The Natural History of Pregnancy Loss

Abstract

The Natural History of Pregnancy Loss Katherine Jane Sapra Pregnancy loss, the demise of a pregnancy at any time between implantation and delivery, is a common event in women’s lives, affecting approximately one in three pregnancies. Pregnancy loss often causes profound psychological distress to women, their partners, and their families. However, despite its frequency and troubling nature, relatively little is known about the natural history of pregnancy loss, especially the multitude of signs and symptoms that precede a loss and distinguish it from an ongoing healthy pregnancy. One of the challenges in describing the natural history of pregnancy loss is that most losses occur very early, before entry to clinical care, necessitating the use of preconception cohort studies. Few such studies have ever been conducted worldwide. This dissertation aimed to describe the natural history of early pregnancy loss at <20 weeks gestation for the first time using a unique preconception cohort with daily prospective follow-up from the start of the pregnancy attempt through seven weeks post-conception. To accomplish this goal, three specific aims were undertaken. First, a systematic literature review was conducted to synthesize the existing literature on the relationships between the signs and symptoms and pregnancy loss. Two analytic aims were then undertaken to delineate thoroughly the relationships between prospectively ascertained signs and symptoms—namely, vaginal bleeding, lower abdominal cramping, nausea and vomiting (hereafter referred to as “signs and symptoms”)—and subsequent early pregnancy loss. The first analytic aim used a fixed covariate and fixed effect survival analytic approach to estimate the cumulative incidence of early pregnancy loss by the presence of individual, combinations, and patterns of signs and symptoms and the associations between signs and symptoms and the cumulative incidence of pregnancy loss. The second analytic aim used a time-varying covariate and time-varying effect survival analytic approach to estimate the weekly associations between signs and symptoms and pregnancy loss to determine if these relationships were consistent or divergent across gestational ages. The results of the first and second analytic aims were then compared to gain a more complete understanding of the natural history of early pregnancy loss. The literature review revealed a dearth of studies on the signs and symptoms of pregnancy loss. Two preconception and 16 pregnancy cohort studies were identified. The literature suggested that vaginal bleeding, particularly heavy vaginal bleeding, was associated with an increased risk of pregnancy loss while vomiting, and in some studies nausea, was associated with a decreased risk of pregnancy loss. However, reliance on care-seeking cohorts, maternal retrospective reports of signs and symptoms after pregnancy loss, and retrospective recall of signs and symptoms over long periods (e.g., entire trimesters) may have biased the observed associations between signs and symptoms and pregnancy loss leading to incorrect inferences regarding the relationships between signs and symptoms and pregnancy loss. The two analytic aims addressed the data gaps identified in the literature review. The preconception cohort design with prospective daily follow-up from the beginning of the pregnancy attempt facilitated the ascertainment of pregnancies at the earliest stages of gestation and losses prior to clinical care entry through the use of urine-based home pregnancy testing. The daily reporting of multiple signs and symptoms in the first five weeks after a positive home pregnancy test, or approximately two to seven weeks post-conception, allowed for a full description of the relationships between signs and symptoms of pregnancy loss without recall