The Porous Placenta

Before 1962, generations of physicians were taught the comforting myth that the placenta—the organ within the uterus through which a fetus receives its nourishment—was a sort of guardian angel of the umbilical cord, passing needed nutrients through while holding harmful germs and chemicals back. It was long known, of course, that there were some exceptions. The rubella (German measles) virus, for instance, could be transmitted from a pregnant woman to an embryo in the first three months of pregnancy, causing defects in the fetus. But not until 1962 did many physicians pay serious attention to the possibility that other dangerous substances might be passed from pregnant woman to fetus.

In that year the world was shocked to learn that thalidomide, a drug then commonly prescribed in many countries for insomnia and nervous tension, was in fact a teratogen—a substance capable of producing malformations in a fetus. Thousands of babies born to women who took thalidomide early in pregnancy suffered from phocomelia, or "seal limbs"—so called because foreshortened arms and legs resembling the flippers of seals are the most conspicuous result.

Even today, the world is occasionally shocked to learn of new teratogens. Most recently, the anti-acne prescription drug isotretinoin (Accutane) has been found responsible for hundreds of severe and often lethal birth defects in children born to women who became pregnant while taking the drug.

Rather than being a barrier to the transfer of drugs from pregnant woman to fetus, the placenta is "a sieve," according to the late Virginia Apgar, M.D., vice president for medical research of the National Foundation–March of Dimes. Apgar said, "Almost everything ingested by or injected into the mother can be expected to reach the fetus within a few minutes." Alcohol, antibiotics, aspirin, barbiturates, sulfonamides, and tranquilizers are but a few of the common, and possibly harmful, substances known to pass through the placenta. Moreover, certain drugs can be found in even greater concentration in the fetal brain, heart muscle, or other organs than in the maternal tissues. In addition, the capacity of the placenta to allow transfer of some drugs seems to increase with the duration of pregnancy.

Much of this information had long been known to the relatively small group of investigators who studied the physiology of the human fetus; but little of their knowledge filtered through to practicing physicians, or even to those responsible for setting the requirements of drug testing. It took the thalidomide disaster to secure wide clinical acceptance of the established facts of fetal physiology. Today physicians assume that, when they prescribe a drug for a pregnant woman, the drug or its breakdown products—with few known exceptions—will also circulate through the fetus.

When pictures of thalidomide babies first hit the front pages, many pregnant women were frightened and immediately discontinued whatever medication they had been taking. Some pregnant women still refuse to take any drugs at all.

We agree that those who are pregnant—and those who are potentially pregnant—should avoid virtually all medication for the relief of minor symptoms, especially during the first trimester of pregnancy. However, those who are in need of medical treatment should be guided by their physicians. Pregnant women can have any disease other women have. Tuberculosis, diabetes, infectious diseases such as syphilis and gonorrhea, heart disease, epilepsy—these are but a few of the diseases that, if left untreated during pregnancy, may affect a fetus. Both taking prescribed medicines and refraining from unnecessary medication are important.

A diabetic is a prime example of the type of patient who needs close medical supervision during pregnancy. Diabetics should make arrangements for medical care as early as possible in their pregnancy. Studies indicate that meticulous control of blood sugar, by means of proper diet and use of insulin, can reduce the incidence of fetal abnormalities to the same level as in a nondiabetic population. Those who have been taking oral diabetes medication must switch to insulin for the duration of their pregnancies. These oral hypoglycemics—including tolbutamide (Orinase), acetohexamide (Dymelor), chlorpropamide (Diabinese), tolazamide (Tolinase), glyburide (DiaBeta, Micronase), and glipizide (Glucotrol)—are all now considered unsafe during pregnancy.

The Dangers of Drugs in Pregnancy

"Why don't they first test new drugs on pregnant laboratory animals before permitting pregnant women to use them?" This question was often asked at the height of the thalidomide tragedy, and one of the results of the tragedy has been improvements in animal test procedures.

The FDA guidelines for the evaluation of new drugs for use in pregnancy, announced in 1966, were stricter and better designed than earlier FDA recommendations. The guidelines even specified that a new drug be administered to male animals to check its effect on their sperm cells and their offspring. But as more and more animal tests have been conducted, it has become increasingly apparent that their results may not always apply to humans.

That does not mean that animal tests are worthless for protecting humans. They can serve to arouse suspicion and to remind physicians of the need for caution. But no drug can be considered safe during pregnancy unless it has actually been administered to pregnant women under carefully controlled conditions, and until the babies born to these women have been carefully studied for a period of years to check for defects not diagnosable at birth or during infancy.

Since controlled experiments on pregnant women are quite properly frowned upon, the degree of hazard associated with the vast array of drugs in current use has never been adequately investigated. This is why we caution pregnant women against the use of all drugs rather than just those that have been shown to be harmful.

Some drugs prevent implantation of the fertilized ovum in the wall of the uterus, if used in sufficiently high dosage. They thus act as postcoital contraceptives if their use is begun within 72 hours after sexual intercourse. But a woman who wants to become pregnant may use a drug that could have this contraceptive effect, or other as yet undiscovered effects, during the period immediately following conception.

Accordingly, a fertile woman who is sexually active should think of herself as potentially pregnant if she does not use contraceptive measures—and if she would not wish to abort the pregnancy should conception occur. She should discuss with her physician any drug that may be prescribed and at the same time restrict her use of nonprescription drugs. In this way she would enhance the likelihood of having a healthy baby, should she become pregnant. Most fetal malformations, of course, are caused by factors other than drugs and are not easily avoided. But drug-caused malformations are avoidable.

The First Trimester

The thalidomide disaster served to focus popular attention on one kind of drug-related malformation—the kind likely to follow when a drug is taken between the third and twelfth weeks of pregnancy, in the first trimester. During these crucial weeks the fetus begins to assume recognizable form; the basic structures of the brain, heart, arms, legs, eyes, glands, and other organs are laid down day by day. As a result, the malformations produced also vary, depending on the stage of fetal development at which the drug was taken.

The FDA has warned doctors that certain minor tranquilizersmeprobamate (Equanil, Miltown), chlordiazepoxide (Librium), and diazepam (Valium)—should not be prescribed for pregnant patients. Studies have found an association between use of these drugs and fetal malformations, such as cleft lip. The FDA also ordered the manufacturers of these drugs to include a label warning against their prescription during the first trimester.

Examples of other drugs that may be hazardous in the early stages of pregnancy are over-the-counter (OTC) antinausea medications, such as meclizine (Bonine) and cyclizine (Marezine). These drugs can cause fetal abnormalities in experimental animals. Although there is no evidence of harm to human beings, pregnant or potentially pregnant women should not use them.

Other well-known medications, including anticonvulsants such as phenytoin (Dilantin), have been found to be associated with an increased frequency of congenital malformations.

All women, especially pregnant women, should be wary of metronidazole (Flagyl), a drug for treatment of a vaginal infection and sold as pills and as vaginal inserts. Studies have shown it to-be carcinogenic in laboratory animals; other studies suggest possible genetic damage. Methotrexate, a potent medication that has been prescribed for certain types of cancer as well as severe cases of psoriasis, has been shown to cause fetal malformation. Other anticancer drugs, including azathioprine (Imuran), cyclophosphamide (Cytoxan), and mercaptopurine (Purinethol), when taken in the first few months of pregnancy, have been associated with a high rate of miscarriage.

Vaccination against rubella is inadvisable for pregnant women because of a theoretical risk of fetal abnormalities, particularly when administered during the early stages of pregnancy. Women who are vaccinated against rubella should avoid becoming pregnant for at least three months following vaccination. Women who expect to become pregnant and who are concerned about whether they need vaccination against rubella should be tested for the presence of antibodies to the disease if, as is often the case, they are unsure whether they had rubella in childhood. If the blood test detects the presence of rubella antibodies, the vaccine need not be administered. Many states require this blood test of women who are planning to marry to determine their susceptibility to rubella.

Many other vaccines—including polio, typhoid fever, yellow fever, plague, and cholera—also pose a risk of infection to the developing fetus. If possible, pregnant women should avoid any vaccination for three months before pregnancy and during the first trimester. For vaccination after the first trimester, they should consult their obstetrician.

The Second Trimester

Because rubella and thalidomide—the two most publicized causes of prenatal malformations—have been identified as hazards in the first trimester of pregnancy, many people have gained the impression that drugs taken during later stages of pregnancy are harmless. Not so. While malformations arise mostly during the first three months—even before the first menstrual period is missed—hazards of other kinds can occur after that.

One authority has characterized the second trimester as "the great unknown." However, at least two examples of drug-induced damage during the second trimester can be cited. Certain hormones of the class known as progestational agents, formerly prescribed in an attempt to avert miscarriage, sometimes produce masculinizing effects such as enlargement of the clitoris in the female fetus. (Such variations can be surgically corrected.) Substances such as iodides—present in some vitamin and mineral supplements—taken during the second or third trimester may adversely affect the thyroid of the fetus.

Radioactive iodine, often used in the diagnosis of thyroid disorders, should absolutely be avoided during all stages of pregnancy because it can destroy the fetal thyroid gland. For that matter, women should avoid all forms of ionizing radiation, including X rays, during all stages of pregnancy, unless a physician determines that such X rays are warranted despite the possible risk of fetal damage. Pelvimetry by X ray (assessment of the pregnant woman's pelvis prior to delivery) has been replaced by ultrasonography, which utilizes sound waves rather than X rays. When possible, women who are potentially pregnant should schedule any essential X-ray procedures or radioactive isotope tests during the 10 days following the start of menstruation.

The Last Trimester

There are special risks at the end of pregnancy too—and even immediately following delivery of the infant. Several antibiotics may pose hazards, ranging from mild to serious, to the fetus as well as to the newborn baby. Sulfa drugs taken by the mother shortly before delivery may increase the possibility of a certain type of jaundice in the infant. The tetracycline class of broad-spectrum antibiotics may cause permanent staining of the unerupted tooth buds of the fetus. For infections that can be combatted only with antibiotics, penicillin remains safe for use in pregnancy—except, of course, for those allergic to that drug. (Erythromycin appears to be a safe alternative to penicillin—although its safety is less well demonstrated. Cephalexin, another class of antibiotic, is considered safe during pregnancy, but may pose allergic potential to those who are allergic to penicillin.)

Central nervous system depressants, such as barbiturates or narcotics, can slow the breathing of the newborn baby if taken by the mother in high doses during labor and delivery. Anticoagulants, such as warfarin (Athrombin-K, Coumadin, Panwarfin), can cause excessive bleeding in both mother and infant at time of birth and, in some instances when given earlier in the pregnancy, facial deformities in the fetus. Use of indomethacin (Indocin) and aspirin by near-term women has been implicated as contributing to pulmonary hypertension of the newborn.

Are Any Drugs Safe?

To list all the drugs now known or suspected to damage the fetus and newborn baby might lead one to falsely assume the safety of other drugs not yet adequately studied. To conclusively separate safe drugs from dangerous ones, intensive surveillance of birth defects, as well as studies of how pregnant women use drugs—both OTC and prescription—are required. There is also a theoretical possibility that some medications taken by men may affect genetic material in sperm and thus influence fetal development. Researchers have found that a diverse group of known teratogens, when given to male animals only, cause birth defects. These teratogens include alcohol, caffeine, lead, and some narcotics. So far no one is certain how substances administered to (or taken by) males can cause birth defects, or whether they actually would cause such defects in humans. A study made at the University of Vermont discussed several possibilities. For example, drugs could directly damage sperm. Pr drugs could be carried in the semen and absorbed through the vaginal walls, thus entering the bloodstream of the female and of the developing fetus. Such theories, though, remain speculative.

A special warning is warranted about the drugs commonly found in the home medicine cabinet. So generally used a drug as ordinary aspirin can interfere with the coagulation mechanism of both mother and baby at delivery. In at least one study aspirin in high dosage has also been associated with an increase in the average length of pregnancy as well as the duration of normal labor. Some learning disabilities have been observed in offspring of laboratory mice given aspirin, although there is no evidence of this in human beings.

No common home remedy, even antacid preparations, should be assumed to be completely safe during pregnancy.

Nutritional Hazards and Other Warnings

Vitamin Overdose and Deficiency Excessive doses of vitamins taken during pregnancy have been known to cause harm to the fetus. If taken in high doses, vitamin C, widely publicized both as a cold treatment and as a cold preventive, may cause scurvy in a newborn infant. This is because the large supply of ascorbic acid to which the infant has become accustomed—because of megadosing during pregnancy—is suddenly stopped at labor. High doses of pyridoxine (vitamin B6) may be associated with withdrawal seizures in the infant. Large doses of vitamin K, if administered near the delivery date, may increase the severity of jaundice in certain infants.

The hazards of excessive amounts of vitamins A and D—which exist for everyone, not just pregnant women—led the FDA in 1973 to set limits on the amounts permitted in OTC vitamin pills: 10,000 International Units for vitamin A and 400 for vitamin D. Physicians could prescribe-higher amounts. In announcing the limitation, the FDA commented that among the disorders in which excessive amounts of these vitamins have been implicated were mental and physical retardation. CU and its medical consultants are dismayed that the FDA restrictions were revoked by Congress in 1978.

There is also evidence that dietary deficiencies of certain nutrients, such as vitamin C and folic acid, may produce defects in the fetus. Many obstetricians therefore prescribe vitamins in conventional therapeutic dosages for their pregnant patients. But it is important not to exceed these dosages.

Topical Medications A word of caution is also in order concerning medicated salves, ointments, nose drops, suppositories, vaginal creams and jellies, and similar products applied to the skin. Such topical medications may contain substances that can be absorbed through the skin into the bloodstream and thus affect fetal development.

To indicate the nature of such hazards, the FDA issues guidelines for drug labels. For example, the labeling suggested by the FDA for ointments containing cortisone and related steroids is: "Although topical steroids have not been reported to have an adverse effect on pregnancy, the safety of their use in pregnancy has not-been established. Therefore, they should not be used extensively on pregnant patients, in large amounts or for prolonged periods of time."

Licit and Illicit Drugs The use of narcotics, hallucinogens, and other mood-altering drugs certainly poses hazards to the fetus. Even the socially acceptable licit drugs—caffeine, alcohol, and nicotine—have been shown to pass the placental barrier. A study conducted by the University of Washington School of Medicine and published in 1973 established a link between maternal alcoholism and birth defects. The researchers concluded that the data point to serious fetal malformations as a possible consequence of alcoholism in the mother.

In 1977 the National Institute on Alcohol Abuse and Alcoholism warned pregnant women that more than two drinks a day may harm their unborn children. The institute has stated that-more than 100 studies show a link between a pregnant woman's alcohol intake and malformed or retarded infants. One University of Southern California researcher, recommending total abstinence from alcohol during pregnancy, put the risk of fetal alcohol syndrome defects at 10 percent if a woman drinks between two and four ounces of liquor daily. The National Academy of Sciences/National Research Council's report, "Alternative Dietary Practices and Nutritional Abuses in Pregnancy," states, "No level of alcohol consumption has been established as safe for the fetus." For years, warning labels on alcoholic beverages were repeatedly proposed and considered by the federal government, but industry pressures prevented adoption of such labeling. As of November 1989, however, every bottle or can of beer, wine, wine cooler, or liquor sold in the United States will be required to carry this warning: "According to the Surgeon General, women should not drink alcoholic beverages during pregnancy because of the risk of birth defects."

Smoking Pregnant cigarette smokers have had ample notice that smoking is associated with an increased risk of fetal and infant mortality. A U.S. Public Health Service report to Congress in 1973 on health implications of smoking reviewed the available research and concluded that about 4600 stillbirths a year in the United States could probably be attributed to smoking. The report referred to a 1972 British study on women who smoked during pregnancy, which showed a 30 percent increased risk of stillborn children and a 26 percent increased risk of infant death within the first few days after birth. However, there is some evidence that women who are able to stop smoking by the fourth month of pregnancy decrease the risk. Smokers, authorities agree, tend to produce babies with a lower average birth weight than do nonsmokers. The Surgeon General's health warnings that now rotate on cigarette packages and advertising include one that reads, "Smoking by pregnant women may result in fetal injury, premature birth, and low birth weight."

Passive Smoking A study reported in 1982 from the Cleveland Metropolitan General Hospital/Case Western Reserve University showed that when a nonsmoking pregnant woman is heavily exposed to so-called secondhand smoke—that is, smoke from other people—the fetal blood contains significant amounts of tobacco smoke by-products. Although there have been no studies of the clinical effects of such passive smoking during pregnancy, the study's findings are "consistent with the possibility that passive smoking might adversely affect the fetus."

Poor Nutrition Adequate maternal nutrition is immensely important in pregnancy. Poor nutrition results in lowered birth weights and decreased growth rates for the newborn. And larger weight gains are now recommended for pregnant women that were once thought acceptable. These findings are especially important in light of some current diet fads. We strongly discourage strenuous dieting, especially low-carbohydrate regimens, during pregnancy. These may result in ketosis (the presence of ketone bodies in the blood due to incomplete burning of body fat), which has been linked with subsequent mental retardation in children born to mothers on such diets.

Food Additives It is extremely difficult to detect such abnormalities as mental retardation and behavioral defects, especially when they are minimal, and to correlate them with ingestion of substances during pregnancy. Some substances may be toxic to the fetus, and these might include a few food additives as well as drugs. Red 2, which was a widely used coloring for foods and beverages (as well as drugs and cosmetics), was judged a possible risk to the fetus, particularly in the period immediately following conception. The possibility that Red 2 might be a cancer-causing agent led the FDA in 1976 to issue a ban on its use. Another additive that may be hazardous during pregnancy is saccharin, which may accumulate in fetal tissue.

Other Hazards Hazards to pregnancy other than those induced by drugs or chemicals are outside the scope of this article, with one exception: toxoplasmosis. This parasitic infection, when contracted in pregnancy, may damage the brain and other organs of the fetus. There is evidence that the organism may be transmitted to the fetus when a pregnant woman eats undercooked meat, handles an infected cat, or tends to the cat's litter pan. Infection can occur through inhalation or from hand-to-mouth contamination. Some authorities estimate that about one-third of all adults are immune to toxoplasmosis because of previous undetected infection.

Dietary practices, environmental pollutants, emotional stress—all of these may interact to produce subtle abnormalities, some of which may not even be recognized until many years after birth. There is evidence that some serious abnormalities do indeed take years to develop. One example is the discovery of a hitherto rare type of vaginal cancer in the teenage daughters of women who took diethylstilbestrol (DES) during pregnancy in an attempt to avert miscarriage. Special techniques are required to diagnose this uncommon form of vaginal cancer. It is undetectable by the customary Pap smear test used to diagnose cervical cancer. Any DES daughter should consult a gynecologist knowledgeable on the subject. Studies of DES sons have shown nonmalignant genital abnormalities in some and evidence of impaired fertility in others.

Proposals for Reducing the Risks

Correlation between drug use, in its broadest sense, and possible damage to the fetus or the child requires a high degree of suspicion and vigilance on the part of practicing physicians. It also requires that they follow up on any suspected side effect or risk and report to the FDA what they believe to be an adverse drug reaction.

Competent authorities have made many suggestions for further reducing the risks of drugs in pregnancy. Here are five proposals CU supports.

1. Increased Understanding About Drugs in Pregnancy on the Part of Physicians and Their Patients. Shortly before the thalidomide disaster, a study made in California showed an incredible number of drugs—nearly 11,000 in all—actually prescribed by physicians to 3072 women whose pregnancies began during the 12-month period ending March 31, 1961. Only 244 of the patients (7.9 percent) went through pregnancy without a prescription; and only 563 (18.3 percent) had only one drug prescribed; 617 women received more than five drugs each; 121 women received 10 or more, and a few received 20 or more.

These totals did not include self-prescribed drugs, OTC drugs, and drugs prescribed before pregnancy that patients continued to take during pregnancy. Some prescriptions contained more than one drug ingredient. The actual number of risks was considerably higher, because one drug alone may be effective and safe but may be rendered ineffective or harmful when taken at the same time as one or more other drugs. Some of the drugs prescribed were no doubt essential for the health or well-being of the patient or her unborn baby. But many others were superfluous.

No one really knows how much more cautious physicians have since become when they write prescriptions for their pregnant patients. But the evidence is not encouraging. Based on several studies, it has been estimated that 90 percent of all pregnant women take at least one prescription medication during the course of their pregnancies.

CU supports educational programs about drugs in pregnancy—for physicians and the general public alike. Doctors should be strongly encouraged to consider the risks when prescribing or advising medication for a pregnant—or a potentially pregnant—patient. And if medication is warranted, a patient should be warned to take drugs only in prescribed amounts and for specified durations. There is urgent need for clearly worded warnings and guidelines to be prepared for distribution to pregnant women by physicians, pharmacists, clinics, and other health agencies.

2. International Cooperation in Testing. Following the thalidomide disaster, the United States, Canada, Great Britain, France, Germany, and other countries tightened up animal test procedures. In many respects, however, foreign test requirements remain less strict than the FDA guidelines. Even so, certain clinical drug studies, performed abroad under guidelines similar to FDA standards, may be acceptable as part of the FDA's review process preliminary to approval of a new drug application.

3. Primate Tests. Most new-drug tests are now performed on pregnant rats, mice, and rabbits. Would tests on monkeys or other primates more closely related to humans secure results more valid for pregnant women? No one really knows. The FDA "encourages" tests on pregnant monkeys but does not require them; they are rarely run because they are so expensive. A large-scale research program designed to determine whether primate tests are worth the extra cost is thus CU's third recommendation.

4. Reporting of Adverse Effects. The thalidomide hazard was unmasked when physicians in West Germany and Australia noted a sudden, startling increase in infant malformations of a type encountered only rarely before. Improved procedures for reporting events of this kind have been instituted. It is unlikely that if another drug like thalidomide comes along its teratogenic effects would be overlooked until 5,000 or 10,000 had been afflicted.

The recent experience with birth defects caused by the anti-acne drug isotretinoin (Accutane) demonstrates how much sooner teratogenicity is likely to be detected. In this case, the animal tests revealed the drug's potential for causing birth defects even before it was marketed. But a warning label and physician education effort proved inadequate to prevent another tragedy—although on a smaller scale than that caused by thalidomide. Between 1982 and 1986, the number of babies born with defects caused by Accutane during pregnancy was anywhere from 62 to 1300—depending on whether you accept the manufacturer's estimates (based on actual reported cases) or the FDA's (based on extrapolation from the data). In 1988, an expert advisory committee to the FDA recommended that distribution of the drug be severely restricted to make it more difficult for young women to obtain.

While the Accutane experience indicates improvement in the system for catching drug hazards during pregnancy, the problem has not been solved. The next teratogen to be discovered may not produce a dramatic and readily recognizable pattern of otherwise rare defects. The next new drug may produce mental retardation, for example, or premature birth, or some other already common misfortune. If so, it could affect thousands of babies without revealing itself; such afflictions could easily go unnoticed among the countless similar cases already occurring. What is needed as an alerting mechanism is continuous registry of the occurrence of all malformations and other perinatal conditions in an entire population. Then, if some common condition is seen to be increasing in frequency, a search for causes can be promptly undertaken.

In the United States, the Birth Defects Monitoring Program, coordinated by the Centers for Disease Control in Atlanta, keeps watch over approximately one million births yearly, based on computer data compiled from records of some 950 participating hospitals. Limitations are built into the monitoring system, however, since hospital records of newborns often may not include such information about the child's mother as age, number of previous pregnancies, and medications taken during pregnancy.

Although the program would undoubtedly discover any disaster on the scale of the thalidomide tragedy, it probably cannot detect the causes of small clusters of birth defects. The system does not provide the kinds of information necessary to establish a clear connection between birth defects and maternal drug use.

Authorities on surveillance of birth defects believe some relatively simple changes would improve the effectiveness of monitoring programs. Procedures for linking birth defects with maternal factors could probably be strengthened if terminology were standardized, hospital records were kept in a uniform fashion, and hospital admission records for infants required information about the mother.

5. Patient Package Inserts. Before any drug can be marketed, the pharmaceutical firm responsible must secure FDA approval of a "package insert" or "product information circular," which lists precautions and contraindications as well as indications, dosages, and other important data. One difficulty with package inserts as a means of alerting busy physicians to a drug's possible hazards for pregnant women has been the question of format and type size. The information about pregnancy could once have been a few words buried in a thousand words or more of small type on other subjects—an unlabeled item under "Warnings" or "Contraindications."

In 1979, new FDA regulations for prescription drug labeling required specific information about a drug's potential for possible harm to the fetus. Listed under "Precautions," a special subsection on pregnancy is now mandated for all drugs absorbed systemically and likely to affect the fetus. Such drugs are labeled according to one of five pregnancy categories—A, B, C, D, or X:

A. The possibility of fetal harm is remote. Adequate and well-controlled studies in pregnant women have shown no increase in risk of fetal abnormalities.

B. The possibility of fetal harm appears remote. Either animal tests have failed to demonstrate a risk to the fetus and there have been no human studies, or animal studies have shown some evidence of risk, but well-controlled tests with pregnant women have provided contrary evidence.

C. Benefits outweigh potential risks. Either there have been no animal or human studies demonstrating adverse effects, or animal studies have shown teratogenic effects but there have been no adequate and well-controlled studies in humans.

D. There is potential hazard to the fetus. Positive evidence of risks based on adverse reactions in humans must be weighed against potential benefit from the drug.

X. Fetal abnormalities have been demonstrated.

Labeling must also include information on the drug's nonteratogenic effects, labor and delivery, and nursing mothers.

All of the above regulations about improving package inserts deal with material addressed to physicians. CU believes that patients have a right to direct access to information about the implications of drug usage. Manufacturers have included FDA-approved package inserts prepared especially for patients in some prescription drugs. Information sheets on many other drugs are made available for physicians to distribute to their patients.

Of course, package inserts are not a panacea; the Accutane tragedy demonstrated that many women—and their physicians—may still overlook or ignore such warnings. Nevertheless, CU endorses patient package inserts and would like to see them extended to cover other medications, starting with those likely to be hazardous during pregnancy. In 1981, however, the Reagan administration withdrew federal support from the FDA-supervised patient, package insert, program, despite strong protests from CU and other consumer organizations.

Recommendations

We have stressed the drug factor in malformations and other problems of fetuses and newborns because something can be done about it right now, both by patients and by health professionals. But it is also important to keep the drug factor in proper perspective.

The great majority of malformations and other unfortunate outcomes of pregnancy are caused by factors other than drugs. And the number of infants with major congenital abnormalities is not the only crucial factor. Drug hazards should be stressed not because the ill effects are so numerous or so likely to occur, but because when they do occur they can be so devastating. And in most instances, the hazards of drug use can be so easily avoided. Pregnant women who follow the precautions listed below and whose physicians use ordinary prudence in prescribing for their patients can be assured that the risks and side effects of drugs in pregnancy will be minimized.

We recommend that the following cautions be observed by pregnant women, as well as by fertile women who engage in sexual intercourse without contraception.

• Do not take any drug unless there is a compelling medical need for it. Be especially careful in the first trimester of pregnancy and just before delivery.
• If there is a medical need, and if your physician prescribes a drug to meet that need, take it only in the amounts and at the times specified. Do not increase or reduce the dosage; do not discontinue usage sooner or continue it longer than directed. Remember that fetal health can be adversely affected by your failure to take a needed drug as well as by your use of unprescribed medication.
• A number of drugs exert their adverse effects during the first weeks following a missed menstrual period—the weeks when you may be wondering whether you are pregnant. Therefore, if pregnancy is a possibility, discontinue all self-prescribed remedies when an expected menstrual period fails to occur, and recheck with your doctor concerning drugs previously prescribed for you. (A simple blood test can now determine pregnancy on the very first day of a missed menstrual period.) If you are trying to become pregnant, be sure to inform your doctor if a drug is prescribed for you.
• During pregnancy and also during the time you may wish to become pregnant, curtail the use of OTC "home remedies," as well as nonessential prescription drugs. Even common self-prescribed medicines, such as aspirin, should be taken sparingly, if at all.
• Mothers who breast-feed their babies should continue to avoid the use of medications as much as possible. Numerous drugs taken by the mother are excreted in her milk and reach the nursing baby. If a nursing mother is prescribed a medication, she should tell her physician that she is breast-feeding her baby.
• Interpret the term drugs broadly to include many things besides oral preparations and injections—for example, lotions and ointments containing hormones or other drugs that may be absorbed through the skin, and vaginal douches, suppositories, creams, and jellies.

Luis Treacy

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