Early Pregnancy Disorders: An Update and Eye to the Future

Kurt T. Barnhart, M.D., M.S.C.E.

Bad things happen to good people. We have all heard this expression. Bad things commonly happen in reproduction. In this series of articles, we explore the diagnosis and management of early reproductive complications and failure. Early reproductive failure in the form or miscarriage and ectopic pregnancy are common. There is a vast literature on the diagnosis and treatment of women at risk for these complications. Most commonly used to differentiate a viable gestation from a nonviable gestation from an extrauterine gestation is ultrasound. In the first article, by Drs. Perriera and Reeves, ultrasound criteria for the diagnosis of early pregnancy failure are described. The key to diagnosing an abnormal gestation promptly is understanding the normal development milestones in early pregnancy as determined by ultrasound. Guidelines regarding the mean sac diameter, the fetal pole, and when cardiac motion should be detected in relation to gestational age, allow a clinician to distinguish a nonviable from a viable gestation.

There are often times, however, when ultrasound diagnosis is unable to assist in the differentiation of the potential complications of an early gestation. Drs. Chung and Allen review the literature on using serial serial human chorionic gonadotropin (hCG) levels to determine patterns that could be used to differentiate a viable gestation from a nonviable gestation. It is of optimum concern when evaluating an early pregnancy to first establish that the gestation is nonviable prior to any intervention that may be necessary to distinguish an intrauterine from an extrauterine gestation. Paramount in the use of these guidelines is that each clinical situation is unique, and many of these signs, although well characterized, are not definitive. Often repeating a serial hCG value or a suspiciously abnormal ultrasound is needed to confirm the diagnosis of a nonviable gestation and will avoid interruption of a desired intrauterine pregnancy. In this case the goal of a diagnostic test is not to balance between the sensitivity and specificity of any given diagnostic test. The goal should be to maximize specificity (avoid classification of a viable pregnancy as nonviable) not to maximize sensitivity (diagnose all nonviable gestations as soon as possible).

Unfortunately, miscarriage is a common occurrence. Although an abnormal chromosome complement or other genetic manifestation is commonly found in conceptuses that miscarry, the true etiology of most miscarriages is unknown. The best a clinician is able to do is to look for associations with miscarriage, as cause is very difficult to establish. In Dr. Brown's article describing miscarriages and associations, he explores this complex issue. Dr. Brown points out the inherent inefficiency of human reproduction and how nonspecific we are in terms of our definitions of miscarriage and its associations. Future studies including much more detailed information regarding abnormalities detected, the gestational age of a miscarriage, and concomitant diagnoses would aid in our understanding and ultimate treatment of a woman at risk for miscarriage.

Once a definitive diagnosis is made of a nonviable pregnancy, there are great advantages to early intervention and to that of medical management. Reductions in cost, morbidity, and time are all benefits to our patients. However, there is subtlety and complexity to medical management of a failing early gestation. Multiple treatment regimens are reported in the literature. Complicating this situation are numerous protocols purporting differences in doses, duration of dose, follow-up, and differential expectations of treatment therapy. In the review by Drs. Dempsey-Fanning and Davis on how to treat and what to expect, the authors discuss treatment-related side effects, expected symptoms to be experienced by patients, as well as potential complications of therapy. In a thorough review, Drs. Chen and Creinin discuss the efficacy of medical management of early pregnancy failure with an eye toward an evidence-based approach of which therapy will provide the best treatment.

Finally, this series goes beyond just attempting to summarize expected complications of early pregnancy. In the final two articles, we explore the potential of adverse reproductive consequences associated with assisted reproductive technologies (ARTs). Although in vitro fertilization has become standard of care and has assisted in the conception of hundreds of thousands of children who may not have otherwise been conceived, there are associations with adverse outcomes. In the systemic review by Drs. Kalra and Molinaro, it is apparent that ARTs may increase perinatal morbidity. This review assesses the impact of ARTs on children conceived in terms of immediate consequences, perinatal consequences, and potential long-term consequences. The intriguing hypothesis that ARTs may alter the milieu of early reproduction and may have longer-term consequences is reviewed by Drs. Rinaudo and Lamb. The developmental origin of health and disease hypothesis suggests that events that occur during the early development of an individual, and specifically during intrauterine life, may have profound consequences on future health. Drs. Rinaudo and Lamb explore the hypothesis that early embryo manipulation in culture during ARTs may represent a stressful event that could be associated with future health problems including an effect on early development and gene expression. We should note that 3 million children have been born via in vitro fertilization, the majority of which are healthy. Whereas the risk associated with in vitro fertilization may be small, it is of paramount research interest both for our understanding of human reproduction and also to improve public health.

In summary, this series of articles regarding early reproductive failure will serve as a review of current standards of care for early diagnosis and treatment. The evidence-based approach can be used now to identify, at a very early stage, a nonviable pregnancy allowing the option for medical management for increased patient convenience and a reduction in morbidity and mortality of these consequences. However, physicians and researchers alike must think beyond the current standard of care and identify potential unanticipated consequences of current treatment. A comprehensive understanding of early reproduction should include identification and treatment of nonviable gestations and an understanding that the consequences of reproductive failure and its treatment may extend beyond the first trimester to include perinatal morbidity and predictors of adult disease. My compliments to the authors in this series for their diligent hard work and their contribution to an excellent series of articles.