Objective
The objective of the study was to provide information on overall medication use throughout pregnancy, with particular focus on the first trimester and specific prescription medications.
Study Design
The study design included the Slone Epidemiology Center Birth Defects Study, 1976-2008, and the National Birth Defects Prevention Study, 1997-2003, which together interviewed more than 30,000 women about their antenatal medication use.
Results
Over the last 3 decades, first-trimester use of prescription medication increased by more than 60%, and the use of 4 or more medications more than tripled. By 2008, approximately 50% of women reported taking at least 1 medication. Use of some specific medications markedly decreased or increased. Prescription medication use increased with maternal age and education, was highest for non-Hispanic whites, and varied by state.
Conclusion
These data reflect the widespread and growing use of medications by pregnant women and reinforce the need to study their respective fetal risks and safety.
Concern about medication use among pregnant women must focus on not only the intended subject, the pregnant woman, but also the unintended subject, the fetus, which is placed at potential risk for a wide range of adverse effects. Although a number of antenatal medication exposures are known to cause birth defects, there is insufficient information on the risks and safety for the vast majority of medications, whether they are obtained by prescription or over the counter (OTC). As a result, pregnant women may unknowingly take a medication that poses risk to their fetus; on the other hand, anxiety about the potential teratogenic effects of medications may discourage women from adhering to beneficial treatments.
Prior studies of medication use in pregnancy have typically focused on drug classes (eg, antibiotics); however, potential fetal effects may differ among medications within a given class, and analyses by class may fail to detect effects limited to 1 or a few class members. Studies based on electronic claims or medical records are subject to considerable exposure misclassification because prescription records may not reflect actual use.
To define research priorities, we need to understand patterns and factors associated with actual use of the wide range of specific medications that are taken during pregnancy and particularly during the first trimester, which includes the period of organogenesis, when concerns about teratogenic effects are greatest. It is also critical to identify the prevalence of exposure to both prescription and OTC medications and how use of medications changes over time.
Despite the importance of prescription and OTC medications, there are surprisingly few data available. We have previously described exposures exclusively to OTC medications and herbal products, as identified through 2 US multicenter, case-control studies: the Centers for Disease Control and Prevention’s (CDC) National Birth Defects Prevention Study (NBDPS) and the Slone Epidemiology Center Birth Defects Study (BDS).
To provide additional critical information, we have used these same studies to identify total exposures to any medication (OTC or prescription) as well as focus particular attention on exposures to prescription medications, both overall and by specific agents. Taking advantage of the 33 year period covered by the BDS and the population-based nature of the NBDPS, we used the former to identify secular patterns and the latter to identify selected demographic characteristics.
Materials and Methods
Birth Defects Study
Since 1976, the Boston University Slone Epidemiology Center BDS has interviewed mothers of infants with any major structural birth defects recruited from birth and tertiary care hospitals in a number of regional study centers (Boston, MA; Philadelphia, PA; Toronto, Canada; the state of Iowa, and San Diego, CA) as well as through birth defects registries in Massachusetts and New York State.
Beginning in 1993, a sample of mothers of infants without birth defects has also been included from each center or registry. Subjects are identified within 5 months after delivery, and mothers are interviewed within 6 months after delivery by trained nurses; interviews were conducted face to face (typically in the subject’s home) until mid-1998 and by telephone thereafter. Spanish interviews were introduced in 2001.
Standardized questions are asked about various maternal factors, with emphasis on medication use for the period beginning 2 months prior to the last menstrual period (LMP) to the end of the pregnancy. Pregnancy is defined as beginning with the LMP. Detailed information on medications is obtained via a series of questions.
Women are asked about illnesses they experienced and medications used in their treatment; medications taken for specified illnesses (eg, infections, seizures, diabetes); categories of medications (eg, antibiotics); and whether they took any agent from a list of specifically named medications. Both brand-name and generic products are recorded. For medications reported to have been taken, women are asked to retrieve the bottle or package if available. In 1999, a booklet containing pictures of a wide range of OTC medications was introduced to assist in identification. The BDS has been approved by the relevant institutional review boards.
To take advantage of the 33 years’ data available in the BDS and because the study did not always include control infants born without birth defects, this analysis included exposures independent of case-control status. Of note, although some increased risks associated with a particular drug and specific birth defect are included within these data, combining cases and controls does not have an appreciable impact on overall patterns of use, as reflected in the Results section as discussed in the following text. Furthermore, the analysis was limited to the Boston and Philadelphia centers because only those centers participated throughout the study period. The study population thus includes 25,313 mothers with LMP dates between 1976 and 2008; 19,297 subjects had infants born with birth defects and 6,016 had infants born without birth defects. Participation rates have varied over the 33 year study period, ranging from approximately 70% to 80%.
National Birth Defects Prevention Study
The NBDPS was initiated in 1997 and is an ongoing, population-based, case-control study comprising data collected by 10 birth defects surveillance systems throughout the United States (Arkansas; California; Georgia/CDC; Iowa; Massachusetts; New Jersey [through 2002]; New York; Texas; and, beginning in 2003, North Carolina and Utah). The catchment areas for California, Massachusetts, and New York do not overlap between the BDS and NBDPS.
Case subjects in the study have at least 1 of more than 30 eligible structural birth defects and include live births, stillbirths, and elective terminations. Control infants are live births without birth defects that are either randomly selected from birth certificates or selected from birth hospitals by using a stratified, random sampling scheme. Each of the 10 study centers enrolls approximately 300 eligible case infants and approximately 100 control infants per year.
Mothers are interviewed by telephone in English or Spanish using a computer-based questionnaire 6 weeks to 24 months after the estimated date of delivery. In addition to information on various maternal factors and behaviors, interviewers ask the women to report medications (prescribed or OTC), vitamins, or supplements taken for selected indications, read them a list of specific medications, and ask them to report other products used from 3 months before conception through the end of their pregnancy. Pregnancy is defined as beginning 2 weeks after the LMP. Estimated dates of use and the frequency and duration of use are recorded.
The NBDPS has been approved by the institutional review boards of the CDC and the participating study centers. Taking advantage of the population-based design in 10 study sites, the NBDPS analyses include only mothers of control subjects (n = 5008) with estimated delivery dates between Oct. 1, 1997, and Dec. 31, 2003.
Medication exposures
In both datasets, a medication was defined as a single product containing 1 or more active ingredients (eg, amoxicillin was considered as 1 medication, and amoxicillin/clavulanate was considered as another). Different salts of the same active ingredient were considered to be the same medication (eg, all salts of amoxicillin were considered as amoxicillin). We excluded vitamins/minerals, blood, and oxygen as well as medications administered topically (except vaginally) or intravenously.
In the instance in which a respondent reported taking a medication within a class (eg, an antibiotic) but could not identify the specific agent, the exposure was recorded as not otherwise specified (NOS) (eg, antibiotic NOS). In such instances, we assigned prescription or OTC status based on the category into which most medications in that class fell (for example, antibiotics NOS were considered prescription medications, whereas pain relievers NOS were considered OTC).
A number of medications were switched from prescription only to OTC availability (primarily during BDS years). For those switched medications used commonly, we added 3 months to the switch approval date (to account for their distribution to patients) and considered the medications to be a prescription or OTC exposure according to whether the subject reported using the medication before or after that latter date, respectively.
Results
All medications (OTC and prescription medications combined)
For the 33 year BDS study, Figure 1 presents secular patterns of use of any medication at any time during pregnancy as well as any medication taken in the first trimester. Overall, the average number used any time in pregnancy increased by 68%, from 2.5 in 1976-1978 to 4.2 in 2006-2008 (range, 0–28); in the last year, 93.9% took at least 1 medication. During the first trimester, the average number of medications increased during those same years by 62.5%, from 1.6 to 2.6 (range, 0–25); 82.3% of women in the last year used at least 1 medication. Comparing study mothers who had malformed or nonmalformed offspring, we found no appreciable differences in the average numbers of medications either over the entire period of the study or by specific year (data not shown).
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