Low-dose aspirin and uterine haemodynamics on the day of embryo transfer in women undergoing IVF/ ICSI: a randomized, placebocontrolled,

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1 Human Reproduction, Vol.24, No.4 pp , 2009 Advanced Access publication on January 18, 2009 doi: /humrep/den489 ORIGINAL ARTICLE Infertility Low-dose aspirin and uterine haemodynamics on the day of embryo transfer in women undergoing IVF/ ICSI: a randomized, placebocontrolled, double-blind study Mervi Haapsamo 1,3, Hannu Martikainen 1, and Juha Räsänen 1,2 1 Department of Obstetrics and Gynecology, University of Oulu, PO Box 24, FIN Oulu, Finland 2 Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, OR 97239, USA 3 Correspondence address. Tel: þ ; Fax: þ ; mervi.haapsamo@oulu.fi background: Increased uterine artery (UtA) vascular impedance at the time of embryo transfer can decrease implantation and pregnancy rates in women undergoing IVF/ICSI. We hypothesized that low-dose aspirin decreases UtA vascular impedance on the day of embryo transfer in unselected IVF/ICSI patients when medication is started concomitantly with controlled ovarian stimulation. In addition, as secondary outcome measures, we investigated whether low-dose aspirin decreases the incidence of non-optimal (bilateral UtA PI 3.0) uterine haemodynamics and whether it affects arcuate, radial and spiral artery vascular impedances and endometrial thickness. methods: A total of 122 women who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n ¼ 61) or placebo (n ¼ 61) daily, starting on the first day of gonadotrophin stimulation. Doppler ultrasonography was performed on the day of embryo transfer. results: Embryo transfer took place in 57 women in the aspirin group and in 56 women in the placebo group. UtA mean PI values did not differ significantly between the groups. The incidence of non-optimal uterine haemodynamics was lower in the aspirin group than in the placebo group (P ¼ 0.03). Other secondary outcome measures did not differ between the groups. conclusions: In unselected IVF/ICSI women, low-dose aspirin therapy, when started concomitantly with controlled ovarian stimulation, did not affect UtA vascular impedance on the day of embryo transfer. However, the incidence of non-optimal uterine haemodynamics was significantly lower in the aspirin group than in the placebo group. ClinicalTrials.gov: NCT Key words: uterine vascular impedance / Doppler ultrasonography / endometrial receptivity / assisted reproduction / low-dose aspirin Introduction The most important factors affecting implantation and pregnancy rates after embryo transfer in cases of IVF and ICSI are the quality of the transferred embryo and receptivity of the endometrium. A favourable endometrial milieu for embryo transfer has been predicted ultrasonographically by measuring blood flow velocities and blood flow velocity waveform indices in the uterine, subendometrial and endometrial arteries (Zaidi et al., 1996; Chien et al., 2002; Merce et al., 2008) and by assessing endometrial thickness, morphology (Zaidi et al., 1995) and volume (Yaman et al., 2000; Schild et al., 2001). Some ultrasonographic studies have demonstrated that a substantial proportion of women with successful implantation have had more optimal uterine blood flow and a thicker endometrium (Noyes et al., 1995) with more organized morphology (Serafini et al., 1994) compared with women without conception. In particular, increased uterine artery (UtA) vascular impedance (Coulam et al., 1994; Cacciatore et al., 1996; Zaidi et al., 1996) and low subendometrial or endometrial blood flow (Zaidi et al., 1995; Chien et al., 2002) have been associated with poor implantation and pregnancy rates. However, other studies have not revealed such associations (Isaksson et al., 2000, 2003; Puerto et al., 2003). Low-dose acetylsalicylic acid (aspirin) irreversibly inhibits the cyclo-oxygenase enzyme in platelets, thus, preventing the synthesis of thromboxane (Vane, 1971; Willis, 1974), which causes vasoconstriction and platelet aggregation. By this mechanism, low-dose aspirin may enhance uterine blood flow and tissue perfusion and thus improve endometrial receptivity for implantation. Randomized controlled studies and meta-analyses concerning the use of & The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org.

2 862 Haapsamo et al. low-dose aspirin therapy to improve uterine haemodynamics have demonstrated controversial results (Check et al., 1998; Rubinstein et al., 1999; Lok et al., 2004; Khairy et al., 2007). In addition, such studies focusing on IVF/ICSI outcome have revealed conflicting results (Rubinstein et al., 1999; Päkkilä et al., 2005; Gelbaya et al., 2007; Khairy et al., 2007; Ruopp et al., 2007). In the present randomized, placebo-controlled double-blind prospective study, we hypothesized that low-dose aspirin therapy (100 mg daily) would decrease UtA vascular impedance on the day of embryo transfer in unselected women undergoing IVF/ICSI when the treatment is started concomitantly with controlled ovarian stimulation. In addition, as secondary outcome measures, we investigated whether low-dose aspirin decreases the incidence of non-optimal (bilateral UtA PI 3.0) uterine haemodynamics and whether it affects arcuate, radial and spiral artery vascular impedances and endometrial thickness. Materials and Methods This randomized, placebo-controlled and double-blind study was conducted at the Infertility Clinic of Oulu University Hospital, Oulu, Finland. The local Ethics Committee (reference number 56/2001) approved the study protocol. Inclusion criteria and recruitment Inclusion criteria were: (i) age,40 years, (ii) less than four previous ovarian stimulations and (iii) no contraindications for aspirin. The women were informed and recruited to the study during their first visit (on the previous cycle) to the clinic. Randomization Eligible patients who signed written informed consent documents were randomly allocated on the first day of gonadotrophin stimulation to receive 100 mg oral aspirin (n ¼ 61) or placebo (n ¼ 61) daily in one dose until menstruation or a negative pregnancy test result. Women who became pregnant continued the medication until delivery. Randomization was carried out by means of computer-generated random numbers in blocks of four by the pharmacist (third-party administrator) at Oulu University Hospital. Concealment of allocation was achieved by using opaque sealed envelopes. Blinding of the participants and investigators was ensured by treating the women with identically appearing tablets of aspirin or placebo (Bayer AG, Leverkusen, Germany). Stimulation protocol Long gonadotrophin-releasing hormone agonist treatment together with recombinant FSH (Gonal-F w, Laboratories Serono; or Puregon w, Organon, Oss, the Netherlands) or human menopausal gonadotrophin (Menogon w, Ferring, the Netherlands) was carried out according to a protocol previously described (Päkkilä et al., 2005). Human chorionic gonadotrophin (hcg) administration was based on ultrasonography (diameter of three follicles over 17 mm). Embryo transfer, which took place in 113 women, was performed 2 days after oocyte retrieval. One top quality embryo (n ¼ 40/113) was electively transferred into the uterine cavity in patients under 39 years and undergoing their first or second stimulation. Otherwise, two (n ¼ 72/113) or three (n ¼ 1/113) embryos were transferred. Natural progesterone (Lugesterone w, Leiras, Finland) was started transvaginally (200 mg 3) for luteal support one day before embryo transfer and was continued for 14 days. Clinical pregnancies were confirmed by transvaginal ultrasonography 5 weeks after embryo transfer. Ultrasonographic examination Ultrasonographic examinations (Acuson Sequoia 512; Mountain View, CA, USA) were performed on the day of embryo transfer by using a 5 8 MHz transvaginal transducer (EV-8C4). The insonation angle was minimized to,308 in every measurement and the high pass filter was set at its minimum. All women were examined before noon and all examinations were performed by a single investigator (M.H.). Both uterine arteries were located by colour Doppler ultrasonography and their blood velocity waveforms were obtained at cervicocorporeal level of the uterus. Arcuate arteries were identified bilaterally and blood velocity waveforms were obtained as distally as possible from the UtA. The radial artery blood velocity waveforms were obtained from the middle of the myometrial region. Then a colour Doppler window was placed over the thickest part of the endometrium. The highest colour intensity from the endometrial/subendometrial area was identified and its blood velocity waveforms were obtained. This vessel represented the spiral artery (Schild et al., 2001). A continuous waveform of at least three consecutive cardiac cycles was required for successful examination. The thickness of the endometrium was measured as the maximum distance between the myometrial/endometrial interfaces through the central longitudinal axis of the uterus (Zaidi et al., 1995). Three consecutive measurements were obtained and their mean value was used for further analysis. Pulsatility index [PI ¼ (peak systolic velocity2end-diastolic velocity)/ time-averaged maximum velocity over the cardiac cycle] values were calculated from three consecutive cardiac cycles, and the mean value was used for further analysis. The side with the lowest PI value was chosen for the final analysis. The incidence of a bilateral UtA PI value 3.0 (non-optimal uterine haemodynamics), which is considered to predict poor outcome in IVF/ICSI (Steer et al., 1992; Zaidi et al., 1996), was determined. To calculate intra-observer variability of the UtA PI measurements, UtA blood flow velocity waveforms were obtained twice, min apart from 10 consecutive patients. Outcomes Primary outcome measure was UtA PI value. Secondary outcome measures were the incidence of non-optimal uterine haemodynmics, arcuate, radial and spiral artery PI values and endometrial thickness. Sample size and statistical analysis Sample size was calculated by Stata Statistics/Data Analysis 8.0 (Stata Corporation, College Station, TX, USA) so as to be able to detect a decrease in the UtA PI value from 3.0 (Steer et al., 1992; Zaidi et al., 1996) to 2.6 (Salle et al., 1998) using a SD value of 0.5 on the day of embryo transfer in favour of the aspirin group. To detect such a decrease a ¼ 0.05 with a power of 90%, we needed 49 subjects in each group. Statistical comparison of the continuous and categorical data between the groups was carried out by Student s two-tailed t-test, Mann Whitney U-test and Pearson s x 2 test when appropriate. Intention-to-treat approach was used in comparisons of characteristic and IVF/ICSI protocol parameters. Ultrasonographic data were obtained from patients who underwent embryo transfer (Fig. 1). Comparison of within-group parameters was carried out by means of Student s two-tailed t-test and Mann Whitney U-test. A P, 0.05 was considered statistically significant. Results Within the study period, a total of 122 women who underwent IVF (n ¼ 76) or ICSI (n ¼ 46) were included in this investigation. Embryo transfer took place in 113 patients, of whom 57 received

3 Low-dose aspirin and uterine haemodynamics 863 aspirin and 56 placebo. Four patients in the aspirin group and five patients in the placebo group failed embryo transfer due to premature ovulation, unsuccessful ovum retrieval or no fertilization/cleavage. In the aspirin group, single embryo transfer took place in 21 (37%) patients and double embryo transfer took place in 36 (63%) patients. In the placebo group, corresponding incidences were 19 (34%) and 36 (64%). In one case (2%), multi embryo transfer was performed in the placebo group (Table III). The flowchart for this randomized study is shown in Fig. 1. There were no statistically significant differences in the characteristics of the women between the aspirin and placebo groups (Table I). Intra-observer variability of UtA PI measurement was 4.1% (95% CI %). UtA mean PI values did not differ significantly between the aspirin and the placebo groups. In addition, there was no statistically significant difference (P ¼ 0.46) in mean PI values of UtA [2.37 (95% CI ) versus 2.51 (95% CI )] between women who conceived after embryo transfer and those who did not. The incidence of non-optimal uterine haemodynamics (bilateral UtA PI 3.0) was more frequent (P ¼ 0.034, 95% CI for proportions %) in the placebo group than in the aspirin group. None of the women with non-optimal uterine haemodynamics had clinical pregnancy. Arcuate, radial or spiral artery PI values or endometrial thickness did not differ significantly between the groups (Table II). Stimulation for IVF/ICSI, and fertilization and pregnancy outcome parameters did not differ between the aspirin and the placebo groups (Table III). In addition, the number of retrieved oocytes [11 (0 31) versus 12 (0 39)] and the number of top-quality embryos [3 (0 8) versus 3 (0 7)] were comparable between the women Figure 1 Flowchart for the randomized study.

4 864 Haapsamo et al. Table I Characteristics of the groups Variable ASA (n 5 61) Placebo (n 5 61)... Age 32 (24 39) 31 (22 39) BMI 24 (18 37) 24 (19 38) Smoking, % (n) 1.6 (1) 3.2 (2) Aetiology of infertility, % (n) Male 21 (13) 25 (15) Tubal 15 (9) 18 (11) Endometriosis 31 (19) 28 (17) Hormonal 10 (6) 10 (6) Unexplained 15 (9) 11 (7) Mixed 8 (5) 8 (5) Duration of infertility (years) 3 (1 11) 4 (1 14) Previous IVF/ICSI cycles, % (n) 48 (29) 52 (32) Pregnancy history, % (n) Patients with previous 31 (19) 33 (20) pregnancy Total number of pregnancies Live births 61 (14) 62 (16) Miscarriage 39 (9) 35 (9) Extrauterine pregnancy 0 4 (1) Data is given as medians (range). with non-optimal (bilateral UtA PI 3.0) and optimal (UtA PI, 3.0) uterine haemodynamics. The implantation rate was 22.6% in the aspirin group and 24.5% in the placebo group, and clinical pregnancy rates per embryo transfer were 26.3% (15/57) and 28.6% (16/56), respectively. There were 13/57 (22.8%) live births in the aspirin group and 13/56 (23.2%) in the placebo group. The incidences of miscarriage (13.3 versus 12.5%) and extrauterine pregnancy (0 versus 6.3%) were comparable between the groups. No adverse events or symptoms were reported. Discussion This randomized, placebo-controlled and double-blind study among unselected IVF/ICSI women revealed that on the day of embryo transfer low-dose aspirin therapy, when started concomitantly with gonadotrophin stimulation, does not significantly affect UtA vascular impedance. However, as a secondary outcome measure, the incidence of bilateral UtA PI value 3.0, which reflects non-optimal uterine haemodynamics and predicts poor outcome in IVF/ICSI, was more common in placebo-treated women compared with women who received 100 mg aspirin daily. We found no statistically significant difference in mean PI values of UtA between the aspirin- and placebo-treated women. In addition, mean PI values of arcuate, radial and spiral arteries were comparable between the groups demonstrating that among unselected IVF/ICSI patients low-dose aspirin therapy does not affect uterine vascular impedance during long gonadotrophin regimen. In contrast to our result, Rubinstein et al. (1999) showed lower UtA PI values on the day of hcg administration and higher pregnancy rate in aspirin-treated women (100 mg/day) with tubal etiology compared with a placebo group. On the other hand, in a study by Lok et al. (2004) with unselected poor IVF-responders, no significant difference was found in UtA PI values or pregnancy rates between the aspirin (80 mg/day) and placebo groups. A recent meta-analysis by Khairy et al. (2007), which included both above-mentioned studies, showed a decrease in UtA PI values. Our findings also demonstrate that arcuate, radial and spiral artery blood velocity waveform indices, which were secondary outcome measures in the present study, did not offer any additional prognostic value in evaluation of uterine receptivity and aspirin did not affect these haemodynamic parameters during gonadotrophin treatment. Our results are also in accordance with those of Isaksson et al. (2000, 2003), who showed that examination of UtA blood flow velocity waveforms on the day of embryo transfer is not useful in prediction of implantation success or pregnancy outcome. A UtA PI value 3.0 at the time of embryo transfer has been shown to predict poor outcome in women with IVF or ICSI (Steer et al., 1992; Coulam et al., 1994; Cacciatore et al., 1996; Zaidi et al., 1996). In this study, we found as a secondary outcome measure that the incidence of non-optimal uterine haemodynamics (bilateral UtA PI value 3.0) was lower among the aspirin-treated women than in the placebo group. Doppler ultrasonographic studies have shown higher UtA blood flow impedance in infertile women compared with fertile women, suggesting that successful implantation requires adequate uterine perfusion (Goswamy et al., 1988; Steer et al., 1994). However, implantation can occur in the presence of nonoptimal uterine haemodynamics at the time of embryo transfer (Isaksson et al., 2003). Kuo et al. (1997) detected significant Table II Uterine haemodynamics and endometrial thickness on the day of embryo transfer Variable ASA (n 5 57) Placebo (n 5 56) P-value... Uterine artery PI 2.35 ( ) 2.51 ( ) 0.28 Bilateral PI 3.0, % (n) 8.8 (5) 23.2 (13) 0.03 ( %) a Arcuate artery PI 2.02 ( ) 1.98 ( ) 0.45 Radial artery PI 1.81 ( ) 1.70 ( ) 0.50 Spiral artery PI 1.47 ( ) 1.43 ( ) 0.52 Endometrial thickness (mm) 9.9 ( ) 9.4 ( ) 0.88 Data are given as medians (95% CI). a 95% CI for proportions. PI, pulsatility index.

5 Low-dose aspirin and uterine haemodynamics 865 Table III The treatment, fresh embryo transfer and pregnancy outcomes in the study groups Variable ASA (n 5 57) Placebo (n 5 56) P-value... Type of FSH, % (n) a rfsh 79 (48) 75 (46) 0.88 hmg 21 (13) 25 (15) 0.74 Initial dose of FSH (IU) a 200 ( ) 150 ( ) 0.22 Mean dose of FSH (IU) a 2200 ( ) 2050 ( ) 0.14 Mean duration of FSH (days) a 11 (8 17) 11 (9 14) 0.35 No. of ovum retrieved a 11 (0 38) 12 (0 39) 0.31 No. of top embryos a 4 (0 7) 4 (0 8) 0.78 Double/multi ET, % (n) 63 (36) 66 (37) 0.49 Single ET, % (n) 37 (21) 34 (19) 0.36 eset 95 (20) 100 (19) Implantation, % PR/embryo transfer, % PR/eSET, % Pregnancy outcome, % Live births/et Miscarriage/clinical pregnancy Extrauterine/clinical pregnancy Data are given as medians (range). eset, elective single embryo transfer; hmg, human menopausal gonadotrophin; PR, pregnancy rate; rfsh, recombinant FSH. a Sample size is 61 patients per group. improvement in uterine haemodynamics during the peri-implantation period among women whose UtA PI value was 3.0 during the previous menstrual cycle and who were treated with low-dose aspirin during subsequent cycles. Furthermore, endometrial cell cultures have shown significantly lower thromboxane levels in women with conception cycles after controlled ovarian stimulation compared with women with non-conception cycles. In addition, among women who became pregnant after successful IVF-embryo transfer, PI values in the UtA were lower than in those subjects who did not conceive (Battaglia et al., 1997). However, further studies with adequate statistical power are needed to show whether decreased uterine vascular impedance improves IVF/ICSI outcomes in patients with nonoptimal uterine haemodynamics. Endometrial thickness is thought to be an important factor for successful IVF and ICSI treatments. However, the variation in endometrial thickness overlaps among women with and without successful IVF/ ICSI treatment. There is a consensus of opinion that endometrial thickness over 6 mm is adequate for normal conception (Friedler et al., 1996). In the present study, endometrial thickness did not differ significantly between the aspirin and placebo groups and every woman had an endometrial thickness of over 6 mm. Our finding is in accordance with those in previous studies (Urman et al., 2000; Lok et al., 2004), which have shown no significant improvement in endometrial thickness in IVF/ICSI women who received low-dose aspirin ( mg/day). Aspirin doses of mg daily in healthy volunteers (Cerletti et al., 2003) and mg/kg daily in hypertensive pregnant women (Vainio et al., 1999) have been shown to increase the prostacyclin thromboxane ratio. Viinikka et al. (1993) noted that an aspirin dose of 50 mg/day inhibited.90% of platelet thromboxane production and significantly decreased urinary excretion of thromboxane metabolites, but did not decrease urinary excretion of prostaglandin. Thus, the dose of 100 mg daily used in the present study was sufficient to demonstrate the possible beneficial effects of aspirin on the prostacyclin thromboxane ratio. The sample size of this study was powered to show about a 14% decrease in UtA PI values on the day of embryo transfer in favour of the aspirin group. To demonstrate that the differences in secondary outcome measures found in this study would be statistically significant, almost 800 patients would be needed for each randomization arm. In conclusion, the results of this randomized, placebo-controlled and double-blind study showed that in unselected IVF/ICSI women, low-dose aspirin therapy, when started concomitantly with controlled ovarian stimulation, did not affect UtA vascular impedance on the day of embryo transfer. However, the incidence of non-optimal uterine haemodynamics (bilateral UtA PI value 3.0) was significantly lower in the aspirin group than in the placebo group. Funding This study was supported by the University of Oulu, Bayer AG, The Academy of Finland and the Sigrid Jusélius Foundation. References Battaglia C, Artini PG, Giulini S, Salvatori M, Maxia N, Petraglia F, Volpe A. Colour Doppler changes and thromboxane production after ovarian

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