Undergoing in vitro fertilization using frozen embryos is linked to a greater risk of hypertensive disorders, including preeclampsia, during pregnancy, according to research published Monday in the journal Hypertension.
While the link between frozen embryo transfers and elevated blood pressure is not new, the research, which included data on millions of women in Norway, provides a clearer understanding of the risk. The study was also the largest to date that included data on women who had multiple pregnancies.
Overall, the risk of hypertensive disorders was low: about 7.4% in women who used frozen embryos, compared with 5.6% in women who used fresh embryos and 4.3% for women who conceived naturally.
But when the researchers adjusted for other factors that could cause hypertensive disorders during pregnancy, such as age, existing high blood pressure and obesity, they found that the risk was about 74% higher when frozen embryos were used, compared with IVF using fresh embryos or a naturally conceived pregnancy. In addition, they found, there was no significant difference in risk between the women who conceived naturally and those who did IVF using fresh embryos.
About 75% of the women who developed hypertensive disorders in the study developed preeclampsia, marked by severely high blood pressure along with signs of liver or kidney damage after the 20th week of pregnancy. It can be deadly if untreated.
“If our study only found that there was an association just for isolated gestational hypertensive disorders, we wouldn’t be that worried, but we found in our extra analysis that there was a strong association between frozen IVF and preeclampsia,” said the study’s lead author, Dr. Sindre Petersen, a doctoral fellow at the Norwegian University of Science and Technology.
Developing high blood pressure in pregnancy does not always lead to complications, but it is important for doctors to monitor these women closely for signs of preeclampsia. About 1 in 12 women in the U.S. have high blood pressure during pregnancy, according to the Centers for Disease Control and Prevention, and about 1 in 25 pregnant women develop preeclampsia, according to the American Heart Association.
The new study looked at data on 4.5 million pregnancies in Norway from 1988 through 2015. The group included 4.4 million naturally conceived pregnancies and compared them to just over 78,000 IVF pregnancies conceived using a fresh embryo and about 18,000 using a frozen embryo. About 33,000 of the pregnancies were in women who had more than one pregnancy.
According to preliminary data from the CDC, nearly 80,000 babies in the U.S. born in 2020 were the result of assisted reproductive technology, which includes IVF.
“The reality is that women are now older when they have their first pregnancy, so they are more likely to potentially need treatments like IVF, which might be more common in the future,” said Dr. Anum Minhas, a cardio-obstetrician at Johns Hopkins Medicine, who was also not involved in the new research.
Exactly why using a frozen embryo increases a woman’s risk of a hypertensive disorder remains unclear, but one hypothesis is the absence of a temporary organ called the corpus luteum.
When a woman ovulates, a follicle in her ovary releases an egg. Shortly after, that follicle develops a corpus luteum, which secretes hormones needed early in pregnancy. These include progesterone and relaxin, which work together to thicken the walls of the uterus and make it an ideal environment for a developing embryo.
“In artificial frozen transfers, that corpus luteum is bypassed. But in fresh transfers, it’s still present,” Petersen said.
A previous study published in Hypertension in 2019 found that women who conceive without a corpus luteum have a higher risk of preeclampsia. It also found that the risk of preeclampsia was elevated in women who had a frozen transfer but not in those who received a fresh embryo during IVF.
How an embryo develops can also play a role in hypertensive disorders, said Dr. Elizabeth Langen, co-director of the cardio-obstetrics program at the University of Michigan, who was not involved in the new research. Embryo freezing could impact the development process, she said.
One limitation of the study is that it included mostly white participants.
“How well it applies to other countries, especially countries with a lot of racial ethnic diversity, is unclear,” said Minha, adding that the increased risk for Black women in the U.S. and South Asian women worldwide could be even greater.
Petersen emphasized that the overall risk for preeclampsia was still low and that the results of the new study should not scare women away from using frozen embryos.