Frozen embryo transfers in IVF linked to greater risk of maternal hypertension

Concerns have been raised that pregnancies derived from frozen embryo transfers in IVF might increase the maternal risk of hypertensive disorders.

Pre-eclampsia is one such condition that causes high blood pressure during pregnancy and after labour and which may have severe consequences for both the mother and the foetus.

The concerns have been raised in recent observational studies comparing the outcomes of fresh and frozen transfers, which, by definition, are subject to statistically confounding variables. Sibling comparisons can remove much of this confounding.

The extensive study based on real-life registry data and a comparison of maternal complications in sibling pregnancies indicate that pregnancies following frozen embryo transfer (FET) do indeed have a substantially higher risk of hypertensive disorders than naturally conceived pregnancies.

This same raised risk was also found in a sub-group analysis of sibling births, which was designed to eliminate the effect of any parental factors in the results.

“Our findings are important because the number of FETs is rapidly increasing throughout the world,” says the study’s first author, Dr Sindre H. Petersen from the Norwegian University of Science and Technology.

He has presented the study results at the 38th annual meeting of ESHRE in Milan on behalf of the Committee of Nordic Assisted Reproductive Technology and Safety group which monitors the health of mothers and children born after assisted reproduction in the Nordic countries.

According to the latest registry report from ESHRE, the proportion of FET cycles relative to fresh is still on the rise in Europe. In 2017 the proportion was 49 per cent, against 38 per cent in 2014. Similar trends are present in the US and most high-income countries.

FETs are increasingly common because of improved cryopreservation methods, facilitation of single embryo transfer, reduction of ovarian hyperstimulation, and the elective freezing of all embryos.

The study analysed more than 4.5 million singleton pregnancies in the registries of three Nordic countries with delivery between 1988 and 2015. Of the conceptions following assisted reproduction, 78, 300 were after fresh embryo transfer and 18,037 were after FET.

The registry birth references – largely unique to the Nordic countries – also allowed the identification of 33,209 sibling deliveries following either fresh or frozen embryo transfer, and natural conception.

“This study was by far the largest sibling analysis to date investigating the association between assisted reproduction treatments and hypertensive disorders in pregnancy,” Dr Petersen adds.

Results of the study showed that the risk of hypertensive disorders in pregnancy were almost twice as high in the pregnancies following FET that in pregnancies following a natural conception. However, the risk of hypertensive disorders in pregnancies following fresh embryo transfer pregnancies was comparable to naturally conceived pregnancies.

Hypertensive disorders in pregnancy comprise gestational hypertension and pre-eclampsia, and the more rare but severe conditions of eclampsia and Hemolysis-Elevated-Liver-enzymes-Low-Platelets (HELLP) syndrome.

Adjustments for maternal body mass index, smoking and time between deliveries did not affect the end results, nor did other methods of assisted reproduction (IVF, ICSI, duration of embryo culture or number of embryos transferred).

Dr Petersen says that the design of the study was not able to assess the relative merits of embryo freezing against the higher risk of hypertensive disorders, but notes that “cryopreservation has facilitated the highly favourable single embryo transfer approach, improving foetal and maternal outcomes by avoiding multiple pregnancies”.

Recent studies have suggested that the risk of hypertensive disorders in FET pregnancies may be associated with therapies to prepare the uterus for embryo implantation. These are usually given in the form of hormone replacement therapy in what has become known as a ‘programmed’ or ‘artificial’ cycle – in which there is no naturally developing corpus luteum to provide hormonal support for the pregnancy.

The presence of a corpus luteum – a mass of cells that forms in an ovary responsible for the production of the hormone progesterone during early pregnancy – is one potentially important difference between natural conception and fresh embryo transfers, on the one hand and FETs, on the other, says Petersen.

He adds: “In our analysis all natural conceptions and fresh embryo transfer pregnancies had a corpus luteum, while a subset of the FET pregnancies did not.

“However, we expect from previous Danish and Swedish publications that in our study, only 15-30 per cent of FET pregnancies were in artificial cycles, which seems unlikely to drive the entirety of the strong association in our results.

“It thus seems possible that some inherent aspect of the freezing and thawing process, for example epigenetic changes, might be responsible as well.”

The doctor has pointed out that it is too early to recommend changes to treatment strategies based solely on this study, and that there are still good reasons why frozen embryo transfers are increasingly used, especially in their facilitation of single embryo transfer.

“I am confident that a well-grounded and individualised decision of whether to go for a fresh or a frozen cycle can be made after dialogue between the clinician and the couple,” he concludes.

“Our study can contribute to informed decision-making for patients and clinicians.”