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By Ronal J. Ruggiero, Pharm.D. |
Approximately 18% of human pregnancies end in miscarriage, and more than 17,000 California infants are born with birth defects each year. According to the California Birth Defects Monitoring Program 1983-1990, 50 of the 1,600 babies born every day in California have birth defects. The cause of most defects is unknown. Of the 50 infants affected, about five will not survive, eight have heart defects, three have oral clefts, two have Downs syndrome, and one has a neural tube defect. Since 15% of all US births occur in California, this program serves as a national benchmark.1
Approximately 3%, or one in 33 of the 1.6 million births monitored in California from 1983-1990 involved an infant with a serious structural defect. Fifty five percent of infants with birth defects had two or more malformations (see Tables 1, 2 and 3).1
Since more than 50% of US pregnancies are unplanned and many of these are unintended, it is very important that women of childbearing age be screened for potential hazards to the fetus. Such screening should include (1) genetic screening (e.g., for sickle cell, Tay-Sachs, B-thalassemia, or cystic fibrosis); (2) serological status of rubella, HIV and hepatitis B, when appropriate; (3) an assessment of work and environmental hazards, such as exposure to potentially toxic chemicals or sources of radiation; (4) risk assessment of prescription and over-the-counter drugs, alcohol, nicotine, and caffeine; and (5) risk assessment of illnesses such as diabetes and phenylketonuria. In addition, women should be instructed to take the recommended daily folic acid supplement (0.4 mg per day).2
Contrary to popular belief, most exposures to potential teratogens (drugs or other agents that cause abnormal development) do not result in birth defects. However, if prompt and adequate counseling concerning the risks of a drug exposure is not available, many mothers will choose to terminate their pregnancies. Once informed that the actual risk to their baby is small, most women decide to continue their pregnancies. The Motherisk Program in Toronto, Canada reported that of 78 women who had less than a 50% desire to continue pregnancy before being counseled, 61 decided to continue their pregnancies after consultation about first trimester exposure to drugs, chemicals, or radiation. After being counseled in early pregnancy, 84.5% of the women chose to continue their pregnancies, compared to 34.3% before counseling. Of the 17 who chose to terminate their pregnancies, only two had been exposed to teratogenic drugs. In most of the other cases, the pregnancy was terminated for reasons unrelated to the teratogen exposure.3
The following risk in pregnancy categories have been assigned to drugs, either by the Food and Drug Administration or by the authors of books dealing with drugs in pregnancy.4-7
(1) Human studies conducted with the drug are negative for teratogenicity. The possibility of fetal harm appears remote.
(2) Either human studies have not been conducted and animal studies with the drug are negative for teratogenicity, or human studies conducted with the drug are negative for teratogenicity and animal studies are positive for teratogenicity.
(3) Human studies have not been conducted with the drug, and animal studies are positive for teratogenicity, or there are no human or animal studies. The drug should be given only if the potential benefit justifies the potential risk to the fetus.
(4) Human studies conducted with the drug are positive for teratogenicity, but the benefits of using the drug may outweigh the risks.
(5) Human and/or animal studies conducted with the drug are positive for teratogenicity, and the risks of using the drug outweigh the benefits. Contraindicated in pregnancy.
| Table 1: Overall Incidence of Structural Defects | |
|---|---|
| Heart | 1 in 200 |
| Cleft lip and/or cleft palate | 1 in 550 |
| Pyloric stenosis | 1 in 550 |
| Down syndrome | 1 in 900 |
| Neural tube defect | 1 in 1400 |
| Limb defect | 1 in 1750 |
| Source: California Birth Defects Monitoring Program registry data, 1990-1994 | |
| Table 2: 55% of Infants with Birth Defects Will Have Two or More Malformations | |
|---|---|
| Muscles, skeletal system | 38% |
| Eyes, ears, face | 33% |
| Heart, circulatory system | 21% |
| Genitals, reproductive system | 18% |
| Digestive system | 15% |
| Central nervous system | 14% |
| Respiratory system | 14% |
| Kidneys, urinary tract | 8% |
| Other abdominal organs | 5% |
| Source: California Birth Defects Monitoring Program registry data, 1990-1994 | |
Several years after the risk in pregnancy categories were formulated, the Over-The-Counter Drug (OTC) Labeling Warning became required on all OTC medications that are systemically absorbed. It reads as follows: AS WITH ANY OTHER DRUG, IF YOU ARE PREGNANT OR NURSING A BABY, SEEK THE ADVICE OF A HEALTH CART PROFESSIONAL BEFORE USING THIS PRODUCT.
Unfortunately, health care providers must contend with the dilemma that there is usually only animal and anecdotal human data about drug exposure during pregnancy, and such exposure is a recognized cause of less than 1% of congenital anomalies. Some expert dysmorphologists, after doing a thorough evaluation of the literature, concluded that the assignment of drugs to risk in pregnancy categories (1), (2), (3), (4) or (5) has no more accuracy than assignment by chance.
| Table 3: Selected Birth Defects | |||
|---|---|---|---|
| Rates per 1,000 births | |||
| Anophthalmia | 0.1 | ||
| Arthrogryposis | 0.3 | ||
| Bladder construction | 0.2 | ||
| Cataract | 0.2 | ||
| Chromosome defects (combined) | 2.2 | ||
| Down Syndrome | 1.3 | ||
| Trisomy 18 | 0.2 | ||
| Trisomy 13 | 0.1 | ||
| Cystic kidney disease | 0.3 | ||
| Diaphragmatic hernia | 0.4 | ||
| Ear anomalies with hearing loss | 0.1 | ||
| Fetal alcohol syndrome (FAS) | 0.2 | ||
| Gastroschisis | |||
| Heart defects (combined) | 4.9 | ||
| Coarctation of the aorta | 0.4 | ||
| Hypoplastic left heart | 0.2 | ||
| Pulmonary atresia/stenosis | 0.7 | ||
| Single ventricle | 0.1 | ||
| Tetralogy of Fallot | 0.4 | ||
| Transposition of the great vessels | 0.5 | ||
| Truncus arteriosis | 0.1 | ||
| Ventricular septal defects | 1.8 | ||
| Holoprosencephaly | 0.1 | ||
| Hydrocephalus | 0.5 | ||
| Hypospadias | 0.3 | ||
| Imperforate anus | 0.5 | ||
| Intestinal atresia | 0.4 | ||
| Limb defects (combined) | 0.5 | ||
| Upper limb defects | 0.4 | ||
| Lower limb defects | 0.2 | ||
| Neural tube defects (combined) | 0.7 | ||
| Anencephaly | 0.3 | ||
| Spina bifida | 0.4 | ||
| Omphalocele | 0.2 | ||
| Oral clefts (combined) | 1.7 | ||
| Cleft lip w/wo cleft palate | 1.1 | ||
| Cleft palate | 0.6 | ||
| Pyloric stenosis | 1.4 | ||
| Renal agenesis (bilateral) | 0.2 | ||
| Tracheo-esophageal fistula | 0.2 | ||
| Source: California Birth Defects Monitoring Program registry data, 1990-1994 | |||
It is beyond the scope of this article to discuss specific drugs. Instead, the following steps are suggested to assess the potential for fetal harm resulting from an exposure during pregnancy.
(a) Obtain a medication history consisting of:
| Forming Part | High Sensitivity to teratogens | Low sensitivity to teratogens |
| Central nervous system | 3-6.5 | 6.5-32 postnatal |
| Heart | 3-6.5 | 6.5-12 |
| Ears | 4-12 | 12-36 |
| Eyes | 4-12 | 12-36 |
| Arms and fingers | 4.5-7.5 | 7.5-8.5 |
| Legs and toes | 4.5-7.5 | 7.5-8.5 |
| Genitalia | 5.5-12 | 12-38 |
| Teeth | 6.5-10 | 10-36 |
| Originally published in "Manual of Clinical Problems in Adult Ambulatory Care," 2nd edition, 1992. Reprinted-with permission of Lippincott-Raven, Philadelphia, PA. | ||
(b) Evaluate the risk using the available resources which include:
(c) If sufficient information cannot be obtained from the literature or data bases:
As discussed above, preconception counseling about fetal drug exposure is ideal. However, postconception counseling following an exposure is extremely important and can serve to reassure the expectant couple that the risks have been evaluated as thoroughly as possible. There is nothing worse than receiving differing risk assessments from several health care providers. Therefore, it is mandatory that me patient understands that the best information available has been found. If the pharmacist is answering questions directly for an expectant couple, it will be in their best interest to include the mother's other health care providers) so that a consensus can be reached about the risk. It should be emphasized that it is difficult to give an accurate risk assessment in most cases due to a general lack of data, but that the risk inherent to human reproduction of having a child with a major malformation is currently approximately 3 % nationwide.
Information on the passage of drugs into breast milk and the effects on me infant is often scarce. When information is not found in the standard resources listed below, the manufacturer or a local drug information center may be helpful.
Certain precautions can be taken to minimize the effect of maternal medications on the nursing infant:
(a) The mother should wait to take the drug until immediately after breast-feeding.
(b) The infant should be observed for unusual signs or symptoms.
(c) Drugs that are safe when given directly to an infant and drugs that are known not to pass readily into breast milk are preferred to other agents.10
Step Two: Identify the Drug, Dose, Regimen, Duration, and Time of Exposure
Without discussing specific drugs, the following steps are suggested to assess the potential for harm of a given exposure to the breast-fed infant.
(a) Evaluate the risk using recognized resources. Recognized resources include:
(b) If sufficient information cannot be obtained from the literature or data bases:
In summary, information is sparse on the effects of drugs both in pregnancy and lactation. Patients should be made aware of this and of the fact that birth defects occur in human reproduction even without exposure to teratogens. A comprehensive risk assessment using the steps outlined above and the references listed is essential. The patient must clearly understand the risks to the fetus or infant that are identified. Communication among all of the patient's health care providers regarding these risks is important to insure that the patient receives consistent information. Accurate and timely counseling on the risks of drugs in pregnancy or breast-feeding allows the patient to make a decision that is in the best interest of her fetus or infant.