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Keywords:

  • aspirin;
  • in vitro fertilization or intracytoplasmic sperm injection

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

Summary.  Background:  It was hypothesized that low-dose aspirin could improve implantation rates in subsequent pregnancies in women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Previous studies have shown inconclusive results or focused on surrogate endpoints. We therefore conducted a systematic review and meta-analysis of the literature investigating the effect of low-dose aspirin on hard outcomes, including live birth rate, pregnancy rate and miscarriage.

Methods:  MEDLINE and EMBASE databases were searched up to November 2011. Randomized controlled trials comparing low-dose aspirin with placebo/no treatment in IVF/ICSI women were included. Pooled odds ratios (ORs) and 95%confidence intervals (CIs) were calculated.

Results:  Seventeen studies with 6403 patients were included. The use of aspirin did not improve live birth pregnancy rate compared with placebo or no treatment (1.08; 95% CI, 0.90, 1.29). Pregnancy rates were significantly increased in patients randomized to low-dose aspirin (OR, 1.19; 95% CI, 1.01, 1.39), but miscarriage rates were not (OR, 1.18; 95% CI, 0.82, 1.68). Results of sensitivity analyses including high-quality studies did not show statistically significant differences in all considered endpoints.

Conclusions:  The results of this study do not show a substantial efficacy of aspirin inwomen undergoing IVF/ICSI and do not support the use of low-dose aspirin to improve the success of IVF/ICSI in terms of pregnancy outcomes. Further high-quality studies evaluating the possible efficacy of aspirin in selected groups of patients are warranted.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

Despite their current popularity, success rates of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) remain low [1]. The clinical pregnancy rate among women undergoing fresh embryo transfer (ET) after IVF or ICSI varies from 20% to 35% per transfer [1]. The main factors that affect the outcome of IVF and ICSI treatments are age, number of oocytes retrieved, quality of the embryos, number of embryos transferred, success of embryo transfer and endometrial receptiveness [2–6].

Suboptimal uterine perfusion has been suggested as a possible cause of infertility [7]. Impaired uterine blood flow may reduce endometrial receptivity, resulting in embryo implantation failure [8,9]. It has been hypothesized that low-dose aspirin may enhance uterine and ovarian blood flow and tissue perfusion by decreasing platelet aggregation and inhibiting vasoconstriction [10,11]. This effect could improve the results of IVF and ICSI treatments [12,13] by increasing endometrial receptivity and blastocyst implantation. However, the evidence supporting the efficacy of low-dose aspirin in women undergoing IVF is inconsistent. A number of papers reported a beneficial effect of aspirin, but many others failed to confirm these findings. Previous randomized controlled trials (RCTs) and meta-analyses have shown inconclusive or inconsistent results or were focused on indirect endpoints such as the implantation rate or the artery pulsatility index [10–16]. To better explore the role of low-dose aspirin in this setting, we carried out a systematic review and meta-analysis of the literature to investigate its effects on hard outcomes only, including rate of live birth, pregnancy rate and rate of miscarriage in women undergoing IVF or ICSI.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

A protocol was prospectively developed, detailing the specific objectives, criteria for study selection, approach used to assess study quality, outcomes and statistical methods. This systematic review was performed according to the guidelines for Quality of Reporting of Meta-analysis (PRISMA) [17].

Study identification

We tried to identify all published studies that evaluated the role of aspirin in the improvement of live birth and pregnancy rates and in the reduction of miscarriages in women undergoing IVF or ICSI, using the MEDLINE (1948 to November 2011, week 3) and EMBASE (1980–2011, week 51) electronic databases. The search strategy was developed without any language restriction and used the subject headings and key words presented in Appendix 1. We supplemented our search by manually reviewing the reference lists of all retrieved articles for additional published or unpublished trials and by searching the abstracts of the International Society of Thrombosis and Haemostasis (ISTH) and of European Society of Human Reproduction and Embryology Scientific Meetings (ESHRE) (from 2003 to 2011).

Study selection

Study selection was performed independently by two reviewers (ERe, ERa), with disagreements resolved through discussion and the opinion of a third reviewer (FD), if necessary. RCTs in women undergoing IVF or ICSI were included if they met the following criteria: (i) low-dose aspirin (< 150 mg) was compared either with placebo or no therapy; and (ii) at least one of the following outcomes was assessed: live birth, pregnancy rate and miscarriage rate.

Studies not including a control group drawn from the same population, animal studies, in vitro studies or trials that exclusively reported other clinical outcomes were excluded. Case reports, editorials, commentaries, letters, review articles, guidelines or secondary prevention trials were also excluded. To assess the agreement between reviewers for study selection, we used the kappa (k) statistic, which measures agreement beyond chance [18]. When multiple papers for a single study had been published, we decided to use the latest publication and to supplement it, if necessary, with data from the earlier publications.

Data extraction

Two reviewers (ERa, ERe) independently extracted data on study (year of publication, design, study centre) and patient characteristics (number of subjects enrolled, mean or median age) and on the aforementioned outcomes (pregnancy rate, rate of live birth and miscarriage).

Study validity assessment

Two unmasked investigators (ERa, ERe) independently completed the assessment of study validity.

We planned quality assessment by means of Jadad’s scale, which evaluates the following three study characteristics: method of randomization, method of blinding and follow-up [19]. To stratify RCTs, we applied the following cut-offs: a total of three points or more defined high-quality studies, whereas studies with two or less points were defined as low-quality studies.

The following additional quality items were also considered for our assessment: the total number of patients lost to follow-up (< 5% of patients, more than 20%, or between 5 and 20%); the use of a commonly accepted definition of clinical pregnancy (increased levels of urinary or plasma β-HCG confirmed by ultrasonography (gestational sac and/or fetal cardiac activity)); and the publication of the study in peer-reviewed journals as opposed to studies only published as an abstract.

Subgroup analyses

We planned a priori a list of subgroup analyses according to the following characteristics of the study populations:

  • 1
    cause of infertility;
  • 2
    type of induction protocol (short vs. long term);
  • 3
    type of assisted reproduction techniques (IVF, ICSI);
  • 4
    time of aspirin introduction and duration of aspirin therapy (at least 1 day before ET or after ET, during the entire period of the pregnancy); and
  • 5
    history of ET failure

Type of induction protocol was defined according to recent guidelines [20] or according to the definition of single studies if not further specified.

Statistical analysis

Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each outcome. The data were pooled using a random-effects model (the DerSimionan and Laird method) [21]. For treatment effects that were statistically significant, we determined the number needed to treat (NNT). Statistical heterogeneity was evaluated using the Cochran’s Q and I2 statistic, which assesses the appropriateness of pooling the individual study results [22]. When heterogeneity was present, we repeated the analysis removing one study at a time to assess the source of heterogeneity. Presence of publication bias was explored using funnel plots of effect size against standard error [23]. The software Review Manager (RevMan, version 5.0.16 for Windows, Oxford, UK; The Cochrane Collaboration, 2008] supported the analysis. Sensitivity analyses including high-quality studies only were performed.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

Study identification and selection

We identified 780 potentially relevant studies from the following databases: 569 from EMBASE and 211 from MEDLINE. We excluded 750 studies after title and abstract screening using the predefined inclusion and exclusion criteria; the remaining 30 studies were retrieved in full for detailed evaluation [3,11,13,14,24–49]. Agreement between reviewers for study selection was optimal (K = 0.91). Of the retrieved studies, 16 were excluded for the following reasons: 10 did not match inclusion criteria [13,24–32], three were editorials or commentaries [33–35], and three [11,44,49] reported duplicate data. Furthermore, 19 abstracts from ISTH and from ESHRE were found using ‘in vitro fertilization’ and ‘intracytoplasmic sperm injection’ search terms. Sixteen abstracts did not meet inclusion criteria, leaving only three for inclusion [50–52].

Seventeen studies were therefore included in this systematic review: 14 were published as full text [3,14,36–43,45–48] and three [50–52] as abstracts. The study identification and selection progression is detailed in Fig. 1.

image

Figure 1.  Selection process.

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Study characteristics

Baseline characteristics of patients included in the studies are summarized in Table 1. Study size ranged from 28 [3] to 2425 [47] patients, for a total of 6610 patients. Ten RCTs were placebo controlled whereas the other seven [3,36–38,40,47,51] compared low-dose aspirin with no treatment. In six studies, aspirin was started at least 1 day before the ET, whereas in the other studies it was started at the time of IVF or ICSI. Aspirin was maintained until the pregnancy test in four studies [39,40,42,46], until ultrasound detection of gestational sac and/or embryonic cardiac activity in three studies [37,45,47], until the 9–12th week of pregnancy in four studies [3,14,43,50] and during the entire period of the pregnancy in three studies [36,41,48], whereas the duration of treatment with aspirin was not specified in three studies [38,51,52].

Table 1.   Baseline characteristics and treatment of patients included in the studies
Study, year (ref)Included patientsMean age, years ± SDInclusion criteriaPrimary outcomeTreatment and doseOnset of therapy and continuation
  1. ASA, acetylsalicylic acid; ET, embryo transfer; FSH, follicle-stimulating hormone; GnRH, gonadotropin releasing hormone; HCG, human chorionic gonadotropin; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; no., number; pts, patients.

Weckstein, 1997 [3]2841.8 ± 3.4 (ASA group) 39.4 ± 4.5 (Placebo)Oocyte donation recipients who failed to develop an endometrial thickness of at least 8 mm during a test cycle receiving oral micronized E2; normal uterine cavityClinical pregnancy rate, delivery rate, implantation rate15 pts ASA (81 mg) vs. 13 pts Control group1 week before starting estrogen treatment. Pts treated until 9 weeks after ET.
Check, 1998 [36]36All the subjects enrolled in the study were at most 42 years oldPts who had not conceived following transfer of embryos in the retrieval cycle, using their own oocytes, not taking any concomitant medications increasing blood flow, such as heparinImplantation and clinical pregnancy rates18 pts ASA (81 mg) vs. 18 pts Control groupOn day 2 of the frozen ET cycle. ASA was continued through the pregnancy if the beta-HCG level was positive.
Rubistein, 1997 [14]298ASA: 35.9 ± 4.2 Placebo: 35.4 ± 3.9Infertility for tubal factor; >1 IVF cycleNo. follicles, no. oocytes retrived, serum E2 levels, uterine and ovarian pulsatility index, cancellation rate, no. ET, implantation and pregnancy ratesAspirin (100 mg) vs. placebo21st day of precedent menstrual cycle. Pregnant patients continued medication through 12 weeks’ gestation
Urman, 2000 [37]30032.5 ± 4.8 (ASA group) 32.4 ± 4.7 (control group)300 pts undergoing their first ICSI cycle with ejaculated spermatozoa for male infertilityClinical pregnancies and clinical pregnancy rate; implantation and implantation rate139 pts ASA (80 mg) vs. 136 pts Control groupBeginning on the 1st day of the gonadotropin stimulation. ASA was continued until the ultrasonographic detection of fetal cardiac activity and it was stopped if the HCG test was negative.
Matassa, 2001 [38]9132.07 ± 3.98 (ASA group) 32.62 ± 3.71 (Control group)91 pts undergoing controlled ovaric hyperstimulationDetermine if the use of low-dose ASA and trans-abdominal ecography can modify outcome in IVF-ET procedures to improve: implantation rate; pregnancy rate46 pts ASA (100 mg) vs. 45 pts Control groupCycle day 21 before stimulation. Not specified until aspirin continued.
Lentini, 2003 [52]8434.6 ± 3.5 (ASA group) 34.2 ± 4.6 (control group)84 pts undergoing IVF from January to December 2002.Oocyte quality; fertilization, implantation and pregnancy rate42 pts ASA (100 mg) vs. 42 pts Control groupA month before the first dose of gonadotropin. Not specified until aspirin continued.
Bordes, 2003 [51]138Mean age similar in both groups138 women undergoing IVF cycles and who underwent controlled ovarian hyperstimulation with a long protocol.Implantation and pregnancy rate69 pts ASA (100 mg) vs. 69 pts PlaceboOn the 21st day of the menstrual cycle preceding the introduction of the GnRH analogue. Not specified until the medication continued
Lok, 2004 [39]6036.0 [33.8–37.3 years] (ASA group) 36.9 [33.0-38.8 years] (Placebo group)Poor responders: pts who had previous IVF cycles cancelled because of the recruitment of fewer than three mature follicles (>o = 17 mm); pts with repeated high basal levels of FSH (>10 IU L−1)To determine if supplementation with low-dose ASA improves utero-ovarian blood flow and ovarian responsiveness (mature follicles; oocytes for retrieval) to gonadotropin stimulation in poor responders undergoing IVF30 pts ASA (80 mg) vs. 30 pts Control groupBeginning at the time of commencement of GnRHa in the preceding cycle and continuing until the day of HCG administration or cancellation
Van Dooren, 2004 [50]17032.0 [22–44 years] (ASA and Placebo groups)Women younger than 39 years with regular cycle, according to national guidelinesDetermine effect of ASA 100 mg, in patients undergoing their first IVF or ICSI cycle, on: ovarian response (number of oocytes); pregnancy rates85 pts ASA (100 mg) vs. 85 pts PlaceboCycle day 16. Continued until menstruation or, in case of pregnancy, up till 10 weeks pregnancy
Waldenström, 2004 [40]102233.5 (ASA group) 33.3 (Control group)Pts neding IVF for: tubal factor; endometriosis; hormonal factor; male factor; unknown causeLive births and live birth rate703 pts Aspirin (75 mg) vs 677 pts Control groupFrom the day of ET until the pregnancy test was administered (18 days after oocyte retrieval). A placebo was not used but the pts were randomized into the treatment group by giving ASA to all pts that accepted inclusion in the study every 2nd day and giving no treatment the other day. Aspirin was discontinued after the pregnancy test irrespective of whether it was positive or negative
Pakkila, 2005 [41]374ASA: 32 Placebo: 31.3 No. oocytes, no. and quality embryos, clinical pregnancy and pregnancy outcome (clinical pregnancy rate per cycle randomized).ASA 100 mg vs. placebo 186 pts Aspirin (100 mg) vs. 188 pts Placebo1st day of ovarian stimulation; Pts continued until delivery, menstruation or negative hCG test
Duvan, 2006 [42]18731.2 ± 5.6 (ASA group) 30.2 ± 5.6 (Placebo) 31.6 ± 6.1 (Prednisolone group) 33.5 ± 6.2 (ASA+prednisolone group)Non-selected infertile pts who were undergoing their first ICSI cycle at Faculty of MedicineDetermine the effects of short-term low-dose aspirin and/or steroid use on implantation and pregnancy rates41 pts ASA (100 mg) vs. 50 pts Prednisolone (10 mg/die) vs. 56 pts (ASA 100+ prednisolone 10) vs 40 pts PlaceboOn embryo transfer day. Pts continued until confirmed clinical pregnancy test
Moini, 2007 [43]14529.3 ± 4.1 (ASA group) 29.9 ± 4.9 (Placebo)Infertility for tubal, male or unexplained factors. No medication for at least 3 months before the studyDetermine the effect of low-dose ASA on: ovarian response, implantation and pregnancy rates in pts undergoing IVF72 pts ASA (100 mg) vs 73 pts PlaceboOn the 21st of their preceding menstrual cycle and continued until menstruation or a negative pregnancy test. Pts with clinical pregnancy go on until 12 weeks
Lambers, 2009 [46]169 IVFASA: 33.04 Placebo:32.96Age < 39, FSH < 10 3rd day cycle, previous IVF or ICSI failed, no contraindication ASA, no previous ongoing pregnancyPregnancy rate, pulsatility index in uterine artery84 pts ASA 100 mg vs. 85 pts placebo 100 mg.1st day stimulation to day pregnancy. Daily medication continued until the day of pregnancy test
Dirckx, 2009 [45]19331.3 ± 3.9 (ASA group) 31.3 ± 3.8 (Placebo group)Dutch-speaking women starting a first or second IVF/ICSI cycleClinical pregnancy rate per cycle97 pts ASA 100 mg vs. 96 pts PlaceboStarted together with the oral contraceptive pill prior to stimulation and continued until confirmation of pregnancy at 6 weeks and 3 days of amenorrhea
Varnagy, 2010 [47]2425Not specifiedSuperovulation cases between 2000 and 2006Determine if the administration of aspirin can be recommended as a prophylactic measure for ovarian hyperstimulation syndrome (OHSS)1503 ASA (100 mg) vs. 922 control group1st day of controlled ovarian stimulation. Aspirin was continued until menstruation, a negative pregnancy test or the ultrasonographic detection of embryonic cardiac activity
Haapsamo, 2010 [48]487< 40 yearsAge < 40 years, < 4 previous ovarian stimulations, no contraindications for ASAIncidence of hypertensive pregnancy complications242 ASA VS 245 PlaceboStarted on the first day of gonadotropin stimulation. Pregnant women continued the medication until delivery

Live birth

The effect of low-dose aspirin on rate of live births was evaluated in six studies for a total of 2600 patients. A live birth occurred in 330 of 1312 (25.2%) patients randomized to low-dose aspirin and in 306 of 1288 (23.8%) patients randomized to placebo or no treatment. The use of low-dose aspirin was not effective in increasing the rate of live birth compared with placebo or no treatment (OR, 1.08; 95% CI, 0.90, 1.29; P = 0.43; I2 = 0%), Fig. 2A. A funnel plot of OR vs. standard error appeared asymmetric with an absence of studies in the right hand corner (Appendix 2a).

image

Figure 2.  Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of the association between low-dose aspirin/placebo or no treatment and live birth (2a), pregnancy rate (2b) and miscarriage (2c).

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Pregnancy rate

The effect of low-dose aspirin on pregnancy rate was evaluated in 17 studies for a total of 6403 patients. Pregnancy occurred in 1139 of 3506 (32.5%) women randomized to low-dose aspirin and in 850 of 2897 (29.3%) women randomized to placebo or no treatment. The use of low-dose aspirin was associated with a significantly higher pregnancy rate in comparison to placebo or no treatment (OR, 1.19; 95% CI, 1.01, 1.39; P = 0.03; I2 = 29%), Fig. 2B. The absolute increase in pregnancy rates was estimated at 3.2% with an NNT of 31 (95% CI, 18, 118). A funnel plot of OR vs. standard error appeared symmetric, suggesting the absence of publication bias (Appendix 2b).

Miscarriage

The effect of low-dose aspirin on miscarriage was evaluated in six studies for a total of 904 patients. Miscarriages occurred in 86 of 471 (18.3%) women randomized to low-dose aspirin and in 67 of 433 (15.5%) randomized to placebo or no treatment. The use of low-dose aspirin did not result in a statistically significant higher rate of miscarriage as compared with placebo or no treatment (OR, 1.18; 95% CI, 0.82, 1.68; P = 0.75; I2 = 0%), Fig. 2C. A funnel plot of OR vs. standard error appeared symmetric, suggesting the absence of publication bias (Appendix 2c).

Study quality and sensitivity analyses

Quality assessment items according to the Jadad scale are summarized in Table 2. Of the 17 studies included in the analysis, seven [14,37,39,45,46,48,50] were defined as high quality, whereas the other 10 [3,36,38,40–43,47,51,52] were defined as low quality. The total number of patients lost to follow-up was < 5% in all the included studies.

Table 2.   Sensitivity and subgroup analyses
PatientsNumber of studiesTotal patientsEndpointOdds ratios (95% CI)
Sensitivity analyses
High-quality studies (JADAD scale)3819Live birth0.91 (0.66–1.24)
71621Pregnancy1.13 (0.86–1.47)
4360Miscarriage1.12 (0.60–2.09)
Clinical pregnancy diagnosed with pregnancy test and US125970Pregnancy1.16 (0.97–1.39)
52572Live birth1.07 (0.89–1.28)
6904Miscarriage1.18 (0.82–1.68)
All studies without abstracts146011Pregnancy1.15 (0.97–1.36)
62600Live birth1.08 (0.90–1.29)
6904Miscarriage1.18 (0.82–1.68)
Subgroup analyses
Only IVF patients31577Live birth1.20 (0.96–1.51)
125024Pregnancy1.35 (1.11–1.65)
2506Miscarriage1.15 (0.74–1.80)
Aspirin administered at least 1 day before ET51220Live birth0.91 (0.70–1.19)
144906Pregnancy1.21 (1.01–1.44)
5452Miscarriage1.12 (0.65–1.92)
At least one preceding ET failure2197Live birth1.02 (0.56–1.88)
6736Pregnancy1.47 (0.91–2.37)
154Miscarriage0.72 (0.19–2.74)
Long induction protocol42379Live birth1.09 (0.90–1.32)
113546Pregnancy1.20 (0.98–1.47)
5843Miscarriage1.13 (0.79–1.62)
Use of Aspirin during the entire period of pregnancy2830Live birth0.90 (0.65–1.26)
3866Pregnancy0.89 (0.65–1.22)
2223Miscarriage1.01 (0.48–2.11)

In the high-quality studies according to the Jadad scale, the use of low-dose aspirin did not result in any improvement, as compared with placebo or no treatment, in the rates of live birth (OR, 0.91; 95% CI, 0.66, 1.24), pregnancy rates (OR, 1.13; 95% CI, 0.86, 1.47) or miscarriages (OR 1.12; 95% CI, 0.60, 2.09).

When the analysis was restricted to studies that used a commonly accepted definition of clinical pregnancy only, the use of low-dose aspirin was again not associated with any statistically significant effect on live birth rate (OR, 1.07; 95% CI, 0.89, 1.28), pregnancy rate (OR, 1.16; 95% CI, 0.97, 1.39) and miscarriage rate (OR, 1.18; 95% CI, 0.82, 1.68) as compared with placebo or no treatment. Similar findings were obtained when the analysis was restricted to studies published in peer-reviewed journals only (OR 1.08, 95% CI 0.90, 1.29; OR 1.15, 95% CI 0.97, 1.36; and OR 1.18, 95% CI 0.82, 1.68, respectively).

Subgroup analyses

Table 2 reports in detail the studies included in each subgroup, the total number of patients, and the main results of each subgroup analysis. We could not perform a subgroup analysis according to the cause of infertility because, in most studies, patients with different causes of infertility were included. However, pregnancy and live birth rates were not significantly different between treatment groups in a study that only included patients with male infertility [37], whereas pregnancy rates were significantly increased by the use of aspirin in a study that only included patients with infertility secondary to tubal causes [14].

The use of low-dose aspirin was again associated with a higher pregnancy rate as compared with placebo when only patients undergoing IVF were considered. Similar results were obtained in the subgroup of studies in which aspirin was administered to patients at least 1 day before the ET. All the other subgroup analyses were not statiscally significant.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

In this systematic review and meta-analysis of the literature, we assessed the effect of low-dose aspirin on hard endpoints in women undergoing IVF or ICSI. Using data from 17 RCTs for a total of more than 6000 patients, we found no benefit with the use of aspirin for the most relevant outcome (i.e. live birth). Although a small but statistically significant increase in the rate of pregnancies was found with aspirin, when compared with placebo or no treatment, this effect was probably offset by the lack of protection against miscarriage. Furthermore, when the analysis was restricted to high-quality studies only, there was no statistically significant difference in any of the selected outcomes, including pregnancy rates, between treatment groups.

Previous meta-analyses assessing the efficacy of aspirin have shown apparently conflicting results [15,16,53]. Khairy et al. [15] and Gelbaya et al. [16] included only six and seven RCTs in their analyses, respectively, and did not find any statistical difference in the rates of pregnancy, miscarriage and live birth between women treated with low-dose aspirin and those treated with placebo or no treatment. In another meta-analysis, Ruopp et al. [12] pooled, using a fixed-effect model, the results of 10 RCTs for a total of about 2800 patients. In this meta-analysis, the use of low-dose aspirin was associated with a significantly increased rate of pregnancies without any significant effect on the rate of miscarriage. However, when the analysis was repeated using the random-effect model, a more conservative approach that takes into account the variance among the studies, the statistical significance for the rate of pregnancies was not reached. Last, a very recent meta-analysis performed on an individual patient basis that included six studies for a total of about 1100 patients failed to find increased pregnancy rates with the use of low-dose aspirin [53].

Overall, the results of the previous studies, as well as the results of this meta-analysis, with a more updated search strategy, with different inclusion and exclusion criteria, and with the inclusion of twice the number of patients, do not support the use of low-dose aspirin in general patients undergoing IVF/ICSI. It may be argued that IVF/ICSI treatment success rates are likely to be variable according to several factors, including age, number of previous cycles, treatment indication and type of protocol. In this study, we observed that the timing of introduction of low-dose aspirin, especially when introduced at least 1 day before ET, may contribute to the efficacy of this approach. Similarly, we observed that the use of aspirin appeared to be potentially more effective in specific subgroups of patients, such as patients undergoing IVF and patients with a previous ET failure, because the observed association seems to be more robust than in the general study population. Although the results of these analyses suggest the possibility that, within well-defined target populations, aspirin may truly be an effective strategy to improve pregnancy rates, we found no signs of an effect in terms of miscarriages and life birth rates in these subgroups, thus making the hypothesis of a true benefit in these specific populations unlikely.

Potential indications for IVF treatment include: male factor fertility problems where medical/surgical management and intrauterine insemination (IUI) have not resulted in a live birth; tubal disease where tubal surgery has not resulted in a live birth or is judged to be inappropriate [54]; and endometriosis where surgery and IUI have not resulted in a live birth. Younger maternal age and the possibility to cryopreserve embryos seem to be determinants of pregnancy after an IVF cycle [55,56]. Unfortunately, in most of the studies included in our systematic review, the indication for IVF was not clearly described and women of different ages were included. Furthermore, only one study reported the use of frozen embryos [36]. Thus, we were unable to analyze the results according to age, IVF/ICSI indication and cryopreservation of embryos, and if low-dose aspirin really is effective in certain subgroups of patients, this remains to be firmly established.

Our meta-analysis has some potential limitations. First, the studies included in our meta-analysis had different inclusion and exclusion criteria. However, the heterogeneity among the studies, calculated using the I2 statistic, was generally low. Furthermore, to partially overcome the existence of clinical heterogeneity among the studies, we decided to pool the results of original studies using the random effect model, an approach that takes into account the potential sources of heterogeneity among the studies. Second, as already discussed above, due to the limitation of a meta-analytic approach we were unable to conclusively explore the possible effects of aspirin in some subgroups of patients.

However, as low-dose aspirin is widely used in clinical practice in assisted conception clinics despite a lack of evidence, the aim of our MA was to assess the evidence sustaining this approach in general patients undergoing assisted reproduction. Furthermore, with a series of hypothesis-generating subgroup analyses, we explored the possibility of a different efficacy of low-dose aspirin in many subgroups of patients according to baseline characteristics, differences in aspirin therapy and types of induction protocol and of assisted reproduction techniques. Unfortunately, to date, notwithstanding the amount of original literature on this topic, only a few studies have properly addressed the efficacy of low-dose aspirin in other subgroups, preventing an adequate evaluation in this meta-analysis.

Finally, because it is recognized that publication bias can affect the results of meta-analyses, we attempted to assess this potential bias using a funnel plot. However, funnel plots appeared symmetric, suggesting the absence of publication bias in the analysis that considered pregnancy and miscarriage rates. In the funnel plot analysis that evaluated differences in live births in patients randomized to low-dose aspirin or placebo/no treatment we observed asymmetry, with an absence of studies in the right corner of the plot. This suggests that unpublished studies likely to demonstrate an efficacy of low-dose aspirin in increasing the rate of live birth were probably not included in our meta-analysis. However, inclusion of these studies and elimination of this bias, if it really existed, would not significantly affect our results.

In conclusion, our results do not support the use of low-dose aspirin in improving the success of IVF/ICSI in terms of pregnancy outcomes. Studies aimed at evaluating the possible effect of aspirin on rate of pregnancy or live births in well-defined settings of patients (with a defined infertility diagnosis, definite induction protocol or definite age) are warranted.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

F. Dentali handled conception and design, analyzed and interpreted the data, drafted the article, critically revised the article for important intellectual content, gave final approval of the article, provided administrative, technical or logistic support, and collected and assembled the data. W. Ageno handled conception and design, analyzed and interpreted the data, drafted the article, critically revised the article for important intellectual content, and gave final approval of the article. E. Rezoagli analyzed and interpreted the data, drafted the article, gave final approval of the article, and collected and assembled the data. E. Rancan drafted the article, gave final approval of the article, and collected and assembled the data. E. Grandone, A. Squizzato, M. Margaglione and S. Middeldorp handled conception and design, drafted the article, critically revised the article for important intellectual content, and gave final approval of the article.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

The authors state that they have no conflict of interests.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices
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Appendices

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
  10. Appendices

Appendix 1

Database: Ovid MEDLINE(R) <1948 to November Week 3 2011>

Search Strategy:

  • 1
    Embryo Implantation/(8365)
  • 2
    Fertilization in vitro/(22994)
  • 3
    Embryo Transfer/(11538)
  • 4
    Ovulation Induction/(8100)
  • 5
    Sperm Injections, Intracytoplasmic/(3817)
  • 6
    Heparin, Low-Molecular-Weight/(6181)
  • 7
    Heparin/(46857)
  • 8
    Anticoagulants/(46963)
  • 9
    Aspirin/(35572)
  • 10
    Platelet Aggregation Inhibitors/(22908)
  • 11
    6 or 7 or 8 or 9 or 10 (131341)
  • 12
    1 or 2 or 3 or 4 or 5 (40560)
  • 13
    11 and 12 (211)
  • 14
    from 13 keep 1-211 (211)

Appendix 2

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