Technology assisted medication adherence in pregnancy Schulz EV1; Ebeling M1; Morella K2; Patel S3; Treiber F3; Annibale DJ1; Wagner CL1 1Neonatology/Perinatology 2Public Health Sciences 3College of Nursing Medical University of South Carolina Good morning! My name is Elizabeth Schulz. I’m currently a 3rd year Neonatology Fellow at the Medical University of South Carolina and today I will be reviewing a recent project of mine, entitled “Technology Assisted Medication Adherence in Pregnancy”.

March 23, 2017 Disclosure statement Speaker: Elizabeth Schulz, MD Dr. Schulz has documented that she has nothing to disclose. Funded by: W.K. Kellogg Foundation NIH Grant UL1TR0000062

Cell phone use in medicine Medication nonadherence remains a serious issue in clinical trials1 Mobile text-messaging interventions are effective when addressing multiple chronic adult diagnoses2 Medication adherence is a generalizable problem throughout medical subspecialties. Whether from lack of patient education or willingness, it’s a topic that unites both adult and pediatric providers across all fields of medicine. In 2015, JAMA published multiple editorials re: a landmark meta-analysis identifying the feasibility of text-messaging interventions designed for health improvement and behavior change. The meta-analysis demonstrated how effective text-messaging interventions can be for patients, in terms of medication adherence, and in more recent studies, we see how text messaging can be utilized for quality improvement initiatives in providers as well. Specifically, this is a hot topic for clinical trials that depend on medication adherence for outcome measures. As health systems evolve to meet the challenges of poor medication adherence, we asked the question of whether or not we could harness this technology to target compliance in clinical trials during pregnancy. 1DeWorsop D, Creatura G, Bluez G, et al. Drug and alcohol dependence. 2016. 2Hall AK, Cole-Lewis H, Bernhardt JM. Annual review of public health. 2015.

VITAMIN d IN PREGNANCY Multiple studies support the association between pregnancy outcomes and circulating maternal 25(OH)D1-3 Dietary supplementation with vitamin D effects on pregnancy Reduction in the risk of premature labor/birth Reduction in combined maternal comorbidities1: Gestational Diabetes Hypertensive disorders Infection Results from multiple investigators and multiple studies have confirmed the results of our center’s original Vitamin D Supplementation in Pregnancy study. In this NICHD trial with vitamin D supplementation during pregnancy we found evidence to support both a reduction in the risk of premature labor and birth as well as other pregnancy related comorbidities with additional vitamin D supplementation, namely 4000 IU/day as compared to the standard prenatal vitamin amount—which is 400 IU/day. These results are clear when looking at the maternal 25-hydroxy-vitamin D [25(OH)D] status but it has been an evolving process to identify the dose of vitamin D3 supplementation associated with these decreased risks. For this reason, there have been many improvement cycles to determine this dose variance; and compliance with the supplement has been at the forefront of this discussion. 1Hollis BW, Wagner C, et al. JBMR. 2011. 2Litonjua AA, Weiss ST. Contemp Clin Trials. 2014. 3Wagner CL, McNeil R, et al. Am J Obstet Gynecol. 2013.

Supplementation compliance Combatting compliance failures Hollis BW, Johnson DD, Wagner CL. Vitamin D Supplementation during Pregnancy. JBMR. 2011. If appt was missed  next month supply mailed to residence If >2 missed appts OR failure to take at least 50% pills  exited study 𝒓𝒆𝒕𝒖𝒓𝒏𝒆𝒅 𝒑𝒊𝒍𝒍𝒔 𝒆𝒙𝒑𝒆𝒄𝒕𝒆𝒅 𝒑𝒊𝒍𝒍𝒔 =% 𝒂𝒅𝒉𝒆𝒓𝒆𝒏𝒄𝒆 As background, in the Hollis/Wagner double-blind, placebo-control randomized clinical trial evaluating vitamin D supplementation during pregnancy, an examination was performed on adherence to daily supplementation. In this study, women were followed monthly from early 2nd trimester throughout pregnancy and delivery, during which time they were randomized to three different supplementation regimens of vitamin D. The number of vitamin D pills returned at each visit was divided by the expected number of pills that would have been taken between study visits to generate a percentage that served as a measure of adherence of medication regimen between study visits. If a woman missed one prenatal visit, her next month supply of vitamins was either mailed to her or dropped off at her residence. If a woman had more than two missed visits or if she failed to take at least 50% of the prescribed vitamin D pills, she was exited from the study. As you can see, secondary to nonadherence, 25% of the enrolled population was exited from the study. Enrolled (n=502) Exited (n=129) 25% of study population

Supplementation compliance Wagner CL, McNeil R. et al. Am J Obstet Gynecol. 2013. Sub-analysis revealed need for alternative methods to enhance medication adherence1 Enrolled (n=257) Exited (n=163) 15% of study population In our subset, Thrasher-funded regional trials with similar study design, those non-compliant narrowed from 25% to 15%. The aforementioned method of adherence measurement (via pill counts) was compared in a separate sub-analysis to an adherence measure of serum metabolite levels in the study population (both the absolute change in 25(OH)D over the study period and the subject's steady-state variation in their 25(OH)D levels). The analysis found pill count was not a reliable predictor of adherence to protocol. That paper demonstrated the impact nonadherence can have on study results and definitely provided implications for the analysis and presentation of clinical trial data. So the question became, why would these women NOT be taking these pills while on protocol? 1Appelgren KE, et al. Int J Endocrinology. 2010.

Compliance improvement initiatives Enhancing compliance Ease of swallowing Taste Ease of use In addition to these compliance measures, TECHNOLOGY assistance was introduced Difficulty swallowing the original large supplement pills was countered with use of Flintstone’s prenatal vitamins in the group receiving 400 IU/day, which led to the trial I will be discussing and the changes made in pill regimen. In our current clinical trial GUMMY vitamins were utilized, in both the control and treatment groups, and compliance was again assessed based on returned pill counts. We found gummy vitamins to be more appealing to patients due to ease of administration as well as the taste, therefore, theoretically increasing compliance. In addition to these measures, technology assistance was introduced in our current overarching study as yet another tiered approach to medication compliance, in the form of a daily text message reminder.

Kellogg Foundation vitamin d in pregnancy project Enrolled mothers (2012-2016): 18-45yrs of age who presented by 14 weeks gestation Singleton pregnancies Double-blind, placebo-controlled RCT with one of two treatment regimens of vitamin D3 supplementation Group A: 400 IU/day Group B: 4,400 IU/day – daily dose shown to achieve optimal production of active vitamin D hormone Study participants were enrolled in our “Kellogg Foundation Vitamin D in Pregnancy” project between 2012-2016. Mothers were 18-45years old who presented to our Obstetrical facilities within the first 14 weeks of their last menstrual period and had to be carrying a singleton pregnancy. This was a double-blind, placebo-controlled RCT. Women were randomized to one of two treatment regimens of vitamin D: either 400 IU/day (found in any standard prenatal vitamin) or the standard dose PLUS 4000 additional IU/day—which was the daily dose shown to achieve optimal production of active vitamin D during pregnancy, which I eluded to earlier as a novel finding from the previous NICHD trial. The study participants were followed monthly during their pregnancy and we utilized the maternal 25-(OH)D levels in our analysis, as this is a much more accurate determinate of maternal vitamin D status.

Technology assisted adherence Study Design A priori designed analysis in the experimental arm of the trial (4,400 IU/day vitD3) Ineligibility: Withdrawal/exited from study and non-English speakers 400 IU/day (n=184) 4,400 IU/day (n=189) Opted to receive text messaging (n=33) Did NOT opt to receive text messaging (n=74) Primary Outcome %∆ 25(OH)D Exited (n=82) We performed an a priori designed analysis, in the experimental arm of the trial, to compare the difference in those who opted to receive text message medication reminders vs those who did not and the % change in maternal 25(OH)D from the first study visit to delivery. Of note, in 2012 (when this trial initiated patient enrollment), cell phone technology for this purpose was a novel concept. This was one of the 1st studies in South Carolina to use texting technology. Exclusion criteria consisted of women who withdrew from the study and those who did not speak English as a primary language, due to the English-only capabilities of the text app at time of enrollment.

Texting intervention Daily supplement/medication reminder Mothers chose the time of day for the reminder Text message format: “Have you taken your vitamin D today? Enter 1 for yes” Our text messaging intervention included a daily reminder for enrolled mothers who opted in to this portion of the study. Each mother who opted in to receive the reminder chose the time of the day, so the message was conducive to their personal schedule. The text message read: “Have you taken your vitamin D today? Enter 1 for yes”, so the application had the capability to respond to the reminder, which was additionally recorded on our database.

Maternal [25(OH)D] throughout pregnancy in treatment group 4,400 IU/day group Maternal 25(OH)D (ng/mL) Opt In Yes No Study Visit This graph highlights the absolute value of maternal 25(OH)D concentrations at each monthly study visit throughout pregnancy in the treatment group, controlling for baseline 25(OH)D. Those identified by the red line, opted to receive text message notifications throughout the study and those identified by the blue line, opted NOT to receive text message notifications.

Association between % change in maternal [25(OH)D] and text reminders % change [25(OH)D] Opt In (n=33) Opt Out (n=74) Mann-Whitney U Test (SAS v9.4). *p=0.03 * 4,400 IU/day group 114 91 The association, our primary outcome, between receiving medication reminders and % change in maternal 25(OH)D concentrations throughout the course of gestation was estimated by Mann-Whitney U test. We found a statistically significant difference between those who opted to receive medication reminders and % change of maternal 25(OH)D concentrations. Of the 33 who opted to receive medication reminders, the median change was 114% and for the 74 who opted NOT to receive medication reminders, the median % change was only 91%, with a p value of 0.03. (click)

Association between % change in maternal [25(OH)D] and text reminders Using a linear regression model and controlling for: Race Insurance status Pill count Opting to receive medication reminders was significantly associated with an increased % change in maternal 25(OH)D concentrations from baseline (p=0.02) Estimated average of 44% greater if mothers opted IN to receive reminders Our next step was to use a linear regression model. After controlling for race, insurance status, and pill count, opting to receive medication reminders was significantly associated with an increased % change in maternal 25(OH)D concentrations (p=0.02). There was an estimated average of 44% greater if mothers opted IN to receive reminders. One potential limitation should be mentioned here: Subjects were not randomized to receive text messaging, rather they OPTED in or out—which may contribute to volunteer bias (i.e. the mother has a compliant personality) vs the actual text message intervention.

conclusions Association between participants who opted to receive text medication reminders (vs those who did not) and improvement in maternal 25(OH)D concentrations during pregnancy Consistent with emerging evidence on the role of technology assistance as a critical role in improving maternal health (and thus fetal health) Highlights importance of multilingual applications 54 out of 190 (28%) mothers in treatment group ineligible due to English-only app In conclusion, our findings support a significant association between participants who opted to receive text medication reminders vs those who did not, and improvement in maternal 25(OH)D during pregnancy. Our findings are consistent with the emerging evidence that technology assistance may play a critical role in improving maternal, and thus fetal, health. This study additionally highlights the importance of multilingual applications appropriate for populations enrolled to RCTs. Since our study only assessed primary English speakers, the generalizability of findings to a more diverse population is needed. Fifty four out of the original 190 eligible mothers in the treatment group, which was 28%, could not be included in the analysis secondary to the English-only capabilities of the text app.

In collaboration with Myla Ebeling: Dept of Pediatrics Kristen Morella, MPH: Public Health Sciences Frank Treiber, PhD: College of Nursing, TACHL Sachin Patel, MSc: College of Nursing, TACHL David Annibale, MD: Dept of Pediatrics, Division of Neonatology Carol Wagner, MD: Dept of Pediatrics, Division of Neonatology A special thank you for the help, assistance, intelligence, skills and mentorship from the above group. Funded by: W.K. Kellogg Foundation NIH Grant UL1TR0000062

questions Thank you again for allowing me to share this data with you. I am happy to answer any questions at this time. Kellogg Exclusion Criteria: pre-existing calcium disease, uncontrolled thyroid disease, parathyroid conditions or who require chronic diuretic/cardiac medications, sickle cell disease, sarcoidosis, Crohn’s disease, ulcerative colitis Current evidence supports the concept that circulating 25-hydroxyvitamin D should be 40-60  ng/ml (100-150  nmol) during pregnancy and a daily intake of 4000  IU vitamin D3 is required to attain that circulating level. Is the question: text messaging improves compliance or is it the act of signing up as surrogate for compliance. Both are important. If texting itself changes compliance, then we need trials to improve compliance with exercise (FitBit), pills, PT exercises. If it's signing up that identifies a group of compliant vs noncompliant people, then we can use that to test interventions and perhaps improve compliance... Graph 1: This repeated measure analysis did not show a statistical significance although there is a definitive trend towards improved maternal 25(OH)D concentrations in those women who opted to receive reminders. p-value 0.5 Linear Regression Model: Parameter estimate 44% with a standard error of 20%.

“There’s an app for that!” Future Endeavors ProPillCap Pregnancy Applications So what’s the future in technology for medication adherence? Our University’s Technology Application Center for Healthful Lifestyles (TACHL) program is testing their development of a customized pill bottle to encourage medication compliance. Interestingly the research of this group suggests the three domains MOST important in people’s lives that contribute to adhering to a medical regimen include: Faith, Family and Friends. These feedback mechanisms mean more to patients than a healthcare provider’s reminder. So the group has developed a pill bottle cap, called the Pro Pill Cap, that integrates with smartphones to provide a series of alerts when it’s time to take the medicine. Even better, the cap “talks” when it is opened with recorded messages providing support and encouragement for taking the pills. Additionally, this application would be utilized, similar to an insulin-pump, for providers to download compliance data at follow-up medical appointments. For maternal and pediatric health, I envision a recording of fetal heart tones with a voice saying “Thanks for taking care of me today mom!” every time a prenatal vitamin bottle is opened.