key: cord-339036-nmmworwk
authors: Fabregues, F.; Peñarrubia, J.
title: ASSISTED REPRODUCTION AND THROMBOEMBOLIC RISK IN COVID-19 PANDEMIC
date: 2020-06-25
journal: Reprod Biomed Online
DOI: 10.1016/j.rbmo.2020.06.013
sha: 
doc_id: 339036
cord_uid: nmmworwk

Covid-19 pandemic has increased significantly to mortality in many countries with the number of infected cases increasing exponentially worldwide. One of the main determining factors of the poor prognosis in these patients is the development of coagulopathy. Moreover, it is well known that ART procedures confer a risk of thromboembolic complications. In this commentary we analize specific coexisting aspects between the thrombotic risk described during virus infection and that one reported in the context of assisted reproduction treatments. Based on known pathophysiological aspects of both virus infection and those identified during ovarian stimulation (OS), we found common elements that deserve to be taken into account. In the present context, any risk of hyperstimulation should be avoided. GnRh agonist triggering should be mandatory in high responders patients and/or with COVID infection. In both cases, the cycle should be segmented. We propose prophylactic with low molecular weigth heparin (LMWH) not only in those cases in which the oocyte recovery has been performed, but also in those in which the cancellation has been decided. In addition, the endometrial preparation to the frozen-thawed embryo transfers (FETs) should be using the transdermal route in order to minimize the higher thrombotic risk of the oral route.

From the first case identified in Wuham (China) in late December 2019 until today, severe acute respiratory syndrome coronavirus 2 (SARS.Co-2) has caused more than 5 million affected, reported in 187 countries, resulting in more tan 300.000 deaths. The outbreak has been brought to global attention and declared a pandemic by the World Health Organization (WHO) on March 11, 2020 (WHO., 2020 . Mortality occurs mainly due to severe lung involvement causing an acute respiratory distress syndrome (ARDS), although sometimes a multi-organ failure occurs with significant coagulation disorders (Zhou et al., 2020) Due to the large increase in reported cases and the impact of the COVID-19 coronavirus on public health, ESHRE on March 19, 2020 and ASRM on March 30, 2020 recommended the cessation of any activity related to assisted reproduction. Recently, both societies, ESHRE on April 23 and ASRM on April 24, have authorized the resumption of healthcare activity with the general safety recommendations established by government authorities in each country. These measures persue minimizing of contagion and are also based on the fact that infertility is a disease whose prognosis can worsen over time. Protocols have been established in order to minimize the risk of contagion for both patients and staff. However, have been established few measures regarding ovarian stimulation protocols, triggering and other considerations related to the clinical management of patients. The aim of this review is to analyze a specific coexisting issue between the thrombotic risk described during virus infection and that one reported in the context of assisted reproduction treatments. Thromboembolic risk in COVID-19 patients. Current understanding of the pathogenesis As mentioned above, Covid-19 has a special affinity for the lung, however, a key factor in the poor prognosis of the infection is the presence of coagulopathy and thromboembolic complications. (Connors and Levy., 2020; Tang et al,.2020 ). The three essential elements of the so-called Virchow's triad for thromboembolic risk occur during virus infection. First, endotelial injury has been related to the virus's affinity for ACE-2 receptors wich are present in many organs, including the vascular endothelium (South et al., 2020) . Secondly, the situation of stasis of blood flow is due to the immobilization during hospitalization of critically ill patients and thirdly, a hypercoagulability state occurs as a consequence of the large number of prothrombotic circulating factors that have been reported in patientes with severe COVID-19 (Thachil et al.,2020) . Based on the currently available literature it has been suggested that some coagulation markers as D-Dimers, prothrombine time and platelet count (in decreasing order of importance) are associated with high mortality in COVID-19 patients. In this line, it has been demostrated that the use of anticoagulant therapy with heparin has shown a decrease mortality suggesting positive effects to endotelial disfunction and inflamation state (Thachil ., 2020) Interestingly high levels of D-dimer could predict the degree of coagulopathy even in asymptomatic COVID-19 patients. In this context , the International Society of Thrombosis and Haemostasis (ISTH) recommends the use of prophylactic low molecular weigh heparin (LMWH) in all patients (including non-critically ill) who require hospital admission and on those who have co-morbidities (Thachil., 2020) Thromboembolic risk in ART. Current understanding of the pathogenesis It is well known that ART procedures confer a risk of thromboembolic complications. Most thrombotic complications have been reported in the context of OHSS and prophylactic guidelines have been established in this regard, which were not considered necessary during ovarian stimulation in abscence of risk factors. Even though the incidence is low in absolute terms, it is similar to the risk of venous thrombosis during pregnancy, and suppos an increase in risk 10 times higher than the women´s risk of reproductive age. Thromboembolic complications can be arterial and venous, with differences in timing and location. Unlike arterial events that occur preferentially at the start of OHSS, venous events can occur weeks later even after resolution of the complication.On the other hand while arterial thromboses are predominantly cerebrovascular accidents, venous events are mostly reported in unusual sites such as the upper extremities. (Chan., 2009) Besides, it is worth noting that the risk of venous thromboembolism (VTE) is higher in pregnant women after IVF compared to women who had normal pregnancies. Studies demostrated that the risk is significantly higher in the first trimester of pregnancy after IVF . In addition, pregnancies complicated by OHSS showed a 100-fold increased risk of VTE, as opposed the fivefold increased risk seen in the abscence of OHSS. Therefore, ovarian stimulation, OHSS and pregnancy exponentially increase the risk of VTE. ( Grandoni and Villani., 2015) Despite the fact the causes of the increased thrombotic risk in the context of ART are not well known, according to the scheme established in the previous section, we can analyze the different aspects outlined in the Virchow's triad. Concerning endothelial injury there is a relevant aspect regarding the OS and OHSS. According to the knowledge about haemodynamic and neurohormonal during severe OHSS , arteriolar vasodilation is a constant finding in patients with severe forms of the syndrome . This produces underfilling of the arterial vascular compartiment (i.e. decreased "effective arterial blood volume") and, resulting arterial hypotension which leads to high-pressure baroreceptor-mediated stimulation of endogenous vasoactive systems (renin-angiotensin-aldosterone ,sympathetic nervous systems and ADH). The simultaneous occurrence of these compensatory mechanisms compose the so-called 'hyperdynamic circulation' that characterizes conditions associated with oedema formation (Schrier et al., 1990) . In this line, it has been shown that this hemodynamic alteration occurs universally during COH in IVF cycles, with significant activation of endogenous vasoactive systems in the luteal phase . The degree of activation of those endogenous vasoactive systems, it was less intense than that observed in patients with severe OHSS. ( Manau et al., 1998) . This suggests that the extreme circulatory dysfunction observed during severe OHSS, appears mor attenuated in all women undergoing IVF. In this context we can speculate that the role of the renin-angiotensin system could be affected by the special affinity of the COVID_19 by ACE-2 receptor and thereby give place to new unknown clinical scenarios (South et al., 2020) . According to what has been previously mentioned, hyperdynamic circulation demonstrated in OS and in more intense cases with OHSS, it has been linked to the tissue factor wich is essential and is now considered to be the primary and most potent activator of the blood system coagulation. It is accepted that, circulating monocytes are the cells of the vascular system that can trigger blood coagulation through the tissue factor-dependent pathway (Witkowski et al.,2016) .The wall shear stress increased in conditions of hyperdynamic circulation and the arteriolar vasodilatation can induce the formation of interstitial oedema by increasing capillary permeability. Due to the surface area for filtration and hydrostatic pressure it is possible that changes in the vessel wall during the OS take place and make the blood monocytes more sensitive to tissue factor activity. On the other hand,Tissue factor pathway inhibitor (TFPI) that play a relevant role regulating haemostatic equilibrium decreases progressively throughout the OS, this would explain the hypercoagulable status, occurring during assisted reproduction (Romagnuolo et al., 2014) Accordingly, a pro-thrombotic state has been demonstrated in cases with OHSS with the increase of markers like thrombin (thrombin-antithrombin complex and prothrombin fragment 1 + 2) and fibrin (D-dimer) (Balasch et al., 1996) . Regarding stasis, it is evident that hospital admission and immobilization represent an added risk of prothrombotic risk, as occurs in cases of severe OHSS. Furthermore, hemoconcentration present in most cases has shown to be a more serious factor in patients with OHSS and should therefore be avoided . This situation should not occur in the absence of OHSS, however it would be prudent to take it into account. The third aspect related to the pathogenesis of hypercoagulability is the hypercoagulable state, that is the changes in the prothrombotic circulating factors that have been reported during the OS and with the OHSS. It has been shown that plasma fibrinogen increases and antithrombin decreases, together with decreasing markers of fibrinolytic activity following controlled ovarian hyperstimulation in IVF (Westerlund et al., 2012) . The increase in coagulation factors indicates a trend towards a procoagulable state. As noted above, an increase of tissue factor and consequently of D-dimer has been demonstrated in OHSS (Balasch et al., 1996) . Furthermore, it has recently been reported that with OS in IVF cycles with its boost of endogenous oestrogens has increased the levels of procoagulant Microparticles (MPs). In this line phenotyping of MPs showed that the increase in the level of estrogens was correlated with platelet-derived MPs, monocyte-derived MPs as well as endothelial-derived MPs (Olausson et al., 2016) . Finally and summarizing we can point out that many aspects related to the hypercoagulability state are present during OS and very prominently in the extreme situation of OHSS Added risk in current clinical practice in ART Government recommendations in the different countries, as well as those of ESHRE and ASRM clearly minimize the risks of COVID-19 transmission. However, there are aspects related to OS and the risk of OHSS that should be highlighted. Having ruled out patients with co-morbidities who should obviously postpone assisted reproduction treatments, there are aspects related to clinical management in the field of assisted reproduction that must be observed. In the present context, any risk of hyperstimulation should be avoided . GnRh agonist triggering should be mandatory in high responders patients and/or COVID infection. In both cases, the cycle should be segmented, which although it does not totally rule out the possibility of OHSS, it does minimize it.

Based on what is mentioned in this article, we would propose prophylactic with LMWH not only in those cases in which the oocyte recovery has been performed, but also in those in which the cancellation has been decided.. COVID-19 infection before oocyte recovery or during the luteal phase would significantly increase the risk in these patients. The association of OS, OHSS , pregnancy and COVID infection would be dramatic, since all our efforts should be directed to avoid this sequence.Even when applying this therapeutic measure, attention should be paid to the luteal phase of these patients, given that the studies have shown that hemodynamic and other aspects related to the hypercoagulability status of these patients, would dramatically increase their risk in the case of infection by COVID-19. Finally, another interesting aspect to address in the current situation is the one referring to endometrial preparation to the frozen-thawed embryo transfers (FETs). Over the last decade, the proportion of FETs has substantially increased and therefore, there is a large number of infertile patients who perform endometrial preparation with hormonal therapy replacement (HTR). In this sense, and based on studies conducted in menopausal patients undergoing HTR, there is evidence that the risk of VTE is closely related to the route of administration, with a threat 4 times higher with the oral vs. transdermal route ( Olie et al., 2010) . Thus, we would suggest the latter, since in the current scenario in which the number of visits to reproduction centers should be minimized, endometrial preparation in the natural cycle should be avoided. In cases of suspected or confirmed COVID infection after FETs thromboprophylaxis with LMWH should also be performed. Furthermore, due to the increased thrombotic risk in case of twin pregnancies, we would suggest SET during the pandemic period. In conclusion, in the current situation of uncertainty and risk, the specialists in the reproductive field should maximize prophylactic measures of thrombotic risk. Based on previous knowledge about thrombogenic risk in the context of assisted reproduction and recent knowledge regarding COVID-19 infection, we could find unexpected clinical scenarios

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