Venous thrombosis during assisted reproduction: Novel risk reduction strategies

doi:10.1016/S0049-3848(13)00023-6

Thrombosis Research

Volume 131, Supplement 1, January 2013, Pages S1-S3

https://doi.org/10.1016/S0049-3848(13)00023-6 Get rights and content

Abstract

Ovarian hyperstimulation syndrome (OHSS) affects 5% of IVF cycles and incurs a 100-fold increase in risk of venous thrombosis over natural conceptions. Identification of women at risk of OHSS can be achieved using antral follicle count (AFC) and anti-Müllerian hormone (AMH). For those women with a high AFC or AMH combining a GnRH antagonist with a conventional hCG trigger will reduce the risk of OHSS and still allow a fresh transfer to occur. Complete abolition of OHSS is however now a reality by avoiding exposure to exogenous hCG. This can be achieved by segmentation of the IVF cycle using a GnRH agonist for final oocyte maturation and then freezing all oocytes or embryos with subsequent replacement of a single embryo in the context of a frozen embryo transfer. This novel approach will ensure a VTE risk equivalent to natural conception and can be combined with conventional thromboprophylaxis strategies.

References (30)

WS Chan et al.
A review of upper extremity deep vein thrombosis in pregnancy: unmasking the “ART” behind the clot
J Thromb Haemost
(2006)
WS Chan et al.
The “ART” of thromboembolism: A review of assisted reproductive technology and thromboembolic complications
Thromb Res
(2008)
K Rova et al.
Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles
Fertil Steril
(2012)
SM Nelson et al.
Artificial reproductive technology and the risk of venous thromboembolic disease
J Thromb Haemost
(2006)
H Kodama et al.
Status of the coagulation and fibrinolytic systems in ovarian hyperstimulation syndrome
Fertil Steril
(1996)
EM Kolibianakis et al.
Triggering final oocyte maturation using different doses of human chorionic gonadotropin: a randomized pilot study in patients with polycystic ovary syndrome treated with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone
Fertil Steril
(2007)
HI Abdalla et al.
The effect of the dose of human chorionic gonadotropin and the type of gonadotropin stimulation on oocyte recovery rates in an in vitro fertilization program
Fertil Steril
(1987)
BS Shapiro et al.
Effects of the ovulatory serum concentration of human chorionic gonadotropin on the incidence of ovarian hyperstimulation syndrome and success rates for in vitro fertilization
Fertil Steril
(2005)
A Delvigne
Epidemiology of OHSS
Reprod BioMed Online
(2009)
J Itskovitz et al.
Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist
Fertil Steril
(1991)

S Segal et al.

Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization

Fertil Steril

(1992)

M Melo et al.

GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study

Reprod BioMed Online

(2009)

DA Lawlor et al.

Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study

Lancet

(2012)

AP Ferraretti et al.

Assisted reproductive technology in Europe, 2008: results generated from European registers by ESHRE

Hum Reprod

(2012)

SM Nelson

Prophylaxis of VTE in women – during assisted reproductive techniques

Thromb Res

(2009)

Cited by (32)

Prothrombotic biomarkers during controlled ovarian stimulation for assisted reproductive technology
2023, Fertility and Sterility
To assess the impact of 3 different ovarian stimulation protocols on surrogate biomarkers of coagulation.
Observational multicenter cohort study.
The study was conducted in assisted reproductive technology (ART) units.
Infertile women undergoing ART in 2017–2019 were included.
None.
Our primary outcome was the endogenous thrombin potential (ETP) assessed by the calibrated automated thrombogram. The ETP was measured at baseline (T1), on the day of ovulation triggering (T2), and 7 days after triggering (T3). Three protocols were prescribed according to the standards used and without hormonal before treatment: agonist protocol with human chorionic gonadotropin (hCG) trigger (ag-hCG), antagonist protocol with hCG trigger (atg-hCG), or GnRH agonist trigger. The evolution of ETP was compared among groups using a mixed-effects linear regression model.
Sixty-four women with a mean age of 37.8 years participated in the study: of which 24, 16, 24 received ag-hCG, atg-hCG, and GnRH agonist triggers, respectively. As expected, the mean serum estradiol levels in GnRH agonist trigger were statistically higher at T2 and lower at T3 than that for both ag-hCG and atg-hCG. Overall, the ETP evolution over time was statistically different between the groups. Values were similar between groups at T1 and increased at T2 in each group. The greatest difference occurred between T2 and T3 in each group. The ETP continued to increase at T3 in ag-hCG (+110 nM/L × min) and atg-hCG (+171 nM/L × min), but it remained stable in GnRH agonist trigger (-2 nM/L × min). Sex hormone-binding globulin showed persistent increase at T3 despite the fall in estradiol levels, particularly in the GnRH agonist trigger group.
The ag-hCG and atg-hCG groups were associated with a higher hypercoagulable state at T3 than the GnRH agonist trigger group. However, our results show the persistence of a hypercoagulable state after the GnRH agonist triggering despite a sharp drop in estradiol levels. These findings may support the use of GnRH agonist trigger protocol in patients with high thrombotic risk and gives new insight into the fact that coagulation parameters could be disturbed for long time periods.
NCT04188444
Biomarcadores protrombóticos durante la estimulación ovárica controlada para tecnología de reproducción asistida
Evaluar el impacto de 3 protocolos de estimulación ovárica diferentes en biomarcadores sustitutos de la coagulación.
Estudio observacional de cohortes multicéntrico.
El estudio se realizó en unidades de tecnología de reproducción asistida (TRA).
Se incluyeron mujeres infértiles que se sometieron a TRA en 2017-2019.
Ninguna.
Nuestro resultado primario fue el potencial de trombina endógena (ETP) evaluado por el trombograma automatizado calibrado. El ETP se midió al inicio (T1), el día del desencadenamiento de la ovulación (T2) y 7 días después del desencadenamiento (T3). Se prescribieron tres protocolos según los estándares utilizados y sin tratamiento hormonal previo: protocolo agonista con desencadenante de gonadotropina coriónica humana (hCG) (ag-hCG), protocolo antagonista con desencadenante de hCG (atg-hCG) o protocolo desencadenante de GnRH agonista. La evolución de la ETP se comparó entre grupos mediante un modelo de regresión lineal de efectos mixtos.
Sesenta y cuatro mujeres con una edad media de 37.8 años participaron en el estudio: de las cuales 24, 16, 24 recibieron desencadenantes agonistas de ag-hCG, atg-hCG y GnRH, respectivamente. Como era de esperar, los niveles séricos medios de estradiol en el activador del agonista de GnRH fueron estadísticamente más altos en T2 y más bajos en T3 que los de ag-hCG y atg-hCG. En general, la evolución de la ETP a lo largo del tiempo fue estadísticamente diferente entre los grupos. Los valores fueron similares entre los grupos en T1 y aumentaron en T2 en cada grupo. La mayor diferencia ocurrió entre T2 y T3 en cada grupo. El ETP continuó aumentando en T3 en ag-hCG (+110 nM/L x min) y atg-hCG (+171 nM/L x min), pero se mantuvo estable en la activación del agonista GnRH (-2 nM/L x min). La globulina transportadora de hormonas sexuales mostró un aumento persistente en T3 a pesar de la caída en los niveles de estradiol, particularmente en el grupo desencadenante del agonista de GnRH.
Los grupos de ag-hCG y atg-hCG se asociaron con un estado de hipercoagulabilidad más alto en T3 que el grupo desencadenante del agonista de GnRH. Sin embargo, nuestros resultados muestran la persistencia de un estado hipercoagulable después de la activación del agonista de GnRH a pesar de una fuerte caída en los niveles de estradiol. Estos hallazgos pueden respaldar el uso del protocolo de activación del agonista de GnRH en pacientes con alto riesgo trombótico y brindan una nueva perspectiva sobre el hecho de que los parámetros de la coagulación pueden alterarse durante largos períodos de tiempo.
Hormones and thrombosis: risk across the reproductive years and beyond
2020, Translational Research
Citation Excerpt :
Treatment of VTE in ART. The current guidelines to prevent VTE in women undergoing ART are based on the guidelines to prevent VTE in pregnancy.20,48,52,53 LMWH is the anticoagulant of choice, and in women with OHSS, LMWH is given for at least 3 months following symptom resolution of OHSS (Tables 3 and 4).20
Endogenous and exogenous hormones have significant effects on coagulation and may tip the hemostatic balance toward thrombosis. The endogenous hormonal changes in pregnancy and polycystic ovary syndrome, and exogenous hormonal contraception, menopause replacement, and transgender cross-hormone replacement may increase thromboembolism risk. Using the lowest effective dose is critical for prevention, but once thrombosis occurs, anticoagulation may be required, in some, long term. We review the relative risk of thrombosis in these conditions, risk factors, and anticoagulation treatment and prevention. Implementation of lowest effective hormonal therapies, thrombosis reduction strategies, and current anticoagulation management are critical for optimal patient outcomes.
Assisted reproductive technologies for women with rheumatic AID
2020, Best Practice and Research: Clinical Obstetrics and Gynaecology
Assisted reproductive technology (ART) procedures are safe for women with rheumatic autoimmune diseases (rAID) when illness is inactive. Medications incompatible with pregnancy should be replaced with alternative pregnancy-compatible medications months before planned ART procedures to allow time to verify the substitute medication's efficacy and tolerability. Medications compatible with pregnancy should be continued, as should anticoagulation (warfarin changed to low-molecular-weight heparin) before pregnancy begins. Protocols that provide details for specific medications are available. All patients with rAID should be screened for diagnosis-relevant organ system damage, and those intending to carry their own pregnancies must be tested for aPL and anti-Ro/La autoantibodies. Patients with organ damage and/or positive tests for aPL and anti-Ro/La should be counseled about fetal and maternal risks, including implications to the child and family of maternal disability or death. Sperm donors with rAID may need to discontinue medications. REI and physicians treating patients with rAID (usually rheumatologists) must work together to plan and accomplish ART.
Is thromboprophylaxis cost effective in ovarian hyperstimulation syndrome: A systematic review and cost analysis
2018, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Patients with OHSS and VTE are likely to be pregnant [14]. The administration of human chorionic gonadotrophin (HCG) for final oocyte maturation and triggering of ovulation may further augment the risk of VTE [15]. VTE is associated with significant morbidity and mortality.
The majority of serious thromboembolic events occurring in assisted reproductive technologies (ART) are in women with ovarian hyperstimulation syndrome (OHSS).
The purpose of this study was to present a thorough review and cost analysis regarding the use of venous thromboembolism (VTE) prophylaxis in OHSS to inform clinical management.
Databases used were Pubmed and Embase, in addition to checking reference lists of retrieved articles (inception to November 2017).
The systematic search strategy identified 365 titles and abstracts. Articles included in the qualitative synthesis had identified venous thrombosis incidence rates or ratios. A separate search for the cost model was conducted recognizing all associated complications of VTE. The decision tree was modeled to best fit the patient population and a sensitivity analysis was performed over a range of variables.
The cost of VTE event per OHSS patient not on prophylaxis was €5940 (range €3405 to €38,727), versus €4134 (€2705 to €23,192) per event per patient on prophylaxis, amounting to a saving of (€19 to €23,192) per VTE per patient. Sensitivity analysis found VTE prophyaxis to be cost effective if the incidence of VTE in the OHSS population was greater than 2.79%. Prophylactic therapy was cost effective through 16 weeks of treatment.
OHSS is infrequent and hence, the incidence of VTE in patients with OHSS is low; therefore, the data used to inform the incidence of VTE in OHSS in the model carry some uncertainty. Further, low molecular weight heparin (LMWH) has side effects therefore individualization of care must be considered.
With the increasing incidence of infertility and requirement for ART, thromboembolism in OHSS poses a major health threat for patients. VTE prophylaxis using enoxaparin was cost effective in patients with severe OHSS over a wide range of costs and incidences. Prophylaxis was also cost effective through the completion of the first trimester of pregnancy.
Assisted reproduction technique outcomes for fresh versus deferred cryopreserved day-2 embryo transfer: a retrospective matched cohort study
2017, Reproductive BioMedicine Online
Citation Excerpt :
After a clinical and paraclinical assessment, some women were given the option of receiving a deferred embryo transfer. Indications for def-ET were risk of ovarian hyperstimulation syndrome (OHSS) (Shapiro et al., 2011b), elevated progesterone (≥1.5 ng/ml) or inadequate endometrium on the trigger day (Roque et al., 2015), endometriosis-related-infertility (Mohamed et al., 2011), two or more previous assisted reproduciton technique failures (Shapiro et al., 2014a), and an autoimmune disease, high risk of thromboembolic disease, or both (Nelson, 2013; Rova et al., 2012). Our def-ET protocol involved carrying out cryopreservation on day-1, at the zygote or two pronuclei stage (2PN) to undertake a day-2 transfer when fewer than seven 2PN were obtained.
Ovarian stimulation could adversely affect endometrial receptivity and consequently embryo implantation. One emerging strategy is the ‘freeze-all’ approach. Most studies have focused on blastocyst transfers, with limited research on day-2 deferred cryopreserved embryo transfers. In this large retrospective cohort study, outcomes were compared between day-2 fresh versus deferred cryopreserved embryo transfers. After matching by age and number of previous cycles, 325 cycles were included in the fresh group and 325 in the deferred cryopreserved embryo transfers group: no significant differences were found between groups in implantation (0.20 ± 0.33 versus 0.17 ± 0.31, respectively) and ongoing pregnancy rates (21.85% versus 18.46%). Independent predictors for ongoing pregnancy after a multiple logistic regression analysis were the women's age (OR = 0.92; 95% CI 0.88 to 0.97), body mass index (OR = 0.94; 95% CI 0.89 to 0.99), the number of two pronuclei embryos (OR = 1.19; 95% CI 1.04 to 1.40) and at least one grade 1 embryo transferred (OR = 1.97; 95% CI 1.26 to 3.05). In the case of a day-2 embryo transfer, outcomes after treatment with assisted reproduction techniques are similar for fresh versus deferred cryopreserved embryo transfers when pre-transfer progesterone exposures are similar in the two groups.
The ART of Thromboprophylaxis in the Prevention of Gestational Venous Thromboembolism
2023, Seminars in Thrombosis and Hemostasis

View all citing articles on Scopus

View full text

Venous thrombosis during assisted reproduction: Novel risk reduction strategies

Abstract

J Thromb Haemost

Thromb Res

Fertil Steril

J Thromb Haemost

Fertil Steril

Fertil Steril

Fertil Steril

Fertil Steril

Reprod BioMed Online

Fertil Steril

Fertil Steril

Reprod BioMed Online

Lancet

Assisted reproductive technology in Europe, 2008: results generated from European registers by ESHRE

Hum Reprod

Prophylaxis of VTE in women – during assisted reproductive techniques

Thromb Res