IVF frozen embryo transfers are associated with an increased risk of pregnancy-related maternal hypertension

IVF frozen embryo transfers are associated with an increased risk of pregnancy-related maternal hypertension

Over the past few years, worries have been expressed that pregnancies resulting from frozen embryo transfers in IVF may boost the risk of hypertensive disorders in women, notably pre-eclampsia, difficulties that could have serious effects on both the mother and foetus. Recent observational studies comparing the results of fresh and frozen transfers, which are by definition vulnerable to statistically confounding variables, have raised these issues. Most of this confusion can be eliminated by comparing siblings.

Now, a sister pregnancy comparison and a sizable study based on real-life registry data show that pregnancies after frozen embryo transfer (FET) do indeed have a significantly higher risk of hypertensive problems than pregnancies that occur spontaneously. In a sub-group examination of sibling births, which was intended to remove the influence of any parental characteristics in the results, the same elevated risk (about doubled) was also discovered.

First author Dr. Sindre H. Petersen stated that "our findings are noteworthy because the number of FETs is quickly expanding throughout the world." On behalf of the CoNARTaS group (Committee of Nordic Assisted Reproductive Technology and Safety), which tracks the health of women and children born following assisted reproduction in the Nordic nations, he will present the study results today at the 38th annual meeting of ESHRE in Milan.

The proportion of FET cycles compared to fresh cycles is continuing to climb in Europe, according to the most recent registry data from ESHRE. The percentage increased from 38 per cent in 2014 to 49 per cent in 2017. The US and the majority of high-income nations both exhibit similar tendencies. Improved cryopreservation techniques, single embryo transfer facilitation, decreased ovarian hyperstimulation, and optional freezing of all embryos ('freeze-all cycles) have all contributed to the rise in popularity of FETs.

The study examined more than 4.5 million singleton deliveries that occurred between 1988 and 2015 in the registries of three Nordic nations. 78,300 of the aided pregnancies occurred after fresh embryo transfer, while 18,037 occurred after FET. The registry birth references, which are mostly exclusive to the Nordic countries, also made it possible to identify 33,209 sibling births that had occurred after either a fresh or frozen embryo transfer or a spontaneous conception. According to Dr. Petersen, "This study was by far the largest sibling analysis to date exploring the link between assisted reproductive technologies and hypertensive problems in pregnancy."

The study's findings revealed that pregnancies using FET had nearly twice the risk of hypertensive problems throughout pregnancy as those following a spontaneous conception (7.4 per cent vs 4.3 per cent ). The risk of hypertensive problems was comparable to that of naturally conceived pregnancies in pregnancies following fresh embryo transfer pregnancies. Results were unaffected by adjusting for mother BMI, smoking, and the interval between delivery, as well as by using other assisted reproductive techniques (IVF, ICSI, duration of embryo culture or number of embryos transferred).

Gestational hypertension, pre-eclampsia, the more uncommon but serious syndromes of eclampsia and Hemolysis-Elevated-Liver-enzymes-Low-Platelets (HELLP) syndrome, and eclampsia are all examples of hypertensive disorders during pregnancy.

However, Dr. Petersen noted that "cryopreservation has facilitated the highly favourable single embryo transfer approach, improving foetal and maternal outcomes by avoiding multiple pregnancies," even though the study's design prevented it from weighing the relative benefits of embryo freezing against the increased risk of hypertensive disorders.

Recent research has revealed that treatments to get the uterus ready for embryo implantation may be linked to the risk of hypertensive problems in FET pregnancies. These are typically administered as hormone replacement therapy in a cycle that has come to be regarded as "programmed" or "artificial" (in which there is no naturally developing corpus luteum to provide hormonal support for the pregnancy). A "hot potato" in recent studies, according to Dr. Petersen, the presence of a corpus luteum "is indeed one potentially critical distinction between natural conception and fresh embryo transfers on the one hand and FETs on the other."

According to his investigation, all pregnancies resulting from normal conception and fresh embryo transfer had corpuses lutea, but other FET pregnancies did not. However, we anticipate from earlier Danish and Swedish studies that only 15–30% of FET pregnancies in our sample were in artificial cycles, which is unlikely to account for the majority of the substantial correlation in our findings. Thus, it appears plausible that a fundamental element of the freezing and thawing process, such as epigenetic alterations, may also be to blame.

According to Dr. Petersen, who described his findings as "just one piece of a great puzzle," it is still early to advise changing treatment plans based solely on the results of this study. Frozen embryo transfers are still popular for many reasons, particularly because they make single embryo transfers easier. "I am certain that, just as in other clinical decision-making, a well-grounded and individualised choice between a fresh or frozen cycle can be made following communication between the clinician and the couple," he added. A decreased risk of pre-eclampsia and other hypertensive diseases may be associated with FET in a natural cycle (as opposed to a controlled cycle), where the corpus luteum secretes vasoactive hormones. Before drawing definite findings, further study should examine this potential process in more detail. In the interim, our findings can help patients and clinicians make well-informed decisions.

In assisted reproduction, embryos are frozen

In the last ten years, vitrification, a fast-freezing technology, has revolutionised assisted reproduction. Its effectiveness and dependability have encouraged single embryo transfers (and thereby a significant reduction in the risk of multiple pregnancies), the safe storage of extra embryos, and, by transferring embryos in a later (non-stimulated cycle), a reduction in the risk of pregnancy-related ovarian hyperstimulation syndrome. The majority of FET transfers—about 50% of all ART—are now "freeze-all," in which every embryo produced during a stimulated cycle is saved for a future transfer. 

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