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Frozen embryos tied to higher risk of pregnancy complications related to high blood pressure, study suggests

An embryologist shows an Ovocyte after it was inseminated at the Virginia Center for Reproductive Medicine, in Reston, Virginia on June 12, 2019 - Freezing your eggs, getting pregnant after the age of 50, choosing the baby's sex: when it comes to in-vitro fertilization and other assisted reproduction procedures in the United States, would-be parents are spoilt for choice. This isn't the case in many other countries, including France, which is hoping to pass legislation that would let single women and lesbian couples benefit from these technologies for the first time. (Photo by Ivan Couronne / AFP) / TO GO WITH AFP STORY by Ivan COURONNE, "In US, relaxed IVF laws help would-be parents realize dreams" (Photo by IVAN COURONNE/AFP via Getty Images)

(CNN) — Pregnancies from in vitro fertilization using frozen embryos appear to be linked to an increased risk of complications related to high blood pressure, or hypertensive disorders, compared with when fresh embryos are used or when a pregnancy is conceived naturally.

That’s according to a study published Monday in the American Heart Association journal Hypertension, which included data on more than 4.5 million pregnancies, spanning almost three decades, across three European nations: Denmark, Norway and Sweden.

The risk of pregnancy complications related to high blood pressure was higher after the transfer of frozen embryos compared with naturally conceived pregnancies, and the risk following fresh embryo transfers was similar to that of naturally conceived pregnancies, the data shows.

More research is needed to determine whether similar findings would emerge in the United States.

The researchers — from the Norwegian University of Science and Technology and other institutions in Europe — analyzed medical birth registries from Denmark that were dated between 1994 and 2014, from Norway dated 1984 to 2015, and from Sweden dated 1985 to 2015. The registries included about 4.4 million pregnancies naturally conceived, 78,300 pregnancies that used fresh embryo transfer and 18,037 pregnancies from frozen embryo transfer.

The researchers compared odds of hypertensive disorders during pregnancy across the groups and found that the unadjusted risk of such disorders was 7.4% after frozen embryo transfer, 5.9% after fresh embryo transfer and 4.3% after natural conception. The data also showed that pregnancies from frozen and fresh embryo transfer were more frequently preterm — 6.6% of the frozen and 8.1% of the fresh, respectively — compared with naturally conceived pregnancies, at 5%.

“Frozen embryo transfers are now increasingly common all over the world, and in the last few years, some doctors have begun skipping fresh embryo transfer to routinely freeze all embryos in their clinical practice, the so-called ‘freeze-all’ approach,” lead study author Dr. Sindre H. Petersen, a Ph.D. fellow at the Norwegian University of Science and Technology in Trondheim, Norway, said in a news release Monday.

“In summary, although most IVF pregnancies are healthy and uncomplicated,” he said, “this analysis found that the risk of high blood pressure in pregnancy was substantially higher after frozen embryo transfer compared to pregnancies from fresh embryo transfer or natural conception.”

Petersen added, “Our results highlight that careful consideration of all benefits and potential risks is needed before freezing all embryos as a routine in clinical practice.”

The findings are “in agreement with earlier population-level studies” showing a higher risk of hypertensive disorders during pregnancy after frozen embryo transfer, the researchers wrote in their study.

Last year, a large study out of France presented at the online annual meeting of the European Society of Human Reproduction and Embryology also found a higher risk of pre-eclampsia and hypertension in pregnancies derived from frozen-thawed embryos — and the risk was found to be greater when the uterus was prepared for implantation with hormone replacement therapies.

“The association between frozen embryo cycles and hypertensive disease in pregnancy has been known for a while, and there is still currently an active debate around the pros and cons of ‘Freeze all for all?’ amongst fertility doctors,” Dr. Ying Cheong, professor of reproductive medicine at the University of Southampton, said in a statement distributed by the UK-based Science Media Centre in July. She was not involved in either study.

“There are two important points to take home here, firstly, whilst frozen embryo transfer technology has transformed reproductive medicine, FET must only be performed where clinically appropriate and secondly, clinicians and scientists need to start joining the dots between what happens at early development and later at birth and beyond, a research area, in my opinion, that is still poorly supported and studied,” Cheong said.

The new study did not evaluate what could be driving this association between frozen embryo transfers and high blood pressure risks, but some IVF doctors question whether it is really fresh vs. frozen.

“There is one thing that is not clear: is it from the actual procedure of freezing the embryo or is it from the protocol used? Most IVF doctors believe from recent studies and evidence that it’s actually the medication protocol, not the IVF procedure,” Dr. Aimee Eyvazzadeh, a San Francisco-based reproductive endocrinologist, who was not involved in the new study, wrote in an email to CNN on Monday.

“There are different ways to prepare a uterus for transfer,” she said. One protocol involves a corpus luteum cyst, a fluid-filled mass that forms in the ovaries and plays an important role during pregnancy, as the corpus luteum produces the hormone progesterone that is needed during pregnancy. Another protocol relies on medications to mimic ovulation.

“Studies show that it’s the lack of corpus luteum that increases the risk and this is potentially why a frozen transfer may have a higher risk of pre-eclampsia,” Eyvazzadeh wrote.

Overall, the new study is “very important” for “anyone taking care of pregnant people after IVF,” she wrote. “Everyone taking care of pregnant people after IVF should pay extremely close attention to this study. More and more studies are showing what IVF doctors already know and that is that IVF after frozen embryo transfer can increase risk of pre-eclampsia.”