Author + information
- Carl J. Pepine, MD∗ ( and )
- Ki Park, MD, MS
- ↵∗Address for correspondence:
Dr. Carl J. Pepine, Division of Cardiovascular Medicine, University of Florida College of Medicine, 1600 Southwest Archer Road, P.O. Box 100277, Gainesville, Florida 32610.
- adverse pregnancy outcome
- assisted reproductive techniques
- cardiovascular disease
- ovarian hyperstimulation syndrome
- risk factors
Infertility remains a source of struggle for many couples, particularly as the average age of childbearing in women increases. Fortunately, the advanced technologies now available, including medications to stimulate ovulation and procedure-based therapies such as in vitro fertilization (IVF), offer hope to those who otherwise would not be able to conceive. Referred to as assisted reproductive therapies, they encompass a broad range of interventions designed to improve various stages of conception. Although these processes offer obvious short-term benefits with regard to fertility, concerns exist regarding the potential to increase long-term maternal cardiovascular (CV) risk. The signal for concern first stemmed from observational studies of women receiving assisted reproductive therapies, but the numbers of subjects studied was limited and their characteristics varied considerably, making definitive conclusions difficult.
In this issue of the Journal, Dayan et al. (1) present a systematic review of the very limited data on the risk of CV events after exposure to fertility therapy. They could identify only 6 observational studies consisting of just over 40,000 women who received fertility therapy. The latter they defined as pharmacological agents, including ovarian stimulation and induction drugs, as well as IVF and intrauterine insemination. The comparison group was women, with or without infertility, who did not receive fertility therapy without specification of whether pregnancy was ultimately achieved. Due to the heterogeneity of the studies included, outcomes were characterized as either CV risk factors, such as hypertension and diabetes mellitus, or overt CV conditions, including outcomes such as heart failure, myocardial infarction, and stroke, among others. Intended statistical analyses of subgroups, such as IVF versus non-IVF treatments and number of treatments, could not be performed due to the limited number of studies and heterogeneous outcomes. A majority of the women evaluated in the reported studies were young, with average ages ranging from 29 to 34 years. An increased incidence of adverse pregnancy outcomes, including pre-eclampsia and gestational diabetes, was noted among those treated with fertility therapy. The outcomes of interest were infrequent, with absolute event rates <2 per 10,000 person-years. Overall, these investigators found no increase in CV events among women exposed to fertility therapy. For stroke, only 2 studies were assessed, but pooled analysis suggested a possible increase in stroke risk in those exposed to fertility therapy. Definitive conclusions regarding venous thromboembolic events could not be made due to excess study heterogeneity. Results regarding the outcomes of CV risk factors critically important to women, such as hypertension and diabetes, were not conclusive.
Overall, the investigators concluded that, based on their analyses, fertility therapy does not increase risk of overall cardiac events or diabetes; however, a suggestion of increased risk of stroke was noted (1). These conclusions were tempered by the marked heterogeneity of the studies and limitations of the available data, including varied CV outcomes in studies not originally designed to assess CV outcomes, differences in comparator groups, and types of fertility therapy included in individual study analyses. Thus, the investigators appropriately note that conclusions regarding the long-term CV safety of fertility therapy cannot be definitively made.
How does this study (1) therefore help us navigate the waters of fertility therapy and CV risk? What we can take away as the most important point is that existing data are insufficient to draw any conclusions regarding the long-term CV safety of fertility therapy. The importance of further study of this topic will only continue to grow as the age of childbearing women increases, with concomitant increases in age-related CV risk. If heightened CV risk is ultimately proven to exist, what is the mechanism? The answer is likely to be complex and multifactorial, but there are some suggestions based on existing data and known short-term side effects of fertility therapy.
For example, ovarian hyperstimulation syndrome is a well-recognized complication of fertility therapy. Excess estrogen exposure in ovarian hyperstimulation syndrome can lead to severe multiorgan dysfunction and massive fluid shifts within the body (2). It is plausible that repeated exposure to fertility therapies may lead to lower grade levels of excess ovarian stimulation and that this scenario may imprint long-term CV dysfunction by affecting vascular function, leading to long-term CV risk. In addition, there is growing evidence suggesting a role of derangements in the renin-angiotensin-aldosterone axis, as well as endothelial dysfunction in the setting of fertility therapy, that also likely plays a role in elevating risk (3).
One must also consider the role of confounding factors when assessing fertility therapy and CV risk. Infertile conditions are multifactorial and encompass a wide variety of illnesses, including thrombotic disorders and placental dysfunction among many others. Any possible association of fertility therapy and CV risk is muddied by the presence of the infertile state itself. In other words, fertility therapy may not simply trigger elevated CV risk insomuch as the underlying condition leading to infertility in the first place. As the importance of sex-specific CV risk stratification has become increasingly recognized, the need for dedicated study of topics such as fertility therapy and their effects on long-term CV risk becomes more apparent. This focus of study is particularly important for younger women who otherwise may appear healthy but, if recognized, pregnancy and fertility history may present a rare opportunity for risk modification at an early age. Thus, the true utility of the present study by Dayan et al. (1) is in its illustration of important knowledge gaps in our current evidence and the critical need for sex-specific studies assessing nontraditional risk factors, such as adverse pregnancy outcomes and fertility history, and long-term CV risk. Collaboration between organizations such as the American College of Cardiology’s Cardiovascular Disease in Women Committee and the American Congress of Obstetrics and Gynecology to promote the creation of registries to capture such data is crucial in the effort to fill such knowledge gaps and promote increased awareness of these topics among practitioners and women.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation