10.4081/btvb.2022.43
The last report on Assisted Reproductive Technologies (ART) showed a steady increase in the annual number of treatment cycles worldwide. The most common techniques of autologous ART - in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) - require the use of exogenous gonadotropins with possible adverse effects [...].
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Elvira Grandone
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Bleeding, Thrombosis and Vascular Biology
Venous thromboembolism
Talking about assisted reproductive techniques and thromboembolic risk: everything we always wanted to know
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2022-09-13
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2022-05-23
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Bleed Thromb Vascul Biol
Elvira Grandone
2022/09/13
10.4081/btvb.2022.43
Thrombosis and Hemostasis Unit, “Casa Sollievo della Sofferenza” Foundation, San Giovanni Rotondo, Italy; Obstetrics and Gynecology, University of Foggia, Italy; Ob/Gyn Department of the First I.M. Sechenov Moscow State Medical University, Moscow
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Piazza G, Grandone E. Thrombophilia, Antithrombotic Therapy, and Recurrent Pregnancy Loss: A Call for Pragmatism in the Face of Unknowns. Semin Reprod Med 2021;39:167-69. doi: 10.1055/s-0041-1735628.
Talking about assisted reproductive techniques and thromboembolic risk: everything we always wanted to know
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                                                                                                                        EDITORIAL

Talking about assisted reproductive techniques and thromboembolic risk:
everything we always wanted to know
Giovanni Tiscia,1 Elvira Grandone1-3
1
  Thrombosis and Hemostasis Unit, “Casa Sollievo della Sofferenza” Foundation, San Giovanni Rotondo, Italy; 2Obstetrics and
Gynecology, University of Foggia, Italy; 3Ob/Gyn Department of the First I.M. Sechenov Moscow State Medical University, Moscow,
Russian Federation




     The last report on Assisted Reproductive Technologies                   risk of venous thromboembolism (VTE) can be up to 100-
(ART) showed a steady increase in the annual number of                       fold higher than that observed in absence of such compli-
treatment cycles worldwide.1 The most common tech-                           cation.3 Actually, severe OHSS, that occurs in 0.5-5% of
niques of autologous ART - in vitro fertilization (IVF) and                  ART cycles, shows quite heterogeneous pathogenetic




                                                                                              ly
intracytoplasmic sperm injection (ICSI) - require the use                    mechanisms leading to thrombosis through a huge imbal-
of exogenous gonadotropins with possible adverse effects.                    ance of coagulation and fibrinolysis.4 ART-induced hy-




                                                                                       on
It is clear that efforts to address infertility in order to give             percoagulability is mainly due to an increase in plasma
the chance of the motherhood should be, however, care-                       levels of several clotting factors and especially factor VIII,
fully weighed against possible complications. Indeed, ex-                    leading to an acquired activated protein C resistance. On




                                                                                 e
ogenous gonadotropins used for controlled ovarian                            the other hand, the downregulation of fibrinolysis and
hyperstimulation, induce hypercoagulable state.2 When an
ovarian hyperstimulation syndrome (OHSS) occurs, the
                                                                            us
                                                                             lowering levels of endogenous natural anticoagulants,
                                                                             such as protein S, further increase the risk.5 All these
                                                                            al
                                                                             changes can be detected by global tests as thrombo-elas-
                                                                             tography-based viscoelastic assays.6
                                                         ci

                                                                                  VTE may be diagnosed up to several weeks after a con-
  Correspondence: Elvira Grandone, Thrombosis and Hemostasis
                                                       er


                                                                             trolled ovarian hyperstimulation or OHSS, whereas arterial
  Unit, Poliambulatorio “Giovanni Paolo II”, Fondazione IRCCS
  “Casa Sollievo della Sofferenza”, Viale Cappuccini, 71013 San
                                                                             thrombotic complications usually occur several days after
                                                      m



  Giovanni Rotondo (Foggia), Italy.                                          ovulation induction.2 Notably, pulmonary embolism (PE)
  Tel. +390882416273                                                         is frequently reported in this setting, independently of the
                                          om




  E-mail: e.grandone@operapadrepio.it                                        presence of deep vein thrombosis in the lower extremity.
  Key words: Assisted reproductive technologies; Hyperstimulation
                                                                             Indeed, the risk of PE is approximately threefold higher
                                                                             than that reported during oral contraception.7
                                    -c




  syndrome; Venous thromboembolism.
                                                                                  Increasing age, overweight or overt obesity, in addi-
                           on




  Contributions: The authors contributed equally.                            tion to smoking and other individual characteristics fur-
  Conflict of interest: The authors declare no potential conflict of in-
                                                                             ther raise the risk.5 Controversial data are so far available
                                                                             about whether and to what extent thrombophilia in-
                     N




  terest.
                                                                             creases the risk.2
  Funding: None.                                                                  More recently, data from several studies have shown
  Received for publication: 15 June 2022.                                    that VTE risk in pregnancies following ART is doubled
  Accepted for publication: 1 August 2022.                                   in comparison to that estimated after spontaneous con-
                                                                             ception, independently of the occurrence of OHSS. VTE
  Publisher’s note: All claims expressed in this article are solely those    risk is tenfold greater in the first trimester in ART preg-
  of the authors and do not necessarily represent those of their affili-
  ated organizations, or those of the publisher, the editors and the re-
                                                                             nancies compared to that recorded in the reference pop-
  viewers. Any product that may be evaluated in this article or claim        ulation.8 Consistent with these findings, VTE risk
  that may be made by its manufacturer is not guaranteed or endorsed         appears significantly lower in unsuccessful cycles com-
  by the publisher.                                                          pared to successful ones.9
  ©
                                                                                  As for antithrombotic prophylaxis in high-risk women,
   Copyright: the Author(s), 2022
  Licensee PAGEPress, Italy                                                  as well as type and duration of treatment in case of OHSS,
  Bleeding, Thrombosis and Vascular Biology 2022; 1:43                       robust data are lacking. Furthermore, there are no conclu-
  doi:10.4081/btvb.2022.43                                                   sive studies focusing on the best management of OHSS, al-
                                                                             though, due to the highest risk of VTE, pharmacological
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                    prophylaxis with low-molecular-weight-heparin (LMWH)
                                                                             is recommended.2,3 For these reasons, current guidelines

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:43
50                                                  G. Tiscia and E. Grandone




often do not report any practical suggestions on strategies
to reduce the risk - both, arterial and venous - in ART nor         REFERENCES
give specific advice to guide the intensity and duration of           1. Chambers GM, Dyer S, Zegers-Hochschild F, et al. Interna-
antithrombotic treatment in case of OHSS. This issue is par-             tional Committee for Monitoring Assisted Reproductive
ticularly relevant, as maternal age is one of the most fre-              Technologies world report: assisted reproductive technol-
quent indirect risk factors for mortality in western countries           ogy. Hum Reprod 2021;36:2921-34.
and the mean age at first childbirth continues to increase.           2. Bates SM, Rajasekhar A, Middeldorp S, et al. American So-
Most importantly, fewer than a third of mothers who gave                 ciety of Hematology 2018 guidelines for management of ve-
birth over the age of 45 receive the recommended care for                nous thromboembolism: venous thromboembolism in the
                                                                         context of pregnancy. Blood Adv 2018;2:3317-59.
older mothers (https://www.npeu.ox.ac.uk/assets/down-
                                                                      3. Royal College of Obstetricians and Gynaecologists. The
loads/mbrrace-uk/reports/maternal-report-2020/MBR-                       management of ovarian hyperstimulation syndrome. Green-
RACE-UK_Maternal_Report_Dec_2020_v10_ONLINE_                             top Guideline No. 5. London: RCOG; 2016.
VERSION_1404.pdf).                                                   4. Delvigne A, Rozenberg S. Epidemiology and prevention of
    In Italy, one of the most frequent indirect causes of                ovarian hyperstimulation syndrome (OHSS): a review. Hum
maternal death is ART (11.3% of fatalities), whereas the                 Reprod Update 2002;8:559-77.
leading causes of direct deaths in pregnancy are hemor-               5. Piazza G. Oh heavy burden: recognizing the risk of venous




                                                                                              ly
                                                                         thromboembolism in women undergoing assisted reproduc-
rhage and VTE (https://www.epicentro.iss.it/en/itoss/ma-




                                                                                       on
                                                                         tion. Thromb Haemost 2018;118:2011-3.
ternal-mortality-surveillance). These data prompted the               6. Zohav E, Almog B, Cohen A, et al. A new perspective on
European Society of Cardiology (ESC) to recommend                        the risk of hypercoagulopathy in ovarian hyperstimulation
avoiding fertility treatments in women with class IV of                  syndrome using thromboelastography. Reprod Sci




                                                                                 e
the modified WHO classification of maternal risk and to                  2017;24:1600-6.
be cautious in those with modified WHO class III or those
who are anticoagulated. Actually, these groups of women
                                                                         us
                                                                      7. Grandone E, Di Micco PP, Villani M, et al. Venous throm-
                                                                         boembolism in women undergoing assisted reproductive
                                                                         technologies: data from the RIETE registry. Thromb
                                                                  al
have a significantly higher risk of superovulation and
                                                                         Haemost 2018;118:1962-8.
therefore of OHSS.10 At variance with ESC, many other
                                                       ci

                                                                      8. Sennström M, Rova K, Hellgren M, et al. Thromboem-
international guidelines do not give particular suggestions              bolism and in vitro fertilization - a systematic review. Acta
                                                     er


on these issues in the absence of ad hoc studies. We deem                Obstet Gynecol Scand 2017;96:1045-52.
it crucial that international guidelines on reproductive              9. Villani M, Favuzzi G, Totaro P, et al. Venous thromboem-
                                                    m



health give reasonable suggestions to provide the best                   bolism in assisted reproductive technologies: comparison
possible counselling, in the light of albeit scarce evidence             between unsuccessful versus successful cycles in an Italian
                                           om




instead of simply stating that there is no evidence. On the              cohort. J Thromb Thrombolysis 2018;45:234-9.
                                                                    10. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al.
other hand, while waiting for randomized controlled trials
                                                                         2018 ESC Guidelines for the management of cardiovascular
                                     -c




in this field, we must be pragmatic and strive to utilize in-            diseases during pregnancy. Eur Heart J 2018;39:3165-241.
novative alternative study designs, aimed at offering our           11. Piazza G, Grandone E. Thrombophilia, antithrombotic ther-
                              on




women safe strategies to get pregnant and mostly to avoid                apy, and recurrent pregnancy loss: a call for pragmatism in
life-threatening situations for mothers and babies.11                    the face of unknowns. Semin Reprod Med 2021;39:167-9.
                         N




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