Case Based Pediatrics Chapter

Chapter IV.4. Teratogens
Jennifer H. Boomsma, MS, CGC
June 2013

The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Greigh I. Hirata. This current second edition chapter is a revision and update of the original author’s work.

Ms. B is a 37 year old G2P0Sab1 who presents in her 19th week of pregnancy seeking prenatal counseling. Her medical record indicates she was prescribed Depakote (divalproex sodium or valproic acid) for bipolar disorder. She states she has been a type II diabetic under poor control for six years and does not regularly take her oral hypoglycemic agent. She also reports that she has been drinking alcohol regularly for the past ten months. She is undecided on her commitment to this pregnancy.

This example demonstrates that there are multiple potential teratogenic exposures that can affect intrauterine fetal development. Maternal disease, prescription medications, environmental exposures, infectious agents, and genetic conditions can play important roles in fetal growth, the pathogenesis of congenital anomalies, as well as cognitive/behavioral and physical function of an individual.

Chapter IV.7. Common Congenital Anomalies in this textbook describes the different pathophysiologic mechanisms that lead to abnormal fetal development. In regard to teratogenic exposures, the risk for the fetus is greatly dependent on the timing of exposure, duration and amount/intensity of the exposure in addition to the underlying genetic susceptibility. Most embryology textbooks provide an overview of the critical periods in human development by illustrating the different organ systems in relation to the timing and duration of formation, which results in marked differences in susceptibility. In general, the first two weeks after conception, before the placental-fetal circulation is established, are considered the "all or none" period of development. This means that an exposure will either be significant enough to result in miscarriage, or not result in fetal damage. Teratogen exposure during the first trimester of development is most critical in terms of the risk of congenital anomalies. However, the developing brain is vulnerable throughout pregnancy.

In this section we will review some of the common human teratogens. For a complete list of teratogens and potential fetal effects, the reader is referred to resources listed in the reference section of this chapter.

Prescription Medications

Valproic acid use in pregnancy may lead to increased risks for specific craniofacial abnormalities, cardiovascular defects, neural tube defects, and cognitive deficits relative to family members (1). It is estimated that the risk for neural tube defects is 1% to 2% (10 to 20 fold increased above the general population). Since valproic acid interferes with folic acid metabolism, patients on this medication may benefit from preconceptional folic acid supplementation.

Phenobarbital may lead to fetal withdrawal in the neonatal period. The possibility of a fetal barbiturate syndrome is currently controversial, although the symptoms are not unique to phenobarbital exposure. Babies exposed to this medication in utero have been found to be relatively vitamin K deficient leading to the recommendation of maternal vitamin K administration at least one month prior to delivery. Symptoms of exposure can include growth retardation, development delays, dysmorphic facies and other minor anomalies.

Fetal hydantoin (phenytoin) syndrome is characterized by growth and developmental delay, microcephaly, cleft lip and palate, hearing loss and hypoplasia of the nails and distal phalanges. Like phenobarbital, vitamin K deficiency has been observed in these neonates and therefore maternal vitamin K administration is recommended one month prior to delivery.

Coumarin (Coumadin, warfarin) is a vitamin K antagonist used for anticoagulation and 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 warfarin embryopathy is estimated to be 5% to 10% if exposure occurs within the first trimester of pregnancy during embryogenesis.

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% to 5% risk of congenital heart defects, particularly Ebstein’s anomaly.

Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, linsinopril), a class of antihypertensive agents, is associated with renal tubular dysplasia resulting in fetal and neonatal oliguria/anuria, oligohydramnios, pulmonary hypoplasia, intrauterine growth retardation, and defects of cranial 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 defects of the eyes, ears, palate, central nervous system, cardiovascular system, and intellectual disability. 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.

Environmental Exposures

Maternal hyperthermia of 101°F (38.3°C) due to fever, intense exercise, or prolonged (more than 10 minutes) exposure to hot saunas, hot baths, or hot tubs in the first trimester increases the incidence of neural tube defects. Specifically, maternal exposure to hot tubs significantly increased the incidence of neural tube defects (relative risk 2.9, 95% confidence interval 1.4 to 6.3) over nonexposed controls (2).

Perhaps the most common avoidable human teratogen is alcohol. It is estimated that the risk for Fetal Alcohol Syndrome (FAS) is 10% if exposed to 1 to 2 drinks per day. The incidence increases to 40% if the exposure increases to 6 drinks per day. Binge drinking, in addition to daily drinking, can cause damage to the fetus. FAS is characterized by intrauterine growth retardation, characteristic craniofacial abnormalities (short palpebral fissures, under development of the philtrum, thin upper lip), developmental delay, and behavioral abnormalities. Other birth defects including congenital heart defects, cleft palate, and skeletal anomalies are also occasionally reported. Fetal Alcohol Syndrome exists along a spectrum of birth and developmental defects termed Fetal Alcohol Spectrum Disorders (FASD). There is no known safe amount of alcohol consumption during pregnancy.

Exposure to illicit recreational drugs such as amphetamines and cocaine is theorized to cause defects in forebrain 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 infarction, intracerebral hemorrhage, intestinal atresias and limb reduction defects. Late exposure has been associated with intrauterine growth retardation (IUGR), preterm delivery, and placental abruption.

Tobacco smoking during pregnancy has been associated with 30% of all infants born small for gestational age (SGA) as well as other adverse pregnancy outcomes (3).

Maternal Medical Conditions

Maternal medical illnesses can increase the risk for newborn birth defects. Counseling prior to conception can be important in reducing this risk.

Maternal diabetes mellitus is the most common maternal condition associated with fetal congenital anomalies. It is well known that pregestational and early gestational glucose control greatly influence the rate of miscarriage and fetal anomalies. In a study performed by Hanson et al. (4), hemoglobin A1c levels for those women seeking prenatal care were positively correlated with the rate of miscarriage and anomalies. Moreover, in a summary of 11 studies by Gabbe (5), the incidence of birth defects were 2.5% in those women achieving glucose control in the preconception period versus 7.8% in those women presenting after conception. The hemoglobin A1c level at 14 weeks, reflecting glycemic control 3 to 4 weeks prior, is predictive of the rate of fetal anomalies. A hemoglobin A1c level greater than 8.5% confers a risk of birth defects of approximately 22% versus 3.4% in women with A1c levels less than 8.5% (6).

The pattern of anomalies secondary to maternal diabetes is characteristic. Infants of diabetic mothers are particularly prone to defects in the cardiovascular system, central nervous system, and skeletal system. The risk for cardiac anomalies is 4.3 times higher compared with normal glycemic controls (7). The relative risks for central nervous system anomalies are 3.3 for anencephaly and 1.4 for spina bifida (7). The rare disorder, caudal regression syndrome, is almost pathognomonic with a relative risk of 175 for maternal diabetes mellitus (7).

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

Maternal seizure disorders are another example of an illness associated with birth defects. The etiology of birth defects in epileptic women is likely due to many factors including genetic disorders in the mother associated with epilepsy and the potential for teratogenesis due to exposure to anti-seizure medications. Most anticonvulsants confer a risk for birth defects; 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. Several anticonvulsants can lead to fetal vitamin K deficiency due to the inhibition of placental transport of vitamin K. These drugs include phenobarbital, phenytoin, carbamazepine, ethosuximide, primidone, and diazepam (1). Maternal and neonatal vitamin K supplementation can avoid perinatal hemorrhagic complications.

Elevated maternal phenylalanine levels associated with phenylketonuria (PKU) is associated with an increased risk of spontaneous abortion and a pattern of malformation including prenatal growth deficiency, microcephaly, structural and functional brain abnormalities, and congenital heart defects. The risk of intellectual disability and congenital anomalies is positively correlated with the maternal phenylalanine level. If target levels of phenylalanine (2 to 5 mg/dL) are achieved prior to conception, the outcome can be normal. The recommendation is "treatment for life" and compliance with phenylalanine restricted diet can prevent these defects.

Maternal depression and anxiety during pregnancy have been associated with a variety of adverse pregnancy outcomes. Women who suffer from psychiatric illness during pregnancy are less likely to receive adequate prenatal care and are more likely to use alcohol, tobacco, and other teratogenic substances. Low birth weight and fetal growth retardation have been observed in this population. Pregnancy complications related to maternal depression and anxiety in late pregnancy have also been described, including an increased risk for having preeclampsia, operative delivery, and infant admission to a special care nursery for a variety of conditions including respiratory distress, hypoglycemia, and prematurity (8).

Infectious Agents

See Chapter III.13. Congenital and Perinatal Infections in the Neonatalogy Section.

Questions:

1. The developing heart is most susceptible to teratogens during this period of development:
. . . . . a. preimplantation
. . . . . b. implantation
. . . . . c. embryogenesis
. . . . . d. organogenesis

2. Ebstein’s anomaly is associated with which teratogenic substance:
. . . . . a. lithium
. . . . . b. ACE inhibitors
. . . . . c. warfarin
. . . . . d. phenobarbital

3. Maternal hyperthermia in the first trimester has been linked to which group of birth defects:
. . . . . a. cognitive/behavioral
. . . . . b. neural tube Defects
. . . . . c. genitourinary defects
. . . . . d. abdominal wall defects

4. The most common fetal vitamin deficiency linked to anticonvulsant use in pregnancy is:
. . . . . a. vitamin A
. . . . . b. folic Acid
. . . . . c. vtamin D
. . . . . d. vitamin K

5. 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

6. The safe level of alcohol consumption in pregnancy is:
. . . . . a. less than 2 drinks per day
. . . . . b. less than 6 drinks per day
. . . . . c. less than 3 drinks per weekend
. . . . . d. there is no safe level

References

1. Minagar, Alireza. Neurological Disorders and Pregnancy. 2011, Burlington, Massachusetts: Elsevier Inc, pp 108-110.

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

3. Tong VT, Jones JR, Dietz PM, et al. Trends in smoking before, during, and after pregnancy - Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 31 sites, 2000-2005. MMWR Surveill Summ 2009;58:1.

4. Hanson U. Spontaneous abortions and congenital malformations in relation to maternal HgbA1c: Presented at Diabetes and Pregnancy, Stockholm, 1985.

5. Gabbe SG. Impact of prepregnancy care on major malformations-11 studies: Presented at 4th Annual Managing the High Risk Pregnant Patient, Hawaii, 1997.

6. 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.

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

8. Bonari, Lori, Koren, Gideon, et al. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 2004;49(11):726-735.