Teratogen Use in Women of Childbearing Potential: An Intervention Study

Methods

This study took place at the St. Vincent Joshua Max Simon Primary Care Center (PCC) in Indianapolis, Indiana, where multidisciplinary health care professionals provide outpatient care, averaging 70,000 patient visits per year. The PCC is a medical residency training facility that consists of several medical disciplines, including family medicine, internal medicine, obstetrics/gynecology, pediatrics, and various specialty clinics. Patient demographics are diverse and include uninsured, Medicare, Medicaid, and privately insured individuals; English- and non-English-speaking individuals; and literate and illiterate individuals.

The study, consisting of a retrospective chart review and a survey to evaluate physician knowledge before and after educational intervention, was reviewed and approved by the St. Vincent Institutional Review Board. The primary outcomes were to quantify the number of women of childbearing age who were prescribed an ACE inhibitor, ARB, or statin and to determine the number of documented teratogenic risk discussions (risk documentation) before and after interventions aimed at prescribing physicians. Secondary outcomes were to determine physician knowledge regarding the teratogenic risks before and after education, to improve physician risk documentation, and to determine physician or patient characteristics affecting risk documentation when prescribing ACE inhibitors, ARBs, or statins.

Female patients 15 to 45 years of age who were prescribed ACE inhibitors, ARBs, and/or statins at a PCC physician clinic visit between January 1, 2007, and March 1, 2009, were identified through computer-generated queries of the electronic medical record (EMR; Allscripts Electronic Health Record, version 10; Chicago, IL). The terms used to identify the patient population included patient appointment and billing encounter, sex, age, and active medication, including brand name or generic, within the targeted class of ACE inhibitor, ARB, or statin. Exclusion criteria were male sex, women not of childbearing age (ie, younger than 15 or older than 45 years of age), and female patients with a documented history of hysterectomy or tubal ligation. Baseline EMR data collected included patient age; targeted medication(s); prescribed contraceptive agent (type/dosage form); documented targeted medication indication (DM, HTN, HLD, other); pregnancy test on prescribing targeted medication; risk documentation with use of targeted medication; postgraduate year (PGY) of resident or faculty physician who prescribed the targeted medication(s); and resident training program.

An anonymous electronic survey was developed in SurveyMonkey to assess only medical residents’ baseline knowledge about the appropriate use and risks associated with prescribing targeted medications to women of childbearing age (see Table 2). After the survey, an educational intervention was presented to family medicine, internal medicine, obstetric/gynecology, and transitional medical residents. Faculty physicians were also invited to attend the educational intervention. For physicians who were unable to attend live sessions, the presented slides were available for review via e-mail and an Intranet site. A clinical pharmacist and medical resident presented the 1-hour educational intervention, reviewing common teratogens, current pregnancy categories and limitations, common references for medication use during pregnancy and emphasized the importance of risk documentation when prescribing potentially teratogenic medications. Limitations of the current pregnancy categories presented were based on FDA-proposed changes for pregnancy labeling with the inclusion of 3 principle components: fetal risk summary, clinical considerations, and a data section.^3,10 A survey was administered to the medical residents approximately 1 month after the educational intervention to assess change in physician knowledge and prescribing habits.

After the educational initiative, individual physicians were provided a memo listing their assigned patients of childbearing age who were prescribed ACE inhibitors, ARBs, and/or statins during the baseline study period. Physicians were asked to review the patients along with the indication for targeted medication use and consider alternatives, if appropriate, with lower teratogenic risk. If the targeted medication was continued, the physician was to have a discussion with the patient about the teratogenic risk versus benefit of the medication and document it in the EMR. To facilitate physician risk documentation, an electronic template was developed through a physician-initiated order for medication counseling. The targeted medication—ACE inhibitor, ARB, and/or statin—was selected from a drop-down menu and the following text was inserted into the EMR: “Patient currently prescribed the specified medication and is of childbearing potential. I have discussed with this patient the teratogenic risk associated with this medication, and I have advised the patient on contraceptive measures to prevent pregnancy while taking this medication. The patient has been instructed to stop this medication and contact our office if she is planning to become or suspects that she is pregnant.” Physicians were educated on this new process for risk documentation during the educational intervention and it was reinforced through the e-mailed memo as well as one-on-one during clinic.

Data were gathered after the intervention through computer-generated queries to evaluate female patients with a physician clinic visit between September 1, 2009, and December 31, 2009. Inclusion and exclusion criteria and data collected were identical to the initial baseline data. Additional data evaluated during the first quarter included frequency of use of the new electronic template for risk documentation and the number of patients from baseline in whom targeted medication was stopped or risk documentation occurred without a physician clinic visit. Ongoing assessment included quarterly data collection and analysis for a minimum of 1 year.

For this study, risk documentation was considered to be present if a teratogenic risk discussion was documented within the discussion or plan section of the EMR physician note or if the physician used the new electronic template described previously. Data collected before and after the intervention were grouped during analysis as follows: age divided into 2 groups (15 to 40 years of age and 41 to 45 years of age); ACE inhibitors and ARBs combined into one medication category; and patients receiving a combination of targeted medications (ACE inhibitor and statin or ARB and statin). Age was divided into 2 categories, as described above, because women ≤40 years of age have increased fertility and are more likely to become pregnant resulting in inadvertent drug exposure if they are prescribed a targeted medication. ACE inhibitor and ARB medication classes were combined into one medication category because there is no difference in their FDA pregnancy category or teratogenic risk. Lastly, if a patient was prescribed a combination of targeted medications (ACE inhibitor and statin or ARB and statin) and risk documentation only occurred for the ACE inhibitor/ARB medication category, the data were included for analysis. Risk documentation was not excluded for these patients because the physician documented teratogenic risk for at least one of the prescribed combination targeted medications.

Results

Approximately 15,000 female patients 15 to 45 years of age are currently registered at the PCC. Based on inclusion and exclusion criteria, 200 patients were included in the analysis before intervention and 131 patients were included in the analysis after intervention (see Figure 1). Patients included in the analyses before and after intervention had been prescribed one or more of the targeted medications: ACE inhibitors, ARBs, or statins.

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Figure 1.

Patient inclusion and exclusion.

Table 3 displays the demographic data of patients and physicians included in the analyses before and after intervention. There was no significant difference in patient populations with regard to age, medication(s) prescribed, disease state(s), use and method of contraception, and pregnancy test. There was no significant difference in physician demographics based on the type of training program; however, there was a significant difference in the PGY of physician training from before to after intervention (P < .001). Overall, these data reveal that a majority of the patients were younger than 40 years of age and were prescribed an ACE inhibitor with HTN indication. In addition, the most frequent prescriber of targeted medications were internal medicine residents both before and after intervention.

Quantifying the number of women of childbearing age who were prescribed a targeted medication(s) and determining the frequency of risk documentation were primary outcomes of this study. There was no difference before or after intervention in the number of women of childbearing age who were prescribed targeted medication(s) (see Table 4). Patients were most frequently prescribed an ACE inhibitor, followed by statin and ARB. Targeted medications prescribed were consistent with disease states treated; HTN was the most common disease state, followed by DM and HLD (see Table 3). Analysis of the presence of risk documentation when targeted medications were prescribed revealed a significant difference after intervention (see Table 4). Before intervention, risk documentation was present in 40 of 200 patients (20%). After intervention, the presence of risk documentation increased to 49 of 131 patients (37.4%). Patients after intervention were 2.4 times more likely to have risk documentation when a targeted medication was prescribed (OR, 2.4; 95% CI, 1.5–3.9).

Further analysis was performed to determine if any patient or physician characteristics affected risk documentation. Both before and after intervention, risk documentation occurred more frequently among patients 15 to 40 years of age (see Figure 2). Before intervention, risk documentation was present in 29.8% of patients 15 to 40 years of age and 3.9% of patients 41 to 45 years of age (P < .001). Compared with before intervention, risk documentation increased after intervention among each age group, to 45.2% of patients 15 to 40 years of age and 23.4% of patients 41 to 45 years of age. Risk documentation continued to occur more frequently for patients 15 to 40 years of age (P = .015). Risk documentation was also affected by drug class (see Figure 2). Risk documentation occurred more frequently before intervention in patients who were prescribed an ACE inhibitor or ARB. Before intervention, risk documentation was present in 27.7% of patients who were prescribed an ACE inhibitor or ARB, 4.5% of patients who were prescribed a statin, and 15.9% of patients who were prescribed an ACE inhibitor/statin or ARB/statin (P = .002). After intervention, risk documentation became more consistent within each drug class for patients who were prescribed targeted medications: 40.7% of patients who were prescribed an ACE inhibitor or ARB, 38.1% of patients who were prescribed a statin, and 27.6% of patients who were prescribed an ACE inhibitor/statin or ARB/statin (P = .484). Other patient and physician characteristics that were evaluated but did not significantly affect risk documentation before or after intervention included rate or method of contraception, PGY of resident training or faculty status, and resident training program.

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Figure 2.

Patient characteristics affecting risk documentation.

Approximately 110 medical residents in internal medicine, family medicine, obstetrics/gynecology, and transitional residency programs were asked to complete the anonymous survey. Thirty-six residents (32.7%) completed the survey before intervention and 38 residents (34.5%) completed the survey after intervention. Table 2 displays the survey results. There was no significant difference in any survey responses or physician demographic data after intervention. Question 6 evaluated how frequently residents remembered prescribing a targeted during the past several months. Before intervention, 22.2% of residents, and after intervention, 26.3% of residents responded that they remembered prescribing targeted medications to women of childbearing age. Questions 7 and 8 addressed the possibility of a woman becoming pregnant while taking targeted medications and risk documentation. Both before and after intervention, approximately 70% of the survey participants considered the potential for pregnancy and responded documenting this risk; however, the retrospective chart review revealed that risk documentation occurred only 20% before and 37.4% after intervention.

In addition to the survey and educational intervention, two other interventions were implemented to increase risk documentation with targeted medications. For patient safety, a memo was sent to physicians with an individualized list of patients who were prescribed targeted medications. Thus, 20 patients who received targeted medications had the medication(s) discontinued independent of an office visit. Creation and implementation of the new electronic template within the EMR was used for 28 of the 49 patients (57.1%) for whom risk documentation occurred after intervention.

Discussion

This study reveals a need to educate physicians regarding the potential dangers of prescribing ACE inhibitor, ARB, and/or statin medications to women of childbearing age. Because the use of these targeted medications continues to increase for the management of HTN, DM, and HLD, prescribers need to evaluate evidence-based guidelines in addition to the patient's childbearing status.¹ This study demonstrated that interventions aimed at increasing prescriber awareness of the teratogenic risk associated with targeted medications significantly improved rates of risk documentation for all prescribers (residents and faculty physicians) from 20% before to 37.4% after intervention.

Risk documentation before and after intervention occurred more frequently among women 40 years of age or younger, demonstrating the need to increase awareness of drug exposure with advanced childbearing age. Risk documentation, although occurring more frequently in women 15 to 40 years of age, was suboptimal before and after intervention at 29.8% and 45.2%, respectively. Though improvements in risk documentation occurred in each age category, more than 50% of women with increased fertility may have inadvertent exposure to targeted medications without knowledge of the teratogenic risk.

Additional considerations with this study include that ACE inhibitors were the most frequently prescribed targeted medication, and HTN was the most commonly treated indication both before and after intervention. It is hard to determine from the retrospective chart review if ACE inhibitors or ARBs were prescribed for HTN, DM, or both. If patients with the diagnosis of HTN alone are evaluated, 88 patients (44%) before and 58 patients (44.2%) after intervention could have been prescribed ACE inhibitors or ARBs for HTN alone with no other compelling indication for this drug choice.^2,11 Among women of childbearing age, safer options exist to treat HTN that may not pose a threat to the fetus should pregnancy occur.¹¹

This study is similar to the previously published studies and continues to demonstrate the need to improve physician awareness of teratogenic risk when prescribing ACE inhibitors, ARBs, or statins for women of childbearing age.^4,6 Martin and colleagues’⁴ study evaluates prescribing in a referral-based HTN clinic, where our study demonstrates prescribing in a primary care setting. Our study also evaluated prescribing and risk documentation among both resident and faculty physicians, finding no difference in the PGY of resident training or faculty physicians. This suggests that increased awareness of prescribing ACE inhibitors, ARBs, and/or statins needs to be reinforced throughout residency training and practice after residency.

There are several limitations to this study that warrant discussion. The demographic data revealed a significant difference in PGY of physician training or faculty physician status from before to after intervention (P < .001). This is attributed to the transition of residents into and out of a residency training program each year. Outliers in the data are the PGY1 residents, residents who graduated in 2009, and residents who graduated at other times throughout the study period. The timing of study data collection included the time frame in which PGY3 residents graduated and new PGY1 residents entered training programs. Though there was a statistically significant difference in PGY of training before and after intervention, this did not affect the rate of risk documentation.

Another limitation of this study is rate of prescribed birth control. National statistics reveal that 36.7% of women of childbearing potential use nonpermanent, prescription methods of birth control (ie, oral contraceptive, injectable contraceptive, or intrauterine device).¹² This study evaluated the use of nonpermanent, prescription methods of birth control and revealed that these agents were prescribed to approximately 25% of the before- and after-intervention populations. The lower prescribing rate may be related to the study setting, a Catholic-affiliated institution. The rate of prescribed methods of nonpermanent birth control in this study may not be reflective of the general population.

In addition to these limitations, the survey and the multiple interventions that took place require further discussion. Both before and after intervention, the survey had slightly more than a 30% response rate. Though the response rate received from this survey is in line with expected survey response,¹³ the physicians who participated in the survey were not reflective of the physicians prescribing targeted medications. The survey was anonymous; therefore, there was no way to link survey participants to the study prescribers. A majority of the survey respondents were PGY1 family medicine residents. A majority of targeted medication prescribers were internal medicine residents, and PGY1 residents were one of the study outliers because of the influx of new residents entering training. This makes it difficult to correlate the survey results to the frequency of targeted medication(s) prescribed or the rate of risk documentation. Other interventions were present in this study that may have affected the rate of risk documentation, including (1) educational sessions aimed at increasing prescriber awareness when prescribing to women of childbearing age in general and when prescribing targeted medications; (2) implementation of an electronic template for risk documentation when targeted medications were prescribed; (3) memo to physicians with an individualized list of patients who had been prescribed targeted medications; and (4) one-on-one interaction with clinical pharmacy staff through daily prospective chart reviews. Analysis of these interventions revealed that after intervention, 28 of 49 prescribers (57.1%) used the electronic template for risk documentation and 20 patients had targeted medications discontinued independent of a physician visit. It was not possible to determine which intervention(s) had the greatest impact on improvements in risk documentation and awareness when prescribing after intervention.

Conclusion

Though interventions in this study demonstrate one method to improve awareness of teratogenic risk when prescribing ACE inhibitors, ARBs, or statins in women of childbearing age, there remains room for improvement. Continued efforts to improve prescribing practices and risk documentation at the PCC include second- through fourth-quarter evaluation of data for the remainder of 2010, sharing quarterly data with resident and faculty physicians, providing physicians with individual lists of patients quarterly, encouraging use of the electronic risk documentation template, and yearly review of data with incoming residents. This study demonstrates the continued need to evaluate prescribing practices of physicians for women of childbearing potential while incorporating evidence-based medicine. Identifying patients at risk as well as providing a teratogenic risk discussion and appropriate documentation within the medical record is aimed at reducing potential teratogenic drug exposure.