Short- and Long-Term Effects of Antibiotics on Childhood Growth (ABX)

The Patient-Centered Outcomes Research Network (PCORnet) Obesity Observational Study: Short- and Long-Term Effects of Antibiotics on Childhood Growth

The objectives of the proposed study are to assess the effects of different types, timing, and amount of antibiotic use in the first two years of life with (Specific Aim 1) body mass index (BMI) and obesity at ages 5 and 10 years and (Specific Aim 2) growth trajectories to age 5 years. In Specific Aim 3, the investigators will address how big the effects of antibiotics on obesity are within subgroups of the population, such as different racial/ethnic groups and whether the child's mother got antibiotics while she was pregnant.

The data for this study will come from electronic medical records of about 600,000 children from 42 healthcare systems within 10 Clinical Data Research Networks (CDRNs) across the United States. The investigators will get information on antibiotic prescribing in the first two years of life, then "virtually" follow these children to ages 5 and 10 years to see what their BMIs are, and how many of them are obese by clinical standards (i.e., body mass index exceeding the 95th percentile for age and sex).

In the main analyses, the CDRNs will not send any individual data to a central site. Rather, using sophisticated computer programs, the study's coordinating center will send "questions to the data," thus protecting the privacy of patients' and the healthcare systems' records. In some analyses, to check how well this "distributed research network" approach works, we will work with individual records whose identifying information has been stripped off ("de-identified data").

In our Secondary Aim, the investigators will employ focus groups of parents and in-depth interviews with clinicians to explore how best to put the findings into everyday practice.

Throughout the study, in addition to employing privacy-protecting approaches to analyzing and sharing data, the investigators will adhere to principles of inclusion, patient-centeredness, stakeholder engagement, effective governance, and protection of human subjects. At the end of the two-year project, the investigators will propose avenues for dissemination of the scientific findings and other products.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Antibiotics exposure

Detailed Description

Antibiotics are among the most valuable medical discoveries. Recent research on understanding of how bacteria in our gut use energy, however, raises concerns about whether broad-spectrum antibiotics, which are over-prescribed for mild infections, prescribed in early infancy may cause obesity during childhood. Obesity is a very common and serious condition among US children, particularly children from disadvantaged populations. Past studies examining the link between antibiotic use and childhood obesity are too small and they lack diversity as well as modern scientific tools to gauge the extent to which prescribing antibiotics can lead to excess weight gain. PCORnet, the National Patient-Centered Clinical Research Network, comprising very large networks of data from electronic medical records, provides an ideal test bed to address this question. Further, it is not clear how caregivers and clinicians will use the results of earlier studies to decide which antibiotics to prescribe when faced with common infections like ear infections.

Specific Aim 1: To evaluate the comparative effects of different types, timing, and amount of antibiotics used during the first two years of life on body mass index and risk of obesity at ages 5 (primary outcome age) and 10 (secondary) years. Hypothesis: There will be a "dose-response" relationship between the number of antibiotic courses given during the first 2 years of life and both higher BMI and the probability of obesity at ages 5 and 10 years. This relationship will be strongest for broad-spectrum antibiotics prescribed in the first 6 months of life.

Specific Aim 2: To assess the comparative effects of different types, timing, and amount of antibiotics used during the first two years of life on the rates and patterns of childhood growth during the first 5 years of life. Hypothesis: There will be a "dose-response" relationship between the number of antibiotic courses given during the first 2 years of life and subsequent growth trajectories of children in a pattern that increases children's risk of later overweight and obesity. This relationship will be strongest for broad-spectrum antibiotics prescribed in the first 6 months of life.

Specific Aim 3: To explore how the effects of different types, timing, and amount of antibiotics on childhood BMI, obesity risk and growth (Aims 1 and 2) vary according to patient socio-demographic, clinical, and maternal characteristics, including: 1) socio-demographic (Child sex, Child race/ethnicity, Geography, based on location of clinical facility); 2) Clinical (Prescription of medications that also cause obesity, esp. corticosteroids, Low birth weight or macrosomia in term infants); 3) Maternal for the subset of data partners listed in section B above that have linked maternal and child records (BMI, Maternal receipt of antibiotics during pregnancy, Type of delivery, i.e., Cesarean v. vaginal). Hypotheses: The antibiotic effects will not vary by socio-demographic or maternal characteristics. Long-term corticosteroid use will potentiate the effect of antibiotics on childhood obesity.

Secondary Aim: Through focus groups and in-depth interviews, to explore how parents and other caregivers and their providers assess information related to current and future benefits and risks, particularly for treatments such as antibiotics in early childhood, which can have substantial near-term benefits along with moderate long-term risks. The investigators will also explore how clinicians, health care organizations, and policy makers should best present study findings to help parents understand its strengths and limitations in the context of shared clinical decision-making.

• Study Type: Observational
• Enrollment (Actual): 681739

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The study population will include children from age 0 to age 11 years. The population will be identified using data from participating sites formatted into the PCORnet Common Data Model (CDM).

Description

Inclusion Criteria:

1. 1 or more encounters with length and weight measured in each of the following age intervals: 0-12 months, 12-30 months, and
2. 1 or more encounters with height and weight measured after 24 months of age (need 1 or more measure at 4.0-5.9 years for the 5 year outcome and 1 or more measure at 9.0 to 10.9 years for the 10 year outcome), or eligible to be followed to these ages using multiple imputation to account for missing data.

Exclusion Criteria:

1. Biologically implausible length/height or weight measurements

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Children from birth to 5 years; Children from birth to 5 years where: 1 or more encounters with length and weight measured in the following age interval: 0-12 m, 12-30 m, and; > 1 encounter with height and weight measured in either or both of the following age intervals: 4.0 to 5.9 y ("age 5 years"), or eligible to be followed to these ages for use in multiple imputation to account for missing data	Drug: Antibiotics exposure
Children from birth to 10 years; Children from birth to 10 years where: 1 or more encounters with length and weight measured in each of the following age intervals: 0-12 m, 12-30 m, and; > 1 encounter with height and weight measured in the following age interval: 9.0 to 10.9 y ("age 10 years"), or eligible to be followed to these ages for use in multiple imputation to account for missing data.	Drug: Antibiotics exposure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Mass Index Z-score Difference at 48-72 Months, Exposed vs. No Antibiotics Less Than 24 Months	BMI z-score measured between 48-72 months Body mass index z-scores are measures of relative weight adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Positive values below indicate a higher BMI z-score in children who received antibiotics versus those who did not.	48-72 Months
Body Mass Index Z-score Difference at 10 Years, Exposed vs. No Antibiotics Less Than 24 Months	BMI measured at 10 years Body mass index z-scores are measures of relative weight adjusted for child age and sex. The Z-score indicates the number of standard deviations away from a reference population in the same age range and with the same sex. A Z-score of 0 is equal to the mean. Positive values below indicate a higher BMI z-score in children who received antibiotics versus those who did not.	10 years

Collaborators and Investigators

• Sponsor: Harvard Pilgrim Health Care
• Collaborators: Patient-Centered Outcomes Research Institute; OneFlorida Clinical Research Consortium; National Patient-Centered Clinical Research Network; Research Action for Health Network (REACHnet); New York City Clinical Data Research Network; Genetic Alliance; Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN); Greater Plains Collaborative Clinical Data Research Network; Mid-South Clinical Data Research Network; PEDSnet: A Pediatric Learning Health System CDRN; Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS); ADVANCE CDRN; PORTAL CDRN; StatLog
• Investigators: Principal Investigator: Jason P Block, MD, MPH, Harvard Pilgrim Health Care Institute; Principal Investigator: Christopher B Forrest, MD, PhD, Children's Hospital of Philadelphia; Principal Investigator: Douglas Lunsford, Nationwide Children's Hospital

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: April 13, 2016
• First Submitted That Met QC Criteria: April 15, 2016
• First Posted (Estimate): April 20, 2016

Study Record Updates

• Last Update Posted (Actual): December 20, 2019
• Last Update Submitted That Met QC Criteria: December 19, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Obesity; Electronic Medical Record; body mass index; pediatric; children; Observational Study; antibiotics; Cohort Study; Comparative Effectiveness Research; Qualitative Research; Growth Trajectory
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: OBS-1505-30699

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared publicly per Patient-Centered Outcomes Research Institute (PCORI) regulations 12 months after study completion. De-identified individual level data and aggregate data will be shared.