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

Letrozole is an aromatase inhibitor with an unapproved use for ovulation induction with infertility. Because of the proximity of this use to conception, the authors selected letrozole to explore the effect of imperfect estimation in the pregnancy start on misclassification in measurement of first-trimester exposure. The authors 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. 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.