Misclassification in Assessment of First Trimester In-Utero Exposure to Drugs used Proximally to Conception - The Example of Letrozole Utilization for Infertility Treatment

Abstract

Letrozole is an aromatase inhibitor with an unapproved use for ovulation induction with infertility. Because of the proximity of this use to conception, we selected letrozole to explore the effect of imperfect estimation in the pregnancy start on misclassification in measurement of first-trimester exposure. Using electronic health data from the United States Sentinel database (2001-2015), we identified live-birth pregnancies conceived through in-vitro fertilization or intrauterine insemination. The pregnancy start was calculated using 1) a validated algorithm to estimate the last menstrual period (LMP), 2) LMP+14 days (i.e. conception estimate), and 3) the fertility procedure date. We identified 47,628 live-births after intrauterine insemination (n=24,962) and in-vitro fertilization (n=22,666), 2,458 (5.3%) of which received letrozole. The algorithm-based conception estimate occurred within ±14 days of the fertility procedure for 78.3% of pregnancies. Defining pregnancy start as LMP (45.7/1000 pregnancies) or LMP+14 days (12.7/1000 pregnancies) overestimated letrozole exposure during pregnancy by 8.4-fold and 2.3-fold, respectively, compared to the fertility procedure (5.5/1000 pregnancies). While most pregnancy utilization studies use LMP as the conventional pregnancy start, this introduced substantial exposure misclassification in the example of letrozole. LMP+14 was less biased. Researchers should carefully consider the impact of pregnancy start date selection on potential for exposure misclassification.