Archive | Pharmacoepidemiology

Pediatric Pharmacoepidemiology at ICPE 2017 Annual Meeting

For the third year, the ISPE annual meeting (ICPE 2017 Montreal) will offer the pre-conference course in Pediatric Pharmacoepidemiology.

Mark your calendars for Sunday, August 27, 2017 (register here).

Brief Overview of Course

The increasing use of medications by children and the history of excluding children from clinical trials have created the need for pediatric pharmacoepidemiology, a sub-specialty within pharmacoepidemiology. Unique challenges in studying children, accessing data, defining outcomes, and designing studies require specialized methodologic skills and operational approaches. This half-day course will introduce participants who have a good understanding of pharmacoepidemiology to the specialized methodologic and operational approaches used to study medications in children.

Pediatric Pharmacoepidemiology

Age is not a simple variable when studying children

Educational Objectives

The course will be taught in an interactive format with ample opportunities for questions and discussion. Regulatory issues around use of medications in children will be highlighted throughout the course. Participants will gain an understanding of key issues in pediatric pharmacoepidemiology including:

  • An overview of pediatric pharmacoepidemiology and how it differs from pharmacoepidemiology in older age groups
  • Study design and databases to monitor safety
  • Defining, measuring and validating outcomes in pediatric pharmacoepidemiology
  • Variables critical to pediatric pharmacoepidemiology such as month of birth, seasonality, growth and development

Target Audience

ICPE attendees interested in gaining a basic understanding of the need for and approaches to pediatric pharmacoepidemiology.

Course Faculty/Presentations

  • Tamar Lasky, PhD Owner, MIE Resources Why Pediatric Pharmacoepidemiology? Age Sub-groups in Children: Methodologic Considerations
  • Alan Kinlaw, PhD Post-doctoral Research Fellow, Sheps Center for Health Services Research, University of North Carolina at Chapel Hill Leveraging granular birthdate information for studies of young children
  • Rachel E. Sobel, DrPH Senior Director, Epidemiology, Worldwide Research and Development / Pfizer Inc. Monitoring Drug Safety: Study Design, Data Sources and Case Study
  • Timothy Beukelman, MD, MSCE Associate Professor of Pediatrics, Division of Pediatric Rheumatology, Department of Pediatrics, University of Alabama at Birmingham The Need for Validation in Pediatric Outcomes
  • Daniel B. Horton, MD, MSCE Assistant Professor of Pediatrics and Epidemiology, Rutgers University Growth and Development: Variables of Particular Importance in Pediatric Pharmacoepidemiology



NHANES – beyond nutrition to prescription meds

NHANES prescription medication data hasn’t always been on my radar.

I’m not sure why this was so. NHANES is a well known national survey that began as a nutrition survey and quickly expanded to include a range of health variables, including results of a physician exam and laboratory tests. It is a national probability based sample, which means that one can generalize from the NHANES to the entire United States, and its methodologic standards are of the very highest. Perhaps the reason that I overlooked the prescription medication data is that there is so much data, and also, that NHANES was known primarily for nutrition data. Getting past my own blind spot, I decided to take a closer look at the prescription medication data collected in NHANES.

Here are some key points.

The survey

NHANES began in the 1960s and was conducted in waves, with a NHANES I, NHANES II and NHANES III. We love it so much that it became a permanent fixture. Since 1999 it has been conducted continuously in two-year cycles, and is now called NHANES continuous, or just NHANES. The US population is sampled over a two-year cycle and the data need to be analyzed using the full two-year sample. The sample is representative of the non-institutionalized, U.S. population and for example, does not include residents in nursing homes, or people in prison.

Sample size

Sample size is critical to being able to estimate drug utilization. Unweighted sample sizes by age group are listed in the table below. While the numbers are large (every one of these people was interviewed in their homes), they may not be large enough for many purposes in pharmacoepidemiology. For those of us interested in pediatric medication use there were 4,194 people under 20 included in the sample. When stratified into age groups, the sample might not be large enough to study medications taken by small percentages (fewer than 1%) of children. The table below is taken from the NHANES website and shows unweighted sample sizes.

Table 2. Unweighted sample size and percents by age groups from NHANES 2005-06, 2007-08 and 2009-2010 for examined participants

NHANES prescription medications

NHANES prescription medication information

The medication information is collected during an in person interview in the participant’s home. During the interview, survey participants are asked if they have taken medications in the past 30 days for which they needed a prescription. Those who answer “yes” are asked to show the interviewer the medication containers of all the products used. For each medication reported, the interviewer enters the product’s complete name from the container into a computer. If no container is available, the interviewer asks the participant to verbally report the name of the medication. Participants are also asked how long they had been taking the medication and the main reason for use. This is in contrast to databases that rely on billing or claims data, or electronic health records. Documentation about the 2011-2012 data files containing prescription medication can be found here.

Using NHANES prescription medication data for pharmacoepidemiology

The pros and cons of using NHANES for pharmacoepidemiology are straight forward. On the pro side, NHANES may be the only probability based population sample in the United States with medication information. This alone makes it extremely valuable, and useful in conjunction with other types of data. The second strength, is that unlike health records, claims, or prescription data bases, the NHANES documents the presence of the medication in the patient’s home, demonstrating the the prescription was purchased and brought home. Along the continuum of measures, beginning with prescriptions written and prescriptions filled, documenting the prescription in the patient’s home brings us closer to understanding true exposures and levels of use. Another positive that needs to be explored is the availability of information from the physical exam and laboratory tests for the person using a given prescription.

On the con side, the sample sizes may be too small to provide stable estimates of many medications, especially if one wishes to study use within a sub-group. In terms of bias, my first thought is that this method of estimating use will result in underestimates of use, with people forgetting, omitting or otherwise not reporting their medication use to an interviewer. Misclassification in the other direction might occur when a person has filled a prescription and shows the prescription to the interviewer, but does not take the prescription. This latter source of bias would lead to an over-estimate of use but would also effect each of the other types of measures of prescription medication use (prescriptions written or prescriptions filled also over-estimate the numbers of people actually using the medication.

Recent publications using NHANES prescription medication data

A quick search turns up several publication analyzing prescription medication data in NHANES, but not as many as one might expect. An interesting use of the data is that of Bateman and colleagues (2012) focusing on a group with a risk factor, hypertension, and describing the medication use within that group. This usage may have applications for people working in health economics and outcomes research.

  • Farina EK, Austin KG, Lieberman HR, “Concomitant Dietary Supplement and Prescription Medication Use Is Prevalent among US Adults with Doctor-Informed Medical Conditions” J Acad Nutr Diet 2014 Apr 4 S2212-2672(14)
  • Bertisch SM, Herzig SJ, Winkelman JW, Buettner C, “National use of prescription medications for insomnia: NHANES 1999-2010” Sleep. 2014 Feb 1;37(2):343-9
  • Chong Y, Fryer CD, Gu Q, “Prescription sleep aid use among adults: United States, 2005-2010” NCHS Data Brief. 2013 Aug;(127):1-8
  • Gu Q, Burt VL, Dillon CF, Yoon S, “Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health And Nutrition Examination Survey, 2001 to 2010” Circulation. 2013 Jun 18;127(24)
  • Bateman BT, Shaw KM, Kuklina EV, Callaghan WM, Seely EW, Hernandez-Diaz S, “Hypertension in women of reproductive age in the United States: NHANES 1999-2008” PLoS One. 2012;7(4):e36171
  • Kinjo M, Setoguchi S, Solomon DH, “Antihistamine therapy and bone mineral density: analysis in a population-based US sample” Am J Med. 2008 Dec;121(12):1085-91

Pain meds used by children while in the hospital

Pediatric pain medications

When children are in the hospital, they often need pain relief or sedation, yet most drugs used for pain relief or sedation in children have not been studied in children. A first step in understanding the overall use of pain medications is to document the medications used and their frequency of use. Our publication, “Use of Analgesic, Anesthetic, and Sedative Medications During Pediatric Hospitalizations in the United States 2008”, published in the journal, Anesthesia and Analgesia in  2012, describes medications used in over 800,000 hospitalizations.

We describe use of analgesics, anesthetics, and sedatives in pediatric inpatients by conducting a statistical analysis of medication data from the Premier database. We identified all uses of a given medication, selected the first use for each child, and calculated the prevalence of use of specific medications among hospitalized children in 2008 as the number of hospitalizations in which the drug was used per 100 hospitalizations. Dose and number of doses were not considered in these analyses.

The dataset contained records for 877,201 hospitalizations of children younger than 18 years of age at the time of admission. Thirty-three medications and an additional 11 combinations were administered in this population, including nonsteroidal antiinflammatory drugs, local and regional anesthetics, opioids, benzodiazepines, sedative-hypnotics, barbiturates, and others. The 10 most frequently administered analgesic, anesthetic, or sedative medications used in this population were acetaminophen (14.7%), lidocaine (11.0%), fentanyl (6.6%), ibuprofen (6.3%), morphine (6.2%), midazolam (4.5%), propofol (4.1%), lidocaine/ prilocaine (2.5%), hydrocodone/acetaminophen (2.1%), and acetaminophen/codeine (2.0%).

Use changed with age, and the direction of change (increases and decreases) and the type of change (linear, u-shaped, or other) appeared to be specific to each drug.

Figure 1 shows the number and percentage of pediatric hospitalizations with nonsteroidal antiinflammatory drug (NSAID) use, by age group. Bars indicate number of hospitalizations. Lines indicate percentage of hospitalizations. Acetaminophen was considered in these analyses as an NSAID for the sake of categorical simplicity; however, pharmacologically, the antiinflammatory activity of acetaminophen is minimal, such that some do not consider it a true NSAID.

Pediatric pain medications by age group.

Figure 1. Number and percentage of pediatric hospitalizations with non steroidal anti-inflammatory drug (NSAID) use, by age group.

Figure 2 shows the number and percentage of pediatric hospitalizations with opioid use, by age group. Bars indicate number of hospitalizations. Lines indicate percentage of hospitalizations.

hospitalizations with use of pediatric pain medications (opioids), by age group.

Figure 2. Number and percentage of pediatric hospitalizations with opioid use, by age group.

See the accompanying editorial by Joseph Tobin, MD, “Pediatric Drug Labeling: Still an Unfinished Need”. As he says,

Chronic pain in children is seriously underrecognized in comparison with the prevalence of chronic pain in adults. This is one more circumstance in which labeling in children would be very beneficial to anesthesiologists and their patients.

Morphine Use in Pediatric Inpatients

Pediatric morphine use in the hospital

As with so many medications used widely to treat children, morphine is not labeled for pediatric use. Describing patterns of use helps us understand how many children are receiving a drug that is not approved for pediatric use by the FDA.

A statistical analysis of 877,201 pediatric hospitalizations in the United States in 2008 estimated that morphine was used in 54,613 (6.2%) hospitalizations in the database. If this percentage is applied to the total number of children’s hospitalizations in the US in 2008, as many as 476,205 children will have received morphine during their hospital stay that year. Fractures and appendicitis were two of the diagnoses most frequently listed for children receiving morphine.

While morphine can be used safely for pain management during hospital procedures, and has been used for this purpose for several decades, the lack of pediatric labeling is undesirable. In a discussion about whether the off-label use of a drug constitutes experimentation and research, the American Academy of Pediatrics Committee on Drugs noted that “discussion about the off-label status of a drug may, as a matter of professional judgment, be part of the information provided to the patient or parents.”

The article reporting statistical analysis on morphine use in pediatric inpatients can be found here:”Morphine Use in Hospitalized Children in the United States: A Descriptive Analysis of Data From Pediatric Hospitalizations in 2008″Lasky T, Greenspan J, Ernst FR, and Gonzalez L Clinical Therapeutics 2012, 34(3): pp.720-727.

The American Academy of Pediatrics discussion on “Uses of drugs not described in the package insert (off-label uses)” can be found here. Pediatrics. 2002;110: 181–183.

Geographic Variation in Prescribing Practices

The authors used HEDIS quality measures, and mapped them by hospital referral region.

The map above shows variation in quality of prescribing high-risk drugs (medications considered to be high-risk for the elderly), and the map below shows variation in prescribing drugs with potentially harmful drug-disease interactions.

NEJM November 2010