Clinical Expert Series

Continuing medical education is available online at www.greenjournal.org

Medications in Pregnancy and Lactation

Part 2. Drugs With Minimal or Unknown Human Teratogenic Effect
Catalin S. Buhimschi,
MD,

and Carl P. Weiner,

MD, MBA

This is the second of a two-part series on the use of medication during pregnancy and lactation. Pregnancy risk factors together with an increased incidence of chronic diseases and the rise in mean maternal age predict an increase in medication use during gestation. However, as highlighted in the first installment of this series, relatively few medications have specifically been tested for safety and efficacy during pregnancy, and, therefore, responses to those inquiries can be uninformed and inaccurate. Whereas the first installment provided new insight into the nature of medications with known human teratogenic effects, this part concentrates on drugs with minimal or no known human teratogenic effect. It is important that clinicians become familiar with all of the aspects of the drugs they prescribe, in addition to the controversies surrounding them, through consultation with maternalfetal medicine specialists and through references and Web sites providing up-to-date information in an effort to promote safer prescribing practices.
(Obstet Gynecol 2009;113:41732)

atients commonly inquire during prenatal care as to the effects of certain medications on their pregnancies. Unfortunately, clinicians typically have insufficient information about the risks and benefits of all the medications they prescribe. To help overcome this obstacle, the U.S. Food and Drug Administration introduced a classification of medications associated with fetal risks during pregnancy (Table 1). This system suffers many weaknesses, however, which were reviewed in the first part of this series. Part I provides new

From the Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine, New Haven, Connecticut; and Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, Kansas. The authors thank Kelly Horvath, MA, for her assistance with the writing and editing of the manuscript. Continuing medical education is available online at http://links.lww.com/A677. Corresponding author: Catalin S. Buhimschi, MD, Director, Perinatal Research, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, LLCI 804, New Haven, CT 06520; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. 2009 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/09

insight into the nature of medications with known human teratogenic effects (Category X). This second installment concentrates on drugs with minimal or unknown human teratogenic effects. Table 2 lists some of the most common medications (in alphabetical order) with minimal or unknown human teratogenic effects. Categories A and B generally are considered safe in humans as approved by the U.S. Food and Drug Administration. Category C medications have not been definitively shown to be harmful to human fetuses, but reasons exist to be cautious when prescribing them. Category D drugs are those with evidence of human fetal risk based on well-controlled human studies, but the benefits of treatment outweigh the risks. Table 3 provides a summary of commonly prescribed drugs with minimal or unknown teratogenic effect. This information is based on the best available evidence at the time this report was written. The research strategy included computerized bibliographic searches (generic and dominant trade names) of MEDLINE (1966 2008), PubMed (1966 2008), and references of published articles. Meta-analysis studies were included only if the guidelines of the Meta-analysis of Observational Studies in Epidemiology Group were appropriately applied. The Ameri-

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Table 1. United States Food and Drug Administration Drug Classification System
FDA Category*
A B

Pregnancy Category Definition

Controlled studies showed no risk to humans. Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities. No evidence of risk in humans. Animal studies have revealed no evidence of harm to the fetus. However, there are no adequate and wellcontrolled studies in pregnant women. or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Risks cannot be ruled out in humans. Animal studies have shown an adverse effect, and there are no adequate and well-controlled studies in pregnant women. or No animal studies have been conducted, and there are no adequate and well-controlled studies in pregnant women. Clear evidence of risk in humans. Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. Drugs contraindicated in human pregnancy. Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.

FDA, U.S. Food and Drug Administration. * Please verify the FDA categorization for each drug.

can College of Obstetricians and Gynecologists Committee Opinion and Practice Bulletins also were used. For clinical relevance, trade names for the commonly used drugs also are included. Table 2. Commonly Prescribed Drugs With Minimal or Unknown Teratogenicity*
Drug
Analgesics Aspirin, acetaminophen, ibuprofen Antibiotics Penicillin-G, tetracyclines, ciprofloxacin, metronidazole, nitrofurantoin, azithromycin Anticholinergics Albuterol, atropine, dimenhydrinate Antihypertensive agents Methyldopa, hydralazine, labetalol, propranolol Antihistamines Cetirizine, diphenhydramine Antivirals Acyclovir Corticosteroids Prednisone, betamethasone, dexamethasone

CONCLUSION
Whether or not to prescribe a drug for a pregnant or breast-feeding woman is a decision that must be made in consideration of many factors, including but not limited to, gestational age of the embryo or fetus, route of drug administration, absorption rate of the drug, whether the drug crosses the placenta or is excreted in breast milk, the necessary effective dose of the drug, molecular weight of the drug, whether monotherapy is sufficient or if multiple drugs are necessary to be effective, and even the mothers genotype. Potential harm to the fetus or nursing infant is paramount among these factors. Large registries and case-control studies with longer follow-up periods are necessary before concluding definitively whether a medication is safe. Equally important is assessment of the potential harm to the mother that withholding a drug can cause. The decision, then, typically comes down to, Does the benefit of the drug outweigh its risks? However, accurately weighing benefit against risk requires a thorough understanding of those benefits and risks. Current methods to assess and classify drug risk are spotty at best. Pharmaceutical companies gain approval to market drugs before follow-up studies have been conducted on their long-term effects. Moreover, pregnant and breast-feeding women are not appropriate test participants precisely because of the risk of drug teratogenicity. This investigation scruti-

FDA Classification
BD (see class) BD (see class)

BC (see class) BC (see class)

B B B

FDA, U.S. Food and Drug Administration. * Drugs or drug groups with minimal or unknown human teratogenic effect (see Table 1 for an explanation of the safety categories). Please verify the FDA categorization for each drug.

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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect

Drug
Analgesics Whole category (aspirin, acetaminophen, ibuprofen)

Maternal Considerations
Y Lack of consensus regarding management of women who have both antiphospholipid antibodies and a history of recurrent pregnancy loss reflects the wide range of clinical manifestations. Y A large cohort study concluded the antenatal use of nonsteroidal antiinflammatory drugs such as ibuprofen, naproxen, and aspirin but not acetaminophen increased the risk of spontaneous abortion.1

Fetal Considerations

Breast-Feeding Considerations

Aspirin

Y Collectively, large trials Y Crosses human placenta. Y Compatible with demonstrate low-dose aspirins Y Associated with an breast-feeding.16,17,18 Y Some experts suggest relative safety during increased risk of fetal breast-feeding mothers use pregnancy and generally vascular disruptions, the lowest effective dose positive effects on reproductive particularly gastroschisis, and for the shortest outcomes. small intestine atresia, and duration taken after Y Understanding the mechanism possibly premature closure feeding. of action still incomplete.2,3 of the ductus Y Gastrointestinal lesions, renal or Y Women requiring high arteriosus.6,14,15 Y Should be avoided in the hepatic dysfunction, asthma, doses such as that used for first trimester to prevent hypoprothrombinemia, arthritis or rheumatic gastroschisis.15 tachypnea, hyperthermia, and fever should avoid breastlethargy are the most significant feeding because neonatal risks.4 salicylate levels may reach Y Has small but significant effect on toxic levels. reducing the rate of preterm delivery but not perinatal death.5 Y Used to improve pregnancy outcomes in women who have both antiphospholipid antibodies and a history of recurrent pregnancy loss: theorized that aspirin interferes with the potential of these antibodies to compromise implantation and placental angiogenesis.6,7 aspirin plus heparin remains the most efficacious treatment8 for women with a history of at least two spontaneous miscarriages or one intrauterine fetal death without apparent cause other than inherited or acquired thrombophilias.9 however, in a 2002 randomized trial, a high success rate was achieved when low-dose aspirin alone was used for the treatment of antiphospholipid syndrome; the addition of low molecular weight heparin did not improve outcome.10
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Analgesics Aspirin (continued)

Maternal Considerations
Y Prescribed to reduce the risk of maternal thrombosis: alone is not sufficient to prevent thrombosis. not without risk: may contribute to maternal bleeding due to its effect on platelet cyclooxygenase enzymes, and clinicians often avoid recommending it during the third trimester. Y Use for prevention of preeclampsia also remains controversial: several meta-analyses suggest a modest reduction in preeclampsia and intrauterine growth restriction.11,12 but most recent meta-analysis indicates that antiplatelet agents are associated with moderate but consistent reductions in the relative risk of preeclampsia.13 Y One of the most widely used medications during pregnancy. Y Most common maternal problems relate to chronic abuse and overdose: damage appears secondary to free radical toxicity with the consumption of glutathione during the acetaminophen metabolism. N-acetylcysteine is the treatment of choice for an acute overdose.19

Fetal Considerations

Breast-Feeding Considerations

Acetaminophen (Tylenol, Apacet)

Y Used to treat the fever of Y Compatible with chorioamnionitis during breast-feeding.16,17,18 labor and associated with Y Some experts suggest breast-feeding mothers use improved umbilical blood the lowest effective dose gases (improvements in and for the shortest the umbilical cord duration taken after bicarbonate concentration feeding. and base deficit)20 apparently by reducing fetal oxygen demand as the maternal core temperature declines. Y Former suggestion that first trimester exposure in combination with propoxyphene is associated with clubfoot and digital abnormalities is not sustained by large series tests.21 Y Possible link between acetaminophen, gastroschisis, and small bowel atresia in the offspring of genetically predisposed mothers exposed to the drug early in pregnancy.22 Y The drug has no antiplatelet activity and does not pose a hemorrhagic risk to the fetus.23
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Ibuprofen (Advil, Alaxan, Brofen, Motrin, Paduden)

Maternal Considerations

Fetal Considerations

Breast-Feeding Considerations

Y Compatible with Y Drug of choice for management Y Crosses human placenta. Y Fetal levels are dependent on breast-feeding.16,17,18 of postabortal pain, acute Y Some experts suggest maternal because postoperative pain, and breast-feeding mothers use nonsteroidal postpartum pain.24,25 the lowest effective dose antiinflammatory drugs are and for the shortest not efficiently metabolized by duration taken after the fetal kidney. feeding. Y As effective as indomethacin in closing the ductus arteriosus but possibly with less adverse effect on renal function.26 Y Chronic exposure of the fetus to the drug requires close follow-up because of its potentially lifethreatening effect (fetal right heart decompensation after critical constriction of the ductus arteriosus). Y Most penicillins cross Y Penicillin and its derivatives human placenta.31,32 (ampicillin, cephalosporins) are safe Y Large clinical experience and commonly used during with this drug is pregnancy.27,28,29,30 reassuring.33 Y Broad-spectrum antibiotic generally avoided during pregnancy because of fetal considerations.36 Y Alternative for the treatment of gonorrhea, syphilis, Listeria monocytogenes, clostridium species, Bacillus anthracis, Fusobacterium fusiforme (Vincents infection), and actinomyces species. Y When penicillins and fluoroquinolones are contraindicated, erythromycin(a tetracycline-class agent without the fetal sequelae) is an alternative for the treatment of gonorrhea and syphilis37,38; there is consensus that a test for cure is needed in both adolescents and pregnant women.39 Y High-risk conditions that require the treatment of bacterial vaginosis with oral clindamycin and erythromycin include women with prior preterm birth associated with symptomatic cervicitis, body mass index less than 19.8, and women with evidence of endometritis before pregnancy; a test for cure should be obtained 1 month later.40 Y Trace amounts enter human breast milk.34 Y Believed that exposure of the infant from a mother treated with this drug is minimal.35

Antibiotics Penicillin-G

Tetracycline (Achromycin, Telmycin, Tetocyn, Tetracap)

Y Crosses human placenta. Y Enters human breast milk. Y May cause a yellow-gray- Y Considered compatible brown discoloration of the with breast-feeding.43 41 permanent adult tooth. Y Unlikely that topically applied tetracycline achieves a clinically relevant systemic level. Y Oxytetracycline (but not doxycycline) is associated with an increased risk of neural tube defects, cleft palate, and cardiovascular defects. Y Treatment with a tetracycline derivative, such as doxycycline, carries little if any teratogenic risk.42

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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Ciprofloxacin (Ciloxan, Cipro)

Maternal Considerations
Y Bacteriocidal antibiotic belonging to the fluoroquinolone group; recommended when penicillinclass agents have no effect on gram-negative rods (eg, gonorrhea), and it has the best safety profile of second-line drugs for drug-resistant tuberculosis.44 Y Drug of choice for prophylaxis among asymptomatic pregnant women exposed to B anthracis and treatment of Q fever during pregnancy.45,46 Y Because fluoroquinoloneresistant gonorrhea disease is being identified more frequently, fluoroquinolones are no longer recommended by the U.S. Centers for Disease Control and Prevention as first-line therapy (http://www.cdc. gov/std/treatment/2006/updatedregimens.htm).

Fetal Considerations

Breast-Feeding Considerations

Y Concentrated in human Y Only a small fraction of breast milk.50 fluoroquinolones Y Neonatal Clostridium (ciprofloxacin, ofloxacin, difficile pseudomembranous and levofloxacin) cross the colitis has been reported in human placenta.47 Y Short-duration treatment neonates breast-fed by with ciprofloxacin appears mothers treated with this free of adverse fetal drug.51 responses. Y The new quinolone, trovafloxacin, crosses the placenta but does not appear to be associated with an increased risk of malformation or musculoskeletal problems in either animals or humans.47,48 Y There are no clinically significant musculoskeletal dysfunctions reported in children in utero.48,49 Y Because these studies included a relatively small number of children exposed during the first trimester, longer follow-up and magnetic resonance imaging of the joints may be warranted to exclude subtle cartilage and bone damage.

Metronidazole (Flagyl)

Y Used widely during pregnancy Y Crosses human placenta. Y Excreted into human to treat bacterial vaginosis, Y Does not appear to have a breast milk. trichomoniasis, inflammatory teratogenic risk when used Y Considered compatible bowel disease, C difficile colitis, at the recommended with breast-feeding.63 62 and anaerobic and protozoal doses. infections.52,53 Y Several large randomized trials sought to determine whether the successful treatment of bacterial vaginosis reduced the prevalence of adverse outcomes, such as preterm birth, with mixed results:54,55,56,57 treatment of women with asymptomatic bacterial vaginosis but no prior preterm birth apparently does not alter their risk of preterm delivery.58 women who deliver preterm in association with symptomatic bacterial vaginosis have a lower risk of recurrent preterm birth if treated with clindamycin and erythromycin but not when treated with metronidazole.59
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Metronidazole (Flagyl) (continued)

Maternal Considerations
metronidazole failed to prevent preterm birth in women with asymptomatic trichomoniasis.60 of major concern is the observation that, in the great majority of randomized trials, the drug was actually associated with an increased rate of preterm birth.56,61 Y The absence of benefit coupled with a potential serious complication indicates that the drug should be avoided in preterm women. Y Safe and effective for the treatment of asymptomatic bacteriuria as well as acute and recurrent urinary tract infections: resistance rates are less than 10%. women with recurrent urinary tract infections are candidates for long-term antibiotic prophylaxis. Y Acute pulmonary reactions to the drug, presumably immunemediated, are uncommon but potentially life-threatening. Y Patients with glucose-6phosphate dehydrogenase deficiency may experience hemolytic reactions. Y Remains unclear how long a woman with asymptomatic bacteriuria should be treated; some suggest that short-term administration combined with continued surveillance for recurrent bacteriuria is sufficient. Y Pyelonephritis occurs in approximately 7% of women despite adequate treatment.

Fetal Considerations

Breast-Feeding Considerations

Nitrofurantoin (Furadantin, Furantoin, Macrodantin, Macrobid)

Y Unknown whether it Y Actively transported into crosses the human human milk. placenta. Y Clinical experience Y Generally considered suggests that maternal oral compatible with pregnancy. ingestion is not associated Y No evidence of being a with neonatal adverse human teratogen. event. Y Although contraindicated Y Concern remains for during labor and in breast-feeding women newborns, there are no welltreated therapeutically if documented cases of they have a family history hemolytic reactions in of glucose-6-phosphate neonates. dehydrogenase deficiency or sensitivity to this drug.

Azithromycin (Aruzilina, Y Treatment of choice for Y Less than 3% of maternally Y Small amounts are Zithromax) chlamydia. administered azithromycin excreted in breast milk in crosses the placenta. a dose-dependent fashion. Y Used in combination with artesunate for malaria prophylaxis. Y No adverse effects reported Y No neonatal adverse effects in humans. have been reported. Y Proved an ineffective treatment to reduce lower genital tract colonization with Ureaplasma urealyticum in women with preterm labor. Y When combined with doxycycline, it reduces the risk of postcesarean endomyometritis.
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Anucholinergics Whole category (albuterol, atropine, dimenhydrinate)

Maternal Considerations
Y This class of pharmaceutical compounds reduces the effects mediated by acetylcholine in the central and peripheral nervous systems. Y Previously used for asthma control Y during pregnancy.64 Y Mean maternal blood pressures and heart rates were unaffected. Y Y In some countries, the drug is used as a tocolytic agent but there is no evidence that it retards either pretermY or term labor.

Fetal Considerations

Breast-Feeding Considerations

Albuterol (Proventil, Ventolin)

Crosses the human placenta, Y though the kinetics remain to be elucidated. Y Less than 10% is absorbed when administered by inhalation. No convincing evidence of teratogenicity after first trimester exposure. Y In general, long-term followup studies of infants exposed to beta-mimetic tocolysis are reassuring.

Unknown whether it enters human breast milk. Generally considered compatible with breast-feeding.

Atropine (Atropen, Y No adequate reports or wellAtropinol, Atropisol, controlled studies in pregnant Borotropin) women. Y Generally used for treatment of symptomatic bradycardia and organophosphate poisoning and as an adjunct to anesthesia. Dimenhydrinate (Amosyt, Y Biodramina, Dimetabs, Wehamine) Y

Y Rapidly crosses the human Y Unknown whether it enters placenta. human breast milk. Y Fetus will respond to the direct administration of this medication with tachycardia.

Y Popular agent for the relief of nausea and vomiting during Y pregnancy. Recent randomized trial concluded that ginger is as effective as the drug for the treatment of hyperemesis gravidarum and has fewer side effects.65 Y Both dimenhydrinate and diphenhydramine are considered treatment options for severe migraine headache during pregnancy.66 Y Caution is warranted because several investigators have reported an increase in uterine activity with dimenhydrinate.67

Unknown whether it Y crosses human placenta. No indication that this drug increases the risk of fetal abnormalities when given Y at any stage of pregnancy.

Excreted in small quantities into human breast milk, though the kinetics are yet to be elucidated. Long clinical experience is reassuring.

Antihypertensives Whole category Y Approximately 3% of women take an (methyldopa, antihypertensive during pregnancy.68 hydralazine, labetalol, Y ACOG recommends treatment for women with a systolic blood pressure propanolol) higher than 170 mmHg and/or a diastolic blood pressure above 109 mmHg. 69

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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug Maternal Considerations Fetal Considerations Breast-Feeding Considerations

Whole category Y There is no consensus whether (methyldopa, lesser degrees of hypertension hydralazine, labetalol, require treatment during propanolol) pregnancy because (continued) antihypertensive therapy improves only the maternal, not the fetal, outcome in women with mild to moderate chronic hypertension.69 Methyldopa (Aldomet, Alfametildopa) Y One of the best-studied antihypertensives during pregnancy, remaining a popular agent for the treatment of moderate to mild hypertension.70,71 Y Leads to blockage of the sympathetic nervous system (centrally and peripherally) through an alpha-2 receptornegative feedback mechanism. Y Depending on the patient, the drug may be suboptimal because at least 48 to 72 hours are required to see an effect. Y Less effective than metoprolol but as effective as nifedipine, labetalol, and ketanserin in decreasing both systolic and diastolic blood pressure in women with chronic hypertension.72 Y Most antihypertensive Y Enters human breast milk. agents cross the placenta. Y Breast-fed neonates are Y Considered safe for use normotensive.76 during the first trimester of Y Increases the risk of neonatal hypoglycemia, pregnancy.73 Y Neither significantly alters but this effect may be fetal cardiac activity nor blunted by supplementing produces fetal with glucose-fortified hemodynamic changes as formula.77 measured by Doppler velocimetry.74 Y Recently, the effects of various antihypertensive medications on fetoplacental circulation were studied in vitro:75 in contrast to labetalol, hydralazine, nifedipine, and magnesium sulfate, methyldopa was less likely to produce significant direct effects on fetal vasculature. Y Other studies suggest the drug decreases placental vascular resistance in mild preeclampsia and in chronic hypertension. Y Enters human breast milk. Y Breast-fed neonates are normotensive.76

Hydralazine (Apresoline) Y Hydralazine and labetalol are Y Most antihypertensive the most widely used drugs for agents cross the placenta. the treatment of acute Y Clinical experience hypertension during suggests the drug is safe pregnancy.78 during the first trimester. Y Mechanism of action is incompletely understood, but it has been proposed that hydralazine works through a cyclic guanosine monophosphatemediated mechanism, resulting in smooth muscle relaxation. Y In two recent randomized trials, the drug was as safe and as effective as diazoxide and labetalol for the treatment of hypertensive emergencies during the antenatal and postpartal periods.79,80

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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Labetalol (Coreton, Normo-dyne, Trandate)

Maternal Considerations
Y Hydralazine and labetalol are the most widely used drugs for the treatment of acute hypertension during pregnancy.78 Y Combines alpha- and betaadrenoceptor antagonist properties. Y When given intravenously, the drug is associated with a higher risk of hypotension and cesarean delivery than diazoxide.81

Fetal Considerations

Breast-Feeding Considerations

Y Enters human breast milk. Y Most antihypertensive Y Breast-fed neonates are agents cross the placenta. normotensive.7 Y Large doses given intravenously can cause fetal bradycardia, hypoglycemia, hypotension, pericardial effusion, myocardial hypertrophy, and fetal death due to acute hypotension:82,83 based on these risks, an initial intravenous dose of 510 mg is recommended similar responses are unlikely with oral therapy. Y Overall, neonatal outcome is similar to that achieved with hydralazine.84 Y May be useful for the treatment of fetal thyrotoxicosis.85 Y Enters human breast milk. Y Breast-fed neonates are normotensive.76

Propanalol (Inderal)

Y Used extensively during Y Most antihypertensive pregnancy for the treatment of agents cross the placenta. maternal hypertension, arrhythmia, and migraine headache.66 Y Generally considered safe unless the dose given compromises maternal cardiac output. Y Also used acutely to provide relief of symptoms from thyrotoxicosis and pheochromocytoma.86,87 Y Studies of use for hypertension are small; it appears as effective as methyldopa and is often coupled with other hypotensive agents such as hydralazine.88 Y Unknown whether it Y Not adequately studied in crosses the human human pregnancy. placenta. Y Commonly prescribed for Y Not known as a human allergic rhinitis during teratogen. pregnancy. Y The advantage of this drug over many other antihistaminic drugs is that it does not cause clinically significant cardiac QTinterval prolongation.89

Antihistamines Cetirizine (Zyrtec)

Y Enters human breast milk. Y Irritability is the most common adverse reaction reported in the newborns of women using antihistamines while breast-feeding. .

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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Cetirizine (Zyrtec) (continued)

Maternal Considerations
Y The product label may state that medications for allergic rhinitis should be avoided during pregnancy because of a lack of fetal safety, but the majority of human data refutes this position. Y Not adequately studied in human pregnancy. Y Useful adjunct for women who have allergic reactions to local anesthesia, laminaria, and serum albumin and for the treatment of severe migraine headaches.90,91

Fetal Considerations

Breast-Feeding Considerations

Diphenhy-dramine (Benadryl)

Y Crosses the human placenta Y Unknown whether it enters but, the kinetics remain to breast milk. be elucidated. Y Irritability is the most Y No evidence of increased common adverse reaction fetal risk if administered reported in the newborns of during any stage of women using antihistamines pregnancy. while breast-feeding Y May cause neonatal depression if administered during labor. Crosses the human placenta. Y Concentrated in the amniotic fluid, but there is no evidence Y of preferential drug accumulation in the fetus.95 Long-term follow-up studies have not revealed any increase in or pattern of malformations after exposure during the first trimester.96 Secreted and achieves concentrations in breast milk higher than maternal serum.97 Considered compatible with breast-feeding.

Antivirals Acyclovir

Y Y All suspected herpes virus Y infections should be confirmed through viral or serological testing.92 Y Treatment of genital herpes with this drug during pregnancy is not Y curative but does reduce the duration of symptoms and viral shedding.93 Y Long clinical experience is reassuring. Y Based on several studies, ACOG recommends prophylactic acyclovir at 36 weeks to reduce the risks of recurrent genital herpes and thus potentially avoid cesarean delivery.94 Y Suppression therapy is both effective and cost-effective whether or not the primary infection occurs during the current pregnancy. Y Corticosteroids may increase the Y risk of maternal infection in women with preterm premature rupture of the fetal membranes, though most large studies reveal Y no such increased risk.98 Y Can transiently cause an abnormal glucose tolerance test, 99 worsen existing diabetes mellitus, and are Y associated with pulmonary edema when given with a tocolytic agent Y in the setting of an underlying infection.100 Y Repeat doses of corticosteroids do not reduce the maternal perception of fetal movements.101

Corticosteroids Whole category (prednisone, betamethasone, dexamethasone)

The evidence that corticosteroids are human teratogens is weak and confined to cleft lip.102,103,104,105 An increased risk of neonatal sepsis is suggested but not confirmed despite large prospective studies. Multiple courses of corticosteroids are not recommended.106 Adverse effects noted in animal and human studies include a profound suppression of fetal breathing, movement, impaired
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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Drug
Corticosteroids Whole category (prednisone, betamethasone, dexamethasone) (continued)

Maternal Considerations

Fetal Considerations
Y myelination, intrauterine growth restriction, and microcephaly.107,108 Y There is controversy as to the earliest gestational age at which corticosteroids can be administered to improve fetal outcome:109 the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Medical Applications of Research of the National Institutes of Health recommend a single course of corticosteroids to all pregnant women between 24 and 34 weeks of gestation who are at risk of preterm delivery within 7 days.110 Y Repeat corticosteroid courses, including so-called rescue therapy, should not be used routinely. Y Recently, it was demonstrated that repeat doses of corticosteroids are accompanied by a reduction in birth weight and an increase in the prevalence of small for gestational age infants.111

Breast-Feeding Considerations
There are no adequate reports or well-controlled studies in breast-feeding women.

Prednisone (Cortan, Dacortin)

Y No adequate well-controlled Y Human placenta metabolizes Y Unknown whether enters studies during pregnancy. prednisone reducing fetal human breast milk. Y Several trials show that women exposure to less than 10% of Y Long clinical experience with antiphospholipid syndrome the maternal level.113 suggests this drug is treated with prednisone and compatible with breastaspirin have higher loss rates feeding. than women treated with heparin and aspirin.112 Y Crosses the human placenta Y Still unclear whether Y Routinely used for the and is proven to enhance maternal treatment with acceleration of fetal lung perinatal outcome after this drug increases the maturity; administration is preterm birth.116 concentration of cortisone standard of care for threatened Y Some studies suggest this in breast milk. preterm birth.114,115 drug can alter fetal breathing when administered for the enhancement of lung maturation.117
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Betamethasone (Celestone)

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Table 3. Considerations for Drugs with Minimal or Unknown Teratogenic Effect (continued)
Breast-Feeding Considerations Drug
Dexamethasone (Decadron)

Maternal Considerations

Fetal Considerations

Y Routinely used for the Y Crosses the human placenta Y Still unclear whether acceleration of fetal lung and is proven to enhance maternal treatment with maturity; administration is perinatal outcome after this drug increases the standard of care for threatened preterm birth.116 concentration of cortisone Y Complete fetal heart block has preterm birth.114,115 in breast milk. Y Effective antiemetic after been treated successfully with general anesthesia for this drug:121 after corticosteroid pregnancy termination.118 administration, the fetal heart rate pattern may become transiently nonreactive.122 Y Can prevent or diminish virilization due to congenital adrenal hyperplasia if administered early during the first trimester.123,124 Y Some reports show that the drug intravenously modifies the clinical course of the hemolytic anemia, elevated liver enzymes, and lowplatelet count syndrome during both the antenatal and postpartal periods119; however, a more recent study contradicts that conclusion.120

ACOG, American College of Obstetricians and Gynecologists.

nized drugs currently classified as safe for pregnant and breast-feeding women. As demonstrated, that classification is not always warranted or is applied before adequate evidence proves it so. As discussed in Part I, novel approaches in the field of theranostics are being developed to address this research shortfall. Meanwhile, physicians should look more critically at a drugs classification and evidence of its teratogenicity before prescribing it. Clinicians should become familiar with all of the aspects of the drugs they prescribe, in addition to the controversies surrounding them, through consultation with maternalfetal medicine specialists and through references and Web sites providing up-to-date information in an effort to promote safer prescribing practices. REFERENCES
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