Drugs in Pregnancy and Lactation
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
The ideal time to address medication exposure and consider alternative treatment is prior to conception. Many pharmacologic agents have teratogenic potential as well as the potential to induce fetal harm later in gestation with effects that may be lethal or cause long-term handicaps. Many women will present already pregnant, thus providing a narrow window of time in which to evaluate the fetal risks and weigh them against the maternal benefits of continuing the medication. This chapter reviews the risks of commonly used medications during pregnancy, highlights medications with particularly high risk, and reviews the evaluation of fetuses who are exposed. (1)
Nearly all drugs cross the placenta to some degree. Placental transfer is related to the molecular weight, charge and lipid solubility of an agent. Fetal adverse effects from exposure to maternal medications depend on genetic susceptibility of the fetus, maternal metabolism, timing of exposure, and dose of the drug. Fetal development is often divided into three periods, during which the fetal effects of potential teratogens differ. Days 0 to 30 (from last menstrual period) are considered the "all-or-none" period. A significant exposure in this time period will either result in fetal loss or have no apparent effect on embryonic development. Days 30 to 71 are referred to as the "classic teratogenic" period. Organogenesis is occurring, and during these critical weeks of gestation, the developing organs are at risk of malformation from exposure to environmental influences that have teratogenic potential. The timing of exposure within this period is important, as the development of various organ systems occurs at different points within this 40-day time frame. For example, the critical period for cardiac development is days 33 to 54, while the highly sensitive period for development of external genitalia is days 60 to 78. The developmental period of fetal life begins on day 72 and ends at birth. While the structural formation of most organ systems is complete by day 71, growth is ongoing, and development of the central nervous system continues throughout the period and for the first few postnatal years. Exposure to pharmacologic agents that affect neurological development may have significant effects during this time period.
Each time a medication is prescribed to a pregnant woman, the benefits of its use must be weighed against the potential fetal risk, as well as the risk to mother and fetus of withholding treatment or using an alternate and potentially less effective agent.
Drug Risk Categories:
The United States Food and Drug Administration (FDA) has created a risk factor evaluation system consisting of five categories. These categories follow in the order of generally increasing fetal risk.
Category A: Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester, and there is no evidence of a risk in later trimesters. The possibility of fetal harm appears to be remote. The only commonly used agents classified as Category A are vitamins taken at or below the US Recommended Daily Allowance and levo-throxine, which does not cross placenta.
Category B: Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester, and there is no evidence of risk in later trimesters.
Category C: Either study in animals has revealed adverse effects on the fetus (teratogenic, embryocidal or other), and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
Most commonly used drugs are classified into Category B or C. In many cases, there is little useful data. An individualized decision is necessary for each patient.
Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). A good example of a Category D agent is phenytoin. While the fetal risks are recognized, the benefit of treating the maternal seizure disorder usually outweighs the potential fetal risk. The counseling around the use of phenytoin and other anticonvulsants in pregnancy is made more difficult by the fact that the risk of congenital anomalies appears to be increased in untreated epileptic women as well.
Category X: Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. Category X medications include the retinoids, etretinate and isotretinoin, thalidomide, and androgenic and estrogenic steroids.
Commonly Prescribed Medications:
Some of the medications commonly used in pregnant women are discussed below: (2)
Most antimicrobial agents are listed in FDA Category B or C. Extensive use of the penicillin and macrolide families of antibiotics has shown no evidence of fetal harm. Tetracycline and members of its family are considered FDA Category D agents, due to a risk for permanent staining of the fetal teeth and potential impairment of bone growth. Some studies have suggested that doxycycline is not a terotogen when used in the second and third trimesters of the pregnancy.
Metronidazole (Flagyl) is another agent whose use has been questioned in pregnancy, despite its status as an FDA Category B agent. Concerns about Metronidazole stem from its mutagenicity in bacteria and carcinogenicity in rodents; these concerns have not been substantiated in human pregnancy. Most authorities believe that oral metronidazole is the only appropriate therapy for bacterial vaginosis in pregnancy. In light of current knowledge regarding the association of bacterial vaginosis with an increased risk for preterm birth, it seems imprudent to withhold appropriate treatment during pregnancy, even in the first trimester.
Genital herpes simplex is a common sexually transmitted disease for which acyclovir or valacyclovir usually are prescribed. The studies have shown that there is neither an increased risk of congenital anomalies or spontaneous abortions among pregnancies followed prospectively nor a suspicious pattern of anomalies.
Major depression is common among women of reproductive age. While a number of antidepressant agents exist, current pharmacologic treatment of depression usually entails the use of a selective serotonin reuptake inhibitor (SSRI).
Tricyclic antidepressants are used less commonly due to their anticholinergic side effects. The studies have not shown antidepressants to be teratogenic.
Fluoxetine (Prozac) is the most commonly used antidepressant agent in the United States and the member of the selective serotonin reuptake inhibitor class for which the most reproductive data is available. The studies show the rate of congenital malformations and spontaneous abortions is not significantly different from the general population. However, long term follow-up is limited thus far, so it is unclear whether inhibition of serotonin reuptake could have effects on the developing brain that may only become manifest later in childhood. Finally, the data for the other members of this drug class is more limited, and the data for fluoxetine may or may not be applicable to these agents. The largest prospective studies of pregnancies exposed to fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft) showed no increased risk of congenital anomalies or spontaneous abortions.
Cough and Cold Medications:
Among the most frequent requests for medication advice during pregnancy are those for relief from the symptoms of the common cold. Over-the-counter medications are utilized most often. Acetaminophen is the antipyretic and mild analgesic of choice during pregnancy. Because of its lack of inhibition of prostaglandin synthetase, it does not have the potential to induce oligohydroamnios, constriction of the ductus arteriosus, or bleeding complications, as do aspirin and the nonsteroidal anti-inflammatory drugs. Nasal congestion is usually treated with oral pseudoephedrine (Sudafed), and a long history of use during pregnancy suggests that this is a low-risk agent. It is listed as a Category C agent. An alternative treatment for nasal congestion throughout pregnancy is the use of intranasal oxymetazoline or xylometazoline. When used according to instructions, systemic absorption and the potential for fetal effects are minimal. Cough is usually treated with a combination of guaifenesin and dextromethorphan. These agents are Category C. If needed for a severe or prolonged cough, a preparation containing codeine may be prescribed for several days use. Prescribers should be aware that a number of over-the-counter preparations contain significant quantities of ethanol.
Medication for Thyroid Disease:
Women with hypothyroidism will rarely be newly diagnosed during pregnancy because of the frequent association between hypothyroidism and oligomenorrhea. Most women will begin their pregnancy already taking thyroid replacement with levo-thyroxine. Pregnant hypothyroid women will generally require an increase in their levo-thyroxine dose as gestational age advances. Thyroid function should be followed each trimester. Levo-thyroxine does not cross the placenta and poses no risk of fetal harm.
Hyperthyroidism occurs in about 1% of women, with most cases caused by Grave's disease. Treatment during pregnancy centers around the administration of the lowest dose of a thioamide required to keep the free thyroxine (T4) at the upper limit of normal and the thyroid stimulating hormone (TSH) at the lower limit of normal. Using the lowest possible dose will help to avert the complication of fetal goiter. Because of altered physiology of pregnancy, it is not useful to follow total T4 or triiodothyronine (T3) or T3 resin uptake; the physiologic increase in T4-binding globulin may as much as double these values. Propylthiouracil has long been considered the drug of choice for treating hyperthyroidism in pregnancy. In women who are thyrotoxic or who exhibit thyroid storm, treatment with beta-adrenergic antagonists is frequently required to control tachycardia. Atenolol (Category D) and propranolol (Category C/D) are the most commonly used beta-blockers during pregnancy. Some reports link the use of these agents to the development of fetal growth restriction, bradycardia, and hypoglycemia. The risk to benefit ratio must be weighed carefully before treating with beta-blockers in pregnancy.
In general, women with chronic hypertension who have been diagnosed prior to pregnancy and started on treatment may continue their pre-pregnancy medications. The majority of antihypertensive drug classes are Category B or C, and long-term use has not demonstrated evidence of fetal adverse effects. This statement applies to the more commonly used antihypertensive agents, including calcium channel blockers and diuretics. The main exception to continuation of pre-pregnancy therapy is the angiotensin converting enzyme (ACE) inhibitors and by extension, the angiotensin receptor antagonists. These agents have not demonstrated evidence of risk with use in the first trimester but have been implicated in the development of oligohydroamnios, renal tubular dysplasia, skull defects, and profound anuria in the neonatal period. If ACE inhibitor use is identified late in pregnancy, it should be discontinued and fetal surveillance should be initiated.
Women with newly diagnosed chronic hypertension in pregnancy are usually started on alpha-methyldopa if treatment is necessitated by persistently elevated blood pressure above 160/100. This agent has long been the first choice in pregnancy because of its long record of use without evidence of fetal harm. More recently, agents such as the mixed alpha and beta antagonist, labetalol, are employed to treat hypertension in pregnancy, with beneficial effects and a notable lack of effect on uterine blood flow.
Exposure to Teratogens:
Maternal ingestion of certain medications is a recognized cause of growth restriction; the incidence and severity vary by substance, gestational age at exposure, duration of exposure, and dosage. Therapeutic agents known to be associated with growth restriction include anticonvulsants (eg, trimethadione, phenytoin), folic acid antagonists (eg, methotrexate), and warfarin (3). Most medications are easily absorbed during pregnancy, and serum concentrations of albumin for drug binding are lower than in the non-pregnant state. Pharmacokinetic changes during pregnancy include: higher volume of distribution; lower maximum plasma concentration; lower steady-state serum concentration; shorter plasma half-life; higher clearance rate. The small spatial configuration and high lipid solubility of most medications permit easy transfer of unbound concentrations of the drug in the fetal serum similar to the level in maternal serum -- sometimes even higher. A few drugs with high molecular weight do not cross the placenta in significant amounts (eg, glyburide, interferon, thyroid supplements, insulin). The Physician Desk Reference (PDR) is a common source of information about the use of prescription drugs in pregnancy (4). But be aware that, to avoid liability, pharmaceutical manufacturers do not encourage use of their drugs during pregnancy unless the benefit clearly outweighs the risk. It would be unrealistic for them to market a medication for specific use during pregnancy because it would require considerable time and cost, and raise ethical objections, to conduct research in a vulnerable population that is limited in number.
Prescribing strategies for your pregnant patients:
Few drugs are major teratogens, but heightened vigilance is crucial to protect your pregnant patient. Detrimental effects can occur beyond the critical embryo stage as cells continue to divide in the hematologic, reproductive, and central nervous systems. We also lack consistent information about long-term effects such as learning or behavioral problems (eg, functional teratogenesis) that may result from chronic prenatal exposure to a certain medication. First-trimester screening, chorionic villus sampling (CVS), maternal serum quadruple screening, amniocentesis, and fetal blood sampling are not predictive of a drug's fetal effects. Avoid prescribing multiple medications, if possible, and choose "safe" drugs from among the options in categories that include a number of teratogenic medications, such as anticonvulsants (5). Determine the best method to monitor therapy; for example, use a peak flow meter for asthma, a portable blood pressure monitor for hypertension, and so on. Focus on keeping the patient healthy; the healthiest mother is most likely to deliver the healthiest babies. Keep the underlying disorder in mind, as well as the drug, when choosing a drug. Know which drugs are clearly linked to birth defects -- these include phenytoin, warfarin, alcohol, methotrexate, diethylstilbestrol, cis-retinoic acid, valproic acid, and carbamazepine. Pay attention to the first trimester. Too little is known about the first-trimester effects of the vast majority of drugs for them to be considered safe.
Each prescribing decision must be made with a knowledge of the potential effects of the drug on the developing fetus, the risk to mother and fetus of withholding treatment, and the benefits to both of appropriate treatment. Most drugs do not demonstrate a consistent pattern of teratogenic effect, but the data is often limited and confounded by the effects of other medications, the underlying maternal illness, and other exposures such as tobacco and alcohol. For pregnant women or those planning a pregnancy, the best suggestion is to consult their healthcare provider before taking any medication.
- World Health Organization
Breastfeeding and Maternal Medications (pdf)
- March of Dimes
Drugs in Pregnancy and Breastfeeding
- American Council for Drug Education
Facts for Parents
- U.S. Food and Drug Administration
Reporting Adverse Experience to FDA
- Briggs GG, Freeman RK, Yaffee FJ. ReproTox Database. Vol. 13. No. 1. Bethesda, MD: Reproductive Toxicology Center; 2000
- Briggs GG, Freeman RK, Yaffee FJ. Drugs in Pregnancy and Lactation: Reference Guide to Fetal and Neonatal Risk. 7th ed. Baltimore: Williams & Wilkins; 2005
- ACOG Practice Bulletin. Exposure to Teratogens; In: Intrauterine Growth Restriction. Number 12, January 2000
- PDR for Nonprescription Drugs, Dietary Supplements, and Herbs. 28th ed. Montvale, NJ: Medical Economics: 2007
- Physician's Desk Reference: 62nd ed. Montvale, NJ: Medical Economics; 2008
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