Modern Pregnancy Pharmacoepidemiology: Non-Live Birth Outcomes

‎1. Course Aim ‎
In this course, faculty will present and discuss considerations related to designing studies on the safety of ‎medical products in pregnancy focusing on non-live pregnancy outcomes: spontaneous abortions, stillbirths, ‎elective terminations. Studying these outcomes is subject to a specific set of challenges and biases and ‎requires special design considerations. ‎

The course will consist of three presentations followed by a practical component in which course registrants ‎will apply the core course concepts in groups focusing on a specific research question.‎

The overarching goal of the Modern Pregnancy Pharmacoepidemiology course is to keep up with advances in ‎the field. We cover new topics each year, from overviews of issues that are particular to research on the safety ‎of medical products in pregnancy (2015, 2020) to deeper dives into specific aspects, such as study design ‎‎(2018), exposure measurement (2016), various maternal, neonatal and childhood outcomes (2017, 2021), and ‎significance testing and analytical approaches to address biases (2019). In 2022, the course discussed ‎pregnancy pharmacoepidemiologic research within the framework of target trial emulation. This year, the ‎focus will be on non-live birth outcomes.‎

‎2. Requisites Statement ‎
This is an intermediate level pharmacoepidemiology course. ‎

‎3. Course Objectives‎
‎a.‎ To be better equipped to critically assess the validity of studies on the safety of medical products in ‎pregnancy
‎b.‎ To learn key clinical aspects of non-live birth outcomes
‎c.‎ To identify the structure of potential biases in the study of non-live birth outcomes
‎d.‎ To understand operational and logistic challenges in research on non-live birth outcomes ‎
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4. Syllabus Outline‎
‎1.‎ The clinical presentation and pathophysiology of non-livebirth and the relation to drug exposures.‎
In this portion of the course, we will review the clinical presentation and risk factors for non-livebirths with an ‎eye to how these inform the design and interpretation of studies of medication safety. Topics considered ‎include mechanisms by which medications cause spontaneous abortion or stillbirth and the etiologically ‎relevant time window for exposures. Examples of medications associated with an increased risk of non-‎livebirth will be discussed.
Instructor: Brian Bateman, Stanford University School of Medicine

‎2.‎ On the roles of non-live births: outcome, competing event, and source of bias
Fetal losses may be our outcome of interest, or they may occur before or after other outcomes of interest. ‎These three scenarios present distinct challenges of left and right truncation that may lead to selection and ‎misclassification biases. In addition, fetal losses compete with later outcomes, which may complicate the ‎conceptualization of research questions and the corresponding data analysis. We provide a framework that ‎may facilitate the discussion of solutions, interpretations and assumptions. We will discuss examples of ‎selection (survivor) bias when the follow-up starts after conception and of immortal time bias when time ‎between conception and exposure initiation is misclassified as exposed. ‎
Instructor: Sonia Hernandez-Diaz, Harvard T.H. Chan School of Public Health

‎3.‎ Challenges when studying non-live birth outcomes in case-control, registry and database studies
During this section, we will discuss some of the key operational and logistical challenges faced with when ‎studying non-live birth outcomes in the context of different study designs and review potential solutions. ‎Issues that will be covered include amongst others identification of non-live birth outcome and gestational age ‎estimation (database studies), potential selection bias associated with prospective enrolment throughout ‎pregnancy and lack of power (registries), potential recall bias and lack of generalizability (case-control studies).‎
Instructor: Krista Huybrechts, Brigham and Women’s Hospital, Harvard Medical School

‎4.‎ Practical session
During the final session, participants will discuss in small teams a request to study the potential association ‎between a medical product and non-live birth outcomes posed by a regulatory agency at the time of marketing ‎authorization. Experiences will be shared and discussed with the entire group. ‎
Led by: Andrea Margulis, RTI Health Solutions‎