Infertility affects about 6.1 million people in the U.S., equivalent to 10% of the reproductive age population. As a result, the use of assisted reproductive technologies (ART), including in vitro fertilization (IVF) has risen dramatically, so that nearly 1% of babies born in the US are conceived using IVF. These pregnancies are at increased risk of adverse outcomes, including low birth weight, preeclampsia, placental abruption, placenta previa, preterm delivery, and perinatal mortality, many of which may be attributed to abnormalities of placentation and trophoblast differentiation in the first trimester, and also have increased risks for major structural birth defects, imprinting disorders and possibly additional long term health consequences. The goal of this study is to determine the molecular mechanisms which may contribute to these increased risks, and whether these result from the use of ART, or from the underlying infertility. Through our Prenatal Biorepository, we have unique access to discarded tissue remaining from chorionic villus sampling (CVS). Significantly, these samples are coupled to a database of pregnancy-related data and pregnancy outcomes, and term placental samples are available from the same pregnancies, as up to 45% of CVS patients deliver at Cedars-Sinai. This enables us to examine first trimester trophoblasts obtained during the period in which placentation occurs, in ongoing pregnancies which can be followed to term and beyond. Our preliminary data show significant differences between gene expression profiles of CVS trophoblast cells in a) pregnancies conceived via IVF, b) infertility-associated pregnancies conceived in vivo, and c) pregnancies conceived spontaneously. In this application, we will use genome-wide genetic, epigenetic, and gene expression profiling to differentiate the impact of infertility genetics and IVF-induced epigenetic changes on placental function and ultimately fetal development. Specifically, we propose to quantify and compare gene expression and CpG DNA methylation, as well as genome-wide SNP and copy number variation (CNV) profiles and exome-wide non-synonymous SNP profiles, in CVS samples from pregnancies conceived with infertility and in vitro versus in vivo fertilization, as compared to spontaneous pregnancies. To distinguish the effects of intrauterine environment, we will also quantify and compare gene expression and CpG DNA methylation in term placental samples from a subset of the same pregnancies. Lastly, we will identify the functional activity of genes whose expression is found to be altered, using primary trophoblast cultures and trophoblast cell lines, and evaluate their roles in trophoblast cell migration, invasin and apoptosis, which may lead to aberrant placentation. This truly integrated and innovative approach will allow us to elucidate the molecular mechanisms that contribute to pregnancy-related complications and adverse outcomes, and to determine whether these are altered in pregnancies conceived using ART or related to the underlying infertility.

Public Health Relevance

Almost 1% of babies born in the US are conceived using ART, which has been linked to increased risks for placentation defects, pregnancy-related complications, birth defects and imprinting disorders. By determining the molecular basis for these risks in ART pregnancies, and whether these result from ART or the underlying infertility, our studies may lead to the development of new treatment modalities, and possibly the development of biomarkers that can be evaluated at the time of CVS, which could have significant clinical benefits both for infertile couples and for the general population.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Taymans, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cedars-Sinai Medical Center
Los Angeles
United States
Zip Code
Gonzalez, Tania L; Sun, Tianyanxin; Koeppel, Alexander F et al. (2018) Sex differences in the late first trimester human placenta transcriptome. Biol Sex Differ 9:4
Wang, Erica T; Ramos, Lauren; Vyas, Nina et al. (2018) Maternal and neonatal outcomes associated with infertility. J Matern Fetal Neonatal Med :1-4
Sundheimer, Lauren W; Pisarska, Margareta D (2017) Abnormal Placentation Associated with Infertility as a Marker of Overall Health. Semin Reprod Med 35:205-216
Wang, Erica T; Kathiresan, Anupama S Q; Bresee, Catherine et al. (2017) Abnormal implantation after fresh and frozen in vitro fertilization cycles. Fertil Steril 107:1153-1158
Xu, Ning; Barlow, Gillian M; Cui, Jinrui et al. (2017) Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments. Reprod Sci 24:996-1004
Wang, Erica T; Sundheimer, Lauren W; Spades, Carla et al. (2017) Fertility Treatment Is Associated with Stay in the Neonatal Intensive Care Unit and Respiratory Support in Late Preterm Infants. J Pediatr 187:309-312
Singh, Krishna; Williams 3rd, John; Brown, Jordan et al. (2017) Up-regulation of microRNA-202-3p in first trimester placenta of pregnancies destined to develop severe preeclampsia, a pilot study. Pregnancy Hypertens 10:7-9
Churchill, Sara J; Wang, Erica T; Akhlaghpour, Marcy et al. (2017) Mode of conception does not appear to affect placental volume in the first trimester. Fertil Steril 107:1341-1347.e1
Lee, Bora; Kroener, Lindsay L; Xu, Ning et al. (2016) Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation. Biol Reprod 95:113
Pisarska, Margareta D; Akhlaghpour, Marzieh; Lee, Bora et al. (2016) Optimization of techniques for multiple platform testing in small, precious samples such as human chorionic villus sampling. Prenat Diagn 36:1061-1070

Showing the most recent 10 out of 12 publications