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Antioxidants for female subfertility

  1. Marian G Showell1,*,
  2. Julie Brown1,
  3. Jane Clarke1,
  4. Roger J Hart2

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 5 AUG 2013

Assessed as up-to-date: 15 APR 2013

DOI: 10.1002/14651858.CD007807.pub2


How to Cite

Showell MG, Brown J, Clarke J, Hart RJ. Antioxidants for female subfertility. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD007807. DOI: 10.1002/14651858.CD007807.pub2.

Author Information

  1. 1

    University of Auckland, Obstetrics and Gynaecology, Auckland, New Zealand

  2. 2

    The University of Western Australia, King Edward Memorial Hospital and Fertility Specialists of Western Australia, School of Women's and Infants' Health, Subiaco, Western Australia, Australia

*Marian G Showell, Obstetrics and Gynaecology, University of Auckland, Park Road Grafton, Auckland, New Zealand. m.showell@auckland.ac.nz.

Publication History

  1. Publication Status: New
  2. Published Online: 5 AUG 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 
Summary of findings for the main comparison. Antioxidant(s) versus placebo or no treatment/standard treatment for female subfertility

Antioxidant(s) versus placebo or no treatment/standard treatment for female subfertility

Population: Subfertile women
Settings: Attending a reproductive clinic
Intervention: Antioxidant(s) versus placebo or no treatment/standard treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Control

Placebo or no treatment/standard treatment
Antioxidant(s)

Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)367 per 1000420 per 1000
(99 to 827)
OR 1.25
(0.19 to 8.26)
97
(2 studies)
⊕⊝⊝⊝
very low1,2,3,4

Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)231 per 1000281 per 1000
(217 to 357)
OR 1.3
(0.92 to 1.85)
2441
(13 studies)
⊕⊝⊝⊝
very low1,2,3,4

Adverse events - Miscarriage63 per 100056 per 1000
(37 to 84)
OR 0.88
(0.57 to 1.36)
1456
(8 studies)
⊕⊕⊝⊝
low1,3,4

Adverse events - Multiple pregnancy67 per 100048 per 1000
(29 to 80)
OR 0.7
(0.41 to 1.21)
1022
(2 studies)
⊕⊕⊝⊝
low3,5

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Most trials described the randomisation adequately but did not describe methods of allocation concealment
2 The I squared statistic was >50%
3 Trials contained women with different indications of subfertility and the antioxidants used were also different.
4 There were wide confidence intervals in some of the trials
5 One trial described method of randomisation but not allocation concealment and the other described allocation concealment but not randomisation

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of the condition

A couple that has tried to conceive for a year or longer without success is considered to be subfertile (Evers 2002) or less fertile than a typical couple. Over the past two decades, the reported prevalence of subfertility has increased markedly. Forty to fifty percent of cases of subfertility are due to female causes. Influencing factors include ovulatory failure, tubal damage, endometriosis, poor egg quality and unexplained subfertility. It is suggested that up to 25% of couples who are planning a baby have difficulty (Hart 2003).

To overcome these fertility problems, many couples undergo assisted fertility techniques (assisted reproductive techniques (ART)). These include ovulation stimulation, intrauterine insemination, in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI).

Women use antioxidant supplements in preparation for ART and/or simultaneously with the treatment, and some women use supplements alone with no ART in an attempt to improve their fertility.

The global vitamin and supplement market is a growth industry estimated to be worth $68 billion (US) (Reportlinker 2010). In 2009 sales of vitamins and dietary supplements in the United Kingdom "totalled £674.6 million, a growth of about 16% over the previous five years, with the two biggest selling areas being multivitamins (£138.6 million) and fish oils (£139.1 million)" (NHS News 2011).

Vitamins and supplements are not regulated and are dispensed through various retail outlets, including health food shops, online retailers, health centres, fitness clubs, supermarkets and pharmacies.

 

Description of the intervention

Antioxidants are biological and chemical compounds that reduce oxidative damage. They are a group of organic nutrients that include vitamins, minerals and polyunsaturated fatty acids (PUFAs). Some of the predominant antioxidants used in female subfertility are N-acetyl-cysteine; melatonin; vitamins A, C and E; folic acid; myo-inositol; zinc and selenium. They may be administered as a single antioxidant or as combined therapy.

PUFAs are classified into omega-3, omega-6 and omega-9. Omega-9 is synthesised by animals, but omegas-3 and -6 need to be supplemented in the diet. The main sources of omega-6 are vegetable oils. Sources of omega-3 are vegetable and fish oils. The ratio of omega-6 to omega-3 has risen in recent times (as the result of increased intake of vegetable oils) to the point where there is a reduced need for intake of omega-6 and an increased need for intake of omega-3 (Wathes 2007).

Pentoxifylline is a conventional medicine, a tri-substituted xanthine derivative usually prescribed for intermittent claudication (Drugs.com). Pentoxifylline is also used in fertility treatment as it is known to have a strong antioxidant effect by generating reactive oxygen species (Vircheva 2010). It has been shown to benefit men who have varicocoele-associated infertility (Oliva 2009).

The amino acid L-arginine also has antioxidant properties that aid in the inflammatory response and act against oxidative damage (Ko 2012).

When oxidative damage occurs, toxins are produced as a consequence of all cells using oxygen to survive. Toxic end products may include molecules that have unpaired electrons, which may lead to the formation of free radicals. Free radicals may cause further harmful reactions with lipids in membranes, amino acids in proteins and carbohydrates within nucleic acids. An antioxidant molecule is thought to be capable of slowing or preventing the oxidation of other molecules and potentially of reducing the production of free radicals, which may cause this cellular damage.

Two major types of free radicals have been identified: reactive oxygen species (ROS) and reactive nitrogen species (RNS). Reactive oxygen species are products of normal cellular metabolism and consist of oxygen ions, free radicals and peroxides. The addition of one electron to oxygen forms the superoxide anion radical, which then can be converted to hydroxyl radical, peroxyl radical  or hydrogen peroxide. Free radicals seek to participate in chemical reactions that relieve them of their unpaired electron, resulting in oxidation (Ruder 2008; Tremellen 2008). The presence of ROS within the ovary and the endometrium has significant physiological and pathological implications for women when they try to conceive. Oxidative stress is a result of an imbalance between the amount of ROS and the quantity of natural antioxidants present within the body. Natural antioxidants present in the body include catalase, glutathione peroxidase, superoxide dismutase and glutathione reductase, in addition to some non-enzymic agents such as vitamins C and E and ferritin and transferrin (Gupta 2007).

Indirect evidence from smoking and alcohol trials suggests that these factors have a negative impact on female fertility, potentially through the generation of excessive oxidative stress (Ruder 2008). Other lifestyle factors such as diet, disease, pollution, stress and allergies also contribute to increased levels of free radicals.

In an effort to enhance fertility, couples are increasingly resorting to ART; however, these techniques do not cure the causes of subfertility; rather they may overcome some of its barriers. Adjunct measures, including courses of dietary supplements such as oral antioxidants, may be beneficial (Ebisch 2007). However, most antioxidant supplements are uncontrolled by regulation, and thus their effects may be unpredictable in the population.

 

How the intervention might work

Antioxidants are said to have an important role in the regulation of all processes involved in the birth of a healthy baby (Gupta 2007). The local development of oxidative stress will have significant adverse effects on these processes. Conditions with which the adverse effects of oxidative stress may be associated in subfertile women include endometriosis, hydrosalpinges (dilated fallopian tubes), polycystic ovarian syndrome (PCOS), fetal malformations and potentially unexplained subfertility (Ruder 2008; Zhao 2006).

At the time of conception, oxidative stress can lead to cell membrane lipid peroxidation, cellular protein oxidation and DNA damage, causing a negative effect upon the oocyte, the embryo and implantation (Ruder 2008). Antioxidants would be expected to counteract the negative impact of oxygen free radicals by acting as free radical scavengers.

Supplementary antioxidants may have several methods of action. Fertility benefits of vitamin E include improvement in epithelial growth in blood vessels and in the endometrium (Ledee-Bataille 2002). Higher vitamin D levels are associated with an increased likelihood of successful pregnancy and may be of particular benefit to women with PCOS in lowering hyperandrogenism (Thomson 2012). Myo-inositol helps ovarian function and decreases hyperandrogenism and insulin resistance (Nestler 1998); L-arginine improves endometrial blood flow (Battaglia 1999); N-acetyl-cysteine is needed for fertile cervical mucus and ovulation (Badawy 2007); and PUFAs influence prostaglandin synthesis and steroidogenesis and also play a role in the composition of cell membranes of the sperm and oocyte, which is important during fertilisation (Wathes 2007). Cohort studies have shown some evidence suggesting that in some instances, taking a multivitamin tablet may increase fertility (Haggarty 2006) or even regulate ovulation (Charvarro 2008).

 

Why it is important to do this review

Currently evidence as to whether antioxidants improve fertility is limited, and ongoing trials in this area show varied results. This review assessed the effectiveness of different antioxidants and different dosages.

Subfertile women are highly motivated to explore all avenues of treatment in their desire to have a healthy baby. Antioxidants are mostly unregulated and are readily available for purchase by consumers. Research has suggested that a significant number of women undergoing fertility treatment are taking oral supplements in the expectation that this will improve their chances of conception (Stankiewicz 2007). Consumer perception is that antioxidant therapy is not associated with harm and is associated only with benefit. It is important to establish whether or not this therapy does improve fertility and whether it is associated with any harm.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant will improve fertility outcomes for subfertile women.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

 

Inclusion criteria

  • Randomised controlled trials (RCTs).
  • Cross-over trials were included; however, only first-phase data were used in the analysis. Achieving outcomes such as pregnancy and live birth would preclude entry of couples into the next trial phase (Dias 2006).

 

Exclusion criteria

  • Any quasi-randomised trials.

 

Types of participants

 

Inclusion criteria

  • Trials that included subfertile women who had been referred to a fertility clinic and might or might not be undergoing assisted reproductive techniques (ART) such as in vitro fertilisation (IVF), intrauterine insemination (IUI) or intracytoplasmic sperm injection (ICSI).

 

Exclusion criteria

  • Trials enrolling only fertile women attending a fertility clinic exclusively as the result of male partner infertility.

 

Types of interventions

We included trials if they investigated the following:

  • Any type of oral antioxidant supplementation versus control-placebo (plus or minus a co-intervention) or no treatment/standard treatment (standard treatment includes folic acid < 1 mg);
  • Individual or combined oral antioxidants versus any antioxidant (head-to-head trials); or
  • Pentoxifylline versus control (placebo or no treatment/standard treatment).

On clinical advice, trials that used folic acid (standard treatment) and those that included a co-intervention (a fertility drug such as clomiphene citrate or metformin) in both arms were analysed in the antioxidant versus placebo or no treatment/standard treatment comparison and not in the head-to-head comparison, as the controls were not considered to be active treatments. Pentoxifylline trials were analysed as a separate comparison as it was not possible to separate the antioxidant effects from the other medical effects of the drug.

 

Exclusion criteria

  • Interventions that included antioxidants alone versus fertility drugs as controls. These fertility drugs included metformin and clomiphene citrate.

 

Types of outcome measures

 

Primary outcomes

Live birth rate per woman randomly assigned (defined as the delivery of one or more living infants).

 

Secondary outcomes

  • Clinical pregnancy rate per woman (as confirmed by the identification of a gestational sac on ultrasound at ≥ 7 weeks' gestation).

  • Any adverse effects reported by the trial. These events were subgrouped by the type of adverse event reported.

 

Search methods for identification of studies

We searched for all reports, published and unpublished, that described RCTs investigating oral antioxidant supplementation for subfertile women and its impact on live birth, pregnancy and adverse events rates. Both indexed and free text terms were used, and no language restriction was applied.

This review used the information in the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Module regarding search strategies (www.mrw.interscience.wiley.com/cochrane/clabout/articles/MENSTR/frame.html).

 

Electronic searches

  • The Cochrane Menstrual Disorders and Subfertility Group's Trials Search Co-ordinator searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials from inception to April 2013 (Appendix 1). This register contains published and unpublished trials and abstracts.
  • We searched the following databases using the Ovid platform:

    • Cochrane Central Register of Controlled Trials (CENTRAL) (from inception to April 2013) (Appendix 2);
    • MEDLINE (1950 to April 2013) (Appendix 3);
    • EMBASE (inception to April 2013) (Appendix 4);
    • CINAHL (1982 to September 2010) (Appendix 5);
    • PsycINFO (from inception to April 2013) (Appendix 6); and
    • AMED (Allied and Complementary Medicine) (1985 to April 2013) (Appendix 7).

  • CINAHL EBSCO Platform search September 2010 to April 2013 (Appendix 5).
  • International trial registers: 'ClinicalTrials.gov', a service of the US National Institutes of Health (http://clinicaltrials.gov/ct2/home) (last searched April 2013) and 'The World Health Organization International Trials Registry Platform search portal' (www.who.int/trialsearch/Default.aspx) (last searched April 2013), using the following simple search strategies: 'antioxidants and subfertility', 'antioxidants and infertility', 'vitamin and subfertility', 'vitamin and infertility', 'N-acetyl-cysteine and subfertility', 'N-acetyl-cysteine and infertility', 'myo-inositol and subfertility', 'myo-inositol and subfertility', 'fatty acids and subfertility' and 'fatty acids and infertility'.
  • Web of Knowledge for conference proceedings and published trials.
  • Google, using the keywords 'antioxidants female infertility' and 'antioxidants female subfertility'.Database for Abstracts of Reviews of Effects (DARE) for other reviews on this topic.

The MEDLINE search was limited by the Cochrane highly sensitive search strategy filter for identifying randomised trials, which appears in the Cochrane Handbook of Systematic Reviews of Interventions (Version 5.1, Chapter 6, 6.4.11) (Higgins 2011). The EMBASE and CINAHL (OVID platform only) searches were combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk/mehodology/filters.html#random). The RCT filters used are also found in the Cochrane Menstrual Disorders and Subfertility Group module (MDSG) .

 

Searching other resources

  • Handsearching of selected journals in obstetrics, gynaecology and reproductive medicine, as well as conference proceedings (for abstracts) of the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM).
  • Grey literature through the openGREY database (http://www.opengrey.eu/).
  • Known experts and personal contacts regarding any unpublished materials.
  • Citation lists of all articles for any relevant references

 

Data collection and analysis

We conducted data collection and analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The flow of information through the different phases of this systematic review can be seen in Figure 1.

 FigureFigure 1. Study flow diagram.

 

Selection of studies

Two of three review authors (JC, MGS and JB) independently reviewed titles and abstracts of trials for inclusion eligibility. We obtained the full texts of trials that we considered for potential inclusion. We sought further information from the authors of trials that did not contain sufficient information to make a decision about eligibility. Any disagreements for resolution were referred to a third review author. The selection process was documented with a "PRISMA" flow chart.

 

Data extraction and management

Two of three authors (JC, MGS and JB) independently extracted data from the included trials using a data extraction form. We compared the two sets of extracted data and resolved discrepancies by discussion. The review authors screened the trials to ensure that there were no duplicate publications.

The data extraction forms were designed to extract data regarding study characteristics and outcomes. We have included this information and presented it in the Characteristics of included studies and the Characteristics of excluded studies tables, in keeping with the guidance provided by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If any information on trial methodology or any trial data were missing, the study authors were contacted by email and by post. The predominant questions for trial authors concerned live birth data, clinical pregnancy, methods of randomisation and allocation concealment.

 

Assessment of risk of bias in included studies

The included studies were assessed for risk of bias using the Cochrane risk of bias assessment tool to assess selection bias (sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (completeness of outcome data); reporting bias (selective outcome reporting); and other potential sources of bias. Two of three authors (JC, MGS and JB) assessed the included studies according to these six criteria; any disagreements were resolved by discussion with a third author. We sought published protocols.

Care was taken to search for within-study selective reporting, such as trials failing to report outcomes such as live birth or reporting them in insufficient detail to allow inclusion. Where protocols were available, studies were assessed for differences between published results and study protocols.

In cases where included studies failed to identify the primary outcome of live birth but did report pregnancy rates, we carried out an informal assessment to determine whether pregnancy rates were similar to those in studies that reported live birth.

 

Measures of treatment effect

The dichotomous data for live birth, pregnancy rate, miscarriage and adverse events were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs) and were combined in a meta-analysis with RevMan software using the Peto method and a fixed-effect model (Higgins 2011). This effect measure is appropriate when subfertility is considered. These data were displayed on forest plots.

 

Unit of analysis issues

Outcomes of live birth, pregnancy and adverse events were analysed as per woman randomly assigned. Multiple births were counted as one live birth event.

 

Dealing with missing data

In cases where trial data were missing, we first sought information from the original trial investigators. Details of authors contacted and the questions asked of them are contained in Characteristics of included studies. In addition, and where possible, we performed analyses on all outcomes on an intention-to-treat basis. It was our intention to include in the analyses all women randomly assigned to each group and to analyse all women in the group to which they were allocated, regardless of whether or not they received the allocated intervention.

 

Assessment of heterogeneity

We considered whether the clinical and methodological characteristics of included studies were sufficiently similar for meta-analysis to provide a clinically meaningful summary. Statistical heterogeneity was assessed according to the guidelines set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We examined heterogeneity between the results of different trials by visually assessing the forest plots and the overlap of confidence intervals (poor overlap suggested heterogeneity), by considering the P value (a low P value or a large Chi2 statistic relative to the degree of freedom suggests heterogeneity) and by identifying the I2 statistic. If I2 was ≥ 50%, we assumed high heterogeneity, and a sensitivity analysis with a random-effects model was used to assess the possible reasons. A high I2 statistic suggests that variations in effect estimates were due to differences between trials rather than to chance alone.

 

Assessment of reporting biases

The search strategies covered multiple sources without language or publication restrictions. We were alert to the possibility of duplication of data. We used a funnel plot to explore the possibility of small study effects in cases where estimates of intervention effect can be more beneficial in smaller studies (Higgins 2011).

 

Data synthesis

Statistical analysis of the data was carried out using Review Manager 5 (RevMan 5). Pregnancy outcomes were considered positive, and higher numbers of pregnancy rates were considered a benefit. The outcomes of miscarriage and adverse events were negative effects, and higher numbers were considered harmful. These aspects were considered when the summary graphs were assessed.

Data from primary studies were combined using a fixed-effect model in the following comparisons:

  • Antioxidants versus control (placebo or no treatment/standard treatment);
  • Antioxidants versus antioxidants or head-to-head stratification by type of antioxidant; and
  • Pentoxifylline versus control (placebo or no treatment/standard treatment).

Increases in the odds of a particular outcome, which may be beneficial (e.g. live birth) or detrimental (e.g. adverse effects), were displayed graphically in meta-analyses to the right of the centre line, and decreases in the odds of a particular outcome were displayed to the left of the centre line.

The aim was to define analyses that were comprehensive and mutually exclusive so that all eligible study results could be slotted into one stratum only. Comparisons were specified, so that any trials falling within each stratum could be pooled for meta-analysis. Stratification allowed for consideration of effects within each stratum, as well as or instead of an overall estimate for comparison.

In trials with multiple arms, intervention groups were pooled versus the control group.

If individuals had been re-randomly assigned after failed cycles, we would not have pooled the data in a meta-analysis.

 

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses were carried out:

  • Type of antioxidant, whether individual or combined (three or more antioxidants combined);
  • Trials that enrolled women with different indications for infertility (i.e. PCOS, endometriosis, unexplained infertility or poor responders); and
  • Trials that enrolled women who were also undergoing IVF or ICSI.

If we detected substantial heterogeneity, we explored possible explanations by performing sensitivity analyses.

 

Sensitivity analysis

Sensitivity analyses (using the random-effects model in RevMan software) were performed on the primary outcomes if a high degree of heterogeneity was noted (where the I2 statistic was ≥ 50%), excluding studies:

  • with a high risk of bias; or
  • that used antioxidants plus folic acid versus standard treatment (folic acid < 1 mg); or
  • that used antioxidants plus a fertility drug (a co-intervention) versus placebo plus a fertility drug.

 
Overall quality of the body of evidence: Summary of Findings Table

A Summary of findings table was generated using GRADEPRO software. This table evaluated the overall quality of the body of evidence for main review outcomes, using GRADE criteria (study limitations; i.e. risk of bias, consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality ('high', 'moderate', 'low' or 'very low') were justified, documented and incorporated into reporting of results for the outcomes of live birth, clinical pregnancy and adverse events.

The protocol for this review was provided by Clarke 2009.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

 

Results of the search

The search retrieved 2127 abstracts and titles. These were screened to identify trials that met inclusion criteria. We retrieved the full manuscripts of 67 trials for appraisal. This process is shown in the PRISMA flow chart (Figure 1). Only one study was not published in English (Bonakdaran 2012). The full text was in Persian; however, the English abstract contained enough information to show that it did not meet the inclusion criteria, and the study was therefore excluded. Of the 67 studies assessed, 28 were included and 39 were excluded. Please see Characteristics of included studies and Characteristics of excluded studies for study details. A repeat search in April 2013 revealed seven studies that were placed into the awaiting classification section of the review (Characteristics of studies awaiting classification). A total of 12 ongoing trials were found in searches of the trials registers (see Ongoing studies).

 

Included studies

A total of 28 trials met the criteria for inclusion. Seven trials were based in Italy (Battaglia 2002; Ciotta 2011; Gerli 2007; Lisi 2012; Papaleo 2009; Rizzo 2010; Unfer 2011). Five were based in Iran (Alborzi 2007; Aleyasin 2009; Firouzabadi 2012; Rashidi 2009; Salehpour 2009), four in Egypt (Aboulfoutouh 2011; Badawy 2006; Rizk 2005; Nasr 2010), four in Turkey (Batioglu 2012; Cicek 2012; Eryilmaz 2011; Ozkaya 2011), two in Korea (Kim 2006; Kim 2010), two in Spain (Creus 2008; Balasch 1997) and one each in the UK (Agrawal 2012), Hungary/Austria (Griesinger 2002), Mexico (Mier-Cabrera 2008) and the USA (Westphal 2006).

Three of these trials did not provide data for meta-analysis (Kim 2006; Kim 2010; Ozkaya 2011), and two did not report on the outcomes included in this review (Salehpour 2009; Firouzabadi 2012). Attempts were made to contact all authors of included trials to obtain further details and clarification. In one trial (Gerli 2007) (see  Table 1), only half of the participants declared that they wanted to become pregnant before the study began; therefore, this trial was included, but the data have not been used in the meta-analysis (see Characteristics of included studies).

Duration of treatment ranged from 12 days (Battaglia 2002) to two years (Firouzabadi 2012).

 

Participants

The trials randomly assigned 3548 subfertile women who were attending a fertility clinic and might or might not be undergoing ART procedures such as IVF, IUI or ICSI. The age range of randomly assigned participants was 18 to 42 years.

Four trials (Nasr 2010; Papaleo 2009; Rizk 2005; Unfer 2011) included women with PCOS. Other participants in the trials were enrolled as the result of endometriosis, ovulation failure, tubal blockages and unexplained subfertility. One trial included women aged 35 to 42 years with poor oocyte quality (Rizzo 2010). Five trials included women with more than one fertility problem: these reasons included male partner subfertility, unexplained subfertility, ovulatory problems and endometriosis (Agrawal 2012; Aleyasin 2009; Batioglu 2012; Griesinger 2002 and Westphal 2006). One trial (Gerli 2007) included participants in whom "infertility was an ailment in only half of the participants in each group". The author of this trial states that there was "no difference in the proportions of infertile women in the groups".

Four trials included a percentage of women whose subfertility was caused by the male partner (Aleyasin 2009; Creus 2008; Balasch 1997 and Griesinger 2002).

Further details of inclusion and exclusion criteria are found in the Characteristics of included studies table.

 

Interventions

A variety of antioxidants were used in the included trials. Comparisons consisted of antioxidants versus placebo, no treatment or standard treatment (folic acid < 1 mg), head-to-head comparisons (antioxidant vs antioxidant) and pentoxifylline versus placebo, no treatment or standard treatment.

Comparison antioxidants versus placebo, no treatment and standard treatment included the following: combinations (OctatronR , multiple micronutrients and Fertility Blend-details of these combination antioxidants are given in the Characteristics of included studies), N-acetyl-cysteine, melatonin, L-arginine, vitamin E, myo-inositol, vitamin C, vitamin D+calcium and omega-3 polyunsaturated fatty acids.

The comparison 'antioxidants versus antioxidants' included the antioxidants myo-inositol, melatonin and d-chiro-inositol and differing doses of vitamin C. The head-to-head comparisons were included in an attempt to assess whether one antioxidant was more effective than another:

 

Outcomes

 
Live birth

The primary outcome for this review was live birth. Four trials reported on live birth (Aleyasin 2009; Battaglia 2002; Nasr 2010; Unfer 2011). Emails and letters were sent to all other authors of included trials to ask whether they had any data on live birth. Live birth data from Battaglia 2002 were received by email.

 
Pregnancy

21 trials reported on 'clinical pregnancy' or 'ongoing pregnancy' rates in the text of the trial reports or through direct communication with the authors (Aboulfoutouh 2011; Agrawal 2012; Aleyasin 2009; Badawy 2006; Balasch 1997; Batioglu 2012; Battaglia 2002; Cicek 2012; Creus 2008; Eryilmaz 2011; Gerli 2007; Griesinger 2002; Kim 2010; Lisi 2012; Nasr 2010; Papaleo 2009; Rashidi 2009; Rizk 2005; Rizzo 2010; Unfer 2011; Westphal 2006). Two trials reported only biochemical pregnancy or conception (Ciotta 2011; Firouzabadi 2012), and another two trials reported only 'pregnancy rates' (Alborzi 2007; Mier-Cabrera 2008) (see data from these four trials in  Table 2). Three trials did not report any pregnancy outcomes (Kim 2006; Ozkaya 2011; Salehpour 2009). Attempts were made to contact all authors of the trials that did not report clinical pregnancy rates.

Adverse events

The following adverse events were reported:

Attempts were made to contact all authors of the trials that did not report adverse events. We could not conclude that there were no adverse events in cases where these were not reported.

 

Design

All 28 included trials were of parallel-group design. One trial (Griesinger 2002) was a four-arm trial in which different dosages of vitamin C versus placebo were used.

The sample size of the included trials ranged from 36 participants (Mier-Cabrera 2008) to 804 participants (Badawy 2006). Only nine trials included in the meta-analysis (Agrawal 2012; Battaglia 2002; Cicek 2012; Ciotta 2011; Eryilmaz 2011; Lisi 2012; Mier-Cabrera 2008; Nasr 2010; Papaleo 2009) reported carrying out a power calculation.

 

Excluded studies

We retrieved the full text of trials that were identified as potentially eligible for inclusion (see Figure 1). We excluded 39 trials; 23 of these were excluded because the population did not meet criteria for inclusion in this review (Ardabili 2012; Baillargeon 2004; Bonakdaran 2012; Cheang 2008; Ciotta 2012; Costantino 2009; Elgindy 2008; Elgindy 2010; Genazzani 2008; Hernndez-Yero 2012; Iuorno 2002; Kilicdag 2005; Le Donne 2012; Moosavifar 2010; Nestler 1999; Nestler 2001; Nordio 2012; Oner 2011; Santanam 2003; Vargas 2011; Yoon 2010; Kamencic 2008; Thiel 2006). Many of these trials recruited women with PCOS who were not attending a subfertility clinic and whose main concern was not pregnancy but rather ways to control their symptoms of PCOS. Seven were found to be quasi-controlled trials and therefore were not randomised (Aksoy 2010; Al-Omari 2003; Crha 2003; Henmi 2003; Nazzaro 2011; Papaleo 2007; Tamura 2008). Four had inappropriate controls for inclusion (Elnashar 2007; Hashim 2010; Papaleo 2008; Raffone 2010). Two had an inappropriate treatment for inclusion (Farzadi 2006; Twigt 2011). Two were conference abstracts of another published trial (Elnashar 2005; Rezk 2004). We excluded Nichols 2010 after the lead investigator confirmed that this trial had been abandoned before recruitment because of lack of funding.

 

Ongoing trials

Twelve trials are ongoing (Agrawal 2012a; Bentov 2010; Lindqvist 2009; Mahdian 2012; Mane 2012; Ortega 2013; Unfer 2011a; Mohammadbeigi 2011; Pasha 2011; Pourghassem 2010; Unfer 2010; Youssef 2011). We may be able to include data from these trials in future updates of this review. One ongoing trial (Youssef 2011) was in press, and any published article will supersede the included conference abstract (Aboulfoutouh 2011).

 

Trials awaiting classification

Seven trials are awaiting classification (see Characteristics of studies awaiting classification).

 

Risk of bias in included studies

See Figure 2 for a summary of risk of bias in individual trials and Figure 3 for a summary of each risk of bias item across all included trials.

 FigureFigure 2. Methodological risk of bias summary: review authors' judgements about each methodological bias item for each included study.
 FigureFigure 3. Methodological risk of bias graph: review authors' judgements about each methodological bias item presented as percentages across all included trials.

Sequence Generation

All of the 28 included trials were randomised with a parallel design. 19 trials describe their methods of sequence generation, which typically were computer generated or used a random number table (Aboulfoutouh 2011; Agrawal 2012; Aleyasin 2009; Balasch 1997; Batioglu 2012; Battaglia 2002; Cicek 2012; Ciotta 2011; Creus 2008; Eryilmaz 2011; Firouzabadi 2012; Gerli 2007; Lisi 2012; Nasr 2010; Ozkaya 2011; Papaleo 2009; Rashidi 2009; Rizzo 2010; Unfer 2011). Eight trials (Badawy 2006; Griesinger 2002; Kim 2006; Kim 2010; Mier-Cabrera 2008; Rizk 2005; Salehpour 2009; Westphal 2006) simply reported the trial as randomised with no description of method. One trial (Alborzi 2007) reported the method, but it remained unclear whether randomisation was performed by coin flip or with the use of odd and even numbers. Sensitivity analysis was performed on exclusion of trials that lacked a clear explanation of randomisation.

 

Allocation

Six trials (Aleyasin 2009; Badawy 2006; Battaglia 2002; Creus 2008; Griesinger 2002; Lisi 2012) described their allocation concealment as using 'sequentially numbered closed opaque envelopes'. Seven trials described the envelopes as sealed but did not mention sequential numbering (Aboulfoutouh 2011; Agrawal 2012; Balasch 1997; Ciotta 2011; Nasr 2010; Rizk 2005; Unfer 2011). Attempts were made to contact these authors regarding the numbering. One trial (Eryilmaz 2011) replied through email correspondence that no allocation concealment was used. The remainder did not describe any methods of allocation concealment, and unsuccessful attempts were made to contact these authors regarding allocation concealment techniques.

 

Blinding

We did not consider that blinding was likely to influence findings for the outcomes of live birth or pregnancy; however, for adverse effects, blinding status could have affected the findings. In all, 17 trials from the 28 included trials described some form of blinding of participants and/or investigators. Four were triple-blinded, with participants, clinicians/investigators and outcome assessors blinded (Agrawal 2012; Badawy 2006; Battaglia 2002; Mier-Cabrera 2008). Seven were double-blinded with blinding of participants and clinicians (Alborzi 2007; Ciotta 2011; Griesinger 2002; Nasr 2010; Rizk 2005; Salehpour 2009; Westphal 2006). Four stated that they were double-blinded but did not declare who was blinded (Creus 2008; Gerli 2007; Griesinger 2002; Unfer 2011). Three were single-blinded: the participants were blinded in Balasch 1997, the embryologist was blinded in Papaleo 2009 and the outcome assessors were blinded in Lisi 2012.

Five trials (Aboulfoutouh 2011; Aleyasin 2009; Batioglu 2012; Cicek 2012; Eryilmaz 2011) used no treatment as the control; therefore, there was no blinding in these trials. The six remaining trials did not report any blinding (Firouzabadi 2012; Kim 2006; Kim 2010; Ozkaya 2011; Rashidi 2009; Rizzo 2010).

 

Incomplete outcome data

Thirteen trials (Alborzi 2007; Aleyasin 2009; Badawy 2006; Batioglu 2012; Ciotta 2011; Firouzabadi 2012; Lisi 2012; Nasr 2010; Papaleo 2009; Rashidi 2009; Rizk 2005; Rizzo 2010; Westphal 2006) had no losses to follow-up. Three trials reported losses but used intention-to-treat (ITT) analysis (Aboulfoutouh 2011; Agrawal 2012; Unfer 2011). Four trials (Balasch 1997; Battaglia 2002; Creus 2008; Mier-Cabrera 2008) had losses and described from which groups they were lost but did not use ITT in the reporting of trials; however, ITT was used in the meta-analysis. Salehpour 2009 also had explained losses, but because outcomes reported in the trial were different from outcomes in this review, this study was not included in the meta-analysis. Four trials had loss to follow-up with no explanation as to which groups these women were lost from. Data were taken from Cicek 2012; Eryilmaz 2011 and Griesinger 2002, as totals were given after dropouts, and the assumption was made that the groups were equal on allocation. The remaining four trials were not included in the meta-analysis: Gerli 2007 had greater than 30% dropout from the treatment group, and data were unavailable from Kim 2006; Kim 2010 and Ozkaya 2011. Attempts were made to contact authors when the data were unavailable.

 

Selective reporting

Trial protocols were unavailable for all 28 included trials; therefore, it cannot be claimed that on the basis of published reports alone, the authors included all expected outcomes. Failure to report live birth in subfertility trials is common, is a major source of bias (Clarke 2010) and should be the default primary outcome in fertility trials. Only four trials reported live birth (Aleyasin 2009; Battaglia 2002; Nasr 2010; Unfer 2011). Mier-Cabrera 2008 and Papaleo 2009 stated that they would report live birth, but then they reported only pregnancy. Adverse events were not well reported.

A funnel plot for clinical pregnancy (Figure 4) was nearly symmetrical, indicating that there may not be a small study effect. Estimates of the intervention effect tend to be more beneficial in smaller studies and thus introduce the potential for selective reporting and publication bias; however, this does not seem to be the case in this review.

 FigureFigure 4. Funnel plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).

 

Other potential sources of bias

Funding sources were reported by only six of the 28 included trials. One trial was self-funded (Agrawal 2012), and the remaining five gained funding from their institutions (Aleyasin 2009; Creus 2008; Mier-Cabrera 2008; Salehpour 2009; Westphal 2006). See details in Characteristics of included studies.

 
Studies included within the review but not in the analysis

Gerli 2007 (see  Table 1) was not incorporated into the analysis, as only half the women randomly assigned reported a desire to become pregnant. 92 women were randomly assigned, 45 to the treatment group and 47 to the control group. 23 from the treatment group and 19 from the control wished to conceive; four from the treatment group and one from the control group became pregnant. This trial also had greater than 30% dropouts from the treatment group.

Rashidi 2009 reported on clinical pregnancy; however, there were no events in either the antioxidant or no treatment arms of the trial.

 

Effects of interventions

See:  Summary of findings for the main comparison Antioxidant(s) versus placebo or no treatment/standard treatment for female subfertility

 

1. Antioxidant supplement versus placebo, no treatment/standard treatment

 

Primary outcome: Live birth

 
1.1 Live birth; antioxidants versus placebo or no treatment/standard treatment

See  Analysis 1.1.

Antioxidants were not associated with an increased live birth rate compared with placebo or no treatment (OR 1.60, 95% CI 0.70 to 3.69, P = 0.27, 2 RCTs, 97 women, I2 = 75%, very low-quality evidence). As the I2 statistic was greater than 50%, we repeated the analysis using a random-effects model, and here again, antioxidants were not associated with an increased live birth rate compared with placebo or no treatment (OR 1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I2 = 75%, very low-quality evidence) (Figure 5). This suggests that among subfertile women with an expected live birth rate of 37%, the rate among women using antioxidants would be between 10% and 83% ( Summary of findings for the main comparison). Heterogeneity remained high, with an I2 statistic of 75%.

 FigureFigure 5. Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.1 Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).

In the two trials that reported live birth (Battaglia 2002; Nasr 2010), the OR for live birth was 1.25 and for clinical pregnancy was 1.26. However, when we pooled all 16 studies that reported clinical pregnancy, the OR for clinical pregnancy was higher, at 1.30. This suggests that the clinical pregnancy rate in the two trials that reported live birth was not an overestimation of the effect of the antioxidants, and hence that the live birth rate in these trials is probably not an overestimate.

 
1.1.1 Live birth; antioxidants versus placebo

No evidence of a statistically significant difference in live birth was noted between antioxidant and placebo groups (OR 1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I2 = 75%). The high heterogeneity was possibly due to the differing populations. Battaglia 2002 enrolled women with tubal infertility undergoing IVF, and Nasr 2010 enrolled women with PCOS undergoing laparoscopic ovarian drilling. We could not perform a sensitivity analysis as only two trials were included in the placebo analysis.

 
1.2 Live birth; type of antioxidant

See  Analysis 1.2.

Subtotals only were used for this analysis. Each comparison included only one trial.

1.2.1 Nasr 2010; N-acetyl-cysteine versus placebo (OR 2.87, 95% CI 1.05 to 7.84, P = 0.04).

1.2.2 Battaglia 2002; compared L-arginine with placebo (OR 0.45, 95% CI 0.10 to 2.00, P = 0.30).

 
1.3 Live birth rate; indications for subfertility

See  Analysis 1.3.

Battaglia 2002 enrolled women with tubal subfertility undergoing IVF (OR 0.45, 95% CI 0.10 to 2.00, P = 0.30, 37 women), and Nasr 2010 enrolled women with PCOS (OR 2.87, 95% CI 1.05 to 7.84, P = 0.04, 60 women).

 
1.4 Live birth; IVF/ICSI

See  Analysis 1.4.

Only one trial (Battaglia 2002) compared antioxidants with placebo or no treatment in women having IVF/ICSI treatment and reported live birth (OR 0.45, 95% CI 0.10 to 2.00, P = 0.30, 1 RCT, 37 women) (Battaglia 2002).

 

Secondary outcome: Clinical pregnancy

 
1.5 Clinical pregnancy; antioxidants versus placebo or no treatment/standard treatment.

See  Analysis 1.5.

Antioxidants were not associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 1.12, 95% CI 0.92 to 1.36, P = 0.27, 13 RCTs, 2441 women, I2= 67%, very low-quality evidence). As the I2 statistic was greater than 50%, we repeated the analysis using a random-effects model, and here again, antioxidants were not associated with an increased clinical pregnancy rate when compared with placebo or no treatment (OR 1.30, 95% CI 0.92 to 1.85, P = 0.14, 13 RCTs, 2441 women, I2= 55%, very low-quality evidence) (Figure 6). This suggests that among subfertile women with an expected clinical pregnancy rate of 23%, the rate among women using antioxidants would be between 22% and 36% ( Summary of findings for the main comparison). However, the 12 statistic in the random-effects model of 55% remained high.

 FigureFigure 6. Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).

Westphal 2006 was the only included trial reporting on clinical pregnancy where the women conceived naturally without ovulation induction, IVF/ICSI or laparoscopic ovarian drilling.

 
Sensitivity analysis for trials with a high risk of bias

Two trials (Rizk 2005; Westphal 2006) did not describe details of sequence generation or allocation concealment in their reports and were removed in a sensitivity analysis. This result indicated that antioxidants were not associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment when high risk studies were removed (OR 1.11, 95% CI 0.83 to 1.50, P = 0.47, 11 RCTs, 2198 women, I2 = 37%).

 
Sensitivity analysis for trials using placebo plus co-intervention as a control

Two trials (Badawy 2006; Rizk 2005) used placebo plus a co-intervention as a control and were removed in a sensitivity analysis (OR 1.32, 95% CI 0.94 to 1.85, P = 0.11, 11 RCTs, 1487 women, I2 = 35%). On removal of these trials from the analysis, the heterogeneity decreased but there remained no association with antioxidants and clinical pregnancy rates in this comparison.

 
Sensitivity analysis for trials using folic acid (standard treatment) as a control

On removing the three trials (Agrawal 2012; Lisi 2012; Papaleo 2009) that reported using folic acid (standard treatment) as a control, we found no evidence of an association between antioxidants and the clinical pregnancy rate (OR 1.24, 95% CI 0.83 to 1.85, P = 0.30, 10 RCTs, 2229 women, I2 = 59%).

 
1.5.1 Clinical pregnancy; antioxidants versus placebo

No evidence was found of a statistically significant difference in clinical pregnancy rates between the antioxidant and placebo groups (OR 1.34, 95% CI 0.69 to 2.61, P = 0.39, 6 RCTs, 1763 women, I2 = 75%).

 
1.5.2 Clinical pregnancy; antioxidants versus no treatment or standard treatment

Antioxidants were not associated with an increased clinical pregnancy rate compared with no treatment or standard treatment (OR 1.37, 95% CI 0.98 to 1.92, P = 0.06, 7 RCTs, 678 women, I2 = 0%). Six of the seven trials in this analysis enrolled fewer than 50 women.

 
1.6 Clinical pregnancy; type of antioxidant

See  Analysis 1.6.

Only subtotals were used in the stratification by antioxidant type (Figure 7).

N-acetyl-cysteine was not associated with an increased clinical pregnancy rate when compared with placebo, no treatment or standard treatment (OR 1.10, 95% CI 0.80 to 1.53, P = 0.55, 3 RCTs, 1014 women, I2 = 92%). Heterogeneity was extremely high, perhaps as a result of the high risk of bias in Badawy 2006 and Rizk 2005 or the additional treatment of laparoscopic drilling that women received in Nasr 2010.

Combined antioxidants (similar antioxidants were combined in each trial) were associated with an increased clinical pregnancy rate (OR 1.66, 95% CI 1.07 to 2.58, P = 0.02, 3 RCTs, 369 women, I2 = 43%). However, heterogeneity was moderately high, and the trials enrolled small numbers of women.

No association of increased clinical pregnancy rates was seen in those women receiving melatonin (OR 1.30, 95% CI 0.65 to 2.60, P = 0.45, 2 RCTs, 145 women, I2 = 0%).

Myo-inositol plus folic acid was not associated with an increased clinical pregnancy rate (OR 1.22, 95% CI 0.60 to 2.48, P = 0.59, 2 RCTs, 154 women, I2 = 0%).

Only one trial was included in each of the other subgroups; therefore results could not be pooled. Vitamin E (OR 1.42, 95% CI 0.50 to 4.00, P = 0.51, 103 women); ascorbic acid (OR 0.75, 95% CI 0.49 to 1.14, P = 0.18, 619 women); and L-arginine (OR 0.45, 95% CI 0.10 to 2.00, P = 0.30, 37 women).

 
1.7 Clinical pregnancy rate; indications for subfertility

See  Analysis 1.7.

 
1.7.1 Clinical pregnancy rate; polycystic ovary syndrome

Antioxidants were associated with an increased pregnancy rate in women with PCOS (OR 3.40, 95% CI 1.84 to 6.29, P < 0.0001, 3 RCTs, 270 women, I2 = 71%) ( Analysis 1.7). However, heterogeneity was very high, and this was assumed to be due to the very wide confidence intervals in Rizk 2005. This trial had 16 events in the treatment group and nil in the control group, which is unusual. The trials in this analysis all had small numbers of women randomly assigned.

 
1.7.2 Clinical pregnancy rate; unexplained subfertility

Antioxidants were not associated with an increase in clinical pregnancy rate in women with unexplained subfertility (OR 0.82, 95% CI 0.59 to 1.14, P = 0.23, 3 RCTs, 967 women, I2 = 0%) ( Analysis 1.7).

 
1.7.3 Clinical pregnancy rate; tubal subfertility

Only one trial (Battaglia 2002) enrolled women with tubal subfertility (OR 0.45, 95% CI 0.10 to 2.00, P = 0.30).

 
1.7.4 Clinical pregnancy rate; varying indications

Five trials (Aboulfoutouh 2011; Agrawal 2012; Batioglu 2012; Griesinger 2002; Westphal 2006) enrolled women who presented with different indications within the trials. Antioxidants were not associated with an increase in clinical pregnancy rate in women enrolled in trials with varying indications of subfertility (OR 1.14, 95% CI 0.85 to 1.52, P = 0.38, 5 RCTs, 1073 women, I2 = 62%) ( Analysis 1.7).

 
1.8 Clinical pregnancy rate; IVF/ICSI

See  Analysis 1.8.

No evidence was found of an effect of antioxidants versus placebo or no treatment in the subgroup of women undergoing IVF/ICSI (OR 0.97, 95% CI 0.74 to 1.27, P = 0.83, 7 RCTs, 1173 women, I2 = 0%) ( Analysis 1.8).

 

Secondary outcome: Adverse events

 
1.9 Adverse events

See  Analysis 1.9.

Adverse event data were subgrouped according to the types of events that occurred, as reported by the trial. These included miscarriage, multiple pregnancy, gastrointestinal disturbances and ectopic pregnancy. No evidence suggested an association between antioxidants and adverse events, but data were limited, with 8 trials reporting on miscarriage, two trials reporting on multiple pregnancy, and one reporting on gastrointestinal upsets and ectopic pregnancy. Only subtotals were used in the analysis.

 
1.9.1 Miscarriage

Antioxidants were not associated with miscarriage (OR 0.88, 95% CI 0.57 to 1.36, P = 0.56, 8 RCTs, 1456 women, I2 = 0%, low-quality evidence) (Figure 7). This means that given the rate of 5% miscarriages in the control population, the use of antioxidants would be expected to result in a miscarriage rate of between 4% and 8% ( Summary of findings for the main comparison). Most of the trials in this analysis were small, ranging from 60 women to 218 women randomly assigned; however, one trial (Badawy 2006) did enrol 804 women.

 FigureFigure 7. Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.9 Adverse event.

Battaglia 2002 also reported on miscarriage but described no events in the treatment or control groups; therefore, this study could not be added to the meta-analysis.

 
1.9.2 Multiple pregnancy

No association was noted between antioxidants and multiple pregnancy (OR 0.70, 95% CI 0.41 to 1.21, P = 0.20, 2 RCTs, 1022 women, I2 = 0%, low-quality evidence) (Figure 7). This means that of 7% multiple pregnancies in the control population (with a range from 5% to 14%), use of antioxidants instead would be expected to result in a multiple pregnancy rate between 3% and 8% ( Summary of findings for the main comparison). Nasr 2010 also reported on multiple pregnancy events, but no events were reported in the treatment or control groups; therefore this study could not be added to the meta-analysis.

 
1.9.3 Gastrointestinal disturbances

Two trials (Cicek 2012; Westphal 2006) reported on gastrointestinal disturbances, but no events were reported in treatment or control groups in Cicek 2012; therefore, meta-analysis was not possible for this adverse event; Westphal 2006 (OR 2.14, 95% CI 0.29 to 15.99, P = 0.46).

 
1.9.4 Ectopic pregnancy

One trial (Agrawal 2012) reported on ectopic pregnancy (OR 6.91, 95% CI 0.14 to 349.18, P = 0.33, 58 women).

 

2. Head-to-head antioxidants

 

Primary outcome: Live birth

Only one trial reported on live birth (Unfer 2011).

 
2.1 Live birth; type of antioxidant

See  Analysis 2.1.

2.1.1 Myo-inositol versus d-chiro-inositol

Unfer 2011 reported on live birth (OR 3.44, 95% CI 1.27 to 9.34, P = 0.02), measuring the effects of myo-inositol versus d-chiro-inositol.

 
2.2 Live birth; indications for subfertility

See  Analysis 2.2.

2.2.1 Polycystic ovary syndrome

Unfer 2011 enrolled women with PCOS.

 
2.3 Live birth; IVF/ICSI

See  Analysis 2.3.

The women who were enrolled in Unfer 2011 were also undergoing ICSI.

 

Secondary outcome: Clinical pregnancy

Two trials (Unfer 2011; Rizzo 2010) reported on clinical pregnancy in the antioxidant versus antioxidant comparison. Only subtotals were used in this analysis, and meta-analysis was not possible as each trial used a different antioxidant.

 
2.4 Clinical pregnancy; type of antioxidant

See  Analysis 2.4.

2.4.1 Myo-inositol versus d-chiro-inositol

One trial (Unfer 2011) reported on clinical pregnancy, measuring the effects of myo-inositol versus d-chiro-inositol (OR 3.44, 95% CI 1.27 to 9.34, P = 0.02).

2.4.2 Myo-inositol plus folic acid plus melatonin versus myo-inositol plus folic acid

Rizzo 2010 reported on the effects of myo-inositol plus folic acid plus melatonin versus myo-inositol plus folic acid (OR 1.85, 95% CI 0.65 to 5.25, P = 0.25).

 
2.5 Clinical pregnancy; indications for subfertility

See  Analysis 2.5

Two trials reported on the indications for subfertility; these included PCOS and poor responders; however, only one trial was included in each subgroup.

2.5.1 Polycystic ovary syndrome

Unfer 2011 enrolled women with polycystic ovary syndrome (OR 3.44, 95% CI 1.27 to 9.34, P = 0.02).

2.5.2 Poor responders

Rizzo 2010 was the only trial to report on clinical pregnancy rate in women who were poor responders (OR 1.85, 95% CI 0.65 to 5.25, P = 0.25).

 
2.6 Clinical pregnancy; IVF/ICSI

See  Analysis 2.6.

Antioxidant 'a' was associated with an increased clinical pregnancy rate in women also having IVF/ICSI compared with antioxidant 'b' (OR 2.56, 95% CI 1.24 to 5.26, P = 0.01, 2 RCTs, 149 women, I2 = 0%) ( Analysis 2.6). However, these two trials were very small, and antioxidant 'a' was very different from antioxidant 'b'. Unfer 2011 compared myo-inositol (antioxidant 'a') with d-chiro-inositol (antioxidant 'b') in women with PCOS. Rizzo 2010 enrolled women who were poor responders and compared myo-inositol plus folic acid plus melatonin (antioxidant 'a') with myo-inositol plus folic acid (antioxidant 'b'), so no conclusions regarding the use of antioxidants for women undergoing IVF/ICSI can be drawn on the basis of this analysis.

 

Secondary outcome: Adverse events

See  Analysis 2.7.

Adverse event data were subgrouped according to the type of event that occurred, and only subtotals were used in the analysis.

 
2.7 Adverse events

2.7.1 Miscarriage

Antioxidant 'a' was not associated with miscarriage when compared with antioxidant 'b' (OR 1.19, 95% CI 0.35 to 4.04, P = 0.78, 2 RCTs, 149 women, I2 = 0%) (Figure 8). Antioxidant 'a' was myo-inositol in Unfer 2011 and melatonin plus myo-inositol plus folic acid in Rizzo 2010.

 FigureFigure 8. Forest plot of comparison: 2 Head to head antioxidants, outcome: 2.7 Adverse events.

No evidence suggested a difference between the interventions used for miscarriage, but data were limited.

 

3. Pentoxifylline supplement versus placebo, no treatment/standard treatment

 

Primary outcome: Live birth

 
3.1 Live birth; pentoxifylline versus placebo or no treatment/standard treatment

See  Analysis 3.1

3.1.1 Live birth; pentoxifylline versus no treatment

Only one trial (Aleyasin 2009) performed this comparison in the pentoxifylline versus no treatment subgroup (OR 1.53, 95% CI 0.68 to 3.44, P = 0.30, 112 women).

 
3.2 Live birth; type of antioxidant

See  Analysis 3.2

3.2.1 Pentoxifylline plus vitamin E versus no treatment.

The type of antioxidant used in Aleyasin 2009 was pentoxifylline plus vitamin E versus no treatment.

 
3.3 Live birth; indications for subfertility

See  Analysis 3.3

3.3.1 Varying indications

The trial Aleyasin 2009 enrolled women with varying causes of subfertility, and the cause of subfertility in 45% of these women was the male partner.

 
3.4 Live Birth: IVF/ICSI

See  Analysis 3.4

The women enrolled in Aleyasin 2009 were also undergoing IVF/ICSI.

 

Secondary outcome: Clinical pregnancy

 
3.5 Clinical pregnancy; pentoxifylline vs placebo or no treatment/standard treatment

See  Analysis 3.5

Pentoxifylline was associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.03, 95% CI 1.19 to 3.44, P = 0.009, 3 RCTs, 276 women, I2 = 0%) (Figure 9).

 FigureFigure 9. Forest plot of comparison: 3 Pentoxifylline versus placebo or no treatment/standard care, outcome: 3.5 Clinical pregnancy; pentoxifylline vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).

Sensitivity analysis for trials with a high risk of bias

When Balasch 1997 was removed from the analysis (as it did not describe methods of allocation concealment) there remained an association with pentoxifylline and clinical pregnancy rate (OR 2.01, 95% CI 1.11 to 3.64, P = 0.02, 2 RCTs, 216 women, I2 = 0%).

3.5.1 Clinical pregnancy; pentoxifylline versus placebo

No evidence was found of a statistically significant difference in effect of pentoxifylline versus placebo on clinical pregnancy rate (OR 2.02, 95% CI 0.95 to 4.33, P = 0.07, 2 RCTs, 164 women, I2 = 0%).

3.5.2 Clinical pregnancy rate; pentoxifylline versus no treatment

Aleyasin 2009 was the only trial in this subgroup (OR 2.03, 95% CI 0.97 to 4.25, P = 0.06, 112 women).

 
3.6 Clinical pregnancy; type of antioxidant

See  Analysis 3.6

3.6.1 Pentoxifylline

Two trials reported on pentoxifylline alone and there was no association with pentoxifylline and clinical pregnancy rate (OR 2.02, 95% CI 0.95 to 4.33, P = 0.07, 2 RCTs, 164 women, I2 = 0%).

3.6.2 Pentoxifylline plus vitamin E

Only one trial reported on pentoxifylline plus vitamin E and there was no association clinical pregnancy rate (OR 2.03, 95% CI 0.97 to 4.25, P = 0.06, 112 women).

 
3.7 Clinical pregnancy; indications for subfertility

See  Analysis 3.7

3.7.1 Clinical pregnancy rate; endometriosis

Pentoxifylline did not show an association with an increased clinical pregnancy rate (OR 2.02, 95% CI 0.95 to 4.33, P = 0.07, 2 RCTs, 164 women, I2 = 0%) in women with endometriosis ( Analysis 3.7).

3.7.2 Clinical pregnancy rate; varying indications

Only one trial enrolled women who presented with different indications within the trial (OR 2.03, 95% CI 0.97 to 4.25, P = 0.06, 112 women).

 
3.8 Clinical pregnancy rate; IVF/ICSI

See  Analysis 3.8

Only one trial enrolled women who were undergoing IVF/ICSI (OR 2.03, 95% CI 0.97 to 4.25, P = 0.06) .

 

Secondary outcome: Adverse events

See  Analysis 3.9

Adverse event data were subgrouped according to the types of events that occurred, as reported by the trial. These included miscarriage, multiple pregnancy and ectopic pregnancy. No evidence suggested an association with antioxidants and adverse events, but data were limited, with 3 trials reporting on miscarriage, one trial reporting on multiple pregnancy, and one reporting on ectopic pregnancy. Only subtotals were used in the analysis.

3.9.1 Miscarriage

No evidence suggested an association with antioxidants and miscarriage, but data were limited with only 3 trials reporting on this outcome (OR 1.37, 95% CI 0.46 to 4.05, P = 0.58, 3 RCTs, 276 women, I2 = 0%) (Figure 10).

 FigureFigure 10. Forest plot of comparison: 3 Pentoxifylline versus placebo or no treatment/standard care, outcome: 3.9 Adverse events.

3.9.2 Multiple pregnancy

Only one trial reported on multiple pregnancy (OR 0.79, 95% CI 0.20 to 3.06, P = 0.73).

3.9.3 Ectopic pregnancy

Only one trial reported on ectopic pregnancy (OR 1.97, 95% CI 0.20 to 19.35, P = 0.56).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Summary of main results

 

Effectiveness of antioxidants versus placebo or no treatment

The findings of this review indicate that for subfertile women, the use of supplemental antioxidants is not effective in increasing the rates of live birth. Only two trials with a total of 97 women reported on live birth, and the differences between the trials (heterogeneity) were very high (I2 = 75% with fixed-effect and 75% with random-effects model). We assumed that this was so because each trial enrolled women with different indications for subfertility and administered varying types of antioxidants. The quality of the evidence in this analysis was deemed to be 'very low' ( Summary of findings for the main comparison). As a result of inconsistency between the trials, subgroup analysis was performed by type of antioxidant, indications for subfertility and women who were undergoing IVF or ICSI. No association of an increased live birth rate was noted between antioxidants and placebo or no treatment in any of these subgroups.

Antioxidants were not associated with an increased clinical pregnancy rate when compared with placebo or no treatment; however, the quality of this evidence was assessed to be 'very low' ( Summary of findings for the main comparison). A sensitivity analysis was performed excluding trials with high risk of bias and those using standard treatment as their control; there remained no association of clinical pregnancy rates with antioxidants in the analysis when we removed the trials with a high risk of bias and the trials that used a co-intervention plus a placebo as their control.

In the subgroup 'type of antioxidant', only one group, 'combined antioxidants', showed an association with clinical pregnancy rate; however, only three trials were included in this meta-analysis. No association was seen with N-acetyl-cysteine, melatonin, vitamin E, ascorbic acid, L-arginine or myo-inositol. At most, these subgroups contained only three trials.

In the analysis for the subgroup 'indications for subfertility', an association was seen between antioxidants and clinical pregnancy in women with PCOS; however, heterogeneity here was extremely high. No association was seen between antioxidants and clinical pregnancy rates in women with endometriosis, unexplained subfertility or tubal subfertility or in trials that enrolled women with varying indications.

No association was evident between antioxidants and clinical pregnancy rates in women undergoing IVF or ICSI.

There was no evidence to suggest that antioxidants were associated with miscarriage, multiple pregnancy or ectopic pregnancy when compared with placebo or no treatment/standard treatment. Evidence for miscarriage and multiple pregnancy was considered to be of 'low' quality ( Summary of findings for the main comparison). Meta-analysis was not possible in the area of adverse effects of gastrointestinal disturbances, as one of the two trials that reported this reported no events in the treatment or control groups.

 

Effectiveness of antioxidants versus antioxidants-head to head

Only one trial reported on live birth; therefore, pooling was not possible.

Two trials reported on clinical pregnancy rate; however, pooling could not be performed in the subgroups of 'type of antioxidant' or 'indications for subfertility' as only one trial was included in each group. Antioxidant 'a' was associated with an increased clinical pregnancy rate compared with antioxidant 'b' in women undergoing IVF/ICSI. However, these trials were very small, including only 149 women in total. Moreover, antioxidant 'a' and antioxidant 'b' were different in each trial.

No apparent evidence suggested harm when antioxidant 'a' was compared with antioxidant 'b' in the reported adverse event of miscarriage. However, only two trials (149 women) reported this.

 

Effectiveness of pentoxifylline versus placebo/no treatment

Only one trial reported on live birth; therefore, pooling was not possible. Pentoxifylline was found to be associated with an increased clinical pregnancy rate; however, there were only three trials reporting on this outcome, two reported on pentoxifylline and one reported on pentoxifylline plus vitamin E. No association was found between pentoxifylline and clinical pregnancy rate in women with endometriosis and there was no apparent evidence to suggest that pentoxifylline was associated with miscarriage.

 

Overall completeness and applicability of evidence

Of the 28 trials included in this review, 21 provided data on clinical pregnancy, but only four trials reported on live birth. Miscarriage, harmful events and costs of the included trials generally were not well reported. A total of 15 reported on miscarriage, five reported on multiple pregnancy and two trials discussed gastrointestinal disturbances and ectopic pregnancy. The trials were generally quite small, and heterogeneity between the trials was moderately high overall.

We tried to assess which type of antioxidant might have a beneficial effect on the outcomes of interest in this review; however, only three trials at most could be pooled in this subgroup. Data on the effectiveness of antioxidants for women with different indications for subfertility were limited, as again only a maximum of three trials could be pooled. Within the subgroup of women undergoing IVF/ICSI, we pooled seven trials in the antioxidant versus placebo or no treatment/standard treatment comparison, and the meta-analysis showed no evidence of effects of antioxidants for this group of women.

The indications for subfertility within the trials were representative of the general subfertile population. However, only seven of the included trials were specific to one indication for subfertility (three for PCOS, three for unexplained subfertility and one for tubal subfertility), and when pooling was possible within these indications, we had to take into account that the women were also receiving different types of antioxidants and differing adjunct interventions such as laparoscopic ovarian drilling, timed intercourse or IVF/ICSI; therefore it was difficult to show any benefit or harm from antioxidants for a particular indication of subfertility.

Only two trials, each using different antioxidants, were included in the head-to-head analysis. No conclusions could be reached about benefits or harms in this comparison.

In the pentoxifylline versus placebo/no treatment comparison there was evidence of association with clinical pregnancy; however, as this agent is a medicine and has actions above and beyond the reactive oxygen species-scavenging capabilities of antioxidants it is difficult to say that this result is due to the antioxidant action of the drug.

 

Quality of the evidence

Overall the risk of bias within the evidence (because of methodological limitations) was moderately high (see Figure 2; Figure 3 and Characteristics of included studies). Not all trials described the sequence generation or allocation concealment methods, and most trials randomly assigned only small numbers of women.

The funnel plot for clinical pregnancy (Figure 4) was nearly symmetrical, which suggested that the high number of small studies was not having an overly positive effect on the overall results.

The quality of the evidence according to the summary of findings table ( Summary of findings for the main comparison) ranged from 'very low' to 'low', and heterogeneity in the many of the analyses was quite high; three of the main analyses had low heterogeneity with an I2 of 0%, however; the heterogeneity for the live birth outcome in the antioxidant versus placebo/no treatment comparison was 75% and for clinical pregnancy, for this comparison, the I2 statistic was 55%.

This high risk of bias in the included trials is also described in other antioxidant reviews (Showell 2011; Lu 2012) and seems to be common in this area of complementary medicine.

 

Potential biases in the review process

There may have been some potential for bias in the review process, as there were some changes to the protocol. These included additions and deletions to inclusion/exclusion criteria and to the subgroup analyses. Please see Differences between protocol and review. None of these changes were made as a result of the findings of included studies, but rather they were made to improve the structure of the review.

 

Agreements and disagreements with other studies or reviews

The results of our review were in agreement with those of other published reviews. Sekhon 2010 concluded that, despite numerous advances made in this area, there is a need for further investigation using randomised controlled trials within a larger population to determine efficacy and safety of these supplements. A Cochrane review 'Pentoxifylline versus medical therapies for subfertile women with endometriosis' (Lu 2012) stated that evidence was still insufficient to support the use of pentoxifylline in the management of premenopausal women with endometriosis in terms of subfertility and relief of pain outcomes. Another Cochrane review 'Antioxidants for male subfertility' (Showell 2011) found a small significant effect in favour of antioxidants for pregnancy and live birth and no apparent association with any reported adverse events; however, there were too few similar trials to provide conclusive evidence.

A systematic review (Thomson 2012) looked at vitamin D for PCOS. This review reported, "there is some but limited evidence for the beneficial effects of vitamin D supplementation on menstrual dysfunction" but concluded that "current evidence is limited and additional randomised controlled trials are required."

Another systematic review concentrating on women with PCOS was prepared by Unfer 2012. This review looked specifically at the effects of myo-inositol for PCOS, and the review authors concluded that myo-inositol provided a beneficial effect for PCOS, this was "mainly based on improving insulin sensitivity of target tissues, resulting in a positive effect on the reproductive axis..." The meta-analysis in this review did not reveal an effect of myo-inositol. Only three studies were included for this intervention, and one was a head-to-head trial.

Two Cochrane reviews (Bjelakovic 2008; Bjelakovic 2012;) reported an increased risk of mortality associated with the use of supplemental antioxidants. Bjelakovic 2012 found this association with beta-carotene and possibly vitamin E and vitamin A; however, not with vitamin C or selenium. The review included healthy participants and participants with various stable diseases. The Cochrane review Bjelakovic 2008 reported on the use of antioxidants (beta-carotene, vitamin A, vitamin C and vitamin E) to prevent gastrointestinal cancers and found that there may be an increased risk of mortality for those participants taking these antioxidants. The review authors found that selenium may have preventative effects on gastrointestinal cancers.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

In this review, there was no evidence that taking an antioxidant may provide benefit for subfertile women; however, there did not appear to be any evidence of obvious adverse effects. At this time, there is no evidence to recommend supplemental oral antioxidants for subfertile women.

 
Implications for research

Further appropriately powered and well-designed randomised placebo-controlled trials are needed to assess any evidence for benefits and/or harms of supplemental antioxidants for subfertile women. New trials should state a priori that they are going to report and follow up on the outcomes of live birth, clinical or ongoing pregnancy and adverse events.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

The authors wish to thank the following people for providing valuable information that assisted in the writing of this review:

Dr Mustafa Nazıroğlu for providing information on the trial  Ozkaya 2011;

Aboubakr Elnashar for providing information on the trials Elnashar 2005 and Elnashar 2007;

Dr Rina Agrawal for providing information on the trial Agrawal 2012 and for informing me of her new ongoing trial;

Dr Mohamed Youssef for providing information on the trial Aboulfoutouh 2011 and for informing me that this trial is about to be published;

Dr Gianfranco Carlomagno for providing information on the trial Unfer 2011;

Dr Mariagrazia Stracquadanio for providing information on the trial Ciotta 2011;

Dr Badawy for providing information on the trial Badawy 2006;

Dr Balasch for providing information on the trial Balasch 1997;

Dr Papaleo for providing information on the trial Papaleo 2009;

Dr Lisi for providing information on the trial Lisi 2012;

Dr Battaglia for providing data on the trial Battaglia 2002; and

Dr Eryilmaz for providing information on the trial Eryilmaz 2011

Professor Joanne Barnes

The Cochrane Menstrual Disorders and Subfertility Group.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Antioxidant(s) versus placebo or no treatment/standard treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)297Odds Ratio (M-H, Random, 95% CI)1.25 [0.19, 8.26]

    1.1 Placebo
297Odds Ratio (M-H, Random, 95% CI)1.25 [0.19, 8.26]

 2 Live birth; type of antioxidant2Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    2.1 N-acetyl-cysteine
160Peto Odds Ratio (Peto, Fixed, 95% CI)2.87 [1.05, 7.84]

    2.2 L-arginine
137Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.10, 2.00]

 3 Live birth; indications for subfertility2Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    3.1 Polycystic ovary syndrome
160Peto Odds Ratio (Peto, Fixed, 95% CI)2.87 [1.05, 7.84]

    3.2 Tubal subfertility
137Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.10, 2.00]

 4 Live birth; IVF/ICSI137Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.10, 2.00]

 5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)132441Odds Ratio (M-H, Random, 95% CI)1.30 [0.92, 1.85]

    5.1 Placebo
61763Odds Ratio (M-H, Random, 95% CI)1.34 [0.69, 2.61]

    5.2 No treatment/standard treatment
7678Odds Ratio (M-H, Random, 95% CI)1.37 [0.98, 1.92]

 6 Clinical pregnancy; type of antioxidant13Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    6.1 N-acetyl-cysteine
31014Peto Odds Ratio (Peto, Fixed, 95% CI)1.10 [0.80, 1.53]

    6.2 Combined antioxidants
3369Peto Odds Ratio (Peto, Fixed, 95% CI)1.66 [1.07, 2.58]

    6.3 Melatonin
2145Peto Odds Ratio (Peto, Fixed, 95% CI)1.30 [0.65, 2.60]

    6.4 Vitamin E
1103Peto Odds Ratio (Peto, Fixed, 95% CI)1.42 [0.50, 4.00]

    6.5 Ascorbic acid
1619Peto Odds Ratio (Peto, Fixed, 95% CI)0.75 [0.49, 1.14]

    6.6 L-arginine
137Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.10, 2.00]

    6.7 Myo-inositol plus folic acid
2154Peto Odds Ratio (Peto, Fixed, 95% CI)1.22 [0.60, 2.48]

 7 Clinical pregnancy; indications for subfertility12Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    7.1 Polycystic ovary syndrome
3270Peto Odds Ratio (Peto, Fixed, 95% CI)3.40 [1.84, 6.29]

    7.2 Unexplained
3967Peto Odds Ratio (Peto, Fixed, 95% CI)0.82 [0.59, 1.14]

    7.3 Tubal subfertility
137Peto Odds Ratio (Peto, Fixed, 95% CI)0.45 [0.10, 2.00]

    7.4 Varying indications
51073Peto Odds Ratio (Peto, Fixed, 95% CI)1.14 [0.85, 1.52]

 8 Clinical pregnancy; IVF/ICSI71173Peto Odds Ratio (Peto, Fixed, 95% CI)0.97 [0.74, 1.27]

 9 Adverse events8Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    9.1 Miscarriage
81456Peto Odds Ratio (Peto, Fixed, 95% CI)0.88 [0.57, 1.36]

    9.2 Multiple pregnancy
21022Peto Odds Ratio (Peto, Fixed, 95% CI)0.70 [0.41, 1.21]

    9.3 Gastrointestinal disturbances
193Peto Odds Ratio (Peto, Fixed, 95% CI)2.14 [0.29, 15.99]

    9.4 Ectopic pregnancy
158Peto Odds Ratio (Peto, Fixed, 95% CI)6.91 [0.14, 349.18]

 
Comparison 2. Head to head antioxidants

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments)184Peto Odds Ratio (Peto, Fixed, 95% CI)3.44 [1.27, 9.34]

    1.1 Myo-Inositol versus d-chiro-inositol
184Peto Odds Ratio (Peto, Fixed, 95% CI)3.44 [1.27, 9.34]

 2 Live birth; indications for subfertility1Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    2.1 Polycystic ovary syndrome
184Peto Odds Ratio (Peto, Fixed, 95% CI)3.44 [1.27, 9.34]

 3 Live birth; IVF/ICSI184Peto Odds Ratio (Peto, Fixed, 95% CI)3.44 [1.27, 9.34]

 4 Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments)2Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    4.1 Myo-Inositol versus d-chiro-inositol
184Peto Odds Ratio (Peto, Fixed, 95% CI)3.44 [1.27, 9.34]

    4.2 Myo-inositol plus folic acid plus melatonin versus myo-inositol plus folic acid
165Peto Odds Ratio (Peto, Fixed, 95% CI)1.85 [0.65, 5.25]

 5 Clinical pregnancy; indications for subfertility2Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    5.1 Polycystic ovary syndrome
184Peto Odds Ratio (Peto, Fixed, 95% CI)3.44 [1.27, 9.34]

    5.2 Poor responders
165Peto Odds Ratio (Peto, Fixed, 95% CI)1.85 [0.65, 5.25]

 6 Clinical pregnancy; IVF/ICSI2149Peto Odds Ratio (Peto, Fixed, 95% CI)2.56 [1.24, 5.26]

 7 Adverse events2Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    7.1 Miscarriage
2149Peto Odds Ratio (Peto, Fixed, 95% CI)1.19 [0.35, 4.04]

 
Comparison 3. Pentoxifylline versus placebo or no treatment/standard care

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live birth; pentoxifylline vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

    1.1 No treatment/standard treatment
1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

 2 Live birth; type of antioxidant1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

    2.1 Pentoxifylline plus vitamin E
1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

 3 Live birth; indications for subfertility1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

    3.1 Varying indications
1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

 4 Live birth; IVF/ICSI1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.53 [0.68, 3.44]

 5 Clinical pregnancy; pentoxifylline vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)3276Peto Odds Ratio (Peto, Fixed, 95% CI)2.03 [1.19, 3.44]

    5.1 Placebo
2164Peto Odds Ratio (Peto, Fixed, 95% CI)2.02 [0.95, 4.33]

    5.2 No treatment
1112Peto Odds Ratio (Peto, Fixed, 95% CI)2.03 [0.97, 4.25]

 6 Clinical pregnancy; type of antioxidant3Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    6.1 Pentoxifylline
2164Peto Odds Ratio (Peto, Fixed, 95% CI)2.02 [0.95, 4.33]

    6.2 Pentoxifylline plus vitamin E
1112Peto Odds Ratio (Peto, Fixed, 95% CI)2.03 [0.97, 4.25]

 7 Clinical pregnancy; indications for subfertility3Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    7.1 Endometriosis
2164Peto Odds Ratio (Peto, Fixed, 95% CI)2.02 [0.95, 4.33]

    7.2 Varying indications
1112Peto Odds Ratio (Peto, Fixed, 95% CI)2.03 [0.97, 4.25]

 8 Clinical pregnancy; IVF/ICSI1112Peto Odds Ratio (Peto, Fixed, 95% CI)2.03 [0.97, 4.25]

 9 Adverse events3Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only

    9.1 Miscarriage
3276Peto Odds Ratio (Peto, Fixed, 95% CI)1.37 [0.46, 4.05]

    9.2 Multiple pregnancy
1112Peto Odds Ratio (Peto, Fixed, 95% CI)0.79 [0.20, 3.06]

    9.3 Ectopic pregnancy
1112Peto Odds Ratio (Peto, Fixed, 95% CI)1.97 [0.20, 19.35]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Menstrual Disorders and Subfertility key word search

Inception to 15.04.13

Keywords CONTAINS "antioxidants"or "antioxidant" or "antioxidant levels" or "vitamin" or "vitamin A" or "vitamin B" or "Vitamin-B-12" or "Vitamin-B-12-Therapeutic-Use" or "vitamin B6" or "vitamin C" or "Vitamin D" or "vitamin E" or "vitamins" or "selenium" or "folic acid" or "glutathione" or "Menevit anti-oxidant" or "carnitene" or "carnitine" or "ascorbic acid" or "zinc" or "fatty acids" or "oil" or "fish oils" or "plant extracts" or "tocopherol"or"ubiquinol "or"coenzyme Q10"or "multivitamins"or "N-acetyl cysteine"or "L-acetyl-carnitine"or"acetyl L-carnitine"or "acetylcysteine"or"pentoxifylline"or"alpha tocopherol"or"pycnogenol"or"Myo-inositol"or "inositol"or "melatonin" or Title CONTAINS "antioxidants" or "antioxidant"or"antioxidant levels" or "vitamin" or "vitamin A" or "vitamin B" or "Vitamin-B-12" or "Vitamin-B-12-Therapeutic-Use" or "vitamin B6" or "vitamin C" or "Vitamin D" or "vitamin E" or "vitamins" or "selenium" or "folic acid" or "glutathione" or "Menevit anti-oxidant" or "carnitene" or "carnitine" or "ascorbic acid" or "zinc"or "Myo-inositol"or "inositol"or "melatonin"

AND

Keywords CONTAINS "IVF" or "ICSI" or "in-vitro fertilisation " or "in-vitro fertilisation procedure" or "in vitro fertilization" or "intracytoplasmic sperm injection" or "intracytoplasmic morphologically selected sperm injection" or "superovulation" or "superovulation induction" or "IUI" or "insemination, intrauterine " or "Intrauterine Insemination" or "ART" or "artificial insemination" or "assisted reproduction techniques" or "subfertility-Female" or "Polycystic Ovary Syndrome" or "PCOS" or "endometriosis"or "subfertility" or "unexplained and endometriosis related infertility" or"unexplained infertility" or"unexplained subfertility" or Title CONTAINS"IVF" or "ICSI" or "in-vitro fertilisation " or "in-vitro fertilisation procedure" or "in vitro fertilization" or "intracytoplasmic sperm injection" or "intracytoplasmic morphologically selected sperm injection" or "superovulation" or "superovulation induction" or "IUI" or "insemination, intrauterine " or "Polycystic Ovary Syndrome" or "subfertility"

262 records found

 

Appendix 2. CENTRAL

Inception to 15.04.13

1 exp antioxidants/ or free radical scavengers/ (9281)
2 (antioxidant$ or radical scavengers).tw. (3411)
3 exp vitamins/ or exp ascorbic acid/ or exp dehydroascorbic acid/ or exp vitamin a/ or exp vitamin e/ or exp vitamin u/ or exp alpha-tocopherol/ or exp beta carotene/ or exp beta-tocopherol/ or exp gamma-tocopherol/ (10370)
4 vitamin$.tw. (8540)
5 exp Zinc/ (1038)
6 (zinc or selenium).tw. (2819)
7 exp Selenium/ (385)
8 exp Glutathione Peroxidase/ or exp folic acid/ (2185)
9 (Glutathione$ or folate).tw. (2144)
10 exp Ubiquinone/ (244)
11 (ubiquin$ or folic acid).tw. (1262)
12 coenzyme q10.tw. (225)
13 exp Carnitine/ (409)
14 (carnitine$ or carotenoid$).tw. (1083)
15 (astaxanthin$ or lycopene$).tw. (280)
16 multivitamin$.tw. (449)
17 (betacarotene$ or beta carotene$).tw. (1032)
18 ascorbic acid.tw. (816)
19 n-acetylcysteine.tw. (543)
20 exp Acetylcysteine/ (474)
21 alpha-tocopherol$.tw. (902)
22 exp Pentoxifylline/ (386)
23 Pentoxifylline$.tw. (642)
24 (fish adj2 oil$).tw. (1134)
25 omega$.tw. (1103)
26 exp fatty acids/ or exp fish oils/ or exp cod liver oil/ or exp fatty acids, omega-3/ or exp plant oils/ (14892)
27 fatty acid$.tw. (5704)
28 (plant adj4 oil$).tw. (52)
29 l-arginine$.tw. (853)
30 flavonoid$.tw. (275)
31 riboflavin$.tw. (265)
32 pycnogenol$.tw. (59)
33 lutein$.tw. (1540)
34 lipoic acid$.tw. (154)
35 exp Inositol/ (234)
36 (Inositol or myoinositol).tw. (193)
37 mesoinositol.tw. (0)
38 myo inositol.tw. (65)
39 n acetyl cysteine.tw. (82)
40 d chiro inositol.tw. (15)
41 melatonin.tw. (858)
42 or/1-41 (43448)
43 exp Infertility, Female/ (819)
44 female$ subfertil$.tw. (0)
45 female$ infertilit$.tw. (20)
46 subfertil$ women.tw. (13)
47 infertil$ women.tw. (326)
48 female$ fertility.tw. (3)
49 (in vitro fertilisation or intracytoplasmic sperm injection$).tw. (530)
50 intrauterine insemination$.tw. (399)
51 (ivf or icsi or iui).tw. (2495)
52 in vitro fertilization.tw. (1222)
53 ART.tw. (947)
54 Artificial reproduc$ technique$.tw. (0)
55 or/43-54 (4722)
56 42 and 55 (372)

 

Appendix 3. MEDLINE

Inception to 15.04.13

1 exp antioxidants/ or free radical scavengers/ (330361)
2 (antioxidant$ or radical scavengers).tw. (101777)
3 exp vitamins/ or exp ascorbic acid/ or exp dehydroascorbic acid/ or exp vitamin a/ or exp vitamin e/ or exp vitamin u/ or exp alpha-tocopherol/ or exp beta carotene/ or exp beta-tocopherol/ or exp gamma-tocopherol/ (264949)
4 vitamin$.tw. (139453)
5 exp Zinc/ (46748)
6 (zinc or selenium).tw. (92277)
7 exp Selenium/ (15844)
8 exp Glutathione Peroxidase/ or exp folic acid/ (41759)
9 (Glutathione$ or folate).tw. (102666)
10 exp Ubiquinone/ (6205)
11 (ubiquin$ or folic acid).tw. (19643)
12 coenzyme q10.tw. (1933)
13 exp Carnitine/ (7634)
14 (carnitine$ or carotenoid$).tw. (22030)
15 (astaxanthin$ or lycopene$).tw. (3855)
16 multivitamin$.tw. (2590)
17 (betacarotene$ or beta carotene$).tw. (8645)
18 ascorbic acid.tw. (22280)
19 n-acetylcysteine.tw. (7320)
20 exp Acetylcysteine/ (9543)
21 alpha-tocopherol$.tw. (11448)
22 exp Pentoxifylline/ (3622)
23 Pentoxifylline$.tw. (3534)
24 (fish adj2 oil$).tw. (7176)
25 omega$.tw. (29276)
26 exp fatty acids/ or exp fish oils/ or exp cod liver oil/ or exp fatty acids, omega-3/ or exp plant oils/ (379560)
27 fatty acid$.tw. (138058)
28 (plant adj4 oil$).tw. (1435)
29 l-arginine$.tw. (28928)
30 flavonoid$.tw. (18313)
31 riboflavin$.tw. (7206)
32 pycnogenol$.tw. (244)
33 lutein$.tw. (31314)
34 lipoic acid$.tw. (2734)
35 exp Inositol/ (20428)
36 (Inositol or myoinositol).tw. (30608)
37 mesoinositol.tw. (35)
38 myo inositol.tw. (4698)
39 n acetyl cysteine.tw. (1956)
40 d chiro inositol.tw. (122)
41 melatonin.tw. (16367)
42 or/1-41 (1239820)
43 exp Infertility, Female/ (22690)
44 female$ subfertil$.tw. (35)
45 female$ infertilit$.tw. (991)
46 subfertil$ women.tw. (198)
47 infertil$ women.tw. (3052)
48 female$ fertility.tw. (1268)
49 (in vitro fertilisation or intracytoplasmic sperm injection$).tw. (5857)
50 intrauterine insemination$.tw. (1711)
51 (ivf or icsi or iui).tw. (18797)
52 in vitro fertilization.tw. (14872)
53 ART.tw. (42946)
54 Artificial reproduc$ technique$.tw. (69)
55 or/43-54 (90627)
56 42 and 55 (4177)
57 randomized controlled trial.pt. (347097)
58 controlled clinical trial.pt. (85769)
59 randomized.ab. (265050)
60 placebo.tw. (147404)
61 clinical trials as topic.sh. (163996)
62 randomly.ab. (192945)
63 trial.ti. (113213)
64 (crossover or cross-over or cross over).tw. (56490)
65 or/57-64 (853363)
66 (animals not (humans and animals)).sh. (3711406)
67 65 not 66 (786854)
68 67 and 56 (463)

 

Appendix 4. EMBASE

Inception to 15.04.13

1 exp antioxidants/ or free radical scavengers/ (103607)
2 (antioxidant$ or radical scavengers).tw. (130000)
3 vitamin$.tw. (166429)
4 exp vitamin/ or exp ascorbic acid/ or exp carotenoid/ or exp tocopherol/ (432169)
5 exp Zinc/ (75273)
6 (zinc or selenium).tw. (106356)
7 exp Selenium/ (26722)
8 exp Glutathione Peroxidase/ or exp folic acid/ (62168)
9 (Glutathione$ or folate).tw. (116792)
10 exp Ubiquinone/ (6514)
11 (ubiquin$ or folic acid).tw. (22527)
12 coenzyme q10.tw. (3023)
13 exp Carnitine/ (10125)
14 (carnitine$ or carotenoid$).tw. (25360)
15 (astaxanthin$ or lycopene$).tw. (4669)
16 multivitamin$.tw. (3250)
17 (betacarotene$ or beta carotene$).tw. (11613)
18 ascorbic acid.tw. (25154)
19 n-acetylcysteine.tw. (8893)
20 exp acetylcysteine/ (22243)
21 n-acetyl-cysteine.tw. (2448)
22 alpha-tocopherol$.tw. (13936)
23 exp Pentoxifylline/ (10809)
24 Pentoxifylline$.tw. (4357)
25 (fish adj2 oil$).tw. (8913)
26 omega$.tw. (14166)
27 fatty acid$.tw. (154677)
28 exp edible oil/ or exp castor oil/ or exp cod liver oil/ or exp fish oil/ or exp lyprinol/ or exp olive oil/ or exp safflower oil/ or exp fatty acid/ or exp essential fatty acid/ or exp arachidonic acid/ or exp linoleic acid/ or exp linolenic acid/ or exp gamma linolenic acid/ or exp unsaturated fatty acid/ or exp omega 3 fatty acid/ or exp omega 6 fatty acid/ or exp polyunsaturated fatty acid/ (425301)
29 (plant adj4 oil$).tw. (2056)
30 l-arginine$.tw. (32378)
31 flavonoid$.tw. (26182)
32 riboflavin$.tw. (7713)
33 pycnogenol$.tw. (352)
34 lipoic acid$.tw. (3265)
35 exp inositol/ (8444)
36 (Inositol or myoinositol).tw. (34393)
37 mesoinositol.tw. (36)
38 myo inositol.tw. (5416)
39 melatonin.tw. (19303)
40 d chiro inositol.tw. (142)
41 or/1-40 (1344153)
42 exp Infertility, Female/ (34044)
43 (female$ adj2 subfertil$).tw. (94)
44 (female$ adj2 infertilit$).tw. (1554)
45 (subfertil$ adj2 women).tw. (348)
46 (infertil$ adj2 women).tw. (5126)
47 (female$ adj2 fertility).tw. (2010)
48 (vitro fertilisation or intracytoplasmic sperm injection$).tw. (7363)
49 (intrauterine adj3 insemination$).tw. (2295)
50 (ivf or icsi or iui).tw. (26704)
51 vitro fertilization.tw. (17633)
52 Artificial reproduc$ technique$.tw. (117)
53 exp artificial insemination/ or exp fertilization in vitro/ or exp intracytoplasmic sperm injection/ or exp intrauterine insemination/ (52724)
54 exp Superovulation/ (2032)
55 Superovulation.tw. (1744)
56 or/42-55 (91018)
57 Clinical Trial/ (876796)
58 Randomized Controlled Trial/ (340260)
59 exp randomization/ (61167)
60 Single Blind Procedure/ (17227)
61 Double Blind Procedure/ (114019)
62 Crossover Procedure/ (36637)
63 Placebo/ (216063)
64 Randomi?ed controlled trial$.tw. (85514)
65 Rct.tw. (11229)
66 random allocation.tw. (1227)
67 randomly allocated.tw. (18541)
68 allocated randomly.tw. (1874)
69 (allocated adj2 random).tw. (717)
70 Single blind$.tw. (13168)
71 Double blind$.tw. (135429)
72 ((treble or triple) adj blind$).tw. (310)
73 placebo$.tw. (187097)
74 prospective study/ (230049)
75 or/57-74 (1319736)
76 case study/ (19249)
77 case report.tw. (241847)
78 abstract report/ or letter/ (864231)
79 or/76-78 (1120296)
80 75 not 79 (1283559)
81 41 and 56 and 80 (785)

 

Appendix 5. CINAHL

Inception to 2010 OVID Platform

1 exp antioxidants/ or free radical scavengers/(3884)
2 (antioxidant$ or radical scavengers).tw.(2881)
3 exp vitamins/ or exp ascorbic acid/ or exp dehydroascorbic acid/ or exp vitamin a/ or exp vitamin e/ or exp vitamin u/ or exp alpha-tocopherol/ or exp beta carotene/ or exp beta-tocopherol/ or exp gamma-tocopherol/(12571)
4 vitamin$.tw.(7275)
5 exp Zinc/(1145)
6 (zinc or selenium).tw.(1670)
7 exp Selenium/(584)
8 exp Glutathione Peroxidase/ or exp folic acid/(2519)
9 (Glutathione$ or folate).tw.(1901)
10 exp Ubiquinone/(360)
11 (ubiquin$ or folic acid).tw.(1043)
12 coenzyme q10.tw.(164)
13 exp Carnitine/(294)
14 (carnitine$ or carotenoid$).tw.(641)
15 (astaxanthin$ or lycopene$).tw.(237)
16 exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ or exp Insemination, Artificial, Homologous/(1013)
17 (in vitro fertilisation or intracytoplasmic sperm injection$).tw.(162)
18 (intrauterine adj3 insemination$).tw.((46)
19 (ivf or icsi or iui).tw.(360)
20 in-vitro fertilisation.tw.(99)
21 in vitro fertilization.tw.(306)
22 ART.tw.(5953)
23 Artificial reproduc$ technique$.tw.(1)
24 or/1-15(20136)
25 or/16-23(7140)
26 24 and 25(38)
27 exp clinical trials/(66862)
28 Clinical trial.pt.(35432)
29 (clinic$ adj trial$1).tw.*(15232)
30 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$3 or mask$3)).tw.(8971)
31 Randomi?ed control$ trial$.tw.(12969)
32 Random assignment/(19621)
33 Random$ allocat$.tw.(1370)
34 Placebo$.tw.(12376)
35 Placebos/(4758)
36 Quantitative studies/(4326)
37 Allocat$ random$.tw.(78)
38 or/27-37(91904)
39 38 and 26(8)

40 from 39 keep 1-8 (8)

CINAHL EBSCO Platform search 27.09.10 to 15.04.13


# Query Results

S18S7 and S17(205)

S17S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16(7142)

S16TX timed intercourse(13)

S15TX IUI(52)

S14""intrauterine insemination"" or (MM "Insemination, Artificial")(419)

S13TX intracytoplasmic sperm injection*(197)

S12TX icsi(186)

S11(MM "Fertilization in Vitro") OR "ivf"(1443)

S10TX Infertil*(5861)

S9TX subfertil*(342)

S8(MM "Infertility")(2886)

S7S1 or S2 or S3 or S4 or S5 or S6(57291)

S6TX fatty acid*(12539)

S5(MH "Fatty Acids, Omega 3") OR (MH "Fatty Acids, Unsaturated+")(12971)

S4TX vitamin*(26133)

S3(MH "Vitamins+")(25710)

S2TX antioxidant*(12063)

S1(MH "Antioxidants+")(9509)



 

 

Appendix 6. PSYCINFO

Inception to 15.04.13

1 exp Antioxidants/ (1289)
2 (antioxidant$ or radical scavengers).tw. (2536)
3 exp Vitamins/ (2994)
4 vitamin$.tw. (4313)
5 exp Zinc/ (472)
6 (zinc or selenium).tw. (1360)
7 (Glutathione$ or folate).tw. (1988)
8 (ubiquin$ or folic acid).tw. (508)
9 coenzyme q10.tw. (101)
10 (carnitine$ or carotenoid$).tw. (439)
11 multivitamin$.tw. (148)
12 (betacarotene$ or beta carotene$).tw. (45)
13 ascorbic acid.tw. (330)
14 n-acetylcysteine.tw. (141)
15 alpha-tocopherol$.tw. (58)
16 Pentoxifylline$.tw. (53)
17 (fish adj2 oil$).tw. (138)
18 omega$.tw. (909)
19 exp Fatty Acids/ (2614)
20 fatty acid$.tw. (2322)
21 l-arginine$.tw. (754)
22 or/1-21 (15067)
23 exp Infertility/ (1531)
24 female$ subfertil$.tw. (2)
25 female$ infertilit$.tw. (40)
26 subfertil$ women.tw. (2)
27 infertil$ women.tw. (187)
28 female$ fertility.tw. (95)
29 (vitro fertilisation or intracytoplasmic sperm injection$).tw. (92)
30 intrauterine insemination$.tw. (13)
31 (ivf or icsi or iui).tw. (353)
32 vitro fertilization.tw. (435)
33 Artificial reproduc$ technique$.tw. (6)
34 or/23-33 (2032)
35 22 and 34 (12)

 

Appendix 7. AMED

Inception to 15.04.13

1 exp Antioxidants/ or exp Free radicals/ (1454)
2 (antioxidant$ or radical scavengers).tw. (2082)
3 exp Vitamins/ or exp Dietary supplements/ (2999)
4 exp Ascorbic acid/ (252)
5 vitamin$.tw. (2113)
6 exp Zinc/ (100)
7 (zinc or selenium).tw. (421)
8 (Glutathione$ or folate).tw. (638)
9 exp Selenium/ (88)
10 (ubiquin$ or folic acid).tw. (149)
11 coenzyme q10.tw. (73)
12 exp Carnitine/ (16)
13 (carnitine$ or carotenoid$).tw. (171)
14 multivitamin$.tw. (54)
15 ascorbic acid.tw. (410)
16 n-acetylcysteine.tw. (26)
17 Acetylcysteine.tw. (27)
18 alpha-tocopherol$.tw. (80)
19 Pentoxifylline$.tw. (10)
20 (fish adj2 oil$).tw. (154)
21 omega$.tw. (211)
22 exp Fatty acids/ (432)
23 exp Fish oils/ (86)
24 fatty acid$.tw. (661)
25 (plant adj4 oil$).tw. (782)
26 l-arginine$.tw. (109)
27 flavonoid$.tw. (1049)
28 riboflavin$.tw. (20)
29 (Inositol or myoinositol).tw. (45)
30 pycnogenol$.tw. (16)
31 or/1-30 (7934)
32 exp Infertility female/ (150)
33 female$ subfertil$.tw. (0)
34 female$ infertilit$.tw. (18)
35 subfertil$ women.tw. (0)
36 infertil$ women.tw. (13)
37 female$ fertility.tw. (6)
38 (vitro fertilisation or intracytoplasmic sperm injection$).tw. (19)
39 intrauterine insemination$.tw. (5)
40 (ivf or icsi or iui).tw. (31)
41 in vitro fertilization.tw. (15)
42 Artificial reproduc$ technique$.tw. (0)
43 or/32-42 (186)
44 31 and 43 (4)

 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 2, 2009
Review first published: Issue 8, 2013


DateEventDescription

22 April 2008AmendedConverted to new review format.

9 August 2007New citation required and major changesSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Marian Showell conducted the searches, assessed studies for inclusion, extracted data, analysed the data and wrote the review.

Julie Brown assisted with assessing the trials for inclusion, extracted the data, assisted with the data analysis and helped with writing of the review.

Jane Clarke initiated and conceptualised the review, extracted the initial pool of data and wrote the first draft of the review.

Roger Hart helped with the writing of the review and provided clinical advice.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known. This review was not funded by any organisation.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • NZ GOVT MOH, New Zealand.

 

External sources

  • None, Not specified.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Two of the five protocol authors (Agarwal A, Gupta S) withdrew from involvement in the review.

The secondary outcome of stillbirth rate per woman has been removed.

The exclusion criterion 'Trials that exclusively reported on women who have previously had chemotherapy' has been removed as not clinically relevant to this review.

The inclusion criteria for participants were expanded to include women undergoing ART. Exclusion criteria now include trials that enrol exclusively fertile women attending a fertility clinic because of male partner infertility.

Exclusion criteria for interventions now include antioxidants versus fertility drugs alone as controls, as they are themselves active agents. They might include metformin or clomiphene citrate.

The review includes a subgroup analysis based on the type of subfertility problem, including women with PCOS, endometriosis, poor responders and tubal and unexplained subfertility, as well as a subgroup of women who are undergoing IVF or ICSI.

A separate comparison for pentoxifylline was created as there was a concern that this medicine does not have purely antioxidant capabilities.

The search strategy has been updated.

A Summary of findings table has been added.

Where we had data from multi-armed trials, the intervention arms were pooled versus the control arm. This differs from the protocol, where we said that we would divide the intervention arms. This was done with the advice of a statistician.

A decision was made with clinical advice that trials using folic acid (< 1 mg) as a control would be treated as assessing standard treatment and would be included in the 'no treatment' subgroup.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
Aboulfoutouh 2011 {published data only}
  • Aboulfoutouh I, Youssef M, Khattab S. Can antioxidants supplementation improve ICSI/IVF outcomes in women undergoing IVF/ICSI treatment cycles? Randomised controlled study. Fertility and Sterility 2011; Vol. 96, issue Suppl 3:S242-9.
Agrawal 2012 {published data only}
  • Agrawal R, Burt E, Gallagher AM, Butler L, Venkatakrishnan R, Peitsidis P. Prospective randomized trial of multiple micronutrients in subfertile women undergoing ovulation induction: a pilot study. Reproductive Biomedicine Online 2012;24(1):54-60.
Alborzi 2007 {published data only}
  • Alborzi S, Ghotbi S, Parsanezhad ME, Dehbashi S, Alborzi S, Alborzi M. Pentoxifylline therapy after laparoscopic surgery for different stages of endometriosis: a prospective, double-blind, randomized, placebo-controlled study. Journal of Minimally Invasive Gynecology 2007;14(1):54-8.
Aleyasin 2009 {published data only}
  • Aleyasin A, Aghahosseini M, Mohseni M, Mahavi A. Effects of pentoxifylline and vitamin E on pregnancy rate in infertile women by ZIFT: a randomized clinical trial. Iranian Journal of Reproductive Medicine 2009;7:175-9.
Badawy 2006 {published data only}
  • Badawy A, El Nashar AB, El Totongy M. Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial. Fertility and Sterility 2006;86(3):647-50.
Balasch 1997 {published data only}
  • Balasch J, Creus M, Fabregues F, Carmona F, Martinez-Roman S, Manau D, et al. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis. Human Reproduction 1997;12(9):2046-50.
Batioglu 2012 {published data only}
  • Batioglu AS, Sahin U, Gurlek B, Ozturk N, Unsal E. The efficacy of melatonin administration on oocyte quality. Gynecological Endocrinology 2012; Vol. 28, issue 2:91-3.
Battaglia 2002 {published data only}
  • Battaglia C, Regani G, Marsella T, Facchinetti F, Volpe A, Venturoli S. Adjuvant L-arginine treatment in controlled ovarian hyperstimulation: a double-blind randomized study. Human Reproduction 2002;17(3):659-65.
Cicek 2012 {published data only}
  • Cicek N, Eryilmaz OG, Sarikaya E, Gulerman C, Genc Y. Vitamin E: effect on controlled ovarian stimulation of unexplained infertile women. Journal of Assisted Reproduction and Genetics 2012; Vol. 29, issue 4:325-8.
Ciotta 2011 {published data only}
  • Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of myo-inositol supplementation on oocyte's quality in PCOS patients: a double blind trial. European Review for Medical & Pharmacological Sciences 2011;15(5):509-14.
Creus 2008 {published data only}
  • Creus M, Fabregues F, Carmona F, Del Pino M, Manau D, Balasch J. Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility: a preliminary trial. Human Reproduction 2008;23:1910-6.
Eryilmaz 2011 {published data only}
  • Eryilmaz OG, Devran A, Sarikaya E, Aksakal FN, Mollamahmutoglu L, Cicek N. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. Journal of Assisted Reproduction & Genetics 2011; Vol. 28, issue 9:815-20.
Firouzabadi 2012 {published data only}
  • Firouzabadi RD, Aflatoonian A, Modarresi S, Sekhavat L, Mohammad Taheri S. Therapeutic effects of calcium & vitamin D supplementation in women with PCOS. Complementary Therapies in Clinical Practice 2012;18(2):85-8.
Gerli 2007 {published data only}
  • Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial.. European Review for Medical & Pharmacological Sciences 2003;7(6):151-9.
  • Gerli S, Papaleo E, Ferrari A, Di Renzo G. Randomized, double blind placebo-controlled trial: effects of Myo-inositol on ovarian function and metabolic factors in women with PCOS. Eurpoean Review for Medical and Pharmacolgical Sciences 2007;11:347-54.
Griesinger 2002 {published data only}
  • Griesinger G, Franke K, Kinast C, Kutzelnigg A, Riedinger S, Kulin S, et al. Ascorbic acid supplement during luteal phase in IVF. Journal of Assisted Reproduction and Genetics 2002;19(4):164-8.
Kim 2006 {unpublished data only}
  • Kim C, Lee S, Koo Y, Lee H, Lee Y, Jeon I, et al. N-acetyl-cysteine treatment improves insulin sensitivity, ovarian response to gonadotrophin and IVF outcome in patients with polycystic ovary syndrome. ESHRE Conference Proceedings. 18-21 June 2006; Vol. I:178.
Kim 2010 {published data only}
  • Kim CH, Yoon JW, Ahn JW, Kang HJ, Lee JW, Kang BM. The effect of supplementation with omega-3-polyunsaturated fatty acids in intracytoplasmic sperm injection cycles for infertile patients with a history of unexplained total fertilization failure.. Fertility and Sterility 2010;94(4):S242. Abstract no P-518.
Lisi 2012 {published data only}
  • Lisi F, Carfagna P, Oliva MM, Rago R, Lisi R, Poverini R, et al. Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study. Reproductive Biology and Endocrinology 2012; Vol. 10, Article no: 52.
Mier-Cabrera 2008 {published data only}
  • Mier-Cabrera J, Geenera-Garcia M, De la Jara-Diaz, Perichart-Perera Otilla, Vadillo-Ortega F, Hernandez-Guerrero C. Effect of vitamins C and E supplementation on peripheral oxidative stress markers and pregnancy rate in women with endometriosis. International Journal of Gynecology and Obstetrics 2008;100:252-6.
Nasr 2010 {published and unpublished data}
  • Nasr A. Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study. Reproductive BioMedicine Online 2010;20:403-9.
Ozkaya 2011 {published data only}
  • Ozkaya MO, NazIroglu M, Barak C, Berkkanoglu M. Effects of multivitamin/mineral supplementation on trace element levels in serum and follicular fluid of women undergoing in vitro fertilization (IVF). Biological Trace Element Research 2011; Vol. 139, issue 1:1-9.
  • Ozkaya MO, Nazrolu M. Multivitamin and mineral supplementation modulates oxidative stress and antioxidant vitamin levels in serum and follicular fluid of women undergoing in vitro fertilization. Fertility and Sterility 2010;94(6):2465-6.
Papaleo 2009 {published data only}
  • Papaleo E, Unfer V, Baillargeon J, Fusi F, Occhi F, De Santis L. Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles: a prospective, controlled, randomized trial. Fertility and Sterility 2009;91(5):1750-4.
Rashidi 2009 {published data only}
  • Rashidi B, Haghollahia F, Shariata M, Zayeriia F. The effects of calcium-vitamin D and metformin on polycystic ovary syndrome: a pilot study. Taiwanese Journal of Obstetrics and Gynecology 2009;48(2):142-7.
Rizk 2005 {published data only}
  • Rizk A, Bedaiwy M, Al-Inany H. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate–resistant patients with polycystic ovary syndrome. Fertility and Sterility 2005;83(2):367-70.
Rizzo 2010 {published data only}
  • Rizzo P, Raffone E, Benedetto V. Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles: a prospective, clinical trial. European Review for Medical & Pharmacological Sciences 2010;14(6):555-61.
Salehpour 2009 {published data only}
  • Salehpour S, Tohidi M, Akhound M, Amirzargar N. N acetyl cysteine, a novel remedy for polycystic ovary syndrome. International Journal of Fertility and Sterility 2009;3(2):66-73.
Unfer 2011 {published data only}
  • Unfer V, Carlomagno G, Rizzo P, Raffone E, Roseff S. Myo-inositol rather than D-chiro-inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles: a prospective, controlled, randomized trial. European Review for Medical and Pharmacological Sciences 2011;15/4:452-7.
Westphal 2006 {published data only}
  • Westphal LM, Polan ML, Trant AS. Double-blind, placebo-controlled study of Fertilityblend: a nutritional supplement for improving fertility in women. Clinical and Experimental Obstetrics & Gynecology 2006;33(4):205-8.
  • Westphal LM, Polan ML, Trant AS, Mooney SB. A nutritional supplement for improving fertility in women: a pilot study. The Journal of Reproductive Medicine 2004;49(4):289-93.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
Aksoy 2010 {published data only}
  • Aksoy AN, Kadanali S. Evaluating the effects of vitamin E addition to clomiphene citrate on endometrial receptivity: a prospective controlled study.. Turkiye Klinikleri Jinekoloji Obstetrik 2010;20(2):71-6.
Al-Omari 2003 {published data only}
  • Al-Omari W, Abdul-Qadder A, Sulaiman W, Taher M. Antioxidants improve metabolic and ovarian response in polycsytic ovary syndrome. ESHRE. 2003; Vol. xviii:84.
Ardabili 2012 {published data only}
  • Ardabili HR, Gargari BP, Farzadi L. Vitamin D supplementation has no effect on insulin resistance assessment in women with polycystic ovary syndrome and vitamin D deficiency. Nutrition Research 2012;32(3):195-201.
Baillargeon 2004 {published data only}
  • Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Apridonidze T, He N, Nestler JE. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism 2004; Vol. 89, issue 1:242-9.
Bonakdaran 2012 {published data only}
  • Bonakdaran S, Khorasani ZM, Davachi B, Shakeri MT. Comparison of calcitriol and metformin effects on clinical and metabolic consequences of polycystic ovary syndrome. Iranina Journal of Obstetrics Gynecology and Infertility 2012;14(8):16-24.
Cheang 2008 {published data only}
  • Cheang KI, Baillargeon J-P, Essah PA, Ostlund Jr RE, Apridonize T, Islam L, et al. Insulin-stimulated release of d-chiro-inositol-containing inositol phosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism: Clinical and Experimental 2008; Vol. 57, issue 10:1390-7.
Ciotta 2012 {published data only}
  • Ciotta L, Stracquadanio M, Pagano I, Formuso C, Di Leo S, Cianci A. D-Chiro-Inositol treatment in patients with polycystic ovary syndrome. Giornale Italiano di Ostetricia e Ginecologia 2012;34(1):145-8.
Costantino 2009 {published data only}
  • Costantino D, Minozzi G, Minozzi F, Guaraldi C. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial.. European Review for Medical and Pharmacological Sciences 2009;13(2):105-10.
Crha 2003 {published data only}
  • Crha I, Hruba D, Ventruba P, Fiala J, Totusek J, Visnova H. Ascorbic acid and infertility treatment. Central European Journal of Public Health 2003;11(2):63-7.
Elgindy 2008 {published data only}
  • Elgindy EA, El-Huseiny AM, Mostafa MI, Gaballah AM, Ahmed TA. N-acetyl cysteine: could be an effective adjuvant therapy in ICSI cycles. ASRM. September 2008; Vol. 90:suppl 1.
Elgindy 2010 {published data only}
  • Elgindy EA, El-Huseiny AM, Mostafa MI, Gaballah AM, Ahmed TA. N-acetyl cysteine: could it be an effective adjuvant therapy in ICSI cycles? A preliminary study. Reproductive Biomedicine Online. 2010;20(6):789-96.
Elnashar 2005 {published data only}
  • Elnashar A, Fahmy M, Mansour A, Ibrahim K. N-acetyl cysteine versus metformin in treatment of clomiphene citrate–resistant polycystic ovarysyndrome: a randomized study. 12th Annual Meeting of the Middle East Fertility Society. 2005; Vol. 10 Suppl 1.
  • Elnashar A, Fahmy M, Mansour A, Ibrahim K. N-acetyl cysteine vs. metformin in treatment of clomiphene citrate–resistant polycystic ovarysyndrome: a prospective randomized controlled study. Fertility and Sterility 2007;88(2):407-11.
Elnashar 2007 {published data only}
  • Elnashar A. Fahmy M. Mansour A. Ibrahim K. N-acetyl cysteine vs. metformin in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective randomized controlled study. Fertility and Sterility 2007;88(2):406-9.
Farzadi 2006 {published data only}
  • Farzadi L, Salman Zadeh S. Metformin-therapy effects in 50 clomiphene citrate resistant PCOS patients. Journal of Medical Sciences 2006;6(5):765-71.
Genazzani 2008 {published data only}
  • Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecological Endocrinology 2008;24(3):139-44.
Hashim 2010 {published data only}
  • Hashim HA, Anwar K, El-Fatah RA. N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial. Journal of Women's Health 2010;19(11):2043-8.
Henmi 2003 {published data only}
  • Henmi H, Endo T, Kitajima Y, Manase K, Hata H, Kudo R. Effects of ascorbic acid supplementation on serum progesterone levels in patients with a luteal phase defect. Fertility & Sterility 2003;80(2):459-61.
Hernndez-Yero 2012 {published data only}
  • Hernndez-Yero A, Santana Perez F, Ovies Carballo G, Cabrera-Rode E. Diamel therapy in polycystic ovary syndrome reduces hyperinsulinaemia, insulin resistance, and hyperandrogenaemia. International Journal of Endocrinology 2012; Vol. Article No: 382719.
Iuorno 2002 {published data only}
  • Iuorno MJ, Jakubowicz DJ, Baillargeon JP, Dillon P, Gunn RD, Allan G, et al. Effects of d-chiro-inositol in lean women with the polycystic ovary syndrome. Endocrine Practice 2002;8(6):417-23.
Kamencic 2008 {published data only}
  • Kamencic H, Thiel JA. Pentoxifylline after conservative surgery for endometriosis: a randomized, controlled trial. Journal of Minimally Invasive Gynecology 2008;15(1):62-6.
Kilicdag 2005 {published data only}
  • Kilicdag EB, Bagis T, Tarim E, Aslan E, Erkanli S, Simsek E, et al. Administration of B-group vitamins reduces circulating homocysteine in polycystic ovarian syndrome patients treated with metformin: a randomized trial. Human Reproduction 2005; Vol. 20, issue 6:1521-8.
Le Donne 2012 {published data only}
  • Le Donne M, Alibrandi A, Giarrusso R, Lo Monaco I, Muraca U. Diet, metformin and inositol in overweight and obese women with polycystic ovary syndrome: effects on body composition. Minerva Ginecologica 2012;64(1):23-9.
Moosavifar 2010 {published data only}
  • Moosavifar N, Mohammadpour AH, Jallali M, Karimiz G, Saberi H. Evaluation of effect of silymarin on granulosa cell apoptosis and follicular development in patients undergoing in vitro fertilization. Eastern Mediterranean Health Journal 2010;16(6):642-5.
Nazzaro 2011 {published data only}
  • Nazzaro A, Salerno A, Marino S, Granato C, Pastore E. The addition of melatonin to myo-inositol plus folic acid improves oocyte quality and pregnancy outcome in IVF cycle: a prospective clinical trial. Human Reproduction 2011;26:i227-8.
Nestler 1999 {published data only}
  • Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. New England Journal of Medicine 1999; Vol. 340, issue 17:1314-20.
Nestler 2001 {published data only}
  • Nestler J, Gunn R, Bates S, Gregory J, Jacobson W, Rogol A. D-chiro-inositol (INS-1) enhances ovulatory rate in hyperandrogenemic, oligomenorrheic women with the polycystic ovary syndrome. Fertility & Sterility 2001; Vol. 76, issue 3 Suppl 1:S110-1.
Nichols 2010 {published data only}
  • Nichols J. A randomised controlled trail to compare conception rates for preconceptional folic acid 400 mg daily versus Pregnacare Plus in assisted conception. World Health Organization International Clinical Trials Registry Platform 2010. [: ISRCTN23488518]
Nordio 2012 {published data only}
  • Nordio M, Proietti E. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. European Review for Medical & Pharmacological Sciences 2012;16(5):575-81.
Oner 2011 {published data only}
  • Oner G, Muderris II. Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome. European Journal of Obstetrics & Gynecology and Reproductive Biology 2011;159(1):127-31.
Papaleo 2007 {published data only}
  • Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C, et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecological Endocrinology 2007;23(12):700-3.
Papaleo 2008 {published data only}
  • Papaleo E, De Santis, Baillargeon JP, Zacchè M, Fusi FM, Brigante C, et al. Comparison of myo-inositol plus folic acid vs clomiphene citrate for first-line treatment in women with polycystic ovary syndrome. Human Reproduction ESHRE 24th Annual Meeting, Barcelona, 6-9 July 2008. 2008; Vol. 23 Suppl 1 Abstract No: O-251 Oral.
Raffone 2010 {published data only}
  • Raffone E, Rizzo P, Benedetto V. Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women. Gynecological Endocrinology 2010;26(4):275-80.
Rezk 2004 {published and unpublished data}
  • Rezk A, Bedaiwy M, El Enany H. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate–resistant patients with polycystic ovary syndrome. Abstracts of the 20th Annual Meeting of the ESHRE, June 27-30. 2004.
Santanam 2003 {published data only}
  • Santanam N, Kavtaradze N, Dominguez C, Rock J, Partasarathy S, Murphy A. Antioxidant supplementation reduces total chemokines and inflammatory cytokines in women with endometriosis. Fertility & Sterility 2003; Vol. 80, issue Suppl 3:S32-3. Abstract no: O-85.
Tamura 2008 {published data only}
Thiel 2006 {published data only}
  • Thiel JA, Kamencic H. Pentoxifylline (trental) after conservative surgery for endometriosis: a randomized control trial [abstract]. Journal of Minimally Invasive Gynecology 2006;(13 Suppl 5):S10.
Twigt 2011 {published data only}
  • Twigt JM, Hammiche F, Sinclair KD, Beckers NG, Visser JA, Lindemans J, et al. Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation. Journal of Clinical Endocrinology and Metabolism 2011;96(2):E322-9.
Vargas 2011 {published data only}
  • Vargas ML, Almario RU, Buchan W, Kim K, Karakas SE. Metabolic and endocrine effects of long-chain versus essential omega-3 polyunsaturated fatty acids in polycystic ovary syndrome. Metabolism 2011;60(12):1711-8.
Yoon 2010 {published and unpublished data}
  • Yoon JW, Kim CH, Ahn JW, Kang HJ, Song BM. Effect of omega-3-polyunsaturated fatty acids and metformin on ovarian morphology and intraovarian blood flow in patients with polycystic ovary syndrome. Fertility & Sterility. 2010; Vol. 94/4 Abstract no. P-346:S194. [ISSN: 0015-0282]

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
Beigi 2012 {published data only}
  • Beigi RM, Afkhamzadeh A, Daneshpour NS. The effect of calcium-vitamin D in efficacy of induction ovulation in infertile women with polycystic ovary syndrome. Iranian Journal of Obstetrics Gynecology and Infertility 2012; Vol. 15, issue 14:7-13.
Carlomagno 2012 {published data only}
  • Carlomagno G, Montanino Oliva M, Roseff SJ, Unfer V. Myo-inositol: ovarian stimulation and IVF outcomes. Fertility and Sterility 2012; Vol. (98 Suppl 1):S74-5. Abstract no O-251.
Choi 2012 {published data only}
  • Choi S-Y, Kim CH, Ahn J-W, Kwon S-K, Lee K-H, Kang B-M. Effect of calcium and vitamin D supplementation on follicular fluid tumor necrosis-alpha and interleukin-6 and IVF/ICSI outcomes in infertile patients with polycystic ovary syndrome. Fertility and Sterility 2012; Vol. (98 Suppl 1):S208-9. Abstract no P-326.
Rosalbino 2012 {published data only}
  • Rosalbino I, Raffone E. Does ovary need D-chiro-inositol?. Journal of Ovarian Research 2012; Vol. 5, issue 1:14.
Salehpour 2012 {published data only}
  • Salehpour S, Sene AA, Saharkhiz N, Sohrabi MR, Moghimian F. N-acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. Journal of Obstetrics and Gynaecology Research 2012; Vol. 38, issue 9:1182-6.
Salem 2012 {published data only}
  • Salem HT, Ismail A. L-carnitin as a treatment in clomiphene resistant PCO for improving quality of ovulation and pregnancy outcome; a novel treatment. Human Reproduction 2012; Vol. 27 Suppl 2:ii302-ii337. Abstract no P-529.
Schachter 2007 {published data only}
  • Schachter M, Raziel A, Strassburger D, Rotem C, Ron-El R, Friedler S. Prospective, randomized trial of metformin and vitamins for the reduction of plasma homocysteine in insulin-resistant polycystic ovary syndrome. Fertility & Sterility. 2007; Vol. 88, issue 1:227-30.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
Agrawal 2012a {published data only}
  • Unknown.. Ongoing study 2011..
Bentov 2010 {published data only}
  • Bentov YH. The effect of co-enzyme Q10 together with fertility drugs on pregnancy outcome of in vitro fertilization. ClinicalTrials.gov.
Lindqvist 2009 {unpublished data only}
  • Lindqvist P. Vitamin D during in vitro fertilisation (IVF) - a prospective randomised trial (delivery). ClinicalTrials.gov - http://clinicaltrials.gov/show/NCT01019785. [ClinicalTrials.gov : NCT01019785]
Mahdian 2012 {unpublished data only}
  • Mahdian A. Impacts of calcium-vitamin D supplementary on ovulation in polycystic ovary syndrome. IRCT.
Mane 2012 {unpublished data only}
  • Mane Y. Nutritional supplement for women with polycystic ovary syndrome or subfertility. CTRI.
Mohammadbeigi 2011 {unpublished data only}
  • Mohammadbeigi R. Effect of calcium-vitamin D in efficacy of induction-ovulation in infertile women with polycystic ovary syndrome. International Clinical Trials Registry Platform Search Portal. [IRCT: IRCT201105096426N1]
Ortega 2013 {published data only}
  • Ortega I. Effect of Resveratol on metabolic parameters and oocyte quality in PCOS patients (RES-IVF). ClinicalTrials.gov.
Pasha 2011 {unpublished data only}
  • Pasha NG. Assessment the effect of Ca-vitamin D and metformin on PCOS. International Clinical Trials Registry Platform Search Portal. [IRCT: IRCT201009131760N9]
Pourghassem 2010 {unpublished data only}
  • Pourghassem B. Effect of vitamin D3 supplementation on polycystic ovarian syndrome. International Register of Clinical Trials. http://www.irct.ir/searchresult.php?id=3140&number=2.
Unfer 2010 {unpublished data only}
  • Unfer V. Improving oocyte retrieval using a combined therapy of recombinant follicle stimulating hormone (rFSH) and inositol and melatonin. Clinicaltrials.gov. [: NCT01267604]
Unfer 2011a {published data only}
  • Unfer V. Role of myo-inositol and D-chiro-inositol on oocyte quality. ClinicalTrials.gov.
Youssef 2011 {unpublished data only}
  • Youssef M. Can antioxidants supplementation improve ICSI/IVF outcomes in women undergoing IVF/ICSI treatment cycles? Randomised controlled study. International Clinical Trials Registry Platform Search Portal (ICTRP). [NTR: NTR2816]

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. References to ongoing studies
  23. Additional references
Badawy 2007
Battaglia 1999
  • Battaglia C, Salvatori M, Maxia N, Petraglia F, Facchinetti F, Volpe A. Adjuvant L-arginine treatment for in-vitro fertilization in poor responder patients.. Human Reproduction 1999;14(7):1690-7.
Bjelakovic 2008
  • Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD004183.pub3]
Bjelakovic 2012
Charvarro 2008
Clarke 2009
  • Clarke J, Showell MG, Hart RJ, Agarwal A, Gupta S. Antioxidants for female subfertility (Protocol). Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD007807]
Clarke 2010
  • Clarke J, Van Rumste M, Farquhar C, Johnson N, Mol B, Herbison P. Measuring outcomes in fertility trials - can we rely on clinical pregnancy rates?. Fertility and Sterility 2010;94(5):1647-51.
Dias 2006
Drugs.com
  • http://www.drugs.com/pro/pentoxifylline.html. Pentoxifylline official FDA information, side effects and uses. Drugs.com, Accessed 26.06.13.
Ebisch 2007
  • Ebisch I, Thomas C, Peters W, Braat D, Steegers-Theunissen R. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Human Reproduction Update 2007;13(2):163-74.
Evers 2002
Gupta 2007
  • Gupta S, Agarwal A, Banerjee J, Alvarez JG. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstetrical and Gynecological Survey 2007;62:335-47.
Haggarty 2006
  • Haggarty P, McCallum H, McBain H, Andrews K, Duthie S, McNeill G, et al. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 2006;367:1513-9.
Hart 2003
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org.
Ko 2012
Ledee-Bataille 2002
  • Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Human Reproduction 2002;17:1249-53.
Lu 2012
MDSG
  • Cochrane Menstrual Disorders and Subfertility Group. www.mrw.interscience.wiley.com/cochrane/cochrane_clsysrev_crglist_fs.html.
Nestler 1998
  • Nestler JE. Myo-inositolphosphoglycans (IPGs) as mediators of insulin’s steroidogenic actions. Journal of BasicClinical Physiological Pharmacology 1998;9:197-204.
NHS News 2011
  • Supplements: who needs them? NHS choices. http://www.nhs.uk/news/2011/05May/Documents/BtH_supplements.pdf.
Oliva 2009
Reportlinker 2010
  • Reportlinker. Vitamin and supplement industry: market research reports, statistics and analysis, 2010. http://www.reportlinker.com/ci02037/Vitamin-and-Supplement.html.
Ruder 2008
Sekhon 2010
  • Sekhon L, Gupta S, Kim Y, Agarwal A. Female infertility and antioxidants. Current Women’s Health Reviews 2010;6:84-95.
Showell 2011
Stankiewicz 2007
Thomson 2012
Tremellen 2008
Unfer 2012
  • Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecological Endocrinology 2012;28(7):509-15.
Vircheva 2010
Wathes 2007
Zhao 2006