INTRODUCTION
It was thought for many years that drugs taken during pregnancy might influence the development of the fetus; however, it was not until the thalidomide tragedy of the early 1960s that conclusive proof of such action was available. The agent thalidomide, was an effective sedative drug used in Europe to treat pregnant women suffering from anxiety. Some 10,000 offspring of mothers, who consumed thalidomide in the first trimester (first three months) of their pregnancy, were born with an array of congenital defects; the most common being phocomelia (malformed or absent limbs). This tragedy made people aware of the delicate processes associated with fetal development and how easily these processes can be disrupted when exposed to certain drugs.
Ten years later, these concerns were reinforced by the discovery that cancer in the vagina of adolescent females could be caused by fetal exposure to diethylstilbesterol (DES), an agent that was administered to pregnant women to prevent spontaneous abortion. The fact that the actions of this drug on the fetus did not become apparent until some 15-20 years following exposure demonstrates the frightening complexity of fetal-drug interactions.
It is likely that the extent of the problem is still not fully understood. Most certainly other specific examples of drug-induced congenital defects will be discovered in the future. Yet, in spite of these past and prospective tragedies, many women and health professionals are still somewhat casual about drug use during pregnancy. More than 90% of the women consume drugs during pregnancy (the average is 3 to 4 drugs during the 9 month period). In addition, substances are frequently consumed that are viewed by pregnant users as nonpharmacological but which contain drugs that are potentially dangerous to the fetus; these include products such as tea, alcohol, coffee, and cigarettes. Thus, in this country 20% of pregnant women smoke and 18% drink alcohol. Because drug usage is so common, it is almost impossible to determine what relationships exist between abnormalities present in infants and the drugs consumed by the mothers during their pregnancies. It is known that 25% of all pregnancies end by spontaneous abortion and 90% of these aborted fetuses appear malformed. In addition, birth defects appear in approximately 3-4% of all live births. While 65% of these congenital malformations are of unknown origins, it is currently thought that only a small fraction (2-3%) of these abnormalities are drug-related. One estimate puts the frequency of drug-caused birth defects at 1/1000 total live births, or a total of about 3,000 incidences each year. Even more difficult to assess is the possibility that drugs consumed during pregnancy may have subtle effects on the fetal development that alter characteristics such as personality and susceptibility to disease. It will require much more sophisticated analytical techniques than currently available to evaluate accurately all influences of prenatal drug consumption.
On the other hand, some health professionals believe we have become excessively cautious, to the extent pregnant women are sometimes deprived of needed medication for fear of unproven adverse drug effects on the fetus. It has been claimed that for every instance a drug is given to a pregnant woman inappropriately, there are 20 instances when a women is deprived of a needed drug. Clearly, a rational balance between caution and beneficial drug therapy is required.
FETAL SUSCEPTIBILITY
Although we know very little about how drugs are able to alter the fetus, we do know that several factors are critical in determining if there is prenatal impact; these include:
- dosage
- route of administration
- duration of treatment
- concurrent use of other agents
- maternal metabolism (ability of the mother to metabolize drug before it enters fetal circulation)
- placental transport (how easily does it pass through the so-called placental barrier)
- fetal metabolism
Fetal structures and organs develop during specific intervals following conception; if this development is interrupted by a drug, or for that matter any outside influence, structural abnormalities can result.
From the time of fertilization until implantation on day seven, the embryo is primitive and without a placental connection to the maternal blood; consequently, drugs consumed by the mother during this period are unlikely to have significant access to the developing child - susceptibility to drug effects is thought to begin at days eleven or twelve. Once the placenta has developed, biochemical communication between mother and embryo begins. While there is some selective screening that occurs at the level of the placenta, this is based on the molecular size and the water versus fat solubility properties of substances. Most drugs, because they have relatively small molecular weights, pass with ease through the placental barrier by simple diffusion and enter the fetal circulation.
Drug-induced gross, anatomical defects in the child are most likely to occur during the first 24 weeks of pregnancy; however, until the end of fetal development, the functions of fetal systems can theoretically still be altered by pharmacological influences. Unfortunately, many women are not aware of their gravid state until well into the critical second month of pregnancy and unknowingly expose a developing embryo to damaging compounds. For this reason, many experts advise all women of child-bearing age to keep drug use to a minimum even though pregnancy is not suspected.
DRUG-INDUCED CHANGES
TERATOGENIC EFFECTS
BIOCHEMICALLY: These defects can be very subtle and often difficult or impossible to detect. They might consist of alterations in enzymes within the body and interfere with normal biochemical functions. For example, some drugs taken during the development of the brain could possibly alter the transmitter systems that have a messenger function in the central nervous system; as a result, certain brain functions would be compromised (e.g., memory could be impaired or motor function may be damaged).
CHROMOSOMAL ABERRATIONS: Some drugs are known for their ability to alter the genetic structures of cells. Because the genes or chromosomes control the cells, their functions, development and division, any genetic changes caused by drugs in the fetus could have long-term effects. Conceivably, chromosomal defects might be masked initially, but passed to offspring and be expressed in subsequent generations. The possibility of such congenital defects is frightening, however, the potential is real.
REVERSIBLE PHYSIOLOGICAL EFFECTS
Drugs that enter into the fetal circulation exert pharmacological effects on the developing child much like those induced in the mother. For example, if a pregnant women were to consume a barbiturate, her brain activity would be suppressed due to the CNS depressive actions of the drug: a similar effect would occur in the fetal brain. Because the capability of the fetus to metabolize substances, such as drugs, is poorly developed (e.g., the liver is not yet mature and totally functional) pharmacological actions of drugs consumed by the mother are often exaggerated in the fetus. However, such drug effects usually are reversible and eventually subside in both mother and offspring. Generally, this has little practical significance except in cases where the mother chronically consumes a drug during pregnancy that causes severe withdrawal symptoms when it is abruptly discontinued (e.g., narcotics or alcohol); with such drugs, severe withdrawal symptoms are likely to occur to neonates (new born infants) following birth because they no longer are exposed to the drug through the maternal circulation.
ANALYSIS OF TERATOGENIC POTENTIAL
Although it is important that drugs with teratogenic potential be identified, there are several reasons why it is difficult to make this determination accurately:
Window Effect: In order for most teratogens to cause a congenital defect they must be given during a short critical period of the pregnancy. For example, an agent might only affect fetal development on the 25th and 26th days following conception. This is known as a window effect and can be very difficult to detect.
Individual Variability: Even the potent teratogen, thalidomide, affected only 25% of the offspring of mothers who consumed the agent during pregnancy. There is a great deal of variability in responses to teratogens. Certain factors may predispose the developing fetus to the adverse effects of the drug. For example, genetic traits, or a poor nutritional state might increase susceptibility of the fetus to teratogenic effects of drugs.
Delayed Expression: Some drug-related congenital defects are not apparent at birth and might not be expressed for years. An example of this is the vaginal cancer which occurs in the offspring of mothers who used diethylstilbesterol (DES) during their pregnancy. This cancer does not develop until 15-22 years following birth. It is difficult to establish an association between cause and effect when there is a multi-year gap between them.
Atypical Expressions: There is a possibility that some adult-onset diseases, such as hypertension or diabetes, are the result of exposure to drugs during fetal development. However, it is almost impossible to distinguish diseases that develop naturally and those that occur due to teratogenic effects of drugs.
TYPES OF ANALYSIS
Two possible analytic approaches for detecting drug teratogenicity are:
PROSPECTIVE ANALYSIS: The teratogenic properties of a drug are determined in a controlled study, usually employing animals such as the rat, mouse, or rabbit. Pregnant animals are given either the drug or an inactive substance for comparison. The incidence and types of defects in the offsprings are compared in the groups of animals that did and did not receive the drug being tested. Prior to an FDA ruling in 1993 that reversed its policy barring women of child-bearing age from participation in clinical trials for new drugs, few prospective studies were done to test the effects of drugs taken during pregnancy. Since the ruling, many more prospective studies have been and will be conducted. Hopefully, this change in policy will help to increase our knowledge of which drugs are safe or dangerous when used during pregnancy.
RETROSPECTIVE ANALYSIS: This approach utilizes medical histories to examine the population of children with congenital deformities and determines the fraction of mothers who, during pregnancy, consumed the drug being studied. This value is compared to the frequency of usage of that drug during pregnancy by mothers who give birth to unaffected offspring. Such a comparison indicates if use of the drug by an expectant mother increases the likelihood of having offspring with congenital defects. The lack of control in this type of study makes it very difficult to evaluate accurately the results.
AGENTS LINKED TO BIRTH DEFECTS
No drug has been proven to be completely harmless to the developing fetus. Because of the analytical difficulties described above, it is impossible to assure absolute safety of a fetus exposed to any drug taken by the mother during pregnancy. Consequently, most medical experts would discourage the use of any unnecessary medication during pregnancy. However, there are occasions when drug use by the pregnant patient is necessary. In such situations agents that have been studied and found to have little risk to the fetus should be administered, if possible. Unfortunately, the teratogenic potential for most drugs has not been assessed. Over 50% of the prescription drugs have not even been evaluated for effects during pregnancy and thus no statement as to their safety can be made. Less than 1% of prescription drugs, based on scientific evaluation, have been declared to be safe for use during pregnancy.
In an effort to inform the users of prescription drugs about the level of risk to the fetus and the extent of caution necessary if these agents are to be used during pregnancy, the FDA has established five categories (A, B, C, D, and X) to indicate a drug's potential for causing birth defects. While some experts argue that this classification is too simplistic and often misleading, it can be useful if used only as a general guide. Most prescription drugs should carry this information. Briefly, the pregnancy categories have the following meanings:
B - Animal studies do not indicate a risk to the fetus and there are no controlled human studies; or animal studies do show an adverse effect on the fetus but well controlled studies in pregnant women have failed to demonstrate a risk to the fetus.
C - Studies have shown the drug to have animal teratogenic or embryocidal (kills embryo) effects; but there are no controlled studies in women, or no studies are available in either women or animals. The FDA is considering eliminating this category due to its ambiguity. Two-thirds of the ranked drugs are in this category.
D - Positive evidence of human fetal risk exists, but benefits in certain life-threatening situations or for serious diseases may make use of the drug acceptable despite its risk.
X - Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk outweighs any possible benefit.
Many individuals erroneously assume that a drug's teratogenic potential reflects the overall safety of the agent. In other words, a drug that possesses a wide margin of safety for general use is less likely to cause damage to a developing fetus if taken during pregnancy. Consequently, the public believes that OTC drugs, because of their high level of safety, pose little teratogenic threat and can be consumed during pregnancy without danger of harming the fetus. The overall safety of a drug is no guarantee that the agent will be harmless to the fetus. In fact, some relatively safe OTC compounds have been shown to disrupt normal fetal development and should be avoided by the pregnant woman. Consequently, the FDA requires a general pregnancy warning to appear on the labels of most OTC drugs intended for systemic use. These products are to display the following advisement:
"As with any drug, if you are pregnant or nursing a baby, seek the advice of a health professional before using this product."
The following list includes a few common agents that have been evaluated for potential chemical toxicity to the human fetus:
ANALGESICS (OTC): Some experts have included aspirin in their list of suspected teratogens. Consequently, when an OTC analgesic is required by a woman during pregnancy many physicians recommend the use of acetaminophen-containing products. However, most experts question the teratogenicity of aspirin and feel that its use during pregnancy will not directly damage the fetus.
ANTIBIOTICS: Tetracyclines bind calcium and as a consequence they can cause discoloration of the teeth and impair bone formation. Streptomycin can cause damage to the auditory cranial nerves which results in a hearing loss in the offspring. In contrast, the antibiotic, penicillin, appears to be relatively free of influence on the fetus.
ANTIHISTAMINES: These agents are commonly used as antiemetic drugs in the treatment of nausea and vomiting during the early stages of pregnancy. There is retrospective evidence that some of these agents are teratogenic. However, other studies have not supported these original findings. As a rule though, use of antihistamines should be avoided during pregnancy without consulting a physician (note: many OTC cold medicines and sleep aids contain antihistamines).
CAFFEINE: Babies born to mothers who consume moderate-to-high quantities of caffeine (300-600mg daily) tend to be slightly premature with slow muscular reflexes. Higher doses of this drug can even result in miscarriages.
CIGARETTES: The regular use of cigarettes during pregnancy increases the likelihood of miscarriages, stillborn, or prematurely born offspring. The children of cigarette smokers are usually born less well developed than the offspring of nonsmoking mothers. The reason for these effects is likely due to the vasoconstriction of blood vessels in the placenta caused by compounds such as nicotine in the inhaled cigarette smoke.
DRUGS OF ABUSE: Thousands of offspring are being born to drug-dependent women who consumed high doses of psychoactive drugs during their pregnancy. Many of these children are subsequently abandoned and left to be cared for by the state. It is only now becoming apparent that many of these unfortunate children have been adversely affected by their mothers' drug habits and will become enormous burdens on federal, state and local social services.
The hallucinogen LSD (lysergic acid diethylamide) has received a great deal of attention due to its previous widespread use. It has been shown that LSD can cause chromosome damage. Even so, the evidence is not yet convincing that LSD consumption will cause the birth of a malformed infant. Stimulants that are commonly abused likely can alter the fetal development of nervous system structures; these include cocaine, and amphetamines. A great deal of additional research is required to determine the exact nature of these drug-induced defects and society must decide how best to deal with these innocent victims of drug abuse.
ETHANOL (see Chapter 7): Numerous studies have found that consumption of alcohol during pregnancy, especially in the early months, can harm the fetus. Included in the findings are:
- significant increases in spontaneous abortions (observed at levels of alcohol consumption as low as one ounce twice per week)
- High consumption of alcohol, consistent with the diagnosis of alcoholism, risks bearing a child with a cluster of severe physical and mental defects known as fetal alcohol syndrome (FAS). Associated birth defects include retarded postnatal growth, small head (microencephaly), mental retardation, facial abnormalities, heart defects, joint anomalies, and other malformations.
INSULIN: This hormone is used to treat diabetic patients and at one time was thought to adversely affect the fetus. However, there is currently no clinical evidence that controlled insulin therapy has teratogenic effects in humans.
SEX HORMONES: The exposure of the fetus to testosterone (male hormone) or estrogen (female hormone) causes sterility and masculinization in female offspring. Use of birth control pills during the first trimester of pregnancy can cause heart and limb deformities in the fetus. Use of oral contraceptives should be stopped immediately if pregnancy is suspected.
ENVIRONMENTAL TOXINS: some chemicals to which pregnant women might be exposed in the general environment are teratogenic in animals. Included in this group are dioxin, a contaminant in some herbicides, the fungicide, captan, as well as mercury and lead.
DRUG PRESCRIBING FOR CHRONIC MEDICAL DISORDERS DURING PREGNANCY
While it is desirable for pregnant women to avoid exposure to drugs during the gestation period, often this is not possible. Frequently, women of reproductive age experience medical disorders that require pharmacotherapy for maternal well-being. In such cases, it is recommended that the attending physicians prescribe drugs that provide maximal safety to the fetus and adequate therapeutic benefit for the mother. The selection of the best therapeutic agents for such instances can be difficult because of a lack of reliable information concerning the effects of such drugs on fetal development. The following are some medical conditions that often require some pharmacological intervention even during pregnancy:
- chronic hypertension
- diabetes
- thyroid disease
- epilepsy
- asthma
- migraine headaches
- cardiovascular disease
CONCLUSION
While we do not fully appreciate all of the risks of exposing a human fetus to drugs during pregnancy, it has been convincingly demonstrated that tragic consequences can occur. However, proper perspective should be maintained and we should remember that the proven instances of such tragedies are few and far between. Consequently, a conservative approach to using prescription and nonprescription medications as well as many recreational and beverage drug products during gestation is recommended. If a drug needs to be administered to an expectant mother, the safety record of the medication and the stage of pregnancy, should be evaluated carefully by the physician to assure the greatest possible safety for both mother and fetus.