How is drug safety during pregnancy determined in the absence of definitive evidence, and what are the best resources for clinicians and women?
| Response from Joanna M. Pangilinan, PharmD
Pharmacist, Department of Pharmacy, University of Michigan, Ann Arbor
You may be surprised how common it is for women to take medications during pregnancy. Mitchell and colleagues found that over 70% of women take at least 1 over-the-counter (OTC) or prescription medication during the first trimester of pregnancy, and about 50% take at least 1 prescription medication during pregnancy. Over the past 3 decades, medication administration during the first trimester has increased dramatically: Use of 4 or more medications has tripled, and use of prescription medications has increased over 60%.[1,2]
Determination of fetal risk associated with medication use can be complex. Even with available data from human and animal studies, case reports, postmarketing surveillance, and voluntary reporting systems, clinical information often is lacking. Adam and colleagues found that the fetal risk of over 95% of medications approved in the past 10 years, if taken during pregnancy, was "undetermined."
Some of the factors that influence the amount of fetal exposure to medications include maternal drug pharmacokinetics, drug pharmacology, active transport of drug with respect to placental circulation, and fetal clearance. Consequences of drug exposure and fetal risk may depend on embryonic state; drug use during the first trimester, the period of organogenesis, is potentially the most teratogenic.
Although prescription and OTC medications are tested for general safety before approval, most drug trials, with the exception of those for conditions specific to pregnancy, actively exclude pregnant women and remove women from investigation if pregnancy occurs. Testing on pregnant animals may be done for some medications, but these results may not always be relatable to human processes and development. Thus, information regarding the safety of prescription and OTC medication use on the growing fetus is sparse, particularly for drugs that are newly available on the market. In addition, animal testing may not be performed on OTC medications or dietary supplements, rendering safety determinations even more challenging for such agents. Women should be counseled that safety information and general guidance regarding OTC medication use during pregnancy can be found on the Drug Facts label.
Clinicians should consult many sources when evaluating the safety of medication use during preconception and pregnancy. Most clinicians are probably familiar with the fetal risk categories (A, B, C, D, and X) developed by the US Food and Drug Administration (FDA).
Table 1. FDA Pregnancy Category Definitions
|A||AWC 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).|
|B||Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no AWC studies in humans, and the benefits of use of the drug in pregnant women may be acceptable despite its potential risks. Or, animal studies have not been conducted and there are no AWC studies in humans.|
|C||Animal reproduction studies have shown an adverse effect on the fetus, there are no AWC studies in humans, and the benefits of use of the drug in pregnant women may be acceptable despite its potential risks.|
|D||There is positive evidence of human fetal risk on the basis of 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 (eg, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective).|
|X||Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk on the basis of 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 (eg, safer drugs or other forms of therapy are available).|
AWC = adequate and well-controlled; FDA = US Food and Drug Administration. Adapted from FDA. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Fed Regist. 2008;73:30831-30868. https://www.gpo.gov/fdsys/pkg/FR-2008-05-29/pdf/E8-11806.pdf Accessed March 18, 2013.
However, a new system has been proposed to replace fetal risk categories, owing to limitations in the accuracy and consistency of the description of risk and benefit. Product labeling is proposed to contain a fetal risk summary and lactation risk summary to better aid the clinician on prescribing decisions. Clinicians can review a fictitious example here; the date for release of this new system is unknown.
Product labeling is an important resource. In addition, excellent online resources to guide safe use during pregnancy are listed in Table 2. Such tools as patient information in Spanish, may also be available on certain sites. Clinicians may also refer to textbook references, such as Drugs in Pregnancy and Lactation (Lippincott Williams & Wilkins, 2011) and Drugs for Pregnant and Lactating Women (Saunders Elsevier, 2009). Online subscription services include Reprorisk® from Micromedex®, REPROTOX®, and TERIS. A literature search for newly published information also may provide important information not found elsewhere.
Table 2. Selected Online Resources for Safe Use of Medication During Pregnancy
|Type of Information||Website Overview|
|CDC: Pregnancy Information for Healthcare Providers and Researchers||Lists comprehensive resources on pregnancy issues, such as prenatal, maternal, and pediatric medical and preventive care.|
|National Center on Birth Defects and Developmental Disabilities||Provides resources on prenatal care, infant and child development, disabilities, and blood disorders.|
|CDC: Spotlight scientific articles on medications in pregnancy||Lists "spotlight articles" on medication use in pregnancy, disease management during pregnancy, and clinical guidelines.|
|Motherisk||Healthcare professional-oriented site that provides such resources as information on safe medication use during pregnancy and breastfeeding and a link to clinical trials evaluating specific medications or disease states during pregnancy.|
|National Birth Defects Prevention Study||A study that seeks to determine causes of birth defects.|
|MotherToBaby||A service of OTIS that provides evidence-based information on medications and exposures during pregnancy and lactation.|
|US National Library of Medicine, Toxicology Data Network (TOXNET): Developmental and Reproductive Toxicology Database (DART)||Allows searching of drugs or outcomes (eg, neural tube defect) in the reproductive and developmental toxicology literature.|
|CDC: Digital Press Kit -- Safe Medication Lists on the Internet||Promotional materials about questionable validity of safe medication use lists found on the Internet.|
|CDC: Medication Use During Pregnancy||Discusses how common medication use during pregnancy has become.|
|CDC: Information on vaccines in pregnant women||Provides general information for the patient regarding vaccine use during pregnancy.|
|CDC: Medication and Pregnancy||Offers general information for the patient regarding medication use and safety in pregnancy.|
|CDC: Birth Defects||Discusses topics on birth defects.|
|Motherisk||Patient-oriented site that provides general pregnancy and medication safety information.|
|FDA: Pregnancy||Gives medication, food, and product safety information to the patient during pregnancy.|
|Womenshealth.gov: Pregnancy||A project of the US Department of Health and Human Services Office on Women's Health that offers comprehensive guidance regarding optimal health for mother and baby before, during, and after pregnancy.|
|MedlinePlus: Pregnancy||A service of the US National Library of Medicine and National Institute of Health that provides comprehensive resource regarding health and other topics related to pregnancy.|
CDC = Centers for Disease Control and Prevention; FDA = US Food and Drug Administration; OTIS = Organization of Teratology Information Specialists
To increase the available safety data, clinicians are strongly encouraged to refer women who have taken or must take medications during pregnancy to pregnancy exposure studies. The Organization for Teratology Information Specialists (OTIS) is currently studying the effects of treatments for autoimmune diseases and asthma and vaccines during pregnancy. The ongoing National Birth Defects Prevention Study enrolls women in a case/control manner to help elicit potential risk factors for and causes of birth defects. A list of pregnancy exposure registries is available from the FDA.
Determination of fetal risk is often complex and challenging for clinicians. Women who are pregnant or are considering becoming pregnant should be counseled to discuss any medication (including OTC), dietary supplement, or herbal use with their healthcare professional. Resources are available to guide the clinician regarding potential risks and benefits of medications being considered for women who require drug therapy during pregnancy.
Medscape Pharmacists © 2013 WebMD, LLC
Cite this: Which Medications Are Safe During Pregnancy? - Medscape - Apr 22, 2013.