PRE-ECLAMPSIA

Pre-eclampsia is now a well recognised adverse pregnancy risk associated with IVF. A huge retrospective cohort study of more than 100,000 pregnant women delivering between 2013 and 2018 at a Chinese hospital found a significantly higher incidence of pre-eclampsia in the IVF pregnancies than in the spontaneous (6.1% vs 1.0%, p <0.01).(1) Such results have been similarly seen in studies of maternal and infant health based on the registries of the Nordic countries.(2) Although the Chinese authors concede that the pathophysiology of pre-eclampsia ‘remains indefinite’, they reiterate that ‘abnormal placentation is widely recognized as the primary pathogenesis of PE’.

Now, a new systematic review has also found a significantly higher risk of pre-eclampsia after egg donation than after spontaneous or even routine IVF conceptions.(3) Indeed, the risk appeared so great – affecting nearly one in six egg donation pregnancies – that the authors conclude that ‘women who can conceive naturally could be advised to reconsider’. Moreover, the pooled prevalence of pre-eclampsia in multiple pregnancies – 28% following egg donation and 9.7% following IVF – was so great that the authors advise that single embryo transfer should now ‘be the standard’ after egg donation, particularly in women with primary ovarian insufficiency.

The study reviewed 27 eligible studies involving 7089 egg donation, 1,139,540 naturally conceived and 72,742 IVF pregnancies. All studies found a higher risk of pre-eclampsia following egg donation: a significant association with mild and severe events, in singleton and multiple pregnancies and in pregnancies at all maternal ages. An overall pre-eclampsia prevalence of 11% in singletons and 28% in multiples was described by the authors as ‘a large increase’ when compared to naturally conceived and IVF pregnancies.

The authors note several limitations to their study, one of which is an inconsistent definition of pre-eclampsia in their source studies. Moreover, only a few of these studies actually reported on severe cases, which were nevertheless found in this latest analysis to be between 2.3 and 5.6% after egg donation and 0.5% after natural conception.

While pre-eclampsia in spontaneous pregnancy has been cautiously attributed to impaired placental development (possibly in response to hormonal signalling or genetic factors), an explanation for such an exaggerated response in egg donation is not clear. The authors of this meta-analysis cite an earlier suggestion that the higher incidence of pre-eclampsia in egg donation is because the transferred embryos are completely allogenic to the recipient. This was similarly proposed in a meta-analysis of 2016 from Spain, which cited the immunogenic ‘allogenicity of the fetus to the mother’ as one possible explanation – though adding that the relationship between egg donation and pre-eclampsia ‘remains unclear’.(4) At the level of routine IVF, they noted ‘several differences’ between natural and assisted conceptions, notably the effects of stimulation on the endometrium, embryo transfer, and that the process of trophoblast formation begins in vivo, not in vitro. And of course in ART there is the ever-present variable of advanced maternal age and multiple pregnancy lurking in the analysis. However, the Spanish authors were not as proscriptive in their conclusions as the latest meta-analysts, and, in recognition of their calculated risk (three-fold higher than IVF), advised that egg donation patients should be provided with ‘strict obstetrical surveillance’.

It is worth adding that some of the recent studies of freeze-all embryos in IVF have also found a higher rate of pre-eclampsia than in fresh transfers, summarised in a systematic review in 2019.(5) More recently, a large cohort study based on French registry data, presented at ESHRE’s online annual meeting last year, also found a higher incidence of pre-eclampsia in pregnancies from frozen embryo transfers, but only in those in ‘artificial’ cycles prepared with hormone therapy.(6) The study authors here proposed that the hormone therapy given to prepare the uterus for embryo transfer suppresses ovulation and thus the formation of the corpus luteum, a cluster of ovarian cells which form after ovulation and release several vasoactive factors in addition to progesterone in support of the pregnancy and blood flow.


1. Gui J, Ling Z, Hou X, et al. In vitro fertilization is associated with the onset and progression of preeclampsia. Placenta 2020; 89: 50-57.
doi.org/10.1016/j.placenta.2019.09.011
2. Henningsen AK, Romundstad LV, Gissler MA, et al. Infant and maternal health monitoring using a combinedNordic database on ART and safety. Acta Obstet Gynecolol 2011; 90: 683–691.
doi:10.1111/j.1600-0412.2011.01145.x
3. Keukens A, Van Wely M, Van der Meulen C, Mochtar MH. Pre-eclampsia in pregnancies resulting from oocyte donation, natural conception or IVF: a systematic review and meta-analysis. Hum Reprod 2021; doi.org/10.1093/humrep/deab267
4. Blazquez A, Garcia D, Rodriguez A, et al. Is oocyte donation a risk factor for preeclampsia? A systematic review and meta-analysis. J Assist Reprod Genet 2016; 33: 855–863.
doi:10.1007/s10815-016-0701-9
5. Roque M, Haahr T, Geber S, et al. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2-14.
doi:10.1093/humupd/dmy033
6. See https://www.eshre.eu/Annual-Meeting/ESHRE-2021/2021-Press-releases/Epelboin