Use of real-world evidence from healthcare utilization data to evaluate drug safety during pregnancy

Abstract

Purpose: Because preapproval clinical trials typically exclude pregnant women, the evidence on drug safety during pregnancy required to inform drug labeling must come from postapproval controlled observational studies. Common designs have included pregnancy registries and case-control studies. Recently, pregnancy cohorts nested within healthcare utilization databases are increasingly being used. Despite clear advantages, these databases share some important limitations that may threaten the validity of studies emerging from them.

Methods: This paper describes the distinctive methodological aspects of conducting drug safety studies in healthcare utilization databases with special emphasis on design and analytic approaches to minimize biases.

Results: We describe considerations for study design, cohort definition, and follow-up. We then address issues related to exposure ascertainment based on prescription fills, including the importance of the etiologically relevant window and of properly accounting for preterm births. This is followed by a discussion of advantages and challenges when ascertaining maternal and infant outcomes based on secondary data. We then explore useful approaches to address confounding within the context of pregnancy research and of the potential for selection bias when restricting the cohort to live births. Finally, we consider issues related to external validity and statistical significance. The examples are mainly drawn from a pregnancy cohort nested in the Medicaid Analytic Extract.

Conclusions: The approaches presented provide guidance regarding the important methodological considerations that need to be attended to in order to generate valid, minimally biased risk when using large healthcare utilization databases for drug safety surveillance in pregnancy.

Keywords: drug safety; guidance; healthcare utilization; pharmacoepidemiology; pregnancy.

FIGURE 1

Impact of maternal and infant eligibility criteria on the size of the mother-infant linked Medicaid Analytic Extract (MAX) pregnancy cohort (2001-2007) [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Approaches to operationalizing the definition of medication exposure using databases when studying the risks of congenital malformation [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Prevalence of major congenital malformations in the Medicaid Analytic Extract (MAX) defined on the basis of a single diagnostic claim or an algorithm requiring multiple codes or a single code plus a corrective procedure and/or infant death [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Adjusted relative risk of neonatal drug withdrawal according to maternal exposure to antipsychotic medications in addition to prescription opioids versus prescription opioids alone during the 45 days before delivery, according to level of adjustment for confounding. Medicaid Analytic Extract, 2000-2010. Partially adjusted: adjusted for specific opioid compound and dose; fully adjusted: adjusted for all predefined potential confounding variables. (Adapted from Huybrechts KF et al. Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study. BMJ 2017;358:j3326) [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

External adjustment of the observed crude relative risk (RR_ED). Graph presents the adjustment of a hypothetical observed RR_ED of 1.50 (eg, between antidepressants and cardiac malformations) for smoking considering a range of associations between this confounder and the outcome (RR_CD) from 1 to 2, assuming an estimated prevalence of smoking of 22.0% among unexposed subjects, and a range of smoking (20%-70%) among exposed subjects

FIGURE 6

Impact of restriction to live births showing the corrected relative risk as a function of the probability of live birth for infants with malformations among the unexposed, modeling a 10% and 20% lower probability of live birth among the exposed. Probability of live birth in nonmalformed fetuses is assumed to be 80%. Probability of live birth in malformed, unexposed fetuses is assumed to range from 75% to 55%. The potential impact of a 10% to 20% lower frequency of live birth among the medication exposed on relative risk estimates is estimated