for a manic disorder and has been drinking alcohol regularly for the past 6 months. She is undecided on her commitment to this pregnancy.

This example demonstrates that there are multiple opportunities to effect fetal development. Medical illnesses, prescription medication and environmental exposures play important roles in the pathogenesis of birth defects. In this section we will review the broad topic of teratogens and congenital anomalies.

Physiologic Basis of Birth Defects

The development of birth defects is greatly dependent on the gestational age, nature of the teratogens and the intensity and duration of exposure. The reader is strongly encouraged to review human development, particularly embryology as it relates to organogenesis, to better understand how and when environmental factors may influence fetal development. Organ systems differ in the timing and duration of formation, which results in marked differences in susceptibility. For example, the cardiovascular system undergoes a lengthy and complex developmental phase which probably explains why this organ system has the highest incidence for birth defects. Also as general rule, significant early insults (less than 8 gestational weeks) result in spontaneous miscarriages, whereas exposure later in the gestation (typically after organogenesis or approximately 14-16 weeks gestation) has less of an effect. There are, however, many exceptions to these basic rules.

It is essential to understand the pathophysiologic mechanisms for fetal mal-development, which may be divided into malformation, deformation, disruption or dysplasia. A malformation is commonly defined as a single localized poor formation of tissue that initiates a chain of subsequent defects (1). Anencephaly, for example, is a result of a failure of closure of the anterior neural tube prior to 26 days of fetal life which ultimately results in the degeneration of the forebrain. The recurrence risk for malformations generally range from 1 to 5 per cent. In comparison, a deformation is a result of extrinsic mechanical forces on otherwise normal tissue. This is illustrated in the characteristic pattern of abnormalities including the abnormal facies, pulmonary hypoplasia, and limb contractures that result from prolonged oligohydramnios, either secondary to renal agenesis (Potter syndrome) or premature rupture of membranes (Potter sequence). A disruption results from an extrinsic insult, which destroys normal tissue altering the formation of a structure. The patterns of findings that result from amniotic bands and limb strangulation (a condition in which torn amniotic tissue strands surround a portion of the of body, often digits or extremities, resulting in deep grooves or amputations) are good examples of a disruption type birth defect. Finally, if the primary defect is a lack of normal organization of cells into tissue, a dysplasia will result. This is best illustrated by the pattern of bony abnormalities found in achondroplasia where a defect in the gene encoding fibroblast growth factor receptor 3 results in abnormal cartilage formation.

It is also important to recognize the differences between a "syndrome" and an "association". Syndromes are typically a result of a single genetic abnormality whereas associations are nonrandom collections of birth defects, which may have resulted from a number of genetic factors. This is illustrated when one compares Down syndrome (a result of an extra copy of chromosome 21) with VATER Association (a nonrandom association of vertebral anomalies, imperforate anus, and esophageal atresia with tracheoesophageal fistula). The understanding of these pathophysiologic mechanisms and nomenclature is important in the study of birth defects.

Medical Conditions Affecting Fetal Development

Medical illnesses are seldom thought of as fetal teratogens. This is not the case in the following examples demonstrating how important pre-conceptual counseling is in prevention of birth defects.

Diabetes mellitus: It is well known that pre-gestational and early gestational glucose control greatly influence the rate of miscarriage and fetal anomalies. In a study performed by Hanson et al (2), hemoglobin A1c levels for those women seeking prenatal care were linearly correlated with the rate of miscarriage and anomalies. Moreover, in a summary of 11 studies by Gabbe (3), the incidence of birth defects were 2.5% in those women seeking glucose control pre-conceptually versus 7.8% in those women presenting after conception. The hemoglobin A1c level at 14 weeks, reflecting glycemic control 3-4 weeks prior, is predictive of the rate of fetal anomalies. A hemoglobin A1c level >8.5% confers a risk of birth defects of approximately 22% versus 3.4% in women with A1c levels <8.5% (4).

The pattern of anomalies secondary to diabetes are characteristic. Infants of diabetic mothers are particularly prone to defects in the cardiovascular system, central nervous system and skeletal system. The relative risk for cardiac anomalies is 4.3 times higher compared with normal glycemic controls (5). The relative risk for central nervous system anomalies such as anencephaly (3.3 RR) and spina bifida (1.4 RR) are also increased (5). The rare disorder, caudal regression syndrome is almost pathognomonic (RR 175) for maternal diabetes mellitus (5).

The goals of pre-conceptual treatment are euglycemia and avoidance of glycemic fluctuations. Pre-prandial capillary glucose should be <110 mg/dl with the one-hour post-prandial levels <140 mg/dl. Because of these strict goals and concerns regarding transplacental exposure, oral hypoglycemic agents are deemed inadequate. The optimal treatment would involve preconceptual counseling and glycemic control at least 3 months prior to conception.

Seizure Disorders: Maternal seizure disorders are another example of an illness associated with birth defects. There is some evidence suggesting that epilepsy in and of itself may be teratogenic. However, the pattern of abnormalities encountered with this disease is not well defined. Of major concern is the potential for teratogenesis because of exposure to anti-seizure medications. Most anticonvulsants have significant risk for birth defect formation. However, the ultimate goals of any treatment are first and foremost, control of seizure activity. Moreover, if at all possible monotherapy is preferred over polytherapy.

The fetal effects of valproic acid include increased risks for specific craniofacial abnormalities, cardiovascular defects and neural tube defects. It is estimated that the risk for neural tube defects is 1-2%. Since valproic acid interferes with folic acid metabolism, patients on this medication may benefit from preconceptual folic acid administration.

Phenobarbital may lead to fetal withdrawal in the neonatal period. The possibility of a fetal barbiturate syndrome is currently controversial. Babies exposed to this medication in utero have be found to be relatively vitamin K deficient leading to the recommendation of maternal vitamin K administration at least one month prior to parturition.

The hydantoin (phenytoin) syndrome consisting of the constellation of growth and performance delays, cranio-facial abnormalities, and hypoplasia of the nails and distal phalanges has been well recognized. Like phenobarbital, vitamin K deficiency has been observed in these neonates and therefore maternal vitamin K administration is recommended one month prior to birth is recommended.

Carbamazepine is generally well tolerated and safe in pregnancy. There is an estimated 1% risk for neural tube defect which may be amenable to reduction by preconceptual administration of folic acid. There has also been a suggestion of a pattern of malformations similar to that seen with phenytoin exposure.


In this section we will review a compilation of some of the common teratogens. Remember that the risk for the fetus is greatly dependent on the timing of exposure, duration and intensity of the agent, and genetic susceptibility. For a complete list of teratogens and potential fetal effects, the reader is referred to resources listed in the reference section of this chapter.

Coumarin (coumadin, warfarin) is a vitamin K antagonist used for anticoagulation which has been linked to a well described pattern of malformations including nasal hypoplasia, intrauterine growth retardation, developmental delay and a characteristic stippling of the bone epiphyses. The incidence of this pattern is estimated to be 10% if exposure occurs within the first trimester of pregnancy.

Lithium is commonly used in the treatment of bipolar or manic disorders. Exposure to this medication in the first and early second trimester of pregnancy is associated with a 1-5% risk of congenital heart defects, particularly Ebstein anomaly.

Angiotensin-converting enzyme (ACE) inhibitors, a class of antihypertensive agents, is associated with renal tubular dysplasia/anuria, oligohydramnios, intrauterine growth retardation, and defects of ossification when the fetus is exposed in the late second and third trimester of pregnancy.

Fetal exposure to retinoic acid, such as isotretinoin (Accutane) is associated with characteristic craniofacial abnormalities, central nervous system defects, cardiovascular abnormalities and mental retardation. The estimated risk is 35% if taken beyond the 15th day following conception. Similar types of birth defects are also seen in women who ingest large amounts of other forms of vitamin A.

Maternal pyrexia is not commonly thought of as a fetal teratogen but there are a number of experimental and observational studies suggesting otherwise. In laboratory guinea pigs, Edwards et al has shown that heat exposure to fetal pup at a critical stage in development has induced a number of neurologic developmental abnormalities and vascular disruption defects such as bowel atresias (6). In humans, maternal exposure to hot tubs significantly increased the incidence of neural tube defects (relative risk 2.9, confidence interval 1.4-6.3) over nonexposed controls (7).

Perhaps the most common avoidable human teratogen is alcohol. It is estimated that the risk for fetal alcohol syndrome is 10% if exposed to 1-2 drinks per day. The incidence increases to 40% if the exposure increases to 6 drinks per day. The syndrome consists of small for gestational age/intrauterine growth retardation, characteristic craniofacial abnormalities, congenital heart defects, and developmental delays. A greater number of infants are born with fetal alcohol effect, a clinically milder but similar form of fetal alcohol syndrome. This uncertainty has prompted the recommendation that there is no safe amount of alcohol consumption during pregnancy.

Exposure to illicit recreational drugs such as amphetamines and cocaine is theorized to cause defects in prosencephalic development or neuronal migration resulting in abnormalities such as agenesis of the corpus callosum and brain clefts. It is also hypothesized that the incidence of fetal vascular accidents is increased resulting in cerebral infarcts, intracerebral hemorrhage, and intestinal atresias and limb reduction defects. Late exposure has been associated with intrauterine growth retardation, preterm delivery and placental abruption.

Genetic basis of fetal teratogen susceptibility

It has long been observed that exposure to many teratogens results in a wide range of effects. It has been speculated that certain individuals carry a genetic susceptibility. These are two examples of how genetic predisposition may interact with the environment and result in the formation of a birth defect.

In epoxide hydrolase deficiency, (this enzyme is critical in the metabolism of anticonvulsant medications such as phenytoin), it has been speculated that a deficiency in this enzyme may result in an accumulation of oxidative metabolites. Bueher, et al has found that in 19 women on phenytoin, four fetuses with low levels of enzyme activity were found to have clinical features of the phenytoin embryopathy whereas 15 fetuses similarly exposed with enzyme activity above 30% of controls (i.e., more normal enzyme levels) were normal (8).

Methylenetetrahydrofolate reductase (MTHFR): A common abnormal variant of this enzyme leads to elevation of homocysteine levels through inhibition of the folate-mediated remethylation of that compound. It is very common, with an estimated 30-40% of the general population heterozygous and 10% homozygous for this mutation. There is evidence that elevated homocysteine levels may be teratogenic in laboratory animals and humans. It is speculated that fetuses homozygous for the MTHFR mutation born to folate deficient mothers are at increased risk for defective neural tube formation.


1. Achondroplasia is an example of a:
. . . . . a. Malformation
. . . . . b. Deformation
. . . . . c. Disruption
. . . . . d. Dysplasia

2. Amniotic Band Syndrome is an example of a:
. . . . . a. Malformation
. . . . . b. Deformation
. . . . . c. Disruption
. . . . . d. Dysplasia

3. An "association" is a:
. . . . . a. result of a single genetic abnormality.
. . . . . b. nonrandom collection of birth defects.

4. Anencephaly is an example of a:
. . . . . a. Malformation
. . . . . b. Deformation
. . . . . c. Disruption
. . . . . d. Dysplasia

5. A significant fetal insult in the first trimester of pregnancy most commonly results in a:
. . . . . a. severe birth defect
. . . . . b. minor birth defect
. . . . . c. no birth defect
. . . . . d. miscarriage

6. The most common organ systems involved with diabetic embryopathy include:
. . . . . a. the cardiovascular system
. . . . . b. the central nervous system
. . . . . c. the spinal system
. . . . . d. all of the above
. . . . . e. none of the above

7. The safe level of alcohol consumption in pregnancy is:
. . . . . a. less than 2 drinks per day
. . . . . b. less than 6 drinks per day
. . . . . c. there is no safe level


1. Jones KL. Chapter 1-Introduction including dysmorphology approach and classification. In: Smith's Recognizable Patterns of Human Malformation, fifth edition. 1997, Philadelphia: W.B. Saunders Co, pp. 1-7.

2. Hanson U. Spontaneous Abortions and Congenital Malformations in Relation to Maternal HgbA1c: Presented at Diabetes and Pregnancy, Stockholm, 1985.

3. Gabbe SG. Impact of Prepregnancy Care on Major Malformations-11 studies: Presented at 4th Annual Managing the High Risk Pregnant Patient, Hawaii, 1997.

4. Miller E, Hare JW, Cloherty JP, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. New Engl Med J 1981;304(22):1331-1334.

5. Kucera J. Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971;7(2):73-82.

6. Edwards MJ. Congential defects in guinea-pigs following induced hyperthermia during gestation. Arch Pathol Lab Med 1967;84:42-48.

7. Milunsky A, Ulcickas M, Rothman KJ, et al. Maternal heat exposure and neural tube defects. 1992;268(7):882-885.

8. Buehler BA, Delimont D, Van Waes M, et al. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990;322(22):1567-1572.

Suggested reading

Jones KL. Smith's Recognizable Patterns of Human Malformation, fifth edition. 1997, Philadelphia: W. B. Saunders Co.

Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation, fourth edition. 1994, Baltimore: Williams & Wilkins.

Shepard TH. Catalog of teratogenic Agents, seventh edition. 1992, Baltimore: The Johns Hopkins Press Ltd.


Answers to questions

1.d, 2.c, 3.b, 4.a, 5.d, 6.d, 7.c

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