DR. ERNESTO GIL DEZA DATOS PERSONALES Nombre: 1602, Florida - Provincia de Buenos Aires ESTUDIOS CURSADOS Colegio del Sagrado Corazón. San Miguel de Tucumán de 1965 a 1976. Facultad de Medicina de la Universidad Nacional de Tucumán de 1977/1984. Residencia en Oncología Clínica: Sanatorio Güemes de 1985 a 1988 y Clínica Independencia de 1988 a 1989. En ambos casos bajo
041698 drugs in pregnancyT h e New E n g l a n d Jo u r n a l o f Me d i c i n e before pregnancy. Furthermore, for pregnant wom-en with certain conditions once believed to be in-compatible with pregnancy, such as systemic lupus A L A S T A I R J . J . W O O D , M . D. , Editor erythematosus and heart diseases, the outcome ofpregnancy has improved dramatically in the past fewdecades.4 DRUGS IN PREGNANCY
In this article, we review current knowledge of the fetal and neonatal effects of prescription and over-the-counter drugs given to pregnant women, with GIDEON KOREN, M.D., ANNE PASTUSZAK, M.SC., an emphasis on the approaches used to determine safety and risk. In addition, we review approaches tocommunicating such information to pregnant wom-en and their families.
EFORE marketing a new drug, the manufac-turer almost never tests the product in preg- HUMAN TERATOGENESIS
nant women to determine its effects on the fe- Teratogenesis is defined as the dysgenesis of fetal tus. Consequently, most drugs are not labeled for organs as evidenced either structurally or function- use during pregnancy. Typically, descriptions of drugs ally (e.g., brain functions).5 The typical manifesta- that appear in the Physicians’ Desk Reference and tions of teratogenesis are restricted growth or death similar sources contain statements such as, “Use in of the fetus, carcinogenesis, and malformations,6 de- pregnancy is not recommended unless the potential fined as defects in organ structure or function. These benefits justify the potential risks to the fetus.” Since abnormalities vary in severity (e.g., hypospadias that the risk has been adequately established for only a is mild and may be missed, or is severe, necessitating few drugs, physicians caring for pregnant women several corrective operations). Major malformations have very little information to help them decide may be life-threatening and require major surgery or whether the potential benefits to the mother out- may have serious cosmetic or functional effects.
weigh the risks to the fetus. These typical disclaim-ers, although understandable from the medicolegal A HISTORICAL PERSPECTIVE
standpoint, put large numbers of women and their Several milestones highlight the problems of drug physicians in difficult situations for several reasons.
therapy facing pregnant women, their families, and One is that at least half the pregnancies in North America are unplanned,1 and every year, hundreds ofthousands of women therefore expose their fetuses Thalidomide
to drugs before they know they are pregnant. Such For decades it was believed that the placenta women often interpret the statement that use during served as a barrier that protected the fetus from the pregnancy is not recommended as meaning that the adverse effects of drugs. The thalidomide disaster drug is not safe during pregnancy. There is evidence drastically changed this perception by demonstrat- that this perception of fetal risk causes many women ing that fetal exposure to the drug during critical pe- to consider or even seek termination of otherwise riods of development resulted in severe limb defects wanted pregnancies.2,3 Another reason is that with and other organ dysgenesis (e.g., kidney and heart the recent increase in the age at which women have defects).6,7 Despite the high rates of malformations children, conditions that necessitate long-term drug (20 to 30 percent) and their characteristic pattern, therapy are diagnosed in larger numbers of women the teratogenicity of thalidomide was not suspectedfor years. The suffering it caused has prompted thebelief that every drug has the potential to be a newthalidomide.2,3 From the Motherisk Program, Division of Clinical Pharmacology and Most known human teratogens are associated Toxicology (G.K., A.P., S.I.), the Departments of Pediatrics and Population with much lower rates of malformations, and the Health Sciences (G.K., S.I.), and the Research Institute (G.K., S.I.), Hos- syndromes they cause are not always so pathogno- pital for Sick Children; and the Departments of Pediatrics (G.K., S.I.),Pharmacology (G.K., S.I.), and Medicine (G.K.), University of Toronto — monic, making causation more difficult to confirm.
both in Toronto. Address reprint requests to Dr. Koren at the Division of Yet 35 years after the recognition of thalidomide- Clinical Pharmacology, Hospital for Sick Children, 555 University Ave.,Toronto, ON M5G 1X8, Canada.
associated embryopathy, fewer than 30 drugs have 1998, Massachusetts Medical Society.
been proved to be teratogenic in humans when used Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. D R U G T H E R A PY
in clinically effective doses, and even fewer are cur- tion (FDA) for the treatment of nausea and vomit- rently in clinical use (Table 1). Many other com- ing. The rate of hospitalization for severe nausea and monly used drugs, including salicylates, glucocorti- vomiting during pregnancy increased by a factor of coids, and spermicides, were once thought to be 2 in both the United States and Canada after Ben- teratogenic but have been shown to be safe in sub- dectin was withdrawn from the market (Fig. 1).
sequent studies that were larger and better con- The drug was withdrawn despite a substantial trolled than the initial studies (Table 2).
body of evidence that the rate of major malforma-tions among the children of women who had re- Bendectin
ceived Bendectin during pregnancy did not differ One example of the gap between the perception from the rate in the general population.24,25 With- of teratogenic risk and evidence-based proof of safety drawal of the drug from the American market did is the case of Bendectin. During the late 1950s and not decrease the rate of any specific category of mal- the 1960s, this drug, a combination of an antihista- formation, as would be expected for a truly terato- mine (doxylamine) and pyridoxine, was the most genic drug estimated to have been used by up to 40 widely used medication in the United States for nau- percent of pregnant women at one time.26,27 sea and vomiting associated with pregnancy. During In Canada, the drug continues to be marketed un- the 1970s, many lawsuits claiming that Bendectin der the trade name Diclectin. A review committee has was teratogenic were filed against the manufacturer advised the Canadian Minister of Health that the in American courts. Therefore, the drug was with- drug is safe.27 A recent study revealed that severe nau- drawn from the market by its manufacturer in 1982, sea and vomiting of pregnancy often lead women to which left millions of pregnant women without a terminate or consider the termination of otherwise drug approved by the Food and Drug Administra- wanted pregnancies.28 Other formulations of dox- TABLE 1. DRUGS WITH PROVEN TERATOGENIC EFFECTS IN HUMANS.*
Angiotensin-converting–enzyme inhibitors Prolonged renal failure in neonates, decreased skull Antithyroid drugs (propylthiouracil and meth- Fetal and neonatal goiter and hypothyroidism, apla- Vaginal carcinoma and other genitourinary defects Constriction of the ductus arteriosus‡, necrotizing Psychoactive drugs (e.g., barbiturates, opioids, Neonatal withdrawal syndrome when drug is taken Systemic retinoids (isotretinoin and etretinate) CNS, craniofacial, cardiovascular, and other defects Limb-shortening defects, internal-organ defects Skeletal and CNS defects, Dandy–Walker syndrome *Only drugs that are teratogenic when used at clinically recommended doses are listed. The list includes all drugs proved to affect neonatal morphology or brain development and some of the toxicmanifestations predicted on the basis of the pharmacologic actions of the drugs. Data are from Briggset al.8 CNS denotes central nervous system.
†The drug is not currently in clinical use.
‡Sulindac probably does not have this effect.
Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e TABLE 2. COMMON DRUGS INITIALLY THOUGHT TO BE TERATOGENIC BUT SUBSEQUENTLY PROVED SAFE.
INITIAL EVIDENCE OF RISK
SUBSEQUENT EVIDENCE OF SAFETY
No increase in risk in large cohort and case– Birth defects involving the vertebrae, anus, No association between first-trimester expo- sure to oral contraceptives and malforma- limbs13; masculinizing effects on female fe- tions in general or external genital mal- tuses resulting in pseudohermaphroditism14 Cleft palate19 and congenital heart disease No increase in risk in two meta-analyses24,25 *Diazepam taken near term may cause the neonatal withdrawal syndrome or cardiorespiratory instability.
ylamine in combination with pyridoxine are available this belief became evident after isotretinoin was in- in other countries (e.g., South Africa, Spain, and troduced in North America in the early 1980s for the treatment of acne. For years before its clinical in-troduction, this drug had been known to cause mal- Isotretinoin
formations in animals.29 Despite explicit warning la- The experience with thalidomide led drug regula- bels, scores of children with retinoid embryopathy tors, drug manufacturers, and the medical commu- were born in the years after the drug was intro- nity to believe that appropriate labeling of terato- duced.30 Such warnings are not sufficient, because genic drugs, with warnings not to take them around women taking isotretinoin may not plan their preg- the time of conception, would be effective in pre- nancies, or their birth-control methods may fail. In venting fetal exposure to the drugs. The naiveté of addition, some women and men are functionally il-literate, and they may not read or understand thecontent of a drug label.31 The initial experience with isotretinoin led to the development of a more comprehensive program to prevent teratogenesis. The Retinoid Pregnancy Pre-vention Program includes explicit and detailed print- ed warnings as well as a line drawing of a malformed child,32 and as part of the program, women are asked to sign a consent form indicating that they agree to use two effective methods of contraception before therapy is started. Since the program was implement-ed in 1989, a substantial number of fetuses have been exposed to the drug. As many as 30 percent ofthe women with exposed fetuses did not use any mode of contraception, even though they were cog-nizant of the high fetal risk.32 Many of these women explained that they did not believe they were fertile, since they had not conceived during periods of months or years when they had not used contracep-tive methods.33 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 CURRENT TRENDS IN PREVENTING FETAL
EXPOSURE TO TERATOGENS
Figure 1. Rates of Hospitalization among Pregnant Women
with Severe Nausea and Vomiting and Numbers of Prescrip-
The advent of effective injectable hormonal con- tions for Bendectin and Diclectin in North America, 1979 traceptives has made it possible to minimize the risk of an unplanned pregnancy during therapy with a Bendectin was withdrawn from the U.S. market in 1982, where- known teratogen. This approach was first implement- as Diclectin, the same drug, remained on the market in Cana-da. Adapted from Neutel and Johansen with the permission of ed in South America, where sexually active women with cutaneous leprosy were injected with medroxy- Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. D R U G T H E R A PY
progesterone before receiving a prescription for tha- licylates78-80 cause cardiac malformations in animals lidomide.34 Yet numerous new cases of thalidomide- but not in humans.20,21 Such discrepancies have led associated embryopathy have been reported in the to unwarranted anxiety on the part of women, their children of women who continued to take the drug families, and physicians and may have contributed to after the period of contraceptive efficacy (three unnecessary terminations of pregnancies.3 Although months) or who received the drug from their male studies in animals may identify teratogenic effects, it can be difficult to extrapolate these effects to humans.
Because any new drug may be teratogenic, it is important to develop more effective methods to pre- Epidemiologic Studies
vent fetal exposure. One such method may be the In addition to studies in animals, a variety of other use of implantable hormonal compounds (e.g., approaches are used to identify possible drug terato- levonorgestrel implants), which can provide long- genicity and to assess the relation between drug ex- term, reversible contraception for up to five years.
posure and fetal outcome. The first accounts of ad- Levonorgestrel implants have documented efficacy verse fetal outcomes after exposure to a marketed in young women in whom oral methods of contra- drug are usually published in the form of case re- ception are likely to fail.35 Implants should be con- ports. These reports can be either very useful or use- sidered by sexually active women who are taking a less in establishing teratogenic risk on the basis of teratogen medicinally (e.g., phenytoin or warfarin) relatively simple statistical considerations. If the drug or as part of a pattern of substance abuse (e.g., alco- in question is taken by relatively small numbers of hol or cocaine). Furthermore, women taking terato- women (e.g., isotretinoin30) or causes a rare malfor- genic drugs who are not sexually active should be in- mation (e.g., ear agenesis81), then a small number of formed of the availability of effective postcoital cases can establish a strong association. Warfarin,9 diethylstilbestrol,82 and isotretinoin83 were originallyidentified as human teratogens on the basis of case THE PROCESS OF ESTABLISHING RISK
reports. If, on the other hand, the drug is taken by OR SAFETY OF DRUGS IN PREGNANCY
many pregnant women (e.g., Bendectin), a small Every year, many new drugs are approved and number of case reports of abnormalities may simply marketed. By this stage, several thousand people reflect the spontaneous occurrence of malformations have usually participated in studies of the drugs, but in the general population, which ranges from 1 to the majority have been men. Since there are scarcely 5 percent, unless there is a characteristic pattern of any data on fetal effects at the time of marketing, malformations (as, for example, with alcohol or tha- data from studies in animals provide the initial lidomide). To date, prenatal exposure to many of the known human teratogens has been associated withcharacteristic patterns of malformations, and this has The Value of Studies in Animals
become an important tenet in establishing terato- Typically, studies of reproductive toxicology in an- imals compare the outcome of pregnancy in groups Epidemiologic studies are typically designed to de- of animals receiving a range of doses of the drug in termine whether mothers who took a specific drug question during the period of organogenesis with during pregnancy have a larger number of mal- the outcome in untreated (control) animals. The oc- formed children than mothers who did not (cohort currence of thalidomide-associated embryopathy led studies) or whether mothers of children with a spe- to the erroneous belief that human teratogenicity cific malformation took the drug more often than could not be predicted on the basis of studies in an- mothers of children without the malformation (case– imals. However, every drug that has since been found to be teratogenic in humans has caused simi- With the international development of teratology- lar teratogenic effects in animals (Table 3), except information services,84 a new source of data for pro- misoprostol, which causes a morphologic pattern spective observational research has emerged. Preg- known as the Moebius sequence in humans. In at nant women taking prescription or over-the-counter least one case, that of isotretinoin, the studies in an- drugs voluntarily call these centers for risk-assess- imals probably prevented a disaster similar to that of ment counseling, usually during the first trimester.
Since the exposure data are recorded prospectively, However, there are drugs that have teratogenic ef- the probability of recall bias is reduced, and follow- fects in animals when administered in high doses up of exposed pregnancies can extend well beyond that are not teratogenic in humans given clinically parturition. Collaboration among these services can relevant doses. For example, high doses of gluco- yield the large samples needed to study rare events corticoids19,70-75 or benzodiazepines76,77 can cause oral clefts in animals, but clinically relevant doses in Drug manufacturers may perform postmarketing humans have no such effects.10-12,75 Similarly, sa- cohort studies of prospectively reported exposures.
Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e TABLE 3. TERATOGENIC EFFECTS OF DRUGS IN ANIMALS AND HUMANS.*
EFFECTS IN ANIMALS
EFFECTS IN HUMANS
Prolonged renal failure and hypotension in the newborn, decreased skull ossification, hypo- Cleft palate, dilated cerebral ventricles, Growth retardation involving weight, length, and head circumference43; placental tension, and tachycardia in sheep41; reduced fetal weight, fetal edema, and increased resorption in rats and mice42 Fetal alcohol syndrome: prenatal and postnatal growth deficiency, CNS anomalies (micro- cephaly, behavioral abnormalities, and mental retardation), characteristic pattern of facial features (short palpebral fissures, hypoplastic philtrum, and flattened maxilla), and major organ-system malformations49; with age, facial features may become less distinctive, but short stature, microcephaly, and behavioral abnormalities persist50 Retinoid embryopathy resulting in some or all of the following abnormalities30: CNS defects (hydrocephalus, optic-nerve blindness, retinal defects, microphthalmia, posterior fossa de-fects, and cortical and cerebellar defects); craniofacial defects (microtia or anotia, low-set ears, hypertelorism, depressed nasal bridge, microcephaly, micrognathia, and agenesis or stenosis of external ear canals); cardiovascular defects (transposition of great vessels, te-tralogy of Fallot, and ventricular or atrial septal defects); thymic defects (ectopia and hy-poplasia or aplasia); and miscellaneous defects (limb reduction, decreased muscle tone, spontaneous abortion, and behavioral abnormalities) Ebstein’s anomaly and other heart defects52,53 CNS abnormalities in rats54; growth re- Fetal Minamata disease: diffuse neuronal disintegration with gliosis, cerebral palsy, micro- cephaly, strabismus, blindness, speech disorders, motor impairment, abnormal reflexes, Cleft palate, micromelia, renal defects, Fetal hydantoin syndrome60: prenatal and postnatal growth deficiency, motor or mental de- ficiency, short nose with broad nasal bridge, microcephaly, hypertelorism, strabismus, epicanthus, wide fontanelles, low-set or abnormally formed ears, positional deformities of limbs, hypoplasia of nails and distal phalanges, hypospadias, hernia, webbed neck, low hairline, impaired neurodevelopment and low performance scores on tests of intelligence61 Limb-shortening defects,63 loss of hearing, abducens paralysis, facial paralysis, anotia, micro- tia, renal malformations, congenital heart disease Fetal warfarin syndrome: skeletal defects (nasal hypoplasia and stippled epiphyses), limb hy- poplasia (particularly in distal digits), low birth weight (Ͻ10th percentile), hearing loss, and ophthalmic anomalies69; CNS defects with exposure after first trimester; dorsal mid-line dysplasia (agenesis of corpus callosum and Dandy–Walker malformations) or ventral midline dysplasia (optic atrophy)6 *CNS denotes central nervous system.
†Initial studies in animals failed to show teratogenicity; hence, documentation in humans preceded that in animals.
Such studies were useful in establishing the safety ment can have a more devastating effect on children and risk of Bendectin, isotretinoin, fluoxetine, and and their families than structural anomalies. To date, several drugs have been shown to affect brain devel- Because most studies of teratogenic risk are limit- opment, including carbamazepine, isotretinoin, phen- ed in size, meta-analyses of studies of similar design ytoin, valproic acid, and warfarin (Table 1). Carba- are becoming more frequent. A detailed, stepwise mazepine and valproic acid may cause cognitive methodologic approach to meta-analysis of terato- brain dysfunction as part of the neural-tube defects logic studies has been described.24 The appropriate they induce. Originally, isotretinoin was found to use of this approach depends to a large extent on es- cause structural abnormalities that affected brain de- tablishing sound a priori criteria for methodologic velopment, but recent studies have suggested that quality and ensuring the inclusion of data from all even phenotypically normal children may have ab- available studies, in order to obviate any publication normal neurodevelopment.87 Warfarin was initially associated with chondrodysplasia punctata and men- Long-term studies are increasingly important, be- tal retardation and has subsequently been found to cause it is becoming clear that the long-term effects cause the Dandy–Walker brain malformation in an of teratogenic drugs on neurobehavioral develop- estimated 1 to 2 percent of exposed fetuses.6,69 Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. D R U G T H E R A PY
Common Methodologic Issues
Nonrandomized Observational Studies
No single approach can definitively establish the With prospective observational studies, the treat- safety or risk of drugs, because of several underlying ment decisions have not been made by the investi- gators collecting the data. As a result, the indica-tions for treatment and concurrent exposures are not Sample Size
standardized. Therefore, in comparisons of treated Most congenital malformations occur rarely, and and untreated pregnant women or pregnant women many teratogens, even when known to be associated who received two different drugs, preexisting con- with an increased risk of a given malformation, do founding factors are not randomly distributed be- not affect the great majority of exposed fetuses. In tween the two groups. For example, in comparing fact, very few drugs increase the total malformation the outcome of pregnancy in women who received rate by a factor of more than two (isotretinoin and carbamazepine and women who received phenytoin, thalidomide are two such drugs). If, for example, one must address the issue of whether the two the risk of major malformations in a given popu- groups of women had the same type and severity of lation is 3 percent, then at least 220 pregnancies with the specific exposure and a similar number of Observational studies of neurobehavioral develop- control pregnancies will be required to show a risk ment require longer follow-up than observational that is increased by a factor of 2.5, with a power of studies of other abnormalities, and interpretation of the results is often complicated by numerous con-founding factors. Maternal and paternal IQ, socio- Effect of Maternal Diseases
economic status, and educational levels all affectcognitive development in children.91 Any attempt to Apart from drug therapy, many medical condi- address the developmental effects of drugs without tions themselves increase fetal risks. For example, controlling for these factors is likely to be futile.
pregnant women with hypertension or cancer aremore likely to have infants with intrauterine growth Voluntary Reporting
retardation, and pregnant women with epilepsy ordiabetes mellitus are more likely to have infants with The information received by drug manufacturers is malformations.88 Therefore, any attempt to establish often a mix of prospective and retrospective case re- the role of fetal exposure to drugs must also address ports. The quality of the information about exposure the contributing and confounding risk of the under- is usually poor, and outcome data are sparse because of high rates of loss to follow-up. Most important,women and health professionals who contact manu- Recall Bias in Retrospective Studies
facturers are likely to report adverse fetal outcomes, There is ample evidence of partial memory and not uneventful ones. For example, the pivotal study bias in the way women recall the drugs they took that described retinoid embryopathy contained two during pregnancy. For example, women treated with parts: prospectively collected data from a study co- a prescribed drug for a chronic illness tend to recall hort, with a malformation rate of 36 percent, and data their treatment better than women who took an from voluntary retrospective reporting to the manu- over-the-counter drug.89 Women who have given facturer, with a malformation rate of 80 percent.30 birth to malformed children may be more likely to Meta-Analyses
remember the course of their pregnancies, in the ef-fort to understand what went wrong, than women A common concern regarding the use of meta- who have given birth to healthy children, thus giv- analysis is the inevitable combination of data from ing rise to false positive associations. The initial sug- studies that are not equivalent in terms of quality and gestions that benzodiazepines, spermicides, and Ben- methods. In addition, there is the concern that neg- dectin, for example, were teratogenic were based on ative studies (i.e., those that do not reject the null retrospective case–control studies subsequently re- hypothesis) are less likely to be published than posi- futed by other, larger studies (Table 2).
tive studies and that an overall positive association With improved epidemiologic methods, the reli- may therefore merely reflect unbalanced reporting.
ability of the case–control design has improved. Forexample, recruiting mothers of infants with a differ- COUNSELING WOMEN
ent major malformation as controls may eliminate or ABOUT TERATOGENIC RISKS
at least reduce the problem of differential maternal In one study, women exposed to nonteratogenic recall. In a recent study, this approach was used to drugs who sought counseling estimated, on average, document the effect of the mothers’ knowledge of that they had a 25 percent risk of major malforma- the study hypothesis (that folic acid deficiency caus- tions, which is in the range of the teratogenic risk as- es spina bifida) on the information they reported.90 sociated with thalidomide.2 After counseling, this es- Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e timate was substantially reduced, thereby preventingnumerous terminations of otherwise wanted preg- TABLE 4. SELECTED TERATOGEN-INFORMATION
nancies.2,3 The same women correctly estimated the risk of major malformations in the general popula-tion (5 percent), indicating that the high risk they Canada
Motherisk Program, Toronto
assigned to their own pregnancies was not due to a misunderstanding of the concept of base-line risk.
World Wide Web address: http://www.motherisk.org What are the sources of this misperception? Nu- United States
merous lay publications misinform women by as- Organization of Teratology Information Services signing risks to drugs not known to be teratogenic (801) 328-2229 (for referral to nearest service)World Wide Web address: http://orpheus.ucsd.edu/ctis/ in humans.2,3 Women often report that their physi- cians have encouraged them to terminate otherwise wanted pregnancies just to be on the safe side, sug- gesting that many physicians are unfamiliar with the District of Columbia Reproductive Toxicology Center(202) 293-5137 current literature on the safety of drugs taken during Physicians counseling women who are pregnant or are planning a pregnancy should make sure that Illinois Teratogen Information Service(312) 908-7441 they understand clearly the nature and magnitude of a risk associated with a drug. Women’s attitudes toward voluntary abortion differ. In addition, the same information about the nature and magnitude Massachusetts Teratogen Information Service(781) 466-8474 of a teratogenic risk may prompt different decisions by different women, according to the clinical situa- tion and specific circumstances. For example, wom- en with epilepsy that has been treated effectively New York Teratogen Information Service(716) 874-4747 (ext. 477) with phenytoin since their childhood may be glad to (800) 724-2454 (ext. 270) (only in New York) hear that although the drug is teratogenic, the over- all risk of malformations is not high.61 In contrast, women who have been treated with phenytoin for a single grand mal seizure and who have normal chil- dren born before phenytoin was prescribed may find it unacceptable to continue an unplanned pregnancy after learning about the higher-than-normal risk ofadverse effects.
During counseling, it is important to ensure that a woman understands the concept of base-line ter-atogenic risk and the fetal or perinatal risks, if any, the FDA has established a system that classifies associated with her medical condition. For example, drugs on the basis of data from humans and animals, a woman with manic depression treated with lithium ranging from class A drugs, which are designated as in the first trimester will need to understand not only safe for use during pregnancy, to class X drugs, the slightly increased risk of fetal cardiac anomalies which are contraindicated during pregnancy because associated with the drug (less than 1 percent)53 but of proven teratogenicity. This system has resulted in also the increased genetic risk of manic depression in ambiguous statements that may be difficult to inter- her child. The counselor should be sure to commu- pret and use for counseling and that can cause anx- nicate the same information to the woman’s physi- iety among women. In addition, the classification is cian so that she does not receive conflicting advice.
often not changed when new data become available.
To receive up-to-date, evidence-based information For example, until recently, combined oral contra- on the safety and risk of drugs during pregnancy, ceptives were classified as class X drugs. Yet meta- physicians can consult a teratogen-information serv- analyses revealed that these combinations of estro- ice. Table 4 lists the World Wide Web addresses and gen and progestin were not associated with an telephone numbers of services in the United States increased risk of major malformations, in general,15 or genitourinary malformations, in particular.16 Eachyear, thousands of women become pregnant while THE FDA CLASSIFICATION
taking these contraceptive hormones because of non- OF TERATOGENICITY
compliance or less-than-perfect efficacy, and their To guide physicians in the interpretation of the fetuses are exposed to the drugs during embryogen- teratogenic risk associated with prescription drugs, esis. In a similar fashion, tricyclic antidepressant Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. D R U G T H E R A PY
drugs are classified as D (“positive evidence of hu- DRUGS OF CHOICE IN PREGNANCY
man fetal risk”), even though no such evidence ex- Many pregnant women require drug therapy be- ists and the available data suggest that these drugs cause of pregnancy-induced conditions such as nau- are safe.85 The Teratology Society has proposed that sea and vomiting, chronic conditions diagnosed be- the FDA abandon the current classification system fore pregnancy, or acute conditions (e.g., those that in favor of more meaningful, evidence-based, narra- require surgical treatment with the use of anesthetic tive statements.92 At an FDA hearing held on Sep- tember 15, 1997, this proposal received public sup- Several principles should guide the selection of port. Other countries (e.g., Sweden, Australia, the therapy during pregnancy. Since fetal safety is a ma- Netherlands, Switzerland, and Denmark) have dif- jor concern, effective drugs that have been in use for ferent classification systems, although all are based long periods are preferable to newer alternatives. Ta- on a hierarchy of estimated fetal risk.
ble 5 lists selected drugs considered to be safe on the TABLE 5. SELECTED DRUGS THAT CAN BE USED SAFELY DURING PREGNANCY, ACCORDING TO CONDITION.*
DRUGS OF CHOICE
lyn, decongestants, xylometazo-line, oxymetazoline, naphazo-line, phenylephrine; systemic: diphenhydramine, dimenhydri-nate, tripelennamine, astemizole in, sorbitol, lactulose, mineral oil, magnesium hydroxide When lithium is used in first trimester, fetal echocardiography and ultrasonography are recommended because of small risk of cardio-vascular defects Aspirin and nonsteroidal antiinflammatory drugs b-adrenergic–receptor antagonists and Limited experience with ergotamine has not revealed evidence of teratogenicity, but there is concern about potent vasoconstriction and uterine contraction b-adrenergic–receptor antagonists, Angiotensin-converting–enzyme inhibitors should be avoided because of risk of severe neonatal renal insufficiency b-adrenergic–receptor antagonists (for Surgery may be required; radioactive iodine If lithium is used in first trimester, fetal echo- cardiography and ultrasonography are recom- mended because of small risk of cardiac anomalies; valproic acid may be given after neural-tube closure is complete aluminum hydroxide, calcium carbonate, ranitidine lotions, aluminum acetate, zinc oxide cream or ointment, cal-amine lotion, glucocorticoids; systemic: hydroxyzine, diphen-hydramine, glucocorticoids, astemizole Streptokinase is associated with a risk of Downloaded from www.nejm.org on March 4, 2007 . Copyright 1998 Massachusetts Medical Society. All rights reserved. T h e New E n g l a n d Jo u r n a l o f Me d i c i n e basis of either single large cohort studies or meta- 9. Saxen I. Associations between oral clefts and drugs taken during preg-
analyses of several studies. Newer drugs may be more nancy. Int J Epidemiol 1975;4:37-44.
10. Rosenberg L, Mitchell AA, Parsells JL, Pashayan H, Luvik C, Shapiro
specific or have fewer adverse effects in adults, but S. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl their safety for fetuses is less likely to be known. For J Med 1983;309:1282-5.
11. Shiono PH, Mills JL. Oral clefts and diazepam use during pregnancy.
example, although acetaminophen with or without codeine may not be effective in many patients with 12. Czeizel A. Lack of evidence of teratogenicity of benzodiazepine drugs
migraine, it is widely used during pregnancy. Other, in Hungary. Reprod Toxicol 1987;1:183-8.
13. Nora JJ, Nora AH, Blu J, et al. Exogenous progestogen and estrogen
more potent antimigraine drugs are either too new implicated in birth defects. JAMA 1978;240:837-43.
(e.g., sumatriptan) or have known reproductive risks 14. Schardein JL. Congenital abnormalities and hormones during preg-
(e.g., ergotamine alkaloids that cause uterine con- nancy: a clinical review. Teratology 1980;22:251-70.
15. Bracken MB. Oral contraception and congenital malformations in off-
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