Your Family Physician

Introduction

Drug use is an uncommon cause of birth defects, yet approximately 200,000 children (3-5% of live births) are born with birth defects each year.¹

While some papers estimate that 1-3% of birth defects are thought to be caused by medications taken during pregnancy, the authors could not find a source for this statement that was based on study data.

The purpose of this article is to provide an organized source of information about medication use in pregnancy, with data regarding commonly used medications and pregnancy categories established by the US Food and Drug Administration (FDA).

Approach to Patients Needing Medication During Pregnancy

Because any medication can present risks in pregnancy, and because not all risks are known, the safest pregnancy-related pharmacy is as little pharmacy as possible. However, women with a history of psychiatric, seizure-related, or hematologic illnesses frequently require medication throughout pregnancy. In such patients, care must to be taken to select the safest drug from the necessary class of medication. Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist.²

As an example of this difficulty, Mahadevan reviewed medications commonly used to treat GI disease.³ Most were FDA pregnancy category B and C, and a few were pregnancy category D. (See FDA Rating System for the Teratogenic Effects of Drugs below.) The author suggested that some medications should never be used during pregnancy because of their clear risk of teratogenicity or adverse events. Particular drugs are bismuth, castor oil, sodium bicarbonate, methotrexate, ribavirin, doxycycline (and by extension minocycline and tetracycline), and thalidomide.

Each area of pharmacologic therapy intervention must be assessed separately and specifically for each patient. For example, gastroesophageal reflux disease (GERD) is common during pregnancy and presents difficulties in choosing optimal medications.⁴

For most patients, lifestyle modifications are useful, but these are usually insufficient to control symptoms, and medication is often required. First-line medical therapy for pregnant woman with GERD entails antacids. If antacids fail, use of histamine-2 receptor antagonists and proton-pump inhibitors can be attempted; these drugs do not seem to be associated with clinically significant risks in pregnancy. In rare cases, promotility agents can be prescribed, though the risks and benefits must carefully be discussed with the patients before the drugs are started. Similar assessments must be made with drug therapy for inflammatory bowel disease⁵ and even constipation⁶ .

A physician caring for a pregnant patient who requires medication should take care in choosing dosages and types of drugs that maximize effectiveness while minimizing fetal risk. It is essential to understand the effect of medications and to know the point in fetal development when drugs are most toxic and when fetal organs are most susceptible. In addition, healthcare providers who treat pregnant women must be familiar with methods of gathering information about drugs, and they must be aware of online databases that are most useful for this purpose.

Several resources are available to expand one’s knowledge of teratology. Teratogen Information System (TERIS) and Reprotox are Internet databases that cover this subject. The Organization of Teratology Information Specialists is a network of risk-assessment counselors in the United States and Canada who specialize in researching and communicating the risks associated with drug exposures in pregnancy. All of these are useful resources to learn about drug use in pregnancy. They are frequently updated and should be referenced frequently, particularly when one is prescribing unfamiliar drugs in pregnancy.

General guidelines for choosing dosages and types of drugs within a class are lacking. Each drug should be assessed, and its risks and benefits should be weighed. Various organizations, including the Organization of Teratology Information Specialists, have performed many studies in this area. Specific drugs should be investigated before they are used.

Risk-benefit assessment and counseling should involve the patient and her current state of health. Counseling should actively involve the patient and the physician. The physician must consider the effects of drug exposure on the developing fetus or embryo and acknowledge specific susceptibilities at each point in fetal development, as balanced against the risks of worsening maternal illness.

In a 2008 Canadian study, 19.4% of women were found to have used FDA category C, D and X medications at least once during pregnancy, the most common of these being albuterol, co-trimoxazole, ibuprofen, naproxen and oral contraceptives.⁷ Analyzing the same data, Yang noted that woman who had such exposure were more commonly characterized by chronic diseases, younger age, increased parity, and receipt of social assistance.⁸

Combinations of medications rather than individual medicines are possibly associated with increased risk of birth defects.

Oberlander et al performed a study to determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor antidepressants used alone and in combination with benzodiazepines. In this study, population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births in British Columbia during a 39-month period (1998-2001). Even after controlling for maternal illness profiles, infants exposed to prenatal serotonin reuptake inhibitors in combination with benzodiazepines had an increased incidence of congenital heart disease versus controls who had not been exposed. Serotonin reuptake inhibitor monotherapy was not associated with an increased risk for major congenital anomalies, but was associated with an increased incidence of atrial septal defects, and researchers did not associate risk with first trimester medication dose/day.⁹

Example Mechanisms of Teratogenesis

The teratogenic effects of medications vary temporally. The fetus' susceptibility to injury depends on its period of development. Different organs have different critical periods, though the span from gestational day 15 to day 60 is critical for many organs. The heart is most sensitive during the third and fourth weeks of gestation, whereas the external genitalia are most sensitive during the eighth and ninth weeks. The brain and skeleton are sensitive from the beginning of the third week to the end of pregnancy and into the neonatal period.

Genetic defects and medications can cause similar abnormalities, such as those resulting from warfarin and Happle syndrome. Several studies are related to axial defects in mice.^10,11 In mice, axial malformations can result from mutations in certain HOX genes or from exposure to retinoids. Happle syndrome, or human X-linked dominant chondrodysplasia punctata (CDPX2; see Skeletal Dysplasia), is associated with mutations in the human emopamil-binding protein, a delta-delta-sterol isomerase involved in cholesterol biosynthesis. Happle syndrome is a genetic disease of bone and cartilage characterized by defective bone mineralization, telebrachydactyly, and facial dysmorphism with nasal hypoplasia. Maternal ingestion of warfarin can result in a fetal phenotype similar to that of this syndrome.¹²

Teratogens, such as cyclophosphamide, result in fetal demise due to excessive apoptosis. Tumor necrosis factor-alpha, transforming growth factor-beta, and other cytokines may mediate excessive apoptosis. Granulocyte-macrophage colony-stimulating factor has been reported to prevent teratogenesis in laboratory animals. That is, studies showing that granulocyte-macrophage colony-stimulating factor may prevent teratogenesis in animals.¹³

Both immunomodulation and hormonal support (eg, with progesterone or human chorionic gonadotropin supplements) have been used to improve the rate of live births in women who have had recurrent abortions. Each can modulate the balance between the manifold cytokines. Neither hormonal support nor immunopotentiation has been proven beneficial. The results and role of cytokines themselves must be assessed in trials of karyotypically normal embryos.

Drug Exposures in the Male Partner

Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy. Certain exposures may alter the size, shape, performance, and production of sperm. This observation suggests that drug exposure in the male may put the fetus at risk. Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to develop. However, unlike teratogenic agents affecting pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development. Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure.^14,15

At present, no evidence shows that paternal exposure directly increases the risk of birth defects. However, agents such as recreational drugs do affect sperm quality and, to a limited degree, indirectly expose the developing fetus to the substance. Rather than affecting the developing fetus, teratogens like drug and alcohol seem to lower the likelihood of a woman's becoming pregnant.^14,15

Paternal alcohol use may increase the risk of heart defects in newborns. In one study, paternal smoking was associated with heart defects. Chemotherapy or radiation therapy to treat cancer in a father may increase the risk chromosomal abnormalities of the fetus. Studies have demonstrated less-than-normal numbers of chromosomes and damage to the structure of chromosomes in the sperm of men with cancer. No data suggests an increased rate of birth defects in fetuses conceived with sperm from male chemotherapy patients.^16,17

Paternal exposure to prescription medications, such as cholesterol- and blood pressure–lowering drugs, has not been linked to a risk of birth defects. Additional research must clearly be conducted to assess the safety of drugs recently released onto the market. Regardless of the lack of evidence supporting a direct influence of paternal exposure on fetal risk, caution is warranted, and the father's physician should provide counseling and active involve the patient.

FDA Rating System for the Teratogenic Effects of Drugs

The FDA, the government agency that oversees the safety of drugs, provides the most widely used system to grade the teratogenic effects of medications. The FDA assigns a safety category for medications by using a 5-letter system: A, B, C, D, and X. This safety category must be displayed on the labels of all drugs.

Table 1. FDA Pregnancy Categories

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Source.—Center for Devices and Radiological Health, FDA, 2007.¹⁸

Most FDA-approved teratogenic drugs are in categories D or X. However, some medications are in category C. In the discussions that follow, some drugs are considered both individually and as part of broad categories (eg, antifolate agents, anticonvulsant agents).

Although some medications rarely cause birth defects and others commonly cause them, all are considered together in the sections below. The incidence of defects is stated when available. Note that drugs are used to treat disease and that the disease (eg, infection) and not the drug may cause certain birth defects. However, parsing causation and correlation is often difficult.

The Australian Drug Evaluation Committee (ADEC) splits FDA category B into B1, B2, and B3. These categories may be helpful with respect to counseling individual patients.

Table 2. ADEC Pregnancy Subcategories B1, B2, and B3

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Source.—Therapeutic Goods Administration, ADEC, 1999.¹⁹

Drugs That Reportedly Cause Birth Defects

Data for specific agents in the sections that follow were assembled to assist the provider in weighing the risks and benefits before beginning or continuing their use pregnancy. Information was compiled by selecting commonly used drugs, with an emphasis on recently approved agents.

Discussion of Specific Agents: Acamprosate Calcium to Aminoglycosides

Acamprosate calcium

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications: Possible hydronephrosis, malformed iris, retinal dysplasia, and retroesophageal subclavian artery
• Studies: Acamprosate calcium (Campral; Merck Santé, Subsidiary of Merck KGaA, Darmstadt, Germany; Lyon, France) has been shown to be teratogenic in rats when given in doses that are approximately equal to the human dose (on a milligram-per–square meter basis) and in rabbits when given in doses that are approximately 3 times the human dose (on a milligram-per–square meter basis). Acamprosate calcium produced a dose-related increase in the number of fetuses with malformations in rats at oral doses of 300 mg/kg/d or greater (approximately equal to the maximum oral recommended human daily dose (RHDD) on a milligram-per–square meter basis). Malformations included hydronephrosis, malformed iris, retinal dysplasia, and a retroesophageal subclavian artery. No findings were observed at an oral dosage of 50 mg/kg/d (approximately one fifth the maximum oral RHDD on a milligram-per–square meter basis).An increased incidence of hydronephrosis was also noted in Burgundy Tawny rabbits at oral doses of 400 mg/kg/d or greater (about 3 times the maximum oral RHDD on a milligram-per–square meter basis).No developmental effects were observed in New Zealand White rabbits at oral dosages up to 1000 mg/kg/d (approximately 8 times the maximum oral RHDD on a milligram-per–square meter basis).No adequate and well-controlled studies have been conducted in pregnant women. Acamprosate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.A study conducted in pregnant mice given oral acamprosate calcium starting on day 15 of gestation through the end of lactation on postnatal day 28 demonstrated an increased incidence of stillborn fetuses at doses of 960 mg/kg/d or greater (approximately 2 times the maximum oral RHDD on a milligram-per–square meter basis). No effects were observed at a dose of 320 mg/kg/d (approximately half the maximum RHDD on a milligram-per–square meter basis). The potential for acamprosate to affect the duration of labor and delivery is unknown.

Angiotensin-converting enzyme (ACE) inhibitors

• Pregnancy category - C or D
• Trimesters of risk - First trimester (category C); second and third trimesters (category D)
• Associated defects and complications: Reported complications in pregnancy included oligohydramnios, intrauterine growth restriction (IUGR), premature labor, and fetal and neonatal renal failure. Reported birth defects included bony malformations, limb contractures, persistent patent ductus arteriosus, pulmonary hypoplasia, respiratory distress syndrome, prolonged hypotension, neonatal death, fetal calvarial hypoplasia or aplasia, oligohydramnios, and renal anomalies.
• Studies: One study demonstrated successful pregnancy outcomes (ie, live, healthy infant without severe disability at 2 y after delivery) in 87.5% of patients taking ACE inhibitors at any time during pregnancy. Boix et al reported a case of exencephaly and unilateral renal agenesia in a fetus of a woman with diabetes who became pregnant while taking irbesartan.²⁰

Acetohydroxamic acid

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications: Cardiac anomalies included atrial septal defects, ventricular septal defects, and atrial and ventricular septal defects. Skeletal anomalies included coccygeal hemivertebrae and fused coccygeal vertebrae, supernumerary vertebrae, supernumerary ribs, duplicated sternebrae, and lumbar hemivertebrae.
• Studies: A study showed teratogenic effects after oral administration of 25 mg/kg/d to 5 clinically normal beagles from the onset of proestrus until parturition.

Aminocaproic acid

• Pregnancy category – D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Possible fetal hemorrhage
• Studies: Animal teratologic studies have not been conducted. Also unknown is whether aminocaproic acid can cause fetal harm when administered to a pregnant woman or whether it can affect reproduction capacity. Aminocaproic acid should be given to a pregnant woman only if it is clearly needed.

Aminoglycosides

• Pregnancy category - D
• Trimester of risk - Not consistent
• Associated defects and complications: Some neonates have had hearing defects, whereas others have had vestibular problems. Some offspring had inner ear damage, whereas others did not.
• Studies: Since 1950, approximately 50 cases of fetal ototoxicity have been described after maternal exposure to either streptomycin or its congener dihydrostreptomycin. Ten cases of fetal ototoxicity have been described with kanamycin, a related drug. These cases occurred when high doses were used to treat tuberculosis. Gentamicin may be ototoxic to adults and to developing fetuses. Evidence indicates that fetal kidney selectively takes up gentamicin, which can result in cellular damage (probably reversible) to immature nephrons. In addition, inner ear damage or hearing defects have been induced in utero in rats and guinea pigs exposed to streptomycin and/or kanamycin.

Discussion of Specific Agents: Amlodipine/Atorvastatin to Azacitidine

Amlodipine/atorvastatin

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Variable; spina bifida
• Studies: Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Because 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Amlodipine/atorvastatin (Caduet; Pfizer Inc, New York, NY) should be administered to women of childbearing only if they are highly unlikely to become pregnant and if they have been informed of the potential hazards associated with ingestion during pregnancy. If the patient becomes pregnant while taking this drug, therapy should be discontinued, and the patient should be informed of the potential hazards to the fetus.

Angiotensin II receptor antagonists (angiotensin II receptor blockers [ARBs])

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Hypotension, renal dysplasia, anuria or oliguria, oligohydramnios, IUGR, pulmonary hypoplasia, patent ductus arteriosus, incomplete ossification of the skull, and intrauterine or neonatal death
• Studies: Data from recent animal studies confirmed that intrauterine or neonatal exposure to ACE inhibitors or the ARB losartan can cause death and serious irreversible organ damage. Data from animal studies suggested that the toxic actions were most common after exposure during the last trimester. Because of the severity of these complications, use of ARBs should be avoided throughout pregnancy and in women who are breastfeeding.

Antineoplastics (busulfan, chlorambucil, cyclophosphamide, mechlorethamine)

• Pregnancy categories - D and X
• Trimesters of risk - First, second, and third
• Associated defects and complications: Observed problems included IUGR, cleft palate, renal agenesis, digital malformations, cardiac anomalies, and cloudy corneas. First-trimester exposure to antimetabolites (aminopterin, 5-fluorouracil, methotrexate, methylaminopterin, and cytarabine) produced a risk for cleft lip and palate, low-set ears, cranial anomalies, and anencephaly.
• Studies: Case series show that 10-50% of fetuses exposed to antineoplastic alkylating agents are malformed. The malformation rate for first-trimester exposure is 11.6%. Only case reports are available for antineoplastic antimetabolites; however, a mean of 40% of neonates were malformed.

Anticonvulsants, first-generation

• Pregnancy category - D in general
• Trimesters of risk - First, second, and third
• Associated defects and complications - Facial dysmorphia, gingival hyperplasia, neurological hyperexcitability and multiple malformations including (for valproic acid) predominantly temporal atrophy in the left brain hemisphere
• Studies: In a retrospective cohort study published in the New England Journal of Medicine, investigators examined newborns who were exposed to anticonvulsants in utero, born to mothers with epilepsy who did not take anticonvulsants, or born to mothers without epilepsy or a history of seizures. Birth defects occurred most frequently in infants exposed to anticonvulsants. About 20% of neonates exposed to 1 drug had birth defects; 28% exposed to 2 or more drugs had birth defects. Major birth defects were found in 4% of 223 babies whose mothers had taken 1 drug during pregnancy and in 8.6% of 93 whose mothers had taken 2 or more drugs.²¹ Others researchers state that the risk doubles when 2 drugs are taken and that the risk is 10-fold higher than the risk in the control population when women take 4 anticonvulsants. Babies of mothers with epilepsy who were not treated with anticonvulsants were at no greater risk for having birth defects than were babies of mothers without epilepsy.

Apomorphine

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: Reproduction studies have not been conducted with apomorphine (Apokyn; Vernalis Pharmaceuticals Inc, Morristown, NJ). In addition, whether apomorphine causes fetal harm when administered to a pregnant woman or whether it affects reproductive capacity is unknown. Apomorphine should be given to a pregnant woman only if it is clearly needed. Whether apomorphine is excreted in human milk is unknown. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from apomorphine, a decision should be made whether to discontinue nursing or to discontinue the drug; the importance of the drug to the mother should be taken into consideration.

Aspirin

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Unclear; may be associated with an increased risk of gastroschisis
• Studies: In a meta-analysis, no evidence of an overall increase in the risk of congenital malformations was reported associated with aspirin. Aspirin exposure during the first trimester may be associated with an increased risk of gastroschisis.

Atenolol

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - IUGR
• Studies: Animal and human studies have shown growth retardation in humans and animals, as well as growth and structural abnormalities in animals. Reduced fetal size is a function of the length of exposure to the medication. The earlier the treatment starts, the greater the incidence of defects.

Azacitidine

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - CNS anomalies (eg, exencephaly and/or encephalocele), limb anomalies (eg, micromelia, club foot, syndactyly, oligodactyly), and others (eg, micrognathia, gastroschisis, edema, rib abnormalities)
• Studies: Early embryotoxicity studies of azacitidine (Vidaza; Pharmion Corporation, Boulder, CO) in mice revealed an intrauterine embryonal death (increased resorption) rate of 44% after a single intraperitoneal injection of 6 mg/m² (approximately 8% of the RHDD on a milligram-per–square meter basis) on gestational day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine (3-12 mg/m², approximately 4-16% of the RHDD on a milligram-per–square meter basis) on or before gestational day 15.In rats, azacitidine was clearly embryotoxic when given intraperitoneally on gestational days 4-8 after implantation at a dose of 6 mg/m² (approximately 8% of the RHDD on a milligram-per–square meter basis), though treatment in the preimplantation period on gestational days 1-3 was not associated with adverse effects on the embryos.Azacitidine caused multiple fetal abnormalities in rats after a single intraperitoneal dose of 3-12 mg/m² (approximately 8% of the RHDD on a milligram-per–square meter basis) given on gestational day 9, 10, 11, or 12. In this study, azacitidine 3-12 mg/m² caused fetal death when administered on gestational days 9 and 10; the mean number of live animals per litter was reduced to 9% of control rates at the highest dose on gestational day 9.

Discussion of Specific Agents: Benzodiazepines to Corticosteroids

Benzodiazepines

• Pregnancy category - D or X
• Trimesters of risk: The first, second, and third trimesters are times or risk for flurazepam, temazepam, and triazolam (category X). Chlordiazepoxide seems to be safe during pregnancy. Avoidance of alprazolam during pregnancy seems prudent.
• Associated defects and complications - Unclear; potential for isolated oral cleft
• Studies: The information currently available is insufficient to determine whether the potential benefits of benzodiazepines to the mother outweigh the risks to the fetus. Pooled data from cohort studies show no association between fetal exposure to benzodiazepines and a risk of major malformations or oral cleft. However, pooled data from case-control studies demonstrated that the risk for major malformations is significantly increased, particularly for isolated oral cleft. Until additional research data are reported, level 2 ultrasonography is useful for assessing the patient for a cleft lip.

Bevacizumab

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Decrease in maternal and fetal body weights, increased number of fetal resorptions, and an increased frequency of specific gross and skeletal fetal alterations
• Studies: Bevacizumab (Avastin; Genentech, Inc, South San Francisco, CA) was teratogenic in rabbits when administered in doses 2-fold greater than the recommended human dose on a milligram-per-kilogram basis. Adverse fetal outcomes were observed at all doses tested. No adequate and well-controlled studies have been performed in pregnant women. Bevacizumab should not be used during pregnancy or in any woman not using adequate contraception unless the potential benefit justifies the potential risk to the fetus.Whether bevacizumab is secreted in human milk is unknown. Because human immunoglobulin G1 is secreted into human milk, the potential for absorption and harm to the infant after ingestion is unknown.Women should be advised to discontinue nursing during treatment with bevacizumab and for a prolonged period afterward. patients who discontinue bevacizumab should be counseled regarding prolonged exposure afterward (half-life of approximately 20 d; range 11-50 d) and regarding the possible effects of bevacizumab on fetal development.

Birth control pills (oral contraceptives) and hormone replacement therapy

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Variable; inflammatory complications common
• Studies: Little direct data are available because of the lack of models for estrogen-deficient pregnancy.

Bromides

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Polydactyly, GI anomalies, clubfoot, and congenital dislocation of the hip, IUGR
• Studies: A study showed substantial delays in postnatal development in all bromide-treated animals. Permanent deficits were recorded for body weight, brain weight, and protein content of the brain tissue. Results suggest that prenatal and perinatal exposure of rats to NaBr may interfere with postnatal development, including that of brain.

Carbamazepine

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Unique facial appearance and underdevelopment of the fingers, toes, and nails; developmental delay
• Studies: One study revealed a 2-fold increase in the rate of major congenital anomalies (12 of 160 carbamazepine subjects vs 18 of 560 unexposed control subjects, relative risk of 2.24, 95% confidence interval: 1.1-4.56%). Another finding was a birthweight reduction of approximately 250 g. Other reports indicated an increased risk for spina bifida of up to 1 (1%) per 100 compared with the population risk of 1-2 cases per 1000 births.

Cetuximab

• Pregnancy category - C
• Trimesters of risk - Unknown
• Associated defects and complications - Unknown
• Studies: Cetuximab (Erbitux; ImClone Systems Incorporated, New York, NY) has not undergone studies with regard to animal reproduction. Cetuximab has the potential to be transmitted from the mother to the developing fetus. Whether cetuximab can cause fetal harm when administered to a pregnant woman or whether cetuximab can affect reproductive capacity remains unknown. No adequate and well-controlled studies of cetuximab have been performed in pregnant women. Cetuximab should be given to a pregnant woman or any woman not using adequate contraception only if the potential benefit justifies the potential risk to the fetus.Before therapy is started, all patients should be counseled regarding the potential risks to the developing fetus. If the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus and/or the potential risk for loss of the pregnancy.

Cidofovir

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Possible external, soft tissue, and skeletal anomalies (ie, meningocele, short snout, short maxillary bones) of the fetus
• Studies: No adequate and well-controlled studies of cidofovir (Vistide; Gilead Sciences, Inc, Foster City, CA) have been performed in pregnant women. This drug was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/d and in rabbits at 1 mg/kg/d, dosages which were also maternally toxic with daily intravenous dosing during the period of organogenesis. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg/d) and in rabbits (0.25 mg/kg/d) were respectively about 0.04 and 0.05 times the clinical dosage (5 mg/kg every other wk) based on the AUC. An increased prevalence of fetal external, soft tissue, and skeletal anomalies (ie, meningocele, short snout, short maxillary bones) occurred in rabbits at the high dosage of 1 mg/kg/d, which was also maternally toxic.Cidofovir should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Cinacalcet

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Possible reduced postnatal maternal weight gain
• Studies: No adequate and well-controlled studies of cinacalcet (Sensipar; Amgen Inc, Thousand Oaks, CA) have been performed in pregnant women. In pregnant female rats given oral gavage doses of 2, 25, and 50 mg/kg/d during gestation, no teratogenicity was observed at dosages up to 50 mg/kg/d (exposure 4 times that resulting with a human oral dose of 180 mg/d based on AUC comparison). A decrease in fetal body weight was observed at all doses (<1-4>

Colchicine

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Generally unknown; potential chromosome aberrations
• Studies: Colchicine has been shown to cause birth defects in animals. Only a few reports describe it as causing birth defects in humans. The drug can lower sperm counts and cause sperm defects, affecting the ploidy of sperm and resulting in birth defects.

Corticosteroids

• Pregnancy category - C
• Trimester of risk - First
• Associated defects and complications - Reduced birth weight, increased risk of preeclampsia, and increased risk of oral and lip clefts
• Studies: A study of 35 women demonstrated various defects in 9 infants. Concerns have been expressed that neonatal adrenal hyperplasia or insufficiency may result from maternal corticosteroid use. The meaning of these results is uncertain. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 34 of whom had first-trimester exposure to cortisone. No evidence of a relationship to congenital defects was observed.

Discussion of Specific Agents: Danazol to Folic Acid Antagonists

Danazol

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications: Danazol can cause virilization of the external genital organs, and it has been linked to pseudohermaphroditism.
• Studies: Clinical findings suggest the development of salt-losing congenital adrenal hyperplasia. In one child, basal levels of the adrenal steroids were normal after 1 year. It may be hypothesized that danazol transiently blocked the steroid 21- and 11-beta-monooxygenases in this child.

Duloxetine

• Pregnancy category - C
• Trimesters of risk - First, second, and third
• Associated defect and complications - Variable
• Studies: No adequate and well-controlled studies have been conducted on pregnant women. In animal reproduction studies, duloxetine (Cymbalta; Eli Lilly and Company, Indianapolis, IN) adversely affected embryonic/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, no evidence of teratogenicity was noted at dosages up to 45 mg/kg/d (7 times the maximum recommended human dose [MRHD] of 60 mg/d and 4 times the human dose of 120 mg/d on a milligram-per–square meter basis in rats; 15 times the MRHD and 7 times the human dosage of 120 mg/d on a milligram-per–square meter basis in rabbits). However, fetal weights were decreased at this dosage, with a no-effect dosage of 10 mg/kg/d (2 times the MRHD and 1 times the human dosage of 120 mg/d on a milligram-per–square meter basis in rats; 3 times the MRHD and 2 times the human dosage of 120 mg/d on a milligram-per–square meter basis in rabbits).When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dosage of 30 mg/kg/d (5 times the MRHD and 2 times the human dosage of 120 mg/d on a milligram-per–square meter basis); the no-effect dosage was 10 mg/kg/d.Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups after maternal exposure to 30 mg/kg/d.Maternal duloxetine treatment did not adversely affect postweaning growth and reproductive performance of the progeny. Neonates exposed to selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately on delivery.Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors or, possibly, a drug-discontinuation syndrome. In some cases, the clinical picture is consistent with that of serotonin syndrome.When administering duloxetine to a pregnant woman in her third trimester, the physician should carefully consider the potential risks and benefits of treatment. The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used only during labor and delivery if the potential benefits justify the potential risks to the fetus.Duloxetine, its metabolites, or both are excreted into the milk of lactating rats; whether this occurs in humans is unknown. However, nursing while taking duloxetine is not recommended.

Ergotamine

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Low birth weight and preterm birth
• Studies: Studies have shown a possible association between low birthweight and/or preterm birth. Ergotamine treatment may be connected with ergotamine-induced vasoconstriction in the placenta of pregnant women. The effect of ergotamine was most obvious in male newborn infants, particularly after treatment in the third trimester.

Estradiol gel 0.06%

• Pregnancy category - C
• Trimesters of risk - First, second, and third
• Associated defects and complications - Decrease in the quantity and quality of milk
• Studies: No adequate and well-controlled studies of estradiol gel 0.06% (EstroGel; ASCEND Therapeutics, Inc, Herndon, VA) have been performed in pregnant women.

Exenatide

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Possible skeletal effects
• Studies: Exenatide (Byetta; Amylin Pharmaceuticals, Inc, San Diego, CA) has been shown to reduce fetal and neonatal growth and cause skeletal effects in mice at systemic exposures 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/d, as based on the area under the concentration-time curve (AUC). Exenatide caused skeletal effects in rabbits at systemic exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/d, based on AUC. There are no adequate and well-controlled studies in pregnant women. Exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Finasteride

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Abnormalities of the sex organs
• Studies: Studies in animals demonstrated that pregnancies sired by male rats given large doses of finasteride did not result in offspring born with birth defects. As of this writing, no such studies have been conducted in humans. Animal studies have shown that pregnant monkeys given large doses of oral finasteride had male offspring with abnormalities of the sex organs.Although highly unlikely, a theoretical risk exists for birth defects of a male fetus' sex organs if a man taking finasteride has intercourse during the stage of pregnancy when the sex organs are developing (8-15 wks of gestation). However, the amount of the drug found in the semen is small and not considered to be enough to harm a male baby.

Fluoxetine

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Variable; possible self-limited neonatal behavioral syndrome
• Studies: Reports of more than 1000 pregnancies exposed to fluoxetine (Prozac; Eli Lilly and Company) during the first trimester have been recorded. No study revealed an increased risk for major structural birth defects (ie, those requiring surgery or reducing function). One study has shown an increased rate of 3 or more minor birth defects (ie, those not medically or functionally significant) among children exposed to fluoxetine in the first trimester. When 3 or more minor birth defects are seen together, the likelihood of a major birth defect (including learning problems) increases, though this effect was not observed in the fluoxetine study.Follow-up studies have been started to investigate the possible long-term effects on infants exposed to fluoxetine during pregnancy. The available evidence indicates that in utero exposure to serotonin reuptake inhibitors during the last trimester through delivery may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care.

Fluconazole

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Craniofacial, skeletal, and cardiac effects
• Studies: Fluconazole has been associated with various problems in animals, including craniofacial ossification defects; thin, wavy ribs; and renal pelvis defects. Fetal anomalies have most often been observed when high-dose parenteral therapy is used (eg, treatment of the mother for coccidioidomycosis meningitis). Reassuring results from several studies have shown that fluconazole exposure in the first trimester of pregnancy does not materially increase the risk of congenital disorders in infants.

Folic acid antagonists

• Pregnancy category - D in general
• Trimester of risk - First, during normal closure of the fetal neural tube
• Associated defects and complications - Variable; neural tube defects
• Studies: Dietary factors, such as cholesterol and folic acid, appear to be critical for normal closure of the fetal neural tube. Approximately 50% of neural tube defects can be prevented. To prevent them, a pregnant woman should take supplemental folic acid. The US Public Health Service recommends that all women of childbearing age take 0.4 mg of folic acid per day. The following drugs interfere with folic acid metabolism:
  • Phenobarbital, phenytoin (Dilantin; Parke-Davis, Division of Pfizer Inc), carbamazepine (Tegretol; Novartis Pharmaceuticals Corporation, East Hanover, NJ), and primidone (Mysoline; Valeant Pharmaceuticals International, Aliso Viejo, CA) - Primarily used to prevent seizures
  • Antibiotic combination of trimethoprim and a sulfonamide (eg, Bactrim; AR Scientific, Philadelphia, PA, and Septra; Monarch Pharmaceuticals, Inc, Bristol, TN) - Commonly used to treat urinary tract infections
  • Triamterene (Dyrenium; WellSpring Pharmaceutical Corporation, Bradenton, FL) - Diuretic used to treat high blood pressure
  • Sulfasalazine (Azulfidine; Pharmacia & Upjohn Company, Division of Pfizer Inc) - Used to manage ulcerative colitis and other inflammatory conditions
  • Valproic acid (Depakote; Abbott Laboratories, North Chicago, IL)
  • Cimetidine (Tagamet; GlaxoSmithKline, Research Triangle Park, NC) - Used to treat ulcers and acid reflux
  • Beta-blockers and calcium channel blockers - Used to manage high blood pressure and certain heart disorders
  • Cholestyramine (LoCholest; Warner Chilcott Laboratories, Rockaway, NJ, and Questran; Bristol-Myers Squibb, New York, NY) - Used to lower cholesterol levels
  The prevalence of birth defects after use of the drugs listed above is highly variable. Defects can often be prevented with folic acid supplementation. Anticonvulsant medications on this list can cause a host of birth defects independent of their effects on folic acid.

Discussion of Specific Agents: Ibandronate to Lithium

Ibandronate

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: No adequate and well-controlled studies have been conducted in pregnant women.

Lanthanum carbonate

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Possible kidney dysfunction
• Studies: No adequate and well-controlled studies of lanthanum carbonate (Fosrenol; Shire US Inc, Wayne, PA) have been performed.

Lenalidomide

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Possible reduction in fetal body weight and increase in postimplantation losses and fetal variations
• Studies - In New Zealand White rabbits, of lenalidomide 10 and 20 mg/kg/d was maternally toxic (reduced body weight gain and feed consumption). At 20 mg/kg/d, weight loss and 1 abortion was reported.

Leukotriene receptor antagonists

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: In a study by Bakhireva et al, perinatal outcomes among 96 women who took montelukast or zafirlukast were compared with those of 122 women who exclusively took short-acting beta2-agonists and 346 women without asthma.²² No specific pattern of major structural anomalies in their offspring or a large risk of other adverse perinatal outcomes was found.

Lithium

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Variable; possible cardiac effects
• Studies: In 1973, an International Register of Lithium Babies was established to monitor the outcome of fetuses exposed in the first trimester of pregnancy. As of 1990, 225 cases were registered, with 25 instances of malformation. Of these, 18 involved the great vessels of the heart. Six were Ebstein anomalies, defects affecting the tricuspid valve. These numbers suggest a greatly increased risk compared with the normal frequency of Ebstein anomaly (1 in 20,000 births). However, this claim has been contested on the grounds of overreporting of abnormal cases and because 2 studies returned negative findings. The question remains whether lithium is a human teratogen. The best estimate comes from cohort studies, one of which suggested an increased rate (4-12%) of congenital malformations compared with the rate observed in the general population (2-4%).In 1992, a prospective study of pregnancy outcomes after exposure to lithium carbonate during the first trimester of pregnancy was reported.²³ In it, 138 patients were successfully followed up to the end of pregnancy. The rate of congenital malformations was the same between lithium-exposed subjects (2.8%) and maternal age-matched control subjects (2.4%). However, 1 Ebstein anomaly was reported in the lithium group. Birth weight was notably increased in the lithium group despite identical gestational ages.One cohort study showed positive relative risks of 3 for all types of congenital malformations and 7.7 for cardiac malformations. None of the subjects had an Ebstein anomaly. Findings from a second cohort study were negative. Four case-control studies performed to test the association between lithium and Ebstein anomaly have also been reported. No cases of Ebstein anomaly were observed in 208 lithium-exposed embryos, though 2 cases were found among 398 control subjects.

Discussion of Specific Agents: Methimazole to Nelarabine

Methimazole

• Pregnancy category - D
• Trimesters of risk - First, possibly second, and third
• Associated defects and complications - Prematurity, small-for-gestational-age infants, and scalp defects; possible choanal and esophageal atresia
• Studies: One study indicated that the prevalence of choanal and esophageal atresia may be higher than expected in fetuses exposed to methimazole during gestational weeks 3-7. Some researchers gave stated that no deleterious effects on thyroid function or on the physical and intellectual development occurred when mothers were treated with dosages up to 20 mg/d during pregnancy. Propylthiouracil can be used instead.

Methylene blue

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Intestinal atresias
• Studies: Methylene blue is reported to cause intestinal atresias when it is injected into the amniotic fluid during amniocentesis. It poses a small risk of causing birth defects.

Mifepristone, RU-486

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Unknown; possible sexual function
• Studies: Whether mifepristone has teratogenic effects is not known for certain. Children whose mothers used it have been born without birth defects. However, experiments in rats have shown different results. Rats that were exposed to the drug were born normal in one study. However, in another study, sexual function was affected. Therefore, this medication appears to impart some increase in an undefined risk if it is ingested during pregnancy.

Minoxidil

• Pregnancy category - C
• Trimesters of risk - First, second, and third
• Associated defects and complications - Hypertrichosis of the back and extremities, dysmorphic facial features, uneven fat distribution, omphalocele, and cardiac anomalies
• Studies: Few studies have been conducted, with conflicting results.

Misoprostol

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Möbius syndrome
• Studies: In a case-control study, researchers compared the frequency of misoprostol use during the first trimester between mothers of 96 Brazilian infants with Möbius syndrome and mothers of 96 infants with neural tube defects. Among the former, 47 (49%) had taken misoprostol during pregnancy, compared with just 3 (3%) of the mothers from the other group. Other investigators have stated that misoprostol use causes a 30-fold increase in the prevalence of Möbius syndrome, though this effect is still rare.

Mycophenolate mofetil

• Pregnancy category - D
• Trimester of risk - First
• Associated defects and complications - External ear and facial defects; cleft lip and palate; heart, esophagus, kidney and distal limb defects
• Studies: The pregnancy category of mycophenolate mofetil was recently changed from C (risk of fetal harm from the drug cannot be ruled out) to D (existing evidence of fetal risk). Previous studies showed supporting results; most studies involved the use of mycophenolate mofetil during the preconception period and the first trimester.

Mysoline

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Variable
• Studies: The teratogenic potential of mysoline is not fully known, but it is thought to be similar to that of phenobarbital.

Natalizumab

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: No adequate and well-controlled studies of natalizumab (Tysabri; Elan Pharmaceuticals, Inc, San Diego, CA) have been performed in pregnant women. In reproductive studies of monkeys and guinea pigs, no evidence of teratogenic effects was observed at dosages up to 30 mg/kg (7 times the human clinical dose based on body-weight comparison). In a study in which female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at postnatal day 14 compared with controls (3 pups per litter for the group treated with 30 mg/kg natalizumab and 4.3 pups per litter for the control group).In 1 of 5 studies in which monkeys or guinea pigs were exposed during pregnancy, the abortion rate in monkeys treated with 30 mg/kg was 33% versus 17% in controls. No effects on abortion rates were noted in any other study.Natalizumab underwent transplacental transfer and yielded in utero exposure in developing guinea pigs and cynomolgus monkeys.When pregnant dams were exposed to natalizumab at approximately 7 times the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum levels.A study of pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetuses. The changes included mild anemia, reduced platelet counts, increased splenic weights, and reduced hepatic and thymic weights in association with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. Platelet counts were also reduced in offspring born to mothers treated with natalizumab at 7 times the clinical dose. This effect was reversed upon clearance of natalizumab. The offspring had no evidence of anemia.Because results of animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if it is clearly needed. If a woman becomes pregnant while taking natalizumab, discontinuation should be considered.Whether natalizumab is excreted in human milk is unknown. Because many drugs and immunoglobulins are excreted in human milk and because the potential for serious adverse reactions is unknown, a decision should be made about whether nursing or natalizumab should be discontinued; this should depend on the importance of therapy to the mother.

Nelarabine

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Variable; disrupting DNA synthesis in rapidly diving cells
• Studies - Unknown

Discussion of Specific Agents: Pegaptanib to Statins

Pegaptanib

• Pregnancy category - B
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: Pegaptanib (Macugen; Pfizer Inc) produced no maternal toxicity and no evidence of teratogenicity or fetal mortality in mice at intravenous dosages of up to 40 mg/kg/d (approximately 7000 times the recommended human monocular ophthalmic dose of 0.3 mg per eye). Pegaptanib crossed the placenta in mice. No studies have been conducted on pregnant women. The potential risk to humans is unknown. Pegaptanib should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.Whether pegaptanib is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be used when pegaptanib is administered to nursing women.

Pemetrexed (for injection)

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: No adequate and well-controlled studies of pemetrexed (Alimta; Eli Lilly and Company) have been performed in pregnant women

Penicillamine

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Variable; possible connective-tissue defects, cerebral palsy, hydrocephalus, skeletal defects, cleft palates, and fetal toxicity (resorptions)
• Studies: No controlled studies have been conducted on the use of penicillamine in pregnant women. Although normal outcomes have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine should only be used in women of childbearing potential when the expected benefits outweigh the possible hazards.

Phenobarbital or methylphenobarbital

• Pregnancy category - D
• Trimester of risk - Late in pregnancy
• Associated defects and complications - Phenobarbital or methylphenobarbital slightly increases the risk of cleft palate or lip and congenital heart disease. These drugs can cause fetal addiction and newborn withdrawal symptoms or newborn hemorrhage
• Studies: Long-term use of phenobarbital late in pregnancy has been associated with transient neonatal sedation or withdrawal symptoms in infants. Features observed in these infants include hyperactivity, irritability, and tremors. Perinatal or neonatal hemorrhage has occasionally been observed in infants of women who took phenobarbital late in pregnancy. This phenomenon has been attributed to drug-induced suppression of synthesis of vitamin K–dependent clotting factors.

Phenytoin

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Varied Hand and foot defects include fingerlike thumbs, aplasia or hypoplasia of the distal phalanges, supernumerary phalangeal epiphyses, and clubfoot.Dermatoglyphic abnormalities consist of abnormal palmar creases and nail hypoplasia or aplasia.General defects include growth retardation, atypical facial appearance, hirsutism, and low hairlines.Facial problems include microcephaly, brachycephaly, midfacial hypoplasia, wide fontanels, metopic ridging, mild micrognathia, low-set deformed ears, blepharoptosis, mild hypertelorism, strabismus, short nose with a broad depressed bridge and epicanthal folds, cupid's bow of the upper lip, and occasionally cleft lip and palate.Reported torso abnormalities include short neck with mild webbing, widely spaced nipples, umbilical or inguinal hernia, and rib anomalies.Internal abnormalities include variable coarctation of the aorta, endocardial cushion defect, double-outlet right ventricle, ventricular septal defect, atrial septal defect, bicuspid pulmonic valve, and intestinal malrotation.Ambiguous genitalia are rarely associated with this syndrome.A patient with the dysmorphic characteristics of fetal hydantoin syndrome presented with unusual hyperpigmentation of several fingernails. Another neonate presented with gum hypertrophy, digitalization of the thumbs, hypoplasia of the distal phalanges and nails, epicanthal folds, pseudohypertelorism, epidermoid cyst, and geographic tongue.Onychopathy can be a monosymptomatic or mild form of this syndrome. This syndrome may be associated with neonatal acne.
• Studies: Phenytoin affects folate and vitamin K metabolism, which may increase fetal bleeding. Some investigators have suggested that vitamin K be administered to mothers taking phenytoin in the third trimester to prevent hemorrhage. However, the available evidence does not justify this policy of giving vitamin K throughout the last third of pregnancy to all women being treated with anticonvulsants. When used in pregnancy, phenytoin can cause a syndrome of birth defects referred to with various names, such as Dilantin congenital defects, fetal hydantoin syndrome (FHS), Meadow syndrome, congenital hydantoin syndrome, Dilantin syndrome, fetal Dilantin syndrome, fetal phenytoin syndrome, and hydantoin syndrome. Various malformations have been reported to occur because of phenytoin intake during pregnancy.

Potassium iodide

• Pregnancy category - D
• Trimester of risk - Unknown
• Associated defects and complications - Hypoplasia, goiter
• Studies: Studies have shown that medications containing potassium iodide (as a radiocontrast agent) can affect the fetal thyroid gland and lead to hypoplasia and goiter.

Progesterones

• Pregnancy category - D or X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Possible cardiovascular defects, hypospadias
• Studies: Various forms of progesterone are used as contraceptive agents and are classified as pregnancy category D or X. They have been linked to birth defects (eg, cardiovascular defects, hypospadias), but this has not been proven.

Ramelteon

• Pregnancy category - C
• Trimesters of risk - Unknown
• Associated defects and complications - Unknown
• Studies: No adequate and well-controlled studies have been performed in pregnant women.

Retinoids

• Pregnancy category - X
• Trimesters of risk: The first, second, and third trimesters are times of risk. The critical window of exposure is at 3-5 weeks of pregnancy.
• Associated defects and complications - Deformities of the cranium, ears, face, limbs, and liver; hydrocephalus; microcephalus; heart defects; cognitive defects without dysmorphology; craniofacial alterations; cleft palate; neural tube defects; cardiovascular malformations; thymic aplasia; psychological impairments; absent or defective ears; small jaw; and kidney alterations
• Studies: Retinoic acid is teratogenic in humans at low doses. Of affected children, 50% have an intelligence quotient (IQ) of less than 85. The mean IQ score is 100-110. Retinoic acid is the active ingredient in Accutane (Roche Laboratories Inc, Nutley, NJ), a drug used to treat severe acne. Since its introduction in September 1982, an estimated 160,000 women of childbearing age have used it. From 1982-1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions, and 5000-7000 elective abortions were attributed to exposure to this drug. Exposed children may have had hydrocephaly, ear malformations, cardiovascular defects, and decreased IQ scores. Accutane carries a pregnancy category X warning; it is a known human teratogen.Dosages of 25,000 IU/d or more, given in the form of retinol or retinyl esters, should be considered potentially teratogenic.Another strategy involves the administration of drugs during pregnancy while accounting for its pharmacologic effects in relation to the gestational period. Examples are avoidance of chemotherapy during the first trimester, avoidance of nonsteroidal anti-inflammatory drugs in the third trimester, avoidance of high doses of benzodiazepines in the period when events are imminent.Only a minimal amount of tazarotene is absorbed into the circulation.Although animal studies have found tazarotene to be nonmutagenic and nonteratogenic, women of childbearing potential should be counseled regarding the potential risks of retinoid use during pregnancy.

Rifaximin

• Pregnancy category - C
• Trimesters of risk - Unknown
• Associated defects and complications - Possible cleft palate, agnathia, jaw-shortening, hemorrhage, eyes partially open, small eyes, brachygnathia, incomplete ossification, and increased thoracolumbar vertebrae
• Studies: No adequate and well-controlled studies have been performed in pregnant women. Rifaximin (Xifaxan; Salix Pharmaceuticals, Inc., Morrisville, NC) was teratogenic in rats at doses of 150-300 mg/kg (approximately 2.5-5 times the clinical dose adjusted for body surface area) and in rabbits at doses of 62.5-1000 mg/kg (approximately 2-33 times the clinical dose adjusted for body surface area). Rifaximin tablets should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Solifenacin succinate

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: Whether solifenacin succinate (VESIcare; GlaxoSmithKline and Astellas Pharma US, Inc, Deerfield, IL) is harmful to an unborn baby is not known. Pregnant women should not take solifenacin succinate, and women should not become pregnant while taking solifenacin succinate without first consulting a physician. Whether solifenacin succinate harms a nursing infant remains unknown. Women who are breastfeeding should not take solifenacin succinate without first talking to their physician.

Sorafenib

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Variable
• Studies: Sorafenib is a multikinase inhibitor that targets a number of serine-threonine and receptor tyrosine kinases. Inhibition of the involved systems inhibits division and growth of tumoral cells, and potentiates cellular apoptosis. This drug is specifically indicated for the treatment of advanced renal cell carcinoma.

Statins (HMG-CoA reductase inhibitors)

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Possible spina bifida
• Studies: The causal nature of these defects remains to be fully defined. These drugs did no cause birth defects in rabbit testing.

Sulfasalazine (used in inflammatory bowel disease)

• Pregnancy category - B
• Researchers in Iran performed a meta-analysis to explore the risk of adverse pregnancy outcomes in women with IBD following exposure to 5-ASA drugs (mesalazine, sulfasalazine, balsalazide, and olsalazine). This meta-analysis suggests that women taking 5-ASA drugs had no more than a 1.16-fold increase in congenital malformations, a 2.38-fold increase in stillbirth, a 1.14-fold increase in spontaneous abortion, a 1.35-fold increase in preterm delivery, and a 0.93-fold increase in low birth weight.²⁴

Discussion of Specific Agents: Telithromycin to Warfarin

Telithromycin

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Variable; potential liver failure and liver damage in the mother.
• Studies: No adequate and well-controlled studies of telithromycin (Ketek; Sanofi-Aventis U.S., Bridgewater, NJ) have been performed in pregnant women.

Tetracyclines

• Pregnancy category - D
• Trimesters of risk - Second and third (20th gestational week or later)
• Associated defects and complications - Dental staining
• Studies: As little as 1 g/d of tetracycline for 3 days during the third trimester can produce yellow staining of deciduous teeth. After their eruption, yellow-stained teeth gradually darken to brown. Calcification of deciduous teeth begins at the end of the fourth month of gestation and ends at approximately 11-14 months of age. Administration of tetracycline to pregnant women in the second and third trimesters results in staining of dentine, with calcification of the enamel at the time of administration. Because the permanent teeth begin calcifying after birth, they are not affected by prenatal exposure.Although several case reports have described malformations (including enamel hypoplasia) after tetracycline use in pregnancy, findings from relatively large studies have mostly been negative. Despite this finding, tetracycline has been referred to as a teratogen in numerous publications.

Thalidomide

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Malformed intestines, hearing defects, absent ears, and/or ocular and renal anomalies, phocomelia
• Studies: Many mechanisms of action have been proposed for thalidomide, yet the true mechanism remains unknown. One theory suggests that neural crest cells are affected. Another mentions an alteration in metanephros-limb interaction that stunts the limb’s outgrowth. Other possibilities include a reduction in the size of ganglia (which inhibits limb development because limb growth depends on neuronal growth) or an inhibition of cell-to-cell interactions and reduced quantities of cell adhesion molecules; these alterations make limb growth impossible.

Tinidazole

• Pregnancy category - C
• Trimesters of risk - First, second, and third
• Associated defects and complications - Variable
• Studies: Use of tinidazole (Tindamax; Mission Pharmacal Company, San Antonio, TX) has not been studied in pregnant patients. Because tinidazole crosses the placental barrier and enters fetal circulation, it should not be administered to pregnant patients in the first trimester. Studies of pregnant mice indicated no embryonic-fetal toxicity or malformations at the highest dose level of 2500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based on body surface area conversions).In a study of pregnant rats, a slightly elevated frequency of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5 times the highest human therapeutic dose based on body surface area conversions).No biologically relevant neonatal developmental effects were observed in rat neonates after maternal doses as high as 600 mg/kg (3 times the highest human therapeutic dose based on body surface area conversions).Because results of animal reproduction studies are not always predictive of human responses and because some evidence indicates mutagenic potential, tinidazole should be used during pregnancy only if the potential benefits outweigh the possible risks to both the mother and the fetus.

Tiotropium bromide

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: No evidence of structural alterations was observed in rats and rabbits at dosages of inhalation tiotropium (Spiriva HandiHaler; Pfizer Inc and Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) of up to 1.471 and 0.007 mg/kg/d, respectively. These dosages corresponded to approximately 660 and 6 times RHDD on a milligram-per–square meter basis, respectively. However, in rats, fetal resorption, litter loss, decreases in the number of live pups at birth and mean pup weights, and a delay in pup sexual maturation were observed at inhalation dosages of 0.078 mg/kg (approximately 35 times the RHDD on a milligram-per–square meter basis). In rabbits, an increase in postimplantation loss was observed at an inhalation dosage of 0.4 mg/kg/d (approximately 360 times the RHDD on a milligram-per–square meter basis). Such effects were not observed at inhalation dosages of 0.009 and up to 0.088 mg/kg/d in rats and rabbits, respectively. These doses corresponded to approximately 4 and 80 times the RHDD on a milligram-per–square meter basis, respectively. These dosage multiples may have been overestimated because of difficulties in measuring deposited doses in animal inhalation studies.No adequate and well-controlled studies have been performed in pregnant women. Tiotropium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The safety and effectiveness of tiotropium has not been studied during labor and delivery.

Trimethadione

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Malformed ears, cleft palate, cardiac defects, urogenital malformations, and skeletal abnormalities; delayed mental and physical development also observe
• Studies: The rate of fetal loss is reportedly as high as 87%.

Trospium chloride

• Pregnancy category - C
• Trimester of risk - Unknown
• Associated defects and complications - Unknown
• Studies: No adequate and well-controlled studies have been performed in pregnant women. Trospium chloride (Sanctura; Esprit Pharmaceuticals, East Brunswick, NJ, and Indevus Pharmaceuticals, Inc, Lexington, MA) has been shown to cause maternal toxicity and decrease fetal survival in rats given approximately 10 times the expected clinical exposure (AUC). No-effect levels for maternal and fetal toxicity were approximately equivalent to the expected clinical exposure in rats and were approximately 5-6 times the expected clinical exposure in rabbits. No malformations or developmental delays were observed. Trospium chloride 2 mg/kg given orally and 50 mcg/kg given intravenously were excreted to a limited extent (<1%)>

Valproic acid

• Pregnancy category - D
• Trimesters of risk - First, second, and third
• Associated defects and complications - Lumbosacral spina bifida with meningomyelocele or meningocele, often accompanied by midfacial hypoplasia, deficient orbital ridge, prominent forehead, congenital heart disease, and decreased postnatal growth
• Studies: Data from one study suggested that exposure to valproate during the first trimester of pregnancy may have changed the ultrastructure of the placenta by altering the migration of trophoblast cells. Another demonstrated that some of the effects may be due to alterations of folate metabolism.
• Meador et al found that in utero exposure to valproate as compared with other antiepileptic agents is associated with a lower IQ25

Warfarin

• Pregnancy category - X
• Trimesters of risk - First, second, and third
• Associated defects and complications - Deformities of the axial and appendicular skeleton; also, a hypoplastic nose, eye abnormalities, mental retardation, brachydactyly, and scoliosis
• Studies: Malformations are reported in 16% of exposed fetuses; hemorrhages, in 3%; and stillbirths, in 8%. The embryopathy described above results from maternal use during early pregnancy, whereas CNS disorders are due to ingestion at a later stage in pregnancy. The teratogenic mechanism of warfarin is unknown, but one proposed theory is that an alteration in posttranslational carboxylation of proteins may result in the chondrogenic disorders.

Drugs Approved in 2006 and 2007

Table 3. Drugs Approved in 2006 and 2007 With Their FDA Pregnancy Categories

Open table in new window

Keywords

teratogenic, teratogenicity, human X-linked dominant chondrodysplasia punctata, Happle syndrome, Happle's syndrome, Conradi-Hunermann-Happle syndrome, CDPX2, emopamil-binding protein, EBP, fetal ototoxicity, intrauterine growth retardation, IUGR, intrauterine growth restriction, fetal growth restriction, birth defects, pregnancy complications, Dilantin congenital defects, phenytoin toxicity, fetal phenytoin syndrome, fetal hydantoin syndrome, FHS, meadow syndrome, congenital hydantoin syndrome, Dilantin syndrome, fetal Dilantin syndrome, hydantoin syndrome, fetal trimethadione syndrome, fetal warfarin syndrome, warfarin toxicity

seizure disorders in pregnancy, FDA pregnancy category, pregnancy category D, pregnancy category X, drug use during pregnancy and lactation, drug adverse effects, drug exposure during pregnancy, psychosocial and environmental pregnancy risks.

Source : http://emedicine.medscape.com/article/260725-overview