1 Department of Obstetrics and Gynecology, University of Oulu, 2 Infertility Clinic, Family Federation of Finland, 90220 Oulu, 3 Department of Obstetrics and Gynecology, University of Kuopio, 70211 Kuopio and 4 Department of Obstetrics and Gynecology, University of Tampere, 33521 Tampere, Finland
5 To whom correspondence should be addressed. Email: mervi.pakkila{at}oulu.fi
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Abstract |
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Key words: ICSI/IVF/low-dose aspirin/ovarian response/pregnancy rate
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Introduction |
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Low-dose acetylsalicylic acid (aspirin) irreversibly inhibits the enzyme cyclo-oxygenase in platelets, preventing the synthesis of thromboxane (Vane, 1971; Willis, 1974
), which is the most potent vasoconstrictive agent in the human body. By decreasing platelet aggregation and inhibiting vasoconstriction, low-dose aspirin may enhance uterine and ovarian blood flow and tissue perfusion and thus improve the results of IVF and ICSI treatments (Wada et al., 1994
; Rubinstein et al., 1999
). Previous studies have shown that low-dose aspirin started in the second trimester of pregnancy in high-risk populations decreases the incidence of pre-eclampsia and preterm labour, and increases the birth weight of the newborn (Italian Study of Aspirin in Pregnancy, 1993
; Collaborative Low-dose Aspirin Study in Pregnancy Collaborative Group, 1994
). Low-dose aspirin has also been found to improve endometrial receptiveness in cases of thin endometrium (Weckstein et al., 1997
). Furthermore, women with recurrent miscarriages and antiphospholipid syndrome may benefit from low-dose aspirin therapy, especially when combined with low-molecular weight heparin (Sher et al., 1994
; Rai and Regan, 1997
; Tulppala et al., 1997
). However, the results of low-dose aspirin treatment as regards ovarian responsiveness and pregnancy rate in unselected subjects undergoing artificial reproduction techniques have remained controversial (Rubinstein et al., 1999
; Urman et al., 2000
).
In the present randomized double-blind prospective study, we hypothesized that low-dose aspirin therapy (100 mg daily) improves ovarian responsiveness and the clinical PR in unselected subjects undergoing IVF/ICSI when started concomitantly with controlled ovarian stimulation.
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Materials and methods |
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Randomization was carried out in blocks of four with sealed envelopes by the pharmacist at Oulu University Hospital. The women were treated with identical looking tablets of aspirin or placebo (Bayer AG, Leverkusen, Germany). The patients were randomized on the first day of gonadotrophin stimulation to receive 100 mg of oral aspirin (n=186) or placebo (n=188) daily in one dose until menstruation or a negative pregnancy test result (Figure 1). Pregnant women continued the medication until delivery. Fertilized oocytes were cultured in MediCult Medium® (Medi-Cult A/S, Copenhagen, Denmark), IVF-500 Medium® (Scandinavian IVF Science, Gothenburg, Sweden) or Sydney IVF Medium® (Cook IVF, Queensland, Australia). In two centres, one top quality embryo (n=82 out of 193) was electively transferred into the uterine cavity 4650 h after oocyte retrieval in subjects under 39 years undergoing their first or second stimulation. In the other two centres, single ET was performed in 21 out of 181 cases. Otherwise, in all centres, two (n=227 out of 374) or three (n=9/374) embryos were transferred. The criteria for a top quality embryo were: normal fertilization (2PN), 45 blastomeres on day 2, <20% fragmentation and no multinuclear blastomeres (van Royen et al., 1999). Natural progesterone (Lugesterone®, Leiras, Finland) was given transvaginally (200 mg x3) for luteal support for 14 days. Clinical pregnancies were confirmed by transvaginal ultrasonography 5 weeks after ET.
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Results |
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No significant difference was observed in the pregnancy outcome between the aspirin and placebo groups. There were 32 out of 174 (18.4 %) live births per ET in the aspirin group and 37 out of 175 (21.1 %) in the placebo group. The incidence of miscarriage per clinical pregnancy was 18.2% (eight out of 44) in the aspirin group and 16.7% (eight out of 48) in the placebo group, and the incidence of extrauterine pregnancy per clinical pregnancy was 9.0% (four out of 44) and 6.3% (three out of 48), respectively.
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Discussion |
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The findings are in agreement with those in a study by Urman et al. (2000), who found no difference in the number of oocytes or PR between aspirin-treated (80 mg, n=139) and non-treated (n=136) ICSI subjects, whose main indication for treatment was male factor, in 85% of the cases. Generally the couples with male infertility have a good result in ICSI treatment and, according to the mechanism of action of low-dose aspirin, it is possible that male infertility cases would benefit less from aspirin treatment compared with other infertility etiologies.
Some selected groups of patients, such as poor responders, ageing women or patients with previous implantation failures, could benefit from low-dose aspirin treatment. By altering the balance of prostacyclin and thromboxane, low-dose aspirin may enhance uterine and ovarian blood flow (Wada et al., 1994; Rubinstein et al., 1999
) and improve endometrial receptivity and ovarian responsiveness to hormonal stimulation. However, the randomized and placebo-controlled study by Lok et al. (2004)
has revealed that low-dose aspirin (80 mg/day) started at the time of commencement of gonadotrophin stimulation does not improve ovarian responsiveness (mature follicles, oocytes retrieved and total number of embryos) or PR in poor responders undergoing IVF (Lok et al., 2004
). Accordingly, we did not find any statistical significance in ovarian responsiveness or PR between aspirin and placebo groups in patients with previous IVF/ICSI failures or in women aged
35 years.
In contrast, Rubinstein et al. (1999) reported a remarkable increase in number of oocytes and an improvement in pregnancy rate after controlled ovarian stimulation in aspirin- (100 mg daily) treated IVF subjects with tubal factor, versus placebo. A recent randomized study showed increased birth rate per ET in aspirin-treated patients with a short regimen compared with the no treatment group in a non-selected IVF population with 1380 cycles (1022 patients) (Waldenstrom et al., 2004
). However, in this study, there are many aspects which make the interpretation of the results difficult. First, in the aspirin group, the number of embryos transferred was significantly higher than in the no-treatment group, which could contribute to the higher PR in the aspirin group. Secondly, the randomization method used did not allow an equal possibility for every patient to receive either aspirin or no treatment randomly. Thirdly, the study was open and not placebo controlled, both of which may increase the risk for study bias.
As regards the dose of aspirin, 80160 mg daily in healthy volunteers (Cerletti et al., 2003) and 0.52.0 mg/kg daily in hypertensive pregnant women (Vainio et al., 1999
) have been shown to increase the prostacyclinthromboxane ratio. Thus, the dose of 100 mg daily used in the present study should have been sufficient to demonstrate the possible beneficial effects of aspirin.
The sample size of this study is able to demonstrate a 15% increase in PR in the aspirin-treated group. It is obvious that a smaller increase would have been clinically significant. However, to prove a 5% increase in PR in favour of the aspirin group, almost 1200 patients would have been needed in each randomization arm to demonstrate the significance with 80% power (=0.05).
In conclusion, the results of this randomized, placebo-controlled, double-blind study showed that low-dose aspirin does not improve ovarian responsiveness, clinical PR or pregnancy outcome in subjects undergoing IVF/ICSI treatments.
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Acknowledgements |
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References |
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Submitted on August 9, 2004; resubmitted on March 9, 2005; accepted on March 14, 2005.
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