More adults in the United States are taking prescription medications over the past two decades.1 Most pregnant women take prescription medications also with rates as high as 95%.2–4 In addition, in some populations, the majority of women have been found to take more than three prescription medications during pregnancy.5,6 The use of over-the-counter medication is likewise increasing in the general population as are the total dollars spent on over-the-counter medicines.7,8
Although several reports described prescription and other medication use in pregnancy, they have some limitations. Many prior studies reported on single-site cohorts of pregnant women, were case–control designs, or used larger databases of administrative or prescription data.3,4,9–11 A prospectively evaluated study of nulliparous women beginning in the first trimester of pregnancy, the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) cohort, is ideally positioned to provide a snapshot of the use of both prescription and nonprescription medications in pregnancy. The objective of this study was to characterize medication use in a geographically and ethnically diverse cohort of women in their first pregnancy enrolled in the nuMoM2b study. A secondary objective was to chronicle trends in medication use over the course of pregnancy.
MATERIALS AND METHODS
The nuMoM2b study was designed as a prospective, longitudinal cohort study whose aim was to determine maternal characteristics, including genetic, physiologic, and environmental factors that predict adverse pregnancy outcomes. A full description of the study methods and visits is reported elsewhere.12 Briefly, 10,038 nulliparous women were recruited in the first trimester of pregnancy between October 2010 and September 2013. Women had study visits between gestational weeks 6 0/7 and 13 6/7 (study visit 1), 16 0/7 and 21 6/7 (study visit 2), and between 22 0/7 and 29 6/7 (study visit 3). Study visits were not part of clinical care. At each study visit, a trained research team member administered several questionnaires and surveys and collected an array of biological samples. The study team also captured data and specimens from antepartum and delivery hospitalizations. At least 30 days after delivery, certified chart abstractors reviewed antenatal, intrapartum, and postpartum medical records to corroborate existing interview data and collect obstetric and infant outcome data.12
In the nuMoM2b study, women were recruited from eight geographically diverse clinical centers in the United States to obtain a racial–ethnically diverse population of pregnant women. Sites were located in New York or Delaware (combined site), Pennsylvania (two), Ohio, Indiana, Illinois, Utah, and California. Women were recruited from both private practices and academic practices located near the main clinical site. Women could be recruited as young as age 13 years into the cohort. Local governing institutional review boards approved the protocol at each clinical site and at the data coordinating center and all participants gave written informed consent. The study was registered on clinicaltrials.gov (NCT01322529).
At each study visit, a log of medical conditions and prescription and other medication use was completed. At the time the study visit was scheduled, participants were encouraged to bring in all medications that they had taken since becoming pregnant or since the previous study visit, as applicable. At the study visit, participants were also asked to recall other medications, including any over-the-counter medications or supplements (including, eg, prenatal vitamins, micronutrients, herbals), they had taken or their health care provider had recommended in that same period. At the time of the delivery, women were asked to recall any medications taken up to the time of the delivery hospitalization. Research personnel recorded all answers on the data capture form, which was kept in the study file and added to or clarified at each subsequent study visit. Participants were asked the reason that the medications were taken, and answers were coded from a list of conditions on the data capture form (see Appendix 1, available online at http://links.lww.com/AOG/B82). At the time of final chart abstraction, additional prescribed medications that were used at any time during the pregnancy were recorded.
Medications were categorized based on typical use or medication classification. This was to allow for ease of grouping. An individual taking two different medications for a condition would have two different notations made for that medication category and reason. A key was provided with common examples of certain types of medications. For example, a number of calcium channel blockers (nifedipine, amlodipine) was listed for inclusion in the medication category of “Ca-Channel Blocker” in the Manual of Operations to facilitate data collection and abstraction.
Collected data underwent rigorous quality control review by a subset of investigators (D.M.H., D.J.M., D.T.D., C.B.P., A.L., and U.M.R.) to eliminate misspellings and miscategorizations. Questions about medication categorizations or indications for medication use were resolved through consensus discussion. For the purposes of this analysis, we did not include illicit or recreational drugs (such as marijuana and heroin) but included opioid prescription medications and medication-assisted treatment with opioids.
We restricted this analysis to nulliparous women followed through pregnancy from the first trimester with medication use data forms completed. Descriptive statistics for individual medication category (during pregnancy and during the first trimester, including 95% CIs) and indications for medication use are presented for both prescription and nonprescription medications and supplements taken at any time during the pregnancy. We excluded reports of vaccinations received during pregnancy for statistics pertaining to general medication use. Trends of medication use throughout the pregnancy and most common reasons for taking medications during pregnancy are also presented. Prevalence rates of medication use (overall, in the first trimester, and polypharmacy) were compared by ethnicity, geographic region, and other demographic characteristics. Polypharmacy was defined as use of at least five medications during the same epoch, a threshold commonly used in the literature.1,13 Trends by demographic characteristics were evaluated using χ2 tests. McNemar test was used to evaluate differences in proportion of women using medications during the first trimester compared with the second. There was no adjustment for multiple comparisons. Analyses were conducted using SAS 9.4.
Of the 10,038 participants in nuMoM2b, medication data were available for 9,546 women followed through pregnancy from the first trimester with medication data. Restricting to women who were followed until the end of their pregnancy excluded 444 women. Restricting to women with medication data further excluded 48 women. Characteristics of this final cohort and comparison of rates of medication use are presented in Table 1. The mean age of the cohort was 27.0 (±5.66) years.
In total, 9,262 (97.0%, 95% CI 96.7–97.4%) took at least one medication during pregnancy, 9,133 (95.7%, 95% CI 95.3–96.1%) took a medication during the first trimester, and 2,195 (30.5%, 95% CI 29.6–31.5%) met the definition for polypharmacy in taking five or more medications during pregnancy. The overall mean number of total medications taken during pregnancy was 3.74±2.71 (range 0–27; median 3; interquartile range 2–5). Women in the cohort took a mean of 2.54±1.96 (range 0–21; median 2; interquartile range 1–3) medications during the first trimester. Two thousand two hundred fifty-five (23.6%) women only took prenatal vitamins during pregnancy. Additionally, 193 (2.0%) women took some type of herbal or probiotic supplement. The mean number of medications taken by women was 2.54±1.96 (range 0–21; median 2; interquartile range 1–3) at the first study visit, 2.50±1.78 (range 0–18; median 2; interquartile range 1–3) at the second study visit, 2.59±1.93 (range 0–24; median 2; interquartile range 1–3) at the third study visit, and 2.71±2.00 (range 0–26; median 2; interquartile range 1–4) at the time of delivery.
Excluding prenatal vitamins, multivitamins, additional iron, and folic acid, 7,007 (73.4%, 95% CI 72.5–74.3%) of women took a medication during pregnancy with 5,263 (55.1%, 95% CI 54.1–56.1%) taking at least one medication in the first trimester (Appendix 2, available online at http://links.lww.com/AOG/B82). In this group, 1,240 (13.0%, 95% CI 12.3–13.7%) of women met the definition of polypharmacy.
The number of women taking medications any time during pregnancy varied by maternal age, race–ethnicity, educational attainment at the time of pregnancy, method of payment for health care, and geographic region (Table 1). Women who were younger and non-Hispanic reported higher rates of taking medications in pregnancy. The number of women taking medications in the first trimester also varied by age, race–ethnicity, method of payment for health care, and region. The number of women reporting polypharmacy (five or more medications) also varied by age, race–ethnicity, educational attainment, method of paying for health care, household income, and region. Women who were older, white, had commercial insurance, and more education tended to take more medication. Women in the Northeast tended to take less medication.
The most commonly prescribed medications were gastrointestinal or antiemetic agents (3,279 [34.3%]; 1,866 [19.5%] in the first trimester) followed by antibiotics (2,439 [25.5%]; 1,199 [12.6%] in the first trimester) and analgesics (2,265 [23.7%]; 1,485 [15.6%] in the first trimester). Table 2 presents grouped medication code category data recorded. Appendix 3 (available online at http://links.lww.com/AOG/B82) details all individual medication codes and prevalence of use. Regarding gastrointestinal and antiemetic agents, 5-HT3 antagonists were the most prescribed specific class of medications (1,167 [12.2%] women). The most common indication for this class of medication was nausea and vomiting. Penicillin-derivative antibiotics were the most commonly reported antibiotic group (715 [7.5%]) and were most commonly prescribed for urinary tract infection. However, they were not the most prevalently prescribed antibiotic group for such infections. Acetaminophen was reportedly taken during pregnancy by 1,903 (19.9%) of women with 1,121 (11.7%) having taken it in the first trimester. Otherwise, nonsteroidal antiinflammatory drugs were the most commonly reported specific class of analgesics (6.6%) with opioids reported by 3.6% of women before delivery. Antihistamines (n=1,219 [12.8%]) were also commonly prescribed. Additional iron supplements were noted for 1,548 (16.2%) women.
Vitamin consumption early in pregnancy was nearly universal with 8,800 women taking a prenatal vitamin in the first trimester of pregnancy (92.2%) (Table 2). Additionally, 543 (5.7%) and 1,859 (19.6%) women took another type of multivitamin or other vitamin, respectively, during the first trimester. In total, 9,001 (94.3%) women took some type of vitamin or additional folic acid during the first trimester of pregnancy.
Excluding medications taken that were marked as being taken for preventive reasons, “other” reasons, or from “provider recommendation,” the specific condition most often cited as the reason for taking a medication during pregnancy was nausea and vomiting (n=1,599 [16.8%]). This was followed by urinary tract infections (1,132 [11.9%]), anemia (924 [9.7%]), respiratory infections (737 [7.7%]), yeast infections (717 [7.5%]), mental health conditions (706 [7.4%]), and asthma (653 [6.8%]) (Table 3).
Table 4 shows the classes of medications that demonstrated a significant increase or decrease in use between the first trimester and the second trimester (when participants may have previously received counseling on appropriate medication use in pregnancy). The number of women who had taken nonsteroidal antiinflammatory drugs, selective serotonin reuptake inhibitors, and progesterone (not for contraception) decreased between study visits 1 and 2 (Table 4). The greatest absolute increase in medication class reported occurred for other analgesics (category including acetaminophen) and gastrointestinal agents.
Our results from a large, diverse, prospective cohort of nulliparous women in the United States detail that prescription or other medication use is nearly universal during pregnancy. The ubiquitous use of at least one medication during pregnancy and especially in the first trimester highlights the need for more attention to medication use in pregnancy. Even when vitamins, supplements, and vaccines are excluded, 73.4% of women took at least one medication during pregnancy with 55.1% taking a medication in the first trimester, a critical time in fetal development. Our findings support the need for more information on medications specific to pregnant women and counseling to limit exposure to medically unindicated medications in pregnancy.14–17
Our findings are consistent with other studies showing that greater than 90% of women take at least one medication during pregnancy.3–6 However, we noted a similar or higher rate of nonvitamin or supplement medication use than in other studies.3,4 This observation may have been because of our prospective, study visit interview-based methodology where all participants were encouraged to bring in all medications and supplements they were taking. Glover et al4 used interviews but studied a relatively small rural population of 578 women and found that only 59.7% of women used a prescription medication excluding vitamins and iron supplements. Our rate also may have been higher because we included prescription and nonprescription medications. We sought to obtain a more comprehensive picture of all medications being consumed in this national cohort. Glover et al4 noted a very high rate of over-the-counter medication use (92.6%). Using a survey of 418 postpartum women, Refuerzo et al found that 76.5% of women took a prescription medication after excluding vitamins and iron, a rate similar to ours.3
Our finding of medications for nausea and vomiting being the most commonly used is not surprising given the high incidence of nausea and vomiting of pregnancy.18 Interestingly, we found that 5-HT3 antagonists were the most commonly used medication for this indication. Current recommendations do not support these medications as first-line therapy for nausea and vomiting.18–20 In this way, these data can help shed light on current practice patterns in relationship to practice recommendations, highlighting areas of need for health care provider education. Taken as a whole medication class category, the high rate of use of gastrointestinal medications (34.3%) is understandable because they treat common conditions such as nausea and vomiting, acid reflux, and constipation. Our finding that antiinfective medications and analgesic medications were the next most commonly used medication classes is also consistent with other studies, nearly all of which have noted these classes as the three most commonly reported.2,4,6,9–11 Vaginal antifungals, penicillin derivatives, and nitrofurantoin were the most common antiinfective medication classes used by women in our cohort. This finding is also consistent with other studies. Interestingly, other cohorts noted higher rates of antibiotic use with Palmsten et al11 reporting almost 50% of women filling prescriptions for such antiinfective agents with nitrofurantoin at 21.6% of women and metronidazole at 19.4% of women. We also found relatively high rates of pregnant women using upper respiratory infection agents (16.4%), asthma medications (9.1%), and antidepressants (6.1%). Other studies have noted increasing rates of use of various classes of medications over time, including these.5 Although differing data collection and categorization methodology prevent a direct correlation, these relatively high rates are consistent with recently published rates from other studies.3,4,11
We found a relatively low rate of opioid use in our cohort (3.6%) compared with some other reports. This may have been the result of our parsing out different types of analgesics methodically by reason codes. It also may be because we did not include medications taken during or after the delivery hospitalization, when many women are given opioids. With the current epidemic of opioid use disorder, it is important to monitor their use in pregnancy.21 Our rate of opioid use in the first trimester is consistent with the 1.3% rate of hydrocodone use reported by Thorpe et al.9 Other groups also found that opiates were commonly used by pregnant women with rates from 8% to nearly 12%.4,11 These results do not include illicit drug use in this class. Rates of illicit drug use have varied but have been found to be as high as 13% in some general obstetric populations.22 These rates are increasing.23 Our rates of reported nonsteroidal antiinflammatory drug use were higher than anticipated. However, other studies have reported rates of over-the-counter ibuprofen use in pregnancy of up to 18%.10
We found that medication use during pregnancy and in the first trimester varied by several demographic factors, consistent with other national data.5 The regional difference in polypharmacy was interesting with rates in the Midwest and West double that of the Northeast. Because there were several centers in each region, this is unlikely to be the result of practice patterns within individual centers. Other studies have also found regional variation in medication use in pregnancy.2 Additionally, racial–ethnic differences are seen in polypharmacy rates. In our cohort, Hispanic and Asian women had a more than 10% lower rate of polypharmacy compared with white non-Hispanic women. These findings bear further exploration.
Our rate of polypharmacy of 13.0% after exclusion of vitamins and vaccines is consistent with the 15% rate found in a national survey of adults.1 Other studies in pregnancy in which polypharmacy was defined as at least four medications reported rates of 13.6–15.7%.3,5 However, vitamins or supplements often were included in this estimate. When including these medications in our cohort, the polypharmacy rate was 30.5%.
We did not classify our medication data by the U.S. Food and Drug Administration Pregnancy Category System. Since June 2015, this system has been replaced by the new Pregnancy and Lactation Rule.24 As such, we did not determine rates of women taking medications in various drug categories per the old A,B,C,D,X system. Other reports consistently showed that pregnant women generally consume category D or X drugs with rates up to 4.5%.2 One study of Medicaid prescription data noted that almost 40% of women received a prescription for a category D drug.11
Our work is subject to the limitations of the study design. We attempted to enhance completeness of the data set by asking women to bring in prescriptions and any other medications taken since the prior study visit. Additionally, the study team had tables of common generic and brand name medications for different conditions to aid with recall. All study team members were trained in this interview process but we cannot know whether all study aids were applied uniformly. We also did not separately categorize medications as being over-the-counter or prescription because we were more interested in ascertaining all medications that had been taken. This report does not include any medications taken during or after the delivery hospitalization. Although there was geographic diversity to the clinical sites within nuMoM2b, there were no clinical sites in the South, potentially limiting generalizability for that region.
The nuMoM2b study comprises a large prospective cohort capturing prescription and over-the-counter medication intake longitudinally from the first trimester in a robust, interview-based manner. Thus, these data help to overcome limitations of other reports that were based on administrative prescription databases, retrospective questionnaires, and teratology databases. Because the nuMoM2b cohort was geographically and ethnically diverse, these data should be generalizable to much of the U.S. population.
In conclusion, our findings indicate that medication use in pregnancy is ubiquitous and that most pregnant women take multiple medications, including during the first trimester. Gastrointestinal medications, antibiotics, and analgesics were the most commonly taken medication classes. Armed with data from this and other studies, research should focus on improving pregnancy-specific knowledge and guidance for prescribers and pregnant women.
1. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999–2012. JAMA 2015;314:1818–31.
2. Lee E, Maneno MK, Smith L, Weiss SR, Zuckerman IH, Wutoh AK, et al. National patterns of medication use during pregnancy. Pharmacoepidemiol Drug Saf 2006;15:537–45.
3. Refuerzo JS, Blackwell SC, Sokol RJ, Lajeunesse L, Firchau K, Kruger M, et al. Use of over-the-counter medications and herbal remedies in pregnancy. Am J Perinatol 2005;22:321–4.
4. Glover DD, Amonkar M, Rybeck BF, Tracy TS. Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population. Am J Obstet Gynecol 2003;188:1039–45.
5. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205:51.e1–8.
6. Lacroix I, Damase-Michel C, Lapeyre-Mestre M, Montastruc JL. Prescription of drugs during pregnancy in France. Lancet 2000;356:1735–6.
7. Aaltonen K, Niemelä M, Norris P, Bell JS, Hartikainen S. Trends and income related differences in out-of-pocket costs for prescription and over-the-counter medicines in Finland from 1985 to 2006. Health Policy 2013;110:131–40.
8. Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC. Changes in prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern Med 2016;176:473–82.
9. Thorpe PG, Gilboa SM, Hernandez-Diaz S, Lind J, Cragan JD, Briggs G, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf 2013;22:1013–8.
10. Werler MM, Mitchell AA, Hernandez-Diaz S, Honein MA. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193:771–7.
11. Palmsten K, Hernández-Díaz S, Chambers CD, Mogun H, Lai S, Gilmer TP, et al. The most commonly dispensed prescription medications among pregnant women enrolled in the U.S. Medicaid program. Obstet Gynecol 2015;126:465–73.
12. Haas DM, Parker CB, Wing DA, Parry S, Grobman WA, Mercer BM, et al. A description of the methods of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). Am J Obstet Gynecol 2015;212:539.e1–24.
13. Viktil KK, Blix HS, Moger TA, Reikvam A. Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems. Br J Clin Pharmacol 2007;63:187–95.
14. Parisi MA, Spong CY, Zajicek A, Guttmacher AE. We don't know what we don't study: the case for research on medication effects in pregnancy. Am J Med Genet C Semin Med Genet 2011;157C:247–50.
15. Endicott S, Haas DM. The current state of therapeutic drug trials in pregnancy. Clin Pharmacol Ther 2012;92:149–50.
16. Haas DM, Gallauresi B, Shields K, Zeitlin D, Clark SM, Hebert MF, et al. Pharmacotherapy and pregnancy: highlights from the third international conference for individualized pharmacotherapy in pregnancy. Clin Transl Sci 2011;4:204–9.
17. Umans JG, Lindheimer MD. Getting to safer and smarter medication use during pregnancy. Am J Obstet Gynecol 2015;213:115–6.
18. Nausea and vomiting of pregnancy. ACOG Practice Bulletin No. 189. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;131:e15–30.
19. Matthews A, Haas DM, O'Mathuna DP, Dowswell T. Interventions for nausea and vomiting in early pregnancy. The Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD007575. doi: 10.1002/14651858.CD007575.pub4.
20. Mayhall EA, Gray R, Lopes V, Matteson KA. Comparison of antiemetics for nausea and vomiting of pregnancy in an emergency department setting. Am J Emerg Med 2015;33:882–6.
21. Opioid abuse and opioid use disorder in pregnancy. Committee Opinion No. 711. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;130:e81–94.
22. Schauberger CW, Newbury EJ, Colburn JM, Al-Hamadani M. Prevalence of illicit drug use in pregnant women in a Wisconsin private practice setting. Am J Obstet Gynecol 2014;211:255.e1–4.
23. Epstein RA, Bobo WV, Martin PR, Morrow JA, Wang W, Chandrasekhar R, et al. Increasing pregnancy-related use of prescribed opioid analgesics. Ann Epidemiol 2013;23:498–503.
24. Food and Drug Administration, HHS. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Fed Regist 2014;79:72064–103.