Extremely high estrogen levels may underlie complications of single-birth IVF pregnancies

Massachusetts General Hospital (MGH) researchers have identified what may be a major factor behind the increased risk of two adverse outcomes in pregnancies conceived through in vitro fertilization (IVF). Two papers published in the journal Fertility and Sterility support the hypothesis that extremely high estrogen levels at the time of embryo transfer increase the risk that infants will be born small for their gestational age and the risk of preeclampsia, a dangerous condition that can threaten the lives of both mother and child. They also outline a protocol that reduced those risks in a small group of patients.

Both papers addressed IVF pregnancies resulting in a single live birth, not multiple-birth pregnancies which continue to be the most significant risk factor of any assisted reproduction technology. But even single-birth IVF pregnancies are more likely than unassisted single-birth pregnancies to result in premature delivery, low birth weight and other serious complications. In the January 2013 issue of the journal, the investigators at the MGH's Vincent Department of Obstetrics and Gynecology report that freezing embryos of women who had excessively elevated estrogen at the time of egg retrieval, followed by embryo transfer in a later reproductive cycle when hormonal levels were closer to those of a natural cycle, significantly reduced the percentage of small newborns and eliminated the incidence of preeclampsia in a small group of patients.

"We've known for a long time that singleton pregnancies conceived by IVF were at higher risk of these adverse outcomes, but the reasons were unknown," says Anthony Imudia, MD, of the MGH Fertility Center, lead author of both articles. "Now we know which facet of IVF might be responsible, which will allow us to identify at-risk patients and implement ways of averting those risks."

At most fertility centers, IVF involves a sequence of coordinated events that stimulate the ovaries in a way that leads to the growth and maturation of several eggs at the same time. Prior to ovulation the eggs are retrieved for fertilization outside the mother's body. If fertilization is successful, embryos that appear to be developing normally are transferred into the woman's uterus within 5 days of egg retrieval in a process called fresh embryo transfer.

Egg cells grow and mature in ovarian sacs called follicles, which release estrogen, so the development of multiple maturing follicles can lead to significantly elevated estrogen levels. Animal studies have suggested that excessively elevated estrogen early in pregnancy can interfere with the development of the placenta, and other research has associated placental abnormalities with increased risk for both preeclampsia and delivery of small newborns.

In the June 2012 issue of Fertility and Sterility, the MGH team reported that – among almost 300 IVF pregnancies that resulted in the birth of a single infant from 2005 through 2010 – the women whose estrogen levels right before egg retrieval were highest had significantly greater incidence of preeclampsia and of delivering infants small for their gestational age. Women whose peak estrogen levels were at or above the 90th percentile had a nine-fold greater risk of a small infant and a five-fold greater risk of preeclampsia than women with lower peak estrogen levels.