A new meta-analysis has confirmed risks found in other studies that pregnancies following frozen embryo transfers in a programmed cycle are associated with a higher risk of pre-eclampsia and other hypertensive disorders than found in natural cycle transfers. Absence of a corpus luteum may offer an explanation.
Just days after a Campus meeting on the luteal phase raised concerns over the association of pre-eclampsia with frozen embryos transferred in a programmed cycle, publication of a meta-analysis confirmed the risk but made no recommendations for a safe endometrial preparation strategy in FET cycles because of ‘methodological weaknesses’ in the studies analysed.(1,2) However, after analysing 19 eligible studies in their review, the authors conclude that programmed FET protocols were indeed associated with a significantly higher risk of hypertensive disorders of pregnancy, pre-eclampsia, post-partum haemorrhage and Caesarean section when compared with natural FET protocols.
Obstetric and perinatal outcomes for this study were assessed against four endometrial preparation protocols in FET: hormone replacement therapy; a non-medicated natural cycle; a modified natural cycle, and a stimulated transfer cycle. However, because of the multiple endpoints and the different preparation protocols, relatively few of the combinations studied had numerical strength behind them following meta-analysis. Thus, the odds ratio for the most common perinatal outcome, hypertensive disorders of pregnancy, was 1.90 (P<0.00001) for FET in a programmed cycle when compared with transfer in a natural cycle, but the result was derived from just 12 ‘very low quality’ studies. The risk of pre-eclampsia, OR 2.11 (P<0.00001), was assessed from eight studies, but of similarly ‘low quality’.
However, despite the numbers, the bottom-line implication here is that the risk of pre-eclampsia is roughly doubled in women exposed to endometrial preparation for FET. This was also the risk found last year in a retrospective study of Danish registry data of gestational hypertension in pregnancies from a programmed FET protocol, along with raised risk associations with postpartum haemorrhage, Caesarean section, and large birthweight.(3)
A similar catalogue of other perinatal complications – classed as primary or secondary outcomes - was also reported in this latest meta-analysis, all showing a higher risk in mothers after programmed FET cycles than after natural. These included pregnancy-induced hypertension (OR 1.46), placenta previa (OR 1.27), Caesarean section (OR 1.62), preterm birth (1.19) and large for gestational age (OR 1.08).
As others have now proposed, and as raised at the luteal phase Campus meeting in May, the common denominator in this raised risk from programmed FET cycles appears to be the corpus luteum, or its absence – although the authors of the meta-analysis make it clear that the ‘mechanisms behind the observed maternal and perinatal risks in FET cycles are still unknown’. Frauke von Versen-Höynck in her own studies and at the Campus meeting proposed that the lack of relaxin and other vasoactive products released by a corpus luteum may determine the higher susceptibility to pre-eclampsia.(4)
While the eligible studies in this meta-analysis involved a variety of endometrial preparations, different HRT formulations and different means of ovarian suppression, the evidence did seem strong enough for the authors to conclude that ‘endometrial preparation protocols with HRT are associated with worse obstetric and perinatal outcomes’, and that the absence of a corpus luteum ‘almost certainly plays a role’. But association, they stress, does not imply causation, and ‘our results should not prompt clinicians to change their treatment attitudes’.
Although the corpus luteum connection has attracted much attention in the past few years, the authors concede that extrapolating any single endometrial preparation as a cause of maternal complication is ‘a difficult task’. But an explanation, they add, remains urgent, as registry data continue to plot ever-rising rates of FETs, whether cumulative or freeze-all. Indeed, a higher risk of pre-eclampsia was notably found in the landmark RCT of Wei et al of freeze-all and fresh transfer in ovulatory women.(5)
In an F&S editorial on the Danish registry study, Frauke von Versen-Höynck acknowledged that recent observational data seem to imply that maternal and neonatal outcomes ‘may be improved by utilizing a protocol that includes the formation of a corpus luteum’.(6) However, she reaffirmed the caveats associated with observational studies and their inability to fully control for confounding factors. And she emphasised too that results from RCTs are now needed to guide practice.
For their part, the meta-analysis reviewers make three proposals for future research to develop that gold-standard endometrial preparation protocol. First, rigorous testing of the association between the various endometrial preparation protocols and the most dangerous obstetric and perinatal complications. Next, prospective studies in women deemed at risk of these maternal complications to develop therapeutic strategies. And third, to test the efficacy of low dose aspirin started before 16 weeks gestation to reduce the rate of preterm pre-eclamspia. If an association with a preventable form of pre-eclampsia could be confirmed, HRT endometrial preparation protocols for FET might be introduced with more confidence, they write.
Meanwhile, hovering above this clinical conundrum lies the everyday applicability of programmed cycles in FET – that they allow greater flexibility in managing the cycle and present a relatively precise window of implantation without the hormonal fluctuation of an ovulatory cycle. Multiple studies have equally shown that FET cycles can substantially reduce the risk of OHSS and of course facilitate single embryo transfer programmes. Against this must now be balanced what appear to be the real risks of a programmed cycle and the ‘suggestion’, as noted by Von Versen-Höynck, that maternal and neonatal outcomes after FET may be better with a protocol that includes ovulation and formation of a corpus luteum.
1. See https://www.focusonreproduction.eu/article/ESHRE-News-Campus-luteal-phase
2. Busnelli A, Schirripa I, Fedele F, et al. Obstetric and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis. Hum Reprod 2022; doi.org/10.1093/humrep/deac073
3. Laub Asserhøj L, Lærke Spangmose A, Henningsen A-KA, et al. Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET. Fertil Steril 2021; 115: 947–956.
4. Van Versen-Höynck F, Schaub AM, Chi Y-Y, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension 2019; 73: 640–649.
5. Wei D, Liu JY, Sun y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet 2019; 393: 1310-1318. doi.org/10.1016/S0140-6736(18)32843-5
6. Van Versen-Höynck F, Conrad KP, Baker VL. Which protocol for frozen-thawed embryo transfer is associated with the best outcomes for the mother and baby? Fertil Steril 2021; 115: 886–887.