Key Abbreviations
Angiotensin-converting enzyme ACE
Birth defects surveillance monitoring system BDSMS
Electroencephalogram EEG
Fetal alcohol syndrome FAS
Food and Drug Administration FDA
Glucose-6-phosphate dehydrogenase G6PD
Neural tube defect NTD
Propylthiouracil PTU
Sudden infant death syndrome SIDS
Saturated solution of potassium iodide SSKI
Thyroid-stimulating hormone TSH
Zidovudine ZDV
Overview
The placenta allows the transfer of many drugs and dietary substances. Lipid-soluble compounds readily cross the placenta, and water-soluble substances pass less well the greater their molecular weight. The degree to which a drug is bound to plasma protein also influences the amount of drug that is free to cross the placenta. Virtually all drugs cross the placenta to some degree, with the exception of large molecules such as heparin and insulin.
Developmental defects in humans may result from genetic, environmental, or unknown causes. Approximately 25% are unequivocally genetic in origin; drug exposure accounts for only 2% to 3% of birth defects. Approximately 65% of defects are of unknown etiology, but most are thought to be combinations of genetic and environmental factors.
The incidence of major malformations in the general population is 2% to 3%. A major malformation is defined as one that is incompatible with survival, such as anencephaly; one that requires major surgery for correction, such as cleft palate or congenital heart disease; or one that produces major dysfunction, such as mental retardation. If minor malformations are also included, such as ear tags or extra digits, the rate may be as high as 7% to 10%. The risk of malformation after exposure to a drug must be compared with this background rate.
Species specificity is marked in drug teratogenesis. For example, thalidomide was not found to be teratogenic in rats and mice but is a potent human teratogen. However, it was thought that the original animal studies were flawed because subsequent studies found teratogenicity in mice, rats, rabbits, and monkeys. Animal studies can be used to estimate human risk in about 24% of drugs.
The Teratology Society suggested abandoning the U.S. Food and Drug Administration (FDA) letter classification, and 20 years later, this has finally occurred. The categories implied that risk increases from category A to X. However, the drugs in different categories may pose similar risks but be in different categories based on risk/benefit considerations. The categories create the impression that drugs within a category present similar risks, whereas the category definition permits inclusion in the same category of drugs that vary in type, degree, or extent of risk, depending on potential benefit. The risks and benefits of a drug’s use in pregnancy are described in this chapter.
The categories were designed for prescribing physicians and not to address inadvertent exposure. For example, isotretinoin and oral contraceptives were both category X based on lack of benefit for oral contraceptives during pregnancy, yet oral contraceptives do not have any teratogenic risk with inadvertent exposure. When counseling patients or responding to queries from physicians, we recommend using specific descriptions from teratogen information databases ( Box 8-1 ).
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Micromedex, Inc. 6200 South Syracuse Way, Suite 300, Greenwood Village, CO 80111-4740; phone 800-525-9083; www.micromedex.com
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Reproductive Toxicology Center (REPROTOX). 7831 Woodmont Avenue, Suite 375, Bethesda, MD 20814; phone 301-514-3081; www.reprotox.org
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Organization of Teratology Information Services (OTIS). Medical Center, 200 W. Arbor Drive, #8446, San Diego, CA 92103-9981; phone 886-626-6847; www.otispregnancy.org
The classic teratogenic period is from day 31 after the last menstrual period (LMP) in a 28-day cycle to 71 days from the LMP ( Fig. 8-1 ). During this critical period, organs are forming, and teratogens may cause malformations that are usually overt at birth. Timing of exposure is important. Administration of drugs early in the period of organogenesis affects the organs developing at that time, such as the heart or neural tube. Closer to the end of the classic teratogenic period, the ear and palate are forming and may be affected by a teratogen.
Before day 31, exposure to a teratogen produces an all-or-none effect. With exposure around conception, the conceptus usually either does not survive or survives without anomalies. Because so few cells exist in the early stages, irreparable damage to some may be lethal to the entire organism. If the organism remains viable, however, organ-specific anomalies are not manifested because either repair or replacement will occur to permit normal development. However, a similar insult at a later stage may produce organ-specific defects.
Basic Principles of Teratology
To understand the etiology of birth defects, it is important to enumerate the principles of abnormal development, or teratogenesis. Wilson’s six general principles of teratogenesis provide a framework for understanding how structural or functional teratogens may act. Each principle is covered here.
Genotype and Interaction With Environmental Factors
The first principle is that susceptibility to a teratogen depends on the genotype of the conceptus and on the manner in which the genotype interacts with environmental factors. This is perhaps most clearly shown by experiments in which different genetic strains of mice have varied greatly in their susceptibility to teratogens that lead to oral clefts. Some of the variability in responses to human teratogens, such as to anticonvulsant drugs such as valproic acid and hydantoin, probably relates to genotype of the embryo. The increasing complexity of these potential interactions is illustrated by a series of elegant studies by Musselman and colleagues.
Timing of Exposure
The second principle is that susceptibility of the conceptus to teratogenic agents varies with the developmental stage at the time of exposure. This concept of critical stages of development is particularly applicable to alterations in structure. Most structural defects occur during the second to the eighth weeks of development after conception, during the embryonic period. For such defects, it is believed that a critical stage in the developmental process exists after which abnormal embryogenesis cannot be initiated. For example, neural tube defects (NTDs) result from the failure of the neural tube to close. Given that this process occurs between 22 and 28 days postconception, any exogenous effect on development must be present at or before this time. The neural tube has five distinct closure sites that may respond differentially to agents and may respond differently in timing. Investigations of thalidomide teratogenicity have clearly shown that the effects of the drug differ as a function of the developmental stage at which the pregnant woman took the drug.
Mechanisms of Teratogenesis
The third principle is that teratogenic agents act in specific ways—that is, via specific mechanisms —on developing cells and tissues in initiating abnormal embryogenesis (pathogenesis). Teratogenic mechanisms are considered separately below.
Manifestations
The fourth principle is that irrespective of the specific deleterious agent, the final manifestations of abnormal development are malformation, growth restriction, functional disorder, and death. The manifestation is thought to depend largely on the stage of development at which exposure occurred; a teratogen may have one effect if exposure occurs during embryogenesis and another if the exposure is during the fetal period. Embryonic exposure is likely to lead to structural abnormalities or embryonic death; fetal exposure is likely to lead to functional deficits or growth restriction.
Despite the importance of teratogen timing on specificity of anomalies, a general pattern usually emerges with respect to any given teratogen. This will be evident throughout this chapter as we consider various agents. If no pattern is evident for a purported teratogen, it increases the suspicion that any purported association is spurious, and the observation reflects confounding variables not recognized and, hence, not taken into account.
Agent
The fifth principle is that access of adverse environmental influences to developing tissues depends on the nature of the influence ( agent ). This principle relates to such pharmacologic factors as maternal metabolism and placental passage. Although most clearly understood for chemical agents or drugs, the principle also applies to physical agents such as radiation or heat. For an adverse effect to occur, an agent must reach the conceptus, either indirectly through maternal tissues or directly by traversing the maternal body.
Dose Effect
The final principle is that manifestations of abnormal development increase in degree from the no-effect level to the lethal level as dosage increases. This means that the response (e.g., malformation, growth restriction) may be expected to vary according to the dose, duration, or amount of exposure. For most human teratogens, this dose response is not clearly understood, but along with the principle of critical stages of development, these concepts are important in supporting causal inferences about human reproductive hazards. Data regarding in utero exposure to ionizing radiation clearly show the importance of dose on observed effects. The potential complexity of relationships between dose and observed effects for teratogens has been noted.
Epidemiologic Approaches to Birth Defects
Teratogens and reproductive toxicants have been identified and are being sought in various ways. Here we enumerate most common approaches, their strengths, and their pitfalls.
Case Reports
Many known teratogens and reproductive toxicants were identified initially through case reports of an unusual number of cases or a constellation of abnormalities. These have often come from astute clinicians who observed something out of the ordinary. Although the importance of astute observations of abnormal aggregations of cases or patterns of malformations must be recognized, we cannot rely on such methods for identifying health hazards. Furthermore, etiologic speculations based on case reports or case series usually do not lead to a causal agent and are often false-positive speculations. Whereas case reports may identify a new teratogen, they can never provide an estimate of the risk of disease after exposure.
Descriptive Studies
Descriptive epidemiologic studies provide information about the distribution and frequency of some outcome of interest, resulting in rates of occurrence that can be compared among populations, places, or times. Defining the population at risk is the first step, and this can be done geographically, such as residents within a state, or medically, such as patients at a particular hospital. Definition of the population at risk includes the period under consideration. The population at risk constitutes the denominator for calculating rates of the occurrence of outcomes of interest.
The second step in a descriptive study is to determine the numerator for calculating rates for comparison. This involves two important concepts: case definition, or what defines a case to be counted, and case ascertainment, or how cases are to be identified.
Relevant examples of descriptive studies are surveillance programs. An at-risk population is identified and then followed over time to detect outcomes of interest, and cases are included in the database. Surveillance programs can develop baseline data and subsequently permit early recognition of potential problems based on ongoing data collection and analysis. Birth defect surveillance monitoring systems (BDSMSs) are designed to identify cases that occur in a defined population, usually by reviewing vital records or hospital record abstracts or charts. In the past 20 years, a dramatic increase has been seen in the number of state-based birth defect surveillance systems, and approximately half the states now have some type of BDSMS. These programs conduct routine reviews of occurrence rates of specific malformations and attempt to identify increases in rates or clusters of cases.
Case-Control Studies
In a case-control study design, groups of individuals (cases) with some outcome or disease of interest (e.g., a congenital malformation) are compared with controls with regard to a history of one or more exposures. This is the most widely used approach in reproductive outcomes research. Controls are ideally as similar as possible to the cases except of course lacking the outcome of interest. After cases and controls have been identified, the hypothesis to be tested is whether these two groups differ in exposure as well as outcome. How accurately exposure and its timing are determined may vary greatly among studies, but in any study, the same methods must be used to establish the exposure of both cases and controls.
Case-control studies are advantageous in testing outcomes of infrequent occurrence. This can be conducted relatively rapidly and inexpensively. A disadvantage is the potential for several important types of bias, including bias in recalling exposure, in selecting appropriate controls, and in ascertaining cases.
These problems can be addressed in part by use of two control groups, one “normal” and the second “abnormal.” Any of several abnormal controls seem equally useful (e.g., infants with mendelian or chromosomal disorders as well as infants with no specific malformations). In the former, mothers have incentive to recall, but teratogenesis is not the etiology. Ideally, case-control studies of potential teratogens should follow descriptive studies. After suspecting on the basis of case observations that thalidomide was teratogenic, Lenz conducted a case-control study. The association between valproic acid use and spina bifida was also verified by case-control studies.
Cohort Studies
In cohort studies, groups are defined by the presence or absence of exposure to a given factor and then are followed over time and compared for rates of occurrence (i.e., incidence rates) of the outcome of interest. Cohort studies have three advantages: (1) the cohort is classified by exposure before the outcome is determined, thereby eliminating exposure recall bias; (2) incidence rates can be calculated among those exposed; and (3) multiple outcomes can be observed simultaneously.
Cohort studies, often called prospective studies, require that groups differing in exposure be followed through time with outcomes observed; therefore these studies tend to be time consuming and expensive. In addition, occurrence rates for many adverse reproductive outcomes, such as congenital malformations, are low; thus large samples must be followed for a considerable period of time. Two main types of cohort studies have been developed, those that identify a cohort and follow it into the future ( concurrent cohort study) and those that identify a cohort at some time in the past and follow it to the present ( nonconcurrent or historical cohort study). In both cases, risks of adverse outcomes are compared between groups. Cohort studies enable investigators to calculate incidence rates that provide a measure of risk of an outcome after the exposure. Risk in the exposed group can be compared with risk in an unexposed group. Most frequently, the ratio of the incidence rate among the exposed to the rate among the unexposed is determined. This ratio, referred to as relative risk, is a measure of how much the presence of exposure increases the risk of the outcome.
In historical prospective studies, the study begins by identifying groups who differ in terms of some past exposure, and these are followed to the present to determine outcomes; exposure groups are defined before outcomes are known. A major advantage is that although the time frame is prospective, investigators do not have to follow the cohort into the future and wait for events to occur. A disadvantage is that these studies require the ability to determine exposure status retrospectively.
Clinical Trials
Ideally, analytic studies—case control or cohort—are followed by a randomized clinical trial in which the efficiency of a prevention or treatment regimen is evaluated; that is, subjects are randomly assigned to different treatment groups. The individuals should be as similar as possible in terms of unknown factors that may affect the response before they are randomly assigned to the treatment groups to receive the different regimens.
Clinical trials of both NTD recurrence and occurrence have shown a protective effect of periconceptional folic acid supplementation, findings that have led to key public health recommendations regarding the use of folic acid to reduce the risk of these often devastating defects.
Medical Drug Use
Patients should be educated about drug alternatives to cope with tension, aches and pains, and viral and other medical illnesses during pregnancy. The risk/benefit ratio should justify the use of a particular drug, and the minimum effective dose should be used. Because long-term effects of drug exposure in utero may not be revealed for many years, caution with regard to the use of any drug in pregnancy is warranted. Also, some drug doses may have a significant effect on the concentrations of analytes routinely used in serum screening for aneuploidy and NTDs. Methadone has been reported to increase screen-positive results for trisomy 18, and screen-positive rates for NTDs were higher for those on corticosteroids, antibiotics, and antidepressants.
Effects of Specific Drugs
Estrogens and Progestins
Studies have not confirmed any teratogenic risk for oral contraceptives or progestins. A meta-analysis of first-trimester sex hormone exposure revealed no association between exposure and fetal genital malformations. However, because of the medicolegal climate and the conflicting past literature, it is wise to exclude pregnancy before giving progestins to an amenorrheic patient.
Androgenic Steroids
Androgens may masculinize a developing female fetus. Danazol has been reported to produce clitoral enlargement and labial fusion when given inadvertently for the first 9 to 12 weeks after conception ( Fig. 8-2 ) in 23 of 57 female infants exposed.
Spermicides
The once touted increased risk of abnormal offspring in mothers who had used spermicides for contraception has not been confirmed. A meta-analysis of reports of sperimicide exposure concludes that the risk of birth defects is not increased.
Antiepileptic Drugs
Women with epilepsy who take antiepileptic drugs (AEDs) during pregnancy have approximately double the general population risk of malformations in offspring. Compared with the general risk of 2% to 3%, the risk of major malformations in women with epilepsy who take AEDs is about 5%, especially cleft lip with or without cleft palate and congenital heart disease. Valproic acid and carbamazepine each carry approximately a 1% risk of NTDs and other anomalies. Valproic acid monotherapy significantly increases risk for spina bifida (odds ratio [OR] 12.7), atrial septal defect (2.5), cleft palate (5.2), hypospadias (4.8), polydactyly (2.2), and craniosynostosis (6.8). A high daily dose or a combination of two or three drugs increases the chance of malformations.
Holmes and colleagues screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to AEDs, those unexposed to AEDs but with a maternal history of seizures, and those unexposed to AEDs with no maternal history of seizures (control group). The infants were examined systematically for the presence of malformations. The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one AED than in 508 control infants (20.6% vs. 8.5%; OR, 2.8; 95% confidence interval [CI], 1.1-9.7). The frequency was also higher in 93 infants exposed to two or more AEDs than in the controls (28.0% vs. 8.5%; OR, 4.2; 95% CI, 1.1-5.1). The greater the number of AEDs, the higher the risk of malformation. The 98 infants whose mothers had a history of epilepsy but who took no AEDs during the pregnancy did not have a higher frequency of abnormalities than the control infants.
Phenytoin decreases folate absorption and lowers serum folate, which has been implicated in birth defects. Therefore folic acid supplementation should be given to these mothers, but this may require adjustment of the AED. Although women with epilepsy were not included in the Medical Research Council study, most authorities would recommend 4 mg/day folic acid for high-risk women. One study suggested that folic acid at doses of 2.5 to 5 mg daily could reduce birth defects in the offspring of women who take AEDs.
Fewer than 10% of offspring show the fetal hydantoin syndrome, which consists of microcephaly, growth deficiency, developmental delays, mental retardation, and dysmorphic craniofacial features ( Fig. 8-3 ). In fact, the risk may be as low as 1% to 2% above background. Although several of these features are also found in other syndromes, such as fetal alcohol syndrome, more common in the fetal hydantoin syndrome are hypoplasia of the nails and distal phalanges ( Fig. 8-4 ) and hypertelorism. Carbamazepine is also associated with an increased risk of a dysmorphic syndrome. A genetically determined metabolic defect in arene oxide detoxification in the infant may increase the risk of a major birth defect. Epoxide hydrolase deficiency may indicate susceptibility to fetal hydantoin syndrome.
In a follow-up study of long-term effects of antenatal exposure to phenobarbital and carbamazepine, no neurologic or behavioral differences were noted between the two groups. However, children exposed in utero to phenytoin scored 10 points lower on IQ tests than children exposed to carbamazepine and nonexposed controls. At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those exposed to other antiepileptic drugs; therefore valproate should not be used as a first-choice drug in women of reproductive age. Also, prenatal exposure to phenobarbital decreased verbal IQ scores in adult men.
Lamotrigine exposures have been compiled in a voluntary registry established by the manufacturer, GlaxoSmithKline. After 1558 exposures in the first trimester, no increased risk of birth defects overall has been observed. Of 1532 infant exposures to newer-generation antiepileptic drugs, 1019 were to lamotrigine, and 3.7% had major birth defects. Of 393 infants exposed to oxcarbazepine, the rate was 2.8%, and for 108 exposed to topiramate, the rate was 4.6%. None of these differences were statistically different from controls. Valproic acid carries significantly higher risks than lamotrigine or carbamazepine. One study suggested a fivefold increased risk of cleft lip and/or cleft palate with use of topiramate. In general, polytherapy exposure is associated with some poorer outcomes in neuropsychological or developmental testing. Minimizing the dose during pregnancy is also critical in preventing birth defects.
Some women may have taken AEDs for a long period without reevaluation of the need for continuation of the drugs. For patients with idiopathic epilepsy who have been seizure free for 2 years and who have a normal electroencephalogram (EEG), it may be safe to attempt a trial of withdrawal of the drug before pregnancy.
Most authorities agree that the benefits of AEDs during pregnancy outweigh the risks of discontinuation of the drug if the patient is first seen during pregnancy. Continuing AEDs depends on the type of seizures, seizure control, adverse effects of the AED regimen, and patient adherence. Adherence can be determined by measuring a serum concentration of the AED. If the level is low or undetected and the patient is seizure free, AED therapy may not be required. Because the albumin concentration falls in pregnancy, the total amount of phenytoin measured is decreased because it is highly protein bound. However, the level of free phenytoin, which is the pharmacologically active portion, is unchanged.
Pediatric care providers need to be notified at birth when a patient has been on anticonvulsants because this therapy can affect vitamin K–dependent clotting factors in the newborn.
Isotretinoin
Isotretinoin is a significant human teratogen. This drug is marketed as Accutane for treatment of cystic acne, and it unfortunately has been taken by women who were not planning pregnancy. Long-acting reversible contraception such as an intrauterine device (IUD) or an etonogestrel implant (Nexplanon) are recommended. Isotretinoin is labeled as contraindicated in pregnancy (FDA category X) with appropriate warnings that a negative pregnancy test is required before therapy. Of 154 exposed human pregnancies, 21 cases of birth defects, 12 spontaneous abortions, 95 elective abortions, and 26 normal infants were reported in women who took isotretinoin during early pregnancy. The risk of structural anomalies in patients studied prospectively is now estimated to be about 25%, and an additional 25% have mental retardation alone. The malformed infants have a characteristic pattern of craniofacial, cardiac, thymic, and central nervous system (CNS) anomalies that include microtia/anotia (small/absent ears; Fig. 8-5 ), micrognathia, cleft palate, heart defects, thymic defects, retinal or optic nerve anomalies, and CNS malformations that include hydrocephalus. Microtia is rare as an isolated anomaly yet appears commonly as part of the retinoic acid embryopathy. Cardiovascular defects include great vessel transposition and ventricular septal defects (VSDs).
Unlike vitamin A, isotretinoin is not stored in tissue. Therefore a pregnancy after discontinuation of isotretinoin is not at risk because the drug is no longer detectable in serum 5 days after its ingestion. In 88 pregnancies prospectively ascertained after discontinuation of isotretinoin, no increased risk of anomalies was noted. Topical tretinoin has not been associated with any teratogenic risk.
Vitamin A
No evidence suggests that vitamin A or β-carotene is teratogenic in normal doses. The vitamin A levels in prenatal vitamins (5000 IU/day) have not been associated with any documented risk. Eighteen cases of birth defects have been reported after exposure to levels of 25,000 IU or more of vitamin A during pregnancy. Vitamin A in doses greater than 10,000 IU/day was shown to increase the risk of malformations in one study but not in another.
Psychoactive Drugs
No clear risk has been documented for most psychoactive drugs with respect to overt birth defects. However, effects of chronic use of these agents on the developing brain in humans is difficult to study, and so a conservative attitude is appropriate. Lack of overt defects does not exclude the possibility of behavioral teratogenesis, and neonatal withdrawal may occur. However, untreated depression carries risks also.
Tranquilizers
Conflicting reports of the possible teratogenicity of the various tranquilizers, including meprobamate and chlordiazepoxide, have appeared, but in prospective studies no increased risk of anomalies has been shown.
A fetal benzodiazepine syndrome has been reported in seven infants of 36 mothers who regularly took benzodiazepines during pregnancy. However, the high rate of abnormality occurred with concomitant alcohol and substance abuse and may not have been caused by the benzodiazepine exposure. In most clinical situations, however, the risk/benefit ratio does not justify the use of benzodiazepines in pregnancy. Use of diazepam in labor has been associated with neonatal hypotonia, hypothermia, and respiratory depression.
Lithium
In the International Register of Lithium Babies, 217 infants were listed as exposed at least during the first trimester of pregnancy, and 25 (11.5%) were malformed. Eighteen had cardiovascular anomalies, including six cases of the rare Ebstein anomaly, which occurs in only 1 in 20,000 in the nonexposed population. Of 60 unaffected infants who were followed to age 5 years, no increased mental or physical abnormalities were noted compared with unexposed siblings.
However, two other reports suggest bias of ascertainment in the registry and a risk of anomalies much lower than previously thought. A case-control study of 59 patients with Ebstein anomaly showed no difference in the rate of lithium exposure in pregnancy from a control group of 168 children with neuroblastoma. A prospective study of 148 women exposed to lithium in the first trimester showed no difference in the incidence of major anomalies compared with controls. One fetus in the lithium-exposed group had Ebstein anomaly, and one infant in the control group had a VSD. The authors concluded that lithium is not a major human teratogen. Nevertheless, we recommend that women exposed to lithium be offered ultrasound and fetal echocardiography.
Lithium is excreted more rapidly during pregnancy, thus serum lithium levels should be monitored. Perinatal effects of lithium have been noted and include hypotonia, lethargy, and poor feeding in the infant. Also, complications similar to those seen in adults taking lithium have been noted in newborns, including goiter and hypothyroidism.
Two cases of polyhydramnios associated with maternal lithium treatment have been reported. Because nephrogenic diabetes insipidus has been reported in adults taking lithium, the presumed mechanism of this polyhydramnios is fetal diabetes insipidus. Polyhydramnios may be a sign of fetal lithium toxicity.
It is usually recommended that drug therapy be changed in pregnant women taking lithium to avoid fetal drug exposure. Tapering over 10 days delays the risk of relapse. However, discontinuing lithium is associated with a 70% chance of relapse of the affective disorder in 1 year as opposed to 20% in those who remain on lithium. Discontinuation of lithium may pose an unacceptable risk of increased morbidity in women who have had multiple episodes of affective instability. These women should be offered appropriate prenatal diagnosis with ultrasound, including fetal echocardiography. Lithium may be withheld for 24 to 48 hours before delivery to reduce neonatal complications and reduce infant hospital stays.
Antidepressants
Imipramine was the original tricyclic antidepressant (TCA) claimed to be associated with cardiovascular defects, but the number of patients studied remains small. Of 75 newborns exposed in the first trimester, six major defects were observed—three cardiovascular—and neonatal withdrawal has been observed.
Amitriptyline has been more widely used, and the majority of the evidence supports its safety. In the Michigan Medicaid study, 467 newborns had been exposed during the first trimester, with no increased risk of birth defects.
No increased risk of major malformations has been found after first-trimester exposure to fluoxetine in several studies. However, one recent study showed a twofold increased risk of VSDs. Chambers and associates found more minor malformations and perinatal complications among infants exposed to fluoxetine throughout pregnancy, but this study is difficult to interpret because the authors did not control for depression. When a group whose mothers received tricyclic agents was used as a control for depression, infants exposed to fluoxetine in utero did not appear to have more minor malformations or perinatal complications. One study suggested an increased risk of low-birthweight infants with higher doses of fluoxetine (40 to 80 mg) throughout pregnancy.
Nulman evaluated the neurobehavioral effects of long-term fluoxetine exposure during pregnancy and found no abnormalities among 228 children aged 16 to 86 months (average age, 3 years). Theoretically, some psychiatric or neurobehavioral abnormality might occur as a result of exposure, but it would be very difficult to ascertain because of all of the confounding variables.
Current data on other selective serotonin reuptake inhibitor (SSRI) exposures show no consistent teratogenic risk. Citalopram is transferred across the placenta the most, followed by fluoxetine. The lowest transfer is found with sertraline, followed by paroxetine, although two studies found an increased risk of cardiac defects after exposure to paroxetine. A recent large, population-based cohort study suggested no substantial increased risk of cardiac defects attributable to antidepressant use in the first trimester. One study showed a twofold increased risk of NTDs after citalopram.
Studies have described neonatal withdrawal in the first 2 days after in utero exposure to these drugs. Infants exposed during pregnancy exhibited more tremulousness and sleep changes at 1 to 2 days of age. However, no abnormalities were found when children were examined at ages of 16 to 86 months after prolonged exposure during pregnancy.
A sixfold increased risk of persistent pulmonary hypertension (PPH) in newborns has been reported in infants exposed to SSRIs after 20 weeks of pregnancy, raising the absolute risk from 1 to 2 per 1000 in unexposed infants to 6 to 12 per 1000 in exposed infants. Another study did not confirm this finding but did confirm a fivefold increased risk of PPH with cesarean section before labor. Exposure to SSRIs in the first trimester did not increase the risk of miscarriage. No major malformations have been reported in 133 infants exposed to bupropion.
When considering the use of antidepressant drugs during pregnancy, it should be noted that among women who maintained their medication throughout pregnancy, 26% relapsed compared with 68% who discontinued medication. Also, fetal alcohol spectrum disorders were 10 times more common in SSRI-exposed offspring than in unexposed offspring. Therefore controversy exists as to whether the risks of antidepressants outweigh the benefits, and counseling may be as effective as drug therapy.
Anticoagulants
Warfarin has been associated with chondrodysplasia punctata, which is similar to the genetically determined Conradi-Hünermann syndrome. Warfarin embryopathy occurs in about 5% of exposed pregnancies and includes nasal hypoplasia, bone stippling seen on radiologic examination, ophthalmologic abnormalities including bilateral optic atrophy, and mental retardation ( Fig. 8-6 ). Ophthalmologic abnormalities and mental retardation may occur even with use only beyond the first trimester. The risk for pregnancy complications is higher when the mean daily dose of warfarin is more than 5 mg.
The alternative drugs, heparin and enoxaparin, do not cross the placenta because they are large molecules with a strong negative charge. Because heparin does not have an adverse effect on the fetus when given in pregnancy, it should be the drug of choice for patients who require anticoagulation, except in women with artificial heart valves. However, therapy with 20,000 U/day for more than 20 weeks has been associated with bone demineralization, and 36% of patients had more than a 10% decrease from baseline bone density to postpartum values. The risk of spine fractures was 0.7% with low-dose heparin and 3% with a high-dose regimen. Heparin can also cause thrombocytopenia.
Low-molecular-weight heparins (LMWHs) may have substantial benefits over standard unfractionated heparin (UFH). The molecules are still relatively large and do not cross the placenta, plus the half-life is longer, which allows for once-daily administration. However, enoxaparin is cleared more rapidly during pregnancy, so twice-daily dosing is advised. LMWHs have a much more predictable dose-response relationship, which obviates the need for monitoring of partial thromboplastin time. The risk of heparin-induced thrombocytopenia and clinical bleeding at delivery is lower, but studies that suggest less risk of osteoporosis are preliminary.
Women with mechanical heart valves, especially the first-generation valves, require warfarin anticoagulation because heparin is neither safe nor effective. Heparin treatment is associated with more thromboembolic complications and more bleeding complications than warfarin therapy.
The risks of heparin during pregnancy may not be justified in patients with only a single remote episode of thrombosis in the past. Certainly, conservative measures should be recommended, such as elastic stockings and avoidance of prolonged sitting or standing.
Thyroid and Antithyroid Drugs
Propylthiouracil (PTU) and methimazole both cross the placenta and may cause some degree of fetal goiter. In contrast, the thyroid hormones triiodothyronine and thyroxine cross the placenta poorly, so that fetal hypothyroidism produced by antithyroid drugs cannot be corrected satisfactorily by administration of thyroid hormone to the mother. Thus the goal of such therapy during pregnancy is to keep the mother slightly hyperthyroid to minimize fetal drug exposure. By the third trimester, 30% of women no longer need antithyroid medication.
Methimazole has been associated with scalp defects in infants and choanal or esophageal atresia as well as a higher incidence of maternal side effects. However, PTU and methimazole are equally effective and safe for therapy of hyperthyroidism. Still, in 2009 the FDA released a black box warning highlighting serious liver injury with PTU treatment, to a greater extent than methimazole. The Endocrine Society is now advocating treatment with PTU only during the first trimester and switching to methimazole for the remainder of the pregnancy.
Radioactive iodine ( 131 I or 125 I) administered for thyroid ablation or for diagnostic studies is not concentrated by the fetal thyroid until after 12 weeks of pregnancy. Thus with inadvertent exposure before 12 weeks, no specific risk to the fetal thyroid results from 131 I or 125 I administration.
The need for thyroxine increases in many women with primary hypothyroidism when they are pregnant, as reflected by an increase in serum thyroid-stimulating hormone (TSH) concentrations. Because hypothyroidism in pregnancy may adversely affect the fetus, possibly by increasing prematurity, it is prudent to monitor thyroid function throughout pregnancy and to adjust the thyroid dose to maintain a normal TSH level. It is recommended that women with hypothyroidism increase their levothyroxine dose by approximately 30% as soon as pregnancy is confirmed (two extra doses each week) and then have dosing adjustments based on TSH levels.
Topical iodine preparations are readily absorbed through the vagina during pregnancy, and transient hypothyroidism has been demonstrated in the newborn after exposure during labor.
Digoxin
In 194 exposures, no teratogenicity of digoxin was noted. Blood levels should be monitored in pregnancy to ensure adequate therapeutic maternal levels.
Digoxin-like immunoreactive substances may be mistaken in assays for fetal concentrations of digoxin. In one study of fetuses with cardiac anomalies, no difference was found in the immunoreactive digoxin levels whether the mother had received digoxin or not. In hydropic fetuses, digoxin may not easily cross the placenta.
Antihypertensive Drugs
For treatment of chronic hypertension in pregnancy, α-methyldopa has been widely used. Although postural hypotension may occur, no unusual fetal effects have been noted. Hydralazine is used frequently in pregnancy, and no teratogenic effect has been observed. For more on antihypertensive drugs, see Chapter 31 .
Sympathetic Blocking Agents
Propranolol is a β-adrenergic blocking agent in widespread use for various indications, for which no evidence of teratogenicity has been found. Bradycardia has been reported in the newborn as a direct effect of a dose of the drug given to the mother within 2 hours of delivery.
Several studies of propranolol use in pregnancy show an increased risk of intrauterine growth restriction (IUGR) or at least a skewing of the birthweight distribution toward the lower range. Ultrasound monitoring of exposed patients is prudent. Studies from Scotland suggest improved outcome with the use of atenolol to treat chronic hypertension during pregnancy.
Calcium channel blockers such as nifedipine have been widely used for chronic hypertension in pregnancy without evidence of teratogenicity. Magnesium sulfate should be used with caution in women taking these agents.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
Fetal exposure to angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in the first trimester has not been associated with an increased risk of birth defects. ACE inhibitors such as enalapril and captopril and angiotensin II receptor antagonists such as valsartan can cause fetal renal tubular dysplasia in the second and third trimesters, leading to oligohydramnios, fetal limb contractures, craniofacial deformities, and hypoplastic lung development. Fetal skull ossification defects have also been described. For these reasons, women taking these medications who plan pregnancy should be switched to other agents.
Antineoplastic Drugs and Immunosuppressants
Mycophenolate mofetil carries a moderate teratogenic risk. Frequent features include microtia or anotia, cleft lip and/or palate, heart defects, and dysmorphic facial features. The numbers are too small to determine the actual rate of malformations.
Methotrexate, a folic acid antagonist, appears to be a human teratogen, although experience is limited. Infants of three women known to have received methotrexate in the first trimester of pregnancy had multiple congenital anomalies, including cranial defects and malformed extremities. Of eight women inadvertently treated with methotrexate after misdiagnosis of ectopic pregnancy, two infants were severely malformed, three patients miscarried, and three chose to terminate the pregnancies. Eight normal infants were delivered to seven women treated with methotrexate in combination with other agents after the first trimester. When low-dose oral methotrexate (7.5 mg/week) was used for rheumatoid disease in the first trimester, five full-term infants were normal and three patients experienced spontaneous abortions.
Azathioprine has been used by patients with renal transplants or systemic lupus erythematosus. The frequency of anomalies in 375 women treated in the first trimester was not increased. Some infants had leukopenia, some were small for gestational age (SGA), and the others were normal.
No increased risk of anomalies in fetuses exposed to cyclosporine in utero has been reported. An increased rate of prematurity and growth restriction has been noted, but it is difficult to separate the contributions of the underlying disease and the drugs given to these transplant patients. The B-cell line may be depleted more than the T-cell line, and one author recommends that infants exposed to immunosuppressive agents be followed for possible immunodeficiency.
Eight malformed infants have resulted from first-trimester exposure to cyclophosphamide, but these infants were also exposed to other drugs or radiation. Low birthweight may be associated with use after the first trimester, but this may also reflect the underlying medical problem.
Chloroquine is safe in doses used for malarial prophylaxis, and no increased incidence of birth defects was reported among 169 infants exposed to 300 mg once weekly. However, after exposure to larger antiinflammatory doses (250 to 500 mg/day), two cases of cochleovestibular paresis were reported. No abnormalities were noted in 114 other infants.
No association was found between administration of tumor necrosis factor (TNF) inhibitors infliximab or adalimumab and congenital anomalies.
When cancer chemotherapy must be used during embryogenesis, the rate of spontaneous abortion and major birth defects is increased. Later in pregnancy, the risk of stillbirth and IUGR is greater, and myelosuppression is often present in the infant.
Antiasthmatics
Terbutaline
Terbutaline has been widely used in the treatment of preterm labor. It is more rapid in onset, has a longer duration of action than epinephrine, and is preferred for asthma in the pregnant patient. No risk of birth defects has been reported with terbutaline, although long-term use has been associated with an increased risk of glucose intolerance.
Cromolyn Sodium
Cromolyn sodium may be administered in pregnancy, and the systemic absorption is minimal. Teratogenicity has not been reported in humans.
Isoproterenol and Metaproterenol
When isoproterenol and metaproterenol are given as topical aerosols for the treatment of asthma, the total dose absorbed is usually not significant. With oral or intravenous (IV) doses, however, the cardiovascular effects of the agents may decrease uterine blood flow. For this reason, they should be used with caution. No teratogenicity has been reported.
Corticosteroids
All steroids cross the placenta to some degree, but prednisone and prednisolone are inactivated by the placenta. When prednisone or prednisolone is given to a pregnant woman, the concentration of active compound in the fetus is less than 10% of that in the mother. Therefore these agents are the drugs of choice for treating medical diseases such as asthma. Inhaled corticosteroids are also effective therapy, and very little drug is absorbed. When steroid effects are desired in the fetus to accelerate lung maturity, betamethasone and dexamethasone are preferred because these are minimally inactivated by the placenta. A meta-analysis of exposure to corticosteroids in the first trimester showed an odds ratio of 3.0 for cleft lip and/or cleft palate.
Iodide
Iodide, such as that found in a saturated solution of potassium iodide (SSKI) expectorant, crosses the placenta and may produce a fetal goiter large enough to produce respiratory obstruction in the newborn ( Fig. 8-7 ). Before a pregnant patient is advised to take a cough medicine, the clinician should be sure to ascertain that it does not contain iodide.
Antiemetics
Remedies suggested to help nausea and vomiting in pregnancy without pharmacologic intervention include eating crackers at the bedside on first awakening in the morning (before getting out of bed), getting up very slowly, omitting iron tablets, consuming frequent small meals, and eating protein snacks at night. None of the current medications used to treat nausea and vomiting have been found to be teratogenic except possibly methylprednisolone used before 10 weeks of gestation.
Vitamin B 6
Vitamin B 6 (pyridoxine) 25 mg three times a day has been reported in two randomized placebo-controlled trials to be effective for treating the nausea and vomiting of pregnancy. In several other controlled trials, no evidence of teratogenicity was found.
Doxylamine
Delayed-release doxylamine 10 mg plus pyridoxine 10 mg (Diclegis) is effective and well tolerated. It has been approved by the FDA for NVP.
Doxylamine is an effective antihistamine for nausea and vomiting of pregnancy and can be combined with vitamin B 6 to produce a therapy similar to Diclegis. Vitamin B 6 (25 mg) and doxylamine (25 mg) at bedtime plus 12.5 mg doxylamine (one-half tablet) with vitamin B 6 (25 mg) in the morning and afternoon is an effective combination.
Meclizine
In one randomized, placebo-controlled study, meclizine gave significantly better results than placebo, and prospective clinical studies have provided no evidence that meclizine is teratogenic in humans. In 1014 patients in the Collaborative Perinatal Project and in an additional 613 patients from the Kaiser Health Plan, no teratogenic risk was found.
Dimenhydrinate
No teratogenicity has been noted with dimenhydrinate, but a 29% failure rate and a significant incidence of side effects, especially drowsiness, has been reported.
Diphenhydramine
In 595 patients treated in the Collaborative Perinatal Project, no teratogenicity was noted with diphenhydramine. However, drowsiness can be a problem.
Phenothiazines
Teratogenicity does not appear to be a problem with the phenothiazines when evaluated as a group. In the Kaiser Health Plan Study, 976 patients were treated, and in the Collaborative Perinatal Project 1309 patients were treated; in both studies, no evidence of association between these drugs and malformations was noted. In 114 mothers treated with promethazine and in 877 mothers given prochlorperazine, no increased risk of malformations was found.
Metoclopramide
Of 3458 infants exposed to metoclopramide during the first trimester, no increased risk of malformations, low birthweight, or preterm delivery was reported.
Ondansetron
Ondansetron is no more effective than promethazine, but it is less sedating. It has not been associated with a significant risk of adverse fetal outcomes. One study showed no increased risk of birth defects after ondansetron exposure. However, a larger study found a doubling in the prevalence of heart defects in exposed children.
In a double-blind randomized trial, ondansetron and metoclopramide demonstrated similar antiemetic effects, but the overall profile of adverse effects was better with ondansetron.
Methylprednisolone
Forty patients with hyperemesis who were admitted to the hospital were randomized to oral methylprednisolone or oral promethazine, and methylprednisolone was more effective. In a larger study in which all patients received promethazine and metoclopramide, methylprednisolone did not reduce the need for rehospitalization. Methylprednisolone should be used only after 10 weeks of pregnancy because of the potential risk of cleft lip and/or cleft palate.
Ginger
Ginger has been used with success for treating nausea, vomiting, and hyperemesis in the outpatient setting. A significantly greater relief of symptoms was found after ginger treatment than with placebo. Patients took 250-mg capsules containing powdered ginger root four times a day.
Acid-Suppressing Drugs
The use of cimetidine, omeprazole, and ranitidine has not been found to be associated with any teratogenic risk in 2261 exposures. Of an additional 3651 infants exposed to proton-pump inhibitors in the first trimester, no increased risk of birth defects was reported. Drugs taken in the study were mostly omeprazole but also included lansoprazole, esomeprazole, and pantoprazole.
Antihistamines and Decongestants
No increased risk of anomalies has been associated with most of the commonly used antihistamines, such as chlorpheniramine. However, in one study, terfenadine was associated with an increased risk of polydactyly. Astemizole did not increase the risk of birth defects in 114 infants exposed in the first trimester. However, an association between exposure to antihistamines during the last 2 weeks of pregnancy and retrolental fibroplasia in premature infants has been reported.
An increased risk of birth defects was noted with phenylpropanolamine exposure in the first trimester, specifically ear defects and pyloric stenosis. In one retrospective study, an increased risk of gastroschisis was associated with first-trimester pseudoephedrine use. Phenylephrine has been associated with endocardial cushion defects. Use of these drugs for trivial indications should be discouraged because long-term effects are unknown. If decongestion is necessary, topical nasal sprays will result in a lower dose to the fetus than systemic medication.
Patients should be educated that antihistamines and decongestants are only symptomatic therapy for the common cold and have no influence on the course of the disease. Other remedies should be recommended, such as use of a humidifier, rest, and fluids. If medications are necessary, combinations with two drugs should not be used if only one drug is necessary. If the diagnosis is truly an allergy, an antihistamine alone will suffice.
Antibiotics and Antiinfective Agents
Because pregnant patients are particularly susceptible to vaginal yeast infections, antibiotics should be used only when clearly indicated. Therapy with antifungal agents may be necessary during or after the course of therapy.
Penicillins
Penicillin, ampicillin, and amoxicillin are safe in pregnancy. In the Collaborative Perinatal Project, 3546 mothers took penicillin derivatives in the first trimester of pregnancy with no increased risk of anomalies. Of 86 infants exposed to dicloxacillin in the first trimester, no increase in birth defects was reported.
Clavulanate is added to penicillin derivatives to broaden their antibacterial spectrum. Of 556 infants exposed in the first trimester, no increased risk of birth defects was observed. Amoxicillin/clavulanate was studied in randomized controlled trials (RCTs) as a potential therapy for chorioamnionitis in women with preterm premature rupture of membranes (PPROM). During this trial, amoxicillin/clavulanate was compared with both placebo and erythromycin. An increased incidence of necrotizing enterocolitis was found in the amoxicillin/clavulanate group when compared with both the placebo and erythromycin groups. It has been suggested that amoxicillin/clavulanate selects for specific pathogens, which leads to abnormal microbial colonization of the gastrointestinal tract and ultimately to the initiation of necrotizing enterocolitis. Therefore amoxicillin/clavulanate should be avoided in women at risk for preterm delivery.
Cephalosporins
In a study of 5000 Michigan Medicaid recipients, a suggestion of possible teratogenicity (25% increased birth defects) was found with cefaclor, cephalexin, and cephradine but not with other cephalosporins. However, another study of 308 women exposed in the first trimester showed no increase in malformations, therefore the consensus is that these drugs are safe.
Sulfonamides
Among 1455 human infants exposed to sulfonamides during the first trimester, no teratogenic effects were noted. However, the administration of sulfonamides should be avoided in women deficient in glucose-6-phosphate dehydrogenase (G6PD) because dose-related hemolysis may occur.
Sulfonamides cause no known damage to the fetus in utero because the fetus can clear free bilirubin through the placenta. However, these drugs might theoretically have deleterious effects if they were to be present in the blood of the neonate after birth. Sulfonamides compete with bilirubin for binding sites on albumin and thus raise the levels of free bilirubin in the serum and increase the risk of hyperbilirubinemia in the neonate. Although this toxicity occurs with direct administration to the neonate, kernicterus in the newborn following in utero exposure has not been reported.
Sulfamethoxazole with Trimethoprim
Trimethoprim is often given with sulfa to treat urinary tract infections. However, one unpublished study of 2296 Michigan Medicaid recipients suggested an increased risk of cardiovascular defects after exposure in the first trimester. In one retrospective study of trimethoprim with sulfamethoxazole, the odds ratio for birth defects was 2.3, whereas in another study it was 2.5 to 3.4.
Nitrofurantoin
Nitrofurantoin is used in the treatment of acute uncomplicated lower urinary tract infections, as well as for long-term suppression, in patients with chronic bacteriuria. Nitrofurantoin is capable of inducing hemolytic anemia in patients deficient in G6PD. However, hemolytic anemia in the newborn as a result of in utero exposure to nitrofurantoin has not been reported.
No reports have associated nitrofurantoins with congenital defects. In the Collaborative Perinatal Project, 590 infants were exposed—83 in the first trimester—with no increased risk of adverse effects. In another study in 1334 women exposed in the first trimester, no increase in malformations was reported. Use in the last 30 days before delivery was associated with increased risk of neonatal jaundice.
Tetracyclines
Tetracyclines readily cross the placenta and are firmly bound by chelation to calcium in developing bone and tooth structures. This produces brown discoloration of the deciduous teeth, hypoplasia of the enamel, and inhibition of bone growth. The staining of the teeth takes place in the second or third trimesters of pregnancy, whereas bone incorporation can occur earlier. Depression of skeletal growth was particularly common among premature infants treated with tetracycline. First-trimester exposure to doxycycline is not known to carry any risk. First-trimester exposure to tetracyclines was not found to have any teratogenic risk in 341 women in the Collaborative Perinatal Project or in 174 women in another study. Alternative antibiotics are currently recommended during pregnancy.
Aminoglycosides
Streptomycin and kanamycin have been associated with congenital deafness in the offspring of mothers who took these drugs during pregnancy. Ototoxicity was reported with doses as low as 1 g of streptomycin twice a week for 8 weeks during the first trimester. Of 391 mothers who had received 50 mg/kg of kanamycin for prolonged periods during pregnancy, nine children (2.3%) were found to have hearing loss.
Nephrotoxicity may be greater when aminoglycosides are combined with cephalosporins. Neuromuscular blockade may be potentiated by the combined use of aminoglycosides and curariform drugs. Potentiation of magnesium sulfate–induced neuromuscular weakness has also been reported in a neonate exposed to magnesium sulfate and gentamicin.
Other than ototoxicity, no known teratogenic effect has been associated with aminoglycosides in the first trimester. In 135 infants exposed to streptomycin in the Collaborative Perinatal Project, no teratogenic effects were observed. Among 1619 newborns whose mothers were treated for tuberculosis with multiple drugs, including streptomycin, the incidence of congenital defects was the same as in a healthy control group.
Antituberculosis Drugs
No evidence suggests any teratogenic effect of isoniazid, para-aminosalicylic acid, rifampin, or ethambutol.
Erythromycin
No teratogenic risk of erythromycin has been reported. In 79 patients in the Collaborative Perinatal Project and 260 in another study, no increase in birth defects was noted.
Clarithromycin
Of 122 first-trimester exposures, no significant risk of birth defects was reported with clarithromycin.
Fluoroquinolones
The quinolones (ciprofloxacin and norfloxacin) have a high affinity for bone tissue and cartilage and may cause arthralgia in children. However, no malformations or musculoskeletal problems were noted in 38 infants exposed in utero in the first trimester, in 132 newborns exposed in the first trimester in the Michigan Medicaid data, or in 200 other first trimester exposures.
Metronidazole
Studies have failed to show any increase in the incidence of congenital defects among the newborns of mothers treated with metronidazole during early or late gestation. Among 1387 prescriptions filled, no increase in birth defects could be determined. A meta-analysis confirmed lack of teratogenic risk.
Antiviral Agents
The Acyclovir Registry has recorded 756 first-trimester exposures with no increased risk of abnormalities in the infants. Among 1561 pregnancies exposed to acyclovir, 229 exposed to valacyclovir, and 26 exposed to famciclovir—all in the first trimester—no increased risk of birth defects was found. The Centers for Disease Control and Prevention (CDC) recommends that pregnant women with disseminated infection (e.g., herpetic encephalitis or hepatitis or varicella pneumonia) be treated with acyclovir.
Lindane
After application of lindane to the skin, about 10% of the dose used can be recovered in the urine. Toxicity in humans after use of topical 1% lindane has been observed almost exclusively after misuse and overexposure to the agent. Although no evidence of specific fetal damage is attributable to lindane, the agent is a potent neurotoxin, and its use during pregnancy should be limited. Pregnant women should be cautioned about shampooing their children’s hair because absorption could easily occur across the skin of the hands. An alternate drug for lice is usually recommended, such as pyrethrins with piperonyl butoxide.
Antiretroviral Agents
Zidovudine (ZDV) should be included as a component in the antiretroviral regimen whenever possible because of its record of safety and efficacy. In a prospective cohort study, children exposed to ZDV in the perinatal period through Pediatric AIDS Clinical Trials Group Protocol 076 were studied up to a median age of 4.2 years. No adverse effects were observed in these children. The International Antiretroviral Registry was established in 1989 to detect any major teratogenic effect of the antiretroviral drugs. Through January 2004, more than 1000 pregnancies had first-trimester exposures to ZDV and lamivudine, and no increase in teratogenicity was reported.
Concerns have been raised regarding the use of other antiretroviral therapies. Efavirenz is not recommended during pregnancy because of reports of significant malformations in monkeys who received efavirenz during the first trimester and also three case reports of fetal NTDs in women who received the drug. In 2001, Bristol-Myers Squibb issued a warning advising against the use of didanosine and stavudine in pregnant women after cases of lactic acidosis were reported, some of which were fatal. These two drugs should only be used if no other alternatives are available.
Antifungal Agents
Nystatin is poorly absorbed from intact skin and mucous membranes, and topical use has not been associated with teratogenesis. Clotrimazole or miconazole use in pregnancy is not known to be associated with congenital malformations. However, in one study, a statistically significant increase in risk of first-trimester abortion was noted after use of these drugs, but these findings were considered not to be definitive evidence of risk. Of 2092 newborns exposed in the first trimester in the Michigan Medicaid data, no increased risk of anomalies was found.
Limb deformities were reported in three infants exposed to 400 to 800 mg/day of fluconazole in the first trimester. However, in systematic studies of 460 patients who received a single 150-mg dose of fluconazole, no increased risk of defects was observed. In one registry study, fluconazole was associated with an increased risk of Tetralogy of Fallot.
Drugs for Induction of Ovulation
In more than 2000 exposures, no evidence of teratogenic risk of clomiphene has been noted, and the percentage of spontaneous abortions is close to the expected rate. Although infants are often exposed to bromocriptine in early pregnancy, no teratogenic effects have been observed in more than 1400 pregnancies.
Mild Analgesics
Some pains during pregnancy justify the use of a mild analgesic. However, pregnant patients should be encouraged to use nonpharmacologic remedies such as local heat and rest.
Aspirin
No evidence suggests any teratogenic effect of aspirin taken in the first trimester. Aspirin does have significant perinatal effects, however, because it inhibits prostaglandin synthesis. Uterine contractility is decreased, and patients taking aspirin in analgesic doses have delayed onset of labor, longer duration of labor, and an increased risk of a prolonged pregnancy.
Aspirin also decreases platelet aggregation, which can increase the risk of bleeding before as well as at delivery. Platelet dysfunction has been described in newborns within 5 days of ingestion of aspirin by the mother. Because aspirin causes permanent inhibition of prostaglandin synthetase in platelets, the only way for adequate clotting to occur is for more platelets to be produced.
Multiple organs may be affected by chronic aspirin use. Of note, prostaglandins mediate the neonatal closure of the ductus arteriosus. In one case report, maternal ingestion of aspirin close to the time of delivery was related to closure of the ductus arteriosus in utero.
Acetaminophen
Acetaminophen has also shown no evidence of teratogenicity. With acetaminophen, inhibition of prostaglandin synthesis is reversible; thus once the drug has cleared, platelet aggregation returns to normal. In contrast to aspirin, bleeding time is not prolonged with acetaminophen, and the drug is not toxic to the newborn. Thus if a mild analgesic or antipyretic is indicated, acetaminophen is preferred over aspirin.
Patients should be counseled on the risks associated with taking excessive amounts of acetaminophen. Doses of greater than 4 g daily (8 extra strength acetaminophen, 12 regular strength acetaminophen) are associated with liver fibrosis, leading to cirrhosis and liver failure. These deleterious effects are only effectively managed by liver transplantation. Patients should understand the doses of acetaminophen in all the products taken for pain. Combination products that contain acetaminophen may be overlooked in calculating the total daily dose, leading to unintentional overdose.
Nonsteroidal Antiinflammatory Agents
No evidence of teratogenicity has been reported for other nonsteroidal antiinflammatory drugs (NSAIDs such as ibuprofen, naproxen, diclofenac, and piroxicam). Chronic use may lead to oligohydramnios, and constriction of the fetal ductus arteriosus or neonatal pulmonary hypertension, as has been reported with indomethacin, might occur.
Codeine
In the Collaborative Perinatal Project, no increased relative risk of malformations was observed in 563 codeine users. In one recent study, maternal treatment with opioid analgesics was associated with an increased risk of heart defects, spina bifida, and gastroschisis. Codeine can cause addiction and newborn withdrawal symptoms if used to excess perinatally.
Sumatriptan
Of 479 exposures to sumatriptan in the first trimester, 4.6% of infants had birth defects—not significantly different from the nonexposed population. For women whose severe headaches do not respond to other therapy, sumatriptan may be used during pregnancy.
Bisphosphonates
The bisphosphonate drug class represents a group of medications used for treating a variety of bone disorders, including osteoporosis and Paget disease, and for controlling excess blood calcium in the setting of cancer or after chemotherapy administration. A published review of case reports for the bisphosphonate drug class—which includes alendronate, ibandronate, risedronate, etidronate, pamidronate, tiludronate, and zoledronic acid—in both short- and long-term use showed no serious fetal or neonatal adverse effects. Marginal decreases in gestational age, birthweight, and neonatal abnormalities may be attributed to bisphosphonate use. The decision to continue bisphosphonate use in pregnancy is based on the patient’s duration and amount of osteopenia or osteoporosis. Patients should also be counseled on appropriate calcium supplementation and the use of vitamin D, which can mitigate the risk of bone-related issues.
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