Drugs in Pregnancy and Lactation - Introduction
Pregnancy and Drugs
Until the middle of the 20th century, most physicians believed that the uterus provided a protected environment for the fetus and served as a shield from the external environment. This belief was questioned in 1941 when an Australian physician, N.M. Gregg, observed that women who contracted rubella during the first trimester of pregnancy frequently gave birth to infants with specific anatomic defects, mainly in the heart, eyes, and ears. This finding forever shattered the concept held previously, and it became clear that the external environment could affect fetal outcome. It is now generally accepted that the developing fetus may be adversely affected by exposure to drugs and environmental chemicals. The stage of development of the intrauterine host is a major determinant of the resultant effect, as are the nature and the concentration of the drug or chemical agent. On a more positive note, fetal therapy (i.e., treatment of fetal disease in utero by administering the drug to the mother or directly to the fetus) has been recognized recently as a rational approach to treat fetal disease.
With rare exception, all foreign compounds are transmitted across the placenta and, depending upon their lipid solubility and chemical structure, achieve varying concentrations in the embryo and fetus. Unfortunately, drug use during pregnancy continued unaffected by Gregg's observations. During the several decades following Gregg's report in 1941, most concerns regarding drug effects upon the embryo and fetus had to do with the perinatal period, particularly with the effect of narcotics and analgesics on the ability of the newborn infant to initiate and sustain respiration following delivery.
In 1948, Professor O. Smith at the Boston Lying in Hospital introduced diethylstilbestrol (DES; a synthetic estrogen) into medical practice as a treatment for the complications of early pregnancy. This therapy, although not validated, was widely adopted. Twenty-three years later, the consequences of this unapproved therapy came to light with the establishment of a relationship between adenocarcinoma of the vagina and in utero exposure to DES. In many ways, the discovery of the adverse effects of DES was fortuitous. Since adenocarcinoma of the vagina in young females had been a rare disease, the causal role of DES was relatively readily elucidated. If maternal therapy with DES had been the cause of an increase in the incidence of some relatively more common adolescent disease, such as diabetes, the relationship would still be undetected today. The adverse effects of DES also serve as an example of long-term delayed effects of in utero drug and chemical exposure, which are difficult to recognize but must always be considered when evaluating drug and chemical exposure during pregnancy.
Then, 40 years ago, the thalidomide catastrophe (limb defects) occurred when this drug was administered to pregnant women as an antianxiety agent during the first trimester. Thalidomide had been evaluated for safety in several animal species, had been given a clean bill of health, and had come to be regarded as a good pharmacologic agent (hypnotic/sedative). It is of interest that this drug is being reevaluated for use in leprosy and approval for this use has been given by the Food and Drug Administration (FDA).
It is important to note that, even though thalidomide induces a distinct cluster of anatomic defects that are virtually pathognomonic for this agent, it required several years of thalidomide use and the birth of many thousands of grossly malformed infants before the cause-and-effect relationship between thalidomide administration in early pregnancy and its harmful effects was recognized. This serves to emphasize the difficulties that exist in incriminating drugs and chemicals that are harmful when administered during pregnancy. Hopefully, we will never have another drug prescribed for use during pregnancy whose teratogenicity is as potent as thalidomide (about one-third of women taking this agent during the first trimester gave birth to infants with birth defects).
Concern about the safety of foreign compounds administered to pregnant women has been increasingly evident since thalidomide. The direct response to this misadventure led to the promulgation of the drug regulations of 1962 in the United States. According to these regulations, a drug must be demonstrated to be safe and effective for the conditions of use prescribed in its labeling. The regulations concerning this requirement state that a drug should be investigated for the conditions of use specified in the labeling, including dosage levels and patient populations for whom the drug is intended. In addition, appropriate information must be provided in the labeling and be available when the drug is prescribed. The intent of the regulations is not only to ensure adequate labeling information for the safe and effective administration of the drug by the physician, but also to ensure that marketed drugs have an acceptable benefit:risk ratio for their intended uses.
In August of 1962, the same year as the congressional revision of the Food and Drugs Laws mentioned above, the Commission on Drug Safety was established with a grant from the Pharmaceutical Manufacturers Association. The commission represented the concern of the pharmaceutical industry regarding adverse effects of drugs administered to pregnant women. The commission served as an independent body of academicians to offer advice regarding the prenatal effects of drugs. Under the chairmanship of Dr. Lowell Coggeshiall, Vice President of the University of Chicago, 13 scientists reported in 1963 after subcommittee deliberation concerning methods to evaluate the safety of drugs administered to the pregnant woman. Their main conclusions are valid today. In general, they agreed that animal tests do not guarantee drug safety to the unborn child, but should not be abandoned because they do offer some insight into adverse effects in the human. The group also strongly endorsed basic and analytical research to support the current (1963) existing empirical approaches to the evaluation of drug safety.
It is clear that any drug or chemical substance administered to the mother is able to cross the placenta to some extent unless it is destroyed or altered during passage or its molecular size and low lipid solubility limit transplacental transfer. Placental transport of maternal substrates to the fetus and of substances from the fetus to the mother is established at about the fifth week of fetal life. Substances of low molecular weight diffuse freely across the placenta, driven primarily by the concentration gradient. It is important to note, therefore, that almost every substance used for therapeutic purposes can and does pass from the mother to the fetus. Of greater importance is whether the rate and extent of transfer are sufficient to result in significant concentrations within the fetus. Today, the concept of a placental barrier must be discarded.v
Experiments with animals have provided considerable information concerning the teratogenic effects of drugs. Unfortunately, these experimental findings cannot be extrapolated from species to species, or even from strain to strain within the same species, much less from animals to humans. Research in this area and the prediction of toxicity in the human are further hampered by a lack of specificity between cause and effect.
Traditionally, teratogenic effects of drugs have been noted as anatomic malformations. It is clear that these are dose and time related and that the fetus is at greater risk during the first 3 months of gestation. However, it is possible for drugs and chemicals to exert their effects upon the fetus at other times during pregnancy. Functional and behavioral changes are much more difficult to identify as to cause and effect. Consequently, they are rarely recognized. A heightened awareness on the part of health providers and recipients will make this task easier.
The mechanisms by which drugs exert teratogenic effects are poorly understood, particularly in the human. Drugs may affect maternal receptors with indirect effects upon the fetus, or they may have a direct effect on embryonic development and result in specific abnormalities. Drugs may affect the nutrition of the fetus by interfering with the passage of nutrients across the placenta. Alterations in placental metabolism influence the development of the fetus since placental integrity is a major determinant of fetal growth. It is noteworthy that the National Institute of Child Health and Human Development (NICHD) has launched a major initiative regarding the molecular mechanisms responsible for deviations in normal development resulting in birth defects. This effort in 2000, combined with a previous (1998) initiative, should lead to an in-depth understanding of drug- and chemical-induced malformations, and in turn enable preventive endeavors.
Administration of a drug to a pregnant woman presents a unique problem for the physician. Not only must maternal pharmacologic mechanisms be taken into consideration when prescribing a drug, but the fetus must always be kept in mind as a potential recipient of the drug.
Recognition of the fact that drugs administered during pregnancy can affect the fetus should lead to decreased drug consumption. Nonetheless, studies conducted in the past few years indicate that drug consumption during pregnancy is increasing. This may be due to several reasons. Most people in the western world are unaware of their drug and chemical exposure. Many are uninformed as to the potentially harmful effects of drugs on the fetus. Also, there are some who feel that many individuals in modern society are overly concerned with their own comfort, so that pregnant women seek pharmacologic solutions to the many symptoms that affect them.
Although considerable attention has been given recently to illegal drug use during pregnancy, use of legal drugs, both prescription and over-the-counter, continues with little apparent diminution. УMost medicines taken by or administered to pregnant women cross the placenta and into the blood stream of the fetus. Thus, when a pregnant woman takes medicine, she not only gives medicine to herself but is also giving the same medicine to her unborn baby. Since the not-fully-developed body systems of the fetus cannot process medicines as the mother's systems do, and since some medicines may affect normal development of the fetus, medicines that cross the placenta may have negative effects on the fetus and newborn. One only has to remember the thalidomide disaster to recognize the possible extent of the potential problemsФ (UNICEF: Drug use in pregnancy. The Prescriber, January 1992). The World Health Organization (WHO) has completed an international survey on drug utilization during pregnancy involving 14,778 pregnant women from 22 countries on four continents. Eighty-six percent of these women took medication during pregnancy, receiving an average of 2.9 (range 1Ц15) prescriptions. This survey did not take into account over-the-counter drugs purchased without the advice of a physician or a prescription. Of the total 37,309 prescriptions in the WHO survey, 73% were given by an obstetrician, 12% by a general practitioner, and only 5% by a midwife. This extremely high drug prescription and utilization rate during pregnancy is then elevated by an increase in drug administration during the intrapartum period, wherein, according to the WHO survey, 79% of the women received an average 3.3 drugs. The WHO survey concludes: УThere can be no doubt that at present some drugs are more widely used in pregnancy than is justified by the knowledge available. This may be one aspect of the medicalization of pregnancy, a process in which the use of a series of techniques and drugs is associated even with normal pregnancies, the employment of one technique or drug readily leading to the use of another. It would seem that whereas pregnancy is usually regarded as dangerous until proven safe, drugs may be regarded as safe in pregnancy provided they have not been proven dangerous, views which are often diametrically opposed to realityФ (Collaborative Group on Drug Use in Pregnancy. An international survey on drug utilization during pregnancy. International Journal of Risk and Safety in Medicine, 1991;1:1). These recent pronouncements are quoted to demonstrate that drug u se in pregnancy continues without letup and most often without a specific rationale, except to treat the many symptoms that accompany the normal pregnancy.
The FDA has proposed significant changes in pregnancy labeling. This will clarify for both the prescribing physician and the patient the risks associated with the administration of an individual drug or chemical to the pregnant woman. Much more information is needed to make pregnancy labeling more meaningful. To this end, the FDA has proposed a new regulation (2001) requiring drug manufacturers to report safety data to a central registry. This regulation, currently under review, will provide the practitioner with significantly more drug safety information.
It is crucial that concern also be given to events beyond the narrow limits of congenital anatomic malformations; evidence exists that intellectual, social, and functional development also can be adversely affected by drug administration during pregnancy. There are examples indicating that toxic manifestations of intrauterine exposure to environmental agents may be subtle, unexpected, and delayed. Concern for the delayed effects of drugs, after intrauterine exposure, was first raised following the tragic discovery that female fetuses exposed to DES are at an increased risk for adenocarcinoma of the vagina (see above). This type of malignancy is not discovered until after puberty. Additional clinical findings indicate that male offspring were not spared from the effects of the drug. Some have abnormalities of the reproductive system, such as epididymal cysts, hypotrophic testes, capsular induration, and pathologic semen.
The concept of long-term latency has been confirmed by investigations conducted previously in our research laboratories at the Children's Hospital of Philadelphia. When the widely used hypnotic/sedative agent phenobarbital was administered to pregnant rats, the offspring were significantly smaller than normal and they experienced delays in vaginal opening. Sixty percent of the females exposed to phenobarbital in utero were infertile.
In male animals, we found lower than normal testosterone levels in the brain and bloodstream of male rats whose mothers were given low doses of phenobarbital late in pregnancy. Even at 120 days of age, these male rats showed abnormal testosterone synthesis, the mechanism responsible for the low concentrations. It is believed that phenobarbital exposure in fetal life may alter brain programming, resulting in permanent changes in sexual function. Phenobarbital is an old drug that is widely prescribed. It is also a component of many multiingredient pharmaceuticals whose use does not abate during pregnancy. The clinical significance of these experiments in animals is admittedly unknown, but the striking effects upon reproductive function warrant careful scrutiny of the safety of these agents during human pregnancy before prescribing them.
The physician is confronted with two imperatives in treating the pregnant woman: alleviate maternal suffering and do no harm to the fetus. Until now the emphasis has been on the amelioration of suffering, but the time has come to concentrate on not harming the fetus. The simple equation to be applied here is to weigh the therapeutic benefits of the drug to the mother against its risk potential to the developing fetus. Since fetal ova may also be exposed to drugs given to the mother, effects may be evident in future generations.
When one considers that more than 1.2 billion drug prescriptions are written each year, that there is unlimited self-administration of over-the-counter drugs, and that approximately 500 new pharmaceutical products are introduced annually, the need for prudence and caution in the administration of pharmaceuticals has reached a critical point. Pregnancy is a symptom-producing event. Pregnancy has the potential of causing women to increase their intake of drugs and chemicals, with the possibility that the fetus will be nurtured in a sea of drugs.
In today's society, the physician cannot stand alone in the therapeutic decision-making process. It now has become the responsibility of each woman of childbearing age to consider carefully her use of drugs. In a pregnant woman, the decision to administer a drug should be made only after a collaborative appraisal between the woman and her physician of the risk:benefit ratio.
Breast Feeding and Drugs
Between 1930 and the late 1960s, there was a dramatic decline in the percentage of American mothers who breast-fed their babies. This was also accompanied by a reduction in the length of breast feeding for those who did nurse. The incidence of breast feeding declined from approximately 80% of the children born between 1926 and 1930 to 49% of children born some 25 years later. For children born between 1966 and 1970, 28% were breast-fed. Indeed, in 1972 only 20% of newborns were breast-fed. As data have become available for the following years, it is clear the decline has been reversed. By 1975, the percentage of first-born babies who were breast-fed rose to 37%. At the present time in the United States, a number of surveys indicate that more than 50% of babies discharged from the hospital are breast-fed, and the number is increasing. Breast feeding is difficult to contemplate, since more than 50% of mothers work and return to work soon after delivery. New solutions must be found by employers to encourage breast feeding and develop the logistics to enable employees to breast-feed on the job.
Any number of hypotheses can be made regarding the decline and recent increase in breast feeding in this country. A fair amount of credit can be given to biomedical research of the past 15 years that has demonstrated and publicized the benefits of breast feeding.
Breast milk is known to possess nutritional and immunologic properties superior to those found in infant formulas. An American Academy of Pediatrics position paper emphasizes breast feeding as the best nutritional mode for infants for the first 6 months of life. In addition to those qualities, studies also suggest significant psychologic benefits of breast feeding for both the mother and the infant.
The upswing in breast feeding, together with a markedly increased concern about health needs on the part of parents, has led to increased questioning of the physician, pharmacist, and other health professionals about the safety and potential toxicity of drugs and chemicals that may be excreted in breast milk. Answers to these questions are not very apparent. Our knowledge concerning the long- and short-term effects and safety of maternally ingested drugs on the suckling infant is meager. We know more now than Soranus did in 150 AD, when he admonished wet nurses to refrain from the use of drugs and alcohol, lest it have an adverse effect on the nursing infant. We must know more! The knowledge to be acquired should be specific with respect to dose administered to the mother, amount excreted in breast milk, and amount absorbed by the suckling infant. In addition, effects on the infant (both acute and chronic) should be determined.
It would be easy to recommend that the medicated mother not nurse, but it is likely that this recommendation would be ignored by the mother and may well offend many health providers, as well as their patients, on both psychosocial and physiologic grounds.
It must be emphasized that many of the investigations concerned with milk secretion and synthesis have been carried out in animals. The difficulty in studying human lactation using histologic techniques and the administration of radioactive isotopes is obvious. There are considerable differences in the composition of milk in different species. Some of these differences in composition would obviously bring about changes in drug elimination. Of great importance in this regard are the differences in the pH of human milk (pH usually >7.0) as contrasted to the pH of cow's milk (pH usually < 6.8), in which drug excretion has been extensively studied.
Human milk is a suspension of fat and protein in a carbohydrate-mineral solution. A nursing mother easily makes 600 mL of milk per day, which contains sufficient protein, fat, and carbohydrates to meet the nutritional demands of the developing infant. Milk proteins are fully synthesized from substrates delivered from the maternal circulation. The major proteins are casein and lactalbumin. The role of these proteins in the delivery of drugs into milk has not yet been completely elucidated. Drug excretion into milk may be accomplished by binding to the proteins or onto the surface of the milk fat globule.
There also exists the possibility for drug binding to the lipid, as well as to the protein components of the milk fat globule. It is also possible that lipid-soluble drugs may be sequestered within the milk fat globule. In addition to lipids and protein, carbohydrates are entirely synthesized within the breast. All of these nutrients achieve a concentration in human milk that is sufficient for the needs of the human infant for the first 6 months of life.
The transport of drugs into breast milk from maternal tissues and plasma may proceed by a number of different routes. In general, however, the mechanisms that determine the concentration of drug in breast milk are similar to those existing elsewhere within the organism. Drugs traverse membranes primarily by passive diffusion, and the concentration achieved will be dependent not only on the concentration gradient but also on the intrinsic lipid solubility of the drug and its degree of ionization, as well as on binding to protein and other cellular constituents.
A number of reviews give tables of the concentration of drugs in breast milk. Many times these tables also give the milk:plasma ratio. Most of the values from which the tables are derived consist of a single measurement of the drug concentration. Important informationЧsuch as the maternal dose, the frequency of dosing, the time from drug administration to sampling, the frequency of nursing, and the length of lactationЧis not given.
The significance of these concentration tables means only that the drug is present in the milk, and they offer no advice to the physician. Because the drug in the nursing infant's blood or urine is not measured, we have little information about the amount that is actually absorbed by the infant from the milk and, therefore, have no way of determining the possible pharmacologic effects on the infant. In fact, a critical examination of the tables that have been published reveals that much of the information was gathered decades ago when analytic methodology was not as sensitive as it is today. Since the discipline of pharmacokinetics was not developed until recently, many of the studies quoted in the tables of the review articles do not look precisely at the time relationship between drug administration and disposition.
Certain things are evident with regard to drugs administered during lactation. It is necessary that physicians become aware of the results of animal studies in this area and of the potential risk of maternal drug ingestion to the suckling infant. Many drugs prescribed to the lactating woman need to be thoroughly studied in order to assess their safety during lactation. It is clear that, if the mother needs the drugs for therapeutic purposes, then she should consider not nursing. The ultimate decision must be individualized according to the specific illness and the therapeutic modality. Nursing should be avoided following the administration of radioactive pharmaceuticals that are usually given to the mother for diagnostic purposes.
The situation with the excretion of drugs into human breast milk might well be considered analogous to that of the prethalidomide era, when the effects on the fetus from maternally ingested drugs were recognized only as a result of a catastrophe. Objective evaluation of the efficacy and safety of drugs in breast milk must be undertaken. Until such data are available, the physician should always weigh the risk:benefit ratio when prescribing any maternal medication. It is also obligatory upon the nursing mother to become aware of the same factors and apply a measure of self-control before ingesting over-the-counter drugs. As stated before, it is quite evident that nearly all drugs will be present in breast milk following maternal ingestion. It is prudent to minimize maternal exposure, although very few drugs are currently known to be hazardous to the suckling child. If, after examining the risk:benefit factor, the physician decides that maternal medication is necessary, drug exposure of the infant may be minimized by scheduling the maternal dose just after a nursing period. More often than not, just as in pregnancy, drugs are prescribed to the nursing mother for the relief of symptoms that do not require drug therapy. If mothers were apprised by their physicians of the potential risk to their infants, most would probably endure the symptoms, rather than take the drug and discontinue breast feeding.
Two basic situations are dealt with throughout this book: (a) risk potential to the fetus of maternal drugs ingested during the course of pregnancy and (b) risk potential to the infant of drugs taken by the mother while nursing.
The obvious solution to fetal and nursing infant risk avoidance is maternal abstinence. However, from a pragmatic standpoint, that would be impossible to implement. Another solution is to disseminate knowledge, in an authoritative manner, to all those involved in the pregnancy and breast feeding processes: physician, mother, midwife, nurse, father, and pharmacist.
This site helps to fill a communication and information gap. We have carefully evaluated the research literature, animal and human, applied and clinical. We have established a risk factor for each of the nearly 900 drugs, in keeping with the FDA guidelines, that may be administered during pregnancy and lactation. This will be changed as new labeling guidelines are promulgated. We believe that this book will be helpful to all concerned parties in developing the risk:benefit decision.
This is but a beginning. It is our fervent hope that the information gained from the use of this book will cause the concerned parties to be more trenchant in their future decision making, before either prescribing or ingesting drugs during pregnancy and lactation.