Assisted Reproductive Technologies and the Developmental Origins of Human Health and Disease

Ten years ago, Seminars in Reproductive Medicine published a monograph examining the evidence regarding epigenetics and reproduction. That review summarized how endocrine disruptors, environmental exposures, and assisted reproductive technologies (ART) could affect reproduction through epigenetic pathways. A decade later, we focus this discussion on updated evidence exploring the specific relationship between ART and developmental origins of human health and disease. To interrogate the full spectrum of modern evidence, we have gathered expert researchers on animal models, epidemiology, male reproduction, and clinical infertility.

Micah J. Hill, DO

The Barker hypothesis is now almost 30 years old. It is clear that paternal, maternal, and fetal exposures have the potential for transgenerational effects. How does this potential for effect translate to ART? As a technology, assisted reproduction is a very young medical field in which to attempt to measure transgenerational effects. However, the timing of erasure, establishment, and maintenance of genomic imprints in gametes and embryos coincide with significant manipulations innate to ART. This is a relationship that cannot be explored through randomized controlled trials for both practical and ethical reasons. Observational human data provides us a one lens through which we can examine these relationships. Animal models provide a different lens to examine intergenerational and transgenerational effects.

In the first of two publications examining ART and developmental origins of human health and disease, we examine this relationship from the clinical perspective. What historical evidence supports the Barker hypothesis and is there evidence for this in ART? What can epidemiologic evidence from ART use in humans teach us and what are the challenges in interpreting this data? How does a fertility specialist interpret these data and how does the magnitude of the risks compare with the benefits of ART? What are the ethical considerations of epigenetic disorders in ART and are those considerations different in infertile patients compared with those electively choosing ART? These are the questions tackled by our expert authors in this edition.

Carpinello, DeCherney, and Hill from the National Institutes of Health summarize the historical evidence that famine and pandemics can result in generational health effects. They discuss the origins of the Barker hypothesis and the aims of the first Council for the Fetal Origins of Adult Disease. This historical review provides the contextual background for the following manuscripts. Yeung and colleagues from the Division of Intramural Population Health Research at the National Institutes of Health review the evidence from an epidemiologic perspective. They discuss the challenges of selecting the right control group, heterogeneous treatments across studies, and the potential for confounding when studying infertility and epigenetics. Morin and Seli, from Reproductive Medicine Associates of Northern California and Yale University respectively, continue this discussion by further exploring the potential for confounding in epigenetic studies and the potential for risks that may be associated with infertility itself. By framing the critique of the literature through the lens of clinical implications, they argue that the overall risks to subsequent generations are small compared with the substantial benefits afforded by ART. Rinaudo and Adeleye from the University of California at San Francisco, discuss animal model data demonstrating increased risks of hypertension and glucose intolerance in offspring and take a unique ethical look at this issue. Given the increase use of ART for social and family planning indications, they argue that the acceptance of these risks and counseling of patients should differ between infertility and non-infertile uses of ART. Mani and Mainigi from the University of Pennsylvania review the evidence that embryo culture conditions affect the epigenome. DeAngelis, Martini, and Owen from the National Institutes of Health review the broader evidence that ART is associated with an increased risk of epigenetic disorders. Ibrahim and Hotaling from the University of Utah explore the potential contribution of sperm epigenetics on male infertility, pregnancy loss, and the health children conceived in couples with male factor infertility. Bartolomei and Riesche from the University of Pennsylvania provide a detailed review of ART and the placenta, focusing on clinical, morphologic, and molecular outcomes. Osman, Franasiak, and Scott from IVI-RMA discuss the potential associations of oocyte and embryo manipulation with epigenetic changes. They also raise a discussion of the relationship between epigenetic aberrancies and embryo ploidy, an area in need of further research.

The manuscripts in this first edition on ART and developmental origins of human health and disease focus on the methodologic challenges of studying this literature and the clinical implications of the associations. There are three themes that emerge from these expert reviews. (1) Studying the relationship between ART and developmental origins of human health and disease is difficult and requires methodologic rigor. (2) The synthesis of the available literature suggests that there are demonstrable relationships between ART and disease risk in subsequent generations. (3) While these risks are demonstrable, the effect sizes are small and interpretation and counseling of these risks may vary based on the indication for ART. The research and expertise of the authors provides a useful framework to consider this important topic.

Note

The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government.