Jerome Yankowitz
PRINCIPLES OF TERATOLOGY
Anything a pregnant woman ingests or is exposed to could affect her fetus. This is problematic for the health care provider who must treat a wide variety of illnesses during pregnancy. In fact, over 60% of American women receive a prescription for at least one medication during pregnancy. This figure is about 99% for women in France and over 70% for Hungarian women. The most common conditions for which medications are prescribed include gastrointestinal, dermatologic, psychological, and psychiatric disorders and pain.
Generally, whatever medication would be given to a nonpregnant women is the appropriate choice in pregnancy. Awareness of the few exceptions and how to choose from available options requires a knowledge of teratology and alterations in drug metabolism related to pregnancy. Teratology is the study of abnormal development or the production of defects in the fetus. Birth defects affect 2% to 3% of all neonates. With longer follow-up, at least 5% of individuals are found to be affected by a birth defect. Exogenous causes of birth defects, including drugs or chemical exposures, account for almost 10% of birth defects. Thus, at least 0.2% to 0.3% of pregnancies are affected by teratogenesis.
The Food and Drug Administration (FDA) introduced a drug classification system in 1979 to discourage nonessential use of medication during pregnancy. Drugs are classified as either A, B, C, D, or X, with the latter being the most teratogenic. There has been growing perception that the FDA classification has led to excessive maternal anxiety and unnecessary pregnancy termination. The FDA is evaluating a revised labeling system for drugs and biologic agents that will include a description of the drugs based on clinical management, summary of risk assessment, and discussion of data.
How much drug the fetus will be exposed to is determined by a complex interaction of many factors, including how the agent is absorbed, the volume of distribution, metabolism, and excretion. Absorption is via the gastrointestinal tract, skin, lungs, or after parenteral administration. Pregnancy alters absorption in a variety of ways, including prolongation of gastric emptying time by the increased progesterone. The volume of distribution is generally increased during pregnancy. Estrogen and progesterone alter hepatic enzyme activity with varying effects on drug metabolism and clearance, depending on the precise pathway. Renal excretion is generally increased during pregnancy. Other factors affect precisely how much drug crosses the placenta. Passage of drugs across the placenta is influenced by several factors. Lipid-soluble substances readily cross the placenta, and water-soluble substances pass less well. Those with greater molecular weight also cross the placenta less easily. The degree to which a drug is bound to plasma protein influences the amount of drug that is free to cross. Virtually all drugs cross the placenta to some degree, with the exception of large organic ions such as heparin and insulin. Active placental transfer must be considered, also.
Other concepts related to teratology include specificity, timing, dosage, maternal physiology, embryology, and genetics. Specificity indicates that a substance may be teratogenic in some species but not others. For example, thalidomide produces phocomelia in primates but not rodents. Often, animal data of safety or teratogenic effect is not necessarily applicable to humans. Timing is also critical. When administered between 35 and 37 days gestation, thalidomide produces ear malformations, but between 41 and 44 days, amelia or phocomelia. Dosage is also important. In most cases, administration of a low dose will result in no effect while malformations occur at intermediate doses and death at higher doses. Death may cause organ-specific teratogenic action to go unnoticed. The route of administration, possibly secondary to absorption, is also important. Small doses over several days may have an effect different than the same total dose given at once. Sequential dosing, as opposed to a bolus, may induce an enzyme to metabolize the substance that potentially causes less damage. Constant exposure may destroy cells that would have catabolized the drug if administered in periodic doses. As noted above for thalidomide, timing of exposure relative to embryologic events is important. Teratogen exposure in the first 2 to 3 weeks after conception is generally thought to have no effect or to result in spontaneous loss (all-or-nothing phenomenon). The period of susceptibility to teratogenic agents is during the period of organogenesis, which occurs primarily at 3 to 8 weeks postconception (35-70 days after the last menstrual period or LMP) or to 10 weeks from the LMP. After this period, embryonic development is characterized primarily by increasing organ size (10-12 weeks); thus, the principal effect of exposure will be growth restriction or effects on the nervous system and gonadal tissue. These systems continue to develop throughout pregnancy. During organogenesis each organ system will have different critical periods of sensitivity. A teratogen can act by causing cell death, altering tissue growth (hyperplasia, hypoplasia, or asynchronous growth), or interfering with cellular differentiation or other basic morphogenic processes.
The genetic make-up of the mother and fetus can affect individual susceptibility to a drug. Fetuses with low levels of the enzyme epoxide hydrolase may be more likely to manifest the fetal hydantoin syndrome than those with normal levels of epoxide hydrolase. Combinations of agents may produce different degrees of malformation or growth restriction than if given individually. Fetuses whose mothers are on combination antiepileptic agents are at the highest risk for malformations, including neural tube defects and facial dysmorphic features.
Most drug therapy does not require cessation of nursing because the amount excreted into breast milk is small enough to be pharmacologically insignificant.
ANTIBIOTICS AND OTHER ANTIINFECTIVE AGENTS
Antibiotics are used widely during pregnancy to treat a variety of disorders including upper respiratory tract infections, urinary tract infections, and others (Table 7.1). Pregnant patients are particularly susceptible to vaginal yeast infections. This is one reason that antibiotics should be used only when clearly indicated. Therapy with antifungal agents may be necessary after the course of antibiotic therapy.
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TABLE 7.1. Antibiotics used for common infections in pregnancy |
Antibiotics
Penicillins
Penicillin derivatives, including amoxicillin and ampicillin, have a wide margin of safety and lack toxicity for both the woman and her fetus. Penicillin is a β-lactam that inhibits bacterial cell wall synthesis and can be administered orally, intramuscularly, and intravenously. It is the drug of choice for the treatment of a wide variety of bacterial infections including group A streptococcal pharyngitis, otitis media, and mild Streptococcus pneumoniae pneumonia. Penicillin is the drug of choice to treat syphilis. Pregnant women with allergy to penicillin should be desensitized to receive their full course when being treated for a syphilis infection. Ampicillin and amoxicillin are good choices for enterococcal urinary tract infections, but many other pathogens are resistant, so they should be used selectively. Amoxicillin-clavulanate (Augmentin) combines the β-lactam with a β-lactamase inhibitor that expands the spectrum of activity. This combination can be used for sinusitis and urinary tract infections.
The extended spectrum penicillins are also safe, but they are much more expensive and generally not used as first-line agents for most disorders during pregnancy. The cephalosporins are safe and used for urinary tract infections, including pyelonephritis, and for gonorrhea.
The penicillins can be used safely during breast-feeding.
Clindamycin
Clindamycin is a macrolide and acts on the bacterial ribosome preventing transcription. It can be used to treat bacterial vaginosis, although metronidazole is the first-line medication. It generally is reserved for anaerobic infections that are not sensitive to other agents. Up to 10% of patients will develop pseudomembranous colitis. Clindamycin is safe during breast-feeding.
Metronidazole
Metronidazole inhibits bacterial protein synthesis. It is used to treat trichomonas and bacterial vaginosis. This agent was found to be positive in the Ames test but has not been proven to be carcinogenic in humans, nor has it been shown to produce birth defects. Although some authorities suggest deferring use past the first trimester, there are no data supporting this suggestion. This medication is safe in breast-feeding, although the American Academy of Pediatrics recommends interrupting breast-feeding for 12 to 24 hours following a 2-gram dose.
Aminoglycosides
Aminoglycosides inhibit bacterial protein synthesis. They can be used to treat pyelonephritis but should be used only when serious gram-negative infection is suspected. Maternal administration has been associated with ototoxicity in the fetus leading to hearing loss. Breast-feeding is safe, because little drug passes to the neonate via the breast milk.
Trimethoprim-sulfamethoxazole
This combination (Bactrim or Septra) inhibits folic acid metabolism and is very active against many organisms that cause urinary tract infections. No definite teratogenic effects have been described, but in 2,296 Michigan Medicaid recipients, first-trimester trimethoprim exposure was associated with a slightly increased risk of birth defects, particularly cardiovascular, and in a retrospective study, the odds ratio was 2.3. Given this and the mechanism of action via the folate pathway, avoidance in the first trimester is prudent. It displaces bilirubin from its protein binding sites in the neonate, potentially contributing to an increased risk of hyperbilirubinemia or kernicterus in newborns. Therefore, it should not be used close to delivery. This theoretic effect has not been substantiated in clinical trials. Trimethoprim-sulfamethoxazole has been used to treat otitis, sinusitis, Shigella colitis, and Pneumocystis carinii infections, in addition to both asymptomatic bacteriuria and acute cystitis. Use of this medication is safe during breast-feeding.
Nitrofurantoin
Nitrofurantoin inhibits bacterial protein and cell wall synthesis. It is eliminated by excretion, and this bactericidal activity makes it highly effective in treating uncomplicated lower urinary tract infections. It can induce hemolytic anemia in patients with glucose 6-phosphate dehydrogenase deficiency and, because the newborn's red blood cells are deficient in reduced glutathione, the label carries a warning against use of the drug at term. However, hemolytic anemia in the newborn after exposure before birth has not been reported. This medication is compatible with breast-feeding.
Erythromycin
Erythromycin and azithromycin inhibit bacterial protein synthesis. They often are used as an alternative to the penicillins and are first-line treatment for mycoplasma and chlamydia infections. These medications also are useful in treating community-acquired pneumonia or severe bronchitis. Use of both erythromycin and azithromycin are compatible with breast-feeding.
Antiviral Agents
The emergence of the human immunodeficiency virus and acquired immunodeficiency syndrome has resulted in development of many antiviral agents. Previously, herpes was one of the few viral infections for which pregnant women might be exposed to treatment (Table 7.2).
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TABLE 7.2. Antiviral agents in pregnancy |
Acyclovir and Valacyclovir
Acyclovir (Zovirax) has resulted in no fetal abnormalities in 601 exposures reported. The Centers for Disease Control and Prevention recommends that pregnant women with disseminated infection (e.g., herpes, hepatitis, or varicella pneumonia) be treated with acyclovir. No human studies during pregnancy have been carried out with famciclovir.
Human Immunodeficiency Virus Treatment
A variety of agents may be used to treat patients with human immunodeficiency virus infection. The medications generally fall into three categories, the nucleoside reverse transcriptase inhibitors (nRTIs), the nonnucleoside analog reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs). Zidovudine is the most widely studied nRTI, and no adverse effects have been seen over 4 years of follow-up. In the same class of medications, didanosine, stavudine, and lamivudine also seem to be safe. Nevirapine, an NNRTI, has had no reported adverse effects. The PI class has not been as extensively studied.
UPPER RESPIRATORY TRACT COMPLAINTS
The common cold is the most frequent acute illness, and most are self-diagnosed and treated. Medicine used to treat symptoms associated with the common cold are among the most commonly used drugs in pregnancy. Most patients complain of fatigue, malaise, rhinorrhea, nasal congestion, cough, and sore throat. The cold can be caused by a variety of viruses, rhinoviruses, coronaviruses, respiratory syncytial virus, adenovirus, parainfluenza and influenza viruses, and others. Therefore, in the absence of a complicating superinfection with bacteria, antibiotic treatment is not appropriate.
The most common treatments are used to alleviate the symptoms listed above and include antihistamines, decongestants, and cough remedies.
Antihistamines
Most antihistamines are safe during pregnancy. Brompheniramine (Bromfed) was associated with an increased relative risk of malformations in the Collaborative Perinatal Project but not the Boston Collaborative Drug Surveillance Program. Other safe antihistamines include chlorpheniramine, clemastine, diphenhydramine, and doxylamine.
There are newer antihistamines with little or no data in pregnancy and are best used as second-line therapy. These include astemizole (Hismanal), cetirizine (Zyrtec), loratadine (Claritin), and fexofenadine (Allegra).
Decongestants
The most common oral decongestants are all sympathomimetic agents and include pseudoephedrine, phenylephrine, and phenylpropanolamine. There have been some reports of an association with gastroschisis and first-trimester maternal exposure to pseudoephedrine. In the first trimester, an alternative would be to try use of topical preparations, including the nasal decongestants oxymetazoline (Afrin) and phenylephrine (Neo-Synephrine).
Cough Suppressants
Codeine and dextromethorphan are the most common cough suppressants. Neither has been associated with a teratogenic effect.
Most cold treatments including the antihistamines, decongestants, and cough suppressants are safe during breast-feeding.
ASTHMA TREATMENT
Although the cold is the most common acute illness during pregnancy, asthma is the most common chronic respiratory condition. About 5% of pregnancies are complicated by asthma, and it may cause increases in preterm birth, low birth weight, and other complications. Whether aggressive and active management reduces these risks to the background level is a controversial issue. Asthma is characterized by airway inflammation and hyperreactivity.
Treatment of the asthmatic should start with reduction of environmental factors that worsen the disease. All patients should receive the influenza vaccination yearly. Allergens should be avoided, as should both active and passive exposures to cigarette smoke. For patients who do not respond optimally to these environmental alterations, a variety of pharmacologic treatments are available (Table 7.3).
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TABLE 7.3. Medications to treat asthma |
β-Sympathomimetic Agents
The short-acting β-sympathomimetic agents are the first-line treatment for acute asthma exacerbations. Albuterol inhalers (Proventil, Ventolin) are commonly used. Terbutaline and metaproterenol inhalers are acceptable alternatives. No teratogenic risks have been ascribed to these medications and all are compatible with breast-feeding. For longer term treatment salmeterol, a long-acting β-sympathomimetic agent, is available and safe.
All of the β-sympathomimetic agents can cause tachycardia and other cardiovascular effects. These are usually mild and self-limited.
Glucocorticoids
Inhaled glucocorticoids are also first-line therapy. They act by reducing inflammation. Agents include beclomethasone, fluticasone, and others. No teratogenicity for inhaled steroids has been seen, and they are compatible with lactation.
Systemic glucocorticoids also can be used for acute exacerbations but may increase the risk for cleft lip and palate up to five-fold.
Theophylline
Theophylline was at one time a first-line agent for treatment of asthma, but with the emergence of the β-agonists and inhaled glucocorticoids, its role has been reduced markedly. This agent can be administered intravenously for acute asthma or orally for chronic suppression. The narrow therapeutic window has contributed to this medication falling out of favor. Used for many years, theophylline has shown no evidence of teratogenicity, and it can be used during breast-feeding.
Cromolyn Sodium
Cromolyn sodium is used for long-term therapy in patients with atopy, functioning as a mast cell stabilizer. Administered by inhaler, there are no known teratogenic or lactation concerns.
Leukotriene Receptor Antagonists and Lipoxygenase Inhibitors
The leukotriene receptor antagonists (zafirlukast, montelukast) and the 5-lipoxygenase inhibitors affect the inflammatory pathways. These agents are new, and human data are few to none. Given sparse data, if these agents can be avoided during pregnancy and lactation, other drugs should be used.
GASTROINTESTINAL DISORDERS
Gastrointestinal problems are extremely common in pregnancy and include nausea, vomiting, hyperemesis gravidarum, gastroesophageal reflux, intrahepatic cholestasis of pregnancy, and inflammatory bowel disease. The clinical picture of several serious disorders may be altered or overlooked during pregnancy and include appendicitis, cholecystitis, pancreatitis, hepatitis, and carcinoma of the gastrointestinal tract.
Nausea and vomiting, or morning sickness, occurs in as many as 90% of pregnancies. Nonpharmacologic treatment can include acupressure at the Neiguan point (2 inches proximal to the wrist crease between the tendons of the flexor carpi radialis and palmaris longus muscles), which may be of benefit. Ingestion of ginger appears to reduce nausea and vomiting in pregnancy. Pyridoxine, vitamin B6, also appears to reduce symptoms. Pharmacologic treatment can include use of antihistamines, antidopaminergics, and other agents (Table 7.4).
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TABLE 7.4. Drugs commonly used for management of nausea, vomiting, and hyperemesis gravidarum |
Antihistamines
Doxylamine (Unisom) is an antihistamine that was a component of Bendectin (doxylamine and pyridoxine). An effective treatment for the nausea and vomiting of pregnancy, Bendectin was withdrawn from the American market in 1983 because of unproved allegations that it increased the risk of malformations. Doxylamine can be combined with pyridoxine, reconstituting the two active ingredients of Bendectin. Other commonly used antihistamines include dimenhydrinate (Dramamine); diphenhydramine (Benadryl); hydroxyzine (Vistaril, Atarax), which has both antianxiety and antihistamine properties; and promethazine (Phenergan), which has a central cholinergic blocking activity.
Antidopaminergic Agents
Several antidopaminergic agents have been used in pregnancy and are probably safe. The list includes prochlorperazine (Compazine), metoclopramide (Reglan), chlorpromazine (Thorazine), perphenazine (Trilafon), droperidol (Inapsine), and haloperidol (Haldol). There tend to me more maternal side effects with these medications than with the antihistaminic agents. There are also some conflicting data about possible minimal increased risks of birth defects with the latter members of the group. I tend to suggest use of the prochlorperazine or metoclopramide as first-choice agents in this class. These agents are probably safe in breast-feeding, but some require observing the neonate for sedation.
Other Agents
Trimethobenzamide (Tigan), which provides nausea inhibition at the chemoreceptor level, and ondansetron (Zofran) have been used, but there is less experience with these agents, and certainly the latter is much more expensive with no greater efficacy than standard antihistamines.
Reflux or heartburn is a common complaint during pregnancy, particularly in later gestation. Up to 80% of women may have some symptoms of reflux or heartburn. As with hyperemesis, starting with the least invasive environmental or lifestyle changes is prudent. Advice includes elevation of the head of the bed while sleeping, wearing loose clothing, eating frequent small meals that are low in fat, and cessation of smoking. Antacids would then be the first-line therapy (Table 7.5) and are not known to be associated with any fetal risk. The next class of agents is the histamine receptor antagonists, which can have a reduced bioavailability following antacid use. Therefore, the antacids and the histamine receptor antagonists should be given at least 1 hour apart. The histamine antagonists include cimetidine (Tagamet), famotidine (Pepcid), ranitidine (Zantac), and nizatidine (Axid). There are limited data concerning nizatidine, so the first three would be initial choices. All are compatible with breast-feeding. Promotility drugs can be used and include metoclopramide (described above) and cisapride (Propulsid), about which little has been reported. Sucralfate (Carafate) inhibits pepsin activity and may improve symptoms. The proton pump inhibitors are relatively new agents and, therefore, I would not recommend them. Misoprostol, a prostaglandin E1 analog, is contraindicated in pregnancy.
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TABLE 7.5. Drugs commonly used for gastroesophageal reflux in pregnancy |
Intrahepatic cholestasis of pregnancy causes itching of the extremities, trunk, palms, and soles. The pruritus can worsen at night and become severe. In the past, cholestyramine (Questran) was the treatment of choice. Cholestyramine is a nonabsorbable anion exchange resin that binds bile acids, which are elevated in cholestasis. There is now some evidence that ursodeoxycholic acid (UDCA, ursodiol), a minor, naturally occurring hydrophilic bile salt, both reduces maternal pruritus and improves biochemical abnormalities without obvious adverse effects on the newborn. Evidence is accumulating from controlled clinical trials that UDCA is safe. When intrahepatic cholestasis is diagnosed, UDCA coupled with close maternal fetal surveillance is indicated due to potential increases in spontaneous preterm delivery, fetal distress with meconium staining of amniotic fluid, and fetal death.
Inflammatory bowel disease in the form of ulcerative colitis and Crohn disease occur commonly during the reproductive years. Sulfasalazine (Azulfidine) is used for the treatment of both ulcerative colitis and Crohn disease. It is composed of 5-aminosalicylic acid and sulfapyridine. It is poorly absorbed from the gastrointestinal tract and is therefore safe in pregnancy. There is a potential for side effects if used during breast-feeding, so the American Academy of Pediatrics cautions women about use of sulfasalazine during lactation. Mesalamine (Asacol) also can be used during pregnancy and may have fewer maternal side effects than the sulfasalazine. Azathioprine is an immunosuppressant and appears safe to use during pregnancy.
ANALGESIC USE
Analgesics, both by prescription and over-the-counter purchase, are among the most commonly used medicines in pregnancy. This class of drugs basically falls into two categories, the nonsteroidal antiinflammatory agents and the opioid family.
Nonsteroidal Antiinflammatory Drugs
Aspirin is one of the nonsteroidal antiinflammatory drugs (NSAIDs) and acts by irreversible inhibition of enzymes in the prostaglandin synthesis pathway. Caution certainly should be advised in use of aspirin beyond the lowest daily dosages, because this drug readily crosses the placenta. First-trimester use has been associated with an increased risk of gastroschisis. Although dosages at or below 100 mg per day have been studied to determine whether there is a reduction in preeclampsia or intrauterine growth restriction without complications, higher dosages have been associated with increased risk of placental abruption. The World Health Organization Working Group on Human Lactation and the American Academy of Pediatrics Committee on Drugs both raise concern about maternal use of aspirin while breast-feeding.
Indomethacin and ibuprofen are commonly used NSAIDs that cause competitive and reversible inhibition of prostaglandin synthesis. These NSAIDs can cause constriction of the fetal ductus arteriosus as gestational age progresses and, therefore, their use is not suggested after about 32 weeks gestation. They have not been shown to cause malformations, but use beyond the first trimester can cause oligo- or anhydramnios secondary to direct renal effects. Both indomethacin and ibuprofen are considered compatible with breast-feeding.
Acetaminophen is widely used in pregnancy. It crosses the placenta but is considered safe in the usual dosages. It can be used routinely in all trimesters to relieve pain and lower fevers. It is usually the analgesic of choice for a wide variety of aches, pains, and headaches. It is compatible with breast-feeding.
Opioid Analgesics
Many narcotic preparations are available and are used during pregnancy. They all cross the placenta but have not been associated with malformations when used in usual dosages. Use close to delivery can result in neonatal depression. The common narcotics, codeine, meperidine, and oxycodone, are all compatible with breast-feeding.
PSYCHIATRIC DISORDERS
Major depression (15% incidence) and schizophrenia (8%-10% incidence) are very common during the reproductive years. As with any medication, there are concerns about teratogenesis, neonatal withdrawal, or long-term neurobehavioral effects, but these issues must be balanced by the risks to the mother and fetus or infant of withdrawing the necessary medication (Table 7.6).
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TABLE 7.6. Starting dosages for psychotropic medications in pregnancy |
The tricyclic agents have been widely used to treat depression and also anxiety, obsessive compulsive disorders, migraines, and other problems. None of the tricyclics has been associated with malformations. If needed, it would be prudent to use the agents with the most accumulated experience, including nortriptyline, desipramine, amitriptyline, and imipramine. There is no evidence to date of clear adverse neonatal effects during breast-feeding, but the American Academy of Pediatrics considers the effects of amitriptyline and imipramine unknown but of concern for the nursing infant.
The selective serotonin reuptake inhibitors (SSRIs) include fluoxetine and the newer agents, fluvoxamine, paroxetine, and sertraline. Extensive experience with fluoxetine shows no clear increased risk of malformations. There is much less experience with the newer agents, but none of the data indicates a teratogenic effect. The effects on the infant of the group of drugs that includes fluoxetine are unknown but may be of concern in relation to breast-feeding. The patient should weigh the strength of her desire to breast feed and the benefits of breast-feeding against the potential effects of continued SSRI use.
Other agents are prescribed for depression. Monoamine oxidase inhibitors have not been studied sufficiently to draw a conclusion about their safety. The psychostimulants may cause problems following in utero exposure and are best avoided. St. John's wort, an extract of the plant Hypericum perforatum, has been touted for antidepressant properties, but recent studies have not proven efficacy, so this medication should also be avoided.
The mood stabilizers, specifically lithium, valproic acid, and carbamazepine, have all been identified as teratogens. The data on lithium causing malformations have weakened with additional studies. Initial reports found a 5% to 10% risk of malformations with a markedly increased risk of Ebstein anomaly. More recent reports show little, if any, increased risk of malformation and have failed to confirm the specific association with Ebstein anomaly. For the patient with a first-trimester exposure to lithium, targeted ultrasonography in the second trimester is warranted. Lithium also has been associated with hydramnios, possibly secondary to fetal diabetes insipidus. Although there is little data, the American Academy of Pediatrics considers lithium to be contraindicated during lactation.
Valproic acid and carbamazepine are both associated with an increased risk of neural tube defects, so second-trimester serum screening for α-fetoprotein and targeted ultrasonography are warranted. Yet many of the neural tube defects are closed and difficult to detect.
The antianxiety agents generally fall into the benzodiazepine family. There have been reports of an increased risk of cleft lip after exposure not substantiated in other reports. Although the odds ratio may have been increased, the absolute rate of clefting would still be low given a rate of only 0.06% in the normal population. The American Academy of Pediatrics states that the effects on the neonate during lactation are unknown but may be of concern.
The antipsychotic agents include the butyrophenones (including haloperidol) and phenothiazines. No clear teratogenic effect has been seen with either group. Haloperidol is classified as having an unknown but possibly concerning effect if used during lactation.
VITAMIN AND MINERAL USE
Prenatal use of multivitamins, often with additional iron, is commonly advocated by many health care providers for pregnant women. There is clear evidence that the folate component reduces the first occurrence and recurrence rate of neural tube defects. Other studies point to possible reduction in cardiac and urinary tract abnormalities. For the woman who eats a balanced diet, most of the recommended daily allowances should be obtained except for folate and iron. However, there are multiple at-risk populations that may not attain the goals, including those patients with eating disorders, vegetarians, the poor, substance abusers, women carrying multiple gestations, and so on.
The only clear teratogenic vitamin is vitamin A which, when used at over 10,000 IU per day, can cause cranial neural crest anomalies. It would be prudent to not exceed 5,000 IU per day in supplementation.
Supplementation of iron can improve hematocrit at the time of delivery and 6 weeks postpartum. Some studies have shown a benefit of calcium in reducing the risk of gestational hypertension and preeclampsia, although other studies fail to confirm this finding. Zinc may increase birth weight and head circumference in populations with zinc deficiency, but probably not in the United States.
RECREATIONAL DRUG USE
Recreational drug use is a major problem in the United States. Anonymous testing studies have found rates of positivity from 7.5% to over 13% in a variety of populations, the drugs found including opiates, cocaine, or cannabinoids.
As concerning as the illicit drugs are, the effects of tobacco also are well described and of great impact. Some studies suggest that one sixth of low birth weight incidence could be prevented if women stopped smoking during pregnancy. Nicotine reduces uteroplacental blood flow and increases the risk of preterm birth, low birth weight, and sudden infant death syndrome.
Maternal alcohol use can cause the fetal alcohol syndrome characterized by craniofacial changes and impaired cognitive development. Although the full-blown picture can be seen with excessive consumption, no safe level of alcohol use has been established.
The effects of recreational opioid use appear to be confined to an increased risk of growth restriction, intrauterine fetal death, and neonatal withdrawal. No clear long-term effects have been proven.
Marijuana use during pregnancy has not been linked with any clear teratogenic effect or long-term developmental consequences.
Cocaine use has been associated with an increased risk of placental abruption, preterm premature rupture of membranes, and low birth weight. A variety of congenital abnormalities have been described with maternal cocaine use, but no definite connection has been established. A variety of neurobehavioral effects have been described also, but long-term problems are not clear.
Amphetamine, described as a stimulant for depressed patients, is becoming a commonly abused drug. Although no clear pattern of malformations has been seen, increases in cleft lip and palate have been seen in some, but not all, studies. Concern has been raised about impact on long-term physical growth and intellectual and behavorial development.
ANTICONVULSANT AGENTS
Epilepsy is the most common neurologic disorder in pregnancy. Five percent of the population report having had a seizure at some point in their lives. All antiepileptic drugs (AEDs) cross the placenta and, therefore, have potential for teratogenicity (Table 7.7). Given the incidence of epilepsy, 1 in 250 fetuses is exposed to an AED. Recent studies are making it clear that the AEDs are responsible for the congenital malformations found in the offspring of pregnant women with epilepsy, not the epilepsy, itself, as has been conjectured in the past.
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TABLE 7.7. Anticonvulsants |
Phenytoin (Dilantin) is a hydantoin AED. The fetal hydantoin syndrome includes a constellation of anomalies including craniofacial, limb, and neonatal growth and performance delays. The risk of teratogenicity is about 2 times the background risk. Phenytoin is compatible with breast-feeding.
Carbamazepine (Tegretol) causes a group of defects similar to the fetal hydantoin syndrome, in addition to the increased risk of spina bifida. The risk of spina bifida is about 0.5% to 1.0%. Carbamazepine is compatible with breast-feeding.
Phenobarbital is in the barbiturate class. It has been associated with findings similar to the hydantoin syndrome, as well as with congenital heart defects and orofacial clefting. Breast-feeding is acceptable unless the infant becomes sedated, in which case breast-feeding should be discontinued.
Valproic acid (Depakote) has a 1% to 2% risk of causing spina bifida. These neural tube defects tend to be in the lumbosacral area. Valproic acid use also has been associated with cardiac defects, orofacial clefting, and genitourinary anomalies. There is a fetal valproate syndrome that includes facial, central nervous system, and limb anomalies. Breast-feeding is permissible while using this medication.
Several newer AEDs have been developed and include felbamate, gabapentin, lamotrigine, and others. Many patients make their first visits to prenatal clinics while taking these medications and having completed the first trimester. We counsel them that, at present, there is no evidence of teratogenicity but that little information is available.
HEADACHES
Headache is a very common problem in pregnancy. Evaluation of headaches requires categorizing the headache as primary or secondary. Secondary headache is due to another condition such as flu, while in the primary category the headache, itself, is the disorder. Primary headaches include migraine, tension-type headache, and cluster headache. Criteria have been developed for differentiating these categories and include frequency, degree of pain, and location of pain.
Sumatriptan is a selective serotonin receptor agonist. There is no evidence that it is a human teratogen, based on limited numbers of patients reported to the Sumatriptan Pregnancy Registry maintained by GlaxoWellcome and patients who contacted a teratogen hotline. Even less data is available about three newer drugs in this class: naratriptan, zolmitriptan, and rizatriptan.
β-Adrenergic blockers, such as propranolol have been used as preventive therapy. β-Blockers, calcium channel blockers, and many of the antidepressants discussed earlier have been used as preventive therapy and appear safe in pregnancy and lactation.
ANTINEOPLASTIC AGENTS
Cancer is relatively common during pregnancy, complicating 1 in 1,000 to 1 in 1,500 pregnancies. The most common malignancies include carcinoma of the cervix and breast, lymphoma, melanoma, leukemia, and carcinoma of the ovary and colon. Chemotherapeutic agents act on rapidly dividing cells and are, therefore, potentially harmful to the fetal tissue. The trimester of exposure is, of course, critically important to what potential effect the drug may have. Teratogenesis is a concern in the first trimester, but impact on the continued development of the brain in the second and third trimester is of import. Delivery planning is also important, because both maternal and neonatal blood counts may be adversely affected by the chemotherapy. For the most part, chemotherapeutic drugs are secreted into the breast milk, making breast-feeding contraindicated for the woman receiving this therapy.
Many classes of drugs can be used as chemotherapy. The alkylating agents cross-link DNA. These drugs, including busulfan, chlorambucil, cyclophosphamide, and nitrogen mustard, are all considered teratogens in the first trimester. The antimetabolites are also teratogenic, possibly due to their effects on folic acid metabolism. This class includes aminopterin and methotrexate. Other antimetabolites that do not affect folic acid metabolism, such as the pyrimidine antagonist 5-fluorouracil, 6-mercaptopurine, and cytarabine, have much less frequently been associated with birth defects.
The taxanes, including paclitaxel, have not been used in pregnancy enough to comment on safety. Cisplatin has been used in pregnancy, but most experience is in the second and third trimesters. Growth restriction is common.
The therapy of a pregnant woman with cancer must be individualized and must be based on collaboration among the primary care provider, perinatologist, oncologist, and neonatologist.
ANTICOAGULATION
Thromboembolism is a leading cause of morbidity and mortality in pregnancy and postpartum. In is the second most common cause of pregnancy-related maternal mortality in the United States. Anticoagulation is used for thromboembolism, valvular heart disease, inherited thrombophilias, and acquired thrombophilias such as antiphospholipid antibody syndrome. The agents available (Table 7.8) are the coumarin derivatives, unfractionated heparin, and low-molecular-weight heparin (LMWH).
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TABLE 7.8. Anticoagulation in pregnancy |
Thromboembolism occurs in 0.5 to 3.0 of every 1,000 pregnancies. Treatment of acute deep vein thrombosis includes bed rest, elevation of the extremity to promote venous return, and heparin. Heparin is used with a target activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times control. For pregnant patients, a switch to subcutaneous heparin takes place after 3 to 5 days, as opposed to the initiation of warfarin in the nonpregnant state.
Anticoagulation in a patient with artificial heart valves can be a difficult dilemma. For those with particularly thrombogenic valves it may be necessary to consider oral anticoagulation. For the inherited and acquired thrombophilias, use of unfractionated or LMWH probably is acceptable.
Use of the oral anticoagulant warfarin sodium (coumadin) is problematic, because there is a known teratogenic effect. This agent easily crosses the placenta. Warfarin depresses the vitamin K-dependent clotting factors (II, VII, IX, and X). Its effectiveness is measured by the prothrombin time (PT), expressed as an international normalized ratio (INR). The first case of teratogenicity of warfarin was reported in 1966, and this infant had nasal hypoplasia, bilateral optic atrophy, blindness, and mental retardation. In a review of all published cases up to 1980, one sixth had abnormalities, and another one sixth ended in stillbirth or spontaneous abortion. Two thirds of exposed pregnancies had a normal outcome. Some reports cite a teratogenic effect in up to two thirds of fetuses exposed between 6 and 12 weeks gestation. Other reports state that the embryopathy affects as few as 5% to 10% of fetuses exposed in the first trimester. The problem is in differing dosages and nature of neonatal evaluation.
It appears that neither unfractionated heparin nor LMWH crosses the placenta to any appreciable degree and is, therefore, not teratogenic. Patients can develop heparin-induced thrombocytopenia at about 2 weeks after initiation of therapy. Osteopenia is a problem with prolonged use. Both of the latter complications are more common with unfractionated heparin.
All three classes of anticoagulants are compatible with breast-feeding.
RADIOLOGIC EXAMINATIONS
Many women require diagnostic imaging studies during pregnancy. The two main concerns are exposure to ionizing radiation and effects of contrast agents. The vast majority of data derives from relatively few pregnant women exposed to high doses of radiation from the atomic bombs dropped over Hiroshima and Nagasaki. From these few individuals it has been extrapolated that there is a threshold dose of at least 5 rads required to cause concerning effect on the developing fetus. The particular effect depends on gestational age at exposure and radiation dose (Table 7.9). Lethality may be possible during preimplantation with doses as low as 5 rads, but by 9 days postconception at least 25 to 50 rads is needed. Malformations occur only between about 9 and 60 days postconception, and the threshold is at least 10 rads. Mental retardation is possible between 61 and 104 days postconception, with a threshold of 12 rads.
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TABLE 7.9. Risks of irradiation per gestational age |
Due to increasing concern about the escalating number of rads of exposure inherent in newer computed tomography (CT) technology, the University of Iowa Department of Radiology has developed a protocol to avoid unnecessary exposures and adequately counsel the pregnant patient. Counseling includes a discussion of a 1.5-fold to 2-fold increased risk in childhood leukemias for a 1-rad to 2-rad exposure in the midtrimester and into the third trimester. It is important to be aware of typical radiation exposures of commonly used examinations (Table 7.10) but also to enlist the expertise of a radiation physicist to assist in calculation of doses in specific cases.
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TABLE 7.10. Typical radiation exposure to the fetus for selected diagnostic studies (1 rad = 1,000 millirads) |
Nuclear medicine studies involve exposure to ionizing radiation from a variety of isotopes. In most cases the fetal dose will be less than 1 rad except for sodium iodide, Ga67, iodinated red blood cells, or Ti201. Iodine-131 can cause fetal thyroid damage, goiter, and local effects when concentrated by the fetal thyroid after 70 days post-LMP. Use of iodine-131 to treat hyperthyroidism or ablate the thyroid can result in substantial fetal dosage.
The most widely used radioisotope in pregnancy is technetium-99. It can cross the placenta, but the amount of radiation from any routine study is small.
Magnetic resonance imaging (MRI) involves exposure to magnetic fields rather than ionizing radiation. There are few studies evaluating the effects of MRI on fetuses. There are also virtually no data on gadolinium, a nonionic contrast agent typically used for MRI evaluations. For this reason, MRI is reserved for situations when it clearly is clinically warranted.
COMPLEMENTARY AND ALTERNATIVE THERAPY
Complementary and alternative therapy includes acupuncture, acupressure, massage, aromatherapy, and herbal preparations (phytomedicine). A wide variety of herbs are used but they have received limited scientific evaluation. Thus, safety and efficacy cannot be addressed clearly. Certain ingredients should be avoided altogether and include anthraquinone and berberine, which may stimulate uterine contractions. Many other herbs are thought to have similar properties and should be avoided. Patients should be queried about use of complementary medicines. An effort should be made to determine the constituents of a preparation and then evaluate the safety of each component.
SUMMARY POINTS
· Disease treatment in the pregnant patient should be similar to that given to other patients.
· Rather than using the FDA Drug Classification System, references and information in databases should be sought for particular medications in specific clinical situations.
· Most drugs are safe to use during pregnancy, including most antibiotics and medications to treat common conditions, such as upper respiratory tract and gastrointestinal complaints.
· A few medications are known teratogens, and the list includes coumadin, lithium, the anticonvulsive medications, several antineoplastic drugs, and vitamin A and its derivatives.
· Most drugs are safe during lactation because the amounts that appear in breast milk are subtherapeutic, approximately 1% to 2% of the maternal dose. One notable exception is lithium.
USEFUL DATABASES AND WEB RESOURCES
REPROTEXT, REPROTOX, TERIS, and Shepard's Catalog of teratogenic agents are useful resources. These and other databases can be purchased and installed in personal computers.
http://www.reprotox.org/. Accessed December 6, 2002.
http://depts.washington.edu/terisweb/. Accessed December 6, 2002.
http://www.rxlist.com/. Accessed December 6, 2002.
http://www.perinatology.com/exposures/druglist.htm
Organization of Teratology Information Services, http://orpheus.ucsd.edu/otis/links.htm
American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–150.http://www.aap.org/policy/0036.html
The Organization of Teratology Information Services has a collection of fact sheets on exposure during pregnancy to a variety of diseases, medications, and herbal remedies.
http://www.OTISpregnancy.org/fact_sheet.htm. Accessed December 6, 2002.
General information regarding drugs and medications during pregnancy:
http://www.vh.org/Patients/IHB/ObGyn/MedicinesPregnancy.html. Accessed December 6, 2002.
http://www.perinatology.com/exposures/druglist.htm. Accessed December 6, 2002.
http://www.motherisk.org. Accessed December 6, 2002.
The National Library of Medicine, http://www.ncbi.nlm.m.nih.gov/PubMed/
The National Center for Complementary and Alternative Medicine, http://nccam.nih.gov/
The NIH Office of Dietary Supplements, http://dietary-supplements.info.nih.gov/
The American Botanical Council, http://www.herbalgram.org/ Accessed December 6, 2002.
The Richard and Hinda Rosenthal Center for Complementary and Alternative Medicine, http://www.rosenthal.hs.columbia.edu/
A drug name and “pregnancy” or “lactation” can be entered into a search engine such as Dogpile (www.dogpile.com) or Google (www.google.com).
RECOMMENDED READINGS
Altshuler LL, Cohen L, Szuba M, et al. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry1996;153:592–606.
American Academy of Pediatrics, Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137.
American College of Obstetricians and Gynecologists. Complementary and alternative medicine. ACOG Committee Opinion No. 227, Nov 1999.
American College of Obstetricians and Gynecologists. Guidelines for diagnostic imaging during pregnancy. ACOG Committee Opinion No. 158, Sept 1995.
American College of Obstetricians and Gynecologists. Management of herpes in pregnancy. ACOG Practice Bulletin No. 8, Oct 1999.
Bennet PN, ed. Drugs and human lactation. New York: Elsevier, 1988.
Berg CJ, Atrash HK, Koonin LM, et al. Pregnancy-related mortality in the United States, 1987–1990. Obstet Gynecol 1996;88:161–167.
Buehler BA, Delimont D, van Waes M, et al. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990;322:1567–1572.
Creizel A. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet 1996;62:179–183.
Delgado-Escueta AV, Janz D. Consensus guidelines: preconceptional counseling, management, and care of the pregnant woman with epilepsy. Neurology1992;42[Suppl 5]:149–160.
Hansen WF, Yankowitz J. Pharmacologic therapy for medical disorders during pregnancy. Clin Obstet Gynecol 2002;45:136–152.
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalalgia 1988;8:1–96.
Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med1996;335:468–474.
Institute of Medicine: Committee on Nutritional Status During Pregnancy and Lactation. Food and Nutrition Board. Nutrition during pregnancy: Part I, weight gain: Part II, nutrition supplements. Washington, DC: National Academy Press, 1990.
National Asthma Education Program. Management of Asthma during Pregnancy. Report of the Working Group on Asthma and Pregnancy, 1993. Pub No. NIH 93-3279.
Schatz M, Zeiger RS, Harden K, et al. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100:301–306.
Schoenfeld A, Bar Y, Merlob P, et al. NSAIDs: Maternal and fetal considerations. Am J Reprod Immunol 1992;28:141–147.
Shepard TH. “Proof” of human teratogenicity. Teratology 1994;50:97–98.
Teratology Society Public Affairs Committee. FDA Classification of drugs for teratogenic risk. Teratology 1994;49:446–447.
The North American Pregnancy and Epilepsy Registry. A North American Registry for Epilepsy and Pregnancy, a unique public/private partnership of health surveillance. Epilepsia 1998;39:793–798.
Watts DH. Management of human immunodeficiency virus infection in pregnancy. N Engl J Med 2002;346:1879–1891.
Yankowitz J, Niebyl JR, eds. Drug therapy in pregnancy, third ed. New York: Lippincott Williams & Wilkins, 2001.
