Does frozen embryo transfer up hypertension risk during pregnancy?

The risk of hypertensive disorders in pregnancy (HDP) is increased following assisted reproductive technology (ART) using frozen embryo transfer (FET) compared with after fresh embryo transfer or natural conception, according to results of a study presented at ESHRE 2022.

Using health registries from Denmark, Norway, and Sweden, the researchers from the CoNARTaS* group identified 4,523,028 singleton pregnancies (and deliveries) that occurred between 1988 and 2015. Of these, 78,300 were conceived after fresh embryo transfer and 18,037 following FET. A total of 33,209 sibling deliveries (sibships) that were conceived following fresh embryo transfer, FET, or natural conception (without ART) served as controls.

In the overall population, there was a higher risk of HDP following FET compared with natural conception (7.4 percent vs 4.3 percent; adjusted odds ratio [adjOR], 1.74, 95 percent confidence interval [CI], 1.61–1.89). An elevated risk of HDP was also noted with FET vs natural conception in the sibship comparison (adjOR, 2.02, 95 percent CI, 1.72–2.39). [ESHRE 2022, abstract O-273]

In contrast, the risk of HDP following fresh embryo transfer was comparable to that following natural conception, both in the overall population (5.9 percent vs 4.3 percent; adjOR, 1.02, 95 percent CI, 0.98–1.07) and in the sibship comparison (adjOR, 0.99, 95 percent CI, 0.89–1.09).

Additional adjustment for maternal BMI and smoking, and restricting the analysis to siblings born to the same mother and father or siblings born within a 3-year interval led to similar outcomes. Adjusting for other ART methods such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) as well as duration of embryo culture and the number of embryos transferred also did not influence the outcome.

“Our findings are important because the number of FETs is rapidly increasing throughout the world,” said first author Dr Sindre Petersen from the Norwegian University of Science and Technology, Trondheim, Norway. “Cryopreservation has facilitated the highly favourable single embryo transfer approach, improving foetal and maternal outcomes by avoiding multiple pregnancies,” he said.

“[In this study,] pregnancies after FET had a substantially higher risk of HDP, also after accounting for constant parental factors in within sibship comparisons,” he continued.

As to the reason for the increased risk of HDP, prior studies have suggested the role of hormone replacement therapies used to prepare the uterus for embryo implantation where the corpus luteum has not developed naturally, said Petersen.

“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 percent of FET pregnancies were in artificial cycles, which seems unlikely to drive the entirety of the strong association in our results,” he pointed out. As such, other factors may be in play including epigenetic changes, he added.

Despite the findings, Petersen suggested that the current study is insufficient to warrant a change in practice and that decisions on using FET or fresh embryo transfer should be individualized and based on discussions between clinicians and patients.

“However, some emerging evidence does suggest that FET in a natural cycle (as opposed to a programmed cycle), where the corpus luteum secretes vasoactive hormones, might imply a lower risk of pre-eclampsia and other hypertensive disorders. Future research should explore this possible mechanism further before making firm conclusions,” Petersen concluded.

*CoNARTaS: Committee of Nordic Assisted Reproductive Technology and Safety