Transcript NMH U MPO - HRVATSKO DRUŠTVO ZA GINEKOLOŠKU

LOW MOLECULAR HEPARIN
IN ASSISTED
REPRODUCTION
HRVOJE VRČIĆ,
MARINA ŠPREM GOLDŠTAJN
I ANA BOBAN
Stimulation protocol
Implantation of embryo
Lutheal phase support
Human Reproduction Uptodate Vol 14 No 6 pp 623-645 2008
Potential role of heparin in assisted conception
Scott M Nelsson and Ian A Greer
Heparin can alter the haemostatic response to controlled ovarian stimulation
and modify the risk of thrombosis.
It can also modulate many of the fundamental physiological processes required for
blastocyst apposition, adherence and implantation and as well as
trophoblast differentiation and invasion due to its similarities with heparan
sulphates and has the potential to improve pregnancy rates and outcomes.
Potential actions of heparin on implantation.
LMWH can modulate many of the fundamental physiological processes
required for blastocyst implantation and trophoblast development
Nelson S M , and Greer I A Hum. Reprod. Update
2008;14:623-645
LMWH and embryo implantation
SELECTINS
LMWH may modulate selectins
produces from blastocyst and
MECA 79 and HECA-152 produced
from endometrium
Wang et al 2002
CADHERINS
LMWH have recently been shown
to down regulate decidual
E-cadherin expression,
thereby potentially explaning the
observation that LMWH can promote
extravillous trophoblast differentiation
Queneby et al 2004
Erden et al 2006
LMWH and embryo implantation
TRANSFORMING GROWTH FACTOR (TGF)
LMWH inhibits TGF-β1
(TGF inhibits trophoblast proliferation and invasion)
Weigert et al 2001
INTERLEUKIN – 1 (IL-1)
LMWH increase IL-1 in activated leukocytes
IL-1 seems to improve blastocyst adhesion
Call et al 1998
Dimitriadis et al 2006
LMWH and embryo implantation
MATRIX METALOPROTEINASES (MMPs)
MMP-9 degrades Collagen IV main component of the basement membrane
and its conjunction with MMP-2 may enable the invasion of trophoblast cells
through decidua and into the uterine vasculature
Isaka et al 2003
Several in vitro studies have shown that MMP-2 and MMP-9 are required for
trophoblast invasion.
LWMH induce MMP-2 and MMP-9 transcription and protein expression
Staun-Ram et al 2004
LMWH and embryo implantation
HEPARIN-BINDING EPIDERMAL GROWTH FACTOR (HB-EGF)
LMWH may potentiate soluble HB-EGF and upregulate sHB-EGF
via increased MMP activity enhancing the development of IVF-derived
embryos to blastocysts and subsequent zona hatching
Martin et al 1998
Armant et al 2006
INSULIN-LIKE GROWTH FACTOR (IGF)
LMWH increase IGF-I, a potent mitogenic and differentiation-promoting
growth factor, implicated in implantation and fetal development
Constancia et al 2002
Moller et al 2006
LMWH in repeated pregnancy loss
Therapy
Life birth rate
Reference
Enoxaparin 40mg vs
No treatment
70% Enoxaparin vs
44% no treatment (p<0,02)
Carp et al 2003
1RPL, Trombophilia (FVL, F
II, Protein S deficiency
Enoxaparin 4000ij vs
ASS 100mg
+ 5mg folic acid
88% Enoxaparin vs
29% ASS (p<0,0001)
Gris et al. 2004
1 late misscariage, > 2RPL,
Trombophilia
LMWH 40mg vs
LMWH 80mg
84% LMWH 40mg vs
78% LMWH 80mg
Brenner et al 2005
>=3RPL, with or without
APL-AK
ASS vs Placebo
70% ASS vs
70% Placebo
Tulpalla et al 1997
Heparin and implantation
Reprod Biomed Online. 2013 Jun;26(6):586-94. doi: 10.1016/j.rbmo.2013.02.007. Epub 2013 Feb 18.
Aspirin and heparin as adjuvants during IVF do not improve live birth rates in unexplained
implantation failure.
Akhtar MA, Eljabu H, Hopkisson J, Raine-Fenning N, Quenby S, Jayaprakasan K
This retrospective cohort-control study recruited 234 consecutive subjects aged ≤ 44 years who had
previously had one or more unsuccessful IVF cycle.
All underwent IVF using conventional protocols. The study group received aspirin and/or heparin post embryo
transfer until the day of pregnancy test or until 12 weeks of pregnancy. The control group did not receive
adjuvant treatment.
Analysis was performed in 206 subjects. There was no statistically significant difference in
the live birth rate (35.0%, 36/103 versus 47.6%, 49/103),
clinical pregnancy rate (40.8%, 42/103 versus 53.4%, 55/103)
and miscarriage rate (14.3%, 6/42 versus 10.9%, 6/55) between the study group and the control group.
The data in this study show that low-dose aspirin and/or heparin as adjuvant therapies during IVF do not
improve live birth rates in an unselected group of subfertile women who have previously had one or more
unexplained implantation failure following IVF
Heparin and implantation
Reprod Biomed Online. 2012 Dec;25(6):572-84.
Effect of heparin on the outcome of IVF treatment: a systematic review and meta-analysis.
Seshadri S, Sunkara SK, Khalaf Y, El-Toukhy T, Hamoda H.
Searches were conducted on MEDLINE, EMBASE, Cochrane Library and Web of Science and identified 10 relevant studies (five
observational and five randomized) comprising 1217 and 732 IVF cycles, respectively. The randomized studies included small
numbers of women and exhibited high methodological heterogeneity
Meta-analysis of the randomized studies showed no difference
in the clinical pregnancy rate (RR 1.23, 95% CI 0.97-1.57),
live birth rate (RR 1.27, 95% CI 0.89-1.81)
implantation rate (RR 1.39, 95% CI 0.96-2.01) and
miscarriage rate (RR 0.77, 95% CI 0.24-2.42) in women receiving heparin compared with placebo during
IVF treatment.
However, meta-analysis of the observational studies showed a significant increase
in the clinical pregnancy rate (RR 1.83, 95% CI 1.04-3.23, P=0.04) and
live birth rate (RR 2.64, 95% CI 1.84-3.80, P<0.0001).
The role of heparin as an adjuvant therapy during IVF treatment requires further evaluation in adequately powered
high-quality randomized studies
Analyses of the data from randomized trials showed no improvement in the clinical pregnancy rate or the
live birth rate in the group that received heparin.
Figure 3
Live birth rate
The effect of heparin versus placebo on the live birth rate (randomized controlled trials).
Figure 4
Live birth rate
The effect of heparin versus placebo on the live birth rate (observational studies).
Figure 5
Live birth rate
The effect of heparin versus placebo on the live birth rate in women with recurrent
implantation failure without coagulation defects.
Figure 6
Clinical pregnancy rate
The effect of heparin versus placebo on the clinical pregnancy rate (randomized
controlled trials).
Figure 7
Clinical pregnancy rate
The effect of heparin versus placebo on the clinical pregnancy rate
(observational studies).
Figure 8
Clinical pregnancy rate
The effect of heparin versus placebo on the clinical pregnancy rate in women with
recurrent implantation failure without coagulation defects.
Conclusion
In conclusion, this systematic review demonstrates that the role of
adjuvant heparin therapy during IVF has not been adequately evaluated
by current literature.
On the basis of published literature, the group of patients who could
benefit from heparin therapy could not be identified with certainty.
Specifically, the role of heparin in subfertile women with known
thrombophilia and those with unexplained recurrent IVF implantation
failure warrants further evaluation with adequately
LMWH vs Cardioaspirin in embryo implantation in women undergoing IVF
without inherited trombophilia: randomized pilot study
Antonio Colicchia
Center of Reproductive Medicine S Anna Rome, Italy
ESHRE 2013, London
Study design
•
•
•
•
•
•
•
•
126 women conventional IVF
BMI < 25
Aged 31-42 years
At least 2 failed previous attemps
No inherited thrombophilia
No male factor
Normal karyotype
Two randomized group
Colicchia A. ESHRE 2013. London
Colicchia A. ESHRE 2013. London
Results
HEPARIN GROUP
Dalteparin 2500IU/day
Progesterone vag 600mg/day
N
ASPIRIN GROUP
Aspirin 100mg/day
Progesterone 600mg vag
Prednisone 10mg/day oral
68
58
AGE
37,4
37,6
N PREVIOUS ATTEMPS
FAILED
2,6
2,8
N EMBRYOS TRANSFERRED
2,3
2,1
EMBRYOS GRADING A
TRANSFERRED
1,24
1,13
All patient started therapy from the day of embryo transfer
Results
HEPARIN
ASPIRIN
p
Β-hCG
47%
20,6%
0,0026
IMPLANTATION
RATE
22%
10%
0,0136
LIVE BIRTH RATE
30%
12%
0,0171
Colicchia A. ESHRE 2013. London
LMWH in the treatment of reccurent IVF-ET failure and trombophilia: a
prospective randomized placebo controlle trial
Qublan H, Amarin Z, Dabbas M et al.
Infertility&IVF Center, King Hussein Medical Center, Amman, Jordan
Hum Fertil (Camb.) 2008 Dec;11(4):246-53
N =83
Group A 42
Group B 41
p
Enoxaparin
40mg
Placebo
0,9%NaCl
Implantation rate
20,9%
6,1%
0,001
Pregnancy rate
31%
9,6%
0,05
Life birth rate
23,8%
2,8%
0,05
No evidence that assisted reproduction increases the risk of thrombosis: a Danish
National cohort study
A.T. Hansen1,*, U.S. Kesmodel2, S. Juul3 and A.M. Hvas1
Hum. Reprod. 2012;27:1499-1503
+ Author Affiliations
1Department of Clinical Biochemistry, Centre of Haemophilia and Thrombosis, Aarhus University Hospital, Brendstrupgaardsvej 100,
Aarhus N 8200, Denmark
2The Fertility Clinic, Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus N 8200, Denmark
3School of Public Health, Department of Epidemiology, Aarhus University, Aarhus C 8000, Denmark
METHODS
A national register-based cohort study was conducted on all women undergoing IVF or ICSI treatment
in Denmark from 1994 to 2005.
Data were obtained from the National Patient Registry and the IVF Registry.
Women with prior malignant or cardiovascular disease were excluded.
Thrombosis occurring within the first 6 and 12 months after assisted reproduction was
considered potentially related to the treatment.
Thromboses during pregnancy as well as the pregnancy-related diagnoses were excluded from the
statistical analysis.
The incidence rates of venous and arterial thromboses were compared with previously published
estimates of the risk of thrombosis among young Danish women.
RESULTS
We analyzed 30 884 Danish women undergoing 75 141 treatments from 1994 to 2005. The mean age of
the women at first treatment was 32.3 years. The delivery rate per cycle was 22%.
The incidence rate ratio, with 95% confidence interval (CI), of venous thrombosis within 6 months
was 0.95 (CI: 0.38–1.95). The incidence rate ratio of arterial thrombosis within 6 months was 0.36 (CI:
0.04–1.30).
Hansen A et al. Hum. Reprod.
2012;27:1499-1503
Information on IVF/ICSI cycles, pregnancies and abortions.
IVF/ICSI-related information
Treatment method
IVF,
ICSI,
n (%)
n (%)
IVF-ICSI,
Total,
49 741 (66)
22 580 (30)
n (%)
2820 (4)
n (%)
75 141 (100)
Number of oocytes aspirated, median (10 and 90 percentiles)
8 (3; 16)
Embryo transfer performed,
66 561 (89)
OHSS within 3 months,
n (%)
n (%)
715 (1)
Information on pregnancies after IVF/ICSI
Serum-hCG positive,
n (%)
Clinical pregnancy achieved,
25 013 (33)
n (%)
Number of pregnancies resulting in children,
18 953 (25)
n (%)
16 836 (22)
Number of live born children
20.912
Delivery rate per cycle (%)
22%
Preterm delivery
2933 (17)
a,
n (% of pregnancies with live born children)
Spontaneous abortion
b,
n (% of clinical pregnancies)
1793 (9)
•IVF, in vitro fertilization; ICSI, intra-cytoplasmic sperm injection; IVF–ICSI, IVF converted to ICSI; hCG, human chorionic gonadotrophin.
•aDefined as birth no later than gestational age of 258 days.
•bDefined as spontaneous termination of pregnancy prior to gestational week 28 (until April 2004) and prior to gestational week 22 (after April 2004).
Cumulative incidence of venous thrombosis (VTE) for the first three years after IVF or ISCI,
compared to the incidence in the reference population.
Hansen A et al. Hum. Reprod. 2012;27:1499-1503
© The Author 2012. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
[email protected]
Cumulative incidence of arterial thrombosis (AT) for the first three years after IVF or ISCI,
compared to the incidence in the reference population.
Hansen A et al. Hum. Reprod. 2012;27:1499-1503
© The Author 2012. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
[email protected]
Hansen A et al. Hum. Reprod. 2012;27:1499-1503
Incidence rates of venous and arterial thromboses within
the first 6 and 12 months after IVF or ISCI.
Venous
thrombosis
Arterial
thrombosis
3.0
2.25
Events
7
2
Time at risk (years)
24 686
24 687
Incidence rate (95% CI)
2.8 (1.1–5.8)
0.8 (0.1–2.9)
Incidence rate ratio (95% CI)
0.95 (0.38–1.95)
0.36 (0.04–1.30)
Events
14
6
Time at risk (years)
36 856
36 861
Incidence rate (95% CI)
3.8 (2.1–6.4)
1.6 (0.6–3.5)
Incidence rate ratio (95% CI)
1.27 (0.69–2.12)
0.72 (0.27–1.57)
Reference incidence rate
Within 6 months
Within 12 months
•Incidence rate ratios were calculated by comparison to reference populations of young Danish females.
•Incidence rates are per 10 000 years at risk.
Hansen A et al. Hum. Reprod.
2012;27:1499-1503
Conclusion
IVF/ICSI treatments do not seem to increase the risk of venous or
arterial thrombosis per se.
Future studies should attempt to identify potential specific subgroups at
high risk of thrombosis among IVF/ICSI patients in order to target
the use of prophylactic anticoagulation therapy.
CASE HISTORY
No family history of DVT.
Infertility 5 years, no male factor
2008. Hysteroscopy endometrial polyp
1st pregnacy
2009. Missed ab 10th week
•2nd pregnacy
2010. Missed abortion at 10th week, 46,XY
PAI-1 5G/4G heterozigot
MTHFR C677T heterozigot
FV R506Q no mutation
FII 20210A no mutation
3rd pregnancy IVF/ET from 5th week of pregnancy dalteparin 5000 IU
39th week M 3300/52 Apgar score 10/10
•Legal case:
•If you screen after second misscariage, why not after first?
•Would you give prophylaxis?
What obstetric events should trigger thrombophilia
screening?
IUD or early neonatal death with placental histology indicating
infarction/thrombosis (maternal side) or perivillous fibrin deposition (fetal
side)
•Preeclampsia requiring delivery before 36 weeks or eclampsia/HELLP at
any gestation
•Placental abruption requiring immediate delivery
•Fetal growth restriction requiring delivery before 36 weeks or SGA
(<5thcentile) with abnormal placental histology
WHAT TESTS?
•Leiden (some labs may screen with APCR V rather than full genetic test)
•Prothrombin gene
•Antithrombin III
•Protein C & S
MTHFR and PAI-I?
•APS (IgG, IgM, Lupus anticoagulant –two abnormal tests 6 weeks apart)
Ideally, tests should be done at least 10 weeks postnatal or after
misscarriage
WHAT MANAGMENT?
Women with confirmed thrombophilia following complicated
pregnancy should have aspirin and LMWH
Women with confirmed trombophilia and IVF should have LMWH?
When should we start with LMWH? – day of embryo transfer or
positive beta hCG?
How long should we continue with LMWH therapy?