Vol. 12: Fall, 1995
Teratogen Update
Medications
About 8,000 drug products are available on the market in the United States. This is a drastic change from the 656 drugs that were available for use in 1961. In the United States, approximately 1.5 billion prescriptions are filled annually, for an average of about six prescriptions per year per person.
This does not include over-the-counter products, cigarette smoking, alcohol, illicit drugs or homeopathic preparations. Surveys have shown that between 35 an 90 percent of pregnant women use medications during pregnancy, not including vitamin and iron supplements, or medications used during delivery.
See References: Medications
Angiotensin-converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are now widely used in the treatment of systemic hypertension. These agents inhibit the conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. The two commonly used agents are captopril and enalapril.
In the 1980s, case reports and series appeared that indicated that ACE inhibitors can produce a unique fetopathy. Based on the relative rarity of the kidney abnormalities seen in these cases and on the known effects of ACE inhibitors on renal vasculature, it is now widely accepted that ACE inhibitors are human teratogens. The phenotype consists of two principal components:
1. Renal abnormalities including oligohydramnios, renal failure, anuria, and often neonatal death due to the renal insufficiency. In some cases of infant death, detailed autopsies have shown renal dysgenesis.
2. A skull ossification defect consisting of hypocalvaria; the skull is markedly underossified and very soft on exam. This is a rather novel finding seen in a small number of syndromes and rarely as an isolated defect.
Based on just over 30 well documented cases, the critical period for the development of these fetal effects is thought to be in the 2nd and 3rd trimester of pregnancy. Preliminary studies of the outcome for women exposed only in the first trimester indicate that these abnormalities are not present.
It is currently hypothesized that the basic mechanism of the production of the renal abnormality involves decreased blood flow to the renal arteries leading to a cascade of secondary effects, including renal tubular disruption. Animal models are being developed to test this hypothesis.
The actual risk for a woman exposed to ACE inhibitors during the 2nd and 3rd trimesters to develop the fetopathy is unknown, but from one small cohort study and a registry of cases in France, the risk is probably less than 30%.
If a woman's pregnancy is discovered while using ACE inhibitors, the possibility for this fetopathy needs to be discussed. Since the effects are primarily in the latter part of the pregnancy, there is time to consider switching to other anti-hypertensives.
In some cases clinicians may decide that the ACE inhibitors are the best agent for a particular patient; if this is the case, the pregnancy can be monitored with ultrasound for amniotic fluid production. As in all such cases, the risks and benefits should be weighed.
See References: Ace Inhibitors
Anticonvulsants
Epilepsy affects at least 2 million people in the US and about 40 million worldwide. Among the 4.03 million annual US births, approximately 0.33% are infants born to women with epilepsy. Most of the infants are born to epileptic mothers who receive anticonvulsant medications during their pregnancy.
Maternal epilepsy has been associated with a two- to three-fold increased risk of birth defects compared to the general population. Orofacial clefts and congenital heart defects are among the congenital anomalies seen with increased frequency.
It is difficult to sort out the relative contributions of the various embryologic/fetal exposures occurring in a pregnancy complicated by epilepsy and anticonvulsant drug therapy: i.e. is it the epileptic state itself, occurrence of maternal seizures, other complications of pregnancy, or the teratogenic effects of the medications which cause the increase in birth defects.
While several drugs used to treat epilepsy are known to be teratogens, it is also important that women at risk of seizures during pregnancy be treated with effective anticonvulsant therapy.
- Phenytoin
Phenytoin was first synthesized in 1908. However, its anticonvulsant activities were not discovered until 1938. The anticonvulsant phenytoin became widely used for all types of seizures, except petit mal epilepsy.
Infants exposed to phenytoin and other hydantoins during pregnancy have exhibited a recognizable pattern of malformation known as the fetal hydantoin syndrome (FHS). The FHS includes dysmorphic facies, hypoplastic nails, and abnormalities of growth and development.
There have been several case reports of various tumors in children with exposure to phenytoin in utero, such as malignant mesenchymoma, neuroblastoma, and Wilms tumor. Controlled studies have not been done to establish the risk associated with anticonvulsants and transplacental carcinogenicity.
Phenytoin has the potential to cause early hemorrhagic disease in the newborn by altering hepatic physiology. About half of all neonates exposed to phenytoin in utero will develop a bleeding disorder due to a deficiency of Vitamin K if not treated with parenteral Vitamin K.
- Valproic Acid
In 1978 valproic acid was approved for use in the US. The drug had been available in Europe for more than a decade before it was available in the US. Valproate has been effective in a wide variety of partial and generalized seizures.
Based on data from the birth defects monitoring system for the Rhone-Aples region of France, an increase in spina bifida in the offspring of mothers who took valproic acid during pregnancy was observed. From this data, the estimated risk of fetal spina bifida for a woman taking valproic acid during the first trimester of pregnancy is 1 - 2%.
This data has been confirmed in subsequent studies. Therefore, valproate exposed fetuses should be monitored for spina bifida and appropriate genetic counseling/prenatal diagnosis offered.
It has also been suggested through other studies that a "Fetal Valproate Syndrome" exists. The features described include facial dysmorphism, limb/neural tube/cardiac defects, and developmental delays.
- Carbamazepine
Carbamazepine has been used since the 1960s for the treatment of trigeminal neuralgia. It was approved in the US as an anticonvulsant in 1974. Carbamazepine is used as a primary drug for the treatment of all types of epilepsy, except absence seizures.
The potential for teratogenicity of carbamazepine is unclear. Several studies have failed to demonstrate an increased rate of malformations, while other studies have documented reduced head circumference, birth weight and length, and isolated case reports of congenital malformations.
A collection of case reports indicated that carbamazepine use was associated with an increased risk of spina bifida, however this data has been questioned. We suggest monitoring carbamazepine exposed pregnancies on a case-by-case basis as there is not clear risk data for spina bifida.
Editorial Comment: A number of clinical teratologists, myself included, believe there is a "Fetal Anticonvulsant Syndrome" - i.e. anticonvulsant medications (e.g. phenytoin, carbamazepine, phenobarbital and related compounds, and to a lesser extent, valproate), produce a recognizable pattern of dysmorhogenesis which was previously termed the Fetal Hydantoin Syndrome.
See References: Anticonvulsants
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Teratogen Update Table Of Contents:
Introduction
Medications
Substances of Abuse
Maternal Infections
Maternal Disorders
Mutagens
Etiology of Congenital Malformations in Humans: (Table 1)
Known Human Teratogens: (Table 2)
References
Facts About Neural Tube Defects and Folic Acid
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