The Legacy of Edwards and Steptoe and the Windy Roads of Assisted Reproduction: Where Do We Stand with Venous Thromboembolism?

The issue of thromboembolic risk after assisted reproductive technique (ART) attempts is very relevant in terms of women health. Data from the RIETE registry have shown an increased prevalence of pulmonary embolism in this setting as compared with estrogen- and/or pregnancy-related venous thromboembolism (VTE).[1]

On the one hand, the risk of potentially life-threatening VTE is increased by the presence of individual as well as technique-related risk factors, on the other hand, pregnancy rates after ART remain relatively low (approximately 34% according to the last report by the European Society of Human Reproduction and Embryology (ESHRE). This figure is even lower (approximately 23%) after frozen embryo replacement, although egg donation is associated with a significantly higher odds of success (approximately 50%).[2] Individual risk factors likely affecting the odds of VTE during the cycle or in pregnancy following ART include age, body mass index, and personal and family history of VTE. The role of increasing age as a risk factor for VTE during ART attempts is plausible and documented by recent data indicating that age and ART are indirect causes of mortality in pregnancy.[3] Existing inconsistencies on this issue in the literature are likely due to paucity of systematically collected data and changes of ART procedures over time.[4]

The risk of VTE is significantly higher in fresh embryo-transfer (ET) procedures as compared with spontaneous pregnancy, but not after frozen ET.[5] If further studies will confirm these data, we should perhaps suggest to women at higher VTE risk to transfer previously frozen embryos in a following spontaneous cycle.

Thrombotic risk is further increased by the use of drugs for the induction of controlled ovulation stimulation (COS), as well as of hormones used to prepare the endometrium for implantation of blastocyst. Indeed, the increments in estradiol and factor VIII during ART are paralleled by an increase in von Willebrand factor antigen and activity, and a decrease in circulating ADAMTS13 antigen and activity, respectively. These modifications partly explain the increased risk of thrombotic events in this setting.[6]

In this issue of the journal, Goaulou et al[4] report the findings from a systematic review of the literature on the magnitude of ART-associated VTE risk and the weight of individual risk factors. This systematic review and meta-analysis of 14 studies shows an overall frequency of VTE associated with ART of 0.23% (95% confidence interval [CI]: 0.07–0.46) and corroborates findings from previous studies that report two- to threefold increased risk of VTE in pregnancies following ART as compared with spontaneous pregnancy. Individual response to ovulation induction varies from an inefficient to an exaggerated one, leading in some cases to the fearsome complication of ovarian hyperstimulation syndrome (OHSS) mainly associated with use of gonadotrophins. OHSS, occurring in 0.5 to 5% of ART cycles, is one of the highest prices paid by women in terms of safety, as it can lead to multiorgan failure and death.[7] Furthermore, it is associated with an absolute risk of VTE of 100-fold higher than that observed during COS (1.7%).[8]

Goaulou et al[4] underscore the relevance of risk factors intrinsically connected to the cause of infertility (i.e., polycystic ovarian syndrome) and to drugs used to induce COS (i.e., OHSS). Taken together, these risk factors represent a common soil for infertility and VTE risk ([Fig. 1]): this should prompt to focus future research toward investigation of factors that cause or worsen infertility, as they should be also relevant for VTE and/or arterial thrombosis.

Fig. 1 Risk factors common to infertility and venous thromboembolism. BMI, body mass index; PCOS, polycystic ovary syndrome; VTE, venous thromboembolism.

The effort to increase the efficiency of ART using modern approaches in animal and human research models[9] is not balanced by adequate research aimed to implement strategies to avoid as much as possible dangerous side effects for women's health. We urgently need independent and well-conducted studies to better identify the role and the weight of each single risk factor, as available evidence on this topic is still mostly based on small case-series or observational studies.[10]

The information that pregnancy after ART is “per se” an additional risk factor for VTE is a relatively recent and misrecognized acquisition[11] with a clinically relevant impact. In the paper by Goaulou et al,[4] the risk estimate is high (odds ratio: 13.94), but we need further studies to give more accurate estimates, as the 95% CI is wide (1.41–137.45). A great effort should be made in this direction, as the age of women at the first pregnancy is constantly increasing; therefore, the overall risk of complications on both sides—maternal as well as fetal—is predicted to increase.

As in other fields of research on VTE, it should be interesting to combine clinical items (including family history), genetic factors, and biomarkers to try to outline the profile of patients at particularly high risk of incident VTE and VTE-related complications, given the intense interest into this area of risk profiling.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] Hence, these could be applied to each woman approaching ART and validate scores that can be helpful in identifying those individuals at higher risk.

Another knowledge gap concerns the risk associated with oocyte donation. This issue is relevant as in many countries, women above >35 years approach ART and the number of women who choose oocyte donation is increasing, due to the natural decline of fertility with age and to the parallel VTE risk associated with ovarian stimulation, age, and/or comorbidities. In this setting, pregnancy complications such as pre-eclampsia, gestational diabetes, as well as superficial vein thrombosis are reported to be higher than in younger women.[22] Also, the hormonal link is reflected by the significant rates of recurrence during pregnancy and puerperium in women with a previous VTE event associated with oral contraceptive-associated VTE.[23] However, these findings on feto-maternal well-being need to be confirmed by more recent and robust evidence.

In conclusion, ART attempts are becoming more frequent in aged women with multiple comorbidities. Therefore, VTE risk and, more in general, adverse events are expected to increase. We urgently need studies aimed at identifying the weight of each risk factor in contributing to individual VTE risk during ART and the following pregnancy. Furthermore, additional data on the role of biomarkers obtained in large international prospective cohorts might be helpful to better define feto-maternal risk. This research should provide a common ground for future interventional studies to manage high-risk cycles and the upcoming pregnancy.

Publikationsverlauf

Eingereicht: 07. Dezember 2022

Angenommen: 07. Dezember 2022

Accepted Manuscript online:
10. Dezember 2022

Artikel online veröffentlicht:
30. Januar 2023

• References

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