Drugs in Pregnacy and Lactation, 6th edition: Gerald G Briggs BPharm, Roger K
.... One of the pleasures of writing a book is the opportunity to thank, in print, the ...
The adverse effects of DES also serve as an example of long-term delayed ...
Drugs in Pregnacy and Lactation, 6th edition: Gerald G Briggs BPharm, Roger K Freeman MD, Sumner J Yaffe MD By Lippincott Williams & Wilkins Publishers (November 2001)
By OkDoKeY
Drugs in Pregnancy and Lactation Contents Author Dedication Foreword Roger K. Freeman, M.D. Preface Introduction Sumner J. Yaffe, M.D. Instructions for Use of the Reference Guide
Appendix
A B C
GERALD G. BRIGGS, B.PHARM. Pharmacist Clinical Specialist, Women’s Hospital Long Beach Memorial Medical Center, Long Beach, California Clinical Professor of Pharmacy University of California, San Francisco Adjunct Associate Clinical Professor of Pharmacy University of Southern California, Los Angeles ROGER K. FREEMAN, M.D. Director, Obstetrics/Gynecology/Normal Newborn Careline Women’s Hospital Long Beach Memorial Medical Center, Long Beach, California Clinical Professor of Obstetrics and Gynecology University of California, Irvine SUMNER J. YAFFE, M.D. Visiting Professor Departments of Pediatrics and Obstetrics School of Medicine University of California, Los Angeles
IN MEMORY Carol Briggs April 26, 1907—December 12, 1999 She led a full life: wife, mother of 5, grandmother of 13, and great-grandmother of 10. Although she had a steely determination and could be stubborn when she knew she was right, the traits that I will always hold dear were her absolute faith in her children and her ever-present smile.
Foreword This book is now in its sixth edition, and has enjoyed great success with physicians and other professionals involved in the care of pregnant and lactating patients. There are more than 100 drugs listed additional to those in the fifth edition, and updates are provided where indicated on all drugs in the book. The reviews are exhaustive, but pertinent to the management of pregnant and lactating patients who have already ingested a drug or who are in need of drug therapy where a cost-benefit analysis may be necessary for appropriate counseling. There are seldom absolute answers to questions a woman may have when she ingests a drug while pregnant or nursing, since human experience is usually, of necessity, somewhat anecdotal. Even though a drug may not show a problem among a large group of exposed patients, one can never rule out individual susceptibility, making the dictum of not using drugs in pregnancy without good cause still important. The effect or lack of effect in animals does not necessarily translate to human risks or safety, resulting in the persistent need to consider both animal and human studies when counseling exposed patients or selecting appropriate drugs for use in pregnant and lactating patients. It is our hope that the sixth edition will continue to provide the practitioner appropriate assistance with questions regarding drugs in pregnancy and lactation. Roger K. Freeman, M.D. Director, Obstetrics/Gynecology/Normal Newborn Careline Women’s Hospital Long Beach Memorial Medical Center Long Beach, California Clinical Professor of Obstetrics and Gynecology University of California, Irvine
Preface With this edition, we start the third decade of work on a never-ending project. It seems appropriate to recall something that we wrote in the very beginning. The first preface, written in 1980–1982 and published in 1983, opened with: “We have always been amazed by the number of drugs and chemicals the fetus is exposed to during its nine month sojourn in the womb. Perhaps just as surprising is the realization that in spite of this chemical bath, the vast majority of newborns enter the world with the correct number of parts, all functioning properly.” After 20 plus years, I am still “amazed” by the number of exposures and still “surprised” by the number of normal outcomes. All new drugs must undergo reproductive testing in animals for teratogenicity and embryo/fetal toxicity, but, rightly so, none are formally studied in this way in human pregnancy. Therefore, we must rely on a variety of information sources to estimate the risk a specific agent presents to a human fetus. These sources include animal reproductive tests, human experience with other similar drugs, and reports and studies of inadvertent or planned exposure in human pregnancies. Of course, this latter data source is, in many ways, an unregulated human experiment, with each patient sometimes acting as her own control. Although teratogenicity and/or toxicity are not the planned outcomes, they are sometimes the end result. Fortunately, there are few therapeutic agents, perhaps 40–50 (from about 16 pharmacologic classes), that can be called “possible or probable human teratogens.” Since the publication of the first edition, a number of additional drugs or classes of drugs have been identified as human teratogens: angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, carbamazepine, fluconazole (high dose), systemic corticosteroids, misoprostol, vitamin A and its derivatives (isotretinoin and etretinate), and methimazole. These and the previously identified human teratogens make up a very short list compared with the thousands of drugs and chemicals that women are exposed to during pregnancy. Even the addition of abuse drugs adds only a few agents to the list (e.g., alcohol, cocaine, cigarette smoking, and toluene inhalation). So how does a pregnant woman protect her developing infant from these agents? Obviously, information is an important element. For three professional organizations, the Teratology Society, the Organization of Teratology Information Services (OTIS), and the European Network of Teratology Information Services (ENTIS), a primary function is providing information to health professionals and the public to prevent teratogenicity and embryo/fetal toxicity. The latter two organizations are also actively involved in conducting studies of human pregnancy exposures to identify new teratogens. Both the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) collect and disseminate data on the effects of drugs on the embryo/fetus. Hundreds of reports from researchers describing human pregnancy exposure and outcomes resulting from these exposures are published in professional journals every year. Several books, including this one, and electronic databases summarize these reports so that they are conveniently available in one source to anyone interested. Health professionals (physicians, genetic counselors, pharmacists, and nurses) routinely provide information daily to the public on the risks of drugs in pregnancy. Drug manufacturers conduct and publish postmarketing surveillance studies on their products, include information in their package inserts, and send out “Dear Doctor” and “Dear Health Professional” letters. Moreover, as directed by the FDA, human pregnancy information in the package insert is undergoing a major transformation and will soon be much more informative. In some cases, manufacturers have erected elaborate barriers to keep especially toxic drugs away from pregnant women (e.g., isotretinoin, thalidomide) or have developed methods to reduce the amount of drugs reaching the embryo after inadvertent exposure (e.g., leflunomide). But, in spite of this information blitz, we continue to see reports on exposures to toxic agents and the resulting adverse pregnancy outcomes. So, how effective are these efforts? I don’t have an exact answer, but I do know there has not been another human reproduction catastrophe of the magnitude witnessed 40 years ago with the thalidomide tragedy. Considering the millions of pregnancies that occur every year in the world, the information blitz appears to have been very effective. No one writes about the countless, potentially hazardous exposures that are prevented each day by health professionals and others using information from one or more sources. Of course, there are lapses and weaknesses in the system, and we can do better in reducing the number of preventable poor outcomes. But from my point of view and the experiences related to me by others, the record should indicate that the public is being very well served. An important milestone occurred just before this edition went to press. For the first time since the partnership was formed in 1980, all three of the authors of this book are in the same time zone and in the same state. Although we have had close communication with each other over the past two decades, the fact that we are within one hour’s drive of each other will make our contacts that much easier. One of the pleasures of writing a book is the opportunity to thank, in print, the individuals who have assisted in producing an edition. A number of persons have sent me references and suggestions on how to improve this book. To all, thank you for your thoughtful comments and your efforts to keep me abreast of the current literature. In addition, many health professionals and patients have asked me questions about drug exposures in pregnancy or lactation. These inquiries have been very helpful in that they served to inform us of your information needs and have often led to the preparation of new reviews. Our appreciation and thanks also go to Dr. Kenneth Lyons Jones for his constructive critique of the thalidomide review. As usual, the library staff at Long Beach Memorial Medical Center continues to be very helpful in retrieving references. The Drug Information Service staff at Memorial (Dr. Susan Van Campen and Dr. Suk Lange) and Dr. Carl Kildoo, the Director of Inpatient Pharmacy Services, have also provided much-appreciated assistance. A sincere thank you is also due my wife, Susan. Without her constant assistance, support, and encouragement, this edition would not have been completed. Finally, I gratefully acknowledge the assistance of Dr. Ema Ferreira, Pharm.D., M.S., who spent a portion of her clinical pharmacy residency with me, and that of my former students (listed below) in the preparation of some of the material that either appears in this edition or will be published in the near future: Kristan Aoki, Pharm.D.; Dawnelle Borkey, Pharm.D.; Dorcas Huang, Pharm.D.; Lisa Kim, Pharm.D.; Suzanne Nazareth, Pharm.D.; Johnny Reyes, Pharm.D.; Mina Solhjou, Pharm.D.; Kelly Tran, Pharm.D.; Susan Van Campen, Pharm.D.; and Linh Vuong, Pharm.D. Gerald G. Briggs, B.Pharm. Pharmacist Clinical Specialist Women’s Hospital Long Beach Memorial Medical Center Long Beach, California
Introduction Drugs in Pregnancy and Lactation
Introduction Sumner J. Yaffe, M.D. Pregnancy and Drugs Breast Feeding and Drugs Conclusions
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. 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. “Most 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 problems” (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 1–15) 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: “There 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 reality” (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 Fetal Risk Summary Acitretin, an oral active synthetic retinoid and vitamin A derivative, is the active metabolite of etretinate (see also Etretinate). It is used for the treatment of severe psoriasis resistant to other forms of therapy and for severe congenital ichthyosis and keratosis follicularis (Darier's disease). Similar to vitamin A and its derivatives, acitretin may cause congenital defects at human dosage levels in various animal species, including the mouse, rat, and rabbit (1). Fertility of rats was not impaired at the highest dose tested (3 mg/kg/day, or about 3 times the maximum recommended human dose). Chronic administration to male dogs (30 mg/kg/day) produced testicular changes: reversible mild to moderate spermatogenic arrest and the appearance of multinucleated giant cells (1). After oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to 13-cis-acitretin (1). When consumed with alcohol, acitretin may be converted back to etretinate, a retinoid with a very long elimination half-life (mean 120 days, but may be as long as 168 days). Because the prolonged elimination would increase the teratogenic potential for women of childbearing age (see also Etretinate), the manufacturer states that alcohol must not be ingested during therapy with acitretin and for 2 months after cessation of therapy because of the long elimination period of acitretin (1). In a 1994 reference, the concentrations of etretinate, acitretin, and 13-cis-acitretin were measured in plasma and subcutaneous fat samples from 37 women of childbearing age (2). Twenty of the women were receiving acitretin and 17 had stopped. Sixteen of the 20 women, current acitretin users, had taken etretinate, but had stopped that drug a mean 45 ± 17 months before sampling, whereas four women had never received etretinate. Among current acitretin users, detectable etretinate levels in the plasma and subcutaneous fat were found in 45% and 83%, respectively. The 17 women who had stopped taking acitretin had been off the drug a mean 12 ± 10 months. Eleven of these women had also used etretinate but had stopped a mean 43 ± 14 months before sampling. The six women who had never taken etretinate stopped acitretin 17 ± 9 months before testing. Among these 17 women, etretinate was detected in 18% and 86%, respectively, of the plasma and subcutaneous fat samples. In some cases, acitretin and/or etretinate were detectable in plasma or subcutaneous fat up to 29 months after acitretin therapy had ceased. Thus, plasma concentrations correlated poorly with concentrations in fat. The findings led the authors to conclude that the recommended contraception period of 2 years after acitretin treatment (in 1994) was too short to avoid the risk of teratogenicity (2). Currently, the manufacturer recommends a contraception period of 3 years, but the human threshold concentration of acitretin below which the drug is not teratogenic has not been established (1). A detailed case report of a pregnancy exposed to acitretin starting 10 days after conception and throughout the 1st trimester was published in 1995 (3). The 34-year-old woman was treated with acitretin (50 mg/day) for severe palmoplantar epidermolytic keratoderma. Pregnancy was diagnosed 6 weeks after stopping acitretin therapy. The pregnancy was terminated at 20 weeks' gestation with delivery of a stillborn, 210-g, 24-cm long male fetus with severe symmetric defects of the upper and lower limbs and craniofacial malformations (3). The extremity defects included bilateral short arms with pterygium formation in the elbows, shortened thumbs and little fingers without nails, contractures of both lower limbs in the groins and knees, irregularly thickened femora and tibiae, and point-shaped feet with only two small toes without nails (3). X-ray of the limbs revealed bilateral humeroradial synostosis and bone defects in the hands and feet. Craniofacial malformations included underdeveloped maxilla and mandibula, a small mouth with a high, arched and narrow palate, low-set ears, bilateral microtia, agenesis of the external ear canals, and bilateral preauricular tags (3). Except for an atrioventricular septal defect type II, no other anomalies were discovered on autopsy. Concentrations of acitretin, 12-cis-acitretin, and etretinate, in the maternal plasma, fetal brain and liver, and amniotic fluid 48 days after stopping therapy, were either undetectable (38.5°C without apparent cause) between 2 and 6 weeks of age. The hypertrichosis, which was much less prominent at 2 months of age, is a known adverse effect of minoxidil therapy in both children and adults, and the condition in this infant was thought to be caused by that drug. The cause of the other defects could not be determined, but a chromosomal abnormality was excluded on the basis of a normal male karyotype (46,XY), determined after a midgestation amniocentesis (11). One case involved a mother with polyarteritis nodosa treated throughout gestation with captopril, hydralazine, and furosemide (12). The pregnancy was electively terminated at approximately 31 weeks' gestation because of worsening maternal disease. A normal, non-growth-retarded infant was delivered who did well in the neonatal period (12). Oligohydramnios developed after 3 weeks of therapy with captopril in a woman who was treated at 25 weeks' gestation (13). Cesarean section at 29 weeks' gestation produced a 1040-g infant with dehydration, marked peripheral vasodilation, severe hypotension, respiratory distress, and anuria. Epidermolysis of the trunk and extremities appeared after birth. Diagnostic studies indicated a normal bladder, but neither kidney was perfused. ACE activity was reported as very low. The infant died on day 8 as a result of persistent anuria. At autopsy, hemorrhagic foci were discovered in the renal cortex and medulla, but nephrogenesis was adequate for the gestational age. A woman was treated at 27 weeks' gestation with daily doses of captopril (200 mg), labetalol (1600 mg), and furosemide (80 mg) (14). Fourteen days after treatment was begun, signs of fetal distress, attributed to the maternal hypertension, appeared and the infant was delivered by cesarean section. No adverse effects of the drug treatment were observed in the infant (14). Captopril and acebutolol were used throughout pregnancy to treat a woman with nephrotic syndrome and arterial hypertension (15). Intrauterine growth retardation (IUGR), most probably because of the severe maternal disease (although a contribution from drug therapy could not be excluded), was identified early in the 2nd trimester and became progressively worse. The growth-retarded male infant was delivered prematurely at 34 weeks by cesarean section. Captopril was found in the cord blood with levels in the mother and fetus less than 100 ng/mL, 4 hours after the last dose. Angiotensin-converting enzyme activity was below normal limits in both the mother and the newborn. Neonatal respiratory arrest occurred 15 minutes after delivery with varying degrees of hypotension persisting over the first 10 days. A patent ductus arteriosus was also present (15). A woman with hypertension secondary to bilateral renal artery stenosis was treated with captopril, 150 mg/day, beginning 6 weeks before conception (16). Daily drug therapy during pregnancy consisted of captopril (600 mg), methyldopa (750 mg), and furosemide (80 mg). Oligohydramnios and IUGR were diagnosed at 35 weeks' gestation, at which time a cesarean section was performed to deliver the 2120-g male infant. Some of the abnormalities in the infant, such as pulmonary hypoplasia, small skull circumference (28.5 cm,110 mm Hg immediately before delivery (15). The mean gestational age in both groups was 36 weeks (range 32–40 weeks). The epoprostenol infusion was started at 0.5 ng/kg/minute and was increased to a maximum of 10 ng/kg/minute within 120 minutes, if needed to control the blood pressure. The initial dihydralazine dose was 0.5 mg/kg/minute and increased to a maximum of 1.5 mg/kg/minute, if needed. Both drugs were continued for 24 hours after delivery and during delivery for those requiring cesarean section. Increases in maternal pulse rate occurred in both groups, but the rise in the epoprostenol patients (6 bpm) was significantly less than the rise with dihydralazine (22 bpm) (p=0.0024). Blood pressures were reduced in both groups, but the difference between them was not significant. Cesarean sections were performed in 13 (60%) (11 for FHR decelerations) of the epoprostenol group and in 20 (80%) (14 for FHR decelerations) of those receiving dihydralazine (difference not significant). One neonatal death occurred in each group, but neither was related to the drug therapy (15). A brief 1992 communication reported the treatment of a 35-year-old woman with thrombotic microangiopathy superimposed on preeclampsia at about 26 weeks' gestation (16). Epoprostenol was started at 2 ng/kg/minute and increased to 20 ng/kg/minute over 24 hours with reduction of her blood pressure and a rise in the platelet count. After stabilization, therapy was stopped but restarted later when her condition worsened. Improvement was again achieved, but she was delivered at 28 weeks' because of oligohydramnios and growth retardation. The baby girl died a week later from respiratory arrest. In addition, the authors described, without details, the successful treatment of a 27-year-old patient with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome (16). Epoprostenol has also been used to treat a severe case of HELLP syndrome in the immediate postpartum period (17). A 1999 publication described the use of epoprostenol for the treatment of pulmonary hypertension in three women in the 3rd trimester (18). One patient, at 28 weeks' gestation, died from severe disease within hours of the diagnosis. The other two women delivered newborns of 3333 g and 2905 g, respectively, but the condition and status of the newborns was not mentioned.
In another case of primary pulmonary hypertension, a 34-year-old woman became pregnant with twins after 1.5 years of continuous IV infusion of epoprostenol (40 ng/kg/hour) (19). She was also taking warfarin, digoxin, furosemide, spironolactone, and ferrous sulfate. She first presented at 15 weeks' gestation at which time the warfarin was discontinued. An ultrasound examination 2 weeks later revealed the death of twin A and hydrocephalus and bilateral clubfeet in twin B. She refused pregnancy termination. She was treated twice for central catheter-related septicemia with vancomycin and gentamicin. The dose of epoprostenol was increased as pregnancy progressed, eventually reaching a dose of 60 ng/kg/hour. Betamethasone was given for lung maturity. Nitric oxide via nasal cannula was started just prior to cesarean section for breech presentation. A live, 2155-g male infant was delivered with Apgar scores of 7 and 8 at one and five minutes, respectively. The infant had severe hydrocephalus and facial anomalies consistent with fetal warfarin syndrome (19). He was alive but still hospitalized at the time of the report. The nitric oxide was discontinued after 40 days and the mother was discharged home 43 days after delivery on epoprostenol 77 ng/kg/hour. In summary, epoprostenol is not teratogenic in animals but the human data are too limited, only one human case of exposure during early gestation has been reported, to assess. The placental transfer of the prostaglandin has not been characterized, but it is unlikely if clinically significant amounts of exogenous epoprostenol reach the fetus. Because the prostaglandin occurs naturally in the fetus, it is also unlikely that maternal administration would produce a direct adverse effect on the embryo or fetus. The adverse fetal outcomes that have been noted (bradycardia, FHR decelerations, and death) were most likely due to severe maternal disease or other factors. Although the maternal benefits obtained from use of epoprostenol for severe preeclampsia have not been well documented, its use for pulmonary hypertension is beneficial and appears to far outweigh any potential risks to the fetus.
Breast Feeding Summary No reports describing the use of epoprostenol during lactation have been located. However, there is potential for its use during breast feeding, such as in postpartum women with pulmonary hypertension on long-term infusions of the drug. However, this situation must be exceedingly rare. Because of its rapid degradation at physiologic pH and probably in the gut, the clinical significance of any transfer into milk to a nursing infant is probably nil. Moreover, the prostaglandin has been given directly by inhalation to a premature neonate with beneficial effects (20). References 1. Product information. Flolan. Glaxo Wellcome, 2000. 2. Varela AF, Runge A, Ignarro LJ, Chaudhuri G. Nitric oxide and prostacyclin inhibit fetal platelet aggregation: a response similar to that observed in adults. Am J Obstet Gynecol 1992;167:1599–604. 3. Jouppila P, Kirkinen P, Koivula A, Ylikorkala O. Ritodrine infusion during late pregnancy: effects on fetal and placental blood flow, prostacyclin, and thromboxane. Am J Obstet Gynecol 1985;151:1028–32. 4. Ekblad U, Erkkola R, Uotila P, Kanto J, Palo P. Ritodrine infusion at term: effects on maternal and fetal prostacyclin, thomboxane and prostaglandin precursor fatty acids. Gynecol Obstet Invest 1988;25:106–12. 5. Randall CL, Saulnier JL. Effect of ethanol on prostacyclin, thromboxane, and prostaglandin E production in human umbilical veins. Alcohol Clin Exp Res 1995;19:741–6. 6. Martin C, Varner MW, Brance DW, Rodgers G, Mitchell MD. Dose-related effects of low dose aspirin on hemostasis parameters and prostacyclin/thromboxane ratios in late pregnancy. Prostaglandins 1996;51:321–30. 7. Tulppala M, Marttunen M, Soderstrom-Anttila V, Foudila T, Ailus K, Palosuo T, Ylikorkala O. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A 2 production. Hum Reprod 1997;12:1567–72. 8. Vainio M, Maenpaa J, Riutta A, Ylitalo P, Ala-Fossi SL, Tuimala R. In the dose range of 0.5–2.0 mg/kg, acetylsalicylic acid does not affect prostacyclin production in hypertensive pregnancies. Acta Obstet Gynecol Scand 1999;78:82–8. 9. Walsh SW, Romney AD, Wang Y, Walsh MD. Magnesium sulfate attenuates peroxide-induced vasoconstriction in the human placenta. Am J Obstet Gynecol 1998;178:7–12. 10. Satoh K, Seki H, Sakamoto H. Role of prostaglandins in pregnancy-induced hypertension. Am J Kidney Dis 1991;17:133–8. 11. Fidler J, Bennett MJ, De Swift M, Ellis C, Lewis PJ. Treatment of pregnancy hypertension with prostacyclin. Lancet 1980;2:31–2. 12. Lewis PJ, Shepherd GL, Ritter J, Chan SMT, Bolton PJ, Jogee M, Myatt L, Elder MG. Prostacyclin and pre-eclampsia. Lancet 1981;1:559. 13. Belch JJF, Thorburn J, Greer IA, Sarfo S, Prentice CRM. Intravenous prostacyclin in the management of pregnancies complicated by severe hypertension. Clin Exp Hypertens Preg 1985;B4:75–86. 14. Jouppila P, Kirkinen P, Koivula A, Ylikorkala O. Failure of exogenous prostacyclin to change placental and fetal blood flow in preeclampsia. Am J Obstet Gynecol 1985;151:661–5. 15. Moodley J, Gouws E. A comparative study of the use of epoprostenol and dihydralazine in severe hypertension in pregnancy. Br J Obstet Gynaecol 1992;99:727–30. 16. De Belder AJ, Weston MJ. Epoprostenol infusions in thrombotic microangiopathy of pregnancy. Lancet 1992;339:741–2. 17. Huber W, Schweigart U, Classen M. Epoprostenol and plasmapheresis in complicated HELLP syndrome with pancreatitis. Lancet 1994;343:848. 18. Easterling TR, Ralph DD, Schmucker BC. Pulmonary hypertension in pregnancy: treatment with pulmonary vasodilators. Obstet Gynecol 1999;93:494–8. 19. Badalian SS, Silverman RK, Aubry RH, Longo J. Twin pregnancy in a woman on long-term epoprostenol therapy for primary pulmonary hypertension. A case report. J Reprod Med 2000;45:149–52. 20. Soditt V, Aring C, Groneck P. Improvement of oxygenation induced by aerosolized prostacyclin in a preterm infant with persistent pulmonary hypertension of the newborn. Intensive Care Med 1997;23:1275–8.
Index
EPROSARTAN Drugs in Pregnancy and Lactation
Name: EPROSARTAN Class: Antihypertensive
Risk Factor:
CM*
Fetal Risk Summary Breast Feeding Summary Reference
Fetal Risk Summary Eprosartan is a selective angiotensin II receptor antagonist that is used, either alone or in combination with other antihypertensive agents, for the treatment of hypertension. Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by preventing angiotensin II from binding to AT1 receptors. Reproduction studies have been conducted in rats and rabbits (1). No teratogenic effects were observed in either species, but dose-related toxicity occurred in pregnant rabbits. In pregnant rats, no adverse effects on the fetus or on the postnatal development and maturation of offspring were observed at oral doses up to approximately 0.6 times the human exposure (based on area under the plasma concentration curve) at the maximum recommended human dose or 800 mg/day (MRHD). Similarly, a dose approximately 0.8 times the MRHD did not result in fetal or maternal toxicity in pregnant rabbits. Increasing the dose to approximately 2.7 times the MRHD in pregnant rabbits, however, caused both maternal (reduced body weight, decreased food consumption, and death) and embryo/fetal (resorptions, abortions, and litter loss) toxicity (1). It is not known if eprosartan crosses the human placenta. The molecular weight (about 521) is low enough that passage to the fetus should be expected. No reports describing the use of eprosartan during human pregnancy have been located. The antihypertensive mechanisms of action of eprosartan and angiotensin converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1 receptors, whereas the latter blocks the formation of angiotensin II itself. Therefore, use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity that is identical to that seen with ACE inhibitors (e.g., see Captopril or Enalapril). Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth retardation, prematurity, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, that is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to eprosartan. Newborn renal function and blood pressure should be closely monitored. [*Risk factor DM if used in 2nd or 3rd trimesters.]
Breast Feeding Summary No reports describing the use of eprosartan during human lactation have been located. The drug is excreted into animal milk (1). The molecular weight (about 521) is low enough that excretion into breast milk should also be expected. The effects of this exposure on a nursing infant are unknown. The American Academy of Pediatrics, however, considers ACE inhibitors, a closely related group of antihypertensive agents, to be compatible with breast feeding (see Captopril and Enalapril). Reference 1. Product information. Teveten. Unimed Pharmaceuticals, 2001.
Index
ERGOCALCIFEROL Drugs in Pregnancy and Lactation
Name: ERGOCALCIFEROL Class: Vitamin
Risk Factor:
Fetal Risk Summary Breast Feeding Summary
Fetal Risk Summary Ergocalciferol (vitamin D2) is converted in the liver to 25-hydroxyergocalciferol, which in turn is converted in the kidneys to 1,25-dihydroxyergocalciferol, one of the active forms of vitamin D. See Vitamin D. [*Risk Factor D if used in doses above the recommended daily allowance.]
Breast Feeding Summary See Vitamin D. Index
A*
ERGOTAMINE Drugs in Pregnancy and Lactation
Name: ERGOTAMINE Class: Sympatholytic (Antimigraine)
Risk Factor:
XM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Ergotamine is a naturally occurring ergot alkaloid that is used in the prevention or treatment of vascular headaches, such as migraine. The oxytocic properties of ergotamine have been known since the early 1900s, but because it produces a prolonged and marked increase in uterine tone that may lead to fetal hypoxia, it is not used for this purpose (1). A semisynthetic derivative, dihydroergotamine, has also been abandoned as an oxytocic for the same reason (2). Small amounts of ergotamine have been reported to cross the placenta to the fetus (3). Ergotamine is not an animal teratogen (4). In pregnant mice, rats, and rabbits, however, doses sufficient to affect maternal weight gain were fetotoxic, producing increased prenatal mortality and growth retardation. The mechanism proposed for these effects was an impairment of blood supply to the uterus and placenta (4). Another study demonstrating fetal death in pregnant rats arrived at the same conclusion (5). Ergotamine (0.25%) fed to pregnant sheep produced severe ergotism, fetal death and abortions (6). Most authorities consider ergotamine in pregnancy to be either contraindicated or to be used sparingly and with caution, due to the oxytocic properties of the drug (7,8,9 and 10). Fortunately, the frequency of migraine attacks decreases during pregnancy, thus lessening the need for any medication (8,9 and 10). The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 25 of whom were exposed to ergotamine during the 1st trimester (11). Two malformed children were observed from this group, but the numbers are too small to draw any conclusion. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 59 newborns had been exposed to ergotamine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of nine (15.3%) major birth defects were observed (two expected). Specific data were available for six defect categories, including (observed/expected) 1/0.6 cardiovascular defects, 0/0 oral clefts, 0/0 spina bifida, 1/0 polydactyly, 0/0 limb reduction defects, and 1/0 hypospadias. The total number of defects is suggestive of an association, but other factors, such as the mother's disease, concurrent drug use, and chance may be involved. A retrospective study published in 1978 evaluated the reproductive outcome of women attending a migraine clinic (12). The study group was composed of 777 women enrolling in the clinic for the first time. A control group composed of 182 wives of new male patients at the clinic was formed for comparison. Of the women with migraine, 450 (58%) had been pregnant vs. 136 (75%) of the women without migraine. The difference in the percentage of pregnancies may have been due to the fact that all of the control women were married while the marriage status of the study women was not known (12). The incidence of at least one spontaneous abortion or stillbirth, 27% vs. 29%, including 1st trimester loss, and the occurrence of toxemia, 18% vs. 18%, were similar for the groups. The total number of pregnancies was 1,142 in the study patients and 342 in the controls, with a mean number of pregnancies per patient of 2.54 vs. 2.51, respectively. The migraine group had 924 (81%) live births compared to 277 (81%) for the control women. Congenital defects observed among the live births totaled 31 (3.4%) for the study group vs. 11 (4.0%) for the controls. The difference was not statistically significant. Major abnormalities, found in 20 (2.2%) of the infants from the women with migraine compared to 7 (2.5%) of the infants from controls, were of similar distribution to those found in the geographic area of the clinic (12). Moreover, the incidence of defects was similar to the expected frequency for that location (12). Although the investigators were unable to document reliable and accurate drug histories during the pregnancies because of the retrospective nature of the study, 70.8% of the women with migraine indicated they had used ergotamine in the past. They concluded, therefore, that ergotamine exposure during pregnancy, especially early in gestation, was highly likely, and that this drug and others used for the prevention or treatment of the disease were probably not teratogenic (12). In contrast to the above study, six case reports have described adverse fetal outcomes attributable to ergotamine (13,14,15,16 and 17,19). An infant, who expired at 4 weeks of age, was delivered at 24 weeks' gestation with a large rugated, perineal mass, no external genitalia or anal orifice, and a small, polycystic left kidney (13). Two separate sacs made up the mass, one of which resembled a urinary bladder with two ureteral and a vaginal orifice, and the other containing bowel, left ovary, uterus and right kidney (13). The mother had used an ergotamine inhaler once or twice weekly during the first 8 weeks of pregnancy for migraine headaches. The inhaler delivered 0.36 mg of ergotamine per inhalation and she received two or three inhalations during each headache for a total dose of 0.72–1.08 mg once or twice weekly. The mother also smoked about 10 cigarettes daily. A female infant with multiple congenital malformations was delivered from a woman who had used a proprietary preparation containing ergotamine, caffeine, belladonna, and pentobarbital during the 2nd month of pregnancy for migraine (14). Two other similar cases in pregnant women who did not receive an ergotamine preparation were included in the report. The birth defects included hydrocephalus, sacral or coccygeal agenesis, digital and muscle hypoplasia, joint contractures, short stature, short perineum, and pilonidal sinus. Because of the similarity of the cases, the authors thought it might be a new syndrome, which they termed cerebroarthrodigital syndrome, in which the primary pathogenetic event is a neural tube-neural crest dysplasia (14). Although they could not determine the cause, they considered an environmental agent, such as ergotamine, or a genetic cause as possibilities (14). A 1983 report described a 27-year-old woman with migraine headaches who consumed up to 8 tablets/day of a preparation containing 1 mg of ergotamine tartrate and 100 mg of caffeine throughout a total of six pregnancies (15). The 1st pregnancy resulted in the birth of a 2200-g female infant, whose subsequent growth varied between the 3rd and 10th percentiles. She had no medical problems other than enuresis and hay fever. The woman's 2nd, 4th, 5th, and 6th pregnancies all ended in spontaneous abortions. A male infant was delivered in the 3rd pregnancy at 35 weeks' gestation. Birth weight, 1892 g, and length, 43 cm, were at the 20th percentile for gestational age. The infant died at 25 days of age secondary to hyaline membrane disease and after two surgical attempts to correct jejunal atresia. At autopsy, a short small intestine with portions of incomplete or absent muscular coat around the bowel lumen was found. The authors could not exclude a hereditary cause for the anomaly, but they believed the most likely cause was a disruptive vascular mechanism resulting from an interruption of the superior mesenteric arterial supply to the affected organ (15). In a suicide attempt, a 17-year-old pregnant woman, at 35 weeks' gestation, took a single dose of 10 ergotamine tablets (20 mg) (16). Five hours after ingestion, the fetal heart rate was 165 beats/minute with fetal movement. Uterine contractions were mild but frequent, with little relaxation between contractions. Fetal death occurred approximately 8.5 hours later, about 13.5 hours after ingestion. The most likely mechanism for the fetal death was impairment of placental perfusion by the uterine contractions resulting in fetal hypoxia (16). However, the authors considered two other possible mechanisms: arterial spasm causing decreased uterine arterial perfusion, and altered peripheral resistance and venous return resulting in fetal myocardial ischemia (16). A 1988 case report described the result of a pregnancy complicated by severe migraine headaches (17). The mother consumed a variety of drugs, including 1–4 rectal suppositories/week during the first 14 weeks of gestation, with each dose containing ergotamine (2 mg), belladonna (0.25 mg), caffeine (100 mg), and phenobarbital (60 mg). Other medications, frequency of ingestion, and gestational weeks of exposure were propranolol (40 mg; 2/day; 0–20 weeks), acetaminophen/codeine (325 mg/8 mg; 6–20/day; 0–16 weeks), and dimenhydrinate (75 mg; 0–3/week; 0–12 weeks). The term, female infant was a breech presentation weighing 2860 g, with a length of 46 cm. The infant was microcephalic and paraplegic with underdeveloped and hypotonic lower limbs. The anal, knee, and ankle reflexes were absent. Sensation was absent to the level of the knees and variably absent on the thighs. This pattern was suggestive of a spinal cord defect in the upper lumbar region (17). Other abnormalities apparent were dislocated hips and marked bilateral talipes equinovarus. Computed tomography of the brain revealed a small organ with lissencephaly, a primitive Sylvian fissure, and ventriculomegaly (17). The above findings were compatible with arrest of cerebral development that occurred after 10–13 weeks (17). The authors concluded that the most likely etiology was a disruptive vascular mechanism, and that the combination of ergotamine, caffeine, and propranolol may have potentiated the vasoconstriction (17). In response to the case report above, a 1989 letter cited prospective and retrospective data from the Hungarian Case-Control Surveillance of Congenital Anomalies, 1980–1986 system (18). Among controls (normal infants, but including those with Down's syndrome), 0.11% (18 of 16,477) had used ergotamine during pregnancy whereas 0.14% (13 of 9,460) of pregnancies with a birth defect had been exposed to the drug (difference not significant). Four of the index cases, however, involved neural tube defects compared to none of the controls (p26 weeks before the last monthly menstrual period). A prospective study published in 1996 compared the pregnancy outcomes of 226 women exposed to fluconazole during the 1st trimester with 452 women exposed to nonteratogenic agents (7). The dosage taken by the exposed group consisted of a single, 150 mg dose (N=105, 47%), multiple doses of 150 mg (N=81, 36%), 50 mg single dose (N=3, 1%), 50 mg multiple doses (N=23, 10%), 100 mg single dose (N=5, 2%), or 100 mg multiple doses (N=9, 4%). Most women (90.7%) were treated for vaginal candidiasis. There were no differences between the two groups in the number of miscarriages, stillbirths, congenital malformations, prematurity, low birth weight, cesarean section, or prolonged hospital stay. Seven (4.0% of live births) of the exposed women delivered infants with anomalies compared to 17 (4.2% of live births) of controls. There was no pattern among the congenital anomalies in the exposed group except for two cases of trisomy 21. A brief 1996 case report described a normal pregnancy outcome in a 24-year-old woman treated with 21 days of fluconazole (600 mg/day) (because of intolerance to amphotericin B) for Torulopsis glabrata fungemia beginning at 14 weeks' gestation (8). Although the patient's course was complicated by shock and intracerebral hemorrhage, she eventually delivered at term a healthy 2.95-kg infant (sex not specified) who was doing well at 18 months of age. In another 1996 case report, a 24-year-old woman at about 19 weeks' gestation had chorioretinitis, candidiasis, fever, pneumonia, and low body weight attributed to Candida albicans sepsis (9). Because of massive nausea and vomiting after a test dose of amphotericin B, she was treated with IV fluconazole (10 mg/kg/day or about 400 mg/day) for 16 days and then the same dosage orally for another 34 days. She responded well to the antifungal therapy and gave birth at 39 weeks' to a healthy 2.834-kg female infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The infant had normal growth and mental development at 2 years of age (9). A regional drug information center reported the pregnancy outcomes of 16 women (17 outcomes, 1 set of twins) who had called to inquire about the effect of fluconazole on their pregnancies (10). The median fluconazole dose was 300 mg (range 150–1000 mg) starting at 4 ± 6 weeks' gestation (range 1–26 weeks). The
twins were stillborn (no malformations) but the other 15 newborns were normal. A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (11). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Fluconazole was taken during the 1st trimester in 48 pregnancies, but the dose and duration of therapy were not specified. The outcomes of these pregnancies included 4 spontaneous abortions, 5 elective abortions, 4 pregnancies lost to follow-up, and 37 normal newborns (3 premature; 2 sets of full-term twins) (11). Although no congenital malformations were observed, the study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late appearing major defects may also have been missed due to the timing of the questionnaires. A short 1998 report described the pregnancy outcome of a 38-year-old woman who had been treated with a single 150-mg oral dose of fluconazole about the date of conception (12). Chorionic villus sampling was conducted at 12 weeks' gestation finding a normal karyotype (46,XY). The male infant, delivered by cesarean section at 39 weeks', had an encephalocele. Echocardiography revealed dextrocardia and that both the pulmonary artery and the aorta emerged from the right ventricle (12). He died at 7 days of age. The cause of the anomalies was unknown, but it could not have been secondary to fluconazole because of the timing of the exposure. A 42-year-old woman with achalasia at 31 weeks' gestation was diagnosed with Candida esophagitis (13). IV fluconazole, 150 mg/day, was given for 14 days with resolution of the vomiting and lessening of her nausea. She was treated before and after fluconazole with parenteral hyperalimentation. An apparently healthy 2.438-kg female infant, Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, was delivered at 38 weeks' gestation. In a 1999 report, fluconazole exposures and pregnancy outcomes were examined using the Danish Jutland Pharmaco-Epidemiological Prescription Database (14). A total of 165 women who had received a single, oral 150-mg dose of fluconazole for vaginal candidiasis just before or during pregnancy from 1991 to 1996 were identified. Of these, 121 had been exposed during the 1st trimester. The outcomes of exposed women were compared to the outcomes of 13,327 women who had not received any prescription medication during their pregnancies (controls). In the comparison of exposed newborns to controls, no elevated risk for preterm delivery (odds ratio [OR] 1.17, 95% confidence interval [CI] 0.63–2.17) or low birth weight (OR 1.19, 95% CI 0.37–3.79) was discovered. Similarly, the prevalence of congenital malformations was 3.3% (4 of 121) in exposed compared to 5.2% (697 of 13,327) in controls (OR 0.65, 95% CI 0.24–1.77) (14). In summary, although the data are very limited, the use of fluconazole during the 1st trimester appears to be teratogenic with continuous daily doses of 400 mg/day or more. The malformations may resemble those observed in the Antley-Bixler syndrome. The published experience with the use of smaller doses, such as those prescribed for vaginal fungal infections, suggests that the risk for adverse outcomes is low, if it exists at all. A 1998 review concurred with this assessment (15). In those instances in which continuous, high-dose fluconazole is the only therapeutic choice during the 1st trimester, the patient should be informed of the potential risk to her fetus.
Breast Feeding Summary Fluconazole is excreted into human milk (16,17). A 42-year-old lactating 54.5-kg woman was taking fluconazole 200 mg once daily (16). On her 18th day of therapy (8 days postpartum), milk samples were obtained at 0.5 hour before a dose and at 2, 4, and 10 hours after a dose. Serum samples were drawn 0.5 hour before the dose and 4 hours after the dose. On her last day of therapy (20 days postpartum), milk samples were again collected at 12, 24, 36, and 48 hours after the dose. Peak milk concentrations of fluconazole, up to 4.1 µg/mL, were measured 2 hours after the mother's dose. The milk:plasma ratios at 0.5 hour before dose and 4 hours after dose were both 0.90. The elimination half-lives in the milk and serum were 26.9 hours and 18.6 hours, respectively. No mention was made of the nursing infant. A 29-year-old woman who was nursing her 12-week-old infant developed a vaginal fungal infection (17). Breast feeding was halted at the patient's request and she was given 150 mg of fluconazole orally. Fluconazole concentrations were determined in milk (pooled from both breasts) and plasma samples obtained at 2, 5, 24, and 48 hours after the dose. Milk concentrations were 2.93, 2.66, 1.76, and 0.98 µg/mL, respectively, while plasma concentrations were 6.42, 2.79, 2.52, and 1.19 µg/mL, respectively. The milk:plasma ratios were 0.46, 0.85, 0.85, and 0.83, respectively, with half-lives of 30 and 35 hours, respectively, in the milk and plasma. The author estimated that after three plasma half-lives, 87.5% of the dose would have been eliminated from a woman with normal renal function, thereby greatly reducing the amount of drug a nursing infant would ingest (17). Although the risk to a nursing infant from exposure to fluconazole in breast milk is unknown, the safe use of this antifungal agent in neonates has been reported (18,19 and 20). A brief 1989 report described a 48-day-old infant, born at 36 weeks' gestation, who was treated with IV fluconazole, 6 mg/kg/day, for disseminated Candida albicans (18). The dosage was reduced to 3 mg/kg/day when a slight, transient increase in serum transaminase values was measured. The infant was discharged home at 80 days of age in good condition. In the second case, IV fluconazole 6 mg/kg/day was administered for 20 days to an approximately 6-week-old, premature infant (born at 28 weeks' gestation) with a disseminated Candida albicans infection (19). Results of follow-up studies of the infant during the next 4 months were apparently normal. In a similar case, a 1-month-old premature infant was treated with IV fluconazole (5 mg/kg for 1 hour daily) for 21 days and orally for 8 days for meningitis caused by a Candida species (20). He was doing well at 9 months of age. The safety of fluconazole during breast feeding cannot be completely extrapolated from these cases, but the dose administered to these infants far exceeds the amount they would have received via breast milk. Since no drug-induced toxicity was encountered in the infants, fluconazole is probably safe to use during breast feeding. References 1. Product information. Diflucan. Pfizer, 2001. 2. Tiboni GM, Iammarrone E, Giampietro F, Lamonaca D, Bellati U, Di Ilio C. Teratological interaction between the bis-triazole antifungal agent fluconazole and the anticonvulsant drug phenytoin. Teratology 1999;59:81–7. 3. Lee BE, Feinberg M, Abraham JJ, Murthy AR. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J 1992;11:1062–4. 4. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996;22:336–40. 5. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 1997;72:253–6. 6. Inman W, Pearce G, Wilton L. Safety of fluconazole in the treatment of vaginal candidiasis. A prescription-event monitoring study, with special reference to the outcome of pregnancy. Eur J Clin Pharmacol 1994;46:115–8. 7. Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, Fusco D. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 1996;175:1645–50. 8. Kremery V Jr, Huttova M, Masar O. Teratogenicity of fluconazole. Pediatr Infect Dis 1996;15:841. 9. Wiesinger EC, Mayerhofer S, Wenisch C, Breyer S, Graninger W. Fluconazole in Candida albicans sepsis during pregnancy: case report and review of the literature. Infection 1996;24:263–6. 10. Campomori A, Bonati M. Fluconazole treatment for vulvovaginal candidiasis during pregnancy. Ann Pharmacother 1997;118–9. 11. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9. 12. Sanchez JM, Moya G. Fluconazole teratogenicity. Prenat Diagn 1998;18:862–3. 13. Kalish RB, Garry D, Figueroa R. Achalasia with Candida esophagitis during pregnancy. Obstet Gynecol 1999;94:850. 14. Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schonheyder HC, Olsen J, Czeizel AE. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 1999;48:234–8. 15. King CT, Rogers PD, Cleary JD, Chapman SW. Antifungal therapy during pregnancy. Clin Infect Dis 1998;27:1151–60. 16. Schilling CG, Seay RE, Larson TA, Meier KR. Excretion of fluconazole in human breast milk (abstract no. 130). Pharmacotherapy 1993;13:287. 17. Force RW. Fluconazole concentrations in breast milk. Pediatr Infect Dis J 1995;14:235–6. 18. Viscoli C, Castagnola E, Corsini M, Gastaldi R, Soliani M, Terragna A. Fluconazole therapy in an underweight infant. Eur J Clin Microbiol Infect Dis 1989;8:925–6. 19. Wiest DB, Fowler SL, Garner SS, Simons DR. Fluconazole in neonatal disseminated candidiasis. Arch Dis Child 1991;66:1002. 20. Gurses N, Kalayci AG. Fluconazole monotherapy for Candidal meningitis in a premature infant. Clin Infect Dis 1996;23:645–6.
Index
FLUCYTOSINE Drugs in Pregnancy and Lactation
Name: FLUCYTOSINE Class: Antifungal
Risk Factor:
CM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary The antifungal agent, flucytosine, was teratogenic in rats at doses 0.27 to 4.7 times the maximum recommended human dose (MRHD), producing vertebral fusions, cleft lip and palate, and micrognathia (1). In mice, a dose 2.7 times the MRHD was associated with a low, nonsignificant, incidence of cleft palate. Flucytosine was not teratogenic in rabbits at 0.68 times the MRHD (1). Following oral administration, about 4% of the drug is metabolized within the fungal organisms to 5-fluorouracil, an antineoplastic agent (1, 2). Fluorouracil is suspected of producing congenital defects in humans (see Fluorouracil). Three case reports of pregnant patients treated in the 2nd and 3rd trimesters with flucytosine have been located (3,4 and 5). No defects were observed in the newborns.
Breast Feeding Summary No reports describing the use of flucytosine during lactation or measuring the amount, if any, excreted in human milk have been located. Because of the potential for serious adverse effects in a nursing infant, breast feeding while taking flucytosine is not recommended. References 1. Product information. Ancobon. ICN Pharmaceuticals, 2000. 2. Diasio RB, Lakings DE, Bennett JE. Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans: possible factor in 5-fluorocytosine clinical toxicity. Antimicrob Agents Chemother 1978;14:903–8. 3. Philpot CR, Lo D. Cryptococcal meningitis in pregnancy. Med J Aust 1972;2:1005–7. 4. Schonebeck J, Segerbrand E. Candida albicans septicaemia during first half of pregnancy successfully treated with 5-fluorocytosine. Br Med J 1973;4:337–8. 5. Curole DN. Cryptococcal meningitis in pregnancy. J Reprod Med 1981;26:317–9.
Index
FLUNITRAZEPAM Drugs in Pregnancy and Lactation
Name: FLUNITRAZEPAM Class: Hypnotic
Risk Factor:
D
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Flunitrazepam is a benzodiazepine (see also Diazepam). No reports linking the use of flunitrazepam with congenital defects have been located, but other drugs in this group have been suspected of causing fetal malformations (see also Diazepam or Chlordiazepoxide). In contrast to other benzodiazepines, flunitrazepam crosses the placenta slowly (1,2). About 12 hours after a 1-mg oral dose, cord:maternal blood ratios in early and late pregnancy were about 0.5 and 0.22, respectively. Amniotic fluid:maternal serum ratios were in the 0.02–0.07 range in both cases. Accumulation in the fetus may occur after repeated doses (1).
Breast Feeding Summary Flunitrazepam is excreted into breast milk. Following a single 2-mg oral dose in five patients, mean milk:plasma ratios at 11, 15, 27, and 39 hours were 0.61, 0.68, 0.9, and 0.75, respectively (1,2). The effects of these levels on the nursing infant are unknown but they are probably insignificant. References 1. Kanto J, Aaltonen L, Kangas L, Erkkola R, Pitkanen Y. Placental transfer and breast milk levels of flunitrazepam. Curr Ther Res 1979;26:539–45. 2. Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with special reference to pharmacokinetic considerations. Drugs 1982;23:354–80.
Index
FLUORESCEIN SODIUM Drugs in Pregnancy and Lactation
Name: FLUORESCEIN SODIUM Class: Diagnostic Agent
Risk Factor:
B
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary The diagnostic agent, fluorescein sodium (Dye and Coloring Yellow No. 8), is available as a topical solution, dye-impregnated paper strips, and as a solution for IV injection. No adverse fetal effects were observed in the offspring of pregnant albino rats administered IV sodium fluorescein (10%) at a dose of 5 mL/kg (1). The agent crossed the placenta and distributed throughout the fetuses within 15 minutes. Using phenobarbital in mature rats exposed in utero to multiple maternal IV doses of 10% sodium fluorescein, the investigators determined that in utero exposure to the dye had no effect on their drug detoxification systems later in life (1). No adverse effects on fetal development were observed when pregnant rats and rabbits were treated by gavage with multiple high doses (up to 1500 mg/kg in rats and up to 250 mg/kg in rabbits) of sodium fluorescein during organogenesis (2). Similarly, no adverse fetal outcomes occurred when pregnant rabbits were administered multiple 1.4-mL IV doses of 10% sodium fluorescein during the first two-thirds of gestation (3). No reports describing the use of fluorescein sodium during human pregnancy have been located. Use of the topical solution in the eye (as well as IV injection) produces measurable concentrations of the dye in the systemic circulation (see reference # 6) and passage to the fetus should be expected.
Breast Feeding Summary Fluorescein sodium is excreted into human breast milk (4,5). A 29-year-old woman, who suffered acute central vision loss shortly after premature delivery of twins, was administered a 5-mL IV dose of 10% fluorescein sodium for diagnostic angiography (4). Her hospitalized infants were not fed her milk because of concern that the fluorescein in the milk could cause a phototoxic reaction if consumed (a severe bullous skin eruption was observed in a premature infant receiving phototherapy for hyperbilirubinemia shortly after administration of IV fluorescein angiography [5]). Milk concentrations of the dye were measured in seven samples collected between 6 and 76 hours after fluorescein administration. The highest and lowest concentrations, 372 ng/mL and 170 ng/mL, were measured at 6 and 76 hours, respectively. The elimination half-life of fluorescein in the woman's milk was approximately 62 hours (4). In a second case, a 28-year-old woman, 3 months postpartum, was administered a topical 2% solution in both eyes (6). Her infant was not allowed to breast-feed on the day of instillation. Absorption into the systemic circulation was documented with plasma fluorescein concentrations of 36 and 40 ng/mL at 45 and 75 minutes, respectively, after the dose. Milk concentrations at 30, 60, and 90 minutes were 20, 22, and 15 ng/mL, respectively. Because of these data, the authors recommended that mothers should not breast-feed for 8–12 hours after fluorescein topical administration. The two mothers in the above cases either did not breast feed or temporarily withheld nursing to allow the dye to clear from their milk because of concerns for a fluorescein-induced phototoxic reaction in their infants. Although the American Academy of Pediatrics considers topical fluorescein to be compatible with breast feeding (7), the much higher milk concentrations obtained following IV fluorescein indicate that a risk may exist, especially in those infants undergoing phototherapy, and feeding should be temporarily withheld (8). References 1. 2. 3. 4. 5. 6. 7. 8.
Salem H, Loux JJ, Smith S, Nichols, CW. Evaluation of the toxicologic and teratogenic potentials of sodium fluorescein in the rat. Toxicology 1979;12:143–50. Burnett CM, Goldenthal EI. The teratogenic potential in rats and rabbits of D and C Yellow no. 8. Food Chem Toxicol 1986;24:819–23. McEnerney JK, Wong WP, Peyman GA. Evaluation of the teratogenicity of fluorescein sodium. Am J Ophthalmol 1977;84:847–50. Maguire AM, Bennett J. Fluorescein elimination in human breast milk. Arch Ophthalmol 1986;106:718–9. Kearns GL, Williams BJ, Timmons OD. Fluorescein phototoxicity in a premature infant. J Pediatr 1985;107:796–8. Mattern J, Mayer PR. Excretion of fluorescein into breast milk. Am J Ophthalmol 1990;109:598–9. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50. Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.
Index
FLUOROURACIL Drugs in Pregnancy and Lactation
Name: FLUOROURACIL Class: Antineoplastic
Risk Factor:
D*
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Fluorouracil was embryotoxic and teratogenic in mice, rats, and hamsters given parenteral doses equivalent to the human dose (1). Although not teratogenic in monkeys, divided doses above 40 mg/kg resulted in abortions. Animal reproduction studies with topical fluorouracil have not been conducted (1). When applied topically in patients with actinic keratoses, the amount of fluorouracil absorbed systemically is approximately 6% (1). The amount absorbed from mucous membranes is unknown. One manufacturer reported an infant with cleft lip and palate from a woman who appropriately used topical fluorouracil and a second infant with a ventricular septal defect from a woman who used the drug topically on mucous membranes (1). In addition, spontaneous abortions (SABs) have been reported following use on mucous membrane areas (1). It is not known if there is a causative relationship between the topically applied drug and these outcomes. Following systemic therapy in the 1st trimester (also with exposure to 5 rad of irradiation), multiple defects were observed in an aborted fetus: radial aplasia; absent thumbs and three fingers; hypoplasia of lungs, aorta, thymus, and bile duct; aplasia of esophagus, duodenum, and ureters; single umbilical artery; absent appendix; imperforate anus; and a cloaca (2). A 33-year-old woman with metastatic breast cancer was treated with a modified radical mastectomy during her 3rd month of pregnancy followed by oophorectomy at 13 weeks' gestation (3). Chemotherapy, consisting of 5-fluorouracil, cyclophosphamide, and doxorubicin, was started at approximately 11 weeks' gestation and continued for six 3-week cyclic courses. Methotrexate was substituted for doxorubicin at this time and the new three-drug regimen was continued until delivery by cesarean section at 35 weeks of a 2260-g female infant. No abnormalities were noted at birth, and continued follow-up at 24 months of age revealed normal growth and development. Toxicity consisting of cyanosis and jerking extremities has been reported in a newborn exposed to fluorouracil in the 3rd trimester (4). In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 14 newborns had been exposed to fluorouracil (includes nonsystemic administration) during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (7.1%) major birth defect was observed (one expected). No anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. In a brief 1997 report, three pregnant women with breast cancer were successfully treated with two or three courses of vinorelbine (20–30 mg/m2) and fluorouracil (500–750 mg/m2) at 24, 28, and 29 weeks' gestation, respectively (5). Delivery occurred at 34, 41, and 37 weeks' gestation, respectively. One patient also required six courses of epidoxorubicin and cyclophosphamide. Her infant developed transient anemia at 21 days of age that resolved spontaneously. No adverse effects were observed in the other two newborns. All three infants were developing normally at about 2–3 years of age (5). A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (6). The first cycle of chemotherapy occurred at a mean gestational age of 26 weeks with delivery occurring at a mean 34.7 weeks. A total of 38 cycles were administered during pregnancy with a median of two cycles per woman. None of the women received radiation therapy during pregnancy. The pregnancy outcomes included two SABs (both exposed in the 1st trimester), one intrauterine death (exposed in the 2nd trimester), and 17 live births, one of whom died at 8 days of age without apparent cause. The 16 surviving children were developing normally at a mean follow-up of 42.3 months (6). Fluorouracil (F), in combination with various other agents (cyclophosphamide [C], doxorubicin [D], epirubicin [E], mitoxantrone [M], or vinorelbine [V]) was administered to 16 of the women at a mean dose of 535 mg/m2 (range 300–750 mg/m2). The outcomes were one SAB (FCE; 1st trimester), one neonatal death (one cycle of FCE 32 days before birth), and 14 surviving liveborn infants (five FEC, four FV, two FAC, two FCM, and one FD in the 2nd or 3rd trimesters). One of the infants, exposed to two cycles of FCE with the last at 25 days before birth, had transient leukopenia and another was growth retarded (1460-g, born at 33 weeks' gestation after two cycles of FCM) (6). Amenorrhea has been observed in women treated with fluorouracil for breast cancer, but this was probably caused by concurrent administration of melphalan (see also Melphalan) (7,8). The long-term effects of combination chemotherapy on menstrual and reproductive function have been described in two 1988 reports (9,10). In one report, only 2 of the 40 women treated for malignant ovarian germ cell tumors received fluorouracil (9). The results of this study are discussed in the monograph for cyclophosphamide (see Cyclophosphamide). The other report described the reproductive results of 265 women who had been treated from 1959–1980 for gestational trophoblastic disease (10). Single-agent chemotherapy was administered to 91 women, including 54 cases in which fluorouracil was the only agent used; sequential (single agent) and combination therapies were administered to 67 and 107 women, respectively. Of the total group, 241 were exposed to pregnancy and 205 (85%) of these women conceived, with a total of 355 pregnancies. The time interval between recovery and pregnancy was 1 year or less (8.5%), 1–2 years (32.1%), 2–4 years (32.4%), 4–6 years (15.5%), 6–8 years (7.3%), 8–10 years (1.4%), and more than 10 years (2.8%). A total of 303 (4 sets of twins) liveborn infants resulted from the 355 pregnancies, 3 of whom had congenital malformations: anencephaly, hydrocephalus, and congenital heart disease (one in each case). No gross developmental abnormalities were observed in the dead fetuses. Cytogenetic studies were conducted on the peripheral lymphocytes of 94 children, and no significant chromosomal abnormalities were noted. Moreover, follow-up of the children, more than 80% of the group older than 5 years of age (the oldest was 25 years old), revealed normal development. The reproductive histories and pregnancy outcomes of the treated women were comparable to those of the normal population (10). Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide). [*Risk Factor X according to manufacturers Allergan and ICN Pharmaceuticals, 2000.]
Breast Feeding Summary No reports describing the use of fluorouracil during lactation have been located. The low molecular weight (about 130) probably indicates that the drug is excreted into milk. Because of the potential for severe toxicity in a nursing infant, women should not breast feed while receiving fluorouracil. References 1. 2. 3. 4. 5. 6. 7.
Product information. Efudex. ICN Pharmaceuticals, 2000. Stephens JD, Golbus MS, Miller TR, Wilber RR, Epstein CJ. Multiple congenital anomalies in a fetus exposed to 5-fluorouracil during the first trimester. Am J Obstet Gynecol 1980;137:747–9. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:435–440. Stadler HE, Knowles J. Fluorouracil in pregnancy: effect on the neonate. JAMA 1971;217:214–5. Cuvier C, Espie M, Extra JM, Marty M. Vinorelbine in pregnancy. Eur J Cancer 1997;33:168–9. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy. Cancer 1999;86:2266–72. Fisher B, Sherman B, Rockette H, Redmond C, Margolese K, Fisher ER. L-Phenylalanine (L-PAM) in the management of premenopausal patients with primary breast cancer. Cancer 1979;44:847–57. 8. Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:109–14. 9. Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:270–5. 10. Song H, Wu P, Wang Y, Yang X, Dong S. Pregnancy outcomes after successful chemotherapy for choriocarcinoma and invasive mole: long-term follow-up. Am J Obstet Gynecol 1988;158:538–45.
Index
FLUOXETINE Drugs in Pregnancy and Lactation
Name: FLUOXETINE Class: Antidepressant
Risk Factor:
CM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is used for the treatment of depression. The chemical structure of fluoxetine is unrelated to other antidepressant agents. All of the antidepressant agents in the SSRI class (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) share a similar mechanism of action although they have different chemical structures. These differences could be construed as evidence against any conclusion that they share similar effects on the embryo, fetus, or newborn. In the mouse embryo, however, craniofacial morphogenesis appears to be regulated, at least in part, by serotonin. Interference with serotonin regulation by chemically different inhibitors produces similar craniofacial defects (1). Regardless of the structural differences, therefore, some of the potential adverse effects on pregnancy outcome may also be similar. Reproduction studies in rats and rabbits revealed no evidence of teratogenicity using up to 1.5 and 3.6 times the maximum recommend human daily dose on a body surface area basis [MRHD], respectively, throughout organogenesis (2,3). In rats, however, doses of 1.5 times the MRHD during gestation or 0.9 times the MRHD during gestation and lactation were associated with an increase in stillbirths, a decrease in pup weight, and a decrease in pup survival during the first 7 days postpartum (2). The no-effect dose for pup mortality was 0.6 times the MRHD (2). There was no evidence of developmental neurotoxicity in the surviving pups exposed to 1.5 times the MRHD during gestation (2). Using uterine rings from midterm (gestation day 14) and term pregnant rats, fluoxetine, and two other antidepressants (imipramine and nortriptyline), were shown to attenuate the activity of serotonin-induced spontaneous uterine contractions (4). Although a direct myometrial role could not be demonstrated for these monoamine reuptake inhibitors, the investigators discussed several other possible pathways that fluoxetine could induce preterm delivery (4). Administration of fluoxetine to pregnant rats produced a down-regulation of fetal cortical 3H-imipramine binding sites that was still evident 90 days after birth (5). The clinical significance of this finding to the development of the human fetal brain is unknown. In a study to determine if fluoxetine increased the bleeding risk in neonates, pregnant rats were administered fluoxetine (5.62 mg/kg/day) from day 7 of gestation until the delivery (6). The dose was approximately 5 times the maximum recommended human dose. Compared to controls, fluoxetine-exposed pups had a significantly higher frequency of skin hematomas. The mechanism was thought to be related to the inhibition of serotonin uptake by platelets (6). Both fluoxetine and the active metabolite, norfluoxetine, cross the placenta and distribute within the embryo or fetus in rats (7). No reports describing the placental transfer of fluoxetine early in gestation have been located. The molecular weight (about 346 for the hydrochloride salt) is low enough, however, that passage should be expected. Moreover, two studies (cited below as references #17 and #18), have documented the human placental transfer of the antidepressant and its active metabolite at term. During clinical trials with fluoxetine, a total of 17 pregnancies occurred during treatment, even though the women were required to use birth control, suggesting lack of compliance (3). No pregnancy complications or adverse fetal outcomes were observed. A prospective evaluation of 128 women treated with a mean daily dose of 25.8 mg of fluoxetine during the 1st trimester was reported in 1993 (8). Two matched control groups were selected, one with exposure to tricyclic antidepressants (TCAs) and the other with exposure only to nonteratogens. No differences were found in the rates of major birth defects (2, 0, and 2, respectively) among the groups. An increased risk was observed, although not statistically significant, in the rate of spontaneous abortion when the fluoxetine group was compared to those in the nonteratogen group, 14.8% vs. 7.8% (relative risk 1.9; 95% confidence interval [CI] 0.92–3.92). Because only 74 TCA 1st trimester exposures were available for matching, comparisons between the three groups were based on 74 women in each group. The rates of miscarriage from this analysis were 13.5% (fluoxetine), 12.2% (TCAs), and 6.8% (nonteratogens), again without reaching statistical significance. Because of the increase in the number of spontaneous abortions observed in both antidepressant groups, additional studies are needed to separate the effects of the psychiatric condition from that of the drug therapy (8). The authors also concluded that exposure to fluoxetine during the 1st trimester was not associated with an increased risk of congenital defects, but that long-term studies were warranted to evaluate the potential neurodevelopmental toxicity of the antidepressant (8). A 1992 prospective multicenter study evaluated the effects of lithium exposure during the 1st trimester in 148 women (9). One of the pregnancies was terminated at 16 weeks' gestation because of a fetus with the rare congenital heart defect, Ebstein's anomaly. The fetus had been exposed to lithium, fluoxetine, trazodone, and L -thyroxine during the 1st trimester. The defect was probably caused by lithium exposure. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 142 newborns had been exposed to fluoxetine, 109 during the 1st trimester (F. Rosa, personal communication, FDA, 1994). Two (1.8%) major birth defects were observed (five expected), but details of the abnormalities were not available. No anomalies were observed in eight defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, hypospadias, brain defects, and eye defects) for which specific data were available. These data do not support an association between the drug and congenital defects. A 1993 letter to the editor from representatives of the manufacturer summarized the postmarketing database for the antidepressant (10). Of the 1103 prospectively reported exposed pregnancies, 761 of which had potentially reached term, data were available for 544 (71%) outcomes, including 91 elective terminations. Among the remaining 453 pregnancies, there were 72 (15.9%) spontaneous abortions, 2 (0.4%) stillbirths, and 20 (4.4%) infants with major malformations, 7 of which were identified in the postperinatal period. Details of the aborted fetuses and stillbirths were not given. The malformations observed in the perinatal period were abdominal wall defect (in one twin), atrial septal defect, constricted band syndrome, hepatoblastoma, bilateral hydroceles, gastrointestinal anomaly, intestinal blockage, macrostomia, stubbed and missing digits, trisomy 18, trisomy 21, and ureteral disorder (2 cases). The postperinatal cases included an arrhythmia, pyloric stenosis (2 cases), tracheal malacia (3 cases), and volvulus. An additional 28 cases of major malformations reported retrospectively to the manufacturer were mentioned, but no details were given other than the fact that the malformations lacked similarity and, thus, were not indicative of a pattern of anomalies (10). A review that appeared in 1996 (before reference #12) examined the published data relating to the safety of fluoxetine use during gestation and lactation in both experimental animals and humans (11). Using previously published criteria for identifying human teratogens, the authors concluded that the use of fluoxetine during pregnancy did not result in an increased frequency of birth defects or effects on neurobehavior (11). A prospective study published in 1996 compared the pregnancy outcomes of 228 women who took fluoxetine with 254 nonexposed controls (12). The rates of spontaneous abortion in the two groups were 10% (exposed) and 8.5% (controls), but 13.6% (23 of 169) among those who were enrolled in the study during the 1st trimester and who had 1st trimester exposure. Major structural anomalies were observed in 5.5% (9 of 164) of live-born infants exposed to fluoxetine during the 1st trimester compared to 4.0% (9 of 226) of live-born infants among the controls (p =0.63). No patterns were evident in either group (12). A total of 250 infants (97 study, 153 controls) were examined (by a physician who was unaware of the infant's drug exposure [13]) for minor anomalies and among those with three or more, 15 (15.5%) were exposed and 10 (6.5%) were not exposed (p =0.03). In comparison to those infants who were exposed during the 1st trimester to fluoxetine or not exposed at all, infants who were exposed late to the drug had a significant increase in perinatal complications, including prematurity (after excluding twins), rate of admission to special-care nurseries (after excluding preterm infants), poor neonatal adaptation, lower mean birth weight and shorter length in full-term infants, and a higher proportion of full-term infants with birth weights at or below the 10th percentile (12). Moreover, two (2.7%) of the full-term infants who were exposed late had persistent pulmonary hypertension, a complication that is estimated to occur in the general population at a rate of 0.07%–0.10% (12). Although the authors concluded that the number of major structural anomalies and the rate of spontaneous abortions were not significantly increased by fluoxetine exposure in this study, the increased rate of three or more minor anomalies, an unusual finding, is indicative that the drug does affect embryonic development and raises the concern of occult malformations, such as those involving brain development (12). Moreover, the use of fluoxetine late in pregnancy was related to an increase in perinatal complications. In an accompanying editorial (14) and subsequent letters (15,16), various investigators cited perceived problems with the above study and were addressed in a reply
(13). A 1993 case report described possible fluoxetine-induced toxicity in a term 3580-g male newborn (17). The infant's 17-year-old mother had taken the antidepressant (20 mg/day) throughout most of her pregnancy for severe depression and suicidal ideation (17). The infant was initially alert and active with mild hypoglycemia (33 mg/dL). Oral 5% dextrose was given and hourly blood glucose samples over the next 4 hours were within normal limits. At 4 hours of age, marked acrocyanosis was noted and the infant became jittery. Tachypnea developed with a respiratory rate of 70. His condition continued to worsen with symptoms peaking at 36 hours. The symptoms included continuous crying, irritability, moderate to marked tremors, increased muscle tone, a hyperactive Moro reflex, and emesis (17). An extensive diagnostic work-up, including a drug screen, was negative. The cord blood fluoxetine and norfluoxetine levels were 26 ng/mL and 54 ng/mL, respectively, both within a nontoxic range for adults (17). The infant was asymptomatic at 96 hours of age at which time the serum levels of the parent drug and metabolite were 1.8 ng/mL, RBC >203 ng/mL). Whole embryo cultures of rats have been tested with valproic acid and folinic acid, a folic acid derivative (76). The anticonvulsant produced a dose-related increase in the incidence of NTDs that was not prevented by the addition of the vitamin. Experiments in embryonic mice, however, indicated that valproic acid-induced NTDs were related to interference with embryonic folate metabolism (77). Teratogenic doses of valproic acid caused a significant reduction in embryonic levels of formylated tetrahydrofolates and increased the levels of tetrahydrofolate by inhibition of the enzyme glutamate formyltransferase. The result of this inhibition would have serious consequences on embryonic development, including neural tube closure (77). A review of teratogenic mechanisms involving folic acid and antiepileptic therapy was published in 1992 (78). Several studies conducted by the authors and others demonstrated that phenytoin, phenobarbital, and primidone, but not carbamazepine or valproic acid, significantly reduced serum and RBC levels of folate, and that polytherapy decreased these levels significantly more than monotherapy. Animal studies cited indicated that valproic acid disrupts folic acid metabolism, possibly by inhibiting key enzymes, rather than by lowering concentrations of the vitamin, whereas phenytoin may act on folic acid by both mechanisms (78). Data from a study conducted by the authors indicated that a significant association existed between low serum and RBC folate levels, especially 750,000 copies/mL plasma) (5). Ten days later, she was started on a prophylactic regimen of indinavir (2400 mg/day), zidovudine (600 mg/day), and lamivudine (300 mg/day). Pregnancy was confirmed 14 days after insemination. The indinavir dose was reduced to 1800 mg/day, 4 weeks after the start of therapy because of the development of renal calculi. All antiretroviral therapy was stopped after 9 weeks because of negative tests for HIV. She gave birth at 40 weeks' gestation to a healthy 3490-g male infant, without evidence of HIV disease, who was developing normally at 2 years of age (5). The experience of one perinatal center with the treatment of HIV infected pregnant women was summarized in a 1999 abstract (6). Of 55 women receiving (³3 antiviral drugs, 39 were treated with a protease inhibitor (5 with indinavir). The outcomes included 2 spontaneous abortions, 5 elective abortions, 27 newborns, and 5 ongoing pregnancies. One woman was taken off of indinavir because of ureteral obstruction and another (drug therapy not specified) developed gestational diabetes. None of the newborns tested positive for HIV or had major congenital anomalies or complications (6). A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (7). Many of the women were substance abusers. Protease inhibitors (indinavir N=6, nelfinavir N=7, and saquinavir N=1 in combination with nelfinavir) were used in 13 of the women. Antiretroviral therapy was initiated at a median of 14 weeks' gestation (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. The outcomes of the pregnancies treated with protease inhibitors appeared to be similar to the 17 cases that did not receive these agents, except that the birth weights were lower (7). Indinavir has frequently produced hyperbilirubinemia in adults, but it is not known whether treatment of the mother prior to delivery will exacerbate physiologic hyperbilirubinemia in the neonate (1). No such effects have been observed in Rhesus monkey neonates exposed in utero to indinavir during the 3rd trimester (1). A public health advisory has been issued by the Food and Drug Administration (FDA) on the association between protease inhibitors and diabetes mellitus (8). Because pregnancy is a risk factor for hyperglycemia, there was concern that these antiviral agents would exacerbate this risk. An abstract published in 2000 described the results of a study involving 34 pregnant women treated with protease inhibitors (4 with indinavir) compared to 41 controls that evaluated the association with diabetes (9). No relationship between protease inhibitors and an increased incidence of gestational diabetes was found. A multicenter, retrospective survey of pregnancies exposed to protease inhibitors was published in 2000 (10). There were 92 live born infants delivered from 89 women (3 sets of twins) at six health care centers. One nonviable infant, born at 22 weeks' gestation, died. The surviving 91 infants were evaluated in terms of adverse effects, prematurity rate, and frequency of HIV-1 transmission. Most of the infants were exposed in utero to a single protease inhibitor, but a few were exposed to more than one because of sequential or double combined therapy. The number of newborns exposed to each protease inhibitor was indinavir (N=23), nelfinavir (N=39), ritonavir (N=5), and saquinavir (N=34). Protease inhibitors were started before conception in 18, during the 1st, 2nd, or 3rd trimesters in 12, 44, and 14, respectively, and not reported in one. Other antiretrovirals used with the protease inhibitors included four nucleoside reverse transcriptase inhibitors (NRTI) (didanosine, lamivudine, stavudine, and zidovudine). The most common NRTI regimen was a combination of zidovudine and lamivudine (65% of women). In addition, seven women were enrolled in the AIDS Clinical Trials Group Protocol 316 and, at the start of labor, received either a single dose of the nonnucleoside reverse transcriptase inhibitor, nevirapine, or placebo. Maternal conditions, thought possibly or likely to be related to therapy, were mild anemia in eight, severe anemia in one (probably secondary to zidovudine), and thrombocytopenia in one. Gestational diabetes mellitus was observed in three women (3.3%), a rate similar to the expected prevalence of 2.6% in a nonexposed population (10). One mother developed postpartum cardiomyopathy and died 2 months after birth of twins, but the cause death was not known. For the surviving newborns, there was no increase in adverse effects over that observed in previous clinical trials of HIV-positive women, including the prevalence of anemia (12%), hyperbilirubinemia (6%; none exposed to indinavir), and low birth weight (20.6%). Premature delivery occurred in 19.1% of the pregnancies (close to the expected rate). The percentage of infants infected with HIV was 0 (95% CI 0%–3%) (10). In summary, although the limited human data do not allow an assessment of the fetal risks of indinavir, the animal data involving birth defects is a concern. The finding of anophthalmia in rat pups at a systemic exposure approximately equivalent to human exposure needs further investigation. The authors of that study also observed anophthalmia in a rat experiment with ritonavir (1 of 113 offspring, unpublished data), another protease inhibitor (2). An editorial, accompanying this study, reviewed how the changes in the treatment of HIV disease (e.g., multiple combinations of drugs; use of agents throughout gestation) were altering the risk:benefit ratio of antiretroviral therapy during pregnancy (11). Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (12,13). In 1998, the Centers for Disease Control and
Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (8). If indicated, therefore, protease inhibitors, including indinavir, should not be withheld in pregnancy (with the possible exception of the 1st trimester) because the expected benefit to the HIV-positive mother probably outweighs the unknown risks to the fetus. For indinavir, these theoretical risks include birth defects, hyperbilirubinemia, complications of maternal diabetes, and renal stones. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. Because of the potential for hyperbilirubinemia with indinavir, one review suggested that ritonavir (see Ritonavir) may be a more appropriate first-choice drug (13). Moreover, indinavir has been associated with the development of renal stones in adults and, if significant human placental transfer occurs, maternal usage near delivery may, theoretically, cause development of renal toxicity in the newborn. The combination of immature neonatal renal function and the potential for suboptimal hydration may allow for high or prolonged concentrations of the drug leading to crystallization and renal stones. Finally, the efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn are unknown, and zidovudine remains the only antiretroviral agent currently recommended for this purpose (12,13).
Breast Feeding Summary No reports describing the use of indinavir during lactation have been located. The antiviral agent is excreted into the milk of lactating rats (1). The molecular weight (about 712 for the sulfate salt) is low enough that excretion into breast milk should be expected. Reports on the use of indinavir during lactation are unlikely because of the potential toxicity in the nursing infant, especially hyperbilirubinemia, and because the drug is indicated in the treatment of patient's with HIV. HIV type 1 (HIV-1) is transmitted in milk, and in developed countries, breast feeding is not recommended (12,13,14,15 and 16). In developing countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies have been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection in spite of breast feeding when compared to controls (see Zidovudine). References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Product information. Crixivan. Merck, 2001. Riecke K, Schultz TG, Shakibaei M, Krause B, Chahoud I, Stahlmann R. Developmental toxicity of the HIV-protease inhibitor indinavir in rats. Teratology 2000;62:291–300. Hayashi S, Beckerman K, Homma M, Kosel BW, Aweeka FT. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS 2000;14:1061–2. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):1–55. Bloch M, Carr A, Vasak E, Cunningham P, Smith D. The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination. Am J Obstet Gynecol 1999;181:760–1. Stek A, Kramer F, Fassen M, Khoury M. The safety and efficacy of protease inhibitor therapy for HIV infection during pregnancy (abstract). Am J Obstet Gynecol 1999;180:S7. McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:641–6. Centers for Disease Control and Prevention. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR;1998:47:No. RR-2. Fassett M, Kramer F, Stek A. Treatment with protease inhibitors in pregnancy is not associated with an increased incidence of gestational diabetes (abstract). Am J Obstet Gynecol 2000;182:S97. Morris AB, Cu-Uvin S, Harwell JI, Garb J, Zorrilla C, Vajaranant M, Dobles AR, Jones TB, Carlan S, Allen DY. Multicenter review of protease inhibitors in 89 pregnancies. J Acquir Immune Defic Syndr 2000;25:306–11. Miller RK. Anti-HIV therapy during pregnancy: risk-benefit ratio. Teratology 2000;62:288–90. Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276:146–54. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89. de Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.
Index
INDOMETHACIN Drugs in Pregnancy and Lactation
Name: INDOMETHACIN Class: Nonsteroidal Anti-inflammatory
Risk Factor:
B*
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID). It is indicated for the relief of the signs and symptoms of moderate-to-severe rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, and acute painful shoulder (bursitis and/or tendinitis). Indomethacin is in the same subclass (acetic acids) as three other NSAIDs (diclofenac, sulindac, and tolmetin). Shepard reviewed four reproduction studies on the use of indomethacin in mice and rats (1). Fused ribs, vertebral abnormalities, and other skeletal defects were seen in mouse fetuses, but no malformations were observed in rats except for premature closure of the ductus arteriosus in some fetuses. A 1990 report described an investigation on the effects of several nonsteroidal anti-inflammatory agents on mouse palatal fusion both in vivo and in vitro (2). All of the compounds were found to induce some degree of cleft palate, although indomethacin was associated with the lowest frequency of cleft palate of the five agents tested (diclofenac, indomethacin, mefenamic acid, naproxen, and sulindac). Indomethacin crosses the placenta to the fetus with concentrations in the fetus equal to those in the mother (3). Twenty-six women, between 23 and 37 weeks' gestation, who were undergoing cordocenteses for varying indications, were given a single 50-mg oral dose approximately 6 hours before the procedure. Mean maternal and fetal indomethacin levels were 218 and 219 ng/mL, respectively, producing a mean ratio of 0.97. The mean amniotic fluid level, 21 ng/mL, collected during cordocenteses, was significantly lower than the maternal and fetal concentrations. Neither fetal nor amniotic fluid concentrations varied with gestational age. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 114 newborns had been exposed to indomethacin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Seven (6.1%) major birth defects were observed (five expected), two of which were cardiovascular defects (one expected). No anomalies were observed in five other defect categories (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. A combined 2001 population-based observational cohort study and a case-control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (4). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with spontaneous abortions (SABs) (see Ibuprofen for details). Indomethacin is occasionally used in the treatment of premature labor (5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26, 27,28,29,30,31,32,33,34,35,36 and 37). The drug acts as a prostaglandin synthesis inhibitor and is an effective tocolytic agent, including in those cases resistant to b-mimetics. Niebyl (30) reviewed this topic in 1981. Daily doses ranged from 100 to 200 mg usually by the oral route, but rectal administration was used as well. In most cases, indomethacin, either alone or in combination with other tocolytics, was successful in postponing delivery until fetal lung maturation had occurred. More recent reviews on the use of indomethacin as a tocolytic agent appeared in 1992 (34) and 1993 (35). The latter review concluded that the prostaglandin synthesis inhibitors, such as indomethacin, may be the only effective tocolytic drugs (35). In a 1986 report, 46 infants exposed in utero to indomethacin for maternal tocolysis were compared with two control groups: (a) 43 infants exposed to other tocolytics and (b) 46 infants whose mothers were not treated with tocolytics (31). Indomethacin-treated women received one or two courses of 150 mg orally over 24 hours, all before 34 weeks' gestation. No significant differences were observed between the groups in Apgar scores, birth weight, or gestational age at birth. Similarly, no differences were found in the number of neonatal complications such as hypocalcemia, hypoglycemia, respiratory distress syndrome, need for continuous positive airway pressure, pneumothorax, patent ductus arteriosus, sepsis, exchange transfusion for hyperbilirubinemia, congenital anomalies, or mortality. A 1989 study compared indomethacin, 100-mg rectal suppository followed by 25 mg orally every 4 hours for 48 hours, with IV ritodrine in 106 women in preterm labor with intact membranes who were at a gestational age of 32 weeks or less (36). Fifty-two women received indomethacin and 54 received ritodrine. Thirteen (24%) of the ritodrine group developed adverse drug reactions severe enough to require discontinuance of the drug and a change to magnesium sulfate: cardiac arrhythmia (N=1), chest pain (N=2), tachycardia (N=3), and hypotension (N=7). None of the indomethacin-treated women developed drug intolerance (p4 cm), severe side effects occurred, or uterine quiescence was achieved (6,7). Ketorolac was significantly better than magnesium sulfate in the time required to stop uterine contractions (2.7 vs. 6.2 hours), but no difference was found between the two regimens for the other parameters (failed tocolysis, birth weight, gestational age at delivery, and neonatal morbidity). There was no difference in the incidence of maternal and neonatal adverse effects between the groups (6,7). Because ketorolac is a prostaglandin synthesis inhibitor, constriction of the ductus arteriosus in utero and fetal renal impairment are potential complications when multiple doses of the drug are administered during the latter half of pregnancy (8) (see also Indomethacin). Premature closure of the ductus can result in primary pulmonary hypertension of the newborn that, in severe cases, may be fatal (8). Other complications that have been associated with NSAIDs are inhibition of labor and prolongation of pregnancy (see above). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ketorolac, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (9,10). Moreover, as noted above, NSAIDs have been associated with SABs. [*Risk Factor D if used in the 3rd trimester or near delivery.]
Breast Feeding Summary Ketorolac is excreted into breast milk (11). Ten women, 2 to 6 days postpartum, were given oral ketorolac, 10 mg 4 times daily for 2 days. Their infants were not allowed to breast-feed during the study. Four of the women had milk concentrations of the drug below the detection limit of the assay (2.5 mmol/L), while the maternal level of haloperidol at delivery was about 1.6 ng/mL (40). The effects observed in the fetus and newborn were attributed to cardiac and cerebral manifestations of lithium intoxication. No follow-up on the infant was reported. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 62 newborns had been exposed to lithium during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (3.2%) major birth defects were observed (three expected), one of which was a polydactyly (0.2 expected). No anomalies were observed in five other categories of defects (cardiovascular defects, oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available. Fetal red blood cell choline levels are elevated during maternal therapy with lithium (41). The clinical significance of this effect on choline, the metabolic precursor to acetylcholine, is unknown but may be related to the teratogenicity of lithium because of its effect on cellular lithium transport (41). In an in vitro study, lithium had no effect on human sperm motility (42). A review published in 1995 used a unique system to assess the reproductive toxicity of lithium in animals and humans (43). Following an extensive evaluation of the available literature, for both experimental animals and humans, up through the early 1990's, a committee concluded that lithium, at concentrations within the human therapeutic range, could induce major malformations (particularly cardiac) and may be associated with neonatal toxicity. The evaluation included an assessment of human reproductive toxicity from lithium exposure in food, mineral supplements, swimming pools and spas, and drinking water, as well as from other environmental or occupational exposures. Because a linear relationship between lithium and toxicity was assumed, these exposures, which produce concentrations of lithium well below therapeutic levels, were not thought to produce human toxicity (43). In the mother, renal lithium clearance rises during pregnancy, returning to pre-pregnancy levels shortly after delivery (44). In four patients, the mean clearance before delivery was 29 mL/minute, declining to 15 mL/minute 6–7 weeks after delivery, a statistically significant difference (p7.0 for congenital malformations, particularly Möbius sequence, was found among 732 children born after 1990 who were attending five outpatient genetic clinics in Brazil (24). About 10% of the children had been exposed in utero to misoprostol. There were 25 cases of Möbius syndrome, 24 cases of reduction of phalanges, and 227 cases with isolated malformations. Associations with misoprostol occurred in 17 (68%), 7 (29%), and 15 (6.6%), respectively, of the cases (24). A below-the-knee amputation was observed in a female newborn delivered at 29 weeks' gestation because of fetal distress (25). An abortion had been attempted at about 13 weeks' under medical supervision. A single misoprostol tablet (strength not specified) had been inserted vaginally for 4 days, but only some vaginal bleeding had occurred on day 4. Spontaneous rupture of the membranes was documented at about 26 weeks' gestation (25). A 1998 study proposed that the abnormalities observed in children exposed in utero during the 1st trimester to misoprostol were induced by uterine contractions that caused vascular disruption in the fetuses, including ischemia of the brain-stem (26). Of the 42 infants with congenital malformations, 17 had equinovarus with cranial nerve defects (usually of nerves 5, 6, and 7), 10 had equinovarus as part of a more extensive arthrogryposis, and 9 had terminal transverse-limb defects. Five children had a distinctive arthrogryposis, without cranial nerve injury, that was confined to the legs. Severe amyoplasia of the legs was confirmed in five children by electromyography, and two of the cases had deficient anterior horn cell activity. Eight had hydrocephalus associated with increased pressure that required shunt placement to relieve. One child had an omphalocele, but no evidence of cranial nerve defects of arthrogryposis (26). A 1997 abstract and 1999 full report described a prospective, observational cohort study of 86 misoprostol-exposed pregnancies compared with 86 pair-matched controls (27,28). All of the women had called a teratogen information service regarding pregnancy exposure to either misoprostol or nonteratogenic agents. There were no statistical differences between the groups in the rates of major (2/67 vs. 2/81) or minor (7/67 vs. 3/81) malformations, gestational age at birth, prematurity, birth weight, low birth weight, sex ratio, or rates of cesarean section. However, there were more abortions in the exposed group, 17.1% vs. 5.8%, relative risk 2.97, 95% CI 1.12–7.88. The sample size had limited power as it was only able to detect an eight-fold increase in the risk of major malformations (28). A study published in 2000 reported the clinical evaluations of 15 children (8 males, 7 females; average age 2 years) from Salvador and Brazil with misoprostol-induced arthrogryposis (29). Their mothers had taken 400–4800 µg of misoprostol, orally or vaginally, from 8 to 12 weeks' gestation for attempted abortions. Common pathologic features in the children were growth retardation, underdeveloped bones, short feet with equinovarus, rigidity of joints with skin dimples and webs, neurologic impaired leg movement, bilateral symmetrical hypoplasia or atrophy of limb muscles, and absent tendon reflexes. Twelve had normal intelligence (information not available for the other three). Other abnormalities included neurogenic bladder/bowel (N=9), hip dislocation (N=6), upper and lower limb deformity (N=5), cryptorchidism (N=2), inguinal hernia (N=2), and single cases of medullar stenosis/syringomyelia, spina bifida, abdominal muscle hypoplasia, and nail hypoplasia. Neurogenic patterns suggestive of anterior horn cell defects were observed on electromyogram in five children (29). In another 2000 report, a multicenter, case-control study compared the frequency of misoprostol exposure in 93 children with vascular disruption anomalies (subjects) and 279 children with other types of defects (controls) (30). All of the children were born after 1992. Congenital malformations classified as vascular disruptions in the subject cases were Möbius syndrome (N=29), transverse limb reduction (N=27), hemifacial microsomia (N=16), arthrogryposis (N=9), microtia (N=9), porencephalic cyst (N=2), and hypoglossia hypodactyly (N=1). Misoprostol exposure (all for attempted abortion) occurred in 32 subject cases (34.4%) compared to 12 controls (4.3%), p100 ng/mL; 10 times the IC50) in the neonates was maintained in all infants at 7 days of age, whether or not they received nevirapine at 72 hours. No serious adverse effects attributable to nevirapine were observed (3). The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (4). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.8–3.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.3–3.0). The prevalence rates for the two periods did not differ significantly, nor did they differ from the rates expected in a nonexposed population (4). There were 162 outcomes exposed to nevirapine (57 in the 1st trimester and 105 in the 2nd and/or 3rd trimesters) either alone (1 in the 3rd trimester) or in combination with other antiretroviral agents (4). There were four infants with birth defects, three exposed in the 1st trimester and one exposed during the 2nd and/or 3rd trimesters. The specific defects and treatments were not identified. In comparing the outcomes of prospectively registered cases to the birth defects among retrospective cases (pregnancies reported after the outcomes were known), the Registry concluded that there was no pattern of anomalies to suggest a common cause (4). (See Lamivudine for required statement.) A 2000 case report described the pregnancy outcomes of two pregnant women with HIV infection who were treated with the anti-infective combination trimethoprim/sulfamethoxazole for prophylaxis against Pneumocystis carinii, concurrently with antiretroviral agents (5). One of the cases involved a 31-year-old woman who presented at 15 weeks' gestation. She was receiving trimethoprim/sulfamethoxazole, didanosine, stavudine, nevirapine, and vitamin B supplements (specific vitamins and dosage not given) that had been started before conception. A fetal ultrasound at 19 weeks' gestation revealed spina bifida and ventriculomegaly. The patient elected to terminate her pregnancy. The fetus did not have HIV infection. Defects observed at autopsy included ventriculomegaly, an Arnold-Chiari malformation, sacral spina bifida, and a lumbosacral meningomyelocele. The authors attributed the neural tube defects to the antifolate activity of trimethoprim (5). A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (6). Many of the women were substance abusers. Nevirapine was used in combination with zidovudine, didanosine, and/or lamivudine in two of the women. Antiretroviral therapy was initiated at a median of 14 weeks' gestation (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. No adverse outcomes were noted in the two nevirapine-exposed cases (6). A 1999 study compared the safety and efficacy of a short course of nevirapine to zidovudine for the prevention of mother-to-child transmission of HIV-1 (7). At the onset of labor, women were randomly assigned to receive either a single dose of nevirapine (200 mg) plus a single dose (2 mg/kg) to their infants 24–72 hours after birth (N=310) or zidovudine (600 mg then 300 mg every 3 hours until delivery) plus 4 mg/kg twice daily for 7 days to their infants (N=308). Nearly all (98.8%) of the women breast-fed their infants immediately after birth. Up to age 14–16 weeks, significantly fewer infants in the nevirapine group were HIV-1 infected, lowering the risk of infection or death, compared with zidovudine, by 48% (95% CI, 24–65) (7). The prevalence of maternal and infant adverse effects was similar in the two groups. In an accompanying study, the nevirapine regimen was shown to be cost-effective in various seroprevalence settings (8). In summary, the limited human data do not allow a prediction as to the safety of nevirapine during early pregnancy even though the drug was not teratogenic in two animal species. The toxic effects on rat fertility and fetal weight gain at systemic levels at or slightly higher than those obtained in humans suggests that there is a potential for risk. Moreover, exposure of the human embryo/fetus is likely to occur because the agent, at least at term, readily crosses the human placenta. Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (9,10). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (11). Although the study cited above (7) has shown that single doses of nevirapine administered to mothers and their infants were more effective in lowering the risk of HIV infection and death than a short course of maternal and newborn zidovudine, confirmation of these findings is required before nevirapine can be recommended for this purpose. Moreover, in utero exposure to nevirapine during the 2nd and 3rd trimesters may induce hepatic cytochrome P450 CYP3A metabolism, thereby increasing the drug's clearance in the newborn (12). Therefore, offspring of pregnant women chronically treated with nevirapine may not receive protection from HIV infection for the full 7 days observed in those not exposed to chronic dosing (12). Because the efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn are unknown, zidovudine remains the only antiretroviral agent recommended for this purpose in developed countries (9,10). A review published in 2000 reviewed seven clinical trials that have been effective in reducing perinatal transmission, five with zidovudine alone, one with zidovudine plus lamivudine, and one with nevirapine (13). Six of the trials were in less-developed countries. Prolonged use of zidovudine in the mother and infant was the most effective for preventing vertical transmission, but also the most expensive. Single-dose nevirapine (in the mother and infant) was the least expensive and the simplest regimen to administer (13).
Breast Feeding Summary Nevirapine is excreted into human breast milk. In a study reported by the manufacturer, nevirapine was found in the breast milk of 10 women with HIV-1 infection given a single oral dose of 100 or 200 mg a mean 5.8 hours before delivery (1). In 21 HIV-infected women who had received a single 200-mg dose of nevirapine during labor, the median milk:maternal plasma ratio was 60.5% (range 25.3%–122.2%) (3). At 48 hours after birth, the median breast milk concentration was 454 ng/mL (range 219–972 ng/mL), declining to 103 ng/mL (range 50–309 ng/mL) 7 days after birth (3). HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (9,10,14,15 and 16). In less-developed countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Zidovudine, zidovudine plus lamivudine, and nevirapine have all been shown to
reduce, but not eliminate, the risk of HIV-1 transmission during breast feeding (see also Lamivudine and Zidovudine) (13). References 1. Product information. Viramune. Roxane Laboratories, 2001. 2. Mirochnick M, Fenton T, Gagnier P, Pav J, Gwynne M, Siminski S, Sperling RS, Beckerman K, Jimenez E, Yogev R, Spector SA, Sullivan JL, for the Pediatric AIDS Clinical Trials Group Protocol 250 team. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998;178:368–74. 3. Musoke P, Guay LA, Bagenda D, Mirochnick M, Nakabiito C, Fleming T, Elliott T, Horton S, Dransfield K, Pav JW, Murarka A, Allen M, Fowler MG, Mofenson L, Hom D, Mmiro F, Jackson JB. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999;13:479–86. 4. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):1–55. 5. Richardson MP, Osrin D, Donaghy S, Brown NA, Hay, Sharland M. Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole. Eur J Obstet Gynecol Reprod Biol 2000;93:215–7. 6. McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:641–6. 7. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795–802. 8. Marseille E, Kahn JG, Mmiro F, Guay L, Musoke P, Fowler MG, Jackson JB. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet 1999;354:803–9. 9. Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276:146–54. 10. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89. 11. Centers for Disease Control and Prevention. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR-2. 12. Taylor GP, Lyall EGH, Back D, Ward C, Tudor-Williams G. Pharmacological implications of lengthened in-utero exposure to nevirapine. Lancet 2000;355:2134–5. 13. Mofenson LM, McIntyre JA. Advances and research directions in the prevention of mother-to-child HIV-1 transmission. Lancet 2000;355:2237–44. 14. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89. 15. de Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7. 16. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.
Index
NIACIN Drugs in Pregnancy and Lactation
Name: NIACIN Class: Vitamin/Antilipemic Agent
Risk Factor:
Fetal Risk Summary Breast Feeding Summary
Fetal Risk Summary Niacin, a B complex vitamin, is converted in humans to niacinamide, the active form of vitamin B3 (see Niacinamide). [*Risk Factor C if used in doses above the RDA or CM for doses typically used for lipid disorders.]
Breast Feeding Summary See Niacinamide. Index
A*
NIACINAMIDE Drugs in Pregnancy and Lactation
Name: NIACINAMIDE Class: Vitamin
Risk Factor:
A*
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Niacinamide, a water-soluble B complex vitamin, is an essential nutrient required for lipid metabolism, tissue respiration, and glycogenolysis (1). Both niacin, which is converted to niacinamide in vivo, and niacinamide are available commercially and are collectively known as vitamin B3. The National Academy of Sciences' recommended dietary allowance for niacin in pregnancy is 17 mg (1). Only two reports have been located that link niacinamide with maternal or fetal complications. A 1948 study observed an association between niacinamide deficiency and pregnancy-induced hypertension (PIH) (2). Other B complex vitamins have also been associated with this disease, but any relationship between vitamins and PIH is controversial (see other B complex vitamins). One patient with hyperemesis gravidarum presented with neuritis, reddened tongue, and psychosis (3). She was treated with 100 mg of niacin plus other B complex vitamins, resulting in the rapid disappearance of her symptoms. The authors attributed her response to the niacin. Niacinamide is actively transported to the fetus (4,5). Higher concentrations are found in the fetus and newborn, rather than in the mother (5,6,7 and 8). Deficiency of niacinamide in pregnancy is uncommon except in women with poor nutrition (6,7). At term, mean niacinamide values in 174 mothers were 3.9 µg/mL (range 2.0–7.2 µg/mL) and in their newborns 5.8 µg/mL (range 3.0–10.5 µg/mL) (6). Conversion of the amino acid tryptophan to niacin and then to niacinamide is enhanced in pregnancy (9). [*Risk Factor C if used in doses above the RDA.]
Breast Feeding Summary Niacin, the precursor to niacinamide, is actively excreted in human breast milk (10). Reports on the excretion of niacinamide in milk have not been located, but it is probable that it also is actively transferred. In a study of lactating women with low nutritional status, supplementation with niacin in doses of 2.0–60.0 mg/day resulted in mean milk concentrations of 1.17–2.75 µg/mL (10). Milk concentrations were directly proportional to dietary intake. A 1983 English study measured niacin levels in pooled human milk obtained from mothers of preterm (26 mothers, 29–34 weeks) and term (35 mothers, 39 weeks or longer) infants (11). Niacin in milk from preterm mothers rose from 0.65 µg/mL (colostrum) to 2.05 µg/mL (16–196 days), whereas that in milk from term mothers increased during the same period from 0.50 to 1.82 µg/mL. The National Academy of Sciences' recommended dietary allowance (RDA) for niacin during lactation is 20 mg (1). If the diet of the lactating woman adequately supplies this amount, supplementation with niacinamide is not needed. Maternal supplementation with the RDA for niacinamide is recommended for those patients with inadequate nutritional intake. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
American Hospital Formulary Service. Drug Information 1997. Bethesda, MD: American Society of Health-System Pharmacists, 1997:2811–13. Hobson W. A dietary and clinical survey of pregnant women with particular reference to toxaemia of pregnancy. J Hyg 1948;46:198–216. Hart BF, McConnell WT. Vitamin B factors in toxic psychosis of pregnancy and the puerperium. Am J Obstet Gynecol 1943;46:283. Hill EP, Longo LD. Dynamics of maternal-fetal nutrient transfer. Fed Proc 1980;39:239–44. Kaminetzky HA, Baker H, Frank O, Langer A. The effects of intravenously administered water-soluble vitamins during labor in normovitaminemic and hypovitaminemic gravidas on maternal and neonatal blood vitamin levels at delivery. Am J Obstet Gynecol 1974;120:697–703. Baker H, Frank O, Thomson AD, Langer A, Munves ED, De Angelis B, Kaminetzky HA. Vitamin profile of 174 mothers and newborns at parturition. Am J Clin Nutr 1975;28:59–65. Baker H, Frank O, Deangelis B, Feingold S, Kaminetzky HA. Role of placenta in maternal-fetal vitamin transfer in humans. Am J Obstet Gynecol 1981;141:792–6. Baker H, Thind IS, Frank O, DeAngelis B, Caterini H, Lquria DB. Vitamin levels in low-birth-weight newborn infants and their mothers. Am J Obstet Gynecol 1977;129:521–4. Wertz AW, Lojkin ME, Bouchard BS, Derby MB. Tryptophan-niacin relationships in pregnancy. Am J Nutr 1958;64:339–53. Deodhar AD, Rajalakshmi R, Ramakrishnan CV. Studies on human lactation. Part III. Effect of dietary vitamin supplementation on vitamin contents of breast milk. Acta Paediatr Scand 1964;53:42–8. Ford JE, Zechalko A, Murphy J, Brooke OG. Comparison of the B vitamin composition of milk from mothers of preterm and term babies. Arch Dis Child 1983;58:367–72.
Index
NIALAMIDE Drugs in Pregnancy and Lactation
Name: NIALAMIDE Class: Antidepressant
Risk Factor:
Fetal Risk Summary Breast Feeding Summary Reference
Fetal Risk Summary No reports describing the use of this monoamine oxidase inhibitor in human pregnancy have been located. No teratogenic effects were observed in the offspring of female rats administered this drug before and during gestation, and to the pups after weaning (1). However, decreased fertility and neurobehavioral changes were observed in the young rats (1).
Breast Feeding Summary No data are available. Reference 1. Tuchmann-Duplessis H, Mercier-Parot L. Modifications du comportement sexual chez des descendants de rats traites par un inhibiteur des monoamine-oxydases. C R Acad Sci (Paris) 1963;256:2235–7. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:447.
Index
C
NICARDIPINE Drugs in Pregnancy and Lactation
Name: NICARDIPINE Class: Calcium Channel Blocker
Risk Factor:
CM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Nicardipine is a calcium channel-blocking agent used in the treatment of angina and hypertension. The drug has also been used as a tocolytic in premature labor. Dose-related embryotoxicity, but not teratogenicity, was observed in reproduction studies using IV nicardipine in rats and rabbits (1). Embryotoxic doses were about 2.5 and 0.5 times, respectively, the maximum recommended human dose (MRHD). At 50 times the MRHD in rats, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted (1). In one type of rabbit, but not in another, high doses (about 75 times the MRHD) were embryocidal (1). Two studies with rats reported that in utero exposure had no effect on postnatal function or subsequent fertility (2,3). Nicardipine 20 µg/kg/minute was infused for 2 minutes in 15 near-term ewes given angiotensin II 5 µg/minute (4). Transient bradycardia was observed in the fetuses, followed by hypercapnia and acidemia. These changes were associated with a decrease in fetal placental blood flow and an increase in fetal vascular resistance, and five fetuses died 65 minutes after nicardipine was given. In the second part of this study in the pregnant ewe, nicardipine was found to reverse maternal angiotensin II–induced systemic vasoconstriction, including that of the renal and endomyometrial vascular beds, but it caused a significant increase in placental vascular resistance (5). The use of nicardipine as a tocolytic agent was first investigated in an experiment using excised rabbit uterus and in laboring (either spontaneous or induced) rats (6). In both species, the calcium channel blocker was effective in abolishing uterine contractions. A 1983 study investigated the effect of nicardipine and nifedipine on isolated human pregnant-term and nonpregnant myometrium (7). Nicardipine was a more potent tocolytic than nifedipine in pregnant myometrium, but its onset of action was slower. Because the cardiovascular and myometrial responses of pregnant rabbits are similar to those observed in human pregnancies (8), a series of studies was conducted in the rabbit with nicardipine to determine its effectiveness as a tocolytic agent and its safety for the mother and the fetus (8,9 and 10). A statistically significant inhibition of uterine contractions was recorded in each study, but this effect was accompanied by maternal tachycardia, an increase in cardiac output, a drop in both diastolic and systolic blood pressure and mean arterial pressure, and a decrease in uteroplacental blood flow. The authors of these studies cautioned that further trials were necessary because the decrease in uteroplacental blood flow would seriously jeopardize the fetus (9,10). In a study to determine the tocolytic effects of nicardipine in a primate species, pregnant rhesus monkeys with spontaneous uterine contractions were treated with an IV bolus of 500 µg, followed by a continuous infusion of 6 µg/kg/minute for 1 hour (11). Placental transfer of nicardipine was demonstrated with peak fetal concentrations ranging from 7 to 35 ng/mL compared with maternal peak levels of 175–865 ng/mL. Although a marked tocolytic effect was observed, significant acidemia and hypoxemia developed in the fetuses. The tocolytic effects of nicardipine have been reported (12,13 and 14). The agent compared favorably to albuterol (12) and magnesium sulfate (13,14). No adverse effects in the newborns attributable to nicardipine were observed. The direct effects of nicardipine on the fetus were investigated in a study using fetal sheep (15). Infusions of nicardipine, either 50 µg or 100 µg, had minimal, nonsignificant effects on mean arterial and diastolic blood pressure and no effect on fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables. The authors concluded that the fetal hypoxia observed in other animal studies, when nicardipine was administered to the mother, was not due to changes in umbilical or ductal blood flow but to a decrease in maternal uterine blood flow (15). A single 10-mg dose of nicardipine was given to eight women with acute hypertension (diastolic blood pressure >105 mm Hg) in the 3rd trimester of pregnancy (16). A significant decrease in maternal diastolic, but not in systolic, pressure was observed during the next 60 minutes with an onset at 15 minutes. Nicardipine has been used in human pregnancy for the treatment of hypertension (17,18). Forty women with mild or moderate hypertension (25 with gestational hypertension without proteinuria, 3 with preeclampsia, and 12 with chronic hypertension) were treated with oral nicardipine 20 mg 3 times a day, beginning at 28 weeks' gestation through the 7th postpartum day, a mean duration of 9 weeks (17). An additional 20 women were treated with IV nicardipine for severe preeclampsia, 5 of whom also had chronic hypertension, beginning at a mean 33 weeks' gestation (range 27–40 weeks). The IV dose used was based on body weight: 2 mg/hour (N=9; 90 kg). The mean duration of IV therapy was 5.3 days (range 2–15 days). Low placental passage of nicardipine was demonstrated in 10 women, 7 on oral therapy and 3 receiving IV therapy, but no accumulation of the drug was observed in the fetus. No perinatal deaths, fetal adverse effects, or adverse neonatal outcomes attributable to nicardipine were observed during treatment. Both umbilical and cerebral Doppler velocimetry remained stable throughout the study (17). A study published in 1994 compared nicardipine and metoprolol in the treatment of hypertension (pregnancy-induced, preeclampsia, and chronic) during pregnancy (18). Fifty patients were treated in each group starting at a gestational age of about 29 weeks. Nicardipine decreased maternal systolic and diastolic blood pressure and umbilical artery resistance significantly more than metoprolol and significantly fewer patients required a cesarean section for fetal distress (6% vs. 28%). The difference in birth weights in the two groups was 201 g (2952 vs. 2751 g) (n.s.) (18). A prospective multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st-trimester exposure to calcium channel blockers (none of whom took nicardipine) was reported in 1996 (19). Compared with controls, no increased risk of congenital malformations was found.
Breast Feeding Summary The manufacturer states that significant amounts of nicardipine appear in milk of lactating rats (1). No reports on the use of nicardipine during nursing in humans or reports measuring the amount excreted into human milk have been located. References 1. Product information. Cardene. Wyeth-Ayerst Pharmaceuticals, 2000. 2. Sejima Y, Sado T. Teratological study of 2-(N-benzyl-N-methylamino) ethyl methyl 2,6-dimethyl-4-m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (YC-93) in rats. Kiso to Rinsho 1979;13:1149–59. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:447. 3. Sato T, Nagaoka T, Fuchigami K, Ohsuga F, Hatano M. Reproductive studies of 2-(N-benzyl-N-methylamino) ethyl methyl 2,6-dimethyl-4-m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (YC-93) in rats and rabbits. Kiso to Rinsho 1979;13:1160–76. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:447. 4. Parisi VM, Salinas J, Stockmar EJ. Fetal vascular responses to maternal nicardipine administration in the hypertensive ewe. Am J Obstet Gynecol 1989;161:1035–9. 5. Parisi VM, Salinas J, Stockmar EJ. Placental vascular responses to nicardipine in the hypertensive ewe. Am J Obstet Gynecol 1989;161:1039–43. 6. Csapo AI, Puri CP, Tarro S, Henzel MR. Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine. Am J Obstet Gynecol 1982;142:483–91. 7. Maigaard S, Forman A, Andersson KE, Ulmsten U. Comparison of the effects of nicardipine and nifedipine on isolated human myometrium. Gynecol Obstet Invest 1983;16:354–66. 8. Lirette M, Holbrook RH, Katz M. Effect of nicardipine HCl on prematurely induced uterine activity in the pregnant rabbit. Obstet Gynecol 1985;65:31–6. 9. Litette M, Holbrook RH, Katz M. Cardiovascular and uterine blood flow changes during nicardipine HCl tocolysis in the rabbit. Obstet Gynecol 1987;69:79–82. 10. Holbrook RH Jr, Lirette M, Katz M. Cardiovascular and tocolytic effects of nicardipine HCl in the pregnant rabbit: comparison with ritodrine HCl. Obstet Gynecol 1987;69:83–7. 11. Ducsay CA, Thompson JS, Wu AT, Novy MJ. Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: fetal plasma concentrations and cardiorespiratory changes. Am J Obstet Gynecol 1987;157:1482–6. 12. Jannet D, Abankwa A, Guyard B, Carbonne B, Marpeau L, Milliez J. Nicardipine versus salbutamol in the treatment of premature labor. A prospective randomized study. Eur J Obstet Gynaecol Reprod Med 1997;73:11–6. 13. Ross EL, Ross BS, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor (abstract). Am J Obstet Gynecol 1998;178:S181. 14. Larmon JE, Ross BS, May WL, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 1999;181:1432–7. 15. Holbrook RH, Voss EM, Gibson RN. Ovine fetal cardiorespiratory response to nicardipine. Am J Obstet Gynecol 1989;161:718–21.
16. Walker JJ, Mathers A, Bjornsson S, Cameron AD, Fairlie FM. The effect of acute and chronic antihypertensive therapy on maternal and fetoplacental Doppler velocimetry. Eur J Obstet Gynecol Reprod Biol 1992;43:193–9. 17. Carbonne B, Jannet D, Touboul C, Khelifati Y, Milliez J. Nicardipine treatment of hypertension during pregnancy. Obstet Gynecol 1993;81:908–14. 18. Jannet D, Carbonne B, Sebban E, Milliez J. Nicardipine versus metoprolol in the treatment of hypertension during pregnancy: a randomized comparative trial. Obstet Gynecol 1994;84:354–9. 19. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, McElhatton PR, Schmidt MA, Koren G. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996;174:823–8.
Index
NICOTINYL ALCOHOL Drugs in Pregnancy and Lactation
Name: NICOTINYL ALCOHOL Class: Vasodilator
Risk Factor:
C
Fetal Risk Summary Breast Feeding Summary Reference
Fetal Risk Summary Nicotinyl alcohol is converted in the body to niacin, the active form. Only one report of its use in pregnancy has been located. The Collaborative Perinatal Project recorded one 1st-trimester exposure to nicotinyl alcohol plus 14 other patients exposed to other vasodilators (1). From this small group of 15 patients, 4 malformed children were produced, a statistically significant incidence (p50 mU/L) compared with bottle-fed infants. The normal iodine content of human milk has been recently assessed (13). Mean iodide levels in 37 lactating women were 178 µg/L. This is approximately 4 times the recommended daily allowance (RDA) for infants. The RDA for iodine was based on the amount of iodine found in breast milk in earlier studies (13). The higher levels now are probably caused by dietary supplements of iodine (e.g., salt, bread, cow's milk). The significance to the nursing infant from the chronic ingestion of higher levels of iodine is not known. The American Academy of Pediatrics, although recognizing that the maternal use of iodides during lactation may affect the infant's thyroid activity by producing elevated iodine levels in breast milk, considers the agents to be compatible with breast feeding (14). References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Wolff J. Iodide goiter and the pharmacologic effects of excess iodide. Am J Med 1969;47:101–24. Herbst AL, Selenkow HA. Hyperthyroidism during pregnancy. N Engl J Med 1965;273:627–33. Selenkow HA, Herbst AL. Hyperthyroidism during pregnancy. N Engl J Med 1966;274:165–6. Mehta PS, Mehta SJ, Vorherr H. Congenital iodide goiter and hypothyroidism: a review. Obstet Gynecol Surv 1983;38:237–47. I'Allemand D, Gruters A, Heidemann P, Schurnbrand P. Iodine-induced alterations of thyroid function in newborn infants after prenatal and perinatal exposure to povidone iodine. J Pediatr 1983;102:935–8. Bachrach LK, Burrow GN, Gare DJ. Maternal-fetal absorption of povidone-iodine. J Pediatr 1984;104:158–9. Jacobson JM, Hankins GV, Young RL, Hauth JC. Changes in thyroid function and serum iodine levels after prepartum use of a povidone-iodine vaginal lubricant. J Reprod Med 1984;29:98–100. Danziger Y, Pertzelan A, Mimouni M. Transient congenital hypothyroidism after topical iodine in pregnancy and lactation. Arch Dis Child 1987;62:295–6. Committee on Drugs. American Academy of Pediatrics. Adverse reactions to iodide therapy of asthma and other pulmonary diseases. Pediatrics 1976;57:272–4. Postellon DC, Aronow R. Iodine in mother's milk. JAMA 1982;247:463. Casteels K, Punt S, Bramswig J. Transient neonatal hypothyroidism during breastfeeding after post-natal maternal topical iodine treatment. Eur J Pediatr 2000;159:716–7. Chanoine JP, Boulvain M, Bourdoux P, Pardou A, Van Thi HV, Ermans AM, Delange F. Increased recall rate at screening for congenital hypothyroidism in breast fed infants born to iodine overloaded mothers. Arch Dis Child 1988;63:1207–10. Gushurst CA, Mueller JA, Green JA, Sedor F. Breast milk iodide: reassessment in the 1980s. Pediatrics 1984;73:354–7. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
Index
POTASSIUM CHLORIDE Drugs in Pregnancy and Lactation
Name: POTASSIUM CHLORIDE Class: Electrolyte
Risk Factor:
A
Fetal Risk Summary Breast Feeding Summary Reference
Fetal Risk Summary Potassium chloride is a natural constituent of human tissues and fluids. Exogenous potassium chloride may be indicated as replacement therapy for pregnant women with low serum potassium levels, such as those receiving diuretics. Because high or low levels are detrimental to maternal and fetal cardiac function, serum levels should be closely monitored. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 35 newborns had been exposed to oral potassium salts during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.9%) infant with major birth defects was observed (one expected), a case of limb reduction and hypospadias.
Breast Feeding Summary Human milk is naturally low in potassium (1). If maternal serum levels are maintained in a physiologic range, no harm will result in the nursing infant from the administration of potassium chloride to the mother. Reference 1. Wilson JT. Production and characteristics of breast milk. In Wilson JT, ed. Drugs in Breast Milk. Balgowlah, Australia: ADIS Press, 1981:12.
Index
POVIDONE-IODINE Drugs in Pregnancy and Lactation
Name: POVIDONE-IODINE Class: Anti-infective
Risk Factor:
Fetal Risk Summary Breast Feeding Summary
Fetal Risk Summary See Potassium Iodide.
Breast Feeding Summary See Potassium Iodide. Index
D
PRAVASTATIN Drugs in Pregnancy and Lactation
Name: PRAVASTATIN Class: Antilipemic Agent
Risk Factor:
XM
Fetal Risk Summary Breast Feeding Summary Reference
Fetal Risk Summary Pravastatin is used to lower elevated levels of cholesterol. It has the same cholesterol-lowering mechanism (i.e., inhibition of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase) as some other agents in this class (e.g., see Fluvastatin, Lovastatin, and Simvastatin) and is structurally related to Lovastatin and Simvastatin. Pravastatin was not teratogenic in rats and rabbits administered doses up to 240 times and 20 times, respectively, the human exposure based on surface area (HE) (1). Similarly, no adverse effects on fertility or reproductive performance were observed in rats with doses up to 120 times the HE (1). No published reports describing the use of pravastatin during human pregnancy have been located. The Food and Drug Administration has received a single report of a fetal loss in a mother taking pravastatin, but further details are not available (F. Rosa, personal communication, FDA, 1995). Because the interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia, and because of the human data reported with another inhibitor of HMG-CoA reductase (see Lovastatin), the use of pravastatin is contraindicated during pregnancy.
Breast Feeding Summary No reports describing the use of pravastatin during lactation have been located. The manufacturer reports that pravastatin is excreted into breast milk in small amounts (1). Because of the potential for adverse effects in the nursing infant, the drug should not be used during lactation. Reference 1. Product information. Pravachol. Bristol-Myers Squibb, 2000.
Index
PRAZIQUANTEL Drugs in Pregnancy and Lactation
Name: PRAZIQUANTEL Class: Anthelmintic
Risk Factor:
BM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Praziquantel is a systemic anthelmintic used in the treatment of parasitic infections involving cestodes (tapeworms), including neurocysticercosis, and trematode (flukes) infestations of the liver and other tissues. The drug is rapidly and nearly completely (80%) absorbed following oral administration (1). The various metabolites are excreted primarily by the kidneys. Praziquantel was not carcinogenic in rats and hamsters, but mutagenic effects in Salmonella tests were observed in one laboratory (1). The mutagenicity was not confirmed in the same tested strain by other laboratories (1). Similarly, a study published in 1982 found no mutagenic effects in five strains of Salmonella exposed to praziquantel (2). A 1984 review also described negative mutagenic results in a variety of tests, including those with mice, rats, and humans, and negative carcinogenic results in tests with rats and hamsters (3). A 1997 review, however, cited studies that observed a co-mutagenic effect between praziquantel and several mutagens and carcinogens (4). Praziquantel has also been shown in in vitro studies to induce micronuclei in hamster embryonic cells and lymphocytes (4). Moreover, in some pigs and humans, praziquantel was found to induce hyperploid lymphocytes and structural chromosomal aberrations (4). Reproduction studies in mice, rats, and rabbits at doses up to 40 times the human dose (human dose 60–75 mg/kg over 1 day) showed no evidence of impaired fertility or teratogenicity (1,3). An increase in the abortion rate in rats, however, was observed at doses 3 times the single human therapeutic dose (1). No teratogenicity was observed in other studies in rats and rabbits with doses up to 300 mg/kg (5,6) or in rats with doses up to 450 mg/kg (2). Compared with controls, the administration of praziquantel and ivermectin (another anthelmintic agent) to possums at 8- to 10-week intervals throughout the breeding season to the time of emergence of young from the pouch had no significant effect on the number of births or survival of the young to emergence (7). Authors of a study published in 1985 concluded that treatment of parasitic disease with potentially teratogenic or toxic drugs may not always be indicated in otherwise healthy pregnant women (8). For example, in their study, they found that treatment of some gastrointestinal parasites, including some tapeworms and liver flukes, could be postponed until after delivery unless the parasite was causing clinical disease or public health problems (8). Similarly, reviews in 1996 and 1997 recommended avoiding praziquantel during pregnancy (9,10). The authors are aware of two cases of neurocysticercosis treated with praziquantel during gestation, but no outcome information is available in either case. A 1996 case report, however, described the use of praziquantel for the treatment of neurocysticercosis in a 17-year-old pregnant woman (11). She received praziquantel, 1050 mg three times daily, for 21 days starting at about 8 weeks' gestation. Seizures, which occurred at the time of presentation and again 4 days after the start of anticysticercus therapy, were successfully controlled with phenytoin and carbamazepine. She eventually delivered a 2.5-kg girl at term. Other than documented anemia, no other abnormalities or malformations were found. The placenta appeared normal on gross examination. In summary, praziquantel is not an animal teratogen, but human data are limited to one case. The lack of published human data prevents any assessment of a human risk. Recent data have indicated that the agent may be mutagenic and carcinogenic in humans, especially in developing countries where infections of trematodes and cestodes are frequent and multiple treatment courses may be prescribed. Moreover, the presence of other environmental mutagens combined with praziquantel may increase the risk for mutagenicity (4). Because of this potential toxicity, the use of praziquantel during pregnancy should be reserved for those cases in which the parasite is causing clinical illness or public health problems.
Breast Feeding Summary Because praziquantel is excreted into breast milk at a concentration of about one-fourth that of the maternal serum, the manufacturer advises holding nursing on the day of treatment and during the subsequent 72 hours (1). The drug is excreted primarily in the urine with 80% of the dose being eliminated within 4 days (12). About 90% of this elimination, however, occurs in the first 24 hours (12). No reports describing the use of praziquantel during nursing have been located, but a 1996 review recommended avoiding praziquantel during lactation (9). The effects, if any, on a healthy, noninfected nursing infant from exposure to the drug via breast milk are unknown. Because adverse reactions induced by the death of an infecting parasite have been observed in treated adults (7), nursing infants with parasitic infections sensitive to praziquantel may be at risk for similar adverse effects. Moreover, the potential for mutagenic and carcinogenic effects of the drug should be considered (see Fetal Risk Summary). References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Product information. Biltricide. Bayer Corporation, 1999. Ni YC, Shao BR, Zhan CQ, Xu YQ, Ha SH, Jiao PY. Mutagenic and teratogenic effects of anti-schistosomal praziquantel. Chin Med J 1982;95:494–8. Frohberg H. Results of toxicological studies on praziquantel. Arzneimittelforschung 1984;34:1137–44. Montero R, Ostrosky P. Genotoxic activity of praziquantel. Mutat Res 1997;387:123–39. Muermann P, Von Eberstein M, Frohberg H. Notes on the tolerance of Droncit. Summary of trial results. Ved Med Rev 1976;2:142–65. As cited by Schardein JL. Chemical Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:402–15. Muermann P, Von Eberstein M, Frohberg H. Notes on the tolerance of Droncit. Summary of trial results. Vet Med Rev 1976;2:142–65. As cited by Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:350. Viggers KL, Lindenmayer DB, Cunningham RB, Donnelly CF. The effects of parasites on a wild population of the Mountain Brushtail possum (Trichosurus caninus) in south-eastern Australia. Int J Parasitol 1998;28:747–55. D'Alauro F, Lee RV, Pao-In K, Khairallah M. Intestinal parasites and pregnancy. Obstet Gynecol 1985;66:639–43. Volkheimer G. Intestinal helminthiasis–general practice problem of the gastroenterologist. Z Gastroenterol 1996;34:534–41. de Silva N, Guyatt H, Bundy D. Anthelmintics. A comparative review of their clinical pharmacology. Drugs 1997;53:769–88. Paparone PW, Menghetti RA. Case report: neurocysticercosis in pregnancy. N J Med 1996;93:91–4. Reynolds JEF, editor. Martindale. The Extra Pharmacopoeia. 31st ed. London, England:Royal Pharmaceutical Society, 1996:123–5.
Index
PRAZOSIN Drugs in Pregnancy and Lactation
Name: PRAZOSIN Class: Sympatholytic (Antihypertensive)
Risk Factor:
C
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Prazosin is an a1 -adrenergic blocking agent used for hypertension. No evidence of teratogenicity was observed in reproduction studies with rats, rabbits, and monkeys at doses more than 225, 225, and 12 times, respectively, the usual maximum recommended human dose (1). A decreased litter size at birth in rats, however, was observed at the maximum dose. The molecular weight of prazosin (about 420 for the hydrochloride salt) is low enough that transfer across the placenta to the fetus is likely. Consistent with this, a 1995 study using a 5-mg delayed release formulation in three women measured umbilical cord blood concentrations at delivery that were 9%–23% of the maternal plasma levels 8–15 hours after the last dose (2). In two studies, prazosin was combined with oxprenolol or atenolol, b-adrenergic blockers, in the treatment of pregnant women with severe essential hypertension or pregnancy-induced hypertension (PIH) (3,4). The combinations were effective in the first group but less so in the patients with PIH. No adverse effects attributable to the drugs were noted. Prazosin, 20 mg/day, was combined with minoxidil and metoprolol throughout gestation to treat severe maternal hypertension secondary to chronic nephritis (5). The child, normal except for hypertrichosis as a result of minoxidil, was doing well at 2 years of age. Prazosin has been used during the 3rd trimester in patients with pheochromocytoma (6,7). In one case, blood pressure was well controlled, but maternal tachycardia required the addition of a b-blocker. A healthy male infant was delivered by cesarean section (6). A case report published in 1986 described the pregnancy of a 24-year-old woman at 30 weeks' gestation who was managed for recurrent pheochromocytoma with a combination of prazosin, metyrosine (a tyrosine hydroxylase inhibitor), and timolol (a b-adrenergic blocker) (7). Hypertension had been noted at her first prenatal visit at 12 weeks' gestation. Because of declines in fetal breathing, body movements, and amniotic fluid volume that began 2 weeks after the start of therapy, a cesarean section was conducted at 33 weeks. The 1450-g female infant had Apgar scores of 3 and 5 at 1 and 5 minutes, respectively. Mild metabolic acidosis was found on analysis of umbilical cord blood gases. Multiple infarcts were noted in the placenta but no evidence of metastatic tumor. The growth-retarded infant did well and was discharged home on day 53 of life (7).
Breast Feeding Summary No reports describing the use of prazosin during lactation have been located. The manufacturer reports that small amounts are excreted into human milk (1). This is consistent with the relatively low molecular weight (about 420 for the hydrochloride salt) of the drug. The effects of on a nursing infant from exposure to the drug from breast milk is unknown. References 1. Product information. Minipress. Pfizer, 2000. 2. Bourget P, Fernandez H, Edouard D, Lesne-Hulin A, Ribou F, Baton-Saint-Mleux C, Lelaidier C. Disposition of a new rate-controlled formulation of prazosin in the treatment of hypertension during pregnancy: transplacental passage of prazosin. Eur J Drug Metab Pharmacokinet 1995;20:233–41. 3. Lubbe WF, Hodge JV. Combined alpha- and beta-adrenoceptor antagonism with prazosin and oxprenolol in control of severe hypertension in pregnancy. NZ Med J 1981;94:169–72. 4. Lubbe WF. More on beta-blockers in pregnancy. N Engl J Med 1982;307:753. 5. Rosa FW, Idanpaan-Heikkila J, Asanti R. Fetal minoxidil exposure. Pediatrics 1987;80:120. 6. Venuto R, Burstein P, Schneider R. Pheochromocytoma: antepartum diagnosis and management with tumor resection in the puerperium. Am J Obstet Gynecol 1984;150:431–2. 7. Devoe LD, O'Dell BE, Castillo RA, Hadi HA, Searle N. Metastatic pheochromocytoma in pregnancy and fetal biophysical assessment after maternal administration of alpha-adrenergic, beta-adrenergic, and dopamine antagonists. Obstet Gynecol 1986;68:15S–8S.
Index
PREDNISONE Drugs in Pregnancy and Lactation
Name: PREDNISONE Class: Corticosteroid
Risk Factor:
C*
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Prednisone is metabolized to prednisolone. There are a number of studies in which pregnant patients received either prednisone or prednisolone (see also various antineoplastic agents for additional references) (1,2,3,4,5,6,7,8,9,10,11,12,13 and 14). Although most reports describing the use of prednisone or prednisolone during gestation have not observed abnormal outcomes, four large epidemiologic studies have associated the use of corticosteroids in the 1st trimester with nonsyndromic orofacial clefts. Specific agents were not identified in three of these studies (see Hydrocortisone for details), but in one 1999 study, discussed below, the corticosteroids were listed. In a case-control study, the California Birth Defects Monitoring Program evaluated the association between selected congenital anomalies and the use of corticosteroids 1 month before to 3 months after conception (periconceptional period) (15). Case infants or fetal deaths diagnosed with orofacial clefts, conotruncal defects, neural tubal defects (NTDs), and limb anomalies were identified from a total of 552,601 births that occurred from 1987 through the end of 1989. Controls, without birth defects, were selected from the same data base. Following exclusion of known genetic syndromes, mothers of case and control infants were interviewed by telephone, an average of 3.7 years (cases) or 3.8 years (controls) after delivery, to determine various exposures during the periconceptional period. The number of interviews completed were orofacial cleft case mothers (N=662, 85% of eligible), conotruncal case mothers (N=207, 87%), NTD case mothers (N=265, 84%), limb anomaly case mothers (N=165, 82%), and control mothers (N=734, 78%) (15). Orofacial clefts were classified into four phenotypic groups: isolated cleft lip with or without cleft palate (ICLP, N=348), isolated cleft palate (ICP, N=141), multiple cleft lip with or without cleft palate (MCLP, N=99), and multiple cleft palate (MCP, N=74). A total of 13 mothers reported using corticosteroids during the periconceptional period for a wide variety of indications. Six case mothers of infants with ICLP and three of infants with ICP used corticosteroids (unspecified corticosteroid N=1, prednisone N=2, cortisone N=3, triamcinolone acetonide N=1, dexamethasone N=1, and cortisone plus prednisone N=1). One case mother of an infant with NTD used cortisone and an injectable unspecified corticosteroid, and three controls used corticosteroids (hydrocortisone N=1 and prednisone N=2). The odds ratio for corticosteroid use and ICLP was 4.3 (95% confidence interval [CI] 1.1–17.2), whereas the odds ratio for ICP and corticosteroid use was 5.3 (95% CI 1.1–26.5). No increased risks were observed for the other anomaly groups. Commenting on their results, the investigators thought that recall bias was unlikely because they did not observe increased risks for other malformations, and it was also unlikely that the mothers would have known of the suspected association between corticosteroids and orofacial clefts (15). In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 143, 236, and 222 newborns had been exposed to prednisolone, prednisone, and methylprednisolone, respectively, during the 1st trimester (F. Rosa, personal communication, FDA, 1993). The number of birth defects, the number expected, and the percent for each drug were 11/6 (7.7%), 11/10 (4.7%), and 14/9 (6.3%), respectively. Specific details were available for six defect categories (observed/expected): cardiovascular defects (2/1, 2/2, 3/2), oral clefts (0/0, 0/0, 0/0), spina bifida (0/0, 0/0, 0/0), polydactyly (0/0, 0/1, 0/1), limb reduction defects (0/0, 0/0, 1/0), and hypospadias (1/0, 0/1, 1/1), respectively. These data do not support an association between the drugs and congenital defects, except for a possible association between prednisolone and the total number of defects. In the latter case, other factors, such as the mother's disease, concurrent drug use, and chance may be involved. Immunosuppression was observed in a newborn exposed to high doses of prednisone with azathioprine throughout gestation (16). The newborn had lymphopenia, decreased survival of lymphocytes in culture, absence of IgM, and reduced levels of IgG. Recovery occurred at 15 weeks of age. However, these effects were not observed in a larger group of similarly exposed newborns (17). A 1968 study reported an increase in the incidence of stillbirths following prednisone therapy during pregnancy (7). Increased fetal mortality has not been confirmed by other investigators. An infant exposed to prednisone throughout pregnancy was born with congenital cataracts (1). The eye defect was consistent with reports of subcapsular cataracts observed in adults receiving corticosteroids. The relationship in this case between the cataracts and prednisone is unknown, but other reports have also described cataracts after corticosteroid use during gestation (see Hydrocortisone). In a 1970 case report, a female infant with multiple deformities was described (18). Her father had been treated several years before conception with prednisone, azathioprine, and radiation for a kidney transplant. The authors speculated that the child's defects may have been related to the father's immunosuppressive therapy. A relationship to prednisone seems remote because previous studies have shown that the drug has no effect on chromosome number or morphology (19). High, prolonged doses of prednisolone (30 mg/day for at least 4 weeks) may damage spermatogenesis (20). Recovery may require 6 months after the drug is stopped. Prednisone has been used successfully to prevent neonatal respiratory distress syndrome when premature delivery occurs between 28 and 36 weeks of gestation (21). Therapy between 16 and 25 weeks of gestation had no effect on lecithin:sphingomyelin ratios (22). In summary, prednisone and prednisolone apparently pose a small risk to the developing fetus. One of these risks appears to be orofacial clefts. Although the available evidence supports their use to control various maternal diseases, the mother should be informed of this risk so that she can actively participate in the decision on whether to use these agents during her pregnancy. [*Risk factor D if used in 1st trimester.]
Breast Feeding Summary Trace amounts of prednisone and prednisolone have been measured in breast milk (23,24,25 and 26). Following a 10-mg oral dose of prednisone, milk concentrations of prednisone and prednisolone at 2 hours were 26.7 and 1.6 ng/mL, respectively (23). The authors estimated the infant would ingest approximately 28.3 µg in 1000 mL of milk. In a second study using radioactive-labeled prednisolone in seven patients, a mean of 0.14% of a 5-mg oral dose was recovered per liter of milk during 48–61 hours (24). In six lactating women, prednisolone doses of 10–80 mg/day resulted in milk concentrations ranging from 5% to 25% of maternal serum levels (25). The milk:plasma ratio increased with increasing serum concentrations. For maternal doses of 20 mg once or twice daily, the authors concluded that the nursing infant would be exposed to minimal amounts of steroid. At higher doses, they recommended waiting at least 4 hours after a dose before nursing was performed. However, even at 80 mg/day, the nursing infant would ingest 35 weeks' gestation, recurrent preterm labor, birth weight, or time spent in the neonatal intensive care unit. No adverse effects were observed in the exposed fetuses (13,14). As demonstrated with other NSAIDs (see also Indomethacin), sulindac reduces amniotic fluid volume by decreasing fetal urine output in a dose-related manner (15). Sulindac, 200 mg twice daily, was given to the mothers of three sets of monoamniotic twins, diagnosed as having cord entanglement, beginning at 24, 27, and 29 weeks, respectively, and continued until elective cesarean section at 32 weeks' gestation. One of the twins had a preexisting heart defect (transposition of the great vessels and a ventricular septal defect). The dose was reduced in one patient to 200 mg/day to maintain an adequate amniotic fluid index. No significant changes in the umbilical artery or the ductus arteriosus Doppler waveforms were observed. All of the newborns had appropriate weights for gestation, had normal renal function during the first week of life, and none required ventilation (15). A 2000 abstract described a retrospective case-cohort study that compared the neonatal effects of sulindac with indomethacin (16). The infants (born between 1994 and 1999) had been exposed to antenatal sulindac (N=25) or indomethacin (N=66) and weighed 1.4 mg/dL (19% vs. 15%), patent ductus arteriosus (17% vs. 28%), and mortality (12% vs. 12%), respectively. However, there was a significant increase in the risk for bronchopulmonary dysplasia after exposure to indomethacin (adjusted odds ratio 4.9, 95% confidence interval 1.01–23.44) (16). Theoretically, sulindac, a prostaglandin synthesis inhibitor, could cause constriction of the ductus arteriosus in utero, as well as inhibition of labor, prolongation of pregnancy, and suppression of fetal renal function (17,18). Persistent pulmonary hypertension of the newborn should also be considered. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including sulindac, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (19,20). Moreover, as noted above, NSAIDs have been associated with SABs. [*Risk Factor D if used in the 3rd trimester or near delivery].
Breast Feeding Summary No reports describing the use of sulindac during breast feeding or analyzing the amount of drug in milk have been located. The mean adult serum half-life of the
biologically active sulfide metabolite is 16.4 hours (1). One reviewer concluded that because of the prolonged half-life, other agents in this class (diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, and tolmetin) were safer alternatives if a nonsteroidal antiinflammatory agent was required during nursing (21). References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
Product information. Clinoril. Merck, 2001. Lione A, Scialli AR. The developmental toxicity of indomethacin and sulindac. Reprod Toxicol 1995;9:7–20. Kramer W, Saade G, Belfort M, Ou C-N, Rognerud C, Knudsen L, Moise K Jr. Placental transfer of sulindac and its active metabolite in humans (abstract). Am J Obstet Gynecol 1994;170:389. Kramer WB, Saade G, Ou C-N, Rognerud C, Dorman K, Mayes M, Moise KJ Jr. Placental transfer of sulindac and its active sulfide metabolite in humans. Am J Obstet Gynecol 1995;172:886–90. Lampela ES, Nuutinen LH, Ala-Kkokko TL, Parikka RM, Laitinen RS, Jouppila PI, Vahakangas KH. Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model. Am J Obstet Gynecol 1999;180:174–80. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:266–70. Carlan SJ, O'Brien WF, O'Leary TD, Mastrogiannis DS. A randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor (abstract). Am J Obstet Gynecol 1992;166:361. Carlan SJ, O'Brien WF, O'Leary TD, Mastrogiannis D. Randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor. Obstet Gynecol 1992;79:223–8. Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. Am J Obstet Gynecol 1995;173:20–5. Kramer W, Saade G, Belfort M, Dorman K, Mayes M, Moise K Jr. Randomized double-blind study comparing sulindac to terbutaline: fetal cardiovascular effects (abstract). Am J Obstet Gynecol 1996;174:326. Kramer WB, Saade GR, Belfort M, Dorman K, Mayes M, Moise KJ Jr. A randomized double-blind study comparing the fetal effects of sulindac to terbutaline during the management of preterm labor. Am J Obstet Gynecol 1999;180:396–401. Carlan S, Jones M, Schorr S, McNeill T, Rawji H, Clark K. Oral sulindac to prevent recurrence of preterm labor (abstract). Am J Obstet Gynecol 1994;170:381. Jones M, Carlan S, Schorr S, McNeill T, Rawji R, Clark K, Fuentes A. Oral sulindac to prevent recurrence of preterm labor (abstract). Am J Obstet Gynecol 1995;172:416. Carlan SJ, O'Brien WF, Jones MH, O'Leary TD, Roth L. Outpatient oral sulindac to prevent recurrence of preterm labor. Obstet Gynecol 1995;85:769–74. Peek MJ, McCarthy A, Kyle P, Sepulveda W, Fisk NM. Medical amnioreduction with sulindac to reduce cord complications in monoamniotic twins. Am J Obstet Gynecol 1997;176:334–6. Sciscione A, Leef K, Vakili B, Paul D. Neonatal effects after antenatal treatment with indomethacin vs. sulindac (abstract). Am J Obstet Gynecol 2000;182:S66. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44. Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Witorsch RJ, editor. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65. Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.
Index
SUMATRIPTAN Drugs in Pregnancy and Lactation
Name: SUMATRIPTAN Class: Antimigraine
Risk Factor:
CM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Sumatriptan (GR 43175) is a selective serotonin (5-hydroxytryptamine1; 5-HT) receptor subtype agonist used for the acute treatment of migraine headaches. It has also been used for the treatment of cluster headaches. The compound is available in oral tablets and as a subcutaneous (SC) injection. Sumatriptan was embryolethal in rabbits when given in daily IV doses approximately equivalent to the maximum recommended single human SC dose of 6 mg on a body surface area basis (MRHD) (1). The doses were at or close to those producing maternal toxicity. Fetuses of rabbits administered oral sumatriptan (at doses greater than 50 times the MRHD) during organogenesis had an increased incidence of cervicothoracic vascular and skeletal anomalies (1). In contrast, embryo or fetal lethality was not observed in pregnant rats treated throughout organogenesis with IV doses approximately 20 times the MRHD. Moreover, no rat embryo/fetal lethality or teratogenicity was observed with daily SC doses before and throughout gestation (1). Shepard described a study in which no fetal adverse effects were observed in rats given up to 1000 mg/kg orally during organogenesis (2). No studies examining the placental transfer of sumatriptan in animals or humans have been located. The molecular weight of the drug (about 414) is low enough, however, to allow passage to the fetus. Individual reports and data from Medicaid studies totaled 14 spontaneous abortions with the use of sumatriptan during early pregnancy (F. Rosa, personal communication, FDA, 1996). Seven birth defect case reports received by the FDA included two chromosomal anomalies (both of which could have been exposed before conception), one infant with an ear tag, one case of a phocomelia, a reduction defect of the lower limbs (tibial aplasia), a case of developmental retardation, and one unspecified defect (some of these defects appear to be also included in data from the Pregnancy Registry cited below). In an interim report of the Sumatriptan Pregnancy Registry, covering the period of January 1, 1996, through October 31, 2000, the outcomes of 361 prospectively enrolled pregnancies exposed to sumatriptan were described (3). Some of the data were also reported in a 1997 abstract (4). The outcomes of 29 pregnancies were still pending and 45 were lost to follow-up. Of the remaining 289 outcomes (287 pregnancies, 2 sets of twins), 264 had earliest exposure in the 1st trimester, 18 in the 2nd trimester, 3 in the 3rd trimester, and 4 were exposed at an unspecified time. In the 1st-trimester group, there were 15 spontaneous abortions (1.5) were found (4, p. 318). Specific malformations with SRR >1.5 were: craniosynostosis, 6 (SRR 2.1); atrial septal defect, 6 (SRR 4.0); cleft lip with or without cleft palate, 9 (SRR 1.6); omphalocele, 5 (SRR 2.4); and any malignant tumors, 7 (SRR 3.3) (4, pp. 473–474). For use anytime in pregnancy, 18,219 mother-child pairs were exposed (4, p. 436). A total of 374 newborns had anomalies (SRR 1.08). Specific malformations with SRR >1.5 were: hypoplasia of limb or part thereof, 24 (SRR 1.6); malformations of thoracic wall, 9 (SRR 2.4); anomalies of the teeth, 8 (SRR 2.0); corneal opacity, 5 (SRR 3.5); and central nervous system tumors, 7 (SRR 17.9) (4, pp. 486–487). The authors of this study cautioned that these data are uninterpretable without independent confirmation from other studies and that any positive or negative association may have occurred by chance (4).
Breast Feeding Summary No data are available. References 1. American College of Obstetricians and Gynecologists. Immunization during pregnancy. Technical Bulletin. No. 160, October 1991. 2. Linder N, Ohel G. In utero vaccination. Clin Perinatol 1994;21:663–74. 3. Centers for Disease Control and Prevention. Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(No. RR-3):1–25. 4. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
Index
VACCINE, POLIOVIRUS LIVE Drugs in Pregnancy and Lactation
Name: VACCINE, POLIOVIRUS LIVE Class: Vaccine
Risk Factor:
CM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Poliovirus vaccine live (Sabin vaccine; OPV; TOPV) is a live, trivalent (types 1, 2, and 3) attenuated virus strain vaccine administered orally (1). Although fetal damage may occur when the mother contracts the disease during pregnancy, the risk to the fetus from the vaccine is unknown (1). A brief 1990 report found no increase in spontaneous abortions or adverse effect on the placenta or embryo following 1st-trimester use of oral poliovirus vaccine (2). Both the American College of Obstetricians and Gynecologists and the Immunization Practices Advisory Committee (ACIP) recommend use of the vaccine during pregnancy only if an increased risk of exposure exists (1,3). If immediate protection against poliomyelitis is needed, the ACIP states that either the inactivated or oral vaccine may be used in accordance with the recommended schedules for adults (see reference for specific details) (3). The inactivated vaccine, however, was preferred over the oral form because of a lower risk of vaccine-associated paralysis. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 1,628 of whom had 1st-trimester exposure to oral live poliovirus vaccine (4, p. 315). Congenital malformations were observed in 114 (standardized relative risk [SRR] 1.11) of the newborns. Malformations identified with SRR >1.5 were gastrointestinal (GI) defects (SRR 1.67) and Downs' syndrome (SRR 1.60) (4, p. 319). Specific malformations with SRR >1.5 were omphalocele, 3 (SRR 5.4); malrotation of the GI tract, 5 (SRR 7.9); and any benign tumors, 7 (SRR 1.8) (4, p. 474). For use anytime in pregnancy, 3,059 mother-child pairs were exposed (4, p. 436). In this group, there were 44 malformed children (SRR 0.81) with the following specific malformations having SRR >1.5: Hirschsprung's disease, 4 (SRR 8.8); any benign tumors, 12 (SRR 1.7); and pectus excavatum, 8 (SRR 2.0) (4, p. 487). The authors of this study cautioned that these data are uninterpretable without independent confirmation from other studies and that any positive or negative association may have occurred by chance (4). The death of a 3-month old male infant because of complications arising from bilateral renal dysplasia affecting predominantly the glomeruli was thought to be possibly caused by maternal vaccination with oral poliovirus vaccine during the 1st or 2nd month of pregnancy (5). A causal relationship, however, could not be established based on the pathologic findings. A 19-year-old previously immune woman inadvertently received oral poliovirus vaccine at 18 weeks' gestation (6). For other reasons, she requested termination of the pregnancy at 21 weeks' gestation. Polio-like changes were noted in the small-for-dates female fetus (crown-rump and foot length compatible with 17.5–19 weeks' gestation) consisting of damage to the anterior horn cells of the cervical and thoracic spinal cord with more limited secondary skeletal muscle degenerative changes in the arm (6). Poliovirus could not be isolated from the placenta or fetal brain, lung, or liver. Specific fluorescent antibody tests for poliovirus types 2 and 3 were positive in the dorsal spinal cord but not at other sites. In response to an outbreak of wild type 3 poliovirus in Finland, a mass vaccination program of adults was initiated with trivalent oral poliovirus vaccine in 1985, with 94% receiving the vaccine during about a 1-month period (7). Because Finland has compulsory notification of all congenital malformations detected during the first year of life, a study was conducted to determine the effect, if any, on the incidence of birth defects from the vaccine. In addition to all defects, two indicator groups were chosen because of their high detection and reporting rates: central nervous system defects and orofacial clefts. No significant changes from the baseline prevalence were noted in the three groups, but the data could not exclude an increase in less common types of congenital defects (7). A follow-up to the above report was published in 1993 and included all structural malformations that occurred during the 1st trimester (8). The outcomes of approximately 9,000 pregnancies were studied, divided nearly equally between those occurring before, during, or after (i.e., one study and two reference cohorts) the vaccination program. Women in the study group had been vaccinated during the 1st trimester (defined as from conception through 15 weeks). A total of 209 cases (2.3%) were identified from liveborns, stillborns, and known abortions. There was no difference in outcomes between the cohorts (the study had a statistical power estimate to detect an increase greater than 0.5%) (8). The analysis of Finish women receiving the oral poliovirus vaccine during gestation was expanded to anytime during pregnancy in a 1994 report (9). The outcomes of three study groups (about 3,000 pregnant women vaccinated in each of the three trimesters of pregnancy) were compared with two reference cohorts (about 6,000 pregnant women who delivered before the vaccination program and about 6,000 who conceived and delivered afterward). No differences were found between the study and reference groups in terms of intrauterine growth or in the prevalences of stillbirth, neonatal death, congenital anomalies, premature birth, perinatal infection, and neurologic abnormalities (9). The authors concluded that the vaccination of pregnant women with the oral poliovirus vaccine, as conducted in Finland, appeared to be safe. A 1993 report described the use of oral poliovirus vaccine in a nationwide (Israel) vaccination campaign, including pregnant women, after the occurrence of 15 cases of polio in the summer of 1988 (10). The investigators compared the frequency of anomalies and premature births in their area in 1988 (controls) with those in 1989 (exposed). In 1988, 15,021 live births occurred, with 204 malformed newborns (1.36%) and 999 (6.65%) premature infants. These numbers did not differ statistically from those in 1989; 15,696, 243 (1.55%), and 1,083 (6.87%), respectively. The authors concluded that oral poliovirus vaccine was preferred to the inactivated vaccine if vaccination was required during pregnancy (10). In a follow-up of the Israel vaccination campaign, investigators measured the presence of neutralizing antibodies to the three poliovirus types in the sera of infants whose mothers had been vaccinated 2–7 weeks before delivery (11). In newborns, higher levels of protecting antibodies were found for poliovirus types 1 and 2 than for type 3, indicating less placental transfer and a greater risk of infection with poliovirus type 3.
Breast Feeding Summary Human milk contains poliovirus antibodies in direct relation to titers found in the mother's serum. When oral poliovirus vaccine (Sabin vaccine, OPV) is administered to the breast-fed infant in the immediate neonatal period, these antibodies, which are highest in colostrum, may prevent infection and development of subsequent immunity to wild poliovirus (12,13,14,15,16,17,18,19,20,21,22 and 23). To prevent inhibition of the vaccine, breast feeding should be withheld 6 hours before and after administration of the vaccine, although some authors recommend shorter times (18,19,20,21 and 22). In the United States, the ACIP and the Committee on Infectious Diseases of the American Academy of Pediatrics do not recommend vaccination before 6 weeks of age (4,24). At this age or older, the effect of the oral vaccine is not inhibited by breast feeding and no special instructions or planned feeding schedules are required (4,24,25,26,27 and 28). References 1. American College of Obstetricians and Gynecologists. Immunization during pregnancy. Technical Bulletin. No. 160, October 1991. 2. Ornoy A, Arnon J, Feingold M, Ben Ishai P. Spontaneous abortions following oral poliovirus vaccination in first trimester. Lancet 1990;335:800. 3. CDC. Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(No. RR-3):1–25. 4. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977. 5. Castleman B, McNeely BU. Case records of the Massachusetts General Hospital. Case 47–1964. Presentation of Case. N Engl J Med 1964;271:676–82. 6. Burton AE, Robinson ET, Harper WF, Bell EJ, Boyd JF. Fetal damage after accidental polio vaccination of an immune mother. J R Coll Gen Pract 1984;34:390–4. 7. Harjulehto T, Aro T, Hovi T, Saxen L. Congenital malformations and oral poliovirus vaccination during pregnancy. Lancet 1989;1:771–2. 8. Harjulehto-Mervaala T, Aro T, Hiilesmaa VK, Saxen H, Hovi T, Saxen L. Oral polio vaccination during pregnancy: no increase in the occurrence of congenital malformations. Am J Epidemiol 1993;138:407–14. 9. Harjulehto-Mervaala T, Aro T, Hiilesmaa VK, Hovi T, Saxen H, Saxen L. Oral polio vaccination during pregnancy: lack of impact on fetal development and perinatal outcome. Clin Infect Dis 1994;18:414–20. 10. Ornoy A, Ben Ishai PB. Congenital anomalies after oral poliovirus vaccination during pregnancy. Lancet 1993;341:1162. 11. Linder N, Handsher R, Fruman O, Shiff E, Ohel G, Reichman B, Dagan R. Effect of maternal immunization with oral poliovirus vaccine on neonatal immunity. Pediatr Infect Dis J 1994;13:959–62. 12. Lepow ML, Warren RJ, Gray N, Ingram VG, Robbins FC. Effect of Sabin type I poliomyelitis vaccine administered by mouth to newborn infants. N Engl J Med 1961;264:1071–8.
13. Holguin AH, Reeves JS, Gelfand HM. Immunization of infants with the Sabin oral poliovirus vaccine. Am J Public Health 1962;52:600–10. 14. Sabin AB, Fieldsteel AH. Antipoliomyelitic activity of human and bovine colostrum and milk. Pediatrics 1962;29:105–15. 15. Sabin AB, Michaels RH, Krugman S, Eiger ME, Berman PH, Warren J. Effect of oral poliovirus vaccine in newborn children. I. Excretion of virus after ingestion of large doses of type I or of mixture of all three types, in relation to level of placentally transmitted antibody. Pediatrics 1963;31:623–40. 16. Warren RJ, Lepow ML, Bartsch GE, Robbins FC. The relationship of maternal antibody, breast feeding, and age to the susceptibility of newborn infants to infection with attenuated polioviruses. Pediatrics 1964;34:4–13. 17. Plotkin SA, Katz M, Brown RE, Pagano JS. Oral poliovirus vaccination in newborn African infants. The inhibitory effect of breast feeding. Am J Dis Child 1966;111:27–30. 18. Katz M, Plotkin SA. Oral polio immunization of the newborn infant; a possible method for overcoming interference by ingested antibodies. J Pediatr 1968;73:267–70. 19. Adcock E, Greene H. Poliovirus antibodies in breast-fed infants. Lancet 1971;2:662–3. 20. Anonymous. Sabin vaccine in breast-fed infants. Med J Aust 1972;2:175. 21. John TJ. The effect of breast-feeding on the antibody response of infants to trivalent oral poliovirus vaccine. J Pediatr 1974;84:307. 22. Plotkin SA, Katz M. Administration of oral polio vaccine in relation to time of breast feeding. J Pediatr 1974;84:309. 23. Deforest A, Smith DS. The effect of breast-feeding on the antibody response of infants to trivalent oral poliovirus vaccine (reply). J Pediatr 1974;84:308. 24. Kelein JO, Brunell PA, Cherry JD, Fulginiti VA, eds. Report of the Committee on Infectious Diseases. 19th ed. Evanston, IL: American Academy of Pediatrics, 1982:208. 25. Kim-Farley R, Brink E, Orenstein W, Bart K. Vaccination and breast-feeding. JAMA 1982;248:2451–2. 26. Deforest A, Parker PB, DiLiberti JH, Yates HT Jr, Sibinga MS, Smith DS. The effect of breast-feeding on the antibody response of infants to trivalent oral poliovirus vaccine. J Pediatr 1973;83:93–5. 27. John TJ, Devarajan LV, Luther L, Vijayarathnam P. Effect of breast-feeding on seroresponse of infants to oral poliovirus vaccination. Pediatrics 1976;57:47–53. 28. Welsh J, May JT. Breast-feeding and trivalent oral polio vaccine. J Pediatr 1979;95:333.
Index
VACCINE, RABIES (HUMAN) Drugs in Pregnancy and Lactation
Name: VACCINE, RABIES (HUMAN) Class: Vaccine
Risk Factor:
CM
Fetal Risk Summary Breast Feeding Summary References
Fetal Risk Summary Rabies vaccine (human) is an inactivated virus vaccine (1,2). Animal reproduction studies have not been conducted with the vaccine. Because rabies is nearly 100% fatal if contracted, the vaccine should be given for postexposure prophylaxis (1,2). Fetal risk from the vaccine is unknown, but indications for prophylaxis are not altered by pregnancy (1). Three reports described the use of rabies vaccine (human) during pregnancy (3,4 and 5). Passive immunity was found in one newborn (titer >1:50) but was lost by 1 year of age (3). No adverse effects from the vaccine were noted in the newborn. The mother had not delivered at the time of the report in the second case (4). A 1990 brief report described the use of rabies vaccine in 16 pregnant women, 15 using the human diploid cell vaccine and 1 receiving the purified chick embryo cell product (5). In 15 cases the stage of pregnancy was known: nine 1st trimester, three 2nd trimester, and three 3rd trimester. Two women had spontaneous abortions, but the causes were probably not vaccine related. The remaining pregnancy outcomes were 12 full-term healthy newborns, 1 premature delivery at 36 weeks' gestation, and 1 newborn with grand-mal seizures on the 2nd day. In the latter case, no antirabies antibodies were detectable in the infant's serum, indicating that the condition was not vaccine related (5). In two reports, duck embryo–cultured vaccine was used during pregnancy (6,7). In 1974 a report appeared describing the use of rabies vaccine (duck embryo) in a woman in her 7th month of pregnancy (6). She was given a 21-day treatment course of the vaccine. She subsequently delivered a healthy term male infant who was developing normally at 9 months of age. The second case was described in 1975 involving a woman exposed to rabies at 35 weeks' gestation (7). She was treated with a 14-day course of vaccine (duck embryo) followed by three booster injections. She gave birth at 39 weeks' gestation to a healthy male infant. Cord blood rabies neutralizing antibody titer was 1:30, indicative of passive immunity, compared with a titer of 1:70 in maternal serum. Titers in the infant fell to 1:5 at 3 weeks of age, then to 1000 mg) daily doses of valproic acid may produce maternal serum concentrations that are much greater than 100 µg/mL (8). However, as pregnancy progresses and without dosage adjustment, valproic acid levels fall steadily so that in the 3rd trimester, maternal levels are often less than 50 µg/mL (8). One study concluded that the decreased serum concentrations were a result of increased hepatic clearance and an increased apparent volume of distribution (8). Fetal or newborn consequences resulting from the use of valproic acid and sodium valproate during pregnancy have been reported to include: major and minor congenital abnormalities, intrauterine growth retardation, hyperbilirubinemia, hepatotoxicity (which may be fatal), transient hyperglycinemia, afibrinogenemia (one case), and fetal or neonatal withdrawal. Before 1981, the maternal use of valproic acid was not thought to present a risk to the fetus. A 1981 editorial recommended sodium valproate or carbamazepine as anticonvulsants of choice in appropriate types of epilepsy for women who may become pregnant (30). Although the drug was known to be a potent animal teratogen (31), more potent than phenytoin and at least as potent as trimethadione (32), only a single unconfirmed case of human teratogenicity (in a fetus exposed to at least two other anticonvulsants) had been published between 1969 and 1976 (33). (An editorial comment in that report noted that subsequent investigation had failed to confirm the defect.) In other published cases, both before and after 1980, healthy term infants resulted after in utero exposure to valproic acid (1,2 and 3,12,19,27,28,32,34,35,36,37 and 38). Moreover, a committee of the American Academy of Pediatrics stated in 1982 that the data for a teratogenic potential in humans for valproic acid were inadequate and that recommendations for or against its use in pregnancy could not be given (39). The first confirmed report of an infant with congenital defects after valproic acid exposure during pregnancy appeared in 1980 (16). The mother, who took 1000 mg of valproic acid daily throughout gestation, delivered a growth-retarded infant with facial dysmorphism and heart and limb defects. The infant died at 19 days of age. Since this initial report, a number of studies and case reports have described newborns with malformations after in utero exposure to either valproic acid monotherapy or combination therapy (4,17,18,19,20,21,22,23,24,25 and 26,36,40,41,42,43,44,45,46, 47,48,49,50,51,52,53,54,55,56,57,58, 59 and 60). The most serious abnormalities observed with valproic acid (or sodium valproate) exposure are defects in neural tube closure. The absolute risk of this defect is approximately 1%–2%, about the same risk for a familial occurrence of this anomaly (37,40,61,62). No cases of anencephaly have been associated with valproic acid (21,62,63). Exposure to valproic acid between the 17th and 30th day after fertilization must occur before the drug can be considered a cause of neural tube defects (64). Other predominant defects involve the heart, face, and limbs. A characteristic pattern of minor facial abnormalities has been attributed to valproic acid (61). Cardiac anomalies and cleft lip and palate occur with most anticonvulsants and a causal relationship with valproic acid has not been established (37,46). In addition, almost all types of congenital malformations have been observed after treatment of epilepsy during pregnancy (see Janz 1982, Phenytoin). Consequently, the list below, although abstracting the cited references, is not meant to be inclusive and, at times, reflects multiple anticonvulsant therapy.
NEURAL TUBE DEFECTS Defects in neural tube closure (17,19,21,22,24,26,40,41 and 42,44,45 and 46,53,54,55,56,57 and (includes entire spectrum from spina bifida occulta to 58) meningomyelocele) CARDIAC DEFECTS Multiple (not specified) (21,24) (26,37,42,44,51) Levocardia (16) Patent ductus arteriosus (4,26,48,50,52) Anomalies of great vessels (51) FACIAL DEFECTS Facial dysmorphism (4,26,42,46,50,53,59) Small nose (16,20,24,26,50,20,53,59), Depressed nasal bridge (18,20,26,50,59) Flat orbits (26) Protruding eyes (16) Hypertelorism (4,26) Low-set/rotated ears (4,16,24,26,50) Micrognathia/retrognathia (16,23,26) Thin upper vermilion border (24,26,48,50,53) Down-turned angles of mouth (50,59)
HEAD/NECK DEFECTS Brachycephaly (24,26) Hydrocephaly (19,21,42,46) Wide anterior fontanelle (18) Abnormal or premature stenosis of metopic suture (24,26,50) UROGENITAL DEFECTS Bilateral duplication of caliceal collecting systems (25) Bilateral undescended testes (23) SKELETAL/LIMB DEFECTS Aplasia of radius (23,26) Dislocated hip (16,26,35) Hypoplastic thumb (20) Hemifusion of second and third lumbar vertebrae (25) Abnormal sternum (16,26) Scoliosis (25) Multiple (not specified) (24) Clinodactyly of fingers (26) Tracheomalacia (53) SKIN/MUSCLE DEFECTS Accessory, wide-spaced, or inverted nipples (20,26) Diastasis recti abdominis (4,25) Syndactyly of toes (16,23,50) Hyperconvex fingernails (24,26) Hypoplastic nails (4,18) Umbilical hernias (4,26) Linea alba hernia (47) Inguinal hernia (4,26,50) OTHER DEFECTS Multiple defects (not specified) (24,51) Mental retardation (4,20,50,51,53)
Valvular aortic stenosis (23,48) Ventricular septal defect (4,20,48) Tetralogy of Fallot (18,51) Partial right bundle-branch block (16) High forehead (24,26) Bulging frontal eminences (16,20 Strabismus (50) Nystagmus (50) Epicanthal folds (4,26,50,53,59) Coarsened facies (20) Cleft lip/palate (18,37,42,44,51) Microstomia (24,26,48,50) Esotropia (50) Depigmentation of eyelashes and brow (16,25) Short palpebral fissure (26,48,50) Long upper lip (26,50,59) Agenesis of lacrimal ducts (51) Microcephaly (4,21,24,38,50,64,65) Short neck (20) Craniostenosis (26) Aplasia cutis (60) Nonspecified (26) Hypospadias (21,23,26,46,50) Bilateral renal hypoplasia (23) Rib defects (24,26) Foot deformity (17,23,24,50) Abnormal digits (23,26,37,42) Shortened fingers, and toes (4,20) Arachnodactyly (24,26) Overlapping fingers/toes (24,26) Broad or asymmetric chest (16,26 Talipes equinovarus (53)
Cutis aplasia of scalp (50) Weak abdominal walls (4) Hirsutism (26) Abnormal palmar creases (16,18,50) Hemangioma (4,25,26,50) Sacral dimple (43) Telangiectasia (4) Omphalocele (59) Withdrawal or irritation (4,50) Duodenal atresia (25) Single umbilical artery (50)
Although a wide variety of minor anomalies, many of which are similar in nature, occurs in infants of epileptic mothers, three groups of investigators have concluded that the deformities associated with valproic acid are distinctly different from those associated with other anticonvulsants and may constitute a valproic acid syndrome (FVS) (26,50,53). The combined features cited in the three reports were: (a) neural tube defects; (b) craniofacial: brachycephaly, high forehead, epicanthal folds, strabismus, nystagmus, shallow orbits, flat nasal bridge, small up-turned nose, hypertelorism, long upper lip, thin upper vermillion border, microstomia, down-turned angles of mouth, low-set/rotated ears; (c) digits: long, thin, partly overlapping fingers and toes, hyperconvex nails; (d) urogenital: hypospadias (in about 50% of males); and (e) other: retarded psychomotor development, low birth weight. Normal psychomotor development has been observed, however, in follow-up studies of children up to 4 years of age after in utero exposure to either mono- or combination therapy with valproic acid (3,34,65,66). A 1995 review listed the facial features seen in the FVS as trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root anteverted nares, shallow philtrum, long upper lip with thin vermilion border, thick upper lip, small, downturned mouth (67). The most common major congenital defects observed were neural tube defects, congenital heart disease, cleft lip and palate, genital anomalies, and limb defects. Other, less common abnormalities were tracheomalacia, abdominal wall defects, and strabismus. Dose-related withdrawal symptoms (irritability, jitteriness, hypotonia, and seizures) were considered to be very common, typically occurring 12–48 hours after birth (67). A correlation between valproic acid dosage and the number of minor anomalies in an infant has been proposed (26). Such a correlation has not been observed with other anticonvulsants (26). The conclusion was based on the high concentrations of valproic acid that occur in the 1st trimester after large doses (i.e., 1500–2000 mg/day). In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 26 newborns had been exposed to valproic acid during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Five (19.2%) major birth defects were observed (one expected), one of which was a hypospadias. No anomalies were observed in five other categories of defects (cardiovascular, oral clefts, spina bifida, polydactyly, and limb-reduction defects) for which specific data were available. Hypospadias has been associated with 1st-trimester valproic acid exposure (see above). A 2000 study, using data from the MADRE (an acronym for MAlformation and DRug Exposure) surveillance project, assessed the human teratogenicity of anticonvulsants (68). Among 8005 malformed infants, cases were infants with a specific malformation, whereas controls were infants with other anomalies. Of the total group, 299 were exposed in the 1st trimester to anticonvulsants. Among these, exposure to monotherapy occurred in the following: valproic acid (N=80), phenobarbital (N=65), methobarbital (N=10), carbamazepine (N=46), phenytoin (N=24), and other agents (N=16). Statistically significant associations (CI not overlapping 1 and p£0.05) were found between valproic acid monotherapy and spina bifida (N=12), hypospadias (N=10), porencephaly/multiple cerebral cysts and other specified anomalies of brain (N=2), microstomia, microcheilia, and other anomalies of face (N=2), coarctation of aorta (N=2), and limb reduction defects (N=5). When all 1st trimester exposures (mono- and polytherapy) were evaluated, significant associations were found between valproic acid and spina bifida (N=14), cardiac defects (N=26), hypospadias (N=14), porencephaly/multiple cerebral cysts and other specific anomalies of brain (N=2), limb reduction defects (N=5), and hypertelorism, localized skull defects (N=2). Although the study confirmed some previously known associations, several new associations with anticonvulsants were discovered and require independent confirmation (see also Carbamazepine, Mephobarbital, Phenobarbital, and Phenytoin) (68). The risk of valproic acid-induced limb deficiencies was estimated in a 2000 study that used data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) collected between 1976 and 1997 (69). A total of 22,294 consecutive malformed infants (excluding genetic syndromes) were compared to 21,937 control infants. A total of 57 malformed infants and 10 controls were exposed to valproic acid during the 1st trimester (odds ratio [OR] 5.62, 95% confidence interval [CI]
2.78-11.71, p25,000 IU/day) consumption continuing past conception. The exception involved a woman who accidentally consumed 500,000 IU, as a single dose, during the 2nd month of pregnancy (29). Twelve of the infants had malformations similar to those seen in animal and human retinoid syndromes (i.e., central nervous system and cardiovascular anomalies, microtia, and clefts) (22). The defects observed in the 18 infants were microtia (N=4), craniofacial (N=4), brain (N=4), facial palsy (N=1), micro/anophthalmia (N=2), facial clefts (N=4), cardio-aortic (N=2), limb reduction (N=4), gastrointestinal atresia (N=1), and urinary (N=4) (22). The Centers for Disease Control and Prevention (CDC) reported in 1987 the results of an epidemiologic study conducted by the New York State Department of Health from April 1983 through February 1984 (3). The mothers of 492 live-born infants without congenital defects were interviewed to obtain their drug histories. Vitamin A supplements were taken by 81.1% (399 of 492) of the women. Of this group, 0.6% (3 of 492) took 25,000 IU/day or more, and 2.6% (13 of 492) consumed 15,000–24,999 IU/day (3). In an editorial comment, the CDC noted that the excessive vitamin A consumption by some of the women was a public health concern (3). Results of an epidemiologic case-control study conducted in Spain between 1976 and 1987 were reported in preliminary form in 1988 (31) and as a full report in 1990 (32). A total of 11,293 cases of malformed infants were compared with 11,193 normal controls. Sixteen of the case mothers (1.4/1000) used high doses of vitamin A either alone or in combination with other vitamins during their pregnancies, compared with 14 (1.3/1000) of the controls, an odds ratio (OR) of 1.1 (n.s.). Five of the case infants and 10 of the controls were exposed to doses less than 40,000 IU/day (OR 0.5, p=0.15). In contrast, 11 of the case infants and 4 controls were exposed to ³40,000 IU (OR 2.7, p=0.06). The risk of congenital anomalies, although not significant, appeared to be related to gestational age as the highest risk in those pregnancies exposed to ³40,000 IU/day occurred during the first 2 months (32). The data suggested a dose-effect relationship and provided support for earlier statements that doses lower than 10,000 IU were not teratogenic (31,32). Data from a case-control study was used to assess the effects of vitamin A supplements (daily use for at least 7 days of vitamin A either alone or with vitamin D, or of fish oils) and vitamin A-containing multivitamin supplements (33). Cases were 2,658 infants with malformations derived, at least in part, from cranial neural crest cells (primarily craniofacial and cardiac anomalies). Controls were 2,609 infants with other malformations. Case mothers used vitamin A supplements in 15, 14, and 10 pregnancies during lunar months 1, 2, and 3, respectively, compared with 6 control mothers in each period (33). Although not significant, the OR in each period was 2.5 (95% confidence interval [CI] 1.0–6.2), 2.3 (95% CI 0.9–5.8), and 1.6 (95% CI 0.6–4.5), respectively. The authors cautioned that their data should be considered tentative because of the small numbers and lack of dosage and nutrition information (33). Even a small increased risk was excluded for vitamin A–containing multivitamins (33). A congenital malformation of the left eye was attributed to excessive vitamin A exposure during the 1st trimester in a 1991 report (34). The mother had ingested a combination of liver and vitamin supplements that provided an estimated 25,000 IU/day of vitamin A. The unusual eye defect consisted of an “hourglass” cornea and iris with a reduplicated lens. A brief 1992 correspondence cited the experience in the Hungarian Family Planning Program with a prenatal vitamin preparation containing 6000 IU of vitamin A (35). Evaluating their 1989 database, the authors found no relationship, in comparison with a nonexposed control group, between the daily intake of the multivitamin at least 1 month before conception through the 12th week of gestation and any congenital malformation. A study published in 1995 examined the effect of preformed vitamin A, consumed from vitamin supplements and food, on pregnancy outcomes (36). Vitamin A ingestion, from 3 months before through 12 weeks from the last menstrual period, was determined for 22,748 women. Most of the women were enrolled in the study between week 15 and week 20 of pregnancy. From the total group, 339 babies met the criteria for congenital anomalies established by the investigators. These criteria included malformations in four categories (number of defects of each type shown: cranial–neural crest defects (craniofacial, central nervous system, and thymic, N=69; heart defects, N=52); neural tube defects (NTDs) (spina bifida, anencephaly, and encephalocele, N=48); musculoskeletal (N=58) and urogenital (N=42) defects; and other defects (gastrointestinal defects, N=24; agenesis or hypoplasia of the lungs, single umbilical artery, anomalies of the spleen, and cystic hygroma, N=46) (36). The 22,748 women were divided into four groups based on their total (supplement plus food) daily intake of vitamin A: 0–5,000 IU (N=6,410), 5,001–10,000 IU (N=12,688), 10,001–15,000 IU (N=3,150), and ³15,001 IU (N=500). Analysis of this grouping revealed that the women who took ³15,001 IU daily had a higher prevalence ratio for defects associated with cranial–neural crest tissue compared with those in the lowest group, 3.5 (95% CI 1.7–7.3). A slightly higher ratio was found for musculoskeletal and urogenital defects, no increase for NTDs or other defects, and for all birth defects combined, a ratio of 2.2 (95% CI 1.3–3.8) (36). Analysis of three groups (0–5,000 IU, 5,001–10,000 IU, and ³10,001 IU) of vitamin A ingestion levels from food alone was hampered by the small number of women and, although some increased prevalence ratios were found in the highest groups, the small numbers made the estimates imprecise (36). A third analysis was then conducted based on four groups (0–5,000 IU, 5,001–8000 IU, 8,001–10,000 IU, and ³10,001 IU) of vitamin A ingestion levels from supplements. Compared with the lowest group, the prevalence ratio for all birth defects in the highest group was 2.4 (95% CI 1.3–4.4) and for defects involving the cranial–neural crest tissue, the ratio was 4.8 (95% CI 2.2–10.5). Of interest, the mean vitamin A intake in the highest group was 21,675 IU. Based on these data, the investigators concluded that following in utero exposure to more than 10,000 IU of vitamin A from supplements, about 1 infant in 57 (1.75%) had a vitamin A–induced malformation. In response to the above study, a note of caution was sounded by two authors from the CDC (37). Citing results from previous studies, these authors concluded that without more data, they could not recommend use of the dose-response curve developed in the above study for advising pregnant women of the specific risk of
anomalies that might arise from the ingestion of excessive vitamin A. Although they agreed that very large doses of vitamin A might be teratogenic, the question of how large a dose remained (37). A number of correspondences followed publication of the above study, all describing perceived methodologic discrepancies that may have affected the conclusions (38,39,40,41 and 42) with a reply by the authors supporting their findings (43). Using case-control study data from California, a paper published in 1997 examined the relationship between maternal vitamin A ingestion and the risk of NTDs in singleton live-born infants and aborted fetuses (44). Although the number of cases was small, only 16 exposed to ³10,000 IU/day and 6 to ³15,000 IU/day, the investigators did not find a relationship between these levels of exposure and NTDs. Referring to the question on the teratogenic level of vitamin A, a 1997 abstract reported the effects of increasing doses of the vitamin in the cynomolgus monkey, a species that is a well-documented model for isotretinoin-induced teratogenicity (45). Four groups of monkeys were administered increasing doses of vitamin A (7,500–80,000 IU/kg) in early gestation (day 16–27). A dose-related increase in abortions and typical congenital malformations was observed in the offspring. The NOAEL (no observed adverse effect level) was 7,500 IU/kg, or 30,000 IU/day based on an average 4-kg animal. A human NOAEL extrapolated from the monkey NOAEL would correspond to >300,000 IU/day (45). A brief 1995 report described the outcomes of 7 of 22 women who had taken very large doses of vitamin A during pregnancy, 20 of whom had taken the vitamin during the 1st trimester (46). The mean daily dose was 70,000 IU (range 25,000–90,000 IU) for a mean of 44 days (range 7–180 days). None of the offspring of the 7 patients available at follow-up had congenital malformations. Data on the other 15 women were not available. Two abstracts published in 1996 examined the issue of vitamin A supplementation in women enrolled in studies in Atlanta, Georgia, and in California, both during the 1980s (47,48). In the first abstract, no increase in the incidence of all congenital defects or those classified as involving cranial–neural crest derived was found for doses 8,000 IU/day or >10,000 IU/day were NTDs (3.3% and 2.0%), other major malformations (3.6% and 1.6%), cranial–neural crest malformations (3.4% and 2.2%), and controls (4.5% and 2.1%), respectively. None of the values were statistically significant, thus no association between moderate consumption of vitamin A and the defect groups was found (49). Several investigators have studied maternal and fetal vitamin A levels during various stages of gestation (5,50,51,52,53,54,55,56,57,58,59,60 and 61). Transport to the fetus is by passive diffusion (61). Maternal vitamin A concentrations are slightly greater than those found in either premature or term infants (50,51 and 52). In women with normal levels of vitamin A, maternal and newborn levels were 270 and 220 ng/mL, respectively (51). In 41 women not given supplements of vitamin A, a third of whom had laboratory evidence of hypovitaminemia A, mean maternal levels exceeded those in the newborn by almost a 2:1 ratio (51). In two reports, maternal serum levels were dependent on the length of gestation with concentrations decreasing during the 1st trimester, then increasing during the remainder of pregnancy until about the 38th week when they began to decrease again (5,53). A more recent study found no difference in serum levels between 10 and 33 weeks' gestation, even though amniotic fluid vitamin A levels at 20 weeks onward were significantly greater than at 16–18 weeks (54). Premature infants (36 weeks or less) have significantly lower serum retinol and retinol-binding protein concentrations than do term neonates (50,55,56 and 57). Mild to moderate deficiency is common during pregnancy (51,58). A 1984 report concluded that vitamin A deficiency in poorly nourished mothers was one of the features associated with an increased incidence of prematurity and intrauterine growth retardation (50). An earlier study, however, found no difference in vitamin A levels between low-birth-weight (2500 g) infants (52). Maternal vitamin A concentrations of the low-birth-weight group were lower than those of normals, 211 vs 273 ng/mL, but not significantly. An investigation in premature infants revealed that infants developing bronchopulmonary dysplasia had significantly lower serum retinol levels as compared with infants who did not develop this disease (57). Relatively high liver vitamin A stores were found in the fetuses of women younger than 18 and older than 40 years of age, two groups that produce a high incidence of fetal anomalies (5). Low fetal liver concentrations were measured in 2 infants with hydrocephalus and high levels in 14 infants with NTDs (5). In another report relating to NTDs, a high liver concentration occurred in an anencephalic infant (59). Significantly higher vitamin A amniotic fluid concentrations were discovered in 12 pregnancies from which infants with NTDs were delivered as compared with 94 normal pregnancies (60). However, attempts to use this measurement as an indicator of anencephaly or other fetal anomalies failed because the values for abnormal and normal fetuses overlapped (54,60). The effect of stopping oral contraceptives shortly before conception on vitamin A levels has been studied (61). Because oral contraceptives had been shown to increase serum levels of vitamin A, it was postulated that early conception might involve a risk of teratogenicity. However, no difference was found in early pregnancy vitamin A levels between users and nonusers. The results of this study have been challenged based on the methods used to measure vitamin A (63). Vitamin A is known to affect the immune system (64). Three recent studies (65,66 and 67) and an editorial (68) have described or commented on the effect that maternal vitamin A deficiency has on the maternal-fetal transmission of human immunodeficiency virus (HIV). In each of the studies, a low maternal level of vitamin A was associated with HIV transmission to the infant. In the one study conducted in the United States, severe maternal vitamin A deficiency (
