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Teratology and Drug Use During Pregnancy
Article Last Updated: Apr 30, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 18  
Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Noah S Scheinfeld is a member of the following medical societies: American Academy of Dermatology
Coauthor(s):
Jessica M Allan, MD, Consulting Staff, Private Practice;
Anne Davis, MD, MPH, FACOG, Assistant Professor, Department Obstetrics and Gynecology, College Physicians and Surgeons, Columbia University;
Rachel Nazarian, BS, Tulane University School of Medicine
Editors: Suzanne R Trupin, MD, Clinical Professor of Obstetrics and Gynecology, University of Illinois College of Medicine-Champaign; CEO and Owner, Women's Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Gail F Whitman-Elia, MD, Professor, Department of Obstetrics and Gynecology, University of South Carolina School of Medicine; Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center; David Chelmow, MD, Professor of Obstetrics and Gynecology, Tufts University School of Medicine; Program Director, Tufts University Affiliated Hospitals OB/GYN Residency Program; Chair, Tufts University Health Sciences Campus Institutional Review Board
Author and Editor Disclosure
Synonyms and related 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
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.51 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.52
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.49
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.7, 8 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.9 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.10 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.11, 12 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.11, 12 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.13, 14 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 | Category | Summary and Labeling |
|---|
| A | Summary: Fetal risk not revealed in controlled studies in humans
Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).
Labeling: "Studies in pregnant women have not shown that [the drug] increases the risk of fetal abnormalities if administered during the first [second, third, or all] trimester(s) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, [the drug] should be used during pregnancy only if clearly needed."
Must describe the human studies.
If animal reproduction studies are available and fail to demonstrate a risk to the fetus, "Reproduction studies have been performed in [animals] at doses up to [X] times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to [the drug]."
Must describe available data on the effect of the drug on the later growth, development, and functional maturation of the child. | | B | Summary: Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.
Labeling: "Reproduction studies have been performed in [animals] at doses up to [X] times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to [the drug]. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed."
If animal reproduction studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), "Reproduction studies in [animals] have shown [findings] at [X] times the human dose. Studies in pregnant women, however, have not shown that [the drug] increases the risk of abnormalities when administered during the first [second, third, or all] trimester(s) of pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is remote, if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, [the drug] should be used during pregnancy only if clearly needed."
Must also describe the human studies and available data on the effect of the drug on the later growth, development, and functional maturation of the child. | | C | Summary: Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Animal reproduction studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.
Labeling: "[The drug] has been shown to be teratogenic (or to have an embryocidal effect or other adverse effect) in [species] when given in doses [X] times the human dose. There are no adequate and well-controlled studies in pregnant women. [The drug] should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
Must describe the animal studies.
If there are no animal reproduction studies and no adequate and well-controlled studies in humans, "Animal reproduction studies have not been conducted with [the drug]. It is also not known whether [the drug] can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. [The drug] should be given to a pregnant woman only if clearly needed."
Must describe any available data on the effect of the drug on the later growth, development, and functional maturation of the child. | | D | Summary: Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective).
Labeling: "See 'Warnings and Precautions' section."
Under the Warnings and Precautions section, "[The drug] can cause fetal harm when administered to a pregnant woman. [Human and any pertinent animal data.] If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus." | | X | Summary: Contraindicated; benefit does not outweigh risk
Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit (for example, safer drugs or other forms of therapy are available).
Labeling: "See 'Contraindications' section."
Under the Contraindications section, "[The drug] may [or can] cause fetal harm when administered to a pregnant woman. [Human and any pertinent animal data.] [The drug] is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus." |
Source.—Center for Devices and Radiological Health, FDA, 2007.15 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 | Category | Definition |
|---|
| B1 | "Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.
Studies in animals have not shown evidence of an increased occurrence of fetal damage." | | B2 | "Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.
Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage." | | B3 | "Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.
Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans." |
Source.—Therapeutic Goods Administration, ADEC, 1999.16
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.17
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 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 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 times a human oral dose of 180 mg/d based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and weight gain).
In pregnant female rabbits given oral gavage dosages of 2, 12, and 25 mg/kg/d during gestation, no adverse fetal effects were observed (exposures less than with a human oral dosage of 180 mg/d based on AUC comparisons). Reductions in maternal food consumption and weight gain were seen at dosages of 12 and 25 mg/kg/d. In pregnant rats given oral gavage dosages of 5, 15, and 25 mg/kg/d during gestation through lactation, no adverse fetal or pup (postweaning) effects were observed at 5 mg/kg/d (exposures less than with a human therapeutic dose of 180 mg/d based on AUC comparisons). Higher doses of 15 and 25 mg/kg/d (exposures 2-3 times a human oral dose of 180 mg/d based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss) and reductions in postnatal maternal and pup body-weight gain. Cinacalcet has been shown to cross the placental barrier in rabbits. Cinacalcet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Studies in rats have shown that cinacalcet is excreted in milk, with a high milk-to-plasma ratio. Whether cinacalcet is excreted in human milk is unknown. Because of the data from studies in rats and because many drugs are excreted in human milk, the potential for clinically significant adverse reactions in infants should be considered, and a decision should be made whether to discontinue nursing or to discontinue cinacalcet therapy. The importance of the drug to the lactating woman should be taken into account.
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
DISCUSSION OF SPECIFIC AGENTS: DANAZOL TO FOLIC ACID ANTAGONISTS
Danazol 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
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