Infertility treatment and cardiovascular disease: What do we know?

At present, the dominating modality of assisted reproductive technology (ART) is in vitro fertilization (IVF). This treatment was introduced in 1978 with the birth of Louise Joy Brown in the United Kingdom [1]. The field of ART has ever since expanded, and today, more than 10 million children have been born as a result of IVF [2].

About a third of embryo transfers after IVF result in a clinical pregnancy, and a fourth in a live-born child [3]. This results in an annual increase of half a million children born after IVF as the result of 2 million annual embryo transfers. The remaining embryos are, in most cases, cryopreserved and available for future embryo transfers [4]. Use of frozen and thawed embryo transfers (FET) was previously considered to lead to fewer successful pregnancies as compared to fresh embryo transfers, but technical advances, such as innovative freezing techniques, vitrification and visual embryo selection of embryos or blastocysts, have improved the success rate of FET to a level on par with that of fresh embryo transfers [5].

The risk of venous thromboembolism (VTE), including pulmonary embolism (PE), is increased in women during pregnancy [6]. The incidence is most pronounced during the third trimester of pregnancy and in the immediate postpartum period. The mortality rate in pregnant women afflicted by VTE has been estimated to be between 0.8 and 1.5 per 100,000 pregnancies, with more than 90% of fatal VTEs being due to PE.

IVF results in a more than eightfold increase in both VTEs and PEs during the first trimester of fresh embryo transfer pregnancies [7]. There was no such increase in the incidence of VTEs and PEs after FET/thawed embryo transfer pregnancies [8]. This indicates that ovarian stimulation, with its oestrogen surge, seems to be a necessary prerequisite to trigger the increase in VTEs and PEs.

Furthermore, gestational hypertension and pre-eclampsia have been reported to increase during IVF pregnancies [9]. A recent interesting observation suggests that this could be related to the absence of a corpus luteum in some pregnancies.

Concerning cardiovascular disease associated with unsuccessful IVF treatment – the majority of embryo transfers – there are conflicting reports. One study showed an increased incidence of PE after unsuccessful IVF, but on the contrary, another study showed a lower incidence of VTE after failed ART.

Furthermore, many women will experience multiple subsequent IVF cycles due to the fact that only a quarter of the embryo transfers result in a live-born child. The cardiovascular effect of multiple subsequent IVF cycles has not yet been studied.

There has been a paucity of studies concerning the long-term effects of IVF on cardiovascular health. The heterogeneity of the few pre-existing studies precluded any final conclusions, but a trend towards a higher incidence of stroke might exist [10, 11]. However, in the present issue of the Journal of Internal Medicine, Yamada et al. [12] reported an association of ART with an increased risk of postpartum hospitalization due to heart disease (HR 1.99, CI: 1.80–2.20). This is the largest retrospective cohort study, including 31,339,991 deliveries, of which 287,813 had received infertility treatment. The greatest risk was observed for hypertensive disease (HR 2.16, CI: 1.92–2.42). The duration of follow-up was 1 year, and the increased risk was apparent already 30 days post-delivery. This is in line with previous studies noting an increased risk of hypertension postpartum [10, 11]. The authors have recently reported an increased incidence of hospitalization for stroke during the first year after ART [13]. This was particularly evident concerning haemorrhagic stroke.

However, a recent large study from the Nordic countries reported findings suggesting that women who had given birth after ART were not at an increased risk of CVD [14]. This study encompassed 2496,441 parous individuals, and 97,474 of them had given birth after ART.

These two large studies might seem to be in conflict. However, it could be noted that the Nordic study did not report the incidence of hypertensive disease, and they also stated that the follow-up was started 2 years after delivery. This means that the two studies could not be compared concerning cardiovascular disease during the first year after delivery. In this context, it could also be noted that one of the previous studies also reported a significant increase in the incidence of hypertensive disease during the first years after delivery [11].

The incidence of ischemic heart disease (IHD) does not seem to increase after IVF pregnancies. However, IHD is primarily a disease of high age, and none of the studies had a sufficient length of follow-up. The median age of the women at the end of follow-up in the Nordic study was 41 years.

In the present context, it is also important to consider a possible effect of infertility per se. Women with infertility have been reported to have a less favourable cardiovascular risk factor profile. Furthermore, women with polycystic ovary syndrome, a common cause of female infertility, often have multiple cardiometabolic risk factors.

To add, infertility seems to be associated with incident cardiovascular disease [15], although there exist some inconsistencies between studies.

A support that increased oestrogen levels during ovarian stimulation might be an actor or initiator of early thromboembolism after fresh embryo transfer IVF is that the oestrogen boost during the ovarian stimulation was followed by a significant increase in oestrogen level during the first two thirds of this trimester as compared to spontaneous pregnancy. This means that an increased oestrogen level should not persist postpartum. However, one might speculate that oestrogen could be an elicitor of hypertensive disorder of pregnancy (HDP) that might continue postpartum.

One important knowledge gap to close is conflicting results concerning the risk for cardiovascular disease after unsuccessful IVFs. This must be tested in nationwide registers. This is of vital importance as, as previously mentioned, unsuccessful IVFs are the majority of IVFs.

Even other types of ART treatments not involving IVF, such as intrauterine insemination, utilize ovarian stimulation protocols to increase the number of mature oocytes. This means that the oestrogen level is increased. The effects of such treatments mandate to be studied.

Further, the recent interesting findings concerning the impact of the presence or absence of a corpus luteum during FET and oocyte donation should be further explored. This seems to be of particular significance as it concerns the risk for HDP and pre-eclampsia.

IVF has, for more than four decades, fulfilled the desire of many women to conceive despite decreased fecundity. However, VTE is a potentially life-threatening disorder during pregnancy in these women. Postpartum, the risk of hypertensive disease and stroke seems to be increased during at least the first year. However, the long-term risk of cardiovascular disease must await a prolonged follow-up in large cohort studies.

Writing – original draft (lead): Peter Henriksson.

The author declares no conflicts of interest.